The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin

The Cutaneous Lymphoid Proliferations

THE CUTANEOUS LYMPHOID PROLIFERATIONS A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin CYNTHIA M. MAGRO, MD Professor of Pathology and Laboratory Medicine Department of Pathology Cornell University Weill Medical College New York, New York

A. NEIL CROWSON, MD Professor of Pathology Departments of Dermatology, Pathology, and Surgery University of Oklahoma, and Regional Medical Laboratory Tulsa, Oklahoma

MARTIN C. MIHM, MD Professor of Pathology Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts

WILEY-LISS John Wiley & Sons, Inc., Publication

Shawn Scully: Photography Editing and Art Design Editorial Assistants Jing Wei Li Katherine Osterman Kay H. Seilstad, M.D. Aimee Sisinger Nina Ananth Copyright  2007 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Wiley Bicentennial Logo: Richard J. Pacifico. Library of Congress Cataloging-in-Publication Data is available. Magro, Cynthia M., Crowson, A. Neil, and Mihm, Martin C. The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin ISBN: 978-0-471-69598-1 Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

CONTENTS

CHAPTER ONE Introduction to the Classification of Lymphoma 1 Martin C. Mihm, Cynthia M. Magro, and A. Neil Crowson Kiel, Lukes–Collins, and Working Formulation Classifications, 1 WHO, Real, and EORTC Classifications, 2

Skin-Directed Therapies, 20 References, 23 CHAPTER THREE Molecular Techniques Carl Morrison Introduction, 25 Immunoglobulin Receptor Structure, 26

Summary, 6

IgH, 26

References, 7

TCR-β, 27

Appendix: Definitions of Key Terms and Techniques, 8

PCR Design for Determination of Clonality, 27 Detection of PCR Products for Clonality, 27 Evaluation of Results, 29

CHAPTER TWO The Therapy of Cutaneous T Cell Lymphoma Pierluigi Porcu and Mark A. Bechtel Introduction, 14

14

Diagnostic Work-up and Staging Procedures, 15 Goals of Therapy in Advanced Stage CTCL, 15 Extracorporeal Photopheresis (ECP), 15 Interferons, 16 Retinoids, 16

Limitations of Clonality Assessment by PCR, 30 Summary, 31 References, 32 CHAPTER FOUR Benign Lymphocytic Infiltrates Cynthia M. Magro and A. Neil Crowson Introduction, 33 Allergic Contact Dermatitis, 33

Monoclonal Antibodies, 17

Pityriasis Rosea, 36

Cytotoxic Chemotherapy, 18

Pityriasis Rosea-like Drug Reaction, 37

Monoclonal Antibodies, 19 TLR Agonists and Cytokines, 19 Histone Deacetylase Inhibitors (HDACi), 19 Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), 20 CTCL Therapies, 20

33

Spongiotic and Eczematous Dermatitis, 33

Immunotoxins, 17

Investigational Therapies, 18

25

Other Spongiotic/Eczematous Tissue Reactions, 37 Photoallergic Reactions, 37 Other Causes of Subacute Eczematous Dermatitis, 38 Nummular Eczema, 38 Small Plaque Parapsoriasis, 39 v

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CONTENTS

Pruritic Urticarial Plaques and Papules of Pregnancy, 39 Superficial Erythema Annulare Centrifugum, 39 Interface Dermatitis: Cell-Poor Vacuolar Interface Dermatitis, 40 Erythema Multiforme, 40 Gianotti–Crosti Syndrome (Popular Acrodermatitis of Childhood), 42 Acute Graft-Versus-Host Disease, 42 Morbiliform Viral Exanthem and Morbiliform Drug Eruption, 44 Collagen Vascular Disease Compatible with Antibody-Dependent Cellular Immunity and/or Anti endothelial Cell Antibodies, 44 Interface Dermatitis: Lichenoid Pattern, 46 Lichen Planus, 46 Lichen Planus-like Eruptions of Hepatobiliary Disease, 47 Lichen Planus-like Eruptions of Secondary Syphilis, 48 Lichenoid Drug Reactions, 48 Lichenoid Connective Tissue Disease Syndromes, 48 Lichenoid (‘‘Chronic’’) Graft-Versus-Host Disease, 51 Diffuse and Nodular Lymphocytic Dermal Infiltrates Without Atypia, 52 Polymorphous Light Eruption as the Prototypic Type IV Immune Reaction, 52 Other Dermal Perivascular Lymphocytic Infiltrates, 54 Gyrate Erythemas, 54 Diffuse and Nodular Lymphocytic Infiltrates Associated with Autoimmune Disease, 55 Nonscarring Discoid Lupus Erythematosus/Tumid Lupus Erythematosus, 55 Morphea, 56 Jessner’s Lymphocytic Infiltrate of the Skin, 58 References, 60 CHAPTER FIVE Reactive Lymphomatoid Tissue Reactions Mimicking Cutaneous T and B Cell Lymphoma Cynthia M. Magro and A. Neil Crowson Lymphomatoid Drug Eruptions, 64 Molecular Profile of Lymphomatoid Drug Eruptions, 66

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Pathogenetic Basis of Lymphomatoid Drug Reactions, 67 Reactive Lymphomatoid Lesions Encountered in Lesions of Collagen Vascular Disease, 68 Lymphomatoid Lupus Erythematosus, 68 Pathogenesis of Lymphomatoid Tissue Response in Collagen Vascular Disease, 69 Lupus Erythematosus Profundus, 69 Viral-Associated Lymphomatoid Dermatitis, 70 Lymphocytoma Cutis, 70 Primary Cutaneous Plasmacytosis, 71 Conclusion, 72 Case Vignettes, 73 References, 89 CHAPTER SIX Precursor Lesions of Cutaneous T Cell Lymphoma 93 Cynthia M. Magro, Joan Guitart and A. Neil Crowson Cutaneous T Cell Lymphoid Dyscrasia, 93 Large Plaque Parapsoriasis, 94 Hypopigmented Epitheliotropic T Cell Dyscrasia/Hypopigmented Large Plaque Parapsoriasis as a Precursor Lesion to Hypopigmented Mycosis Fungoides, 96 Pigmented Purpuric Dermatosis (PPD), 97 Pityriasis Lichenoides Chronica, 100 Syringolymphoid Hyperplasia with Alopecia, 103 Idiopathic Follicular Mucinosis/Alopecia Mucinosa, 104 Atypical Lymphocytic Lobular Panniculitis, 106 Case Vignettes, 109 Additional Molecular and Cytogenetic Studies, 126 References, 138 CHAPTER SEVEN Marginal Zone Lymphoma and Other Low-Grade B Cell Lymphoproliferative Disorders of the Skin Cynthia M. Magro and A. Neil Crowson Marginal Zone Lymphoma, 141 Castleman’s Disease, 148 Primary Cutaneous Plasmacytoma, 149 Case Vignettes, 151 References, 170

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CONTENTS

CHAPTER EIGHT Primary Cutaneous Follicle Center Cell Lymphoma Cynthia M. Magro and A. Neil Crowson Case Vignettes, 178

173

Additional Molecular and Cytogenetic Study, 190

CHAPTER THIRTEEN Primary Cutaneous γ δ T Cell Lymphoma Cynthia M. Magro and A. Neil Crowson Introduction, 259 Case Vignette, 264 References, 266

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259

References, 191 CHAPTER NINE Primary Cutaneous Diffuse Large B-Cell Lymphoma and Precursor Lymphoblastic Lymphoma Cynthia M. Magro and A. Neil Crowson Primary Cutaneous Diffuse Large B-Cell Lymphoma, 192

192

Cutaneous Precursor B Cell Lymphoblastic Lymphoma/Lymphoblastic Leukemia (Precursor B Cell Acute Lymphoblastic Leukemia, 198 Case Vignettes, 203 Additional Molecular and Cytogenetic Studies, 213 References, 216 CHAPTER TEN Intravascular Lymphoma Cynthia M. Magro and A. Neil Crowson Case Vignette, 222

219

References, 224 CHAPTER ELEVEN Chronic Lymphocytic Leukemia of B Cell and T Cell Phenotype (T Cell Prolymphocytic Leukemia) Cynthia M. Magro and A. Neil Crowson B Cell Chronic Lymphocytic Leukemia, 226

226

T Cell Prolymphocytic Leukemia, 228 Case Vignettes, 231 Additional Molecular and Cytogenetic Studies, 244 References, 246

CHAPTER FIFTEEN

CHAPTER TWELVE Cutaneous Mantle Cell Lymphoma Cynthia M. Magro and A. Neil Crowson Case Vignettes, 252 Additional Molecular and Cytogenetic Studies, 256 References, 257

CHAPTER FOURTEEN Mycosis Fungoides 267 Cynthia M. Magro, Martin C. Mihm, and A. Neil Crowson Definition, 267 Historical Perspective, 267 Demographics, 267 Clinical Presentation, 267 Patch Stage, 268 Plaque Stage, 270 Tumor Stage, 270 Extracutaneous Dissemination, 271 Clinical Variants, 271 Papuloerythroderma, 271 Mycosis Fungoides in Childhood, 271 Adnexotropic Mycosis Fungoides, 272 Woringer–Kolopp Disease (Pagetoid Reticulosis), 272 Granulomatous Slack Skin/Granulomatous Mycosis Fungoides, 273 Sezary Syndrome, 273 Extracutaneous Involvement in Mycosis Fungoides, 285 Phenotypic Profile, 286 Molecular Profile, 288 Cytogenetics, 288 Pathogenesis, 288 Case Vignettes, 290 Additional Molecular and Cytogenetic Studies, 292 References, 297

248

Primary Cutaneous Pleomorphic Small/Medium Sized T-Cell Lymphoma And Peripheral T-Cell Lymphoma, Unspecified, Presenting in the SKIN (CD30-Negative Large Cell T Cell Lymphoma) 300 Cynthia M. Magro and A. Neil Crowson Case Vignettes, 306

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CONTENTS

Additional Molecular and Cytogenetic Study, 315 References, 316 CHAPTER SIXTEEN Adult T Cell Leukemia/Lymphoma Cynthia M. Magro Case Vignettes, 322 References, 327

318

Epstein–Barr Virus-Associated B Cell Lymphoproliferative Disease in the Setting of Iatrogenic Immune Dysregulation, 384 Case Vignettes, 390 References, 395 CHAPTER TWENTY-ONE

CHAPTER SEVENTEEN Angioimmunoblastic Lymphadenopathy (AILD)/Angioimmunoblastic T Cell Lymphoma 329 Cynthia M. Magro and A. Neil Crowson Case Vignettes, 334 References, 340 CHAPTER EIGHTEEN CD8 T Cell Lymphoproliferative Disease of the Skin 343 Cynthia M. Magro and A. Neil Crowson Introduction, 343 Primary Cutaneous CD8 Lymphoma, 343 CD8 Variant of Lymphomatoid Papulosis and Other Related CD30-Positive T Cell Lymphoproliferative Disorders of CD8 Subtype, 346 CD8 Prolymphocytic Leukemia, 347 CD8 Pseudolymphoma Related to Underlying HIV Disease, 348 CD8 Cytotoxic Pseudolymphoma Related to Drug Therapy, 348

Nasal and Related Extranodal Natural Killer Cell/T Cell Lymphomas 399 Cynthia M. Magro and A. Neil Crowson Introduction, 399 Biology of NK and NK-like T Cells, 401 NK/T-Cell Lymphoma, 402 Nasal NK/T-Cell Lymphoma, 402 Nasal Type NK/T Cell Lymphoma, 403 Aggressive NK Cell Lymphoma, 403 Role of Epstein–Barr Virus in the Evolution of NK/T Cell Lymphomas, 406 Blastic/Blastoid NK Cell Lymphoma/Agranular CD4-positive CD56-positive Hematodermic Neoplasm, 406 Panniculitis-like T Cell Lymphoma Showing CD56 Positivity, 406 Chronic Granular Lymphocytosis/Large Granular Cell Leukemia, 407 Natural Killer-like T Cell Lymphoma of the CD4 Subset: A Rare Variant of Natural Killer Cell Lymphoma to Be Distinguished from the Hematodermic Neoplasm, 408 Case Vignettes, 410 References, 425

Case Vignettes, 349 References, 364 CHAPTER NINETEEN Subcutaneous Panniculitis-Like T Cell Lymphoma Cynthia M. Magro and A. Neil Crowson Case Vignettes, 372

366

References, 379 CHAPTER TWENTY Epstein–Barr Virus-Associated Lymphoproliferative Disease Cynthia M. Magro and A. Neil Crowson Introduction, 381

381

Hydroa Vacciniforme-Like EBV-Associated T Cell Lymphoproliferative Disease/Mosquito Bite Hypersensitivity, 382

CHAPTER TWENTY-TWO Lymphomatoid Granulomatosis (LYG) Cynthia M. Magro and A. Neil Crowson Introduction, 429 Case Vignette, 434 References, 437

429

CHAPTER TWENTY-THREE CD30-Positive Lymphoproliferative Disorders Including Lymphomatoid Papulosis, Borderline CD30-Positive Lymphoproliferative Disease, Anaplastic Large Cell Lymphoma, and T-Cell-Rich CD30-Positive Large B Cell Lymphoma 439 Cynthia M. Magro and A. Neil Crowson Introduction, 439 Lymphomatoid Papulosis, 440 CD8 Lymphomatoid Papulosis, 444

CONTENTS

Borderline CD30-Positive Lymphoproliferative Disorders (Type C LYP) (Case Vignette 9), 445 Cutaneous Anaplastic Large Cell Lymphoma, 445 CD30-Positive Large B Cell Lymphoma, 450 Case Vignettes, 452 Additional Molecular and Cytogenetic Studies, 468 References, 471

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CHAPTER TWENTY-FOUR Primary Cutaneous Hodgkin Lymphoma 475 Cynthia M. Magro Subtypes of Hodgkin Lymphoma, 477 Classic Hodgkin Lymphoma, 477 Lymphocyte-Predominant Hodgkin lymphoma, 477 Case Vignette, 480 Additional Molecular and Cytogenetic Studies, 484 References, 486 Index, 489

The Cutaneous Lymphoid Proliferations

CHAPTER ONE

INTRODUCTION TO THE CLASSIFICATION OF LYMPHOMA Martin C. Mihm, Cynthia M. Magro, and A. Neil Crowson

KIEL, LUKES–COLLINS, AND WORKING FORMULATION CLASSIFICATIONS The classification of lymphoma has evolved over the last 30 years in light of advances in our understanding of biological behavior, of morphology, and of its clinical, immunophenotypic, and molecular correlates. The earliest classification schemes were based on architectural criteria; specifically, lymphomas were categorized in terms of those that assumed a diffuse versus a nodular growth pattern (Rappaport et al., 1956; Lennert et al., 1975; Lennert, 1978; Lennert and Feller, 1992). In the 1960s, the Rappaport classification scheme, prior to the advent of immunophenotyping, added a consideration of the cell type. In that classification scheme, the large lymphocytes were, not surprisingly, mistaken for histiocytes. Thus, for example, that scheme recognized a diffuse histiocytic lymphoma, which we now know to derive from lymphocytes and to be, most often, a diffuse large B cell lymphoma. With the use of immunophenotyping, and the recognition of the distinction between T and B lymphocytes and histiocytes, new approaches to lymphoma classification emerged. One such scheme, designated the Kiel classification (see Table 1.1), graded lymphoid neoplasms

into low grade versus high grade lymphomas and attempted to relate the cell types identified in any particular lymphoma to their nonneoplastic counterparts in the benign lymph node (Gerard-Marchant et al., 1974; Lennert et al., 1975; Lennert, 1978, 1981; Stansfield et al., 1988; Lennert and Feller, 1992). Popular in the Western hemisphere from the mid-1970s to the mid-1980s, the Lukes–Collins classification emphasized immunophenotypic profiling (Lukes and Collins, 1974). In the early 1980s, the International Working Formulation categorized lymphoid neoplasms into low, intermediate, and high grade malignancies based on clinical aggressiveness in concert with light microscopic findings. The goal was to produce a categorization of hematologic malignancies regardless of site of origin that was clinically useful yet had scientific merit and diagnostic reproducibility (the non-Hodgkin’s pathological classification project 1982). Although the Kiel classification presaged the Working Formulation, this newer classification scheme did not emphasize B and/or T cell ontogeny per se; this was in contradistinction to the updated Kiel classification (Table 1.2). Among the low grade malignancies were small lymphocytic lymphoma, chronic lymphocytic leukemia, small cleaved follicular lymphoma, and follicular lymphoma of mixed cell type. The intermediate grade

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 1

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CHAPTER ONE

Introduction to the Classification of Lymphoma

TABLE 1.1 Kiel Classification of Lymphomas (Lennert 1981) (Musshoff K 1981) B Cell

T Cell Low Grade

Lymphocytic Chronic lymphocytic and prolymphocytic leukemia Hairy cell leukemia

Lymphocytic Chronic lymphocytic and prolymphocytic leukemia Small, cerebriform cell ´ Mycosis fungoides, Sezary syndrome

Lymphoplasmacytic/cytoid (LP immunocytoma)

Lymphoepithelioid (Lennert’s lymphoma)

Plasmacytic

Angioimmunoblastic (AILD, LgX)

Centroblastic/centrocytic Follicular ± diffuse Diffuse

T zone

Centrocytic

Small cell (HTLV-1) High Grade

Centroblastic

Pleomorphic, medium and large cell (HTLV-1 ±)

Immunoblastic

Immunoblastic (HTLV-1 ±)

Large cell anaplastic (Ki-1+)

Large cell anaplastic (Ki-1+)

Burkitt’s lymphoma Lymphoblastic

tumors included malignant lymphoma of follicle center cell origin with a predominance of large cells, diffuse lymphoma of small cleaved cells, and diffuse lymphoma of mixed and/or cleared or noncleared large cell type. The high grade tumors were the diffuse immunoblastic lymphoblastic and Burkitt’s lymphoma. The cytomorphology and architecture were clearly of cardinal importance and, in essence, took precedence over the cell of origin in this classification scheme. By the mid-1990s there was sufficient data gleaned from immunohistochemistry, cytogenetics, and molecular techniques to better categorize these tumors as distinct clinical and pathological entities manifesting reproducible phenotypic, cytogenetic, and molecular features, all defining critical determinants in the clinical course and prognosis. To attempt to evaluate whether a new classification scheme could be devised, a panel of 19 hematopathologists from Europe and the United States met to evaluate the current classification systems to consider whether a synthesis of the prior efforts could be made into a more usable and practical device to aid pathologists and clinicians. The classifications under consideration were the Kiel classification (Lennert et al., 1975; Gerard-Marchant et al., 1974; Lennert, 1978, 1981; Stansfield et al., 1988; Lennert and Feller, 1992), the Lukes–Collins classification (Lukes and Collins, 1974), and the Working Formulation

Lymphoblastic

(non-Hodgkin’s lymphoma pathologic classification project, 1982). What ultimately eventuated from this meeting was the Revised European–American Classification of Lymphoid Neoplasms (REAL classification) (see Table 1.3). It represented a synopsis of the existing hematologic literature allowing categorization based on distinctive forms of hematopoietic and lymphoid malignancy separated on the basis of their peculiar clinical, light microscopic, phenotypic, molecular, and cytogenetic profiles (Harris et al., 1994; Cogliatti and Schmid, 2002).

WHO, REAL, AND EORTC CLASSIFICATIONS The new WHO classification was a modest revision of the REAL classification, once again amalgamating reproducible clinical, light microscopic, phenotypic, molecular, and cytogenetic features into a coherent scheme (Jaffe et al., 2001; Cogliatti and Schmid, 2002). The concept of a classification scheme based purely on morphology was now considered archaic. However, the WHO/REAL classification was deficient from the perspective of cutaneous hematologic dyscrasias, as will be alluded to presently (Cogliatti and Schmid, 2002) (Table 1.3). Hence, in 1997 the European Organization for the Research and Treatment

WHO, Real, and EORTC Classifications

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TABLE 1.2 Working Formulation (Cancer 1982) Low grade

Malignant lymphoma, diffuse Small lymphocytic Consistent with chronic lymphocytic leukemia; plasmacytoid Malignant lymphoma, follicular Predominantly small cleaved diffuse areas; sclerosis Malignant lymphoma, follicular Mixed, small cleaved and large cell diffuse areas; sclerosis

Intermediate grade

Malignant lymphoma, follicular Predominantly large cell Diffuse areas; sclerosis Malignant lymphoma, diffuse Small cleaved Sclerosis Malignant lymphoma, diffuse Mixed, small and large cell Sclerosis; epithelioid cell component Malignant lymphoma, diffuse Large cell Cleaved; noncleaved; sclerosis

High grade

Malignant lymphoma Large cell, immunoblastic Plasmacytoid; clear cell; polymorphous; epithelioid cell component Malignant lymphoma Lymphoblastic convoluted; nonconvoluted Malignant lymphoma Small noncleaved Burkitt’s; follicular areas

Miscellaneous

Composite Mycosis fungoides Histiocytic Extramedullary Plasmacytoma Unclassifiable Other

of Cancer (EORTC) established a scheme for the classification of cutaneous lymphomas (see Table 1.4). This classification scheme was met with criticism for reasons that will be discussed presently. Among the distinct clinical and pathological entities that were recognized by the EORTC classification were mycosis fungoides including specific variants, lymphomatoid papulosis, large cell CD30-positive lymphoma, large cell CD30-negative lymphoma, panniculitis-like T cell lymphoma, marginal zone B cell lymphoma, primary cutaneous follicle center cell lymphoma, primary cutaneous large B cell lymphoma of the leg, and primary cutaneous plasmacytoma (Willemze et al., 1997) (Table 1.4). The main problem with this classification scheme was not the specific entities per se or even their purported clinical behavior. The difficulty was that there were a number of cutaneous hematologic dyscrasias that either were not included

in this classification scheme or were phenotypically and biologically disparate, yet had to be forced into the same category. For example, both diffuse large B cell lymphomas of the trunk without features of follicle center cell origin and CD30-negative large cell T cell lymphoma would be categorized as CD30negative large cell lymphomas. However they are different from a prognostic perspective, the former being indolent and the latter being an aggressive form of lymphoma. Adult T cell leukemia lymphoma, nasal and extranodal NK/T cell lymphoma, nasal type, angioimmunoblastic T cell lymphoma, and T prolymphocytic leukemia commonly involve the skin as part of a disseminated lymphomatous process yet they were not recognized in this classification scheme (Cogliatti and Schmid, 2002; Willemze et al., 2005).

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CHAPTER ONE

Introduction to the Classification of Lymphoma

TABLE 1.3 Revised European–American Lymphoma Classification (REAL) (Harris et al., 2000) Precursor B cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma Mature (peripheral) B cell neoplasms B cell chronic lymphocytic leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B cell lymphoma (+/− villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone lymphoma (+/− monocytoid B-cells) Follicle center lymphoma, follicular, Mantle cell lymphoma Diffuse large cell B cell lymphoma Mediastinal large B cell lymphoma Primary effusion lymphoma Burkitt’s lymphoma/Burkitt’s cell leukemia T cell and natural killer cell neoplasms Precursor T cell neoplasm Precursor T lymphoblastic lymphoma/leukemia Mature (peripheral) T cell and NK cell neoplasms T cell prolymphocytic leukemia T cell granular lymphocytic leukemia Aggressive NK cell leukemia Adult T cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T cell lymphoma Hepatosplenic γ /δ T cell lymphoma ´ Mycosis fungoides/Sezary syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T cell lymphoma, not otherwise characterized Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma, T/null cell, primary systemic type Hodgkin’s lymphoma Nodular lymphocyte predominance Hodgkin’s lymphoma Classical Hodgkin’s lymphoma Nodular sclerosis Hodgkin’s lymphoma Lymphocyte-rich classical Hodgkin’s lymphoma Mixed cellularity Hodgkin’s lymphoma Lymphocyte depletion Hodgkin’s lymphoma

Those who were proponents of the updated WHO classification (i.e., the REAL classification) contended that the WHO scheme was superior to the EORTC classification of cutaneous lymphomas. However, in the REAL/WHO classification scheme, there was only recognition of few distinctive forms of cutaneous lymphoma, namely, mycosis fungoides, S´ezary syndrome, and panniculitis-like T cell lymphoma. All of the other lymphomas were in the context of disease not specifically involving the skin, albeit recognizing that the diagnostic terms rendered could certainly

be applied to various cutaneous lymphomas, including anaplastic large cell lymphoma, peripheral T cell lymphoma, not otherwise specified, NK/T cell lymphoma, extranodal marginal zone lymphoma, follicular lymphoma, diffuse large B cell lymphoma, and extramedullary plasmacytoma. Furthermore, all of the systemic and/or extracutaneous lymphomas that commonly involved the skin such as adult T cell leukemia lymphoma were recognized by the WHO (Harris et al., 1994; Jaffe et al., 2001). Thus, the advantage of this classification scheme was that

WHO, Real, and EORTC Classifications

TABLE 1.4 EORTC Classification for Primary Cutaneous Lymphomas (Willemze 1997) Primary CTCL Indolent MF MF + follicular mucinosis Pagetoid reticulosis Large cell CTCL, CD30+ Anaplastic, Immunoblastic Pleomorphic Lymphomatoid papulosis Aggressive SS Large cell CTCL, CD30− Immunoblastic, Pleomorphic Provisional Granulomatous slack skin CTCL, pleomorphic small/ medium-sized Subcutaneous panniculitis-like T-cell lymphoma

Primary CBCL Indolent Follicle center cell lymphoma Immunocytoma (marginal zone B-cell lymphoma)

Intermediate Large B-cell lymphoma of the leg

Provisional Intravascular large B-cell lymphoma Plasmacytoma

Abbreviations: CTCL, cutaneous T-cell lymphoma; CBCL, cutaneous B-cell lymphoma; MF, mycosis fungoides; SS, Sezary syndrome.

it encompassed a much broader spectrum of hematologic diseases having the potential to involve the skin. The problem was the radical difference in prognosis between the various lymphomas at extracutaneous sites relative to their behavior when presenting as primary cutaneous neoplasms. Perhaps the best example of this is primary cutaneous follicle center cell lymphoma and primary cutaneous diffuse large cell B cell lymphoma which can represent indolent forms of malignancy in the skin. The same potentially benign clinical course may apply to primary cutaneous anaplastic large cell lymphoma and localized peripheral T cell lymphoma in the skin when dominated by small and medium sized lymphocytes. To address the deficiencies in both the WHO and EORTC schemes as they apply to cutaneous hematologic disorders, a group of dermatologists and pathologists met in Lyon, France and Zurich, Switzerland in the years 2003 and 2004. The result was a publication that represents an amicable marriage, falling under the designation of the joint WHO–EORTC classification for cutaneous lymphomas (Jaffe et al., 2001; Cogliatti and Schmid, 2002; Burg et al., 2005; Willemze et al., 2005) (see Table 1.5). The WHO–EORTC classification recognizes 10 types of cutaneous T cell lymphoma and 4 forms of cutaneous B cell lymphoma with clinical outcomes for those neoplasms designated as primary cutaneous lymphomas being

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recognized as distinct and separate from their extracutaneous counterparts. For example, diffuse large B cell lymphoma of follicle center cell origin is an indolent lymphoma while the ‘‘leg’’ type is an intermediate prognosis lymphoma. The WHO–EORTC classification scheme also recognizes hematodermic neoplasm, which is a nonlymphoid tumor. Furthermore, it does include systemic lymphomas that commonly involve the skin such as adult T cell leukemia lymphoma and intravascular large B cell lymphoma. The main deficiencies are the failure to include certain lymphoid neoplasms that characteristically involve the skin, namely, primary cutaneous B cell lymphoblastic lymphoma, angioimmunoblastic lymphadenopathy, lymphomatoid granulomatosis, and T cell prolymphocytic leukemia. In addition, while it does consider folliculotropic mycosis fungoides, there is no mention of syringotropic mycosis fungoides. The scheme does not address primary cutaneous post-transplant lymphoproliferative disease (PTLD) and methotrexate associated lymphoproliferative disease, although most of these in fact would fall in the category of diffuse large B cell lymphoma or anaplastic large cell lymphoma. An regards to PTLD polymorphic variants and plasmacytic hyperplasia, however, would not be recognized. In contrast, the WHO considers these categories of iatrogenic dyscrasia (Jaffe et al., 2001). Other Epstein–Barr Virus (EBV) related disorders such as plasmablastic lymphoma and hydroa vacciniforme-like lesions are not considered. It does not recognize those primary cutaneous small/medium sized pleomorphic T cell lymphomas that are rarely of the CD8 subset and which are to be distinguished prognostically from primary cutaneous aggressive epidermotropic CD8-positive T cell lymphoma. The designation of peripheral T cell lymphoma, type unspecified, refers to as an aggressive form of cutaneous T cell however. The more accurate designation is that of CD30 negative large T cell lymphoma and one could argue that the latter designation would be more apposite. While the new scheme does consider hematodermic neoplasm a tumor of monocytic derivation, there is no consideration of granulocytic sarcoma, the histiocytopathies, or mast cell disease. The endogenous T cell dyscrasias that may presage lymphoma such as syringolymphoid hyperplasia with alopecia, atypical lymphocytic lobular panniculitis, pigmented purpuric dermatosis, and pityriasis lichenoides are not part of the classification scheme. Despite these deficiencies, it is to date the most accurate classification scheme for the categorization of hematologic diseases expressed in the skin (Burg et al., 2005; Willemze et al., 2005).

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CHAPTER ONE

Introduction to the Classification of Lymphoma

TABLE 1.5 WHO–EORTC Classification of Cutaneous Lymphomas (Willemze et al., 2005) Cutaneous T cell and NK cell lymphomas Mycosis fungoides Mycosis fungoides variants and subtypes Folliculotropic mycosis fungoides Pagetoid reticulosis Granulomatous slack skin ´ Sezary syndrome Adult T cell leukemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T cell lymphoma Extranodal NK/T cell lymphoma, nasal type Primary cutaneous peripheral T cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma (provisional) Cutaneous γ /δ T cell lymphoma (provisional) Primary cutaneous CD4+ small/medium sized pleomorphic T cell lymphoma (provisional) Cutaneous B cell lymphomas Primary cutaneous marginal zone B cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B cell lymphoma, leg type Primary cutaneous diffuse large B cell lymphoma, other intravascular large B cell lymphoma Precursor hematologic neoplasm CD4+/CD56+ hematodermic neoplasm (blastic NK cell lymphoma)

SUMMARY Tables 1.1–1.5 summarize the classification schemes as they have evolved over time. It should be apparent to the reader that the most recent classification scheme is certainly apropos but still not globally inclusive. Each of the conditions listed in the classification scheme are discussed in the ensuing chapters, emphasizing the approach that should be given to each hematologic dyscrasia. Specifically, the entities are presented in the context of an integration of clinical, light microscopic, phenotypic, molecular, and

cytogenetic data and, where appropriate, additional considerations are given regarding pathobiology. Each cutaneous disorder truly has its own fingerprint; in this regard we have considered many of the individual hematologic disorders in their own respective chapters and/or considered no more than a few entities in a given chapter to emphasize the truly distinctive nature of so many of these disorders. In addition, we consider other forms of lymphoid dyscrasia that commonly involve the skin, recognizing that they are rare conditions and are still not part of the WHO–EORTC classification scheme.

References

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REFERENCES BURG G, KEMPF W, COZZIO A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005; 32:647–674. COGLIATTI SB, SCHMID U. Who is WHO and what was REAL? A review of the new WHO classification (2001) for malignant lymphomas. Swiss Med Wkly. 2002; 132:607–617. CONNORS JM, HSI ED, FOSS FM. Lymphoma of the skin. Hematology (Am Soc Hematol Educ Program). 2002; 263–282. GERARD-MARCHANT R, HAMLIN I, LENNERT K, RILKE F, STANSFELD A, VAN UNNIK J. Classification of nonHodgkin’s lymphoma. Lancet. 1974; 2:406. HARRIS NL, JAFFEE ES, STEIN H, et al. A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994; 84:1361–1392. HARRIS NL, JAFFE ES, DIEBOLD J, FLANDRIN G, MULLERHERMELINK HK, VARDIMAN J. Lymphoma classification—from controversy to consensus: the R.E.A.L. and WHO classification of lymphoid neoplasms. Ann Oncol. 2000; 11 Suppl 1:3–10. JAFFE ES, HARRIS NL, STEIN H, VARDIMAN JW, eds. World Health Organization of Tumors: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyons, France: IARC Press; 2001. LENNERT K, Malignant Lymphomas Other than Hodgkin’s Disease. New York: Springer-Verlag; 1978. LENNERT KL. Histopathology of the Non-Hodgkin’s Lymphomas: Based on the Keil Classification. New York: SpringerVerlag; 1981. LENNERT K, FELLER A. Histopathology of Non-Hodgkin’s Lymphomas. 2nd ed. New York: Springer-Verlag; 1992.

LENNERT K, MOHRI N, STEIN H, KAISERLING E: The histopathology of malignant lymphoma. Br J Haematol. 1975; 31 Suppl:193. LUKES R, COLLINS RL. Immunologic characterization of human malignant lymphoma. Cancer. 1974; 34:1488. MUSSHOFF K, VON STOTZINGEN W, SCHMIDT-VOLLMERTL, UMBACH H. Investigations results of a comparison made between the Kiel & Rappaport classifications of the non-Hodgkin’s lymphoma, together with clinical data. J Cancer Res Clin Oncol 1981; 100:167–204. Non-Hodgkin’s lymphoma pathologic classification project. National Cancer Institute sponsored study of classification of non-Hodgkin’s lymphomas: summary and description of a Working Formulation for clinical usage. Cancer. 1982; 49:2112. RAPPAPORT W, WINTER WJ, HICKS EB. Follicular lymphoma. A re-evaluation of its position in the scheme of malignant lymphoma based on a survey of 253 cases. 1956; 9:792–821. SLATER DN. The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005; 153(5):874–880. STANSFIELD A, DIEBOLD J, KAPANCI Y, et al. Update Kiel classification for lymphomas. Lancet. 1988; 1:292. WILLEMZE R, JAFFE ES, BURG G, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997; 90:354–371. WILLEMZE R, JAFFE ES, BURG G, et al. WHO–EORTC classification for cutaneous lymphomas. Blood. 2005; 105(10):3768–3785.

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CHAPTER ONE

Introduction to the Classification of Lymphoma

APPENDIX: DEFINITIONS OF KEY TERMS AND TECHNIQUES Cynthia M. Magro & Carl Morrison T Cell Antibodies CD1a (T6, Leu6, OKT6, O10): An immature T cell antigen, found on cortical thymocytes and Langerhans’ cells but not mature T cells. CD2 (T11, Leu5, OKT11, MT910): A pan T cell antigen that corresponds to the sheep erythrocyte rosette receptor. It is present on all normal mature T cells. CD3 (Leu4, T3, OKT3,SP7, PS1, Polyclonal): A pan-T cell antigen that is composed of five polypeptide chains covalently linked to the T cell receptor. All elements of the CD3/T cell receptor must be present for cell surface expression. Most anti-CD3 antibodies are directed toward the epsilon chain of the CD3/T cell receptor complex. The majority of mature T cells are CD3-positive. The CD3 antigen is first expressed in the cell cytoplasm and then on the surface. NK cells will manifest only cytoplasmic expression. TCR-1, BF-1: They are antibodies that recognize the α/β heterodimer of the human T cell antigen receptor. It is expressed on normal mature peripheral blood T lymphocytes and on 50–70% of cortical thymocytes. The vast majority of T cell malignancies are derived from T cells of the αβ subtype. TCR-gamma 1: An antibody that recognizes the γ /δ heterodimer portion of human T cell antigen receptor. It is present on a minor subset of CD3positive T cells in peripheral blood, thymus, spleen, and lymph node. CD5 (T1, Leu1, OKT1, CD5/54/F6, 4C7): A pan T cell antigen present on the majority of thymocytes and mature peripheral blood T cells; a loss of CD5 expression in T cells is indicative of ensuing neoplasia. The CD5 antigen is present on a small subset of normal B cells representing naive B cells with endogenous autoreactive features and which have been implicated in innate immunity. It is also expressed on neoplastic B cell lymphoma cells of chronic lymphocytic leukemia, small lymphocytic lymphoma, rare cases of marginal zone lymphoma, and mantle zone lymphoma. CD43 (DF-T1): This T cell associated antigen is expressed by normal T cells, granulocytes, and a subset of plasma cells but not normal B cells. CD43 expression by a B cell is a feature of B cell neoplasia. Primary cutaneous diffuse large B cell lymphomas some marginal zone lymphomas,

and follicle center cell lymphomas can be CD43positive. CD7 (Leu9, DK24): A pan T cell marker that is expressed by the majority of periperhal T cells. The expression of CD7 is an event that occurs relatively early in T cell ontogeny prior to rearrangement of the TCR-β chain. The CD7 antigen is expressed by both mature and immature T cell neoplasms. The CD7 antigen may not be expressed by memory T cells manifesting selective homing to the skin. Although substantial reduction of this marker is characteristic for mycosis fungoides and primary cutaneous pleomorphic T cell lymphoma, it is diminished in most reactive dermatoses, albeit to a lesser degree than in mycosis fungoides. There is variation in the intensity of staining based on the detection system. CD62L (LECAM-1, LAM-1, MEL-14): CD62L is part of the family of selectins that comprises three subcategories: L-selectin, E-selectin, and P-selectin designated as CD62L, CD62E, and CD62P, respectively. All of the selectins exhibit a similar glycan contributing to their adhesion function and participating in the interactions between inflammatory cells and endothelium. CD62L is expressed on blood monocytes, blood neutrophils, subsets of natural killer cells, and T and B lymphocytes including those of na¨ıve phenotype. Virgin T cells in human peripheral blood uniformly express CD62L, whereas among the memory/effector population, the three predominant subsets are CD62L+/CLA+, CD62L+/CLA−, and CD62L−/CLA−. CD4 (Leu3a, OKT4, MT310): A helper/inducer cell antigen. It is expressed by the majority of peripheral blood T cells and 80–90% of cortical thymocytes. Cortical thymocytes that are CD4positive usually coexpress CD8. The majority of T cell neoplasms are of the CD4 subset. γ δ T cells and NK cells are CD4-negative. CD4 is also expressed by monocytes including, in the context of histiocytic proliferative disorders, myelomonocytic dyscrasias and hematodermic neoplasm. CD8 (Leu 2a, C8/144B): A suppressor/cytotoxic cell antigen. The CD8 antigen is a 32 kilodalton heterodimeric protein that is expressed by approximately 30% of peripheral blood mononuclear cells and 60–85% of cortical thymocytes (P/F). Cortical thymocytes coexpress CD4. γ δ Cells are frequently

Appendix: Definitions of Key Terms and Techniques

CD8-negative. A small percentage of peripheral T cell lymphomas are of the the CD8 subset such as primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphoma, some γ δ T cell lymphomas, and panniculitis like T cell lymphoma. Rarely, classic lesions of cutaneous T cell lymphoma (i.e., mycosis fungoides) will be CD8positive. CD8 cells may be suppressive or cytotoxic in nature. The latter express cytotoxic proteins such as TIA and granzyme. Cutaneous Lymphocyte Antigen (HECA-452): Expressed in memory T lymphocytes with preferrential homing proportion to the skin endothelial cells and epithelial cells. CD52 (VTH34.5, Campath-1G): Expressed in lymphocytes, monocytes, eosinophils, thymocytes, and macrophages. It is most B and T cell lymphoid derived malignancies; expression on myeloma cells is variable. Fox P3 (236A/F7): Constitutive high expression of Foxp3 mRNA has been shown in CD4+CD25+ regulatory T cells (Treg cells), and ectopic expression of Foxp3 in CD4+CD25− cells imparts a Treg phenotype in these cells.

Plasma Cell Markers CD138 (MI15): CD138/syndecan-1 protein backbone is a single chain molecule of 30.5 kDa. Five putative GAG attachment sites exist in the extracellular domain. GAG fine structure appears to reflect the cellular source of the syndecan. Expression of CD138 in human hematopoietic cells is restricted to plasma cells in normal bone marrow. Early B cell precursors in human bone marrow are CD138negative. CD138 is also expressed in endothelial cells, fibroblasts, keratinocytes, and normal hepatocytes.

Natural Killer Cell Associated Markers CD16 (DJ130c): A natural killer cell and myelomonocytic antigen. It is expressed by all resting natural killer cells, neutrophils, and macrophages. It is also the antibody receptor for antibody dependent cellular cytotoxicity. CD56 (MOC1, T199, C5.9): A natural killer cell antigen. This antigen is expressed by all resting and activated natural killer cells a subset of cytotoxic T cells that mediates non-major histocompatibility complex (non-MHC) restricted cytotoxicity, and dendritic monocytes.

9

Cytotoxic Protein Markers TIA Perforin Granzyme

B Cell Markers The immunoglobulin light chains are the most reliable way of distinguishing a malignant B cell process from a reactive one (restricted light chain expression). CD10 (CALLA): This B cell antigen was originally thought to be a tumor-specific marker expressed by neoplastic cells of acute lymphoblastic leukemia. The CD10 antigen can be expressed by follicular lymphomas B cell lymphoblastic lymphomas, normal T cells undergoing apoptosis and certain T cell malignancies namely in the context of angioimmunoblastic lymphadenopathy. CD19 (HD37): The CD19 antigen is expressed initially at the time of immunoglobulin heavy chain gene rearrangement. Anti-CD19 antibodies stain almost all cases of non-T cell acute lymphoblastic leukemia as well as mature B cell leukemias and lymphomas. Restricted to use in flow cytometry or frozen tissues. CD20 (B1, L26, Leu16): A pan B cell antigen that is expressed at the time of light chain gene rearrangement. Anti-CD20 antibodies react with 50% of immature B cell lymphoblastic leukemia cells. CD20 is not expressed by plasma cells. CD22 (4 KB128, To15): A pan B cell antigen that is very similar to the CD20 antigen. Bcl-1: Bcl-1/cyclin D1 belongs to the G1 cyclins and plays a key role in cell cycle regulation during the G1/S transition by cooperating with cyclin-dependent kinases (CDKs). Its overexpression may lead to growth advantage for tumor cells by way of enhanced cell cycle progression, and it has been reported in various human cancers, for example, esophageal, breast, and bladder carcinomas. Among hematolymphoid malignancies, cyclin D1 overexpression resulting from translocational activation has also been recognized in a subset of B-chronic lymphocytic leukemia (BCLL), multiple myeloma, splenic marginal zone lymphoma, hairy cell leukemia, and mantle cell lymphoma. BCL2: The Bcl-2 family of proteins (Bcl-2, Bcl-w, Bcl-xL , Bcl-2 related protein A1, etc.) regulates outer mitochondrial membrane permeability. Bcl2, Bcl-w, Bcl-xL , and Bcl-2 related protein A1 are antiapoptotic members that prevent release

10

CHAPTER ONE

Introduction to the Classification of Lymphoma

of cytochrome c from the mitochondria intermembrane space into the cytosol. Bcl-2 and Bcl-xL are present on the outer mitochondrial membrane and are also found on other membranes in some cell types. Bcl-w is required for normal sperm maturation. In the context of its value in lymphoid infiltrates, it is ubiquitously expressed by small mature lymphocytes. Normal germinal center cells are Bcl-2 negative. In contrast, neoplastic germinal center cells can be Bcl-2 positive and are typically positive in nodal follicular lymphoma. In primary cutaneous diffuse large cell lymphomas, Bcl-2 expression is an adverse prognostic variable. Bcl-6: BCL-6 protein is expressed in B cell lymphomas of folliculae center B cell origin. Bcl-10: Apoptosis regulator B-cell lymphoma 10 (BCL10) may show aberrant nuclear expression in primary cutaneous marginal zone lymphomas associated with extracutaneous dissemination.

Myelomonocytic Markers CD15 (C3D-1): Expressed by Reed–Sternberg cells and Hodgkin’s cells along with a small subset of mature T and B cell lymphomas. CD68 (PGM1, KP1): This antigen is found on monocytes, granulocytes, mast cells, and macrophages (P). CD34 (QBEnd10): The CD34 antigen is a single chain transmembrane glycoprotein that is associated with human hematopoietic progenitor cells. It is present on immature hematopoietic precursor cells and TdT positive B cells and T lymphoid precursors. CD34 expression decreases as these hematopoietic precursors undergo progressive maturation. CD34 myeloid progenitors can differentiate into two major myeloid subsets in the skin: Langerhans cells and dermal interstitial dendrocytes. While these mature antigen presenting cells are CD34 negative, the dermal dendritic and Langerhans cell precursors manifest a CD34+ CD14+ CD116+ phenotype. The quantity of CD34+ progenitor cells in the marrow is closely associated with advancement of disease in patients with chronic idiopathic meylofibrosis. Expectedly patients with myelofibrosis can develop paraneoplastic Sweet’s like reactions whereby the presence of CD34 cells in the infiltrate could be a harbinger of a more accelerated clinical course (personal observations). CD43: CD43 antigen is expressed by T cell lymphomas and about 30% of B cell lymphomas. CD43 is expressed on the membrane and in the cytoplasm of T cells and cells of myeloid lineage.

CD123: The protein encoded by this gene is an interleukin-3 specific subunit of a heterodimeric cytokine receptor. The receptor is composed of a ligand-specific α subunit and a signal transducing β subunit shared by the receptors for interleukin-3 (IL-3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin-5 (IL-5). The binding of this protein to IL-3 depends on the β subunit. The β subunit is activated by the ligand binding and is required for the biological activities of IL-3. This gene and the gene encoding the colony stimulating factor 2 receptor α chain (CSF2RA) form a cytokine receptor gene cluster in a X-Y pseudoautosomal region on chromosomes X or Y. It is positive in hematodermic neoplasm.

Activation/Proliferation Markers CD25 (Tac, ACT-1): An activation marker that detects the α chain of the interleukin-2 receptor. The C25 antigen is a 55 kilodalton glycoprotein that is expressed by activated B and T lymphocytes and weakly by histiocytes. The CD25 antigen is strongly expressed by cutaneous T cell neoplasms undergoing transformation. The CD25 antigen is also expressed by the Reed–Sternberg cells of Hodgkin’s disease. CD30 (Ber-H2, Ki-1): An antigen (glycoprotein) associated with activation of hematopoietic cells of B, T, and monocyte origin. CD71 (Ber-T9): An activation antigen that defines the transferrin receptor. It is expressed on activated T cells, bone marrow blasts, normal histiocytes, and intermediate and higher grade lymphomas, the Reed–Sternberg and Hodgkin cells of Hodgkin lymphoma, and other nonhematopoietic rapidly growing neoplasms. HLA-DR: Expressed normally on B lymphocytes; however, HLA-DR is negative on quiescent T lymphocytes. It is expressed on activated T lymphocytes. Ki-67 (MIB-1): The Ki-67 antibody detects a nuclearassociated antigen that is expressed by proliferating but not resting cells. Ki-67 staining correlates with morphologic grade whereby a higher number of staining cells are associated with a poor survival.

Panels on Paraffin Embedded Tissue T Cell: CD2 CD3 CD43

Appendix: Definitions of Key Terms and Techniques

CD5 CD7 CD62L CD8 CD4 CD30 TdT CD99 Beta F1 CD52: clone, YTH34.5 or Campath-1G; concentration, 1:500 Fox P3: clone, 236A/E7; concentration, 1:100 CLA clone, HECA-452; concentration, 1:25 B Cell: CD20 CD79 CD21 CD23 CD10 CD5 CD43 Cyclin D1 Bcl-1 Bcl-2 Bcl-6 CD30 mRNA κ/λ to ascertain light chain restriction TdT CD99 Cytotoxic Markers: TIA Perforin Granzyme Plasma Cell Markers: mRNA κ/λ CD138 Natural Killer Cell: CD56 CD16 Myeloid: CD34 CD43 CD68 Leder (Chloroacetate esterase) histochemical stain TdT

11

CD99 CD15 Hodgkin Specific: CD15 CD40 clone, 11E9; concentration, 1:10 Fascin clone, 55K-2; concentration, 1:500 CD30 CD45 Ro CD30 & lymphoproliferative disease: CD4 CD8 CD30 granzyme clusterin

Special Techniques Reverse Transcriptase in Situ Hybridization Assays Epstein–Barr Virus-Associated Latent Small Nuclear RNA (EBER): EBER-1 and EBER-2, present in both the productive and various forms of latent EBV infection. We employ EBER rather than LMP1 since EBER is present in both the latent and lytic phases of infection while LMP-1 is typically not present in the lytic stage. EBER-1 and EBER-2 are present in much higher copy numbers than LMP1, potentially providing us with higher sensitivity than testing LMP-1 protein. Viral Thymidine Kinase (vTK Assay): EBV thymidine kinase detected with the probes 5′ -GAACCCGCATGCTCTCCTT- 3′ and 5′ -TCTGGATGATGCCCAAGACA-3′ , respectively, detects lytic infection. HHV8: Detection of HHV8 RNA is accomplished using primers specific for the T0.7 viral message, which is expressed in latent and active infection. Fluorescent in-situ hybridization (FISH) MYC Amplification and Translocation and Trisomy 8: For MYC amplification, a ratio of the total number of MYC signals to the total number of CEP8 signals, in at least 60 interphase nuclei with nonoverlapping nuclei in the tumor cells, is determined. Cells with no signals or with signals of only one color are disregarded. Tumor cells displaying at least two centromeric chromosome 8 signals and multiple MYC signals, with a MYC/CEP8 ratio ≥2, are considered consistent with amplification of the MYC gene. Overamplification of C-MYC is not associated with any particular hematologic malignancy but would only be expected in those

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CHAPTER ONE

Introduction to the Classification of Lymphoma

Summary of Antibodies, Clones, and Dilutions Antibody

Clone

Ig Class

Dilutions

Pretreatment Incubation

Primary AB

Manufacturer

9H6

IgG2a, kappa

1:50

EDTA

30 minutes

Vision Biosystems, Norwell, MA; Novacastra

CD7

CD7-272

IgG1

1:50

EDTA

30 minutes

Vision Biosystems; Novacastra

CD7

C BC.37

IgG2b

1:80

Citra Plus

30 minutes

DakoCytomation, Carpinteria, CA

CD3

PS1

IgG2a

1:400

EDTA

30 minutes

Vision Biosystems; Novacastra

CD62L

hematologic malignancies with a more aggressive course and would not be a feature of a benign lymphoid cell population. Tumor cells displaying multiple centromeric chromosome 8 signals and an approximate equal number of MYC signals with a somewhat random distribution of both probe signals are considered polysomy 8. ALK-1 Breakapart Probe: The LSI ALK (Anaplastic Lymphoma Kinase) dual color, breakapart rearrangement probe contains two differently labeled probes on opposite sides of the breakpoint of the ALK gene. This region is involved in the vast majority of breakpoints for known 2p23 rearrangements that occur in t(2;5) and its variants. The translocation (2;5)(p23;q35) is identified in approximately 50% of cases of anaplastic large cell lymphoma (noncutaneous). The absence of the translocation (2;5)(p23;q35) does not exclude the diagnosis of anaplastic large cell lymphoma. MYC Breakapart Probe: The LSI MYC dual color, breakapart rearrangement probe is a mixture of two probes that hybridize to opposite sides of the region located 3′ of MYC. This region is involved in the vast majority of breakpoints for t(8;22)(q24;q11) and t(2;8)(p11;q24). Translocation involving the C-MYC gene can be expected to occur in the vast majority (>90%) of Burkitt’s lymphoma and atypical Burkitt’s lymphoma. MYC IgH Fusion Probe: The LSI IGH/MYC, CEP 8 tricolor, dual fusion translocation probe is designed to detect the juxtaposition of immunoglobulin heavy chain (IGH) locus and MYC gene region sequences. The IGH probe contains sequences homologous to essentially the entire IGH locus as well as sequences extending about 300 kb beyond the 3′ end of the IGH locus. The large MYC probe extends approximately 400 kb upstream of MYC and

about 350 kb 3′ beyond MYC. A cell harboring the reciprocal t(8;14) with the 8q24 breakpoint well within the MYC probe target is expected to produce a pattern of one orange, one green, two orange/green fusions, and two aqua signals. Translocation involving the C-MYC gene can be expected to occur in the vast majority (>90%) of Burkitt’s lymphoma and atypical Burkitt’s lymphoma. bcl-2 IgH Fusion Probe: The LSI IGH/BCL2 dual color, dual fusion translocation probe (Vysis) is designed to detect the juxtaposition of immunoglobulin heavy chain (IGH) locus and BCL gene sequences. It is detected in most lymphomas harboring a t(14;18). Cyclin D1 IgH Fusion Probe: The LSI IGH/CCND1 dual color, dual fusion XT translocation probe (Vysis) is designed to detect the juxtaposition of immunoglobulin heavy chain (IGH) locus and CCND1 gene sequences. It will detect most t(11;14)bearing cells and is therefore seen in the majority of mantle cell lymphomas. MALT1 Breakapart Probe: The LSI MALT1 dual color, breakapart rearrangement probe consists of a mixture two FISH DNA probes. The first probe, a 460 kb probe labeled in SpectrumOrange, flanks the 5′ side of the MALT1 gene. The second probe, a 660 kb probe labeled in SpectrumGreen, flanks the 3′ side of the MALT1 gene. It will detect cells with t(18q21) and/or aneuploidy of chromosome 18. Translocation involving the MALT1 gene can be expected to occur in approximately 25–50% of extranodal marginal zone lymphomas but is quite uncommon in nodal based marginal zone lymphoma. MALT1 IgH Fusion Probe: The LSI IGH/MALT1 dual color, dual fusion translocation probe is composed of a mixture of a 1.5 Mb SpectrumGreen labeled

Appendix: Definitions of Key Terms and Techniques

IGH probe and a 670 kb SpectrumOrange labeled MALT1 probe. The IGH probe contains sequences homologous to essentially the entire IGH locus, as well as sequences extending about 300 kb beyond the 3′ end of the IGH locus. The LSI MALT1 probe contains sequences that extend from a point telomeric to the D18S531 locus, through the MALT1 and HAK genes, and end proximally at a point centromeric to the HAK locus. This probe is useful in identifying the IGH/MALT1 t(14;18)(q32;q21) translocation.

13

API2 MALT1 Fusion Probe: The LSI API2/MALT1 dual color, dual fusion translocation probe is composed of a mixture of a SpectrumGreen labeled IGH probe and a SpectrumOrange labeled MALT1 probe. This probe is useful in identifying the API2/MALT1 t(11;18)(q21;q21) translocation. It will detect cells with a t(11;18)(q21;q21) translocation.

CHAPTER TWO

THE THERAPY OF CUTANEOUS T CELL LYMPHOMA Pierluigi Porcu and Mark A. Bechtel

INTRODUCTION Cutaneous T cell lymphoma (CTCL) generally is characterized by an indolent presentation and lack of progression. Patients with limited patches or plaques (Stage IA) have a <10% risk of developing progressive disease and have median survival similar to that of matched controls (Kim et al., 1996). In a subset of patients with Stage IB-IIA, however, CTCL may progress over time to more extensive disease and in a small minority of cases it may present de novo with tumors, erythroderma, and peripheral blood or visceral involvement (Kim et al., 2003). In these circumstances CTCL is associated with a significant risk of diseaserelated mortality and shorter survival (Lu et al., 2001; Kim et al., 2003; Vonderheid and Bernengo, 2003; Tancrede-Bohin et al., 2004). S´ezary syndrome (SS), a unique primary leukemic form of CTCL, presents with erythroderma and peripheral blood lymphocytosis (Vonderheid and Bernengo, 2003). Prognosis for these patients is poor, with 5 year survival approaching at best 30% (Tables 2.1 and 2.2). In the absence of molecular biomarkers similar to those available for other hematological malignancies, there are currently no broadly applicable tools for risk stratification in CTCL. Advanced clinical stage, older age, elevated lactate dehydrogenase (LDH) levels, and peripheral blood eosinophilia are all

associated with poor prognosis (Tancrede-Bohin et al., 2004). Histopathologically, the presence of significant numbers of large, atypical CD30-positive cells, suggestive of large cell transformation, is generally indicative of a poor prognosis, although this finding needs to be associated with clinical evidence of tumor development at multiple sites to be significant. Conversely, the expression of the chemokine receptors CCR4, CXCR3, and CXCR4 on malignant T cells is generally restricted to earlier stage lesions and loss of these markers with increased levels of CCR7, a lymph node homing receptor, is observed in patients with tumor stage and lymphadenopathy (Lu et al., 2001; Kallinich et al., 2003). Finally, loss of epidermotropism in advanced forms of MF, such as SS, is a common finding and skin biopsies in these patients may not show any tumor cells within the epidermis. In addition, a number of defects of adaptive and innate immunity can be observed during the clinical progression of CTCL (Kim et al., 2005). Chronic and excessive production of Th2 cytokines, such as IL-4, IL-5, and IL-10, is believed to be an important mechanism by which malignant T cells circumvent antitumor responses and gradual loss of Th1 cytokines (IL-12 and IFN-γ ), CD8-positive cytotoxic T cells (CTL), and natural killer (NK) cells is observed in advanced stage CTCL (Yoo et al., 2001; French et al.,

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 14

Goals of Therapy in Advanced Stage CTCL

TABLE 2.1 CTCL Therapies Skin-directed Topical corticosteroids Topical nitrogen mustard (mechlorethamine) Topical BCNU (carmustine) Topical bexarotene Topical imiquimod PUVA (psoralen plus ultraviolet A) Narrowband UVB Topical skin electron beam Photodynamic therapy Systemic Extracorporeal photophoresis Bexarotene Interferon-α Interleukin-2 Chemotherapy Denileukin diftitox

15

lymphadenopathy, unexplained peripheral blood findings, or clinical signs or symptoms of visceral involvement are present. In patients with non-MFtype CTCL, a comprehensive staging and diagnostic work-up to verify that the disease is limited to the skin should always be performed. The role of T cell receptor (TCR) rearrangement analysis in the routine staging evaluation of CTCL remains to be established. Detection of clonal TCR-β rearrangements in typical skin lesions of patients with suspected CTCL for diagnosis and discovery of identical clones in the peripheral blood, lymph nodes, or bone marrow is unequivocal evidence of extracutaneous extension. However, in the absence of histopathological or immunophenotypical evidence of disease, the clinical significance, and therefore the treatment implications, of finding TCR-β rearrangements in the bone marrow, lymph nodes, or peripheral blood of CTCL patients is the subject of continuous debate (Delfau-Larue et al., 1998; Assaf et al., 2005).

TABLE 2.2 Therapy by Stage of Mycosis Fungoides Stage Stage IA-IB

Stage IIA Stage IIB

Therapy Topical steroids, topical nitrogen mustard, topical BCNU, narrowband UVB, PUVA, total skin electron beam Same as above Interferon-α, retinoids, PUVA, combinations of topical and systemic treatment

2005). Low absolute numbers of peripheral blood or skin CD8-positive T cells, measured by flow cytometry or immunohistochemistry, have been reported to be an accurate predictor of survival (Abeni et al., 2005), and therapy with retinoids has led to increases in CD8-positive T cells in responders.

DIAGNOSTIC WORK-UP AND STAGING PROCEDURES Staging evaluation of CTCL patients should include a comprehensive physical examination, a complete blood count, a comprehensive metabolic panel, and the quantification of circulating malignant T cells by flow cytometry. In patients presenting with typical MF, bone marrow aspirate and biopsy, contrast-enhanced computed tomography (CT) scan, and whole body positron emission tomography (PET) scanning should only be performed if diffuse

GOALS OF THERAPY IN ADVANCED STAGE CTCL It is now established that by the time CTCL has advanced to tumor lesions, the malignant T cells have acquired multiple molecular abnormalities in the pathways that regulate normal cell growth and survival. These defects are responsible for the high resistance to drug-induced apoptosis displayed by malignant T cells and the brief and partial responses typically seen with conventional therapy in CTCL. Intensive cytotoxic chemotherapy, as used in other forms of lymphoma and leukemia, not only results in few durable responses but may actually shorten survival in some patients by virtue of its myelosuppressive effect and its depression of T cell mediated immunity. Thus, the focus of systemic therapy in CTCL has gradually evolved from conventional cytotoxic chemotherapy to agents that not only can induce T cell apoptosis but also enhance the patient’s chances to avoid neutropenia and mount a robust immune response.

EXTRACORPOREAL PHOTOPHERESIS (ECP) ECP is a form of systemic therapy, originally developed by Edelson et al. (1987), that is FDA approved for the treatment of SS. In ECP, patients ingest oral

16

CHAPTER TWO

The Therapy of Cutaneous T Cell Lymphoma

8-methoxypsoralen (8-MOP); then peripheral blood lymphocytes are collected by leukopheresis, exposed ex vivo to ultraviolet A (UVA) light, and reinfused back into the patient. ECP is initially performed on two consecutive days once a month until maximal clearing has occurred. This is followed by an additional 6 months of monthly therapy and then gradually tapered to 2 month intervals and eventually discontinued. In the initial cohort reported by Edelson et al. (1987), the response rate in refractory CTCL (most of whom had SS) was 73% and the median survival was 60 months. The side effects of ECP consist mostly of nausea and vomiting associated with oral 8-MOP. There is now an investigational form of liquid 8-MOP that is administered directly into the photopheresis machine, so patients do not have to ingest the psoralen. The proposed mechanism of action of ECP is twofold: (1) UVA irradiation directly kills malignant T cells sensitized by 8-MOP, and (2) the reinfused leukophoresis product stimulates a selective immune response against the malignant cells. Further studies have retrospectively compared the outcomes of patients treated with or without ECP, generally finding similar survivals. Overall, ECP appears to be effective only in a subset of patients with advanced stage CTCL, specifically SS with near normal CD8+ T cell counts, and a relatively short duration of advanced disease. However, these patients are also more likely to respond to other immune-modifying therapies and the value of ECP vis-`a-vis other treatment modalities has not been prospectively tested in clinical trials (Richardson et al., 2003). Finally, due to the highly encouraging responses seen with alemtuzumab in SS and due to the fact that ECP requires special equipment, not broadly available, it is conceivable that monoclonal antibodies will become more frequently used for this indication than ECP.

INTERFERONS The most active single agent in the treatment of CTCL is IFN-α. Initial studies in heavily pretreated patients with CTCL, with doses ranging from 36 million international units (MIU) per day to 50 MIU three times a week, showed objective response rates of 45–65%, with complete response rates of 10–30% and response duration of 4.5–5.5 months (Olsen and Bunn, 1995). In patients with all stages of CTCL who had not received prior systemic therapy, the overall response rate was as high as 80%. Enthusiasm for the high response rate with IFN-α has been tempered by its significant toxicity profile. Adverse effects to IFNα include malaise, fever, chills, myalgias, depression,

anorexia, and weight loss. Although none of these events are dose-limiting in isolation, their cumulative burden is commonly severe and this fact often leads to substantial dose modification or cessation of therapy. Frequent laboratory abnormalities observed during therapy with IFN-α include dose-related and reversible leukopenia and thrombocytopenia, abnormal liver function tests, and, occasionally, hypothyroidism. There is clearly a dose–response effect with IFN-α in CTCL. The current treatment approach with IFN-α is to start at 3 MIU per day and increase as tolerated, usually to a maximum of approximately 15 MIU per day. Lower doses of IFN-α have been successfully combined with other treatment modalities with excellent results. At Northwestern University, a study combining the use of IFN-α (3–12 MIU three times a week) with PUVA in patients with all stages of MF/SS demonstrated an overall response rate of 88%, with a complete response rate of 62% and median response duration of 28 months, establishing this combination as one of the most active therapies in CTCL (Kuzel et al., 1995). In addition to IFN-α, there is evidence that systemic or topical recombinant IFN-γ may have significant potential for the treatment of CTCL, and that it may be better tolerated than IFN-α (Kaplan et al., 1990; Dummer et al., 2004). In addition to enhancing the CTL function, IFN-γ suppresses excess Th2 cytokine production, enhances CD40 expression, and primes abnormal dendritic cells for IL-12 production, particularly in response to CD40 ligation.

RETINOIDS Retinoids are vitamin A derivatives and have been shown to have antiproliferative and differentiating effects in many hematological malignancies, including CTCL (Zhang and Duvic, 2003). Response rates ranging from 44% to 68% have been reported with isotretinoin (13-cis-retinoic acid) in patients with Stage I-II disease. The most common toxicities include drying of the skin and mucous membranes, conjunctivitis, fatigue, arthralgias, mental status changes, headaches, and elevated triglyceride levels. More recently, bexarotene (Targretin; Ligand Pharmaceuticals), a retinoid X receptor (RXR) selective agonist, was shown to have substantial clinical efficacy in both topical and oral formulations in patients with all stages of CTCL and was approved in 1999 by the FDA for this indication (Duvic et al., 2001). In the pivotal trial 94 patients with CTCL received oral bexarotene at doses ranging from 300 to 650 mg/m2 /day. At the

Monoclonal Antibodies

dose of 300 mg/m2 /day, the response rate observed was 45–55%, depending on stage, with a median time to response of 180 days and a median duration of response of 10 months. There was a nonstatistically significant trend toward a dose–response relationship, with greater complete response rate (13%), shorter time to response (59 days), and longer duration of response (13 months) at doses higher than 300 mg/m2 . However, dose-limiting toxicity (hypertriglyceridemia) prevented continuation of therapy at higher doses (650 mg/m2 /day) of bexarotene and the FDA-approved dosage is 300 mg/m2 /day. Adverse events included hypertriglyceridemia, hypercholesterolemia, central hypothyroidism, and leukopenia. The activity of bexarotene in non-MF/SS-type of CTCL has not been investigated in clinical trials but responses in CD30-positive primary cutaneous ALCL and panniculitis-like T cell lymphoma have been reported. Bexarotene exerts a number of biological effects that may sensitize malignant T cells to other therapies. At clinically relevant concentrations, bexarotene upregulates both the p55 and p75 subunits of the interleukin-2 (IL-2) receptor in vitro, thus enhancing the susceptibility of T cell leukemia cells to denileukin diftitox (see ‘‘Immunotoxins’’) by five- to tenfold. To determine whether this effect could be reproduced in vivo, Foss et al. (2005) completed a small Phase I study of bexarotene (75–300 mg/day) and denileukin diftitox (18 µg/kg per day × 3 days every 21 days) in 14 patients with relapsed or refractory CTCL. Overall response was 67%, with four complete responses. Modulation of IL-2R expression on CTCL cells was observed at or above a bexarotene dose of 150 mg/day. Leukopenia and lymphopenia were observed in a small number of patients, without clinical evidence of opportunistic infections. Thus, the combination of denileukin diftitox and bexarotene was well tolerated and even low doses (150 mg/day) of bexarotene were capable of upregulating CD25 expression. This work by Foss et al. (2005) is of great interest and further studies in larger patient cohorts are needed to establish the clinical value of this combination.

IMMUNOTOXINS Denileukin diftitox (DAB389 IL-2, Ontak, Ligand Pharmaceuticals), a genetically engineered fusion protein combining the enzymatically active domain of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2), efficiently targets cells expressing the high-affinity IL-2 receptor subunits which are

17

highly expressed on the malignant T cells in the majority of cases of CTCL. After binding to the IL-2 receptor, denileukin diftitox undergoes endocytosis followed by release of the diptheria toxin, which results in arrest of protein synthesis and, ultimately, apoptosis of T cells. The initial Phase I study with denileukin diftitox in 35 patients consisted of five daily infusions every 3 weeks for up to six cycles at escalating doses, yielding an overall response rate of 37% with 14% complete responses. Adverse effects of DAB389 IL-2 included fever, chills, hypotension, nausea, vomiting, and elevated transaminases. In the following pivotal Phase III trial in heavily pretreated patients, two different doses of denileukin diftitox (9 µg/kg and 18 µg/kg) were studied (Olsen et al., 2001). The overall response rate was 29.5% with 10% complete responses and no difference between the two dose levels. A mild, self-limited form of vascular leak syndrome (VLS) is frequently observed after the first cycle of denileukin diftitox, with lower extremity edema, hypoalbuminemia, and elevated serum creatinine. The frequency and intensity of VLS can be significantly reduced by premedication with dexamethasone (4–8 mg orally) without compromising the efficacy of therapy. Currently, denileukin difititox is approved for use only in CD25-positive CTCL, as defined by positive staining by immunohistochemistry (IHC) on frozen or paraffin embedded tissue. However, the levels of CD25 expression sufficient to confer sensitivity to denileukin diftitox are likely to be much below the IHC threshold of detection, as suggested by the numerous responses reported in CD25-negative CTCL in early clinical trials. Thus, a postmarketing study is now in progress to prospectively establish respective response rates in CD25-positive versus CD25-negative CTCL. The major mechanism of action of denileukin diftitox in CTCL is believed to be direct killing of malignant T cells. However, part of its activity may also be immunologically mediated through the elimination of CD4/CD25-positive regulatory T cells (Tregs), a normal subset of T cells with constitutive suppressive activity (Dannull et al., 2005). Thus, denileukin diftitox, by depleting Treg cells, may conceivably enhance normal residual antitumor responses in CTCL patients. This hypothesis is being investigated by a number of groups.

MONOCLONAL ANTIBODIES A number of humanized monoclonal antibodies (mAbs) against surface antigens expressed by normal

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The Therapy of Cutaneous T Cell Lymphoma

and malignant T cells have recently become available for clinical use. Alemtuzumab (Campath-1H) is a humanized IgG1 mAb directed against CD52, a glycosylated peptide antigen expressed on most malignant B and T cells. Alemtuzumab was developed primarily for the treatment of patients with B cell chronic lymphocytic leukemia (B-CLL); however, it also showed strong activity in T cell leukemias and lymphomas. Alemtuzumab is probably the single most active agent in T cell prolymphocytic leukemia (T-PLL) and in a Phase II study in heavily pretreated non-Hodgkin lymphoma patients, 4 of 8 CTCL patients responded. More recently, Lundin et al. (2003) prospectively studied alemtuzumab in 22 patients with advanced CTCL. The overall response rate was 55%, with 32% complete responses, and median duration of response approaching 12 months. Impressively, S´ezary cells were cleared from the blood in 86% of the patients. Cytomegalovirus (CMV) reactivation occurred in 18% of patients but without clinical respiratory or gastrointestinal syndromes. Three patients had more significant infectious complications, such as generalized herpes simplex, aspergillosis, and mycobacterial pneumonia. Thus, alemtuzumab shows promising activity, particularly in patients with erythroderma and SS, but its use requires aggressive prophylactic therapy and surveillance for opportunistic infections. Based on this study and preliminary results from other ongoing clinical trials, it appears that alemtuzumab may become one of the drugs of choice for SS patients and further studies are in progress.

CYTOTOXIC CHEMOTHERAPY Systemic cytotoxic chemotherapy has generally been used for palliation of CTCL patients with relapsed or refractory disease or for patients with advanced disease at presentation. Methotrexate, glucocorticoids, cyclophosphamide, cisplatin, etoposide, bleomycin, doxorubicin, vincristine, and vinblastine have all been used as single agents or in combination, with complete response rates up to 30%, but very short remission durations and significant toxicity, mostly due to myelosuppression (Rosen and Foss, 1995). Prednisone alone induces partial remissions in approximately 50% of patients and pulse dexamethasone is effective in obtaining symptomatic relief in patients with severe SS. However, flares are the rule once the dose is tapered and chronic steroid use is associated with significant morbidity. The purine analogs, such as 2′ -deoxycoformycin (pentostatin), 2-chlorodeoxyadenosine (2-CDA), and fludarabine have profound effects on normal and

malignant T cells. Response rates in CTCL have been higher with 2-deoxycoformycin (54–100%) than with the other two compounds but no prospective comparative study has been performed (Grever et al., 1983; Cummings et al., 1991; Kuzel et al., 1996; Quaglino et al., 2004). Major toxicities of these drugs are neurotoxicity and prolonged immunosuppression, leading to opportunistic infections. Trimetrexate (TMTX) is a lipophilic antifolate that enters cells by passive diffusion and achieves intracellular concentrations 10–100 times greater than those of MTX, thus bypassing possible mechanisms of resistance. In addition, TMTX is not polyglutamated and is not retained in cells for prolonged periods, possibly accounting for its relatively low hepatotoxicity. Based on the known clinical activity of MTX in CTCL, a Phase II study of TMTX (200 mg/m2 IV every 14 days up to 12 doses) in patients with relapsed CTCL was recently completed showing a 45% response rate in heavily pretreated patients and tolerable toxicity (Sarris et al., 2002). Although this drug is probably significantly more active than MTX, the intravenous route of administration makes it unlikely to replace MTX. Several small studies have shown that gemcitabine (2′ ,2′ -difluoro-deoxycytidine, Gemzar), a pirimidine analogue with structural similarities to cytarabine, has significant activity in various types of heavily pretreated T cell lymphoma, including CTCL. Recently, Marchi et al. (2005) reported the results of a prospective study of gemcitabine in 32 patients with systemically untreated CTCL. Gemcitabine was given on days 1, 8, and 15 of a 28 day schedule at a dose of 1200 mg/m2 intravenously over 30 minutes for a total of six cycles. The overall response rate was 75% with 22% complete responses and median duration of response 10 months. Overall, although these new agents appear to be promising, the role of cytotoxic chemotherapy in the management of advanced CTCL should be limited to patients who have failed other agents with more selective action (Ontak, alemtuzumab) or with a more favorable immunomodulatory effect (ECP, retinoids, interferons).

INVESTIGATIONAL THERAPIES CTCL has been and remains a paradigm for the development of new agents in T cell leukemia and lymphoma. Among the numerous therapies under study in early clinical trials, those that appear to be most promising at the moment are (1) monoclonal antibodies (mAbs) against T cell surface markers, (2) histone

Investigational Therapies

deacetylase inhibitors, (3) new immunomodulatory agents, such as toll-like receptor (TLR) agonists and cytokines, and (4) allogeneic hematopoietic stem cell transplantation.

Monoclonal Antibodies In addition to alemtuzumab, several additional mAbs targeting T cell markers such as CD2 and CD4 are in clinical development. Preliminary results from a Phase I clinical trial of siplizumab (MEDI-507), a humanized anti-CD2 mAb, in patients with various types of T cell lymphoma were recently presented (O’Mahony et al., 2005). Typical infusional adverse reactions occurred with the first dose and asymptomatic CMV reactivation was seen. Treatment resulted in partial remission or stabilization of disease in several patients. Another mAb in early clinical development is zanolimumab (HuMaxCD4) (Hagberg et al., 2005). Phase II data with this antibody in 47 CTCL patients relapsing after bexarotene show response rates ranging from 22% to 75%, including some complete responses, depending on the dose (280, 560, or 980 mg) and the stage of disease (Obitz et al., 2003). More than 80% of the responses were reached within 8 weeks and median response duration was more than 10 months. Nine patients with SS were treated on this study at all dose levels, four of which obtained minor responses and one a partial response. The observed responses in these patients were generally short-lived and depletion of CD4 T cells was limited, suggesting that this antibody may not be as effective as alemtuzumab in SS.

TLR Agonists and Cytokines Toll-like receptors (TLRs) are transmembrane receptors expressed on innate immune cells, such as monocytes, macrophages, and dendritic cells that recognize conserved pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) and CpG DNA (McInturff et al., 2005). TLR activation triggers the expression of immune response and cytokine genes, which are instrumental in launching innate immune responses and influencing adaptive immunity. TLRs have been identified as potential therapeutic targets in infectious and inflammatory diseases and CpG oligodeoxynucleotides (ODNs) have been studied as immune stimulatory agents by virtue of TLR-9 activation of dendritic cells (Wysocka et al., 2004). In vitro, CpG-ODNs activate dendritic cells, enhancing IFN production and expression of costimulatory molecules, ultimately augmenting T cell responses. In vivo, CpG-ODNs lead to strong antitumor responses in animal models. Recently, Y. Kim et al. (2004) completed a Phase II trial of subcutaneous CpG-ODNs

19

(CPG-7909) in refractory CTCL, demonstrating significant therapeutic efficacy, including complete clinical responses. Imiquimod, a potent TLR-7 agonist, which is FDA approved for the treatment of basal cell carcinoma, actinic keratoses, and condyloma, also has substantial activity as a topical agent in CTCL (Suchin et al., 2002; Dummer et al., 2003). In addition to inducing IFN-α and TNF-α through activation of TLR-7 on antigen presenting cells (Hurwitz et al., 2003), imiquimod can also directly induce apoptosis in a variety of tumor cells (Schon and Schon, 2004). Newer members of this family have the capacity to activate TLR-8 in addition to TLR-7, resulting in broader dendritic cell activation and release of a more extensive array of cytokines. Several clinical trials exploring the use of TLR agonists in CTCL either alone or as part of a multimodality approach are in progress. Interleukin-12 (IL-12) is a cytokine that enhances CTL and NK cell function and induces Th1 cytokines (IFN-γ ). Subcutaneous administration of recombinant human IL-12 to a total of 32 patients with CTCL resulted in a response rate of approximately 50% (Rook et al., 1999). Since malignant T cells often lack the IL-12β2 receptor, the hypothesis is that the clinical responses were not due to a direct effect on malignant cells but to the stimulation of residual normal CD8+ T cells. Indeed, serial skin biopsies during treatment with IL-12 revealed dense infiltrates of CD8-positive T cells that correlated with the time of response. Although IL-12 appears to have significant potential as an immunomodulatory therapy in CTCL, at the present time it is not available from either industry or the NIH for further clinical studies.

Histone Deacetylase Inhibitors (HDACi) The accessibility of nuclear chromatin to transcription factors and RNA polymerase is regulated in part by the balance of acetylation of nucleosomal histones, which is the result of the opposing activities of histone deacetylases (HDACs) and histone acetyl transferases (HATs). Deacetylation-induced silencing of tumor suppressor genes, via HDAC, has been observed in a variety of human cancers and pharmacological restoration of gene expression through inhibition of histone deacetylation is a novel form of therapy that selectively induces growth arrest, differentiation, and apoptosis in malignant cells. Several families of HDACi have been characterized. Compounds such as suberoylanilide hydroxamic acid and depsipeptide have already entered the clinical arena and have shown promising activity in the treatment of T cell lymphoma (Piekarz et al., 2004). In an ongoing Phase II study, 27 patients with advanced CTCL were treated with depsipeptide given as a 4-hour infusion

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CHAPTER TWO

The Therapy of Cutaneous T Cell Lymphoma

on days 1, 8, and 15 of a 28 day cycle (Piekarz et al., 2005). Three patients with S´ezary syndrome achieved a complete response and five other patients had partial responses for an overall response rate of 30%. The median duration of response is 18 months (range 6–48). Overall, depsipeptide was well tolerated, with dose-related but modest nausea, fatigue, neutropenia, and thrombocytopenia. However, a number of severe cardiac adverse events have occurred in clinical trials with this agent and, although the direct cardiotoxicity of depsipeptide has not been proved, safety concerns may prevent further clinical development. Suberoylanilide hydroxamic acid (SAHA), another potent HDACi, is currently in Phase II clinical trial in patients with Stage IA-IVB CTCL refractory to at least one systemic therapy (Duvic et al., 2005). Thus far, 10 of 37 patients treated with various oral dosing regimens of SAHA have achieved a partial response, including decrease of lymphadenopathy. Therapy, however, had to be discontinued in several patients because of fatigue, rash, anemia, neuropathy, thrombocytopenia, and weight loss. The 400 mg daily oral dose was selected for further study. Overall, HDACi appear to be very active in CTCL and further studies are needed to establish the optimal dose and schedule that provide therapeutic efficacy without excessive toxicity.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Allogeneic hematopoietic stem cells from an HLAidentical sibling or a matched unrelated donor have induced complete and durable remissions in CTCL, with disappearance of the malignant clone from the peripheral blood and resolution of cutaneous and visceral lesions (Molina et al., 2005). This effect is likely due to a graft versus T cell lymphoma effect mediated by the host’s reconstituted immune system (Burt et al., 2000). However, only a minority of CTCL patients are eligible for allogeneic HSCT or have an HLA-matched donor. Furthermore, toxicity remains a major problem, with estimated treatment-related mortalities approaching 10–25% for allo-HSCT from sibling donors and 30–50% from unrelated donors. Investigations of allo-HSCT following nonmyeloablative conditioning in T cell lymphoma and studies to identify, activate, and expand autologous effector T cells with antitumor activity offer the promise of extending the benefit of the graft versus T cell lymphoma effect to a larger population. A greater understanding of the molecular biology and immunobiology of CTCL has led to the identification of more relevant cellular targets of therapy and

to the development of new drugs able to affect those targets. Future challenges include the development of well-designed clinical trials to elucidate the optimal combination and timing of these therapies.

CTCL THERAPIES The therapeutic choices for the treatment of CTCL depend on the stage of the disease and the general health and age of the patient. Although the therapies may be effective in controlling the disease, they have not been shown to prolong life. Because CTCL can involve skin, blood, bone marrow, and lymph nodes, proper staging is critical in the management of this disease. The treatment of CTCL can be divided into skin directed and systemic therapies (see Table 2.1). Therapeutic approaches using combination therapies may have synergistic benefits and may reduce toxicity of the single agents. Although combined modalities may increase disease-free survival, they do not change overall survival (Duvic et al., 2003). Therapeutic choices may be challenging due to limited randomized clinical trials for CTCL. The primary goals of therapy are to improve the quality of life, induce disease-free remission, and prolong life. Some patients may be effectively cured. Localized skin-directed therapies can be very successful in managing localized disease. Patients with more widespread disease need total skin-directed therapy or systemic therapy (discussed earlier).

Skin-Directed Therapies Topical Corticosteroids The use of topical corticosteroids is often effective in controlling early stage mycosis fungoides (see Table 2.2). Limited patch and thin plaque disease responds most consistently. A complete response in 60% of patients was reported in early stage disease with topical corticosteroids (Zacheim et al., 1988). The side effects of topical steroids include cutaneous atrophy, telangiectasias, striae, and suppression of the pituitary adrenal axis with systemic absorption. Topical Chemotherapy Topical chemotherapeutic agents, such as mechlorethamine (nitrogen mustard) and carmustine (BCNU) have been demonstrated to be effective in the management of early stages of mycosis fungoides. They can also be used as adjunctive therapy with other modalities. Topical chemotherapeutic agents should be avoided along with ultraviolet light therapy due

CTCL Therapies

to an increased risk of skin cancer. The skin effects of these agents include skin irritation, allergic contact dermatitis, and an increased risk of skin cancer with long-term use. Mechlorethamine has been used for over 30 years in the treatment of mycosis fungoides. Previous studies have demonstrated complete remissions in approximately 60–80% of patients with early patch and plaque stage disease. Most long-lasting remissions occurred in patients with patch or plaque stage mycosis fungoides without palpable lymphadenopathy (Vonderheid et al., 1989). The treatment involves preparing 10 mg of mechlorethamine in 50–60 mL of water and applying with a brush to the entire skin surface, except eyelids, lips, and rectal and vaginal orifices. This is repeated daily for 6–12 months. If patients develop a hypersensitivity reaction manifested as cutaneous erythema and pruritus, the treatment can be briefly interrupted. After the hypersensitivity reaction subsides, a more dilute solution (10 mg in 500 mL of water) can be initiated as tolerated. The concentration can be slowly increased over time. After a complete remission is achieved, the treatments can be gradually tapered, but no tapering schedule has demonstrated superior clinical efficacy. Mechlorethamine can also be applied in an Aquaphor base and may be less irritating. Topical carmustine (BCNU) has proved effective in early stage mycosis fungoides. It can be applied in a stock solution of BCNU in alcohol or prepared in an ointment base with white petrolatum. A complete response was documented in 86% of patients with Stage IA and 47% with Stage IB disease. The median time for a complete response was 11.5 weeks. Approximately 18% of patients were relapse free at five years (Zackheim et al., 1990). The cutaneous side effects of topical carmustine include skin tenderness, erythema, and hyperpigmentation. Many patients develop increased telangiectasias and this should be avoided on the face. Allergic contact dermatitis and primary contact irritation develop similar to topical nitrogen mustard. Myelosuppression can develop with topical use and should be carefully monitored with complete blood counts. Topical Retinoids Bexarotene gel, a synthetic retinoid X agonist, has been approved for the treatment of mycosis fungoides. The retinoid receptors (RAR and RXR) are members of a family of transcription factors belonging to the nuclear hormone receptor family. The nuclear hormone receptor family also includes

21

thyroxine receptor, vitamin D receptor, and peroxisomal proliferators’ activator receptor. Bexarotene induces a RAR–RXR heterodimer complex that activates gene promoter regions encoding transcription factors, structural proteins, and cell receptors. This results in transcriptional modulation of cell function and differentiation, growth inhibition, and apoptosis. The safety and efficacy of topical bexarotene gel was examined in an open-label Phase III study of 50 patients with refractory or persistent early stage CTCL. A partial response was noted in 54% of patients and a complete response in 10% (Heald et al., 2003). In a Phase I/II study of bexarotene gel, 61 patients with early stage CTCL were treated. Partial responses were noted in 42% of patients and complete responses in 21% (Brenenman et al., 2002). Bexarotene gel is initiated at a dose of 1% topical gel every other day and gradually increased in frequency to four times a day at 1–2 week intervals. The drug can cause a retinoid erythema and irritant dermatitis. It may take several weeks to note a clinical response. The immunologic effects of bexarotene are related to a decreased expression of TH2 cytokines and decreased monocyte macrophage inflammatory mediators. There is a decrease in abnormal keratinocyte proliferation and induction of apoptosis of abnormal T cells. Topical Imiquimod Imiquimod 5% cream has been demonstrated to be helpful in limited patch and plaque stage mycosis fungoides (Suchin et al., 2002; Deeths et al., 2005). Imiquimod is a topical immunomodulator, which induces localized interferon production. In one study, 3 of 6 patients with Stage IA to IIB mycosis fungoides were reported to have histologic clearing and significant clinical improvement with imiquimod 5% cream applied three times per week for 12 weeks. Patients responded best to a concomitant therapy with PUVA, systemic retinoids, or systemic interferon (Deeths et al., 2005). Phototherapy Psoralen plus UVA exposure (PUVA) has become a standard therapy for patch and plaque stage CTCL (Herrmann et al., 1995). A long-term study of CTCL and PUVA at Northwestern showed 66 of 104 patients with clinical Stages IA to IIA achieving complete remission. PUVA induced long-term remission. Disease-free survival rates at 5 years and 10 years for Stage IA disease were 56% and 30%, respectively. For Stage IB/IIA, the 5 year disease-free survival was 74% and 10 year disease-free survival was 50%. However,

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CHAPTER TWO

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a 15 year survival rate for Stage IA was 82% and for Stage IB/IIA was 58% (Querfeld et al., 2005). Once the patient achieves a maximal response to treatment, a maintenance therapy is usually required to prevent relapse. Persistent or recurrent lesions particularly favor UV-shielded sites. PUVA therapy can be combined with oral bexarotene, interferon-α, and radiotherapy. The side effects of PUVA include erythema, burn injury, increased frequency of melanoma and nonmelanoma skin cancers, and cataracts. Protection of the eyes with ultraviolet light-absorbing goggles is necessary for 24 hours following ingestion or oral psoralens. Narrowband UVB is an effective treatment for patch and thin plaque mycosis fungoides. It is less effective than PUVA for thick plaque disease. In one study, patients with IA and IB mycosis fungoides achieved complete remission in 81% of cases (Dierderen et al., 2003). Narrowband UVB does not require photoprotection of eyes, unlike PUVA, and may have a lower risk of secondary skin cancers. It may be less effective than PUVA for thicker plaques. Narrowband UVB does require multiple treatments per week, which may be a disadvantage. Extracorporeal Photophoresis Extracorporeal photophoresis is a novel targeted therapy in which leukocytes are isolated and exposed to ultraviolet A. Initially, the patient’s leukocytes are separated by continuous centrifugation. The patient ingests psoralen 2 hours before the procedure or the psoralen is directly instilled into the leukocytes following their separation. The leukocytes are then exposed to ultraviolet A. In patients with treatmentresistant CTCL, an overall response in 27 out of 37 patients was achieved. Patients with S´ezary syndrome have higher response rates (Edelson et al., 1987). Radiation Therapy Total skin electron beam (TSEB) therapy is often very effective for patients with early stages of mycosis fungoides. An energy of 4–6 MeV is delivered to the skin with penetration limited to the upper dermis. The limited penetration of electrons spares deeper parenchymal tissues, bone marrow,

and the gastrointestinal tract. Approximately 3600 cGy are delivered in fractionated doses over 8–12 weeks. Separate exposures may be necessary for difficult to reach areas, including the palms, soles, axillae, perineum, and scalp. Complete remissions were reported in 98% of patients with Stage T1 disease, 71% with Stage T2 disease, and 36% with Stage T3 disease. Approximately 50% of patients with Stage T1 and 20% of with Stage T2 were disease free at 10 years (Hoppe et al., 1979). Relapse is highest in patients with tumors, lymphadenopathy, and visceral involvement. With the highly fractionated approach, patients can receive a second course of electron beam therapy to reinduce remission. Other skin-directed therapies might be added on a maintenance basis after TSEB therapy is completed. The toxic side effects of TSEB therapy may be acute or chronic. Acute side effects include erythema, edema, bullae, and desquamation. Adnexal structures that may be affected include the hair follicles and sweat glands. Patients may experience hypohidrosis, alopecia, and shedding of nails. Chronic side effects include hyperpigmentation, telangiectasias, cutaneous atrophy, xerosis, and anhidrosis. As the total dose of radiation increases, so does the risk for squamous cell carcinoma. Cutaneous lymphomas are often very radiosensitive and local radiotherapy can be utilized for patients with individual tumors or thick plaques. It may be used in combination with other modalities, such as PUVA. Approximately 800–3000 cGy can be delivered in fractionated doses. Photodynamic Therapy Photodynamic therapy (PDT) has been reported to be beneficial in the treatment of mycosis fungoides. PDT involves photosensitization with 5aminolevulinic acid and irradiation with a noncoherent light source. Activation of the photosensitizer leads to the formation of singlet oxygens, which are highly reactive and cytotoxic. PDT has the potential to inhibit the proliferation of malignant T lymphocytes (Ammann and Hunziker, 1995). This may be a useful treatment modality in patients who have reached a partial remission with more conventional therapies. The therapy can be directed to therapyresistant lesions.

References

23

REFERENCES ABENI D, FRONTANI M, SAMPOGNA F, et al. Circulating CD8+ lymphocytes, white blood cells, and survival in patients with mycosis fungoides. Br J Dermatol. 2005; 153: 324–330. AMMANN R, HUNZIKER T. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol. 1995;33: 541. ASSAF C, HUMMEL M, STEINHOFT M, et al. Early TCR-beta and TCR-gamma PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous Tcell lymphoma: diagnostic and prognostic implications. Blood. 2005; 105:503–510. BRENENMAN D, DUVIC M, KUZEL T, et al. Phase I-II trial of bexarothene gel for the skin—directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002; 138:325–332. BURT RK, GUITAR J, TRAYNOR A, et al. Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides: evidence of a graft-versus-tumor effect. Bone Marrow Transplant. 2000; 25:111–113. CUMMINGS FJ, KIM K, NEIMAN RS, et al. Phase II trial of pentostatin in refractory lymphomas and cutaneous Tcell disease. J Clin Oncol. 1991; 9:565–571. DANNULL, J, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest. 2005; 115:3623–3633. DEETHS MJ, CHAPMAN JT, DELLAVALLE PP, et al. Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream. J Am Acad Dermatol 2005;52:275–280. DELFAU-LARUE MH, DALAC S, LEPAGE E, et al. Prognostic significance of a polymerase chain reaction-detectable dominant T-lymphocyte clone in cutaneous lesions of patients with mycosis fungoides. Blood. 1998; 92:3376–3380. DIERDEREN P, VANWEELDEN H, SANDERS CG, et al. Narrow band UVB and psoralen–UVA in the treatment of earlystage mycosis fungoides: a retrospective study. J Am Acad Dermatol. 2003; 48:215–219. DUMMER R, HASSEL JC, fELLENBERG F, et al. Adenovirusmediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood. 2004; 104:1631–1638. DUMMER R, et al. Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology. 2003; 207:116–118. DUVIC M, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational Phase II-III trial results. J Clin Oncol. 2001; 19:2456–2471. DUVIC M, APISARNTHANARAX N, COHEN DS, et al. Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 2003; 49: 35–49. DUVIC M, TALPUR R, ZHANG C, GOY A, RICHON V, FRANKEL SR. Phase II trial of oral suberoylanilide hydroxamic acid (SAHA) for cutaneous T-cell lymphoma (CTCL) unresponsive to conventional therapy. Proceedings of ASCO. 2005. EDELSON R, BERGER C, GASPARRO F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. N Engl J Med. 1987;316:297–303. FOSS F, DEMIERRE MF, DIVENUTI G. A Phase-I trial of bexarotene and denileukin diftitox in patients with

relapsed or refractory cutaneous T-cell lymphoma. Blood. 2005; 106:454–457. FRENCH LE, HUARD B, WYSOCKA M, et al. Impaired CD40L signaling is a cause of defective IL-12 and TNFalpha production in S¯ezary syndrome: circumvention by hexameric soluble CD40L. Blood. 2005; 105:219–225. GREVER MR, BISACCIA E, SCARBOROUGH DA, et al. An investigation of 2′ -deoxycoformycin in the treatment of cutaneous T-cell lymphoma. Blood. 1983; 61:279–282. HAGBERG H, PETTERSSON M, BJERNER T, ERBLAD G. Treatment of a patient with a modal peripheral T-cell lymphoma (angioimmunoblastic T-cell lymphoma) with a human monoclonal antibody against the CD4 antigen (Hu MaxCD4) Med Oncol. 2005; 22: 191–194. HEALD P, MEHLMAUER M, MARTIN AG, et al. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the Phase III clinical trial. J Am Acad Dermatol. 2003;49: 801–815. HERRMANN JJ, RENIGK HH, HURRIA A, et al. Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow up. J Am Acad Dermatol. 1995;33: 234–242. HOPPE RT, COX RS, FUKS Z, et al. Electron beam radiation therapy for mycosis fungoides: the Stanford University experience. Cancer Treat Rep. 1979; 63: 691–700. HURWITZ DJ, PINCUS L, KUPPER TS. Imiquimod: a topically applied link between innate and acquired immunity. Arch Dermatol. 2003; 139:1347–1350. KALLINICH T, et al. Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. J Invest Dermatol. 2003; 121:1045–1052. KAPLAN EH, ROSEN ST, NORRIS DB, et al. Phase II study of recombinant human interferon gamma for treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst. 1990; 82:208–212. KIM EJ, HESS S, RICHARDSON SK, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest. 2005; 115:798–812. KIM Y, et al. TLR9 agonist immunomodulator treatment of cutaneous T-cell lymphoma (CTCL) with CPG7909 [abstract]. Blood 2004; 104:743a. KIM YH, JENSEN RA, WATANABE GL, VARGHESE A, Hoppe RT Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol. 1996; 132:1309–1313. KIM YH, LIU HL, MRAZ-GRENHARDS, VARGHESE A, Hoppe RT Long-term outcome of 525 patients with mycosis fungoides and S¯ezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003; 139:857–86. KUZEL TM, ROEGNIK HHJ, SAMUELSON E et al. Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the S´ezary syndrome. J Clin Oncol. 1995; 13:257–263. KUZEL TM, HURRIA A, SAMUELSON E, et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood. 1996; 87:906–911. LU D, DUVIC M, MEDEIROS LJ, et al. The T-cell chemokine receptor CXCR3 is expressed highly in low-grade mycosis fungoides. Am J Clin Pathol. 2001; 115:413–421.

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The Therapy of Cutaneous T Cell Lymphoma

LUNDIN J, HAGBERG A, REPP R et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/S´ezary syndrome. Blood. 2003; 101:4267–4272. MARCHI E, ALINARI L, TANI M et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma. Cancer. 2005; 104: 2437–2441. MCINTURFF JE, MODLIN RL, KIM J. The role of tolllike receptors in the pathogenesis and treatment of dermatological disease. J Invest Dermatol. 2005; 125:1–8. MOLINA A, et al. Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory S´ezary syndrome and mycosis fungoides. J Clin Oncol. 2005; 23:6163–6171. OBITZ E, KIM YH, IVERSEN L, et al. HuMax-CD4, a fully human monoclonal antibody: early results of an ongoing Phase II trial in CTCL. Blood. 2003; 102: xx–xx. OLSEN EA, BUNN PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995; 9:1089–1107. OLSEN E, DUVIC M, FRANKEL A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001; 19:376–388. O’MAHONY D, et al. A Phase I trial of siplizumab in CD2-positive lymphoproliferative disease. Blood. 2005; 106:3353a. PIEKARZ RL, et al. Completion of the first cohort of patients with cutaneous T-cell lymphoma enrolled on a Phase II trial of depsipeptide. Blood. 2005; 106:231a. PIEKARZ RL, ROBEY RW, ZHAR Z, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood. 2004; 103:4636–4643. QUAGLINO P, FIERRO MT, ROSSOTTO GL, SAVOIA P, BERNENGO MG. Treatment of advanced mycosis fungoides/S´ezary syndrome with fludarabine and potential adjunctive benefit to subsequent extracorporeal photochemotherapy. Br J Dermatol. 2004; 150: 327–336. QUERFELD C, ROSEN ST, KUZEL TM, et al. Long-term follow up of patients with early-stage cutaneous Tcell lymphoma who achieved complete remission with psoralens plus UV-A monotherapy. Arch Dermatol. 2005; 141:205–311. RICHARDSON SK, MCGINNIS KS, SHAPIRO M et al. Extracorporeal photopheresis and multimodality immunomodulatory therapy in the treatment of cutaneous T-cell lymphoma. J Cutan Med Surg. 2003; 7(Suppl 4):8–12.

ROOK AH, WOOD GS, YOO EK, et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood. 1999; 94: 902–908. ROSEN ST, FOSS FM. Chemotherapy for mycosis fungoides and the S´ezary syndrome. Hematol Oncol Clin North Am. 1995; 9:1109–1116. SARRIS AH, PHAN A, DUVIC M, et al. Trimetrexate in relapsed T-cell lymphoma with skin involvement. J Clin Oncol. 2002; 20:2876–2880. SCHON MP, SCHON M. Immune modulation and apoptosis induction: two sides of the antitumoral activity of imiquimod. Apoptosis. 2004; 9:291–298. SUCHIN KR, JUNKINS-HOPKINS JM, ROOK AH. Treatment of Stage IA cutaneous T-cell lymphoma with topical application of the immune response modifier imiquimod. Arch Dermatol. 2002; 138:1137–1139. TANCREDE-BOHIN E, IONESCU MA, DE LA SALMONIERE P, et al. Prognostic value of blood eosinophilia in primary cutaneous T-cell lymphomas. Arch Dermatol. 2004; 140:1057–1061. VONDERHEID EC, BERNENGO MG. The S´ezary syndrome: hematologic criteria. Hematol Oncol Clin North Am. 2003; 17:1367–1389. VONDERHEID EC, TAN E, KANTOR AF, et al. Longterm efficacy, curative potential and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T-cell lymphoma. J Am Acad Dermatol. 1989; 20:416–428. WYSOCKA, M, BENOIT BM, NEWTON S, AZZONI L, MONTANES LJ, ROOK AW. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood. 2004; 104:4142–4149. YOO EK, CASSIN M, LESSIN SR, ROOK AW. Complete molecular remission during biologic response modifier therapy for S´ezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol. 2001; 45:208–216. ZACKHEIM HS, KASHANI-SABET M, AMIN S. Topical corticosteroids for mycosis fungoides: experience in 79 patients. Arch Dermatol. 1988; 134:949–954. ZACKHIEM HS, EPSTEIN EH, CRAIN WR. Topical carmustine (BCNU) for cutaneous T-cell lymphoma: a fifteen year experience in 143 patients. J Am Acad Dermatol. 1990; 22:802–810. ZHANG C, DUVIC M. Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma. Dermatol Ther. 2003; 16:322–330.

CHAPTER THREE

MOLECULAR TECHNIQUES Carl Morrison

INTRODUCTION The diagnosis of B and T cell lymphoproliferative disorders of the skin is supported by the finding of clonally rearranged immunoglobulin (Ig) genes and T-cell receptor (TCR) genes, whereas reactive conditions are generally associated with a polyclonal status. Immunoglobulin gene rearrangement analysis can be performed by either Southern blot or polymerase chain reaction (PCR) based techniques, but the former is not readily applicable to the vast majority of skin biopsies. Therefore, the material presented here concerning evaluation of immunoglobulin gene rearrangements is based on the current PCR standards of practice. In addition, the current standards of practice in regard to a PCR-based approach to the assessment of B to T cell clonality are directed toward the immunoglobulin heavy chain (IgH) and TCR-β loci, which we follow in this chapter. An effective PCR-based laboratory approach to both IgH and TCR-β gene rearrangements needs to utilize a limited standardized set of multiplex master mixes, all of which are run on a single universal thermocycler program, with each targeting a different conserved region or sequence for both loci. In addition, there needs to be a sensitive and reproducible method of product analysis. The methodology employed in our laboratory and the one presented

throughout this chapter is based on primer and multiplex PCR design derived from the European BIOMED-2 collaborative study group (van Dongen et al., 2003). This group has extensively tested a large number of different family specific primers for both IgH and TCR-β and all the different primer combinations. There was an effort in this study to keep the amplicon products under 350 base pairs in size, making the design applicable to both frozen and formalinfixed paraffin embedded tissues. As a result of this study at least one company in North America (InVivoScribe Technologies; http://www.invivoscribe.com) is supplying similar PCR kits for both IgH and TCR-β on a commercial basis. Because of the ready availability of these primer sets, any laboratory with a minimum of experience can set up a robust and reproducible PCR-based B and T cell clonality assay rather quickly. The basic approach for assessing clonality for both IgH and TCR-β based on the European BIOMED2 collaborative study is three multiplex PCRs and subsequent analysis of the products by fragment size analysis (base pair length). A basic understanding of how these assays are designed and implemented is best achieved by an examination of Ig receptor structure, PCR design, product detection, evaluation of results, and limitations of the assay.

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 25

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IMMUNOGLOBULIN RECEPTOR STRUCTURE

that is present in all groups is referred to as the consensus sequence. The sequence that is shared among some but not all VH segments is referred to as the familyspecific sequence. Based on this latter family-specific sequence, the different functional VH segments can be divided into seven VH subgroups (VH1, VH2, VH3, VH4, VH5, VH6, and VH7). Rearrangement of any V to D and J will result in a complex rolling circle splice formation that will delete the intervening chromosomal material but leave any upstream V or downstream constant elements intact. Thus, each mature B cell has a single productive V-D-J rearrangement that is unique to that cell in both length and sequence. If this one cell becomes a clonal population of cells, then one amplified product should be detected by any PCR-based approach to the detection of clonality. Two products can be detected if the initial rearrangement was nonproductive (incomplete rearrangement) for one allele and was followed by a productive (complete) rearrangement of the other allele. Incomplete rearrangements (D to J without V) as opposed to complete rearrangements (V-D-J) are uncommon in lymphomas but do occur with some frequency in B cell leukemias.

IgH The human immunoglobulin heavy (IgH) gene is located on chromosome 14 at 14q32.3 and can be divided into variable (V), diversity (D), joining (J), and constant (C) gene segments (Figure 3.1). The mature B cell goes through a series of D to J and then DJ to V rearrangements in the maturation process. There are over 150 different variable heavy (VH) segments of which only about 50 are functional and commonly used. All VH segments have a unique fragment of sequence referred to as the complementary determining region (CDR), which is the site of frequent somatic mutations in the germinal center maturation process. Since all VH segments were originally derived from one ancestral gene, there is a large amount of identical sequence among the entire group. In addition to the CDR region, all VH segments contain three framework regions (FR1, FR2, and FR3) for which sequence is shared among the different groups. The sequence

Dn

telomeric V1

V2

V3

centromeric Constantn

Vn ...

>50 functional VH members in 7 VH families

FR1

FIGURE 3.1

Jn

26 functional DH members

FR2

6 functional JH members

FR3 D J Constant

IgH locus at 14q32.3. ~65 functional Vb members in ~ 23 families telomeric V1

V2

V3

V-D1-J1

2 functional Db & 2 functional Jb members D1 J1(1.1 to 1.6) D2 J2 (2.1 to 2.7) centromeric

Vn ... D1-J1

Vbn V-D1-J2

D1-J2

Vbn V-D2-J2

D2-J2

Vbn Complete rearrangements

FIGURE 3.2

TCR-β locus at 7q34.

Incomplete rearrangements

27

Detection of PCR Products for Clonality

TCR-β The TCR-β gene is located on chromosome 7 at 7q34 and is divided into variable (V), diversity (D), and joining (J) segments (Figure 3.2). Similar to the IgH locus, the V region contains a large number of elements (∼65 Vβ gene elements). These 65 Vβ gene elements can be grouped into 23 Vβ families based on family-specific sequence identity. This is in contrast to the TCR-γ and TCR-δ loci that contain a very limited number of V elements, making the TCR-β gene a much better target for identifying a true clonal process. As opposed to the IgH locus where the D and J elements are clustered separately, for TCR-β they are intermixed with separate D1J1 and D2J2 elements. The D elements consist of only 2 loci (D1, D2), while the J elements consist of six loci for J1 (J1.1–1.6) and seven loci for J2 (J2.1–2.7). The D1 element can combine with any J1 or J2, while the D2 element is restricted to combination with the J2 element (J2.1–2.7). As opposed to B cell lymphoproliferative disorders, where incomplete rearrangements are relatively uncommon, the case is not so with T cell disorders. Incomplete rearrangement in the TCR-β locus can occur in three variants—D1J1, D1J2, and D2J2. Because of this separate clustering of the D1J1 and D2J2 elements, it is possible that one allele can contain both a complete rearrangement (VβDβ-Jβ) and an incomplete rearrangement (Dβ-Jβ). Theoretically, one T cell clonal process could have two complete and two incomplete clonal rearrangements, but practically this is quite rare. The presence of one complete and an additional incomplete is relatively common, as well as is one complete by itself.

PCR Design for Determination of Clonality The strategy behind any PCR-based Ig receptor clonality assay is to minimize the number of PCR reactions while at the same time covering greater than 95% of all possible rearrangements. The approach to minimizing the number of PCRs for both IgH and TCR-β is to utilize a panel of family-specific primers that bind with specificity to the majority of members of that family. In addition, multiple primers can be combined in one PCR tube in a process referred to as multiplex PCR. While the latter is a major labor and cost reduction step, this can lead to potential problems due to competition for the DNA template. For IgH, the basic clonality assay consists of three PCRs that test for complete rearrangements (Figure 3.3), although multiplex primer kits to test for incomplete rearrangements have been developed and are commercially available. Each multiplex tube for

FR1

FR2

FR3

D J

C

69–129 bp 235–295 bp 290–360 bp

FIGURE 3.3

Primer design for IgH.

IgH clonality assessment consists of one VH familyspecific forward primer from each of the seven VH segments capable of annealing to their corresponding VH segments (VH1–VH7) with no mismatches for most VH segments. These VH family-specific primers are assembled with all VH FR1 primers in tube 1, all VH FR2 primers in tube 2, and all VH FR3 primers in tube 3. This is advantageous, as the product sizes for each multiplex PCR is within a relatively narrow range of 50–75 base pairs. A consensus JH reverse primer is used in all three multiplex PCRs. For TCR-β, the basic clonality assay consists of three PCRs with two tubes that test for complete rearrangements and the third testing for incomplete rearrangements (Figure 3.4). The two multiplex tubes testing for complete rearrangements consist of the same 23 Vβ family-specific primers with a different combination of J1(1.1–1.6)β and J2(2.1–2.7)β reverse primers. Due to problems with PCR optimization, it was not possible to develop separate assays for Vβ-J1(1–6)β and Vβ-J2(1–7)β. The third tube that tests for incomplete rearrangements consists of both Dβ1 and Dβ2 forward primers with all 13 Jβ reverse primers. Due to this combination of primers and the ability for clonal processes to have both complete and incomplete rearrangements on one or different alleles, it is possible and even common to see two clonal peaks in tube C. For both IgH and TCR-β clonality assessment, a set of control gene primers designed to amplify products of 100, 200, 300, 400, and 600 base pairs are also included to test for the overall integrity and amplification of DNA.

DETECTION OF PCR PRODUCTS FOR CLONALITY The detection of the PCR products for both IgH and TCR-β consists of a fragment size analysis of the different amplicons. There are two modes of detection that include heteroduplex analysis by gel

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CHAPTER THREE

Molecular Techniques

Vb

Db

Jb1

Vb

Db

Jb2

Vb family primers

V-D-Jb1

Vb family primers

V-D-Jb2

Tube A: 23 Vb forward & 6 Jb1 & 3 Jb2 labeled reverse // 240–285 bp Tube B: 23 Vb forward & 4 Jb2 labeled reverse // 240–285 bp

Jb1&Jb2 Db1

Db1

Tube C: 2 Db forward & 13 Jb1 & Jb2 labeled reverse // 285–325 & 170–210 bp FIGURE 3.4

Primer design for TCR-β.

electrophoresis and capillary electrophoresis with detection of a fluorescently labeled product. Due the relatively high throughput and lower labor costs associated with capillary electrophoresis, this is the method employed in our laboratory and the one discussed here. Both methods of product analysis have slight advantages and disadvantages but, in the vast majority of cases, have excellent agreement for the final results. Capillary electrophoresis of nucleic acids basically consists of two electrolyte chambers linked by a thin capillary tube that is typically 50–100 micrometers in diameter. The typical setup for this technique is a single or multiple tube capillary sequencer produced by many companies, but most notable is Applied Biosystems (Foster City, CA) (Figure 3.5). The thin capillaries allow for excellent dissipation of heat and avoid the problem of temperature gradients common in other methods of electrophoresis. As an electric field gradient is applied to medium within the capillary tube in continuity with each of the electrolyte chambers, nucleic acids migrate through this field. Based on a complex group of factors, nucleic acids of similar size generally migrate together. Fluorescently labeled nucleic acid PCR products are loaded in one end of the capillary tube with a laser detection apparatus at the other end. As the products migrate based on size and pass the laser, there is an excitation of the fluorescent tag and the emission spectrum is gathered by a charge-coupled device. If any one group of nucleic acids is sufficiently present to reach the threshold of detection, this information is electronically gathered and analyzed by a software detection

FIGURE 3.5

Capillary sequencer.

system (Gene Scanning Software, ABI) and displayed on the computer screen. Known differentially labeled fluorescent-tagged size standards are run in conjunction with the test nucleic acid for calibration of size. For each of the multiplex PCR panels used for IgH and TCR-β clonality analysis, the primers are labeled with a fluorescent tag. The current commercially available PCR kit for TCR-β uses a TET (green) label for Jββ1.1–1.6 and FAM (blue) for Jβ2.1–2.7. This differential labeling allows for detection of specific Jβ usage and can be beneficial for detection of minimal residual disease. While the different multiplex panels used for IgH clonality assessment have different fluorescent tags, this has no clinical utility.

Detection of PCR Products for Clonality

29

TABLE 3.1 Expected PCR Products Gene

Rearrangement

IgH

VH-JH (FR1) VH-JH (FR2) VH-JH (FR3) Vβ-Jβ Vβ-Jβ Dβ-Jβ D-Jβ1 D-Jβ2

TCR-β

a Nonspecific

Tube

Expected Size (bp)

Tube A Tube B Tube C Tube A Tube B Tube C

290–360 235–295 69–129 240–285 240–285 285–325 170–210

Nonspecific Productsa 361 None 69 273 128, 221,337 128, 221,337

products are generally seen only in samples with low numbers of lymphoid cells.

It is important to note that one of the major strengths of fragment size analysis by capillary electrophoresis is determination of the exact fragment size in base pairs of the immunoglobulin rearrangement produced by a clonal population of lymphocytes. This can be particularly useful in follow-up or comparison of multiple samples from one patient.

Evaluation of Results The expected product sizes for each PCR panel using the BIOMED-2 protocol are listed in Table 3.1. Due to the typical in-frame (triplet) pattern of rearrangements in a typical polyclonal population of lymphocytes, the multiplex PCR design of both IgH and TCR-β allows for a Gaussian distribution of fragment sizes over a relatively small interval of product size (Figure 3.6a). In a pure population of neoplastic lymphocytes, one expects and generally finds a single dominant peak (Figure 3.6b). In many instances of clonal lymphoproliferative disorders, particularly cutaneous T cell lymphomas, there is a background of polyclonal lymphocytes making the distinction of the true clonal process more difficult (Figure 3.6c). Some of the more difficult evaluations occur when there is more than one peak in what appears to be a true clonal process, as shown in Figure 3.7a, where there are two dominant peaks and a complete absence of any polyclonal background. There are several possibilities in this situation, all of which are difficult to prove without special techniques and a high quality DNA template for such procedures. A careful review of Figure 3.7a will show that both of these peaks are FAM labeled and thus must be complete Vβ-Jβ2 rearrangements. It is possible and most likely that this represents a complete rearrangement of both alleles, but the presence of two clonal populations of lymphocytes is not totally excluded. Another possibility that cannot

be excluded is one true clonal population, but with an additional relatively large peak caused by J primer annealing to the next downstream (germline) J gene segment. To a large degree, all these different scenarios concerning the differential diagnosis of two dominant peaks in the complete absence of a polyclonal background have no clinical utility at the current time. What is more common, particularly in evaluation of TCR-β, and of clinical concern is the definition and significance of an oligoclonal population or ‘‘restricted T cell repertoire.’’ A reasonable generally accepted definition of such a process is the presence of three or more rather dominant peaks in one multiplex assay (Figure 3.7b). The difficulty with these cases is the possibility of pseudoclonal results due to a paucity of lymphocytes or poor quality DNA template, as can be seen in some formalin-fixed paraffin embedded skin biopsies. One reasonable way to exclude poor quality DNA template as a potential cause is simply to repeat the DNA amplification. In cases with poor quality DNA template, the fragment sizes detected will vary between each round of amplification in the vast majority of cases. Correlation with the histological features is useful for excluding a paucity of lymphocytes as the cause, and in our laboratory one H&E slide is made for every clonality assay performed. Even more useful is comparison of multiple concurrent different skin biopsies from one patient, or multiple skin biopsies over an extended period of time (months to years). The restricted T cell repertoire shown in Figure 3.7b is from the same patient as the results shown in Figure 3.7a, but taken from a related site 2 years later. Although there is some difference in the overall Gene Scanning image, note the identical size of the rearrangements identified. The clinical significance of this is discussed in greater detail elsewhere in this book.

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CHAPTER THREE

Molecular Techniques

(a) Polyclonal

(b) Monoclonal

(c)

Monoclonal peak at 262 base pairs

FIGURE 3.6

Polyclonal background

Gene Scanning images.

LIMITATIONS OF CLONALITY ASSESSMENT BY PCR There are certain limitations to this testing that should always be remembered in the evaluation of a clinical specimen. First is the issue regarding sensitivity, or the ability to detect a clonal population of lymphocytes in a polyclonal background. The BIOMED-2 study group has shown convincingly that these assays as designed have a sensitivity of 1–5%; in other words, one to five clonal lymphocytes can be detected in a population of 100 lymphocytes in which the remaining lymphocytes are benign. A caveat to this is that many of the specimens in this study were lymph nodes with an abundance of lymphocytes for DNA isolation and amplification.

In our opinion, and one given with a considerable degree of experience with formalin-fixed paraffin embedded skin biopsies, the lower limit of sensitivity in such samples is somewhere between 10% and 15%. A second issue, and one for which there is a great deal of debate, is that clonality does not necessarily equate with malignancy. This topic is beyond the scope of this chapter, but some clinically benign lymphoproliferative processes can be clonal. Once again it is important to correlate the molecular results with the histopathological and clinical findings and not to evaluate the results of any clonality assay in a vacuum. A third issue is that IgH and TCR gene rearrangements are not necessarily markers for B or T cell lineage determination, respectively. Dual rearrangements (lineage infidelity)

Summary

(a)

Two dominant peaks 260 & 271 bp

TCR beta Panel B

(b)

31

Peak 196 &188

TCR beta Panel C Peak 302

(c)

Peak 196 &188

TCR beta Panel C

FIGURE 3.7

Peak 302

Gene Scanning images.

can be observed in both B and T cell lymphomas, and the final determination of lineage needs to be based on the immunophenotypic features of the case. A fourth issue that was previously discussed is the pseudoclonality and oligoclonal processes in a lymphocyte poor specimen. Last and probably one of the more concerning issues regarding this testing is false-negative results, or a polyclonal result in the presence of an obvious B or T cell lymphoma. In our experience, this rarely occurs in T cell lymphomas and is more commonly noted in B cell lymphomas and, in particular, follicular lymphoma. The likely cause of this is somatic hyper mutations occurring in primer binding sites.

SUMMARY The technology discussed in this chapter is likely to become a standardized part of the pathological review of suspect lymphoproliferative disorders of the skin in the near future. The BIOMED-2 collaborative study group has made an invaluable contribution to the standardization of this technology. Anyone seriously interested in this topic should review the various publications that have reported using the BIOMED2 primer design (Sandberg et al., 2003; van Dongen et al., 2003; van Krieken et al., 2003; Droese et al., 2004; Matthews et al., 2004; Hodges et al., 2005; Lassmann et al., 2005; McClure et al., 2005).

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CHAPTER THREE

Molecular Techniques

REFERENCES DROESE J, LANGERAK AW, GROENEN PJ, et al. Validation of BIOMED-2 multiplex PCR tubes for detection of TCRB gene rearrangements in T-cell malignancies. Leukemia. 2004; 18:1531–1538. HODGES E, WILLIAMS AP, HARRIS S, SMITH JL. T-cell receptor molecular diagnosis of T-cell lymphoma. Methods Mol Med. 2005; 115:197–215. LASSMANN S, GERLACH UV, TECHNAU-IHLING K, WERNER M, FISCH P. Application of BIOMED-2 primers in fixed and decalcified bone marrow biopsies: analysis of immunoglobulin H receptor rearrangements in Bcell non-Hodgkin’s lymphomas. J Mol Diagn. 2005; 7:582–591. MATTHEWS C, CATHERWOOD M, MORRIS TC, ALEXANDER HD. Routine analysis of IgVH mutational status in CLL patients using BIOMED-2 standardized primers and protocols. Leuk Lymphoma. 2004; 45:1899–1904. MCCLURE RF, KAUR P, PAGEL E, et al. Validation of immunoglobulin gene rearrangement detection by

PCR using commercially available BIOMED-2 primers. Leukemia. 2005; 20(1):176–179. SANDBERG Y, HEULE F, LAM K, et al. Molecular immunoglobulin/T-cell receptor clonality analysis in cutaneous lymphoproliferations. Experience with the BIOMED-2 standardized polymerase chain reaction protocol. Haematologica. 2003; 88:659–670. VAN DONGEN JJ, LANGERAK AW, BRUGGEMANN M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003; 17:2257–2317. VAN KRIEKEN JH, LANGERAK AW, SAN MIGUEL JF, et al. Clonality analysis for antigen receptor genes: preliminary results from the BIOMED-2 concerted action PL 96–3936. Hum Pathol. 2003; 34:359–361.

CHAPTER FOUR

BENIGN LYMPHOCYTIC INFILTRATES Cynthia M. Magro and A. Neil Crowson

INTRODUCTION The majority of lymphocytic infiltrates in the skin are of T cell derivation and reactive in nature, manifesting neither significant cytologic nor architectural atypia. While the main focus of this book is on neoplastic lymphoid infiltrates, it is important in the context of cutaneous lymphocytic infiltrates to consider those that are benign and/or may define a precursor state to lymphoma. This book thus has three chapters devoted to (1) purely reactive lymphocytic infiltrates that do not appear atypical, (2) lymphocytic infiltrates that resemble lymphoma but are reactive, and (3) lymphoid infiltrates that define a state of persistent endogenous atypical T cell clonal infiltration. As regards the second category, the reactive lymphomatoid conditions, it is recognized that any state of persistent ‘‘reactive’’ lymphoid hyperplasia may have the potential to evolve into lymphoma. At some point in the clinical course, these infiltrates, although not malignant, may become clonally restricted. The third category represents an inherent T cell dyscrasia with a limited tendency toward biologic progression to overt lymphoma (see Table 4.1). Important in our approach to the establishment of a diagnosis is consideration of potential pathogenetic mechanisms by which these infiltrates arise. The basis of benign T cell lymphocytic infiltration is one that is immunologically driven, reflecting a type IV cellular cytotoxic interface dermatitis, delayed-type

hypersensitivity, and antibody-dependent cellular immunity (Dvorak et al., 1974, 1976). These benign lymphocytic infiltrates differ significantly from the reactive atypical lymphoid infiltrates, the premalignant disorders encompassing such entities as large plaque parapsoriasis, and of course from fully-transformed lymphoma.

SPONGIOTIC AND ECZEMATOUS DERMATITIS Allergic Contact Dermatitis Clinical Features The hallmarks of spongiotic dermatitis are exocytosis of lymphocytes into an epidermis that shows spongiosis with variable vesiculation and a parakeratotic scale (see Table 4.2). Additional light microscopic features may point to a precise etiology (Figures 4.1 and 4.2). Lesions comprise erythematous papules, vesicles, or exudative plaques, which are often itchy and develop 12–48 hours after reexposure to antigen. Lesions will resolve 2–3 weeks after the allergen is removed and respond quickly to topical steroid application. The specific allergen may be identified in a patch test. Patients with allergic contact dermatitis to nickel and nonallergic individuals display different

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 33

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TABLE 4.1 Classification Scheme for Reactive Lymphocyte-Rich Dermatoses Based on the Implicated Immunologic Mechanism (Primarily Gell and Comb’s Type IV Versus Type II) Type IV delayed reactions to exogenous and/or endogenous neoantigen where the dominant reaction is epidermal: Spongiotic/eczematous dermatitis/eczematoid hypersensitivity response Type IV cytotoxic immune responses where the dominant response is epidermal: Cell poor interface dermatitis including erythema multiforme and acute graft-versus-host disease Lichenoid reactions including lichen planus and lichenoid graft-versus-host disease Type IV delayed reactions where the dominant response is dermal: Polymorphous light reaction Gyrate erythemas Lyme disease Other forms of delayed dermal hypersensitivity Type II immunity where the dominant response is epidermal: Cell-poor interface dermatitis of collagen vascular disease and lichenoid connective tissue disease (i.e., subacute cutaneous lupus erythematosus) Type II immune reactions where the dominant response is dermal: Nonscarring discoid lupus erythematosus

TABLE 4.2 Spongiotic Dermatitis Florid spongiosis with vesiculation and eosinophilic exocytosis Allergic contact dermatitis Allergic eczematous drug reaction Photoallergic dermatitis of contact or drug-based etiology Autoeczematization/id reaction Incipient phase of nummular eczema Moderate spongiosis with vesiculation; no eosinophilic exocytosis Atopic eczema Subacute and chronic nummular eczema Seborrheic dermatitis Moderate spongiosis with parakeratosis, erythrocyte extravasation, and variable keratinocyte necrosis Pityriasis rosea (PR) PR-like drug eruption Superficial erythema annulare centrifugum (EAC) Erythema gyratum repens Viral exanthem/papular acrodermatitis of childhood (Gianotti–Crosti syndrome)

nickel-specific T cell responses. Specifically, patients with nickel allergy exhibit a clonal hyperproliferative response of CD8-positive lymphocytes to nickel while interleukin-10 (IL-10) production by CD4-positive cells is an important regulator of the immune response. The IL-10 production is lower in patients with nickel allergy relative to those without a specific allergy to nickel (Cavani et al., 1998) (Figures 4.1 and 4.2). Cutaneous immune responses involve T helper type 1 (Th1) and type 2 (Th2) cells, the two poles of the Th response system. The Th1 cell produces a lymphocytic and histiocytic response driven through the secretion of interferon-γ (IFN-γ ), IL-1, and IL-2, while

the Th2-driven immune response, via elaboration of IL-3 and IL-4, drives significant mobilization of eosinophils and the production of IgE. IL-4 immunoreactivity has been found in cells in the dermal infiltrate in lesional skin of some patients with allergic contact dermatitis, but not all patients exhibit this pattern of a Th2 dominant cytokine milieu. In addition, the expression of IL-4 receptors by cutaneous mast cells provides a route through which local effects of IL-4 might be mediated (Okazaki et al., 2002; Ulrich et al., 2001). Histomorphology Allergic contact dermatitis characteristically shows spongiotic vesiculation of the epidermis; in

Spongiotic and Eczematous Dermatitis

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FIGURE 4.1 Delayed dermal hypersensitivity. The hallmarks are those of perivascular lymphocytic infiltrates in intimate apposition to the blood vessels of the sampled dermis. Other common accompanying features include papillary dermal edema, mild spongiosis, and tissue eosinophilia.

Low-grade eczematous dermatitis with directed migration of lymphocytes into the suprapapillary plates. This pattern of lymphocyte migration to involve specific epithelial structures associated with preferential processing of antigen is typical for type IV hypersensitivity reactions. This biopsy, one of pityriasis rosea, defines a classic form of low-grade eczematoid hypersensitivity, presumably due to viral antigen.

FIGURE 4.2

consequence, the parakeratotic scale often contains plasma. Acute allergic contact dermatitis shows pronounced exocytosis of lymphocytes and eosinophils, with vesicles comprising lymphocytes, eosinophils, and Langerhans’ cells, an almost ubiquitous finding. The papillary dermis shows variable edema. The dermis contains an interstitial and perivascular lymphocytic, histiocytic, and eosinophilic infiltrate of variable intensity. An allergic contactant such as neomycin, zinc, and nickel can provoke a purely dermal-based reaction with no epithelial spongiosis, but often accompanied by pronounced papillary dermal edema (Hostynyk, 2002). With persistence of exposure to the allergen, epidermal proliferation becomes more striking, the intraepidermal inflammatory infiltrate becomes less exuberant, the degree of spongiosis diminishes, and the intensity of the dermal infiltrate may increase with concomitant fibroplasia. This variable maturation of the process yields subacute dermatitis (when spongiosis is still easily recognized) and chronic dermatitis (when pronounced epidermal hyperplasia with minimal spongiosis ensues). Complicating these pictures may be the presence of excoriation artifacts, namely, wedge-shaped areas of eosinophilia of the superficial layers of the stratum spinosum often imbued with a neutrophilrich crust (Soter and Mihm, 1980; Cohen et al., 1997; Weedon 1997b). Pathogenesis Allergic contact dermatitis represents a delayedtype hypersensitivity reaction following reexposure to an allergen: medication, a plant product, food

stuff, cosmetic or industrial chemical. Delayed-type hypersensitivity reactions (Figure 4.1) occur when an allergen, usually a low molecular weight hapten that is lipid soluble, penetrates the skin and binds to a structural or cell-surface protein to form the complete antigen, which is then processed by Langerhans’ cells that present the modified antigen to memory Th lymphocytes. The latter migrate to regional lymph nodes, where clonal expansion of lymphocytes sensitized to that specific antigen ensues. Following reexposure, a proliferation of T lymphocytes occurs within both the skin and the regional lymph nodes; the activated lymphocytes elaborate cytokines, including IL-2 and IFN-γ , which cause a further influx of inflammatory cells (Dvorak and Mihm, 1972). Homing of lymphocytes to the skin involves specific interactions of lymphocyte function antigens (LFAs) with endothelial adhesion molecules, which are upregulated in the site of inflammation. Another effect of the cytokine elaboration by Th cells is epidermal proliferation (Li and Cruz, 2004; Saint-Mezard et al., 2004). When the mononuclear cell reaction is heavy and/or includes transformed lymphocytes, the appellation ‘‘lymphomatoid hypersensitivity reaction’’ is sometimes applied; these reactions can histologically

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simulate mycosis fungoides. This topic is considered in greater detail in Chapter 5. Allergic contact dermatitis can be mimicked by arthropod-bite responses; on occasion, a wedge-shaped insect bite punctum shows a necrotizing neutrophilic reaction within the epidermis. As well, blood vessels frequently show perivascular and mural fibrin deposition and additional level sections may disclose components of insect mouth parts in the dermis or the stratum corneum (Weedon, 1997b). Differential Diagnosis Oral ingestion, inhalation, or transcutaneous application of a drug to which a person has been previously sensitized via contact exposure may elicit an eczematous dermatitis clinically and microscopically indistinguishable from allergic contact dermatitis. Affected sites frequently correspond to those involved in a prior contact dermatitis, the onset of symptoms being within 2–24 hours after an oral dose. The term baboon syndrome has been used to describe bright red, well-demarcated anogenital lesions associated with a symmetric eczematous eruption involving elbow flexures, axillae, eyelids, and the sides of the neck (Wolf et al., 2003). Among the classic drugs associated with eczematous reactions are antibiotics and ethylene diamine-containing antihistaminic and aminophylline preparations. Oral administration of sulfonyl urea hypoglycemic drugs in patients sensitized to para-immuno compounds such as sulfanilamide results in flare-ups of dermatitis. The histomorphology is indistinguishable from that described for allergic contact dermatitis (Cohen et al., 1997; Weedon, 1997b).

Pityriasis Rosea Clinical Features Pityriasis rosea (PR) is an idiopathic selflimited dermatosis that characteristically manifests salmon-colored macules, papules, and papulovesicles sometimes associated with purpura (Figure 4.2). The characteristic ‘‘herald’’ patch occurs in the central back and extends in a symmetrical fashion to the proximal extremities, often following lines of cleavage and showing peripheral ‘‘cigarette paperlike’’ scales (Chuh and Peiris 2001; Chuh et al., 2001). Histopathology The histopathology of PR comprises a superficial perivascular lymphocytic infiltrate, which shows exocytosis predominantly localized to suprapapillary plates, a slightly acanthotic epidermis, and mounds of parakeratin overlying the areas of epidermal damage. Spongiosis may be significant and plasma may be

seen in the scale. Eosinophils may be present in some cases, but this is an unusual finding and might point more toward one of the differential diagnoses of PR, namely, the pityriasiform drug reaction. Colloid bodies may be scattered throughout the full thickness of the epidermis; dyskeratosis may be pronounced in the basal layers as lesions involute. A characteristic finding is the presence of superficial dermal and intraepidermal hemorrhage. Multinucleated keratinocytes may be seen and may be indicative of human herpes type VII cytopathic changes (Weedon, 1997b). Pathogenesis A viral-based etiology has long been suspected in light of case clustering, occurrence in family members, and an antecedent upper respiratory tract illness. Recently, an infectious etiology was suggested by studies on peripheral blood mononuclear cells from PR patients, which showed ballooning cells and syncytia after 7 days in culture, whereas peripheral blood mononuclear cells from controls and recovered PR patients did not. This cytopathic effect was also documented in a PR patient who relapsed. In serum supernatant, herpesvirus virions were detected by electron microscopy; polymerase chain reaction (PCR) studies identified human herpesvirus 7 (HHV7) DNA in peripheral blood mononuclear cells, plasma, and skin from all of a group of patients with active PR. However, case control studies show no increased incidence of antibodies to HHV-6 or HHV-7 in patients with PR; the issue remains in doubt. Antibodies to parvovirus B19 have been also been described in patients with PR (Drago et al., 1997; Farber-Marcus et al., 1997; Chuh and Peiris, 2001; Chuh et al., 2001). Differential Diagnosis Among the differential diagnoses of PR under the microscope is that of a viral exanthem, for example, that seen in Gianotti–Crosti syndrome. Both entities share lymphocytic exocytosis, spongiosis, and hemorrhage. In our experience, the most helpful discriminating features are the absence of acanthosis, the presence of a cell-poor vacuolar interface dermatitis, the more frequent identification of vesicles within the epidermis, and the lack of alterations of stratum corneum, all of which point toward an acute viral exanthem. In addition, a concomitant interstitial granulomatous dermatitis may be seen within the superficial dermis in patients with acute viral exanthema (Magro and Crowson, 1998). With respect to pityriasiform drug eruptions, tissue eosinophilia is an important clue. It should be emphasized that any elderly patient who manifests a

Other Spongiotic/Eczematous Tissue Reactions

PR-like eruption may have as the etiologic basis a drug reaction; clonidine and aspirin are prototypically implicated (Crowson and Magro, 2004). Other differential diagnostic considerations include the so-called autoeczematization or id reaction. A sudden generalized or localized vesicular dermatitis developing in association with a defined local dermatitis or cutaneous infection is known as an id reaction. If the patient has a remote cutaneous fungal infection, such as tinea pedis, the appellation dermatophytid is used. In some cases, the underlying localized dermatitis leading to generalized autoeczematization is stasis dermatitis. The histopathology is that of an acute spongiotic dermatitis virtually indistinguishable from allergic contact dermatitis. The pathogenetic basis is an abnormal immune response to autologous skin antigens whereby activated T lymphocytes appear to be the mediators of the response.

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FIGURE 4.3 Photoallergic lichenoid dermatitis. If typical lesions of lichen planus manifest a striking photodistribution are noted, consideration of a photoallergic dermatitis with lichen planus-like features should be considered. Such cases may show significant lymphoid atypia. However, mycosis fungoides in a restricted light distribution is virtually unheard of.

Pityriasis Rosea-like Drug Reaction A similar eruption can occur as a result of drug therapy. There are, however, only select drugs that have been implicated in this syndrome. The specific drugs or triggers are gold, captopril, and inoculation with the bacillus of Calmette–Gu´erin (BCG) and the tyrosine kinase inhibitor (STI571, Gleevec). Pityriasis rosea-like eruptions have been described in patients receiving bone marrow transplants. Critical to the diagnosis is the clinical presentation. If the clinical presentation is not consonant with a diagnosis of PR, then we do not use the designation of a pityriasis rosea-like drug reaction. From a morphologic perspective, tissue eosinophilia and the presence of streak dyskeratotic cells are useful morphologic clues (Honl et al., 1996; Konstantopoulos et al., 2002; Crowson et al., 2003; Crowson and Magro, 2004).

OTHER SPONGIOTIC/ECZEMATOUS TISSUE REACTIONS Photoallergic Reactions Pathogenesis Photoallergic dermatitis may be due to the topical application or oral ingestion of an allergen resulting in either a photo-contact dermatitis or photo-drug reaction. The absorption of light energy appears to alter the photo-sensitizing chemical to produce a hapten, which attaches to an endogenous

protein carrier producing a hypersensitivity response (Figure 4.3) (Soter and Mihm, 1980; Cohen et al., 1997). Clinical Features The lesions are characterized by pruritic erythematous papules and plaques in a photo distribution (i.e., the face, dorsal aspects of the arms, and the neck). Such reactions occur within 24–48 hours after sun exposure. Among the topical allergens are fragrances such as musk and sunscreens containing benzophenones. Plants have also been implicated. Systemically administered drugs that may induce photoallergy include quinine, quinidine, chlorpromazine, and tetracycline (Soter and Mihm, 1980; Cohen et al., 1997). Histopathology The eczematous component encompasses changes that are virtually identical to those described for acute allergic contact dermatitis, including marked spongiosis with exocytosis of lymphocytes and eosinophils and Langerhans’cell- and eosinophilcontaining intraepidermal vesicles. Features favoring photoallergy are a deeper extent of the dermal-based inflammatory cell infiltrate and striking vascular changes, namely, endothelial cell swelling, mural edema, and variable fibrin deposition. The intensity of the perivascular lymphocytic infiltrate and the injurious vascular alterations decrease as the base of the biopsy is approached. Certain drugs, specifically the thiazides and antihistamines, may evoke a lichenoid photodermatitis whose histomorphology does not resemble the prototypic photoallergic dermatitis; this

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will be considered in greater detail in the section on interface dermatitis (Soter and Mihm, 1980; Cohen et al., 1997; Crowson and Magro, 1999a).

OTHER CAUSES OF SUBACUTE ECZEMATOUS DERMATITIS Nummular Eczema Pathogenesis Hypersensitivity reactions of diverse type may form annular lesions to which the term ‘‘nummular eczema’’ is applied. The etiology is unknown for many such cases. Possible associations include stasis dermatitis, contactant exposure, an atopic diathesis, and drug therapy (Soter and Mihm, 1980; Weedon, 1997b). The lesions are most frequently biopsied because of a clinical concern regarding cutaneous T cell lymphoma, Bowen’s disease, or superficial basal cell carcinoma. The lesions may be persistent and large, hence leading to appropriate clinical concern regarding an evolving endogenous T cell dyscrasia such as large plaque parapsoriasis. Clinical Features Nummular eczema is characterized clinically by papules and papulovesicular lesions that coalesce to produce one or more coin-shaped plaques, which may have a weeping surface. There is a predilection to involve the dorsum of the hands, the extensor aspects of the forearms, the lower parts of the legs, and the posterior aspect of the trunk. The course is one of chronicity with remissions and exacerbations (Soter and Mihm, 1980). Histopathology The histology is that of an eczematous dermatitis, the precise features of which depend on the age of lesion biopsied. Lesions of early onset can resemble an acute allergic contact dermatitis with marked spongiosis and vesiculation. However, eosinophilic spongiosis as noted in the prototypic allergic contact dermatitis is not common. Lesions are more often biopsied in a chronic or subacute phase and have more florid epidermal hyperplasia and less spongiosis, typically without vesiculation. The superficial dermalbased infiltrate can be quite heavy and comprises a mixed population of lymphocytes, histiocytes, neutrophils, and eosinophils. As the lesions are pruritic, there may be changes indicative of external trauma, as manifested by an impetiginized scale crust, namely, neutrophil imbued parakeratosis with admixed bacteria, wedge-shaped areas of eosinophilic epidermal

necrosis, subepidermal fibrin deposition, and hemorrhage. Old lesions have a morphology defined by lichen simplex chronicus, the hallmarks of which are marked epidermal hyperplasia with hyperkeratosis, a variable dermal-based infiltrate, and the absence of intraepidermal inflammatory cells (Mihm et al., 1976; Soter and Mihm, 1980). Differential Diagnosis The differential diagnosis of nummular eczema includes atopic eczema and seborrheic dermatitis. Regarding atopic eczema, the patients may have other features of the atopic diathesis, such as asthma and allergic rhinitis; in addition, the rash is characteristically accentuated on the extensor surfaces of the arms and legs. Over time, a lichenified dermatitis with a predilection for the flexural surfaces of the arms and legs develops. In later life, the only manifestation of the atopic diathesis may be a hand and foot dermatitis. The etiology is still unclear, however, IgE-mediated late phase responses and a Th2/Th1 imbalance appear to be operative. The histology resembles the chronic phase of nummular eczema by virtue of moderate to marked epidermal hyperplasia with hyperkeratosis and slight spongiosis with some exocytosis of lymphocytes. The dermis shows variable fibroplasia and a superficial perivascular lymphocytic and eosinophilic infiltrate. Seborrheic dermatitis is distinctive clinically, manifesting as erythematous or greasy yellow scaling papules and plaques involving the scalp, ears, eyebrows, eyelid margins, and nasal labial folds (the ‘‘seborrheic’’ areas). Males are more commonly affected. Some cases are associated with human immunodeficiency virus (HIV) infection. The histopathology resembles a subacute or chronic spongiotic dermatitis. Eosinophilic spongiosis is absent. There are usually no eosinophils within the superficial dermis. The spongiotic and parakeratotic changes can manifest perifollicular accentuation. In patients with HIV, focal dyskeratosis and dermal-based plasmacellular infiltrates are diagnostic clues. The neutrophil imbued parakeratosis in concert with granular cell layer diminution may mimic psoriasis, but the areas of neutrophil-rich parakeratosis have a propensity to involve the follicular ostia and perifollicular epidermis, a localization that is not observed in psoriasis. In addition, psoriasis rarely has a concomitant spongiotic eczematous component, and the hallmarks of the psoriatic diathesis—suprapapillary plate attenuation and dermal papillae capillary ectasia—are not observed in seborrheic dermatitis (Mihm et al., 1976; Soter and Mihm, 1980; Cohen et al., 1997; Weedon, 1997b).

Other Causes of Subacute Eczematous Dermatitis

Small Plaque Parapsoriasis Clinical Features Small plaque parapsoriasis characteristically occurs as a chronic eruption composed of round or oval, well circumscribed, red to brown or less commonly yellow flat nonindurated macules or plaques, involving the trunk and proximal extremities and sparing the face and volar surfaces. The plaques measure less than 5 centimeters in diameter. The lesions may follow dermatomes or lines of cleavages. The scale is moderately adherent and may show weeping and crust formation. The lesions are asymptomatic (Raskin, 1996). Histology The epidermis is mildly acanthotic and is typically surmounted by a broad parakeratotic scale that usually overlies a normal basket weave stratum corneum. There is typically a minimal infiltrate in the superficial dermis. A sparse perivascular lymphocytic infiltrate is present in the superficial dermis.

Pruritic Urticarial Plaques and Papules of Pregnancy Clinical Features The most common dermatosis of the gravid state, polymorphous eruption of pregnancy, also called pruritic urticarial papules and plaques of pregnancy (PUPPP), has an incidence of 1 in 20 pregnancies and manifests as pruritic papules and urticarial plaques, sometimes with superimposed vesicles, in and near abdominal striae. It usually develops in the last few weeks of pregnancy and may spread to the extremities or become generalized. Periumbilical sparing and spontaneous resolution are characteristic. The association of this eruption with large babies, twin and triplet pregnancies, and increased maternal weight gain raises the possibility that it relates somehow to excessive abdominal distention. Histopathology Superficial perivascular lymphocytic or lymphocytic and eosinophilic infiltrates with a nondescript appearance, accompanied in one-third of cases by exocytosis and spongiosis, are characteristic. Fibroblast proliferation is an infrequent concomitant. Leukocyte debris may be present, but there is no vascular fibrin deposition to suggest a leukocytoclastic vasculitis. Although potentially nonreactive by direct immunofluorescent testing, lesions of PUPPP may show granular IgM, IgA, or C3 deposition at the dermoepidermal junction and/or in blood vessels, suggesting a delayed-type hypersensitivity reaction or possibly an immune complex contribution to the

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pathogenesis (Crowson, 2004). Analysis of serum hormone levels in one series showed a significant drop in cortisol levels in patients with PUPPP versus normal pregnant control patients; enhanced progesterone receptor expression in lesional as opposed to nonlesional keratinocytes also suggests the possibility that the action of hormones may play a role. Differential Diagnosis The differential diagnosis of PUPPP includes atopic dermatitis, dermal hypersensitivity reactions to drugs, contactants, and arthropod bites, and herpes gestationis. Most of the hypersensitivity reactions cannot be reliably distinguished from PUPPP because they all share a similar histomorphology. Herpes gestationis can occur at any time during pregnancy and often is raised as a clinical consideration. Lesions of herpes gestationis often show subepidermal blisters accompanied by eosinophils in the epidermis, at tips of dermal papillae, and in a perivascular disposition, associated with focal necrosis of basal layer keratinocytes and colloid body formation. Tissue eosinophilia is quantitatively greater in herpes gestationis than in PUPPP. Circulating antibasement membrane IgG is demonstrable by indirect immunofluorescence in 25% of herpes gestationis patients, invariably with linear C3 deposition along the dermoepidermal junction and, in 50% of cases, a similar pattern of IgG deposition (Alcalay and Wolfe, 1988; Magro and Crowson, 1999b). As the linear dermoepidermal junction deposition of C3 and IgG that characterizes herpes gestationis is not seen in PUPPP, direct immunofluorescence testing is thus a valuable adjunct in making this important distinction. Herpes gestationis is associated with increased fetal morbidity and may require systemic steroid therapy, whereas PUPPP is a self-limited eruption with no associated fetal morbidity (Crowson, 2004). A less problematic concern is that of pruritic folliculitis of pregnancy that manifests a follicular-based eruption characterized histologically by a neutrophilic folliculitis.

Superficial Erythema Annulare Centrifugum Clinical Features Erythema annulare centrifugum (EAC), one of the gyrate erythemas, comprises one or more annular fixed or migratory erythematous lesions, often with a ‘‘trailing’’ scale at the advancing edge, which tend to involve the trunk and proximal extremities. Lesions have been divided into superficial and deep types depending on the presence or absence of the superficial scale. Onset is most often in early adulthood or middle age. The initial lesion is a pink infiltrated papule

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that slowly enlarges to form a ring as the center fades. Some lesions reach a diameter of 8.0–10.0 cm over several weeks, while others manifest eccentric expansion to generate an irregular arciform pattern. They may last from days to months and can be associated with purpuric or pigmented residua. The differential diagnoses clinically include erythema gyratum repens, erythema chronicum migrans, annular erythema of infancy, and erythema marginatum (Kim et al., 2002; Weyers et al., 2003). (Hsu S 2001).

suggestive of erythema chronicum migrans include a lymphocytic and plasmacellular neuritis and plasma cells within the dermal infiltrate. Pauci-inflammatory vasculopathic changes accompanied by dermal mucin have been described as an additional morphologic reaction pattern seen in patients with erythema chronicum migrans. Such a morphology is found in the lateral erythematous border of a plaque of ECM (Clark et al., 1974; Hood et al., 1993; Weyers et al., 2003).

Pathogenesis A variety of trigger factors are implicated; with respect to superficial EAC, roughly one-third of cases are associated with superficial fungal infections at remote sites or are temporally associated with the ingestion of bread molds, suggesting that these cases represent a form of fungal id reaction. Similar lesions may be seen clinically in the neonatal period in which they be a sign of maternal lupus erythematosus; however, the histology is one of subacute lupus erythematosus defining the entity of neonatal lupus erythematosus.

INTERFACE DERMATITIS: CELL-POOR VACUOLAR INTERFACE DERMATITIS

Histopathology The deep variant of EAC manifests tight ‘‘sleevelike’’ cuffs of lymphocytes around superficial and deep blood vessels, unaccompanied by exocytosis, spongiosis, or a parakeratotic scale crust, while the superficial variant of EAC characteristically has a similar, but more superficially disposed, perivascular lymphocytic or lymphoeosinophilic infiltrate with pronounced exocytosis, mounds of parakeratin overlying the areas of epidermal damage, and frequent striking edema of the papillary dermis (Crowson, 2004). The epidermis is classically not altered in thickness while, in the cases associated with remote fungal infection, neutrophils are often present in the scale crust as a component of the id reaction. Some vacuolar change along the dermal–epidermal junction may be seen. Endothelial swelling, sometimes accompanied by dermal hemorrhage, completes the picture. With respect to differential diagnosis, the histopathology of erythema gyratum repens closely simulates superficial EAC, although the clinical picture—a migrating eruption with a pattern mimicking marble or the cut surface of a tree trunk—should enable distinction. With respect to erythema marginatum, dyskeratotic cells in the epidermis and a superficial neutrophilrich urticarial tissue reaction are present. The most important distinguishing feature for erythema chronicum migrans is positive Borrelia serology; we rely heavily on serological studies, as opposed to silver stains, in any migratory erythema that develops in locations where Lyme disease is endemic. Features

There are two broad categories of interface dermatitis: a cell-poor or vacuolar interface dermatitis and a cellrich form or lichenoid dermatitis. The cell-poor vacuolar interface dermatitis is defined by basilar keratinocyte and subepithelial vacuolopathy unaccompanied by a significant inflammatory cell infiltrate. Usually, there is some lymphocyte tagging along the dermal–epidermal junction pointing to the immunopathogenetic basis, namely, cellular cytotoxicity. This may be either in the context of a type IV immune reaction or of antibody-dependent cellular cytotoxicity. (Horn TD, 2004). The differential diagnoses of a cell-poor interface dermatitis is broad and includes (1) erythema multiforme, (2) graft-versus-host disease, (3) a morbiliform viral exanthum, (4) a morbiliform drug reaction, and (5) collagen vascular disease—specifically, systemic lupus erythematosus, dermatomyositis, and mixed connective tissue disease. While the aforesaid diagnostic considerations are specific clinical and pathological entities, a type IV immunologic response to circulating exogenous antigen can be associated with vacuolar interface change. Although the morphologic end point of both type IV hypersensitivity and collagen vascular disease is similar, namely, lymphocyte apposition to degenerating keratinocytes, the pathogenetic mechanisms are different. The prototypic type IV cellular cytotoxic interface reaction pattern is erythema multiforme (Crowson, 2004).

Erythema Multiforme Clinical Features Erythema multiforme is a distinctive clinical pathological entity with a wide variety of underlying causes. The classic lesion has a targetoid morphology with a peripheral rim of erythema and a central zone

Interface Dermatitis: Cell-Poor Vacuolar Interface Dermatitis

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seen. In drug-based erythema multiforme, acrosyringeal accentuation of these interface inflammatory and degenerative epithelial changes is typical and streak dyskeratosis is demonstrated, whereby keratinocytes acquire an elongate cigar-shaped morphology with a hypereosinophilic condensed cytoplasm and pyknotic elongated nuclei. Lesions of active herpes not infrequently show areas of interface dermatitis resembling erythema multiforme. Characteristic viral cytopathic changes of herpes, however, are observed (Margolis et al., 1983; Tonnesen et al., 1983; Schuttelaar et al., 1997; Weedon, 1997b; Foedinger et al., 1998; Rodenas et al., 1998).

Erythema multiforme. There is a destructive interface dermatitis with prominent spinous layer epithelial necrosis. The unaltered thickness of the epidermis and only slight alterations of the stratum corneum are characteristic for a skin lesion of short duration as is typical in the setting of erythema multiforme. In contrast, in most lesions of cutaneous T cell lymphoma, features of chronicity are present. FIGURE 4.4

of pallor. Some lesions may manifest a dusky or violaceous appearance with no true central clearing. Blisters may be observed. As the pathogenetic basis of erythema multiforme is one of cellular cytotoxicity, the sites of predilection are those where antigenic processing is maximal, which includes the palms and soles; however, lesions can become widespread. The disease is typically self-limited but it may recur. When the eruption is extensive, there may be severe oral mucosal involvement, which defines Stevens–Johnson syndrome, in which extensive skin necrosis is reminiscent of toxic epidermal necrolysis. There are rare reports of erythema multiforme following allergic contact dermatitis with nickel and poison ivy (i.e., Rhus dermatitis) (Schwartz and Downham, 1981). (Horn TD 2004); (Werchniak 2004). Histopathology In those cases triggered by infection, one typically observes a brisk angiocentric superficial and deep lymphocytic infiltrate along with a cell-poor interface dermatitis and minimal epidermal injury. In contrast, cases of drug-based etiology show a less intense dermal-based inflammatory cell infiltrate with more pronounced degenerative epithelial changes including discrete zones of confluent epidermal necrosis. Foci of basilar vacuolopathy accompanied by lymphocyte tagging along the dermal–epidermal junction are the hallmarks; suprabasilar lymphocytosis around degenerating keratinocytes may also be

Differential Diagnosis The main consideration is a systemic connective tissue disease diathesis. In our experience, in lesions of systemic lupus erythematosus or dermatomyositis, the presence of striking dermal mucin deposition is a helpful distinguishing feature. As well, the degree of epithelial injury in such cases is usually less than that observed in erythema multiforme. Acrosyringeal accentuation, as seen in drug-associated erythema multiforme, is not typical of acute systemic collagen vascular disease. While tissue eosinophilia may be observed in drug-associated erythema multiforme, tissue eosinophilia in the setting of systemic collagen vascular disease is uncommon. In erythema multiforme, there usually is no alteration of the stratum corneum, pointing to the transient and acute nature of the eruption. In contrast, in the interface dermatitis of collagen vascular disease, hyper- and parakeratosis are frequent. Also a function of the transient and acute nature of erythema multiforme is the unaltered architecture of the epidermis with preservation of the retia, in contrast to collagen vascular disease, where one observes an atrophying interface dermatitis with retiform effacement and basement membrane zone thickening. (Crowson and Magro, 2001). The distinction of erythema multiforme from acute graft-versus-host disease may be difficult. One study demonstrated that intraepidermal bile pigment deposition can be seen in biopsies of graft-versushost disease and correlates with hyperbilirubinemia and/or liver involvement. While this finding is only observed in a minority of cases of graft-versus-host disease (i.e., 6% of biopsies), it is a highly specific finding; it is not observed in erythema multiforme unless, of course, there is unrelated liver disease (Dilday and Smoller, 1998; Horn and Haskell, 1998). Autoimmune progesterone dermatitis is temporally associated with the menstrual period. The manifestations are polymorphous and include urticaria, erythema multiforme, and eczema. Histologically, the

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cases show a variable histomorphology dependent on the clinical presentation. Cases resembling erythema multiforme show a vacuolar interface dermatitis with varying degrees of keratinocyte necrosis. During each cycle, the eruptions may appear at previously affected sites, hence mimicking the clinical features of a fixed drug eruption. This rare phenomenon is attributed to an autoimmune reaction to female sex hormones. The condition can improve with tamoxifen, which suppresses ovulation and the postovulation rise in endogenous progesterone levels. In extreme cases an oophorectomy is performed (Margolis et al., 1983; Tonnesen et al., 1983; Schuttelaar et al., 1997; Foedinger et al., 1998; Moghadam et al., 1998; Rodenas et al., 1998). Pathogenesis Erythema multiforme is a type IV cellular cytotoxic reaction provoked by antigenic triggers, which include drugs and infectious agents such as Mycoplasma pneumoniae and herpes simplex virus infection in the context of recurrent herpes labialis. Typical target lesions are more common in patients whose erythema multiforme is triggered by herpes simplex. Drug-induced forms of erythema multiforme can be quite severe and may be compatible with Steven–Johnson syndrome or the most severe variant of erythema multiforme, designated as toxic epidermal necrolysis. A viral etiology is rarely implicated for these two severe forms of erythema multiforme. Herpes-associated erythema multiforme occurs in association with recurrent herpes simplex infection. A recent study has shown herpes DNA polymerase gene (POL) and pol protein expression, the latter through immunohistochemistry using antibody directed against pol in lesional skin of patients with herpes-associated erythema multiforme. In addition, the T cell receptor variable chain repertoire in such patients is composed primarily of vβ2 chain positive cells, suggesting a selective homing of lymphocytes to sites of viral antigen. (Aurelian et al., 1998). Recently, antibodies directed against desmosomal plaque proteins desmoplakin I and II have been described in a subset of patients with erythema multiforme major. Such studies suggest a humoral-based etiology in the propagation of lesions of erythema multiforme in these patients. The epitope is localized at the carboxy terminal domain of desmoplakin and is responsible for the assembly of keratin filaments with desmosomes. Purified human antibody directed against the carboxy terminus of desmoplakin I and II, when injected into newborn mice, produces a constellation of changes that resembles erythema multiforme, suggesting a role for these antibodies in

a subset of patients with erythema multiforme (Margolis et al., 1983; Tonnesen et al., 1983; Schuttelaar et al., 1997; Cohen and Cohen, 1998; Kokuba et al., 1998; Foedinger et al., 1998; Moghadam et al., 1998; Rodenas et al., 1998).

Gianotti–Crosti Syndrome (Popular Acrodermatitis of Childhood) Introduction Like pityriasis rosea, Gianotti–Crosti syndrome is held to be a manifestation of a systemic viral illness, although the evidence for this construction is more compelling in the case of Gianotti–Crosti syndrome (Michitaka et al., 2004). In particular, hepatitis A, B, and C and Epstein–Barr virus infections have been associated with this distinctive acral papular eruption. Other implicated viruses include Cocksackie virus, cytomegalovirus, echovirus, poliovirus, respiratory syncytial virus, and parainfluenza. Clinical Features Typically affecting infants and young children, Gianotti–Crosti syndrome manifests as an eruption of nonitchy red papules involving the face, buttocks, and acral parts with sparing of the trunk, in an eruption that lasts for 3–4 weeks or longer. Other symptomology specific to the implicated microbial pathogen may be present, such as lymphadenopathy and pharyngitis in the case of Epstein–Barr virus, or hepatomegaly and/or jaundice in the setting of hepatitis. The latter is uncommon as most patients do not have severe hepatitic injury and most cases do not progress to chronic hepatitis. Histopathology Like most viral exanthemata, the lesions of Gianotti–Crosti syndrome manifest as sparse to moderate superficial perivascular and interface lymphocytic inflammatory processes associated with variable spongiosis and, in some cases, acanthosis and parakeratosis. These features are not specific and can be seen in a variety of viral exanthemata and spongiotic dermatitides of diverse etiologic basis. Differential Diagnosis As expected, other viral exanthemata, drug reactions and superficial fungal reactions, can mimic this picture.

Acute Graft-Versus-Host Disease Clinical Features Graft-versus-host disease (GVHD) is a serious multiorgan inflammatory and fibrosing disorder that

Interface Dermatitis: Cell-Poor Vacuolar Interface Dermatitis

develops under three specific conditions: (1) following transplantation of donor immunocompetent cells into a host; (2) incompatibility between the host and donor; and (3) immunosuppression of the host. The most common case scenario in which GVHD develops is following allogeneic bone marrow and or stem cell transplantation. However, this condition has also been described in neonates reflecting maternal–fetal transfusion and following platelet and red cell transfusion in immunocompromised hosts. There are risks for the development of GVHD including an older age at receipt of the transplant, a female donor to male recipient transfer, and incompatibility of major and minor histocompatibility antigens. There are two main forms of GVHD: an acute form and a chronic form. The acute form develops within 7 days to 3 months following bone marrow transplantation. It is a multiorgan state of tissue injury mediated by donor lymphocytes, whereby epithelial structures are the prime targets. There are three primary sites involved: the skin, the gastrointestinal tract, and the liver. A grading system has been applied to the clinical severity of acute GVHD. Similarly, there are four histologic grades that closely parallel the clinical grade. Clinically, the typical cutaneous eruption of acute GVHD occurs within the first month after bone marrow transplant and comprises erythematous macules. The skin is the most commonly involved organ in GVHD and offers a window for diagnosis. Although erythematous patches may remain localized to acral sites, they can generalize to cause erythroderma and, with increasing severity, blister formation and complete epidermal necrosis, hence mimicking toxic epidermal necrolysis. These manifestations tend to be more pronounced in allogeneic, as opposed to autologous, bone marrow transplants. Up to one-half of allogeneic bone marrow transplants are associated with GVHD even in HLA-matched recipients. In immunosuppressed patients, transfusion of nonirradiated blood can provoke GVHD. Moderate doses of cyclosporine, possibly by promoting autoreactive T cell clones in the peripheral circulation, can increase the incidence and severity of skin eruptions, a phenomenon further aggravated by the use of interferon (Demircay et al., 1997; Kohler et al., 1997; Aractingi and Chosidow, 1998; Greinix et al., 1998; Hattori et al., 1998; Johnson and Farmer, 1998). Histopathology The histomorphology of cutaneous GVHD ranges from basilar vacuolization to a toxic epidermal necrolysis-like pattern with complete epidermal necrosis. A grading system has been implemented by

43

which skin biopsy specimens from GVHD may be classified, namely: grade 0—no pathological change; grade 1—basilar vacuolization; grade 2—basilar vacuolization with necrotic keratinocytes and dermal inflammation; grade 3—confluence of basilar vacuolopathy; grade 4—separation of epidermis from dermis. A characteristic feature of grades 2 through 4 is lymphocyte satellitosis to apoptic keratinocytes, reflecting the pathophysiologic effect of perforin elaborated by CD8-positive T cells. This particular cytotoxic effect is accentuated in follicular epithelia and frequently in eccrine structures, sometimes including the eccrine coil. Grades 1 and 2 GVHD are indistinguishable from chemotherapy effects. Thus, such changes within the first 30 days of a bone marrow transplant are indeterminate for GVHD versus chemotherapy effect. Loss of polarity of keratinocytes resulting in disordered maturation of the epidermis may reflect drug-induced alterations of the keratinocyte cell cycle and is often accompanied by individual cell keratinocyte necrosis. Similarly, patients recovering from cytoreductive therapy, such as for acute leukemia, show a similar morphology, as do those receiving cyclosporine, coincident with the return of lymphocyte counts in the peripheral stream. Apart from the entities described above, the interface dermatitis of HIV infection, namely, the cell-poor vaculopathic form, mimics acute GVHD. The lesions of chronic GVHD more closely mimic lichenoid eruptions and morpheiform eruptions and will not be discussed in this section (Demircay et al., 1997; Kohler et al., 1997; Weedon 1997b; Yoo et al., 1997; Aractingi and Chosidow 1998; Greinix et al., 1998). Differential Diagnosis Graft-verus-host disease in its early phase (i.e., less than 20 days following bone marrow transplantation) cannot be reliably distinguished from other disorders that could conceivably develop in this setting—specifically, virally mediated infections and drug hypersensitivity and/or toxic reactions. As mentioned previously, the identification of intraepidermal bile pigment may be a useful distinguishing criterion to separate it from the aforesaid other diagnostic possibilities. Among distinctive drug reactions that can impose diagnostic dilemmas with respect to distinction from GVHD are acral erythema of chemotherapy and Grover’s-like disease following high-dose chemotherapy and either allogeneic/autologous bone marrow transplantation or autologous stem cell infusion. In chemotherapy-associated acral erythema, the phenomenon is a purely toxic one and hence the observation of features of cellular cytoxic immunity (i.e., lymphocyte satellitosis around necrotic

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keratinocytes) in the epidermis would be exceptional in contrast with its ubiquitous identification in lesions of GVHD. The Grover’s-like eruption manifests a Darier’s pattern of acantholysis along with scattered chemotherapy-associated toxic epidermal changes such as the etoposide star burst keratinocyte (Kohler et al., 1997; Aractingi and Chosidow, 1998). Pathogenesis The pathophysiological events appear to involve a combination of CD4-positive T helper cells dominantly localized to acrosyngringia and follicular structures early in the infiltrate, followed by a CD8-positive T cell response later in the evolution of the disease. Thus, initial lesions are folliculotropic and eccrinotropic while later lesions involve the interfollicular epidermis. HLA-DR expression in eccrine structures and hair follicles are associated with T-helper-restricted interactions, explaining the distribution of infiltrates early in the GVH reaction. One study demonstrated that donor lymphocytes appeared in the skin of female patients undergoing allogeneic bone marrow transplant starting on day 13. The concept that acute GVHD is an exclusively cytotoxic CD8-mediated disease does not appear to be correct; the effector cells can be either a CD4- or CD8-positive lymphocyte, or a biphenotypic mixture. For example, in grade 2 lesions there appears to be a predominance of CD4-positive lymphocytes in the dermis while a CD8 phenotypic dominant infiltrate is present within the epidermal component. The brunt of injury is borne by the bulge epithelium of hair follicles, possibly reflecting the high concentration of stem cells in this area of the follicle; hence, the stem cell may be a preferential target. Apoptosis appears to be the mechanism of keratinocyte injury as confirmed by endonuclease-mediated DNA fragmentation. The apoptosis has two waves: an initial one is due to the effects of keratinocyte-derived tumor necrosis factor alpha (TNF-α), while the second wave is mediated by cytotoxic T lymphocytes. Both TNF-α and Fas ligand (FasL) have been implicated in the pathogenesis of GVHD. In one study, neutralizing anti-FasL and/or anti-TNF-α monoclonal antibody (MoAb) was given to mice with lethal acute GVHD. Treatment with either anti-FasL or anti-TNF-α MoAb alone significantly delayed the mortality and improved the body weight, whereby complete protection was achieved by the administration of both MoAbs (Demircay et al., 1997; Kohler et al., 1997; Yoo et al., 1997; Aractingi and Chosidow, 1998; Hattoriet et al., 1998; Johnson and Farmer, 1998).

Morbiliform Viral Exanthem and Morbiliform Drug Eruption Clinical Features These two forms of cell-poor interface dermatitis will be considered in concert as they have striking similarities at the light microscopic level. The rashes in morbiliform drug eruptions and viral exanthemata manifest as fine pinpoint diffuse erythema lacking islands of skin sparing. Among the viruses implicated in the morbiliform viral exanthem are coxsackie virus, echovirus, rotavirus, respiratory syncytical virus, and influenza virus. However, in most instances, the culprit virus is not identified. With respect to drugs, they fall primarily into the category of antibiotics and nonsteroidal anti-inflammatory agents (Crowson and Magro 1999a,b; Crowson et al., 2003). Histopathology The epidermal thickness and the stratum corneum are normal. The epidermis shows subtle basilar vacuolopathy with a few lymphocytes tagging along the dermal–epidermal junction. Scattered, randomly disposed necrotic keratinocytes are observed in the epidermis. The phenomenon of lymphocyte satellitosis around necrotic keratinocytes is not typically encountered. If there is a dermal-based infiltrate, it is sparse and confined to the superficial vascular plexus. There is usually no tissue eosinophilia except in those cases of drug-based etiology (Crowson et al., 2003).

Collagen Vascular Disease Compatible with Antibody-Dependent Cellular Immunity and/or Anti endothelial Cell Antibodies Lymphocytic infiltrates in the skin may be a cardinal manifestation of an underlying connective tissue disease diathesis, the spectrum of which encompasses lupus erythematosus, mixed connective tissue disease, and dermatomyositis. The hallmark morphologically is one of basilar vacuolar change with lymphocyte tagging along the dermal–epidermal junction and a concomitant variable perivascular lymphocytic infiltrate. In any of the aforesaid connective tissue disease syndromes and also in the setting of antiphospholipid antibody syndrome, the presence of antiendothelial cell antibodies may be associated with an angiocentric lymphocytic infiltrate as part of the morphologic expression of vasculopathy induced by antiendothelial cell antibodies (Crowson and Magro, 2001; Crowson, 2004). The two main connective tissue disease syndromes that are characterized by a cell-poor vacuolar

Interface Dermatitis: Cell-Poor Vacuolar Interface Dermatitis

Gottron’s papule. There are very characteristic skin manifestations encountered in the setting of collagen vascular disease. One of the most distinctive of these is Gottron’s papule. The characteristic hallmarks are those of erythematous scaly plaques localized over the dorsal aspects of the interphalangeal and metacarpal phalangeal joints.

FIGURE 4.5

interface dermatitis are systemic lupus erythematosus and dermatomyositis (Figure 4.5) (Bohan and Peter, 1975; Crowson and Magro, 1996, 2001; Crowson, 2004). In acute systemic lupus erythematosus, the changes are subtle: the epidermis and the stratum corneum may not show any appreciable alterations save for a focal and often subtle basilar vacuolopathy with a few lymphocytes tagging along the dermal–epidermal junction. What is more striking are alterations of the dermis, comprising splaying of the collagen fibers by mucin, with superficial vascular plexus ectasia. Critical to the diagnosis is the presence of clinical signs and symptoms that fulfill

the American College of Rheumatology criteria for systemic lupus erythematosus (Table 4.3). We have also observed exactly this morphology in patients with constitutional symptoms simulating systemic lupus erythematosus in the setting of parvovirus B19 infection and Lyme disease (Crowson et al., 2000). We recommend that any patient who presents with an acute symptom complex characterized by a skin rash with arthralgia and constitutional symptoms, and a skin biopsy histomorphologically resembling acute systemic lupus erythematosus as defined by the criteria in Table 4.7, should be evaluated for parvovirus B19 infection and Lyme disease, the latter particularly if the patient is from an endemic area. Dermatomyositis can have many of the aforementioned prototypic histological features, that is, a cell-poor interface dermatitis with pan-dermal mucinosis and vascular ectasia (Table 4.4). However, a humoral-based microangiopathy with C5b−9 as the effector mechanism is integral to the pathogenesis of the cutaneous lesions of dermatomyositis; in consequence, an active microangiopathy characterized by endothelial cell necrosis and denudement with zones of reduced vascular density of the superficial plexus is present (Crowson and Magro, 1996; Magro and Crowson, 1997). Similar vasculopathic changes are seen in anti-Ro-associated systemic lupus erythematosus (Magro and Crowson, 1999a–c). Patients with anti-Roassociated systemic lupus erythematosus often have a cell-rich interface injury pattern, that is, a lichenoid dermatitis. In addition, immunofluorescent testing reveals a positive lupus band test in concert with C5b−9 deposition along the dermal–epidermal junction and within blood vessels (Magro and Crowson, 1999a–c).

TABLE 4.3 Revised Criteria of the American Rheumatology Association for the Classification of Systemic Lupus Erythematosus 1. 2. 3. 4. 5. 6. 7. 8. 9.

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Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis: (a) pleuritis or (b) pericarditis Renal disorder: (a) proteinuria >0.5 g/24 h or 3+, persistently, or (b) cellular casts Neurological disorder: (a) seizures or (b) psychosis (having excluded other causes, e.g., drugs) Hematologic disorder: (a) hemolytic anaemia, or (b) leukopenia <4.0 × 109 /L on two or more occasions, or (c) lymphopenia <1.5 × 109 /L on two or more occasions, or (d) thrombocytopenia <100 + 109 /L 10. Immunologic disorders: (a) positive LE cell, or (b) raised antinative DNA antibody binding, or (c) anti-Smith antibody, or (d) false-positive serologic test for syphilis, present for at least 6 months 11. Antinuclear antibody in raised titer

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TABLE 4.4 Criteria for Myopathic Dermatomyositis 1. 2. 3. 4. 5.

Proximal symmetric muscle weakness Elevated serum levels of muscle-derived enzymes Abnormal electromyogram Abnormal muscle biopsy Cutaneous disease compatible with dermatomyositis

Source: Adapted from Bohan and Peter (1975).

INTERFACE DERMATITIS: LICHENOID PATTERN The morphologic reaction pattern of lichenoid interface dermatitis is characterized by a band-like lymphocytic infiltrate in intimate apposition to and obscuring the basal layer of the epidermis with variable epithelial injury. As with cell-poor interface dermatitis, the pathogenetic basis may reflect either type IV immunity or antibody-dependent cellular immunity. Lichenoid interface dermatitis is seen in numerous conditions including lichen planus, lichenoid hypersensitivity reactions of drug or contact-based etiology, lichenoid reactions in the settings of hepatobiliary disease, secondary syphilis, and collagen vascular disease. When a lichenoid interface dermatitis is present, the onus is on the clinician to investigate the patient for various disorders.

FIGURE 4.6 Lichen planus. The lesions of lichen planus are characterized by violaceous flat topped papules that have a tendency to coalesce, assuming an annular configuration.

Lichen Planus Clinical Features Lichen planus is a common eruption of unknown etiology, characterized by violaceous, flattopped papules that are usually pruritic (Figures 4.6 and 4.7). The surface of the papules may manifest a reticulated white scale referred to as Wickham’s striae (Figure 4.8). There is a predilection for the flexor surfaces of the wrists, trunk, thighs, and genitalia; oral lesions are common. Spontaneous resolution of lichen planus is usual within 12 months, although postinflammatory pigmentation may persist. Lichen planus-like eruptions may be observed in various systemic disorders such as infective id reactions and hepatobiliary disease (Requena et al., 1998; LuisMontoya et al., 2005). Pathogenesis Cell-mediated immunity appears to be operative. Initially the response is one of CD4-positive lymphocytes in the dermis, suggesting a delayedtype hypersensitivity reaction. After several weeks, however, a CD8 lymphocyte-dominant infiltrate is

Lichen planus. The findings are those of classic lichen planus. Note the hypergranulosis and hyperkeratosis with an accompanying band-like lymphocytic infiltrate lying in apposition to the basal layer of the epidermis. Associated destructive epithelial changes are present. In mycosis fungoides it would be most unusual to find this pattern of uniform hypergranulosis. As well, the pattern of lymphocyte migration into the epidermis is a principally passive one; the exception would be those cases of mycosis fungoides that fall under the appellation of lichenoid mycosis fungoides.

FIGURE 4.7

present. The presence of degenerative epithelial changes in association with lymphocyte satellitosis around degenerating keratinocytes also suggests a role for cellular cytotoxicity (Figure 4.9). A lichen planus-specific antigen has been detected in the epidermis and a circulating antibody to it has been found

Interface Dermatitis: Lichenoid Pattern

47

Lichen planus. There is lymphocyte satellitosis around necrotic keratinocytes, indicative of an immune based dermatosis, namely, one of cellular cytotoxicity.

FIGURE 4.9

Oral lichen planus. Classic intraoral lichen planus with features of Wickham’s striae.

FIGURE 4.8

in the serum of some individuals with lichen planus; however, this may be an epiphenomenon rather than being of any pathogenetic significance. A subclass of T lymphocytes, the γ δ T lymphocyte, has been identified in established lesions (Bhan et al., 1981; Weedon, 1997a; Requena et al., 1998). Histopathology The epidermis can either be irregularly thickened or demonstrate retiform effacement with epithelial atrophy depending on the age of lesion biopsied. The granular cell layer is increased, often in a wedgeshaped fashion, and the epidermis is surmounted by an orthohyperkeratotic scale. A dense band-like lymphocytic infiltrate in the superficial dermis obscures the dermal–epidermal junction. The destruction of the basal layer results in the exposure of the spinous layer to the dermis, defining the phenomenon of squamotization of the basal layer. Prominent suprabasilar dyskeratosis is unusual, most of the degenerative epithelial alterations being confined to the basilar and parabasilar portions of the epidermis. Mid- and deep dermal perivascular extension is not a feature of idiopathic lichen planus. Eosinophils or plasma cells are either absent or at most infrequently observed. In any given biopsy, alternating zones of epidermal hyperplasia with atrophy is unusual, as would be

alternating zones of lichenoid interface inflammation with areas of a cell-poor interface dermatitis. As the lesions resolve, the intensity of the dermal-based inflammatory cell infiltrate lessens and one can observe laminated superficial dermal fibroplasia with vascular ectasia in a fashion reminiscent of poikiloderma. Necrotic keratinocytes may be seen as PAS-positive colloid bodies within the papillary dermis. When the basilar destruction is acute and confluent, separation of the epidermis from the dermis may be observed, producing clefts referred to as Max–Joseph spaces. Direct immunofluorescence shows changes compatible with interface change, namely, an intense band of fibrinogen along the dermal–epidermal junction and within the papillary dermis with decoration of colloid bodies by all classes of immunoglobulins. There is typically conspicuous acrosyringeal and follicular involvement, the latter associated with follicular hyperkeratosis (Bhan et al., 1981; Weedon 1997).

Lichen Planus-like Eruptions of Hepatobiliary Disease Lichen planus-like eruptions may be observed in the setting of certain underlying hepatobiliary disorders, particularly those associated with a cholestatic picture such as hepatitis C virus infection and primary biliary cirrhosis. Clinically, the lesions are no different from those observed in idiopathic lichen planus. The

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TABLE 4.5 Lichenoid Drug Reactions Clinical Features Extensive violaceous papular eruption, sometimes with psoriasiform appearance Individual lesions resemble lichen planus Postinflammatory hyperpigmentation more pronounced than lichen planus Clear following drug withdrawal

histopathology is similar to idiopathic lichen planus, but there are a few subtle additional light microscopic clues that might point toward the diagnosis, such as a significant admixture of epithelioid histiocytes producing a morphology for which we use the appellation lichenoid and granulomatous dermatitis. Because of possible cross reactivity of eccrine duct epithelium with bile duct epithelium, the antigenic target in the setting of hepatitis C and primary biliary cirrhosis, a concomitant lymphocytic eccrine hidradenitis may be an additional clue (Magro and Crowson 1998; Magro and Crowson, 2000).

Lichen Planus-like Eruptions of Secondary Syphilis Occasionally, patients with secondary syphilis may develop a papulosquamous eruption resembling lichen planus, both clinically and histologically. The main differentiating points at a light microscopic level are the presence of granulomata, typically confined to the superficial dermis, and a conspicuous plasmacellular infiltrate (Magro and Crowson, 2000).

Lichenoid Drug Reactions Clinical Features Lichenoid drug eruptions resemble lichen planus (LP) clinically, with eruptions developing over weeks to months. Individual lesions are violaceous papules, sometimes with a superadded psoriasiform appearance. However, the eruptions are more extensive than LP, and oral involvement is unusual (see Table 4.5). Slow resolution follows drug cessation (see Table 4.6), and postinflammatory pigmentation is often pronounced (Crowson and Magro 1999a; Magro and Crowson, 2000; Crowson et al., 2003). Histopathology The lichenoid drug reaction shows a band-like lymphocytic infiltrate along the dermal–epidermal junction, with vacuolopathic basal layer keratinocyte degeneration and colloid body formation, but with frequent suprabasilar lymphocytosis around degenerating keratinocytes and with globular collections of colloid bodies in the papillary dermis. Unlike

TABLE 4.6 Causes of Lichenoid Drug Eruptions Beta-blockers Captopril Methyldopa Thiazides Lasix Gold Antimalarials Quinidine Oral hypoglycemic agents Phenytoin and carbamazepine Antituberculous agents Phenylbutazone Antipsychotics (including phenothiazines) Bismuth P-aminosalicylic acid Lithium

idiopathic lichen planus, parakeratosis, eosinophils, and plasma cells are frequently present, and deeper perivascular extension is the rule (Magro and Crowson 2000; Crowson et al., 2003). Differential Diagnosis Acanthosis is less striking in the lichenoid drug eruption than in lichen planus, and wedge-shaped hypergranulosis is uncommon. Lichenoid patterns of inflammation may be seen in certain connective tissue diseases, but such cases often manifest at least focal epidermal atrophy and virtually never exhibit tissue eosinophilia, unless they are of druginduced etiology (Magro and Crowson, 2000). This is a lichenoid variant of mycosis fungoides which is discussed in Ch. 14 (Guitart 1997).

Lichenoid Connective Tissue Disease Syndromes Introduction The prototypic lichenoid connective tissue disease syndromes include (1) subacute cutaneous lupus erythematosus (SCLE), (2) anti-Ro associated

Interface Dermatitis: Lichenoid Pattern

(a)

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(b)

FIGURE 4.10 Subacute cutaneous lupus erythematosus. The biopsy is one of an interface dermatitis showing lichenoid and cell-poor areas of interface dermatitis with attendant epithelial attenuation consistent with subacute cutaneous lupus erythematosus. The higher power magnification emphasizes the sequelae of the immune-based destructive interface process, namely, one of prominent colloid body formation with epithelial attenuation.

Subacute cutaneous lupus erythematosus. There is confluent photodistributed erythema. Such cases raise a list of differential diagnostic considerations including dermatomyositis, subacute cutaneous lupus erythematosus, and a drug-induced photoallergic or photoirritant dermatitis. The patient in this case had anti-Ro anbodies in the setting of subacute cutaneous lupus erythematosus associated with calcium channel blocker therapy.

FIGURE 4.11

systemic lupus erythematosus (SLE), and (3) mixed connective tissue disease (MCTD). Clinical Features The lichenoid connective tissue disease syndromes have in common a polycyclic annular and/or papulosquamous photodistributed eruption involving the head, neck, arms, and the ‘‘V’’ of the chest and upper back. In subacute cutaneous lupus erythematosus (SCLE), there are no significant extracutaneous

stigmata of collagen vascular disease (Figures 4.10 and 4.11). Serologic testing reveals anti-Ro antibodies in the majority of cases (Crowson and Magro, 2001). Some cases of SCLE are of drug-based etiology, where the main implicated drugs include calcium channel blockers (Figure 4.11), Griseofulvin, and thiazides (Crowson and Magro, 1997a). In anti-Ro associated systemic lupus erythematosus (SLE), while the cutaneous eruption may be morphologically indistinguishable from SCLE, there are other extracutaneous stigmata indicative of a systemic connective tissue disease syndrome, including renal dysfunction, musculoskeletal complaints, pulmonary disease, and central nervous system manifestations (Magro and Crowson, 1999a). As well, the patients may have cutaneous and extracutaneous stigmata indicative of vascular compromise as manifested by ulceration, digital infarcts, palpable purpura, mononeuritis multiplex, gastrointestinal ulcerations, and myocardial infarction. In mixed connective tissue disease (MCTD), the patients have a constellation of characteristic extracutaneous manifestations, which include Raynaud’s phenomenon, sclerodactyly, and pulmonary hypertension. In MCTD, while patients may have a skin rash that resembles SCLE, other characteristic features allow the distinctions, namely, anti-RNP antibodies, sclerodactyly, variable myositis, Raynaud’s phenomenon, and pulmonary hypertension (Magro et al., 1997). Another important differential diagnostic consideration is that of sclerodermatomyositis (SDM). Sclerodermatomyositis has been defined as an overlap

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of the features of systemic scleroderma and dermatomyositis. Of 32 patients with PM-Scl antibodies in one study, 31 had features of scleroderma and 12 had a dermatomyositis rash. Over the years, sclerodermatomyositis has emerged as a distinctive clinicopathologic entity with characteristic serologic findings. In particular, these patients have clinical features of scleroderma and the dermatomyositis component is less constant. Most patients have a distinctive serologic profile. In particular, anti-Ku and anti-PM-Scl are present in patients with sclerodermatomyositis, with anti-Ku present more frequently in Japanese populations and anti-PM-Scl present more commonly in Caucasian populations (GarciaPatos et al., 1996). Histopathology The prototypic histomorphology of the lichenoid connective tissue disease syndrome is one of variable epidermal hyperplasia and atrophy accompanied by an interface dermatitis that ranges in quality from being lichenoid in nature to a cell-poor vacuolar dermatitis. There is variable mid- and deep dermal perivascular extension of the infiltrate. Dermal mucinosis is ubiquitous. Also characteristic is the presence of suprabasilar dyskeratosis, with lymphocyte satellitosis around degenerating keratinocytes. Other concomitant inflammatory cell elements such as epithelioid histiocytes, plasma cells, and eosinophils are uncommon, although in a small minority of cases of drug-associated SCLE, eosinophils and granulomata may be observed. It has been our experience

that a significant vasculopathy is not present in SCLE (see Table 4.7). In contrast, in both anti-Ro associated systemic lupus erythematosus and MCTD, a microangiopathy similar to that encountered in dermatomyositis is a frequent finding. In particular, one may observe zones of vascular density reduction, endothelial cell necrosis, and variable luminal fibrin deposition (Magro and Crowson, 1997, 1999c; Crowson and Magro, 2001). Immunofluorescent Findings In SCLE, one typically observes nuclear and/or cytoplasmic decorating keratinocytes for IgG and C5b−9 . There is usually no C5b−9 staining of the cutaneous vasculature (Magro et al., 1996) except in cases of drug based etiology. The lupus band test is often negative. In anti-Ro associated systemic lupus erythematosus, the aforementioned epidermal decoration for IgG and C5b−9 is observed in concert with a positive lupus band test and C5b−9 deposition within the cutaneous vasculature (Magro and Crowson, 1999b). In MCTD, a similar pattern of epidermal decoration for IgG and C5b−9 is seen (Magro et al., 1997). The lupus band test is variably positive. As well, decoration of the cutaneous vasculature by C5b−9 is seen (see Table 4.8). Pathogenesis The pathogenetic basis of the lichenoid connective tissue disease syndrome is one of antibodydependent cellular immunity. In particular, with

TABLE 4.7 Histopathologic Criteria for Subtypes of Lupus Erythematosus Systemic lupus erythematosus Pauci-inflammatory interface dermatitis Slight to absent epidermal atrophy Basement membrane zone of normal thickness No follicular plugging Prominent papillary dermal edema and reticular dermal mucin accumulation Subacute cutaneous lupus erythematosus Prominent suprabasilar exocytosis of lymphocytes + dyskeratosis extending into upper spinous layers Prominent epidermal atrophy Follicular plugging or basement membrane zone thickening minimal or absent Mild to moderate mononuclear cell infiltrate confined to the superficial dermis Discoid lupus erythematosus Lymphocyte-rich interface dermatitis Less epidermal atrophy than SCLE; sometimes acanthosis Prominent basement membrane zone thickening Prominent follicular hyperkeratosis Dense superficial and deep perivascular and periadnexal infiltrates with follicular degeneration Dermal fibrosis Source: Adapted from Magro et al. (1996).

Interface Dermatitis: Lichenoid Pattern

51

TABLE 4.8 Criteria for MCTD A diagnosis of MCTD is based on the presence of one criterion from category I, plus the criterion from category II, plus one or more criteria from category III. I. Common symptoms: A. Raynaud’s phenomenon B. Swollen fingers or hands II. Anti-nRNP antibody III. Mixed findings: A. SLE-like findings: 1. Polyarthritis 2. Lymphadenopathy 3. Facial erythema 4. Pericarditis or pleuritis 5. Leukocytopenia or thrombocytopenia B. PSS-like findings: 1. Sclerodactyly 2. Pulmonary fibrosis, restrictive changes of the lung or reduced diffusion capacity 3. Hypomotility or dilatation of the esophagus C. DM-like findings: 1. Muscle weakness 2. Increased serum level of myogenic enzymes (CPK) 3. Myogenic pattern at electromyography

Abbreviations: DM, dermatomyositis; CPK, creatine phosphokinase; PSS, progressive systemic sclerosis; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus.

ultraviolet exposure, specific RNA antigens such as La and Ro are displaced from the nucleus and/or cytoplasm to the surface of the keratinocytes, where the antigen becomes accessible to circulating antibody. The C5b−9 membranolytic attack complex is the effector mechanism of the epidermal injury (Magro et al., 1996, 2000).

Lichenoid (‘‘Chronic’’) Graft-Versus-Host Disease Clinical Features Clinically, chronic graft-versus-host disease (GVHD) is characterized by a cutaneous eruption comprising lichen planus-like erythematous papules generally occurring more than 100 days after bone marrow transplant. One recent study suggested that lichenoid GVHD could be seen in a wide time range (33–832 days) post-transplantation and was associated with an increase in the death rate from GVHD (Horn et al., 1997).

Histopathology Although there are areas of cell-poor interface change focally, the density of the superficial infiltrate is of sufficient magnitude to assume a band-like disposition. A narrow band of subepidermal fibroplasia with pigment incontinence is typical. The intensity of the lichenoid process is not as striking as lichen planus. The lichenoid process may manifest follicular accentuation. In cases that occur earlier in the post-transplantation course (i.e., day 30), the distinction from acute grade II/III GVHD may be difficult. However, a feature that favors chronic GVHD is the absence of gastrointestinal or hepatobiliary symptoms of acute grade II/III GVHD (Horn et al., 1997). Differential Diagnosis The differential diagnosis is that of the lichenoid eruptions, namely, lichen planus, connective tissue diseases with lichenoid infiltrates (i.e., SCLE, discoid lupus erythematosus, systemic lupus erythematosus in the setting of anti-Ro antibodies, and MCTD), postherpetic zosteriform eruptions, and lichenoid hypersensitivity reactions.

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Immunophenotyping can aid in the distinction of chronic GVHD from lichen planus. Specifically, while both types of lichenoid tissue reaction can show CD3 positivity, the infiltrate in chronic GVHD is CD8 dominant while that in lichen planus comprises mainly CD4-positive cells. In addition, the lymphokine natural killer cell activity (LAK) markers anti-CD16 and anti-CD28 are largely nonreactive in lesions of lichen planus and strongly positive in lesions of chronic GVHD (Hitchins et al., 1997; Horn et al., 1997). Pathogenesis Acute GVHD is a critical determinant in the development of chronic GVHD. Regarding the latter, there are two broad categories of skin involvement: the lichenoid lesion and the sclerodermoid tissue reaction. With respect to the latter, dermal fibrosis, loss of cutaneous appendages, and loss of subcutaneous fat are the dominant features of sclerodermoid chronic GVHD. The question obviously arises as to the mechanism of fibrosis in chronic GVHD. Mast cells have always been postulated to play a role in the propogation of tissue fibrosis in sclerodermoid GVHD. One recent study examined the effects of a mast cell stabilizer (sodium chromylate) and a mast cell activator on cutaneous GVHD. Sodium chromylate ameliorated skin features of chronic GVHD while the mast cell activator caused skin changes reminiscent of mild chronic GVHD in control mice. In addition, there are extracutaneous stigmata in chronic GVHD that recapitulate collagen vascular disease, including Sjogren’s syndrome, primary biliary cirrhosis, entrapment neuropathy, polymyositis, lymphopenia, Comb’s hemolytic anemia, autoimmune thrombocytopenia, and variable positive autoimmune serology (i.e., antinuclear antibody, anti-smooth muscle antibodies). The mechanism of extracutaneous chronic GVHD is poorly understood but appears to be mediated by allogenic and autoreactive T cell clones. The emergence of the latter may be due to defective thymic self-deletion of autoreactive T cell clones stemming from acute GVH reactions on thymic epithelium (Horn et al., 1997).

DIFFUSE AND NODULAR LYMPHOCYTIC DERMAL INFILTRATES WITHOUT ATYPIA In this chapter on benign lymphocytic infiltrates, we next consider dominant localization of lymphocytic infiltration within the dermis. The infiltrate, while

prominent, is not really of sufficient magnitude to be categorized as lymphocytoma cutis. The latter is considered in Chapter 5. We do, however, recognize that there are those cases of lymphocytoma cutis that are florid representations of the entities under current consideration. In regard to the latter, the conditions that fall under this rubric of benign dermal-based lymphocytic infiltration are those associated with collagen vascular disease, namely, discoid lupus erythematosus and early inflammatory morphea, and those attributable to type IV hypersensitivity triggered by exogenous antigen or endogenous neoantigen including polymorphous light eruption, erythema annulare centrifugum, Lyme disease, and arthropod bite reactions (Clark et al., 1974; Gilliam and Wood, 2000; LeBoit, 2005). Jessner’s lymphocytic infiltrate of skin is a somewhat nebulous condition but it is likely more closely related to nonscarring discoid lupus erthematosus than to type IV hypersensitivity (Gilliam and Wood, 2000).

Polymorphous Light Eruption as the Prototypic Type IV Immune Reaction Clinical Features and Pathogenesis Polymorphous light eruption (PMLE) is an idiopathic eruption that likely represents the combined effects of phototoxicity and a delayed-type hypersensitivity reaction to ultraviolet light, usually UVA, but also UVB in some patients (Figure 4.12). Clinically, lesions are polymorphous in different individuals but appear monomorphous in a single individual, comprising papules, vesicles, or urticarial plaques that erupt 30 minutes to 3 days after ultraviolet light exposure and characteristically resolve in 7–10 days following discontinuance of sun exposure. Lesions may clinically appear eczematous or may resemble pemphigus, prurigo nodularis, erythema multiforme, or insect bite reactions, thus the epithet ‘‘polymorphous.’’ There is a predilection for the hands, forearms, upper arms, and head and neck regions (see Table 4.9). It is a disease of temperate climates; patients living near the equator are only rarely affected. Females are preferentially affected, characteristically in the third decade of life, with roughly 50% of patients manifesting decreasing photosensitivity over time. Other idiopathic light-induced eruptions include actinic prurigo, actinic reticuloid, juvenile springtime eruptions, and hydroa vacciniforme (Fesq et al., 2003; Stratisgos et al., 2003). Both polymorphous light eruption and lupus erythematosus share in common light sensitivity and at a light microscopic level can be difficult to distinguish apart. A recent study has shown that approximately half of lupus patients reported symptoms compatible

Diffuse and Nodular Lymphocytic Dermal Infiltrates Without Atypia

with polymorphous light eruption, which preceded the features characteristic of lupus erythematosus. Photosensitivity is a well-known manifestation of lupus erythematosus. Conversely, patients with polymorphous light eruption when followed over a 20 year period had only a slightly increased incidence of autoimmune disease; a significantly increased incidence of lupus erythematosus could not be documented. Dietary fish oil rich in omega-3 polyunsaturated fatty acids reportedly increases the resistance to

(a)

53

ultraviolet-induced erythema and rash provocation in polymorphic light eruption and hydroa vacciniforme. The photoprotective effect of fish oil appears to be due to inhibition of prostaglandin E2 production (Clark et al., 1974; Rhodes et al., 1995; Murphy, 2001). Histopathology The characteristic histomorphology of PMLE includes striking papillary dermal edema accompanied in early lesions by a superficial perivascular

(b)

Polymorphous light eruption. There is striking papillary dermal edema. Such findings would be most unusual in the realm of cutaneous T or B cell dyscrasias.

FIGURE 4.12

TABLE 4.9 Polymorphous Light Eruption Clinical Features Erythematous, pruritic papules or papulovesicles and urticarial plaques Eruption occurs 30 minutes to 3 days after sun exposure, and resolves in 7–10 days Predilection for sun-exposed sites: hands, forearms, head and neck area Histopathology Perivascular infiltrates of lymphocytes, eosinophils, and neutrophils Exocytosis, spongiosis, vesiculation, acanthosis, and focal parakeratosis common Some cases show vacuolopathic interface injury pattern or no epidermal changes Marked papillary dermal edema classically Blood vessels show ectasia and endothelial swelling that preferentially affects superficial vasculature Differential Diagnosis Delayed-type hypersensitivity reactions including: Allergic contact reactions Rosacea Other photoallergic/phototoxic eruptions Insect bite reactions Connective tissue diseases including: Discoid lupus erythematosus Subacute lupus erythematosus Jessner’s lymphocytic infiltrate

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lymphoid infiltrate and in late lesions by a more intense superficial and deep infiltrate, which may show a ‘‘sleeve-like’’ morphology mimicking EAC. Eosinophils, neutrophils, hemorrhage, vascular fibrin deposition, and vesiculation owing either to marked papillary dermal edema or epithelial spongiosis may be seen. The epidermis may show acanthosis and parakeratosis, the common alteration being an eczematous one with spongiosis and vesiculation. In rare cases, an interface dermatitis mimicking that of connective tissue disease or erythema multiforme may be present. Juvenile springtime eruption typically shows an erythema multiforme-like interface change. Vascular changes of endothelial swelling and edema, present in the superficial plexus, diminish in the depths of the biopsy. Direct immunofluorescence shows vascular IgM and C3 deposition in the absence of a positive lupus band test (Murphy, 2001). Differential Diagnosis Actinic reticuloid is a pseudolymphomatous tissue reaction associated with psoriasiform alterations of the epidermis accompanied by a superficial lymphomatoid vascular reaction; the dermal-based infiltrate includes numerous transformed lymphocytes, sometimes associated with Pautrier’s microabscess formation. Multinucleated stromal giant cells associated with intervascular fibrosis and confinement of the infiltrates to the perivascular connective tissue are characteristic. Actinic prurigo is an entity seen dominantly in native Americans, and shows an overlap of phototoxic, photoadaptive, and photoallergic features. Thus, hypergranulosis, acanthosis, individual cell necrosis at all levels of epidermis, basilar melanocyte activation with irregular epidermal melanization, and epidermal dysmaturation with architectural disarray form the spectrum of epidermal changes. The infiltrates are variable within the dermis, both in terms of density and composition. Some cases show an interface dermatitis. Biopsies of hydroa vacciniforme characteristically show intraepidermal vesiculation with reticular degeneration leading to confluent epidermal necrosis, vascular thrombosis, and a variable superficial and deep perivascular infiltrate of lymphocytes with occasional eosinophils and, in some cases, a lobular or septal panniculitis. Lesions heal with scarring. The characteristic morphology of juvenile springtime eruption is an interface dermatitis with follicular accentuation accompanied by a brisk superficial and mid-dermal angiocentric lymphocytic infiltrate with endothelial swelling and edema. The presence of interface change in lesions of juvenile springtime

eruption, actinic prurigo, hydroa vacciniforme, and a small percentage of cases of idiopathic PMLE suggests a pathogenetic role for cellular cytotoxicity induced by light exposure (Clark et al., 1974).

Other Dermal Perivascular Lymphocytic Infiltrates Superficial and deep EAC histopathologically manifests discrete perivascular cuffs predominated by lymphocytes, which are tropic to blood vessels producing a ‘‘sleeve-like’’ histomorphology. In addition to these sharply demarcated perivascular lymphoid infiltrates, which spare the overlying epidermis in the deep variant of EAC, endothelial cell swelling and hemorrhage may be present and eosinophils are seen in up to 20% of cases. Although an interstitial component may attend the sharply demarcated perivascular infiltrates, a significant interstitial neutrophilic or eosinophilic infiltrate should call to mind urticarial allergic eruptions, complement-mediated urticaria such as is seen in the setting of collagen vascular disease, and insect bite reactions. The superficial variant has concomitant low-grade eczematous changes with basilar vacuolar change of keratinocytes. With respect to PMLE, a few neutrophils are often seen within the infiltrate and papillary dermal edema may be more striking. In addition, there are concomitant eczematous dermal changes. Similarly, the dermal-based delayed-type hypersensitivity contact reactions generally have a significant interstitial component and lack sharp perivascular definition. In addition to the drugs mentioned previously (see Table 4.6), penicillins, thiazides, and gold are associated triggers for EAC. With respect to differentiating deep EAC from discoid lupus erythematosus and Jessner’s lymphocytic infiltrate, the latter two entities manifest periadnexal infiltrates and significant dermal mucinosis; eosinophils are typically not present (Crowson and Magro, 2001). Discoid lupus erythematosus can be distinguished from Jessner’s infiltrate, however, by degenerative epithelial alterations involving follicular structures predominantly, but also the interfollicular epidermis and the eccrine coil and straight ducts.

Gyrate Erythemas Erythema chronicum migrans, the cutaneous hallmark of Lyme disease, demonstrates prominent perivascular lymphocytic infiltrates with variable plasmacellular infiltration. There may be endothelial cell swelling accompanied by variable dermal mucin deposition. In addition to a prominent angiocentric disposition

Diffuse and Nodular Lymphocytic Infiltrates Associated with Autoimmune Disease

of the infiltrate, a lympholytic neuritis is frequently seen. Erythema gyratum repens manifests as broad polycyclic patches that resemble the rings on the cut surface of a tree. This eruption is associated with internal organ malignancies, tuberculosis, ichthyotic states, pityriasis rubra pilaris, and scleroderma. Clinical mimics include atypical cases of autoimmune bullous dermatoses, such as bullous pemphigoid or linear IgA disease, and SCLE. The histopathology of erythema gyratum repens comprises spongiosis with parakeratosis, focal mild perivascular lymphoid infiltrates, and variable edema or eosinophilia of the dermis (Crowson, 2004). Erythema maginatum is associated with rheumatic fever in less than 10% of cases and comprises erythematous macules with a raised edge and a pale center. Skin biopsies in erythema maginatum show perivascular neutrophilic, lymphocytic, and eosinophilic infiltrates with perivascular debris but absent vascular fibrin deposition. The overlying epidermis shows rare dyskeratotic cells and occasional intraepithelial neutrophils.

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Discoid lupus erythematosus. There is a destructive lymphocyte-rich interface dermatitis involving the hair follicle, compatible with discoid lupus erythematosus.

FIGURE 4.13

Differential Diagnosis With respect to erythema marginatum, other conditions that combine perivascular lymphocytic infiltrates with a neutrophilic and eosinophilic component in the presence of perivascular leukocytoclasia but absent or minimal fibrin deposition include toxic shock syndrome, serum sickness, and urticarial vasculitis (Clark et al., 1974).

DIFFUSE AND NODULAR LYMPHOCYTIC INFILTRATES ASSOCIATED WITH AUTOIMMUNE DISEASE Nonscarring Discoid Lupus Erythematosus/Tumid Lupus Erythematosus Clinical Features We have encountered a distinctive group of patients who manifest skin lesions for which we use the designation nonscarring discoid lupus erythematosus (DLE) (Figures 4.13 and 4.14). These patients present with indurated photosensitive plaques classically involving the head and neck, upper back, and anterior chest, which follow a waxing and waning course and respond to intralesional injection of steroids

Discoid lupus erythematosus. There is a distinctive pattern of lymphocyte apposition to the hair follicle with attendant follicular destruction and hyperkeratosis. The passive pattern of lymphocyte migration characteristic for pilotropic T cell dyscrasia is not seen. FIGURE 4.14

and/or administration of Plaquenil. Patients usually feel well and have no other extracutaneous stigmata of collagen vascular disease. Serologic testing is negative. Lupus band testing may fail to disclose a positive lupus band test. Most consider the entity of tumid lupus erythematosus to be a variant of DLE; this is an exceedingly uncommon form of lupus erythematosus in our experience. It presents clinically as a boggy plaque classically involving the head and neck area (Clark et al., 1974; Crowson and Magro, 2001; Crowson, 2004).

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Histopathology Nonscarring DLE, as discussed above, shows overlap clinically and histologically with Jessner’s lymphocytic infiltrate. In common with Jessner’s lymphocytic infiltrate are dense angiocentric and periadnexal lymphocytic infiltrates accompanied by pandermal mucinosis. In nonscarring DLE, there is evidence of an active interface dermatitis involving the interfollicular epidermis and/or the follicular epithelium with some element of degenerative epithelial alterations although not of a sufficient magnitude to result in scarring. As these patients do not have antibodies to extractable nuclear antigens, demonstration of epidermal staining for C5b−9 or IgG is not demonstrated. The histopathology of tumid lupus erythematosus is one of florid dermal mucinosis with a sparse perivascular and periadnexal lymphocytic

infiltrate without significant degenerative epithelial alterations (Crowson and Magro, 2001).

Morphea Pathogenesis Morphea is the most common form of scleroderma (Figure 4.15). It usually presents as one or several indurated plaques on the trunk or extremities, often with an ivory center and a lilac-colored border. Clinical subtypes include guttate, segmental, generalized, subcutaneous, keloidal, and bullous forms; in some patients more than one type is present at the same time. The guttate form, which manifests as small, pale, indurated papules on the upper trunk resembling lichen sclerosis, is often associated with large plaque-like lesions. The more rare generalized form, seen mainly in children, is often associated with symmetrical large plaques on the trunk and

(a)

(b)

(c)

Morphea. There is deep seated dermal sclerosis with a supervening interstitial and perivascular lymphocytic and plasmacellularis infiltrate. The plasma cells are found in close apposition to nerves, a finding typical for morphea. Also note the extension of the fibrosis into the septae. Interlobular septalfibroplasia is seen in three primary settings: morphea, necrobiosis lipsidica, and erythema nodosum. FIGURE 4.15

Diffuse and Nodular Lymphocytic Infiltrates Associated with Autoimmune Disease

extremities, sometimes associated with atrophy and fibrosis of the soft tissues and underlying bony ankylosis, which can lead to limb growth retardation. Subcutaneous morphea (morphea profunda) comprises one or more ill-defined deep sclerotic plaques with slow but relentless progression. Linear lesions of morphea, which are seen on both the extremities and face (the coup de sabre) comprise generally unilateral segmental lesions associated with dermal atrophy and, in some patients, with facial hemiatrophy (Perry–Romberg syndrome) (Al-Khenaizan and Al-Watban, 2005). Clinically, morphea may be mimicked clinically by the injection sites of pentazocine and vitamin K, the sites of radiation ports, such as for breast carcinoma, and, as regards the guttate variant of morphea, lesions of lichen sclerosus. Finally, the atrophoderma of Pasini and Pierini closely mimics morphea and may be a form of morphea. Papular mucinosos/lichen myxedematosus has been reported as a cardinal manifestation of patients with systemic scleroderma (Colme-Grimmer et al., 1997; Sawada et al., 1998; Tasanen et al., 1998; Zulian, 2005). Histopathology The skin biopsy findings in morphea depend on the age of the lesion biopsied. In its earliest phase, lesions of morphea may be highly inflammatory with a perivascular, interstitial, eccrinotrophic, and perineural array of lymphocytes and plasma cells associated with abundant mesenchymal mucin deposition between collagen bundles. This process most frequently begins in the reticular dermis, where the fibrosing reaction may be first appreciated close to the dermal subcutaneous interface. That initial fibrosing reaction comprises fine wavy collagen fibers beside and parallel to the native collagen bundles of the reticular dermis. Ultimately, the collagen bundles become thickened and the interfascicular spaces become narrowed. At this point, lesions are generally pauciinflammatory; the fibrosing reaction obstructs both the excretion of eccrine products to the surface of the skin and the lymphatic and venous return. Thus, blood vessels become ectatic in the superficial dermis and the eccrine coil becomes dilated; ultimately this progresses to complete effacement of adnexal structures. Immunophenotypically, the dominant lymphoid infiltrate is of T cell derivation. Eosinophils may be seen in some lesions, particularly those associated with drug injection or ingestion. Plasma cells in apposition to perineurium may be a significant clue. With respect to lichen sclerosis/morphea overlap, the aforementioned features are seen depending on lesional age but are accompanied by epidermal atrophy and a lymphocytic interface dermatitis with

57

basilar vacuolar degeneration of keratinocytes and, ultimately, reduction in superficial vascular plexus density mimicking certain systemic collagen vascular diseases as described previously. In lichen sclerosis/morphea overlap, as in lichen sclerosis, the superficial papillary dermis becomes homogenized and edematous. The late lesion of morphea is a noninflammatory fibrotic process with collagen bundles oriented parallel to the epidermis and complete absence of adnexal structures. Similar changes are described in systemic sclerosis (scleroderma) except that dermal inflammation is less intense, and that a conspicuous endarteritis obliterans phenomenon is seen in the deep dermal arterioles and arteries. With respect to the latter, clinical associations include the ingestion of L-tryptophan (eosinophilia-myalgia syndrome) and systemic therapy with bleomycin, with ingestion of rape seed oil, and with polyvinyl chloride exposure. Other diseases with an identical morphology include the sclerodermoid tissue reaction of graft-versus-host disease, porphyria cutanea tarda, and MCTD; the histomorphology most mimics scleroderma in late-stage lesions of the aforementioned disorders. With respect to the early, inflammatory lesions, these may be mimicked by diffuse interstitial granuloma annulare, granulomatous mycosis fungoides, systemic connective tissue diseases with interstitial lymphocytic and histiocytic infiltrates, including both MCTD and systemic lupus erythematosus, and palisading granulomatous drug reactions. We have seen one patient with a longstanding history of inflammatory morphea who ultimately developed granulomatous mycosis fungoides in her morphea lesions. This is obviously a rare occurrence, but it should be emphasized that lymphomas can arise in the setting of lymphoid hyperplasias in patients with underlying collagen vascular disease. With respect to the diffuse interstitial granulomatous drug reaction, lesions are characteristically localized to the intertriginous zones: the inner aspects of the arms, groin, and axillae. The drug history is positive, most typically, for the ingestion of angiotensin converting enzyme inhibitors, beta-blockers, and calcium channel blockers. Other agents are implicated, although with lesser frequency. Such cases do not show dermal sclerosis and a plasma cell neuritis is not observed. In cases of inflammatory morphea showing conspicuous plasmacellular infiltrates, we recommend obtaining Borrelia serology (Akimoto et al., 1998; Sawada et al., 1998; Zheng et al., 1998; Magro et al., 2002). Pathogenesis Tissue growth factor (TGF) is a potent stimulator of collagen synthesis. It is increased in lesions of

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morphea. Tissue ischemia/anoxia is a potent stimulator of TGF-β production. Thus, endothelial injury, in this case likely of immune-based etiology, may be critical to the pathogenesis of the fibrosing reaction in morphea. Platelet-derived growth factor (PDGF) is a critical growth factor for mesenchymal cells, especially fibroblasts. It can promote fibroblast proliferation, hence enhancing extracellular matrix synthesis. It is also a chemoattractant for fibroblasts. Northern blot analysis shows that cultured fibroblasts from scleroderma biopsies have higher expression levels of PDGF β-chain and PDGF βreceptor mRNA than those from normal control. A 2.8 kb PDGF β-chain mRNA transcript that has a more efficient translation ability is the more predominantly expressed one (Zheng et al., 1998). A recent study evaluated the degree and nature of collagen production in lesions associated with increased collagen production, namely, scleroderma, scleredema, and sarcoidosis. It was established that the amount of pro-α1 (I) collagen and β-actin mRNA levels were increased from lesional skin compared to healthy skin by approximately threefold. In the scleredematous stage (grade 1), showing edema in both papillary and reticular dermis with variable homogenization of collagen bundles in the reticular dermis, mast cell (MC) skin density, as a whole, was significantly increased as compared with normal skin. In the sclerotic stage characterized by homogenization of collagen bundles in the entire dermis, MC skin density was significantly decreased as compared with normal skin (Akimoto et al., 1998; Sawada et al., 1998; Zheng et al., 1998; Magro et al., 2002). Some cases, particularly in Europe, appear to be associated with seropositivity for Borrelia burgdorferi; the organism can also be demonstrated in tissue by polymerase chain reaction methodologies. While in our experience the primary tick inoculation site of Lyme disease may indeed show a sclerodermoid tissue reaction closely mimicking morphea, actual cases of morphea or scleroderma in which organisms are demonstrable are uncommon in North America. There is no statistical evidence to support a spirochetal etiology in lesions of morphea in the United States (Goodlad et al., 2002). More important in our view is the recent association of Parvovirus B19 infection with scleroderma; the viral DNA is demonstrable by molecular methods in the bone marrow and skin of scleroderma patients, at least those cases studied by us that represented a select group of Italian patients. It appears that Parvovirus B19 can infect or parasitize endothelial cells in patients who lack a virus-clearing serum

IgM response, most often atopic women and girls. Endothelial parasitism then provokes a humoral-based microangiopathy to reduce oxygen tension and thus leads to the fibrosing process intrinsic to the pathophysiology of morphea and scleroderma (Zheng et al., 1998; Ferri et al., 1999; Crowson et al., 2000; Magro et al., 2002).

Jessner’s Lymphocytic Infiltrate of the Skin Features Jessner’s lymphocytic infiltrate of the skin, first described in 1953, presents clinically as papules and indurated erythematous plaques primarily confined to sun-exposed areas, namely, the neck and upper trunk. Although it can occur in childhood, the majority of patients are in the third through fifth decades of life. Lesions are usually several in number and resolve spontaneously without scarring. Administration of antimalarials can facilitate clearing of the eruption. The question arises as to whether or not Jessner’s lymphocytic infiltrate represents a form of nonscarring DLE. There is a considerable overlap clinically and histologically between Jessner’s lymphocytic infiltrate of the skin and nonscarring DLE. The absence of serologic and/or extracutaneous stigmata of collagen vascular disease are observed in both entities. Furthermore, immunofluorescent testing in lesions of nonscarring/tumid lupus erythematosus is negative (Clark et al., 1974; Higgins et al., 1994; Weedon, 1997a). Histopathology One observes superficial and deep perivascular and periadnexal mature lymphocytic infiltrates. In a minority of cases, there may be extension into the subcutaneous fat. An active interface dermatitis involving the interfollicular epidermis is not observed. Although there may be permeation of the outer root sheath epithelium by lymphocytes, degenerative epithelial changes are not observed (Clark et al., 1973). There is variable splaying of the dermal connective tissue fibers by mucin. Lupus band testing is negative. There is no decoration of the keratinocytes for either IgG or C5b−9 . Immunophenotypic studies show a predominance of T cells. There may be a greater number of B cells in lesions of Jessner’s lymphocytic infiltrate relative to lupus erythematosus (Elder et al., 1997). Differential Diagnosis The differential diagnosis is primarily with nonscarring DLE/tumid lupus erythematosus, reticular erythematous mucinosis, and lymphocytoma cutis.

Diffuse and Nodular Lymphocytic Infiltrates Associated with Autoimmune Disease

With respect to nonscarring DLE, usually some element of interface change with epithelial destruction is observed involving either the interfollicular epidermis or hair follicle. In nonscarring DLE, the degree of epithelial injury is less than in typical DLE, and hence, the absolute light microscopic distinction of Jessner’s lymphocytic infiltrate from this variant of DLE is very difficult. Practically speaking, it likely does not matter as patients with this variant of lupus erythematosus do not have serologic stigmata of collagen vascular disease and extracutaneous symptomology of collagen vascular disease is not present. Both conditions respond to antimalarials. Regarding the distinction from PMLE, perhaps the most useful light microscopic discriminators that would favor PMLE over

59

Jessner’s lymphocytic infiltrate are the striking papillary dermal edema and tissue eosinophilia. As well, there is no tendency for the infiltrate to arrange itself around adnexal structures. With respect to lymphocytoma cutis, likely some cases of exuberant Jessner’s lymphocytic infiltrate could be classified as lymphocytoma cutis. Immunophenotypically, Jessner’s lymphocytic infiltrate of the skin, reticular erythematous mucinosis, and lupus erythematosus are dominated by T cells, whereas in lymphocytoma cutis, there is either an equal distribution of T and B cells or a dominance of B cells. Lymphocytoma cutis may be triggered by various infective stimuli including herpes infection and insect bite reactions (Weedon, 1997a; Crowson and Magro, 2001).

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REFERENCES AL-KHENAIZAN S, AL-WATBAN L. Parry–Romberg syndrome. Overlap with linear morphea. Saudi Med J. 2005;26(2):317–319. AKIMOTO S, ISHIKAWA O, IGARASHI Y, KUROSAWA M, MIYACHI Y. Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation. Br J Dermatol. 1998; 138:399–406. ARACTINGI S, CHOSIDOW O. Cutaneous graft-versus-host disease. Arch Dermatol. 1998; 134:602–612. AURELIAN L, KOKUBA H, BURNETT JW. Understanding the pathogenesis of HSV-associated Erythema. Multiforme. Dermatology 1998; 197:219–222. BHAN AK, HARRIST TJ, MURPHY GF, MIHM MC Jr. T cell subsets and Langerhans cells in lichen planus: in situ characterization using monoclonal antibodies. Br J Dermatol. 1981; 105:617–622. BOHAN A, PETER JB. Polymyositis and dermatomyositis. N Engl J Med. 1975; 292: 344–347. CAVANI A, MEI D, GUERRA E, et al. Patients with allergic contact dermatitis to nickel and nonallergic individuals display different nickel-specific T cell responses. Evidence for the presence of effector CD8+ and regulatory CD4+ T cells. J Invest Dermatol. 1998; 111(4): 621–628. CHUH AA, PEIRIS JS. Lack of evidence of active human herpesvirus 7 (HHV-7) infection in three cases of pityriasis rosea in children. Pediatr Dermatol. 2001; 18:381–383. CHUH AA, CHIU SS, PEIRIS JS. Human herpesvirus 6 and 7 DNA in peripheral blood leukocytes and plasma in patients with pityriasis rosea by polymerase chain reaction: a prospective case control study. Acta Derm Venereol. 2001; 81:289–309. CLARK WH Jr, REED RJ, MIHM MC Jr. Lupus erythematosus, histopathology of cutaneous lesions. Hum Pathol. 1973; 4:157–163. CLARK SH Jr, MIHM MC Jr. REED RJ, AINSWORTH AM. The lymphocytic infiltrates of the skin. Hum Pathol. 1974; 5:25–43. COHEN LM, COHEN JL. Erythema multiforme associated with contact dermatitis to poison ivy: three cases and a review of the literature. Cutis. 1998; 62:139–42. COHEN LM, SKOPICKI DK, HARRIST TJ, CLARK WH Jr. Noninfectious vesiculobullous and vesiculopustular diseases. In: Elder D, Elenitsas R, Jaworsky C, Johnson B, Eds. Lever’s Histopathology of the Skin. 8th ed. Philadelphia: Lippincott-Raven, 1997:209–252. COLOME-GRIMMER MI, PAYNE DA, TYRING SK, SANCHEZ RL. Borrelia burgdorferi DNA and Borrelia hermsii DNA are not associated with morphea or lichen sclerosus et atrophicus in the southwestern United States. Arch Dermatol. 1997; 133:1174. CROWSON AN, MAGRO CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996; 27:15–9. CROWSON AN, MAGRO CM. Subacute cutaneous lupus erythematosus in the setting of calcium channel blocker therapy. Hum Pathol. 1997a; 28:67–73. CROWSON AN, MAGRO CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol. 1997b; 28:474–484.

CROWSON AN, MAGRO CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin. 1999a; 17:537–560. CROWSON AN, MAGRO CM. Lichenoid and subacute cutaneous lupus erythematosus-like dermatitis associated with antihistamine therapy. J Cutan Pathol. 1999b; 26(2):95–99. CROWSON AN, MAGRO CM. The cutaneous pathology of lupus erythematosus. J Cutan Pathol. 2001; 28:1–23. CROWSON AN, MAGRO CM, DAWOOD MR. A causal role for Parvovirus B19 infection in the pathogenesis of adult dermatomyositis and other autoimmune syndromes. J Cutan Pathol. 2000; 27:505–515. CROWSON AN, BROWN TJ, MAGRO CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions: implications for management. Am J Clin Dermatol. 2003; 4:407–428. CROWSON AN, MAGRO CM. Drug eruptions. In: Barnhill R, Crowson AN, eds. Textbook of Dermatopathology. 2nd edn. New York: McGraw-Hill; 2004: 299–318. CROWSON AN. Superficial and deep perivascular dermatitis. In: Barnhill R, Crowson AN, eds. Textbook of Dermatopathology. 2nd ed. New York: McGraw-Hill; 2004: 79–96. DEMIRCAY Z, GURBUZ O, ALPDOGAN TB, et al. Chemotherapy-induced acral erythema in leukemic patients: a report of 15 cases. Int J Dermatol. 1997; 36:593–598. DILDAY BR, SMOLLER BR. Intraepidermal bile pigment in skin biopsy specimens for graft-versus-host disease versus erythema multiforme. Mod Pathol. 1998; 11(10):1005–1009. DRAGO F, RANIERI E, MALAGUTI F, BATTIFOGLIO ML, LOSI E, REBORA A. Human herpesvirus 7 in patients with pityriasis rosea. Electron microscopy investigations and polymerase chain reaction in mononuclear cells, plasma and skin. Dermatology. 1997; 195:374–378. DVORAK HF, MIHM MC Jr. Basophilic leukocytes in allergic contact dermatitis. J Exp Med. 1972; 135:235–254. DVORAK HF, MIHM MC Jr, DVORAK AM, et al. Morphology of delayed type hypersensitivity reactions in man. I. Quantitive description of the inflammatory response. Lab Invest. 1974; 31:111–130. DVORAK AM, MIHM MC Jr, DVORAK HF. Morphology of delayed-type hypersensitivity reactions in man. II. Ultrastructural alterations affecting the microvasculature and the tissue mast cells. Lab Invest. 1976; 34:179–191. ELDER D, ELENITSAS R, JAWORSKY C, JOHNSON B, eds. Lever’s Histopathology of the Skin. 8th ed. Philadelphia: Lippincott-Raven; 1997. FARBER-MARCUS BS, BERGMAN R, PORATH B, et al. Serum antibodies to Parvovirus B19 in patients with pityriasis rosea. Dermatology. 1997; 194:371. FESQ H, RING J, ABECK D. Management of polymorphous light eruption: clinical course, pathogenesis, diagnosis and intervention. Am J Clin Dermatol. 2003; 4(6):399–406. FERRI C, ZAKRZEWSKA K, LONGOMBARDO G, et al. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol. 1999: 718–720. FOEDINGER D, ELBE-BURGER A, STERNICZKY B, et al. Erythema multiforme associated human autoantibodies against

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KOKUBA H, IMAFUKU S, HUANG S, AURELIAN L, BURNETT JW. Erythema multiforme lesions are associated with expression of herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response. Br J Dermatol. 1998; 138:952–964. KONSTANTOPOULOS K, PAPADOGIANNI A, DIMOPOULOU M, KOURELIS C, MELETIS J. Pityriasis rosea associated with imatinib (STI571, Gleevec). Dermatology. 2002; 205(2):172–173. LEBOIT PE. Cutaneous lymphocytic infiltrates: let’s get real. Am J Dermatopathol. 2005; 27(2):182–184. LUIS-MONTOYA P, DOMINGUEZ-SOTO L, VEGA-MEMIJE E. Lichen planus in 24 children with review of the literature. Pediatr Dermatol. 2005; 22(4):295–298. LI LY, CRUZ PD Jr. Allergic contact dermatitis: pathophysiology applied to future therapy. Dermatol Ther. 2004; 17(3):219–223. MAGRO CM, CROWSON AN. The immunofluorescence findings in cutaneous lesions of dermatomyositis: a comparative study versus lupus erythematosus. J Cutan Pathol. 1997; 24:543–52. MAGRO CM, CROWSON AN. Interface and granulomatous dermatitis as a manifestation of antecedent microbial infection: the superantigen id reaction. J Cutan Pathol. 1998; 28:538–544. MAGRO CM, CROWSON AN. The clinical and histological features of 23 non-SCLE patients with anti-Ro antibodies. Am J Dermatopathol. 1999a; 21:129–37. MAGRO CM, CROWSON AN. The clinical and histological spectrum of IgA-associated vasculitis. Am J Dermatopathol. 1999b; 21:234–240. MAGRO CM, CROWSON AN. The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adults patients without subacute lupus erythematosus. Am J Dermatopathol. 1999c; 21:129–137. MAGRO CM, CROWSON AN. Lichenoid and granulomatous dermatitis. Int J Dermatol. 2000; 39:126–133. MAGRO CM, CROWSON AN, HARRIST TJ. The use of antibody to C5b-9 in the subclassification of lupus erythematosus. Br J Dermatol. 1996; 134:855–862. MAGRO CM, CROWSON AN, REGAUER S. The dermatopathology of mixed connective tissue disease. Am J Dermatopathol. 1997; 19:205–212. MAGRO CM, DAWOOD MR, CROWSON AN. The cutaneous manifestations of Parvovirus B19 infection. Hum Pathol. 2000; 31:488–497. MAGRO CM, CROWSON AN, DAWOOD M, NUOVO GJ. Parvoviral infection of endothelial cells in cutaneous lesions—possible role in vasculitis and autoimmune diseases. J Rheumatol. 2002; 29:1227–1235. MARGOLIS RJ, TONNESEN MG, HARRIST TJ, et al. Lymphocyte subsets and Langerhans cells/indeterminate cells in erythema multiforme. J Invest Dermatol. 1983; 81:403–406. MICHITAKA K, HORIIKE N, CHEN Y, et al. Gianotti–Crosti syndrome caused by acute hepatitis B virus genotype D infection. Intern Med. 2004; 43(8):696–699. MIHM MC Jr, SOTER NA, DVORAK HF, AUSTEN KF. The structures of normal skin and the morphology of atopic eczema. J Invest Dermatol. 1976; 67:305–312. MOGHADAM BK, HERSINI S, BARKER BF. Autoimmune progesterone dermatitis and stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 85:537–541. MURPHY GM. Diseases associated with photosensitivity. J Photochem Photobiol B. 2001; 64(2–3):93–98.

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OKAZAKI F, KANZAKI H, FUJII K, et al. Initial recruitment of interferon-gamma-producing CD8+ effector cells, followed by infiltration of CD4+ cells in 2,4,6-trinitro-1chlorobenzene (TNCB)-induced murine contact hypersensitivity reactions. J Dermatol. 2002; 29(11):699–708. RASKIN CA. Small plaque parapsoriasis and mycosis fungoides. Arch Dermatol. 1996; 132(11):1388. REQUENA L, KUTZNER H, ESCALONILLA P, ORTIZ S, SCHALLERI J, ROHWEDDER A. Cutaneous reactions at sites of herpers zoster scars: an expanded spectrum. Br J Dermatol. 1998; 138:161–168. RHODES LE, DURHAM BH, FRASER WD, FRIEDMANN PS. Dietary fish oil reduces basal and ultraviolet B-generated PGE2 levels in skin and increases the threshold to provocation of polymorphic light eruption. J Invest Dermatol. 1995; 105:532–535. RODENAS JM, HERRANZ MT, TERCEDOR J. Autoimmune progesterone dermatitis: treatment with oophorectomy. Br J Dermatol. 1998; 139(3):508–511. SAINT-MEZARD P, ROSIERES A, KRASTEVA M, et al. Allergic contact dermatitis. Eur J Dermatol. 2004; 14(5):284–295. SAWADA Y, SEISHIMA M, FUNABASHI M, NODA T, MAEDA M, KITAJIMA Y. Papular mucinosis associated with scleroderma. Eur J Dermatol. 1998; 8:497–500. SCHUTTELAAR M-LA, LAEIJENDECKER R, HEINHUIS RJ, VAN JOOST Th. Erythema multiforme and persistent erythema as early cutaneous manifestations of Lyme disease. J Am Acad Dermatol. 1997; 37:873–875. SCHWARTZ RS, DOWNHAM TF 2nd. Erythema multiforme associated with Rhus contact dermatitis. Cutis. 1981; 27(1):85–86. SOTER NA, MIHM MC Jr. Morphology of atopic eczema. Acta Derm Venereol (Stockh) Suppl. 1980; 92:11–15. STRATIGOS AJ, ANTONIOU C, PAPATHANAKOU E, et al. Spectrum of idiopathic photodermatoses in a Mediterranean country. Int J Dermatol. 2003; 42(6):449–454. TASANEN K, PALATSI R, OIKARINEN A. Demonstration of increased levels of type I collagen mRNA using

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CHAPTER F I V E

REACTIVE LYMPHOMATOID TISSUE REACTIONS MIMICKING CUTANEOUS T AND B CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Many cutaneous lymphoid infiltrates that manifest cytologic atypia are in fact not neoplastic but instead reflect exuberant immunologic responses to a variety of antigenic triggers in a patient who typically has a state of underlying iatrogenic and/or endogenous immune dysregulation. Most of these infiltrates are dominated by T cells but there is a subcategory of lesions that mimic B cell lymphoma and/or primary cutaneous pleomorphic T cell lymphoma and can be designated lymphocytoma cutis. The superficial T cell dominant infiltrates may have a phenotypic profile similar to that encountered in mycosis fungoides (MF) by virtue of a CD4-positive population that shows significant loss of CD7 and/or CD62L expression (Magro, 2005). Such cases may show T cell clonality, a feature one commonly associates with lymphoma. Clonality in this reactive setting has been demonstrated most frequently using a polymerase chain reaction methodology to assess for rearrangement of the T cell receptor (TCR) γ (Magro, 2003). We have extended these observations of clonality using a different technique, namely, the TCR-β fragment size multiplex assay (Plaza et al., 2006). Most lesions of lymphocytoma containing a significant B cell component can be distinguished from

marginal zone or follicle center cell lymphoma since the phenotypic profile is usually normal and polyclonality is characteristic; any lesion of lymphocytoma cutis showing B cell clonality and/or significant phenotypic aberrations in the B cell populace should be held to represent evolving B cell lymphoproliferative disease. We have seen cases of T-cell-rich B cell lymphoma that may be very difficult to distinguish from lymphocytoma cutis since most of the infiltrate is reactive. Absolute distinction from a solitary lesion of primary cutaneous pleomorphic small and medium sized T cell lymphoma may be problematic and remain an unresolved problem unless one reverts to cytogenetics. There are cases of diffuse T-cell-rich lymphocytoma cutis that may show clonality and variable loss of CD7 and CD62L; categorization as a benign lesion is based on a normal karyotype. The designation reversible T cell dyscrasia is used for drug-associated cases showing this histologic, phenotypic, and molecular constellation. Significant lymphoid atypia can also be seen in the setting of lupus erythematosus and other connective tissue disease syndromes unrelated to a preneoplastic or neoplastic process (Magro CM, 1997). This chapter examines the clinical and morphologic spectrum of

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 63

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atypical lymphoid infiltrates that resemble lymphoma but in which progression to mycosis fungoides and other forms of cutaneous lymphoma is rare. There are always exceptions to any rule and we have seen cases showing progression from a state of reversible T or B cell dyscrasia to a state of endogenous lymphoid dyscrasia. For example we recently described a patient with B cell lymphocytoma cutis related to fluoxetine therapy who subsequently developed marginal zone lymphoma despite drug cessation (Halevy and Sandbank, 1987; Arai et al., 2005; Breza and Magro, 2006). Although most of these atypical reactive infiltrates, in our experience, relate to the immune dysregulatory properties of certain ingested drugs lymphomagenesis is a multistep process with reactive lymphoid hyperplasia as a precursor lesion. The recognition of these infiltrates is important for two main reasons: to avoid misdiagnosis as lymphoma and to allow intervention to attenuate this state of dysregulated lymphoid hyperplasia and therefore, hopefully, to interrupt or delay transformation to lymphoma (Rosenthal et al., 1982; DeVriese et al., 1995; Magro and Crowson, 1996).

Lymphocytoma cutis. This patient developed a nodular lesion on the tip of her nose. She was on antidepressants for many years. Both the clinical presentation and histomorphology are characteristic for lymphocytoma cutis.

FIGURE 5.1

LYMPHOMATOID DRUG ERUPTIONS See Case Vignettes 1–7, 9, 10, and 11 at end of chapter. Clinical Features The concept of the lymphomatoid drug eruption, or drug-associated pseudomycosis fungoides (pseudo-MF), was first recognized when dilantin was linked to lesions that clinically resembled MF (Souteyrand and D’Incan, 1990; Rijlaarsdam et al., 1991; D’Incan et al., 1992; Shapiro et al., 1998). Subsequent reports have described similar lesions associated with the intake of other drugs (see Figures 5.1–5.3), including phenothiazines, antihistaminics, anxiolytics, antidepressants, barbiturates, beta-blockers, calcium channel blockers, and ACE inhibitors (Rijlaarsdam et al., 1992; Crowson and Magro, 1995a, b; Magro and Crowson, 1995, 1996). While the prototypic reaction pattern for the lymphomatoid drug response is one that resembles classic plaque stage MF (Rijlaarsdam et al., 1991), other patterns since recognized include lymphocytoma cutis, follicular mucinosis, pityriasis lichenoides-like, granulomatous slack skin, and atypical pigmentary purpura (Rijlaarsdam et al., 1992; Crowson and Magro, 1995a, b; Magro and Crowson, 1995, 1996; Crowson et al., 1999). The cumulative and/or synergistic effect of polypharmacy on immune dysregulation in

Interstitial granulomatous drug reaction. This patient developed an erythematous symmetrical rash involving the upper back. The biopsy showed an interstitial histiocytic and lymphocytic infiltrate with variable lymphoid atypia. The patient was on an ACE inhibitor. While the clinical presentation was unusual, the findings are most compatible with an interstitial granulomatous drug reaction.

FIGURE 5.2

the propagation of these eruptions has been proposed (Magro and Crowson, 1996). Specifically, the various implicated drugs all have immune dysregulating properties, including in vitro effects on lymphocyte function such as promotion of lymphoid mitogenesis and impairment of T suppressor function. It is always important to remember that a drug-based etiology should be excluded in any case of atypical lymphocytic infiltration unless the clinical history is more typical for endogenous T cell dyscrasia (i.e., the patient has had the eruption for

Lymphomatoid Drug Eruptions

Palisading granulomatous drug reaction. In this image one sees infiltrative violaceous plaques involving the trunk. Such cases raise strong diagnostic consideration, both clinically and histologically, of mycosis fungoides. An regards to the palisading granulomatous drug reaction, the most commonly implicated drugs are ACE inhibitors and/or calcium channel blockers.

FIGURE 5.3

years and the skin rash or lesion antedated the ingestion of the incriminated immune dysregulating drugs) (Crowson and Magro, 1995a, b; Magro and Crowson, 1995, 1996). A temporal association between the development of the skin rash and initiation of drug therapy is often unclear as the patient may have been on the immune dysregulating drug for years before developing the cutaneous infiltrates (see Case Vignettes 1–7, 9). In addition to drugs directly inducing these infiltrates, exacerbation of preexisting MF by fluoxetine has been shown (Vermeer and Willemze, 1996), and it has been our experience that patients with malignant lymphoma who receive drugs from the aforementioned classes may transiently improve when the drug or drugs are withdrawn, only to subsequently relapse. Other drugs emerging as provocative of lymphoid dyscrasia include thiazides, lipid-lowering agents, and additional classes of antidepressants apart from fluoxetine and amitryptiline. Patients who develop lymphomatoid drug reactions may have a preexisting state of endogenous immune dysregulation encompassing connective tissue disease (CTD), lymphoreticular neoplasia, HIV infection, and an atopic diathesis. Histopathology In the setting of plaques clinically resembling MF, biopsies generally show a superficial, band-like lymphocytic infiltrate with variable epitheliotropism typically directed to sites of antigenic processing such as suprapapillary plates, acrosyringea, and hair follicles (Furness et al., 1986; Magro and Crowson,

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1996). In our hands, the intraepidermal lymphoid populace has proved to be less atypical than the dermal lymphocytes and the dermal lymphoid population often includes transformed cells (Magro and Crowson, 1996). Expressing the same observation in another way, investigators from the European Organization for Research and Treatment of Cancer (EORTC) compared the nuclei of the intraepidermal lymphoid populace to the nuclear diameter of keratinocytes; lymphoid nuclear diameters similar to those of adjacent keratinocytes were found to be reasonably specific for MF, while in MF mimics papillary dermal fibrosis or significant numbers of dermal ‘‘blast-like’’ cells were seen (Santucci et al., 2000). (See Case Vignettes 4 and 7.) A relatively common pattern in lymphomatoid drug reactions is one that closely resembles granulomatous MF and has fallen under the designation of interstitial granulomatous drug reaction (Magro et al., 1998). In many cases the drug history is not known and we simply use the designation of granulomatous T cell dyscrasia. Such cases may represent a reversible granulomatous T cell dyscrasia (Magro et al., 1998), a designation that can only apply when the lesions undergo regression with drug cessation, recognizing that the time course between drug cessation and lesional regression may be several months. We found that eosinophils, plasma cells, and a cell-poor interface injury are also common. Papular lesions of drug-induced pseudolymphoma may show a lymphomatoid vascular reaction, namely, dense angiocentric atypical lymphoid infiltrates associated with variable luminal and mural fibrin deposition and ischemic epidermal alterations (see Case Vignettes 1 and 6.) (Magro and Crowson, 1996). Other light microscopic correlates of papular pseudolymphoma include follicular mucinosis accompanied by exocytosis of atypical lymphocytes including those with cerebriform nuclear contours. When nodules are biopsied, a diffuse and/or follicular lymphocytoma cutis pattern is often observed. An additional pattern resembles atypical pigmentary purpura (Crowson et al., 1999). We have seen many cases of reactive perivascular lymphocytic infiltrates containing CD30-positive cells. Among the features separating these cases from an endogenous CD30-positive lymphoproliferative syndrome is the relative confinement of the infiltrate to the superficial and mid-dermis, the truly dominant disposition around vessels, and the relative lack of involvement of the eccrine coil. In addition, there is commonly supervening eczematous

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and/or cytotoxic interface change in the overlying epidermis (Su and Duncan, 2000). (See Case Vignette 6.) Drug-associated atypical pigmentary purpura may mimic idiopathic pigmented purpuric dermatosis and purpuric variants of MF, both of which reflect endogenous T cell dyscrasia. Perhaps the most useful discriminating light microscopic feature favoring MF is the identification of a more atypical intraepidermal lymphoid populace relative to the dermal-based lymphoid infiltrate (Crowson et al., 1999). In idiopathic pigmented purpuric dermatosis, this rule of enhanced intraepidermal lymphoid atypia does not apply; the infiltrate is typically without any supervening plasma cells or eosinophils, and papillary dermal edema and eczematous epidermal changes are unusual. In drugassociated atypical pigmented purpuric dermatosis, the aforesaid features are common. A diagnosis of idiopathic atypical pigmented purpuric dermatosis should only be made after excluding a drug-based etiology. Clinical history is of paramount importance. If the patient has a recent onset of lesions clinically held to be compatible with pigmentary purpura but a drug history is positive (e.g., the patient had been on antidepressant therapy for a period of time), then careful consideration must be given to a drugbased etiology and, more specifically, an eruption that will eventually regress following cessation of the offending dysregulating agent. Protracted therapy with immune dysregulating agents may be a risk factor for the development of endogenous T cell dyscrasia. A case of pigmented purpuric dermatosis associated with antidepressant therapy is illustrated clinically. Phenotypic Profile In some cases the infiltrates show a normal phenotype with a predominance of CD4 over CD8 lymphocytes and no loss of CD7 or CD62L expression. (See Case Vignettes 4–6 and 8.) Other profiles may cause a diagnostic challenge in their separation from endogenous T cell lymphoproliferative disorders; the CD4 to CD8 ratio may be high, similar to MF or other forms of post-thymic cutaneous T cell lymphoma. The neoplastic cells are of T cell lineage and typically show CD2, CD3, CD4, and CD5 expression. One might assume that cases with a dominance of CD8 lymphocytes in the epidermis would typify a reactive infiltrate, but in fact the epidermis in lesions of MF may be populated by CD8-positive lymphocytes while the dermal lymphocytes mainly express CD4. In the setting of MF, the CD8-positive lymphocytes reflect a directed immunogenic host

response to neoplastic CD4 lymphocytes. In our experience, those cases of lymphomatoid drug reaction with a significant intraepidermal CD8-positive lymphoid populace in the epidermis resemble pityriasis lichenoides. (Magro, 2003). It is not uncommon to see a loss of CD7 and/or CD62L expression in the reversible drug-associated T cell dyscrasias. This loss of specific pan T cell marker expression was always held to be a feature of MF (Selvaag, 1997; Leenutaphong and Manuskiatti, 1996; Hindioglu and Sahin, 1998; Agnew and Oliver, 2001). Some citations suggest that CD7 and CD62L expression in less than 50% of an infiltrate indicates MF; the greater the diminution of expression, the more specific is the finding (Leenutaphong and Manuskiatti, 1996). This has not been our experience. In lymphomatoid drug reactions, a substantial diminution of CD7 expression is seen. As well, there may be a reduction in staining for CD62L; this marker, which is now commercially available for use on paraffin embedded tissue, may show a reduction in lesions of drug-associated lymphomatoid hypersensitivity/drug-associated reversible T cell dyscrasia (Magro et al., 2005). In the majority of such cases, the extent of diminution will not be of the magnitude observed in overt cutaneous T cell lymphoma although we have seen cases where it has been striking. We have also seen a number of cases of drug-associated lymphomatoid reaction where there is greater preservation of CD7 than of CD62L expression, the latter potentially showing an extent of reduction analogous to that observed in MF. The basis for this loss of CD7 and CD62L expression is alluded to in the section Pathogenetic Basis of Lymphomatoid Drug Reactions. Scattered CD30-positive cells are often seen in the epidermis and around vessels of the superficial vascular plexus (Nathan and Belsito, 1998). (See Case Vignettes 9 and 11).

MOLECULAR PROFILE OF LYMPHOMATOID DRUG ERUPTIONS Oligoclonality and monoclonality can be observed in drug-induced lymphomatoid hypersensitivity, a finding that substantiates the concept that this form of drug reaction is a drug-induced reversible T cell dyscrasia. (See Case Vignettes 9–11.) (Magro et al., 2003; Plaza et al., 2006). The molecular profiles encountered in the setting of drugassociated reversible T cell dyscrasia most closely resembled that encountered in MF. On occasion, the

Pathogenetic Basis of Lymphomatoid Drug Reactions

profiles are so convincing that a diagnosis of S´ezary syndrome/erythrodermic MF is erroneously made. Unlike the other forms of reactive cutaneous T cell infiltration, monoclonality is detected in almost 50% of cases; in two of our cases, identical T cell clones were identified at different biopsy sites (see Case Vignettes 6–8 and 10) and were procured at different times with the percent of the entire cell population occupied by the clone approaching 100%, a phenomenon that is more characteristic of fully evolved MF. We speculate that the transient cutaneous infiltrates are associated with a series of cytokine-driven events that recapitulate the pathways that lead to T cell infiltration as seen in MF. It would appear that these infiltrates evolve not through a response to the drug hapten per se but rather from drug-associated immune perturbation. It has been hypothesized that these drugs abrogate T suppressor function, leading to overzealous proliferative responses of T helper cells to various antigenic stimuli. The molecular sequela of such events is the emergence of a single or few dominant T cell clones. When the implicated drugs are discontinued, complete resolution is observed in some cases, but it is possible that those cases showing clonality have a greater risk of malignant transformation. Detection of T cell clonality and phenotypic aberrancy is not uncommon. Although both findings are encountered in MF, an alternative basis could be a state of antigen-driven T cell activation leading to emergence of dominant T cell clones responding to specific antigens. We have published separate series proving clonality and/or a restricted T cell repertoire in cases of drug-induced reversible T cell dyscrasia (Brady et al., 1999; Magro et al., 2003; Chen et al., 2004; Plaza et al., 2006). The infiltrates are more often polyclonal compared to cases of endogenous T cell dycrasia. We have used a variety of techniques to demonstrate clonality but find the greatest degree of sensitivity and specificity with TCR-β capillary size fragment analysis. In our experience, clonality or oligoclonality can occur although polyclonality is more common. The dominant clones may arise in a background that is more polyclonal than the minimal polyclonal background seen in cases of cutaneous T cell lymphoma. Nevertheless, we have seen cases where a dominant and/or persistent clone emerges over time and where the background is one of a minimal polyclonal T cell population. Clearly, these cases have to be carefully followed due to the potential for evolution to overt MF. In this regard, we have now at least one case of granulomatous MF and two cases of thiazide-induced lymphomatoid dermatitis progressing to classic MF in one and

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pre-S´ezary syndrome (idiopathic erythroderma) in another. (Case Vignettes 9, 10, 11, 12).

PATHOGENETIC BASIS OF LYMPHOMATOID DRUG REACTIONS The list of implicated drugs is growing and includes minocycline and its analog erythromycin, antidepressants, aromatic anticonvulsants, antihistamines, antihypertensive agents including β-blockers, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers α-antagonists, and lipidlowering agents (Carr et al., 1994; Greaves, 1995; Koopmans et al., 1995; Crowson and Magro, 1999a, b; Crowson and Magro, 2001; Metry et al., 2001; Crowson, 2004). In vitro studies have shown suppression of T cell function with antihistamines, β-blockers, antidepressants, lipid-lowering agents, sex steroid related drugs, and calcium channel blockers (Grier and Mastro, 1985; McMillen et al., 1985; Weedon, 1992; Zurcher and Krebs, 1992; Teraki et al., 1994; Tham et al., 1996; Young et al., 1996; Chan and Tan, 1997; Crowson and Magro, 1997; Pelicano et al., 1997; Russell et al., 1997; Weedon, 1997; Mahoob and Haroon, 1998; Kulling et al., 1999; Bong et al., 2000; Magro and Crowson, 2000; Hamamoto et al., 2001; Crowson et al., 2003). The question arises as to why an apparently aberrant phenotype should emerge in what is essentially a benign condition, namely, transient drug-associated cutaneous lymphoid atypia. The loss of CD7 and CD62L is not really due to an aberrant phenotype per se but rather reflects the intrinsic properties of the reactive cell population that undergoes expansion in the setting of underlying iatrogenic immune dysregulation. There are subpopulations of reactive T lymphocytes that do not express CD7 or CD62L (Leenutaphong and Manuskiatti, 1996; Hindioglu and Sahin, 1998); they comprise memory T cells and T cells proliferating in response to antigenic stimulation. The expression of CD7 and CD62L by lymphocytes correlates inversely with HLADR expression. L-selectin is expressed on blood monocytes, blood neutrophils, subsets of natural killer cells, and T and B lymphocytes, including those of na¨ıve phenotype, but not cells of Th1 memory subtype (Roujeau et al., 1991), and is shed from the surface of activated leukocytes. Hence, T lymphocytes lacking both CD7 and CD62L would be expected in type IV antigendriven inflammatory processes. Selective expansion of CD4+CD7− lymphocytes has been observed in

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certain immune dysregulatory states, namely, HIV disease (Moreau et al., 1995), rheumatoid arthritis (Katagiri and Takayasu, 1996), and following bone marrow and renal transplantation (Blodgett et al., 1997; Park et al., 1997). In contrast, the absence of surface and/or cytoplasmic expression of other pan T cell markers, namely, CD2, CD3, and CD5, would be more indicative of an aberrant phenotype suggestive of ensuing neoplasia. Given the effects of the drugs on immune function, it is likely that the diminution in CD7 and/or CD62L expression reflects excessive expansion of memory T cells responding to antigen due to abrogation of T suppressor function. One study of antigen-driven T cell lymphoid hyperplasia correlated the degree of nuclear contour irregularity with the loss of CD7 and/or CD62L and not with a diagnosis of MF per se (Condon et al., 1998). It is possible that memory and/or activated CD7-ve and CD62L-ve lymphocytes show inherent nuclear contour irregularity. Another phenotypic clue to antigenic stimulation may be the presence of a significant number of CD30- and CD4-expressing lymphocytes accentuated around blood vessels and acrosyringia, both sites of preferential antigen processing (Magro and Crowson, 1996). Large atypical CD30-positive T lymphocytes in a perivascular array were described in the setting of carbamazepine therapy (Nathan and Belsito, 1998). There was a report of a postchemotherapy CD30+/CD4+ lymphomatoid vasculopathy developing in a patient with acute myelogenous leukemia, in whom lesions resolved following cessation of the chemotherapy infusion (Su and Duncan, 2000). We have encountered similar cases in the context of drug associated reversible T cell dyscrasias (Plaza et al., 2006). (See Case Vignettes 9–11.) The differential diagnosis of this reaction pattern is primarily with type A lymphomatoid papulosis, a lymphoproliferative syndrome that also exhibits pan T cell marker deletion, a dominance of CD4- and CD30-positive lymphocytes, and clonality. While clonal rearrangement of the TCR gene is a feature held to be characteristic of MF (Knowles, 1989; Bergman et al., 1998), there are reports describing clonal TCR rearrangement in T cell pseudolymphomata (Landa et al., 1993; Brady et al., 1999). Studies have not shown clonality in this setting (Henni et al., 1988). However clonality in this non-neoplastic setting has been shown using the sensitive denaturing gradient gel electrophoresis PCR and Southern blot analysis of the TCR-β chain and more recently TCR-β capillary size fragment analysis (Landa et al., 1993; Brady et al., 1999; Plaza et al., 2006). Although pseudolymphomatous infiltrates related to drug therapy

have long been recognized, it was formerly assumed that such infiltrates could be distinguished from MF by virtue of a normal phenotype and the absence of clonality. We coined the terms reversible lymphoid dyscrasia and reactive clonal lymphomatoid dermatitis of memory and activated T cells to described atypical clonally restricted T cell infiltrates that resolve following drug cessation. Closely related to this concept are socalled reversible lymphomas seen in the setting of combined iatrogenic and endogenous immune dysregulation (Wood et al., 1990; Burns et al., 1992; Harmon et al., 1996; Moseley et al., 2000) in patients with Crohn’s disease, dermatomyositis, and rheumatoid arthritis receiving cyclosporine, azathioprine, methotrexate, and/or prednisone (Shiroky and Newkirk, 1993; Viraben et al., 1994; Vassilopoulos et al., 1998; Moseley et al., 2000). The designation ‘‘reversible lymphoma’’ seemed justified as the apparently malignant lymphoid infiltrates resolved with cessation of immunosuppressive therapy. (Kamel et al., 1993; Larvol et al., 1994; Viraben et al., 1994; Vassilopoulos et al., 1998).

REACTIVE LYMPHOMATOID LESIONS ENCOUNTERED IN LESIONS OF COLLAGEN VASCULAR DISEASE Lymphomatoid Lupus Erythematosus Dense lymphoid infiltrates in concert with variable cytological atypia of lymphocytes can be observed in lesions of lupus erythematosus (LE) but do not usually signify progression to lymphoma (Friss et al., 1995; Magro et al., 1997). (See Case Vignettes 12 and 13.) Clinically, the lesions are within the spectrum of discoid LE (DLE), subacute cutaneous LE (SCLE), and lupus erythematosus profundus. There are four primary light microscopic patterns encompassing lymphomatoid LE. One is characterized by dense lymphoid infiltrates in a perifollicular and perivascular array with minimal involvement of the interfollicular epidermis, a pattern we designate as folliculotropic lymphomatoid DLE (Magro et al., 1997). The two characteristic clinical presentations are indurated follicular based papules in the malar area and infiltrative transient urticarial plaques involving the upper back and anterior chest. The second histological presentation resembles lichenoid SCLE; however, the band-like infiltrate is of greater intensity, there are foci of striking epitheliotropism, and

Reactive Lymphomatoid Lesions Encountered in Lesions of Collagen Vascular Disease

numerous S´ezary cells are present; clinically, the lesions are typical of SCLE. The third picture is one that mimics an angioimmunoproliferative lesion by virtue of dense angiocentric lymphoid infiltrates accompanied by thrombosis (Harrist et al., 1982; Magro et al., 1997). The lymphocytes are atypical, manifesting polylobated nuclear contours. Usually this pattern is accompanied by an interface dermatitis resembling either DLE or SCLE; lesions also resemble DLE or SCLE on clinical grounds. We have encountered cases of idiopathic perniosis or secondary perniosis misinterpreted as representing a form of angiocentric T cell lymphoma in the clinical setting of purpuric acral nodules in a young woman (Crowson and Magro, 1997). Lymphomatoid vasculitis (Harrist et al., 1982; Magro et al., 1994) is also a characteristic finding seen in patients with lupus erythematosus profundus; this pattern is problematic as regards its distinction from panniculitis-like T cell lymphoma. The final pattern comprises dense infiltration of the fat lobule by lymphocytes with variable lymphoid atypia and fat necrosis; such lesions are categorized as lupus erythematosus profundus and are considered separately. (See Case Vignettes 12 and 13.) (Magro et al., 2004).

Pathogenesis of Lymphomatoid Tissue Response in Collagen Vascular Disease The concept of the restricted T cell repertoire is well established in a variety of autoimmune disorders including rheumatoid arthritis, multiple sclerosis, and LE. For example, clonal expansion of T cells has been observed in murine LE models. In one study using reverse transcription–polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP) analysis, the authors were able to identify identical T cell clonotypes expanding and accumulating in different organs (i.e., kidneys, brain, lung, and intestine) in affected mice (Zhou et al., 2004). The authors concluded that these clonotypes recognized restricted T cell epitopes on autoantigens involved in specific immune responses of SLE. In another study employing a transgenic murine model for rheumatoid arthritis, the authors were able to identify a progressive dominance of certain T cell clones within the synovium as the mice developed more advanced disease (Kobari et al., 2004). In a third study examining the nature of the T cell infiltrate in inclusion body myositis via a reverse transcriptase–PCR methodology, the authors found clonal restriction of TCR gene expression in muscle–infiltrating lymphocytes whereby identical T cell clones predominated in different muscles with a persistence of clones over years (Muntzing et al.,

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2003). Patients with multiple sclerosis have a few expanded T cell clones that remain constant over time and recognize immunodominant myelin basic peptides (Wucherpfennig and Hafler, 1995). A constant T cell clonotype responding to select and persistent antigen, which remains conserved over time, is a defining feature of the autoimmune diathesis and of the organ dysfunction that emanates from this immune response.

Lupus Erythematosus Profundus Clinical Features Lupus erythematosus profundus (LEP) is a distinctive cutaneous marker of LE that characteristically affects the head and neck area, particularly the cheeks, the upper arms, trunk, thigh, and buttocks (Watanabe et al., 1993) (See Case Vignette 13). It may cause diagnostic confusion with panniculitis-like T cell lymphoma and the more recently described entity of atypical lymphocytic lobular panniculitis (Magro et al., 2004). These conditions are discussed in separate chapters. The clinical presentation of LEP is as tan to violaceous plaques mainly afflicting women in the third to fifth decades of life (Rowell and Goodfield, 1992), although LEP may also be seen in infancy. Lesions are typically symmetrical, may ulcerate, and generally heal with atrophy. Lupus erythematosus profundus may herald the onset of LE or occur in isolation. In most instances, it occurs simultaneously with other cutaneous and extracutaneous manifestions of LE. While LEP was, in an earlier era, held to represent a manifestation of DLE confined to the skin (Prysher et al., 1955), other studies have shown LEP to occur with roughly equal frequency in the setting of SLE (Tuffanelli, 1971, 1982, 1985; Sanchez et al., 1981; Izumi and Takiguchi, 1983). A recent study indicates a low frequency of association with SLE and a paucity of serologic abnormalities typically associated with a connective tissue disease diathesis (Martens et al., 1999); 50% of patients had no other clinical features of LE (Martens et al., 1999). Pediatric patients with antiphospholipid antibody syndrome and/or hereditary complement deficiency (Nousari et al., 1999) may present with LEP. Lupus erythematosus profundus affects approximately 1–2% of patients with LE (Prysher et al., 1955; Tuffanelli, 1971, 1982, 1985; Sanchez et al., 1981; Watanabe et al., 1993). Histomorphology Biopsies of LEP show infiltration of the subcutaneous fat lobule by lymphocytes, histiocytes, and plasma cells with interposed zone of granular necrobiotic alteration. Nodules of centroblasts and

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centrocytes with admixed tingible body macrophages recapitulate lymphoid follicles (Harris et al., 1979). The histiocytes include those whose cytoplasms contain nuclear debris and others with serpentine nuclear contours (Magro et al., 2001), which on occasion aggregate to form areas of granulomatous inflammation adjacent to the septa in LEP (Sanchez et al., 1981). Endothelial necrosis, segmental deposits of fibrin, occlusive luminal thrombi of interstitial capillaries and venules, and obliterative lymphocytic angiotropism may be seen, suggesting that a microangiopathy is integral to the histopathology (Sanchez et al., 1981; Izumi and Takiguchi, 1983). It has been our experience that a significant percentage of cases of LEP will manifest lymphoid atypia and strikingly intense lobular infiltration of the panniculus, making the light microscopic distinction from subcutaneous T cell lymphoma (now called panniculitis-like T cell lymphoma) difficult. We have also found that features traditionally associated with LEP, such as extensive lobular fat necrosis, histiocytes containing engulfed nuclear debris, and vasculitis, are common in lesions of panniculitis-like T cell lymphoma (Magro et al., 2001). There are useful features that should aid in the distinction from panniculitis-like T cell lymphoma. For example, erythrocyte phagocytosis, a hallmark of panniculitis-like T cell lymphoma, is rare or absent in LEP. The overlying epidermis often shows classic changes of DLE, namely, a destructive interface dermatitis. Interstitial mucin deposition is not a discriminating feature since this finding is not uncommon in both lesions of panniculitis-like T cell lymphoma and atypical lymphocytic lobular panniculitis. Another useful feature is one of germinal center formation. While it is characteristic for LEP, it is not a feature of panniculitis-like T cell lymphoma (Harris et al., 1979; Magro et al., 2001). From a phenotypic perspective, the infiltrates within the panniculus are a mixture of B and T cells with a predominance of T cells that are mainly of CD4 subtype. Granzyme-expressing cytotoxic T cells of either null cell or CD8 phenotype are uncommon. By the TCR-β PCR technique, a restricted T cell repertoire is characteristic. Using the less sensitive TCR-γ methodology, clonality is not uncommon. (See Case Vignett 13.) Immunofluorescent Studies In our hands, a positive lupus band test in cases of LEP is seen in two settings: (1) when the skin biopsy shows concomitant interface changes and (2) when the LEP lesion arises in concert with symptomatology indicative of SLE (Magro et al., 2001).

Viral-Associated Lymphomatoid Dermatitis Viruses can be associated with unusual cutaneous lymphoid infiltrates either representing direct viral infection, such as by herpes virus, or an id response to viral antigen (See Case Vignette 8). The classic viruses are hepatitis C, parvovirus B19, and Epstein–Barr virus. Only in the setting of herpes infection can specific cytopathic changes be seen, such as in folliculocentric herpes. The infiltrates are lymphocytic and granulomatous in nature. The histiocytes usually have a twisted or serpentine nuclear configuration. The lymphocytes also include a number of transformed cells. The clue to recognizing the herpetic etiology in the absence of viral cytopathic change is the extent of infiltration around the vessels, eccrine coil, and nerves. There is usually some degree of tissue neutrophilia. Viral id responses express varied morphology, but common in such cases are subtle interface change and hemorrhage. A recent case was in the context of a liver transplant recipient with mixed cryoglobulinemic vasculitis in whom there was a background of leukocytoclastic vasculitis with a superimposed lymphomatoid vascular reaction mimicking an angioimmunoproliferative lesion. The molecular profile showed a maintained restricted repertoire from two different biopsies performed at two different points in time. The lesions resolved with a reduction in immunosuppression.

Lymphocytoma Cutis Lesions of lymphocytoma cutis typically present as solitary violaceous plaques (See Case Vignettes 2,3,5, and 8). The alternative appellation is one of Speigler–Fendt lymphocytic infiltrate. Although a solitary lesion may define the extent of the disease process, some patients may have multiple lesions that follow a waxing and waning course. These lesions may not undergo spontaneous resolution, especially those with a facial predilection; the classic scenario is a persistent nodule on the tip of the nose (see Figure 5.1). A variety of triggers have been associated with lymphocytoma cutis including drug therapy, and infections such as molluscum contagiosum, human immunodeficiency virus, hepatitis C virus, and Borrelia sp. Progression to lymphoma has been observed, representing, in most cases, low-grade B cell lymphoma (Breza and Magro, 2006) (See Case Vignettes 3 and 8). The pathogenetic basis is that of excessive lymphoid hyperplasia in response to an antigenic trigger in a patient with an inherent endogenous and/or

Reactive Lymphomatoid Lesions Encountered in Lesions of Collagen Vascular Disease

iatrogenic immune dysregulatory state (Raymond and Goldman, 1988; Henderson and Shamy, 1990; Crowson and Magro, 1995a, b; Gosain et al., 1995; Ploysangam et al., 1998; Braun et al., 2000; Gilliam and Wood, 2000; Grange et al., 2002). Light Microscopic Findings There is a diffuse and/or nodular pan dermal lymphocytic infiltrate. The infiltrate may be accentuated superficially with a gradual diminution as the base of the biopsy is approached, or, less often, is dominant in the deep dermis or subcutis. Small mature lymphocytes, scattered granulomata, and germinal centers of variable size with many tingible body macrophages are frequent, as are mitoses (Grange et al., 2002; Gilliam and Wood, 2000; Crowson and Magro, 1995b; Luelmo et al., 1992). Phenotypic Profile There is an overwhelming dominance of T cells over B cells. A dominance of B cells over T cells or an equal ratio of T to B cells would be a feature suspicious for marginal zone lymphoma or follicle center cell lymphoma. The T cells most often show a normal phenotype without loss of CD2, CD3, CD7, and/or CD62L expression. In the setting of drug therapy, we have seen cases showing some diminution in expression of CD7 and CD62L, although never to the degree observed in primary cutaneous pleomorphic T cell lymphoma. The B cells show a normal phenotype; the germinal centers exhibit weak expression of CD10 and no bcl-2 expression apart from a few small lymphocytes infiltrating them; the centrocytes and centroblasts are typically bcl-2 negative. There should be relative preservation of the CD23- and CD21staining dendritic network. CD30-positive cells are seen throughout the infiltrate; these may be atypical and may be difficult to determine whether they are B or T cells. Expression of CD20 and CD79 stains should be roughly equivalent. Extensive CD20 expression by cells showing loss of CD79 expression may be indicative of an aberrant B cell phenotype suggestive of B cell neoplasia (Arai et al., 2005). In situ hybridization studies for kappa and lambda are an important part of the evaluation; equal kappa and lambda expression may imply an emerging lambda light chain-restricted population, potentially indicating a B cell lymphoma. A mixture of kappa and lambda staining cells with a dominance of kappa expression should be a reassuring sign that a B cell lymphoma is unlikely. Clonality Studies We typically obtain both immunoglobulin heavy chain and TCR-β gene rearrangement studies.

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T cell clonality is not uncommon especially if there is a substantial polyclonal background, but such cases must be carefully evaluated and followed. A heavy chain immunoglobulin rearrangement would be worrisome for a B cell lymphoproliferative disorder and in those cases the lesions are either better reclassified as B cell lymphomas and/or it is stated that a diagnosis of low-grade B cell lymphoproliferative disease cannot be excluded (Landa et al., 1993; Jeng et al., 1996; Holm et al., 2002).

Primary Cutaneous Plasmacytosis Primary cutaneous plasmacytosis is a rare entity with only a few reported cases in the literature. The patients may present with solitary or multiple lesions, manifesting an infiltrative quality with a brownish hue (Aso and Shimao, 1982; Ishii et al., 1984). Facial involvement has been described. Many of the cases reported are in Japanese patients. Polyclonal hypergammaglobulinemia is a frequent serologic accompaniment. Because some cases show a concomitant endocrinopathy, most typically hypothyroidism, a parallel with Castleman’s disease and POEMS syndrome has been described. Both of these entities are discussed in greater detail in Chapter 7. In our experience, patients may exhibit a clinical presentation more analogous to mucosal based plasmacytosis as seen within the spectrum of Zoon’s balanitis circumscripta plasmacellularis and plasma cell orofacialis. Some cases have been successfully treated with topical photodynamic therapy and combination chemotherapy (Carey et al., 1998; Tada et al., 2000; Tzung et al., 2005). Light Microscopic Findings The lesions have many features in common with the idiopathic mucosal-based plasmacytosis entities, namely, Zoon’s balanitis and Zoon’s vulvitis. The infiltrate is very dense, almost effacing the dermal architecture. Scattered plasma cells containing hemosiderin are noted. Iron pigment deposition is a characteristic feature encountered in the mucosal based plasmacytic infiltrates of Zoon’s vulvitis and balanitis. In situ hybridization studies show a mixture of kappa- and lambda-expressing plasma cells, always with a kappa predominance. The kappa to lambda ratio should not exceed 5:1. The differential diagnosis would primarily be with plasmacytoma and plasmacytic marginal zone lymphoma. It is interesting to note that a dominance of lambda is quite frequent in primary cutaneous lesions of plasmacytic marginal zone lymphoma. Any equalization of the kappa to lambda ratio would in fact suggest an emerging lambda light chain restricted plasmacytic

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infiltrate and hence would not support a diagnosis of idiopathic primary cutaneous plasmacytosis.

CONCLUSION Lymphoid atypia in skin biopsies is not uncommon and more often reflects a reactive state than an endogenous T cell dyscrasia. While it is critical to correlate the pathological assessment with the clinical circumstances, the extent of lymphoid atypia impacts the diagnostic assessment; excessive lymphoid atypia qualitatively and quantitatively may indicate a lymphoma, while mild lymphoid atypia points more toward a reactive state. Clonal restriction and preservation of T cell clones over time and at different sites is often indicative of an endogenous T cell dyscrasia but is not the sine que non of malignancy or even of a dyscrasia per se. Clonal restriction in

the setting of drug hypersensitivity should lead the practitioner and patient to be more aggressive regarding drug modulation. While the atypical lymphoid infiltrates attributable to drug therapy or to other inciting triggers should regress with withdrawal of the antigen, any recalcitrant lymphocytic dermatitis unrelated to an identifiable trigger must be considered a form of probable endogenous cutaneous lymphoid dyscrasia. Lymphomagenesis represents a stepwise progression commencing with chronic immune stimulation coupled with immune dysregulation; we postulate that the activation state of lymphocytes may confer biological instability to an infiltrate, from which a state of irreversible lymphoid dyscrasia could develop. Thus for example, patients with rheumatoid arthritis may develop primary juxta-articular lymphoma in the vicinity of inflamed joints (Goodlad et al., 1996).

Case Vignette 1

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 40 year old woman with a recent diagnosis of primary cutaneous CD30- large cell T cell lymphoma who developed a generalized rash on her extremities and trunk following antimicrobial therapy. Diagnosis: Drug associated lymphomatoid hypersensitivity reaction in the setting of underlying endogenous immune dysregulation (Figures 5.4 and 5.5).

FIGURE 5.4 There is an interface dermatitis in association with a superficial angiocentric lymphocytic infiltrate.

Higher power magnification reveals pleomorphism of the angiocentric infiltrate. The cells are in the 20–30 µm size range. Given the temporal association between initiation of drug therapy and lesional onset, a diagnosis was rendered of lymphomatoid drug reaction. A lymphomatoid hypersensitivity reaction may be a sign of underlying endogenous immune dysregulation, which in this case is clearly in the context of the patient’s peripheral T cell lymphoma. The patient died 6 months later of her lymphoma. Lymphoid atypia does not always mean lymphoma; however, it may suggest an iatrogenic and/or endogenous immune dysregulatory state. FIGURE 5.5

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CASE VIGNETTE 2

The patient developed generalized lymphadenopathy followed by the development of multiple skin nodules. Lymph node examination along with bone marrow assessment revealed a reactive process. Serum protein immunoelectrophoresis was also negative. The onset was temporally associated with hydrochlorothiazide therapy. Diagnosis: A form of reactive lymphoid hyperplasia (lymphocytoma cutis-like) manifesting dominant localization to the fat in a fashion mimicking panniculitis-like T cell lymphoma (Figures 5.6 and 5.7).

The biopsy shows striking lymphocytic infiltration of the panniculus. However, the pattern of infiltration is a nodular one, which is unusual in the realm of neoplastic infiltrates that involve the fat. More characteristically, a diffuse pattern of infiltration is observed in panniculitis-like T cell lymphoma.

FIGURE 5.6

(a)

(b)

Phenotypic studies reveal that the infiltrate exhibits a zonation pattern with respect to lymphocyte subset composition. Peripherally, the cells are dominated by CD3-positive T cells while central zones of nodularity are dominated by CD20-positive B lymphocytes. This particular orderly pattern of distribution of lymphocyte subpopulations is characteristic for reactive lymphoid hyperplasia. In essence, it recapitulates the B-cell-rich germinal center and paracortical T cell distribution of a normal lymph node.

FIGURE 5.7

Case Vignette 3

CASE VIGNETTE 3

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The patient is a 48 year old woman with a longstanding history of depression. She had been on fluoxetine for several years. More recently she developed an infiltrative plaque, which was biopsied. Diagnosis: Classic ‘‘nodular’’ lymphocytoma cutis in the setting of antidepressant therapy (Figures 5.8–5.11).

FIGURE 5.8

A dense nodular infiltrate assumes a greater density of infiltration toward the lesional base. One could argue that such changes are more in keeping with marginal zone lymphoma. However, there are exceptions as exemplified by this case. One might be more cautious regarding a definitive interpretation as lymphocytoma cutis and recommend careful clinical follow-up.

FIGURE 5.9

Higher power magnification reveals that the infiltrate is predominated by small mature lymphocytes.

FIGURE 5.10 Phenotypic studies demonstrate a composition comprising a mixture of T and B cells. As noted with the earlier case, there is a distinctive zonation pattern in the distribution of the T and B cells. The CD3-positive T cells are distributed peripherally, while the B cells are positioned more centrally in the nodules as illustrated in Figure 5.11 (CD3 immunostain.)

FIGURE 5.11

The B cells assume a central disposition within the nodules (CD20 immunostain.)

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CASE VIGNETTE 4

The patient is a 53 year old woman who presented with irritation involving the entire body. The clinical differential diagnosis was one of drug reaction versus cutaneous T cell lymphoma. Molecular studies revealed a polyclonal pattern. The rash resolved with drug cessation. Diagnosis: Drug-associated lymphomatoid hypersensitivity with lichenoid and lymphomatoid features (pseudo-mycosis fungoides-like) (Figures 5.12–5.16).

The biopsy shows a band-like lymphocytic infiltrate lying in intimate apposition to the epidermis. There are destructive epithelial changes with prominent lymphocyte satellitosis around necrotic keratinocytes.

FIGURE 5.12

(a)

(b)

Higher power magnification reveals that a number of the lymphocytes have an atypical cerebriform appearance. Occasional eosinophils are also present in the background.

FIGURE 5.13

Case Vignette 4

Higher power magnification shows cerebriform lymphocytes within the epidermis. However, note the concomitant destructive epithelial changes.

FIGURE 5.14

There is no loss of CD7, which would be an exceptional finding in the realm of cutaneous T cell lymphoma. FIGURE 5.15

FIGURE 5.16 This CD4 stain shows that the majority of the lymphocytes are of the CD4 subset.

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CASE VIGNETTE 5

The patient is a 58 year old man who presented with a nodule on the chest. The patient was on antihistamines for seasonal allergies for several years. He ingested antihistamines daily. Diagnosis: T-cell-rich lymphocytoma cutis (Figures 5.17–5.19).

FIGURE 5.17 The biopsy shows a superficial and deep nodular infiltrate lying in close apposition to blood vessels, hair follicles, and the straight eccrine duct.

FIGURE 5.18 Higher power magnification reveals that the infiltrate is composed of a mixture of small mature lymphocytes with interposed larger cells in the 15–20 µm size range.

The infiltrate is dominated by T cells. Illustrated is a CD43 preparation.

FIGURE 5.19

Case Vignette 6

CASE VIGNETTE 6

79

The patient developed a generalized eruption. The clinical impression was one of cutaneous T cell lymphoma. The patient was on fluoxetine, duration unknown. Molecular studies revealed T cell clonality. A diagnosis was made of lymphomatoid hypersensitivity. Recommendation was made for drug cessation. The rash eventually resolved with no recurrence. Diagnosis: Clonally restricted drug-associated lymphomatoid hypersensitivity with features of the lymphomatoid vascular reaction pattern (Figures 5.20–5.22).

FIGURE 5.20 The epidermis showed changes of lichen simplex chronicus. The superficial vascular plexus demonstrated striking injurious alterations. A prominent angiocentric infiltrate is noted involving the superficial and deep dermis.

The infiltrate is predominated by small mature lymphocytes, some of which have a cerebriform appearance.

FIGURE 5.21

FIGURE 5.22 A few of the larger cells are CD30 positive. CD30 positivity is not uncommon in lymphomatoid hypersensitivity reactions. Characteristically, the CD30-positive cells are found in the superficial dermis as opposed to endogenous CD30 lymphoproliferative disease (i.e., lymphomatoid papulosis), where the CD30 cells are also apparent in the deeper aspects of the biopsy.

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CASE VIGNETTE 7

A 49 year old African American man with a longstanding history of eczema presented with multiple hyperpigmented and hypopigmented plaques—subacute eczematous dermatitis with lymphomatoid features. Given the history of drug ingestion with immune dysregulating agents, a diagnosis of lymphomatoid hypersensitivity with eczematous features was made. We recognize that some cases of MF may arise in a background of atopic dermatitis and hence show a mixed picture with a background pattern reminiscent of eczema. In this case, there was neither clonality nor any phenotypic abnormalities. Diagnosis: Polyclonal drug-associated lymphomatoid hypersensitivity reaction (Figures 5.23 and 5.24).

(a)

(b)

The biopsy shows an eczematoid reaction characterized by psoriasiform hyperplasia with directed migration of lymphocytes into the epidermis, and vertically oriented collagen bundles.

FIGURE 5.23

(a)

(b)

FIGURE 5.24 There are a number of small cerebriform lymphocytes within the epidermis and dermis. There is no enhanced atypia in regard to the cells within the epidermis compared to those in the dermis. In addition, a significant large cell component is not identified.

Case Vignette 8

CASE VIGNETTE 8

81

The patient is a 1 year old boy who developed a plaque on the cheek in October 2005. The plaque was temporally associated with an upper respiratory tract infection. The patient’s history was remarkable for multiple episodes of otitis media and hypersensitivity to nuts. There was a dominance of T cells, which were phenotypically normal. Molecular studies revealed T cell clonality. Diagnosis: Clonally restricted T-cell-rich diffuse lymphocytoma cutis (Figures 5.25–5.31).

The biopsy shows a diffuse pandermal lymphocytic infiltrate.

FIGURE 5.25

(a)

(b)

Higher power examination reveals an infiltrate comprising small mature lymphocytes with admixed cohesive collections of histiocytes. FIGURE 5.26

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CASE VIGNETTE 8

(Continued)

FIGURE 5.27 The CD3 preparation shows extensive staining throughout the dermis for CD3.

FIGURE 5.28 The CD20 preparation shows a number of positive staining B lymphocytes including in the context of those assuming a nodular staining pattern at the base of the biopsy specimen.

FIGURE 5.29

sion.

There is preservation of CD62L expres-

FIGURE 5.30

sion.

There is preservation of CD7 expres-

Case Vignette 8

S05-59271 TCR beta Panel A

TCR beta Panel B

TCR beta Panel C

T cell clonality can be seen in lesions of T cell rich lymphocytoma cutis. Molecular studies reveal a dominant T cell peak amid a polyclonal background in panel B compatible with monoclonal T cell population. The case is illustrated in Figures 5.25–5.30. (Molecular gel and interpretation provided by Dr. Carl Morrison.) FIGURE 5.31

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CASE VIGNETTE 9

The patient is a 50 year old woman with a one week history of an intensely pruritic photodistributed rash. The patient was on dilantin. Diagnosis: Clonally restricted drug associated lymphomatoid vascular reaction with numerous CD30 positive staining cells (Figure 5.32).

Panel A peak 253

Panel B minimal polyclonal background

peak 257

Panel C

peak 181

minimal polyclonal background

The molecular profile is an excellent example of how lymphomatoid drug reactions can produce a molecular profile that simulates lymphoma. In this case, the clinical and light microscopic findings were compatible with a drug-associated photoreaction manifesting photoirritant changes, an interface dermatitis, and a concomitant markedly atypical lymphomatoid vascular reaction, the latter showing numerous CD30-positive cells with preservation of CD7 expression. The molecular profile showed a monoclonal T cell population amid a polyclonal background (base pair fragment sizes of 253, 257, 181). The clonally restricted populations are likely largely derived from those around the blood vessels. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

FIGURE 5.32

Case Vignette 10

CASE VIGNETTE 10

85

The patient is a 75 year old man with multiple infiltrative plaques and nodules on the face temporally associated with IDEC/152 Lumilixamb therapy for chronic lymphocytic leukemia. The biopsy showed a very atypical T-cell-rich lymphomatoid follicular reaction with follicular mucinosis. Diagnosis: Clonally restricted drug-associated follicular mucinosis in the setting of underlying chronic lymphocytic leukemia (Figure 5.33).

Panel A

peak 258

Panel B peak 272 minimal polyclonal background

Panel C

peak 178

minimal polyclonal background

The molecular studies showed a monoclonal population of T cells in a minimal polyclonal background (dominant base pair peaks of 178, 272, and 258), recapitulating a molecular profile seen in T cell lymphoma. The molecular profile is from a case of drug-associated follicular mucinosis. The patient’s underlying inherent immune dysregulatory state likely contributed to the development of this unusual clonally restricted T-cell-rich drug reaction. Patients with CLL are known hyper-responders to other stimuli; the most published examples of this concept are in the context of lymphomatoid responses that develop with insect bite reactions (see Chapter 11). The facial rash resolved with IDEC cessation. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

FIGURE 5.33

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CASE VIGNETTE 11

The patient is a 58 year old woman with a generalized pruritic rash of a few months’ duration. She was on Lipitor and a calcium channel blocker. A biopsy was performed to rule out lymphoma. Diagnosis: Clonally restricted lymphomatoid dermatitis favors reversible T cell dyscrasia over endogenous T cell dyscrasia (see Figure 5.34). Follow up recommended.

TCR beta Panel B

TCR beta Panel C

Dominant Peak 260 & 271 bp

Dominant Peak 191 & 195 bp

FIGURE 5.34 The molecular profile is from this case of drug associated reversible T cell dyscrasia. The biopsy light microscopically was quite characteristic for a lymphomatoid drug reaction showing a superficial nodular angiocentric lymphocytic infiltrate with numerous transformed cells around the vessels, minimal epidermal involvement, and sparing of the mid- and deeper dermis. There were no phenotypic abnormalities. However, the molecular studies showed a monoclonal T cell population in a minimal polyclonal background (dominant T cell clones with base pair sizes of 260, 271, 191, and 195). While a clonally restricted drug reaction was favored, additional biopsies were advised if there was lesional persistence after 8–9 months off the implicated drug or drugs. The rash eventually resolved. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

Case Vignette 12

CASE VIGNETTE 12

The patient is a 5 year old boy with multiple hypopigmented patches compatible light microscopically with a lichen sclerosus et atrophicus, morphea overlap. Diagnosis: Oligoclonal restricted T cell repertoire in the setting of collagen vascular disease (Figure 5.35).

FIGURE 5.35 In the setting of collagen vascular disease, a restricted T cell repertoire that is maintained over time can be observed. It does not necessarily imply a neoplastic process or lymphoid dyscrasia per se. It is established that a limited number of T cell epitopes leading to emergence of oligoclonal T cell populations is seen in the setting of autoimmune disease. The two molecular profiles performed a few weeks apart from two different sites in this young child with lichen sclerosus et atrophicus, morphea overlap are an excellent depiction of this concept. Specifically, there is an oligoclonal pattern amid a polyclonal background (the base pair size of the dominant peaks are listed). While there is commonality between the two profiles, there is an additional dominant clone in the latter sample (i.e., base pair size of 191) that is not present in the earlier case. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

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CASE VIGNETTE 13

The patient is a 38 year old woman with upper arm subcutaneous nodules characteristic for lupus profundus (see Figure 5.36).

TCR beta Dbeta-Jbeta panel

peaks 196 & 301

(a)

(b)

(c)

FIGURE 5.36 The molecular studies show two distinct populations of T cells amid a polycolonal background. Clonality can occur in lesions of lupus profundus. The biopsy shows a striking interstitial lymphocytic infiltrate within the fat. Germinal centers are also present although not illustrated. From a phenotypic perspective, the infiltrate is CD4 dominant. In atypical lymphocytic lobular panniculitis and panniculitis-like T cell lymphoma, germinal centers would be very uncommon and there would not be a dominance of CD4 lymphocytes as noted here. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

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PRECURSOR LESIONS OF CUTANEOUS T CELL LYMPHOMA Cynthia M. Magro, Joan Guitart and A. Neil Crowson

CUTANEOUS T CELL LYMPHOID DYSCRASIA The demonstration of clonal restriction of a T cell infiltrate by a molecular methodology was at one time held to be indicative of T cell lymphoma. It subsequently became apparent that there are many conditions that are not lymphoma but in which an emerging clonal population may be observed. While some of these conditions are completely benign, representing entities such as collagen vascular disease and/or drug hypersensitivity, there are those clonally restricted infiltrates, without a specific trigger, that follow a recurrent waxing and waning course whereby small percentage progress to cutaneous T cell lymphoma (CTCL). They encompass a select group of entities that include pityriasis lichenoides, pigmented purpuric dermatosis, syringolymphoid hyperplasia with alopecia, alopecia mucinosa, large plaque parapsoriasis, and idiopathic erythroderma. Inherent to this group of disorders, which we designate as cutaneous lymphoid dyscrasia (CLD), is a constellation of findings that comprise low grade lymphocytic atypia, persistent T cell clones and/or a restricted T cell repertoire, and phenotypic abnormalities that often include a reduction in CD7

and CD62L expression. While T cell clonal restriction is a feature characteristic of CTCL and CLD, it is also a feature of certain inflammatory conditions. The circumstances under which clonal infiltrates develop in the latter scenario, as opposed to CTCL and likely CLD, appear to be different. In particular, dominant T cell clones have been reported in other states of chronic immune stimulation, such as that seen in patients with multiple sclerosis, rheumatoid arthritis, inclusion body myositis, and lupus erythematosus, and in solid organ transplant recipients (Barrou et al., 1995; Gonzalez-Quintial et al., 1996; Hingorani et al., 1996; Masuko-Hongo et al., 1998; Shai et al., 1999; Sawabe et al., 2000; Bakakos et al., 2002; Muntzing et al., 2003; Zhou et al., 2004; Beck et al., 2005). In the latter setting, we have shown that T cell infiltrates in lung allograft biopsies are maintained over time and generate a reproducible restricted T cell repertoire. It has been shown in both experimental animal models and in humans that these T cell clonotypes expand and accumulate at various sites. The critical difference from both CTCL and CLD is the pathogenetic basis, which is one of a response to restricted T cell endogenous ‘‘self’’ epitopes such as immunodominant myelin basic peptide in the setting of multiple sclerosis or alloantigens in the setting of organ transplantation. While it is possible that the

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 93

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inciting trigger in all of the CLDs may have been a specific exogenous or endogenous neoantigen, what is established with reasonable certainty is the failure to demonstrate recognizable T cell epitopes, which could provide an ongoing stimulus for regulated T cell clonal expansion. The persistent T cell clones are maintained independent of normal immune regulatory mechanisms. We have seen cases of what initially appeared to represent a drug-induced reversible T cell dyscrasia develop into an irreversible state of T and/or B cell expansion. Perhaps the most florid example of a drug-triggered endogenous lymphoproliferative disease is angioimmunoblastic lymphadenopathy. The phenotypic abnormalities discussed under each of the CLDs is mainly loss of CD7 and CD62L expression, but as with the demonstration of clonality in immune-driven processes, a diminution in the expression of CD7 is a feature that can be seen in reactive states. Furthermore, there are subpopulations of benign reactive postthymic memory T helper lymphocytes that do not express CD7; such cells have been shown to accumulate preferentially in the skin (Moll et al., 1994; Liu et al., 2000). Endothelial cells manifesting upregulation of TNF-α (as would be seen in the setting of viral infection) demonstrate an increase in the expression of CD62L, the ligand of which is cutaneous lymphocyte related antigen (CLA), which is characteristically expressed by a subset of CD4+/CD7− T lymphocytes (Liu et al., 2000). These CLA-positive CD7-negative CD4-positive lymphocytes have been demonstrated in increased numbers in patients with rheumatoid arthritis, human immunodeficiency virus infection, and other autoimmune conditions, and in the setting of solid organ and bone marrow transplantation (Legac et al., 1992; Reinhold et al., 1993; Moll et al., 1994; Schmidt et al., 1996; Leblond et al., 1997). It has been established that there is a subpopulation of normal peripheral blood lymphocytes that are CD7 negative. As already mentioned, the other marker that shows a diminution in expression among the CLDs is CD62L, one of the selectins. While virgin T cells in human peripheral blood uniformly express CD62L, there is variation in the expression of CD62L among the memory T cell population. Although the vast majority of memory T lymphocytes homing to the skin in response to antigen are CD62L and CLA positive, they may be CD7 negative (Picker, 1993). The accumulation of cells in the dermis which are memory T cells that express neither CD62L nor CD7 defines a phenotypic profile that is more akin to CTCL than to an immune-based dermatosis.

What are the events that allow progression of persistent T cell clones in lesions of CLD to undergo neoplastic transformation in contradistinction to the rarity of such an event when regulated T cell clones respond to antigen? Is there a difference cytogenetically between these different forms of clonotype expansion that confer this increased risk? Does the additional phenotypic abnormality that defies the normal profile of a cutaneous homing T lymphocyte responding to antigen contribute to this enhanced risk? What are the endogenous regulatory mechanisms that maintain these persistent clonal infiltrates at a biologically insidious level in most cases? What allows these clones to persist and expand if there is no immune-based mechanism driving the clonal expansion? Specifically, what are the autochthonous cutaneous factors that maintain these cell populations? It is possible that patients with a proclivity for the development of CLD have some inherent genetic polymorphism that leads to a downregulation of T regulatory activity either because of a qualitative or quantitative defect in this cell population (i.e., the CD4 +/CD25+ lymphocyte)? For example, it has been shown that there is enhanced apoptosis of CD4+/CD25+ regulatory cells in the setting of autoimmune disease (Toubi et al., 2005). Although abnormalities in T cell regulatory activity have been implicated in a variety of neoplastic and inflammatory conditions, such aberrations in the evolution of CLD and CTCL have not been explored. T regulatory cells play a role in maintaining self-tolerance by downregulating Th1-induced proinflammatory effects (Zhai et al., 2001; Toubi et al., 2005). One could postulate that while there may be a reduction in the expression of CD4+/CD25+ regulatory T cells, the degree of diminution in lesions of CLD would be less than that encountered in the setting of CTCL. The role of T regulatory cells in the propagation of CTCL is currently being defined, but some authors view CTCL as a neoplasm T regulatory cells while others contend that only adult T cell leukemia/lymphoma is a true neoplasm of T regulatory cells (Berger et al., 2005; Kohno, 2005; Matsubara et al., 2005).

Large Plaque Parapsoriasis The original term parapsoriasis was introduced by Brocq in the early twentieth century to encompass a broad spectrum of disorders now termed seborrheic dermatitis, psoriasis, pityriasis rubra pilaris, lichen planus, mycosis fungoides, small plaque parapsoriasis, large plaque parapsoriasis, and pityriasis lichenoides (Murphy, 1953; Lambert and Everett,

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TABLE 6.1 Large Plaque Parapsoriasis Key Clinical Features Large irregularly bordered erythematous plaques commonly localized in a more symmetrical fashion. Site predilection: buttocks, major flexural surfaces, axillae, breasts. Quality of lesions: atrophic to slightly indurated. Asymptomatic or mildly pruritic. Light Microscopic Findings Epidermal thickness: variable hyperplasia to zones of attenuation. A superficial lymphocytic infiltrate. Epitheliotropism unaccompanied by significant epidermal changes apart from basilar vacuolar change and focal spinous layer dyskeratosis. Laminated pattern of fibroplasia Lymphocyte nuclear range is 7–9 µm with some nuclear contour irregularity and some hyperconvoluted nuclei. Infiltrate is predominated by CD4 lymphocytes. Diminution in CD7 and CD62L expression. May not be of the magnitude encountered in fully evolved lesions of mycosis fungoides. May be numerous supervening CD8 lymphocytes that are reactive. Molecular Studies Variable polyclonal, restricted repertoire and/or clonality.

1981; Lambert, 1985). All of these have emerged as distinct clinical and pathologic entities. Brocq’s classification addressed disorders whose etiology is even now unknown, and whose course is recalcitrant without proven curative therapies. Large plaque parapsoriasis (LPP) has a distinctive clinical appearance characterized by large irregularly bordered erythematous plaques commonly localized in a more symmetrical fashion, most often to the buttocks, major flexural surfaces such as the axillae, and, in females, the breasts. The lesions can range from atrophic patches with a cigarette paperlike scale to slightly indurated plaques. The lesions are either asymptomatic or mildly pruritic. Intense pruritus may be indicative of progression to lymphoma. Other features indicative of progression to mycosis fungoides include more extensive spread of lesions and elevation or transformation into a thick plaque or nodular lesion. Generalized pruritus has been reported with tumor transformation (see Table 6.1) (Simon et al., 2000). Light Microscopic Findings The epidermis shows hyperplasia and/or zones of attenuation with mild or moderate orthohyperkeratosis and variable parakeratosis. A mild to moderate superficial lymphocytic infiltrate in both a perivascular and interstitial pattern is present; superficially, the infiltrate coalesces to assume a band-like

disposition. There is epitheliotropism largely unaccompanied by significant epidermal changes apart from basilar vacuolar change and focal dyskeratosis. The papillary dermis exhibits a laminated pattern of fibroplasia. Edema is absent. At times there may be mid-dermal extension of the infiltrate whereby the dominant infiltration is an interstitial one, hence resembling an interstitial palisading granulomatous reaction. Cytologically, the lymphocytes are small (in the 7–9 µm size range) and manifest nuclear contour irregularity including a few cells with a frankly cerebriform appearance. Although there is focal colonization of the basal layer, prominent epitheliotropism and Pautrier’s microabscesses are absent. Other inflammatory cell elements such as plasma cells and eosinophils, which can be observed in mycosis fungoides, are noticeably absent (Lambert, 1985; Piamphongsant, 1988; Lazar et al., 1989; Simon et al., 2000). The infiltrate is dominated by CD4 lymphocytes manifesting a significant reduction in CD7 and CD62L expression. However, the extent of reduction is not of the magnitude encountered in fully evolved lesions of mycosis fungoides (Magro et al., 2005). The most atypical cells, especially those showing epidermotropism, are typically CD7 and CD62L negative. The truly clonal neoplastic cellular elements are likely those that do not express CD7 and CD62L, while the cell populace that does express these two pan T cell markers are probably reactive T cells that play a

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role in suppressing, or at least attenuating, the clonal proliferation. The other pan T cell markers, namely, CD3 and CD5, are characteristically preserved (Magro et al., 2005). The surveillance population is typically of the CD8 subset and hence it is not uncommon to see many CD8 lymphocytes in the epidermis and dermis. In a recent study utilizing multiplex polymerase chain reaction, we showed that 6 of 8 cases of large plaque parapsoriasis were monoclonal with a polyclonal background; two additional cases showed a restricted T cell repertoire. In two cases in which multiple biopsies were performed, the same molecular profile was observed at each of the different sites (unpublished observations). Such molecular findings would validate the concept that large plaque parapsoriasis is a form of CLD (see Figure 6.58). Differential Diagnosis It is important to distinguish large from small plaque parapsoriasis; that latter is likely not a form of CLD. It should be emphasized that some contend that small plaque parapsoriasis is an abortive form of T cell lymphoma (Burg and Dummer, 1995). Typically beginning in adulthood, patients manifest erythematous round to oval scaly patches about 1–2 centimeters in diameter on the trunk and/or extremities. With an oval contour, they have the approximate size and shape of fingerprints from the distal phalanges and thus the alternate appellation for this condition is ‘‘digitate dermatosis.’’ Lesions may be larger on the lower extremities (Hu and Winkelmann, 1973; Burg and Schmoeckel, 1992; Magro and Crowson, 1996). The face, palms, and soles are typically spared. An older lesion may, when compressed from the sides, show a wrinkling of fine, cigarette paper-like scale. Lesions may be more prominent in winter and tend to disappear in the summer. Histologically, there is mild acanthosis of the epidermis surmounted by a broad parakeratotic scale; a modest superficial perivascular dermal lymphocytic infiltrate is noted. The parallel fibroplasia typical of large plaque parapsoriasis is not seen; the epidermotropism characteristic of patch lesions of mycosis fungoides is absent. Cerebriform lymphocytes are not observed (Haeffner et al., 1995). It should be emphasized that there can be an overlap clinically with pityriasis lichenoides chronica. Phenotypic and molecular studies can be helpful in this distinction. Cases that truly represent digitate dermatosis/small plaque parapsoriasis should not manifest features characteristic for CLD, thus the absence of a monoclonal or oligoclonal molecular profile and of persistent T cell clones over time, as well as a normal phenotype without significant diminution of CD7 and CD62L, would be expected.

Hypopigmented Epitheliotropic T Cell Dyscrasia/Hypopigmented Large Plaque Parapsoriasis as a Precursor Lesion to Hypopigmented Mycosis Fungoides There are diverse clinical entities mediated by intraepidermal lymphocytes and clinically characterized by hypopigmentation, the latter a form of postinflammatory leukoderma due to antecedent and concurrent damage to melanin-containing keratinocytes and/or the result of aberrent melanin transfer to keratinocytes presumably related to the presence of intraepithelial lymphocytes. It some cases the hypopigmentation may be on the basis of true immune destruction of melanocytes, defining vitiligo (Cribier et al., 2000; Petit et al., 2003). The range of disorders that manifest lymphocyte mediated epidermal reactions include the interface dermatitis of collagen vascular disease, cytotoxic interface dermatitis reflective of type IV immunity to systemic exogenous antigen, eczematous dermatitis, small plaque parapsoriasis, large plaque parapsoriasis, and mycosis fungoides. The latter has fallen under the appellation of hypopigmented mycosis fungoides and manifests a characteristic race, sex, and age predilection. Patients are usually younger and of African American extraction; there is a female predilection (Figure 6.1) (Burns et al., 1992; Quaglino et al., 1999; Bouloc et al., 2000;

FIGURE 6.1 Hypopigmented cutaneous T cell dyscrasia. The patient is an 8 year old African American girl with a longstanding history of waxing and waning plaques on the face and axillae. The biopsy showed features of the so-called hypopigmented interface variant of cutaneous lymphoid dyscrasia. Such cases may be interpreted as representing hypopigmented mycosis fungoides. There is indeed a continuum between the hypopigmented interface variant of cutaneous lymphoid dyscrasia and hypopigmented mycosis fungoides. (Photograph by Dr. Kelley Gallina.)

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TABLE 6.2 Hypopigmented Epitheliotropic T Cell Dyscrasia/Hypopigmented Large Plaque Parapsoriasis Key Clinical Features Hypopigmentation. Younger and of African American extraction. Female predilection. Truncal areas. Light Microscopic Findings Low-density epitheliotropic lymphocytic infiltrate. Colonization of the basal layer unaccompanied by significant destructive epithelial changes; Pautrier’s microabscesses are not seen. Accentuation of migration to involve the follicles and acrosyringia Other inflammatory cell elements are lacking Phenotypic Studies Significant reduction in CD7 and CD62L. There may be a predominance of CD8 lymphocytes over those of the CD4 subset. Molecular Studies Restricted oligoclonal T cell repertoire.

Stone et al., 2001). The lesions often involve truncal areas similar to typical mycosis fungoides (Zackheim et al., 1982). While hypopigmented mycosis fungoides has been described, a hypopigmented variant of large plaque parapsoriasis as a precursor state has not been specifically alluded to in the literature (Bouloc et al., 2000). Many of the cases described in the literature do not manifest a clinical course or even a histology diagnostic of fully evolved mycosis fungoides (Lambroza et al., 1995; Ben-Amitai et al., 2003; Ardigo et al., 2003). Such cases are better characterized as a form of cutaneous lymphoid dyscrasia falling under the designation of hypopigmented large plaque parapsoriasis and/or hypopigmented epitheliotropic T cell dyscrasia (see Table 6.2) (Werner et al., 2005). ‘‘Hypopigmented mycosis fungoides is not always mycosis fungoides’’ (Werner et al., 2005). Light Microscopic Findings The histology comprises a low-density epitheliotropic lymphocytic infiltrate with characteristic colonization of the basal layer unaccompanied by significant destructive epithelial changes. The lack of epithelial injury distinguishes this process from a true immunologically mediated interface dermatitis. There is oftentimes a haphazard single cell pattern of lymphocyte migration into the upper layers of the epidermis. Pautrier’s microabscesses are not seen; the presence of such discrete aggregates of neoplastic lymphocytes in the epidermis would warrant categorization as mycosis fungoides. Many of the cells in the epidermis have a distinctly cerebriform appearance; a small cell dominant infiltrate predominates. There

may be some accentuation of migration to involve hair follicles and acrosyringia (Lambroza et al., 1995; Ardigo et al., 2003; Ben-Amitai et al., 2003). Phenotypic Studies There is a significant reduction in CD7 and CD62L expression; often CD62L shows a greater loss than CD7 (Magro et al., 2005). From a phenotypic perspective there may be a predominance of CD8 lymphocytes over those of the CD4 subset. If the CD8 lymphocytes are reactive and induce lesional resolution, and/or contribute to immunologic surveillance to prevent disease progression, one would expect to see greater epithelial injury of bystander keratinocytes as the basis for the leukoderma (Dummer et al., 2002; El-Shabrawi-Caelen et al., 2002). Molecular Studies We have studied similar cases and have observed the same restricted oligoclonal T cell repertoire between biopsies, adding credence to the designation of these cases as forms of CLD (see Figure 6.55).

Pigmented Purpuric Dermatosis (PPD) Pigmentary purpura is a term used to describe a heterogeneous group of disorders that share petechiae and bronze discoloration of the skin with predominant but not exclusive localization to the legs (Figures 6.2 – 6.5) (Simon, 1992). There are a variety of clinical subsets, including Schamberg’s disease, Majocchi’s purpura, Gougerot–Blum purpura, lichen aureus (Figure 6.4), the eczematoid purpura of Doucas and Kapetanakis, and atypical pigmentary purpura

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FIGURE 6.2 Pigmented purpuric dermatosis. The patient is a 68 year old man with a longstanding history of pigmented purpuric dermatosis. Illustrated are classic lesions of pigmented purpura. Note the petechial quality of the lesions.

FIGURE 6.3 Pigmented purpuric dermatosis. The patient illustrated in Figure 6.2 developed progressive disease eventuating in mycosis fungoides.

(Price et al., 1985; Kim et al., 1998; Crowson et al., 1999; Hale, 2003). Cayenne pepper-like spots are characteristic of Schamberg’s disease. Multiple reddish annular patches or plaques are seen on the buttocks, trunk, and proximal extremities in Majocchi’s purpura annularis telangiectoides (see Table 6.3) (Hale, 2003). Lichen planus-like papules with superimposed

FIGURE 6.4 Lichen aureus. This is a classic clinical image of lichen aureus. Note the large bronze plaque. There are cases of mycosis fungoides that have been presaged by lesions of lichen aureus; the original index case described in the literature was in the context of a patient with a longstanding plaque of lichen aureus.

purpura typify the Gougerot–Blum variant of pigmentary purpura. An indurated or atrophic golden hued plaque localized over the medial malleolus, characteristically in a young or middle-aged man, defines the classical clinical presentation of lichen aureus (Rudolph, 1983; Price et al., 1985). The eczematoid pigmentary purpura of Doucas and Kapetanakis demonstrates eczematous alterations with superimposed purpura (Simon, 1992) (See Case Vignette 2). The pathogenetic basis of pigmentary purpura in a given patient is often obscure. In our experience, drug therapy may be of pathogenetic importance in those cases showing significant lymphoid atypia. Among the implicated drugs are nonsteroidal anti-inflammatory agents, antihypertensive agents, sedatives, lipid-lowering agents, antidepressants, and drugs with antihistaminic properties (Crowson et al., 1999). There is now an emerging body of clinical, phenotypic, and molecular data that suggest that certain forms of idiopathic pigmentary purpura represent a form of CLD analogous to pityriasis lichenoides and large plaque parapsoriasis. It is established that some cases of pigmentary purpura may presage the development of mycosis fungoides (Figure 6.5) (Barnhill and Braverman, 1988; Commens, 1989; Cather et al., 1998; Crowson et al., 1999; Georgala et al., 2001; Lor et al., 2002; Lipsker, 2003), the classic scenario being a young to middle aged male presenting with typical findings of lichen aureus, Schamberg’s disease, lichenoid purpura of Gougerot–Blum, and/or eczematoid pigmentary purpura of Doucas and Kapetanakis. In such cases, despite an initial presentation classical for pigmentary purpura with

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TABLE 6.3 Pigmented Purpuric Dermatosis Clinical Features Bronze discoloration of the skin with predominant but not exclusive localization to the legs (Schamberg’s disease, Majocchi’s purpura, Gougerot–Blum purpura, lichen aureus, and the eczematoid purpura of Doucas and Kapetanakis). Drugs frequently implicated (i.e., anti-inflammatory agents, antidepressants sedatives, lipid-lowering agents). Light Microscopic Findings Band-like lymphocytic infiltrate with supervening dermal sclerosis. Haphazard pattern of lymphocyte migration into the epidermis. Small cerebriform lymphocytes. Phenotypic Studies CD7 and CD62L diminution in most cases. Molecular Studies Fifty percent of cases of PP studied can exhibit monoclonality/oligoclonality maintained T cell clone over time. Cases of PP progressing to MF characteristically show a monoclonal profile.

(a)

(b)

The patient is a 36 year old man with a longstanding history of pigmented purpura who subsequently developed mycosis fungoides. The patient’s biopsy is illustrated histologically in Figures 6.24–6.27. The two images (a,b) are more within the spectrum of pigmented purpuric dermatosis. The eruption was widespread, an important clue to clonal variants of pigmented purpuric dermatosis and to those cases at greater risk for progression to mycosis fungoides.

FIGURE 6.5

lesions localized to the lower extremities, there is progressive disease with extension onto the trunk and upper extremities. Coinciding with the more widespread distribution of lesions is the concomitant development of other lesions characteristic for large plaque parapsoriasis or mycosis fungoides (Barnhill and Braverman, 1988). The time course between initial presentation and disease progression is often of several years’ duration (Barnhill and Braverman, 1988). Light Microscopic Findings The typical histology of those pigmentary purpuras that represent an insidious form of clonal T cell dyscrasia comprises a band-like lymphocytic

infiltrate with supervening dermal sclerosis. The sclerosis is typically laminated, assuming a parallel arrangement to the long axis of the epidermis. There is concomitant hemosiderin deposition in the papillary dermis with erythrocyte extravasation (See Figure 6.24). Although many cases show lymphocytic permeation of the basilar and suprabasilar portions of the epidermis, in other cases the infiltrate has a superficial perivascular disposition with interstitial extension, leaving a narrow grenz zone separating it from the overlying epidermis. At variance with an immunologically mediated interface dermatitis is the lack of basilar dyskeratosis and vacuolar change. Even if a grenz zone appears to

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be present at low magnification, careful scrutiny of the epidermis reveals a focal epitheliotropic lymphocytic infiltrate manifesting a haphazard pattern of epidermal migration (See Figure 6.24). This point is emphasized since immunologically driven lymphocytic infiltrates typically show a directed pattern of migration preferentially involving suprapapillary plates and acrosyringia (Magro and Crowson, 1996). There is usually no significant deep dermal extension. Oil-immersion (100 × objective) microscopy reveals small cerebriform lymphocytes. There may be no differential expression in regard to the degree of lymphoid atypia manifested by the intraepidermal and dermal-based compartments (See Figure 6.25).

et al., 2003), and a chronic progressive variant designated as pityriasis lichenoides chronica (PLC) (Figures 6.6–6.8) (Cozzio et al., 2004; Herron et al., 2005). Some patients are difficult to place in either subcategory and thus some observers do not make a distinction, instead applying the appellation pityriasis lichenoides with no qualifier (Crowson, 2004). The eruption is characterized by the continuous formation of maculopapular lesions that spontaneously involute and occasionally leave atrophic scars. Each crop of lesions lasts from a few weeks to a few months.

Phenotypic Studies The infiltrates are dominated by CD2- and CD3positive T lymphocytes. As with large plaque parapsoriasis, there is usually a diminution of both CD7 and CD62L expression that may approximate that encountered in fully evolved mycosis fungoides (Crowson et al., 1999; Magro et al., 2005). In our experience over 90% of cases show a substantial reduction of one or both markers (See Figure 6.26) (Magro et al., 2005). Molecular Studies Clonality has been described in lesions of pigmentary purpura (Toro et al., 1997; Crowson et al., 1999; Lor et al., 2002; Chen et al., 2004). More recently, we have been using the technique of capillary size fragment analysis to assess for clonal restriction of TCR-β. Approximately 50% of cases of PPD studied by us show monoclonality and/or oligoclonality with the majority demonstrating a truly monoclonal profile (See Figures 6.28, 6.54, and 6.61) (submitted for publication). A significant percentage (i.e., 50%) of the cases of monoclonal PPD studied by us developed mycosis fungoides concurrently with PPD, subsequent to the diagnosis of PPD and/or antedating the morphologic diagnosis of PPD.

FIGURE 6.6 Pityriasis lichenoides chronica. The patient is a 9 year old girl with a 2–3 year history of scaly plaques manifesting truncal, axillary, and extremity localization. The biopsy findings were consistent with pityriasis lichenoides. (Picture provided Dr. Kelley Gallina.)

Pityriasis Lichenoides Chronica Pityriasis lichenoides has been classified in the group of papulosquamous dermatoses along with other conditions like psoriasis or pityriasis rosea. (See Case Vignette 1.) For years pityriasis lichenoides has been considered under the category of Brocq’s parapsoriasis and was distinguished from large plaque parapsoriasis, the latter considered a form of premalignant T cell dyscrasia. Pityriasis lichenoides has traditionally been classified into two subtypes: an acute variant, pityriasis lichenoides et varioliformis acuta (PLEVA), which is more common in the first two decades of life (Romani et al., 1998; Rivera

Pityriasis lichenoides chronica. The patient is an 8 year old boy with multiple persistent scaly oval lesions involving the genital area, lower trunk, and legs. The combined clinical and light microscopic findings are consistent with pityriasis lichenoides. (Picture provided by Mohammed Diab.)

FIGURE 6.7

Cutaneous T Cell Lymphoid Dyscrasia

FIGURE 6.8 Pityriasis lichenoides chronica. Multiple persistent scaly lesions compatible with pityriasis lichenoides (Photographs from courtesy of Dr. Kelley Gallina.)

The lesions of PLC have a characteristic red brown color with an adherent scale, while those of PLEVA are most infiltrative and hemorrhagic (Romani et al., 1998). PLEVA and PLC areis observed in children and young adults and less frequently in older adults. The natural course of pityriasis lichenoides is variable (See Table 6.4). While the chronic variant tends to persist with waxing and waning lesions for many years, PLEVA may resolve after a few eruptive episodes. There is a severe and very rare variant known as febrile ulceronecrotic PLEVA, which is characterized by the sudden onset of diffuse ulcerated confluent patches associated with high fever and constitutional

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symptoms. This presentation may be fatal and has been associated with EBV infection and cytotoxic lymphomas (Tsai et al., 2001; Herron et al., 2005). The etiology of pityriasis lichenoides is not known, but among the proposed pathogenetic bases is an infectious trigger, particularly of viral origin. The molecular and phenotypic findings in pityriasis lichenoides, and the reports of evolution into large plaque parapsoriasis, mycosis fungoides, or other lymphoproliferative disorders, indicate that this condition should be considered a form of premalignant lymphoproliferative disease or a cutaneous lymphoid dyscrasia. The fundamental hallmarks is a tendency to manifest a recurrent or recalcitrant course whereby the eruption may be controlled with various treatment modalities but with recurrence after cessation of therapy (Kiene et al., 1995; Niemczyk et al., 1997; Ko et al., 2000; Magro et al., 2002; Weinberg et al., 2002; Kadin, 2002; Tomasini et al., 2002; Cozzio et al., 2004). Light Microscopy The lesions manifest variable psoriasiform hyperplasia, focal dyskeratosis, parakeratosis, lymphocytic infiltration into the spinous layer, and a perivascular lymphocytic infiltrate in the superficial and mid-dermis accompanied by hemorrhage but without other inflammatory cell elements such as eosinophils and plasma cells (See Figures 6.14–6.21). The epidermis demonstrates little spongiosis and no vesiculation. Occasionally, small aggregates of intraepidermal small to intermediate lymphocytes with admixed Langerhans cells can be noted, but classic Pautrier’s

TABLE 6.4 Pityriasis Lichenoides Chronica PLC: Characteristic red brown color with an adherent scale. PLEVA: infiltrative and hemorrhagic (Romani et al., 1998); observed in children and young adults, may be accompanied by rapid onset of fever. Light Microscopy Psoriasiform hyperplasia, focal dyskeratosis, parakeratosis, lymphocytic infiltration into the spinous layer, and a perivascular lymphocytic infiltrate in the superficial and mid-dermis accompanied by hemorrhage. No other inflammatory cell elements such as eosinophils and plasma cells. Epidermis manifests little spongiosis and no vesiculation. Occasionally, small aggregates of intraepidermal small to intermediate lymphocytes and Langerhans cells are noted; standard Pautrier’s microabscesses are not observed. Epithelial attenuation and poikilodermatous vascular alterations later in the course of lesions. Cerebriform cells are present. Reduction in CD7 and/or CD62 expression can be detected in the majority of cases. Variable CD4 and CD8 expression, more advanced lesions may reveal a dominance of CD4 lymphocytes. Most cases show large numbers of CD8-positive cells. Clonality.

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microabscesses are not observed (see Figures 6.15, 6.19, 6.20, and 6.21). Lesions of longstanding PLC may show epithelial attenuation and poikilodermatous vascular alterations (see Figure 6.17). A small lymphocyte dominates the infiltrate and has a morphology similar to the cells in the dermis. Cerebriform lymphocytes may be present but they maintain a relatively small size; those that infiltrate the epidermis typically manifest a degree of atypia that does not exceed that of the dermal component (see Figure 6.16). The presence of larger cerebriform cells within the epidermis, especially when accompanied by poikiloderma, may signify progression to mycosis fungoides (see Figure 6.18). Although one could argue that cases of pityriasis lichenoides that transform into mycosis fungoides may have been malignant from inception, there are reported cases of patients with typical clinicopathological presentations who, over time, have developed a different set of lesions diagnostic of cutaneous T cell lymphoma (Niemczyk et al., 1997; Tomasini et al., 2002). Phenotypic Profile Cases of PLEVA are often dominated by a CD8positive infiltrate with cytotoxic features (Jang et al., 2001; Magro et al., 2002). This phenotype correlates well with the hemorrhagic and necrotic appearance of lesions, which seem to be self-destructive, resulting in short flares and resolution with scars. Conversely, PLC lesions seen in adults are dominated by CD4positive lymphocytes. We have seen other cases of PLC in which there was a dominance of CD8-positive lymphocytes. It seems likely that the CD8-expressing cells may be a reactive infiltrate responding to a potentially aberrant CD4-expressing population; most cases of mycosis fungoides arising in a background of PLC have been of the CD4 subset (see Figure 6.23). It is nonetheless possible that there is an inherent neoplastic potential of the CD8 populace. We have encountered a cytotoxic CD8-positive variant of mycosis fungoides arising in a background of PLC and others have described a similar process arising in this setting (Wenzel et al., 2005). A reduction in CD7 and/or CD62 expression can be detected in the majority of cases (see Figure 6.22). The clonal nature of the T cell infiltrate in pityriasis lichenoides has been shown in both the acute and chronic forms (Panhans et al., 1996; Magro et al., 2002; Weinberg et al., 2002; Magro et al., 2003). Using the TCR-β gene scan analysis, we have encountered true monoclonality or oligoclonality in 24 of 46 cases studied (unpublished observations), including cases where specimens obtained from two different sites at the same time or at different

times showed the same molecular profile. These molecular profiles were truly monoclonal. In one of the illustrated cases in which samples were taken years apart, an earlier biopsy represented pityriasis lichenoides while a later biopsy represented overt lymphoma, emphasizing the concept of the potential for disease progression in CLD. ´ Idiopathic Erythroderma (Pre-Sezary) Erythroderma is a skin condition often accompanied by fever and lymphadenopathy whereby there is an inflammatory skin reaction resulting in diffuse erythema with variable scale. A male predominance has been reported. The reported incidence is 1 in 100,000. Most cases have an established etiology such as atopic eczema, a drug-based etiology, seborrheic dermatitis, pityriasis rubra pilaris, or cutaneous T cell lymphoma. Some patients have erythroderma with no apparent cause; based on studies showing emerging T cell clones in the peripheral blood of such patients and the progression in some cases to cutaneous T cell lymphoma/S´ezary syndrome, one could consider idiopathic erythroderma as a form of pre-S´ezary syndrome. The main risk factor for progression to S´ezary syndrome is clinical persistence of erythroderma; those patients who have complete remission do not develop lymphoma. The distinction between idiopathic erythroderma and S´ezary syndrome may be difficult. S´ezary syndrome is the leukemic counterpart of mycosis fungoides and is usually defined as erythroderma with more than 1000 circulating S´ezary cells per cubic milliliter; the abnormal cells also have a characteristic phenotype especially in regard to loss of CD7 (Wood et al., 1990). Other hematologic criteria include the detection of T cell clonal restriction in peripheral blood, aberrant phenotype by flow cytometry (i.e., a loss of CD7), and a CD4/CD8 ratio of more than 10 (Vonderheid and Bernengo, 2003). In addition, the authors of the 2005 WHO EORTC classification for cutaneous lymphoma suggested that there must be an absolute criterion for S´ezary syndrome, which is one of established T cell clonality in the peripheral blood and skin, ideally demonstrating the same T cell clones. They proposed that one additional criteria must be present, namely, a peripheral blood count of S´ezary cells as defined above, and/or a CD4/CD8 ratio in the peripheral blood in excess of 10:1 with concomitant loss of pan T cell markers such as CD7 and CD5 (Willemze et al., 2005). Erythrodermic patients who lack the peripheral blood criteria for the diagnosis of S´ezary syndrome are often labeled with pre-S´ezary syndrome (Rajka

Cutaneous T Cell Lymphoid Dyscrasia

and Winkelmann, 1984) and in essence often represent the ‘‘idiopathic erythroderma’’ patients; they present with chronic pruritus, erythroderma, and palmoplantar keratoderma with nail changes. Only a small proportion of these patients (5–10%) develop cutaneous T cell lymphoma (Sigurdsson et al., 1997; Gniadecki and Lukowsky, 2005), namely, those with clinical persistence of erythroderma. A review of the literature does reveal other cases of clonal recalcitrant erythroderma which do not fulfill criteria to warrant the designation S´ezary syndrome or cutaneous T cell lymphoma. In terms of etiopathogenetic factors, it is perhaps na¨ıve to think that idiopathic erythroderma develops de novo. The patients are typically elderly and most are on drug therapy; at least in some cases the inciting trigger likely reflects the ingestion of drugs with immune dysregulating properties. While the initial process may be triggered by a drug, thereby evoking a clonal response to a specific epitope, a state of endogenous clonal T cell dyscrasia may emerge. Often clinicians will not implicate a particular drug because the patient was ingesting the agent for a protracted period of time before the onset of the skin rash, but it is now well established that many drug-induced immune dysregulating states are in the setting of prolonged drug therapy (Crowson and Magro 1995; Magro and Crowson, 1996). In a recent study of erythroderma, a drug-based etiology was only considered in those patients in whom the interval between drug ingestion and the onset of the erythroderma was a few days; half of the cases were attributable to carbamazepine, a classic immune dysregulating drug associated with pseudolymphomata. In another series of elderly patients with monoclonal T cell dyscrasia of undetermined significance, associated with recalcitrant erythroderma (Gniadecki and Lukowsky, 2005) patients manifested characteristics similar to the previously reported pre-S´ezary cases including low counts of S´ezary cells, hyperIgE, and mild eosinophilia. In 5 of 10 patients there was T cell clonal lymphocytosis and an expansion of T cells with phenotypic features of S´ezary cells (CD4+, CD7−, and CD26−) yet the morphology of the isolated cells was that of small lymphocytes with a minority displaying the typical morphology of S´ezary cells. Because of the lesser numbers of these abnormal circulating cells, the patients did not fulfill criteria for the designation of S´ezary syndrome and none developed S´ezary syndrome in a follow-up period that ranged from 4 to 13 years. The presence of T cell monoclonality in this setting is not necessarily a clue to neoplasia, as T cell clones have been reported in

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healthy elderly individuals as well as patients with autoreactive conditions (Wucherpfennig et al., 1994). Light Microscopic Findings We have seen cases in which the density of infiltration was striking, with a combined lichenoid and eczematous reaction and lymphoid atypia. The findings were not held to be diagnostic of mycosis fungoides because the atypia was mild and there were supervening spongiotic changes. We have also encountered cases in which there is a low-density pattern of epidermotropic lymphocytic infiltration and the atypia is mild. Examination of the infiltrate under oil immersion (100× objective magnification) does reveal nuclear aberrations but not of the severity seen in fully evolved mycosis fungoides. Phenotypic and Molecular Profile We are not aware of studies describing the molecular profiles of the lymphocytes found in skin biopsies of patients with idiopathic erythroderma and the histology is poorly defined. One of our patients with idiopathic erythroderma had a lichenoid and epitheliotropic infiltrate of small, slightly atypical lymphocytes showing a loss of CD7 and CD62L. Although a drug-based etiology was initially favored, the erythroderma persisted for more than 1 year after drug withdrawal. Molecular studies revealed persistent T cell clones at four different skin sites procured at three different time periods and also in a lymph node; the patient did not fulfill the hematologic parameters for S´ezary syndrome.

Syringolymphoid Hyperplasia with Alopecia Syringolymphoid hyperplasia (SLHA) was first recognized by Sarkany (Sarkany, 1969), who reported a man presenting with alopecia and anhidrosis; histologic examination revealed a dense lymphocytic infiltrate centered around the eccrine coil with accompanying epitheliotropism involving the eccrine ducts and glands. (See Case Vignette 6.) An interesting aspect of the morphology and what has clearly emerged as a feature of syringotropic lymphoid dyscrasia is concomitant hyperplasia of the epithelium (Figures 6.45 and 6.46). The patient died a few years later of Hodgkin lymphoma. Subsequently, others have described similar cases. The patients characteristically present with localized alopecia with anhidrosis (Esche et al., 1998; Tannous et al., 1999; Haller, 2001; Hobbs et al., 2003; Thien et al., 2004); they may be otherwise clinically asymptomatic. In many of the reported cases there does not appear to be disease progression despite a constellation of light

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Other inflammatory cell elements such as eosinophils can be seen but are less common than in cases of fully evolved syringotropic T cell lymphoma. Granulomata may be seen. Phenotypic Profile The cells are primarily T cells most commonly of the CD4 subset with diminution in the expression of pan T cell markers CD7 and CD62L.

Syringolymphoid hyperplasia with alopecia. Localized asymptomatic plaque with prominence of follicles although without hair and associated dryness.

FIGURE 6.9

microscopic, phenotypic, and molecular features suggesting a form of T cell dyscrasia (Burger and Goette, 1987; Burg and Schmoeckel, 1992). In one study of five cases, clinical impressions included folliculitis, discoid lupus erythematosus, and eczema (Thien et al., 2004) affected sites included scalp, face, forearms, and legs in patients aged from 39 to 72 years with a disease course of 1–4 years’ duration. Three of the patients had limited disease while in two patients the disease was more generalized; two of the latter patients had a history of immunosuppression and one had undergone solid organ transplantation. All cases showed T cell clonality. This series was reported under the designation of syringotropic cutaneous T cell lymphoma. One could argue that at least in three of the cases the localized nature of the lesions and the well-being of the patients would warrant categorization as a form of cutaneous lymphoid dyscrasia. Another characteristic clinical feature is one of punctate erythema involving the palmar aspect of the hands and feet. Some cases of this entity have been reported as representing a forme fruste of Sjogren’s syndrome involving the skin. Light Microscopic Findings There is a dense lymphoid infiltrate around the eccrine coil with hyperplasia of the eccrine epithelium in some cases (see Figures 6.45 and 6.46). Nuclear atypia is variable and may not be prominent; the lymphocytes are primarily small to intermediate in size and some have a cerebriform appearance. Follicular involvement is common and the follicle wall may be hyperplastic with follicular hyperkeratosis resembling a comedo; there may be attendant mucinosis (see Figures 6.43 and 6.44) (Burger and Goette, 1987).

Differential Diagnosis The clinical differential diagnosis includes alopecia areata, keratosis pilaris, and dyshidrotic eczema. Viral hypersensitivity reactions can be associated with a dense eccrinotropic lymphocytic infiltrate (McCuaig et al., 1996), but there is often an interface change with a lymphocytic purpuric vascular reaction in such cases. The combination of lymphocytes infiltrating the eccrine coil with epithelial hyperplasia is likely specific to this entity. Lymphomas of B and T cell lineage can show prominent eccrine coil involvement including primary cutaneous pleomorphic T cell lymphoma, natural killer (NK) cell and NK-like T cell lymphomas, and marginal zone lymphoma. Lesions of lymphomatoid papulosis can demonstrate prominent eccrinotropism. There are rare reports of a cutaneous lymphoepithelial-like lesion in the setting of Sjogren’s syndrome (Huang et al., 1996) in which the infiltrate contains many B cells including a conspicuous plasmacytic component. Other benign conditions of the scalp and hand associated with prominent infiltration of the eccrine coil comprise discoid lupus erythematosus, and morphea, and perniosis respectively (Crowson and Magro, 1997; Magro et al., 2001). Molecular Profile There will be evidence of T cell clonality. We always recommend two or more biopsies to assess for commonality of dominant cell populations. In theory, the same molecular profile should be apparent and maintained over time and at different biopsy sites.

Idiopathic Follicular Mucinosis/Alopecia Mucinosa The terms idiopathic follicular mucinosis and alopecia mucinosa have been used synonymously. It should be emphasized that any inflammatory condition affecting the follicle can be associated with follicular mucinosis. (See Case Vignettes 4, 5, and 7.) Hence, the diagnosis of idiopathic follicular mucinosis and/or alopecia mucinosa is one that must be correlated with the clinical presentation and other aspects of the histopathology (Pinkus, 1957; Jabloska et al.,

Cutaneous T Cell Lymphoid Dyscrasia

1959; Gilliam et al., 1997; Cerroni et al., 2002). It is quite common to see follicular mucinosis in the setting of follicular eczema, eosinophilic folliculitis, and discoid lupus erythematosus and we have described a distinctive pattern of drug reaction manifesting as follicular mucinosis with accompanying lymphoid atypia, namely, in the context of long-term antidepressant therapy (Magro and Crowson, 1995, 1996; Hodak et al., 1999; Francis et al., 2001). There are cases of incipient pilotropic T cell dyscrasia in which the features are insufficient to warrant the designation of pilotropic mycosis fungoides and where the degree of mucin deposition is minimal and may even be absent. We term such lesions pilotropic T cell dyscrasia and do not render a diagnosis of follicular mucinosis in the absence of significant follicular mucin deposition. Such cases may presage overt pilotropic mycosis fungoides. The clinical features are variable; there are cases heralded by patches of scalp alopecia, but not all cases are associated with discernible clinical hair loss (Figures 6.10 and 6.11). (See Case Vignette 4.) An important distinction is between alopecia mucinosa/idiopathic follicular mucinosis and overt piltotropic mycosis fungoides. There are some authors who feel that the documentation of clonality in such lesions would warrant the categorization as lymphoma. We do not agree with this concept, as many cases of idiopathic follicular mucinosis/alopecia mucinosis show T cell clonality. If the hallmark clinically is that of localized disease then the designation as lymphoma is probably not justified (LeBoit, 2004). Light Microscopic Findings There is infiltration of the outer root sheath by lymphocytes with attendant intrafollicular mucin deposition (Jabloska et al., 1959). The infiltrate in true

FIGURE 6.10 Alopecia mucinosa. Scaly plaque on the face compatible with alopecia mucinosa.

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FIGURE 6.11 The patient is a 26 year old man who presented with a 2 year history of waxing and waning plaques on the forehead. The biopsy findings were compatible with alopecia mucinosa with evidence of a TCR-β gene rearrangement.

juvenile classic idiopathic follicular mucinosis is typically brisk and can be accompanied by a significant eosinophilic component (see Figures 6.34–6.36, 6.38, 6.39, 6.47, and 6.48). Follicular dilatation with keratin retention and comedone formation is frequent. There is oftentimes an inverse correlation between the extent of follicular hyperkeratosis and follicular mucin deposition leading us to hypothesize that follicular hyperkeratosis may be a morphologic sequel of antecedent follicular mucinosis. Phenotypic Studies Kossard (1997) introduced the term folliculotropic T cell lymphocytosis to describe cases of what would appear to be clinically and histologically consonant with the entity of follicular mucinosis, although without significant follicular mucin deposition. We have used the term incipient pilotropic T cell dyscrasia to describe similar cases, as this is not a state of benign lymphocytic infiltration per se but rather appears to be a clonal dyscrasia with an undefined risk of disease progression. The characteristic morphologic, phenotypic, and molecular hallmarks are mildly atypical but clonally restricted CD4-positive, CD7-negative T cell folliculotropic infiltrates, typically of low density, unaccompanied by other inflammatory cell infiltrates or mucin (see Figures 6.37, 6.40, and 6.41). The cases lack morphologic criteria to warrant the designation of pilotropic/folliculotropic mycosis fungoides. Molecular Profile We have observed an oligoclonal restricted T cell repertoire in three of five cases of juvenile follicular

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(a)

Atypical lymphocytic lobular panniculitis. The patient is a 36 year old man (see micrographs in Figures 6.17–6.21) with waxing and waning plaques primarily involving the thighs. (Phorograph courtesy of Dr. Mohammad Diab.)

(b)

FIGURE 6.12

mucinosis, while polyclonality was observed in two cases. (see Figures 6.42 and 6.59) In three additional adult cases that showed unequivocal monoclonality, two patients clearly had concomitant cutaneous T cell lymphoma while the other patient developed the eruption temporally associated with chemotherapy in the setting of chronic lymphocytic leukemia, suggesting a form of lymphomatoid drug reaction.

Atypical Lymphocytic Lobular Panniculitis We described a series of patients with lymphocytic lobular panniculitis in whom the clinical course was characterized by waxing and waning bruise-like plaques unassociated with constitutional symptoms in the absence of clinical stigmata of collagen vascular disease (Figures 6.12 and 6.13). (See Case Vignette 3.) Light microscopic, phenotypic, and molecular studies suggest that this entity represents part of a continuum with, but does not equate to, subcutaneous

The patient is a 42 year old female with a history of recurrent panniculitis since high school. She had several biopsies and laboratory evaluations in the past (1988 and 2003). Since her last biopsy she continues to have episodic flares whereby treatment with Motrin has alleviated the symptoms. She presented on January 2005 with a recent episode. The thigh area shows multiple erythematous nodules. See Case Vignette 8. (Photographs courtesy of Dr. David Knox.)

FIGURE 6.13

panniculitis-like T cell lymphoma (Magro et al., 2001, 2004). It would appear that this entity is not uncommon (see Table 6.5). Likely some cases designated in the past as Weber–Christian disease, lupus profundus, and panniculitis-like T cell lymphoma represent this entity. The youngest patient to date that we have encountered began developing waxing and waning subcutaneous lesions at age 1; now 4 years of age, this child continues to have recurrent nodular subcutaneous lesions. We term this condition atypical lymphocytic lobular panniculitis (Magro et al., 2004). There is a predilection to involve the proximal extremities but lesions have a tendency for spontaneous regression

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TABLE 6.5 Atypical Lymphocytic Lobular Panniculitis Clinical Features Younger patients, males more frequently affected. Recurrent painless subcutaneous nodules involving arms and thighs. No constitutional symptoms and/or cytopenias; ensuing fever or cytopenia may herald progression to panniculitis-like T cell lymphoma. Light Microscopic Findings Permeation of the interstitium of the fat by lymphocytes typically with perivenular accentuation. Minimal fat necrosis although occasional cases with more conspicuous fat necrosis can be seen. Some degree of erythrocyte phagocytosis may be present; not of the magnitude seen in panniculitis-like T cell lymphoma. No germinal centers. Overlying skin may show lymphocytic infiltration around the eccrine coil and focal permeation of the interstitium by plump histiocytes with accompanying mucin deposition. Cells show nuclear contour irregularity and hyperchromasia. Phenotypic Profile Mixture of CD4 and CD8 lymphocytes; there can be a dominance of CD8 cells; conversely, the overwhelming dominance of CD4 cells of lupus erythematosus not seen. CD62L CD5 and CD7 deletion is seen in many of the cells. There is granzyme positivity that roughly parallels the CD8 stain. Molecular Studies Clonality and/or at least a restricted T cell repertoire, polyclonal background; same profile at different sites and over time.

in contrast to those of subcutaneous panniculitis-like T cell lymphoma, which remain as persistent and progressive plaques; the distinction from lupus profundus may be more difficult although lesions of lupus profundus will not typically undergo spontaneous regression, but require therapeutic intervention with hydroxychloroquine. Light Microscopic Findings Atypical lymphocytic lobular panniculitis shares with subcutaneous panniculitis-like T cell lymphoma infiltration of the panniculus by small to intermediate sized atypical lymphocytes with extension into the lower dermis characteristically in an epidermotropic and eccrinotropic array. In addition, there are areas of infiltration of the interstitium of the reticular dermis by plump rounded histiocytes typically unaccompanied by lymphocytes (see Figures 6.29, 6.30, 6.49 and 6.50). Epidermal lymphocytic exocytosis is never a conspicuous feature of the histopathology of atypical lymphocytic lobular panniculitis. Unlike subcutaneous panniculitis-like T cell lymphoma, the lymphoid atypia is insufficient for the diagnosis of lymphoma. Other discriminating features allow the distinction of atypical lymphocytic lobular panniculitis from subcutaneous panniculitislike T cell lymphoma. Marked angiodestructive

changes with luminal thrombosis as encountered in subcutaneous panniculitis-like T cell lymphoma are not seen and the extent of fat necrosis observed in subcutaneous panniculitis-like T cell lymphoma is not seen in atypical lymphocytic lobular panniculitis. The density of infiltration is less, although the pattern is similar, being one of permeation of the interstitial spaces of the fat lobule (see Figure 6.28 and 6.49). There can be focal erythrocyte engulfment by histiocytes; prominent erythrocyte phagocytosis is not seen (see Figure 6.51b). It is important to distinguish atypical lymphocytic lobular panniculitis from lupus profundus, where hyalinosis of the fat lobule, germinal centers, prominent dermal and subcuticular mucin deposition, and a true destructive interface dermatitis are often present. Atypical lymphocytic lobular panniculitis lesions may show some mucin, typically in the mid- and deeper reticular dermis, often accompanied by a single cell infiltrate of rounded histiocytes (see Figure 6.51). Direct immunofluorescence in cases of lupus profundus showing an active interface dermatitis will demonstrate a positive lupus band test as defined by the presence of immunoglobulin within the basement membrane zone of the epidermis (Magro et al., 2001, 2004).

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Phenotypic Studies Phenotypically, some cases are similar to subcutaneous panniculitis-like T cell lymphoma by virtue of a significant CD5 and CD7 deletion (see Figures 6.31 and 6.32); it can be substantial with greater than 70% of the infiltrate showing a loss of these markers (Magro et al., 2001, 2004). In addition, while there may be a reduced CD4 to CD8 ratio, the striking dominance of cytotoxic CD8 lymphocytes that typifies most, but not all, cases of subcutaneous panniculitis-like T cell lymphoma is not observed. Also problematic is the double CD4/CD8 negativity observed in panniculitic lymphomas with a gamma-delta T cell phenotype. We have encountered rare cases of atypical lymphocytic lobular panniculitis whereby the lymphocytes do not manifest either CD4 or CD8 positivity (see Figure 6.33). However panniculitis like T cell lymphoma of the gamma delta subtype is characterized by more intense hemorrhage and necrosis with frequent hemophagocytic features that correspond to the histological expression of intense cytotoxic changes.

The lack of β F1 expression is important to confirm the diagnosis. Molecular Studies From a molecular standpoint, clonality is common to both subcutaneous panniculitis-like T cell lymphoma and atypical lymphocytic lobular panniculitis (Magro et al., 2001, 2004). In addition, there can be a persistence of the same T cell clone at different biopsy sites over time (see Figures 6.60 and 6.62). We have had the opportunity to study in greater detail the molecular profile from two different biopsy sites over a 1 year period in the child described earlier who had atypical lymphocytic lobular panniculitis. Of interest, the initial biopsy showed a classic polyclonal pattern while the latter biopsy demonstrated a monoclonal profile. Retrospective review of the polyclonal gel did reveal one of the more prominent peaks to have identical base pair products to the monoclonal peak observed in the later biopsy.

Case Vignette 1

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 33 year old man with a longstanding history of plaques and nodules on the face and extremities. He had biopsies performed in 2000 and was lost to follow-up until we contacted him recently regarding clinical photographs. Five years later he continues to have episodic outbreaks. His skin lesions are scaly and have more or less remained stable. Diagnosis: Pityriasis lichenoides chronica (Figures 6.14–6.23).

The biopsy shows hyperplasia with small zones of epithelial attenuation with overlying orthohyperkeratosis and parakeratosis. At this power one can see a band-like lymphocytic infiltrate and very striking infiltration of the epidermis by lymphocytes although with a largely intact basal layer, indicating that the process is in essence an epidermotropic one rather than representing a true immunologically mediated interface dermatitis.

FIGURE 6.14

There is colonization of the epidermis by lymphocytes. Note the superficially disposed small Langerhans’ cell-rich microabscesses, almost reminiscent of a Pautrier’s microabscess but different by virtue of a composition that includes numerous Langerhans’ cells. There is no edema associated with this microvesicle, which separates it from a spongiotic microvesicle of eczema.

FIGURE 6.15

The extent of intraepidermal lymphocyte migration can be striking. It is not uncommon to see foci where the degree of intraepidermal lymphocytic infiltration exceeds the discernible keratinocyte population. The pattern of migration is largely a passive one, hence warranting the designation of true epidermotropism.

FIGURE 6.16

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CASE VIGNETTE 1

(Continued)

FIGURE 6.17 This biopsy is characteristic for PLC. Note the small zones of epidermal effacement in concert with prominent migration of lymphocytes. While there is focal spinous layer dyskeratosis, there is no true destructive interface dermatitis. Also characteristic is the overlying parakeratotic scale imbued with leukocytes, which can in some cases be neutrophilic in nature. This is an important point since the presence of intracorneal neutrophils could be misconstrued as being compatible with psoriasis.

Higher power magnification in this case reveals the classic cytomorphology of the infiltrating cells, which is a small mature lymphocyte with some degree of nuclear contour irregularity. It is not uncommon to see cells with a cerebriform appearance, although large cerebriform cells, especially when exceeding the degree of dermal-based lymphoid atypia, would be uncommon and would suggest progression to MF.

FIGURE 6.18

The striking tendency for lymphocyte aggregation to involve the superficial layers of the epidermis is typical.

FIGURE 6.19

Case Vignette 1

This photomicrograph emphasizes the pattern of epidermal migration that is really best described as being truly epidermotropic. The cells passively migrate into the epidermis with only a minimal epidermal response.

FIGURE 6.21

There are Langerhans’ cell-rich ‘‘nonspongiotic’’ microvesicles manifesting localization within the superficial layers of the epidermis.

FIGURE 6.20

The lymphocytes may show a substantial loss of CD7 expression.

FIGURE 6.22

FIGURE 6.23 Although the CD4 and CD8 results are variable in many instances, the abnormal clonally restricted cells in the epidermis are likely of the CD4 subset, while the CD8 cells have a countersurveillance regulatory function. It is quite possible that if there is an attenuation in the CD8 response then a predominance of the clonally restricted CD4 lymphocytes may lead to disease progression, specifically in the context of transition into MF. Illustrated is CD4.

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CASE VIGNETTE 2

The patient is a 36 year old man with an 8 year history of petechial lesions involving the lower extremities. He had progressive lesions with a recent onset of pruritus. Diagnosis: Pigmented purpuric dermatosis (Figures 6.24–6.25) evolving into MF (Figures 6.26 and 6.28).

(a)

(b)

(c)

FIGURE 6.24 A biopsy was performed showing a superficial perivascular lymphocytic infiltrate with associated red cell extravasation. There is focal migration of lymphocytes into the epidermis. Overall, the pattern of intraepidermal lymphocyte migration is an epidermotropic one.

(a)

(b)

FIGURE 6.25 Higher magnification reveals that the lymphocytes exhibit some degree of nuclear atypia as defined by nuclear hyperchromasia and nuclear contour irregularity. A few of the cells have a frankly cerebriform appearance.

Case Vignette 2

A CD7 preparation reveals a reduction in expression with virtually no cells in the epidermis or dermis manifesting any staining.

FIGURE 6.26

(a)

(b)

FIGURE 6.27 Over the ensuing years the eruption became more extensive, the patient developed supervening pruritus, a biopsy showed a greater degree of lymphocytic infiltration with more extensive epidermotropism and greater atypia compatible with mycosis fungoides.

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CASE VIGNETTE 2

(Continued)

2003 biopsy TCR beta Panel A Peak 264 bp

2004 biopsy TCR beta Panel A

Peak 264 bp

2005 biopsy TCR beta Panel A Minimal product

(a)

The molecular studies were performed on earlier biopsies and the patient’s more recent skin lesions. The biopsies revealed clonality and more specifically the same persistent T cell clones over a 3 year period including biopsies of classic PPD and those more consonant with a diagnosis of MF, clearly indicative of lesional progression from the same clonally restricted T cell population. This identification of persistent T cell clones is the hallmark of cutaneous lymphoid dyscrasia. While there is monoclonality apparent in all three separate specimens procured over different time periods, the most recent biopsy is that of fully evolved mycosis fungoides showing a stronger peak compared to the monoclonal T cell population identified in the earlier biopsies depicted in 6.28b. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.) FIGURE 6.28

Case Vignette 2

Biopsy in 2003 TCR beta Panel C

Peak 189 bp

Biopsy in 2004 TCR beta Panel C

Biopsy in 2005 TCR beta Panel C

Peak 189 bp

Peak 189 bp

(b) FIGURE 6.28

(Continued)

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CASE VIGNETTE 3

The patient is a 38 year old man who has a 10 year history of episodic lesions involving his thigh and lower leg. The characteristic hallmarks of these lesions were those of induration with some tenderness. The lesions characteristically underwent spontaneous resolution. Diagnosis: Atypical lymphocytic lobular panniculitis (Figures 6.29–6.33).

FIGURE 6.29 The biopsy shows a moderately dense infiltrate within the interstitium of the fat. Most of the infiltrates emanate from zones of angiocentric lymphocytic infiltration.

FIGURE 6.30 Higher power magnification reveals a mixture of small mature and intermediate sized lymphocytes with some degree of nuclear contour irregularity. There is also a smattering of histiocytes with engulfed red cells.

The phenotypic profile reveals that the lymphocytes at least focally are CD3+. However, there are a number of cells that are not staining. The infiltrate probably contains more histiocytes.

FIGURE 6.32 There is a diminution in the expression of CD7. Many of the cells within the panniculus are without any CD7 expression.

FIGURE 6.31

Case Vignette 3

(a)

(b)

FIGURE 6.33 Of interest, the infiltrate is not convincingly CD4 or CD8 positive. There are a few scattered positive staining cells for CD4 or CD8; however, the majority of cells within the infiltrate are both CD4 and CD8 negative. part (a) illustrates CD4 and part (b) depicts CD8.

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CASE VIGNETTE 4

The patient is a 40 year old man who presented with irregular hypo- and hyperpigmented plaques on the face Diagnosis: Mucin poor alopecia mucinosa/pilotropic T cell dyscrasia(Figure 6.34–6.37).

Biopsy shows infiltration of the outer root sheath epithelium by lymphocytes with concomitant perivascular lymphocytic infiltrates. The pattern of migration is largely a passive epidermotropic one.

FIGURE 6.34

(a)

(b)

Higher power magnification reveals infiltration of the adventitial dermis by lymphocytes with focal infiltration of the outer root sheath epithelium by lymphocytes. The pattern is one of epitheliotropism as opposed to a classic follicular interface dermatitis as one would encounter in underlying collagen vascular disease.

FIGURE 6.35

Case Vignette 4

FIGURE 6.36 Higher power magnification reveals rather striking lymphoid atypia. Many of the cells have a cerebriform appearance. This patient is best categorized as having a form of pilotropic T cell dyscrasia compatible a with mucin poor variant of alopecia mucinosa.

The CD7 preparation shows a reduction in expression of CD7. A few of the lymphocytes are positive.

FIGURE 6.37

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CASE VIGNETTE 5

The patient is a 30 year old man with indurated plaques on the face. Diagnosis: Alopecia mucinosa (Figures 6.38–6.42).

FIGURE 6.38 The biopsy shows infiltration of the follicle by lymphocytes with attendant follicular mucinosis.

(a) FIGURE 6.40

Higher power magnification shows mild lymphoid atypia. There is also conspicuous mucin deposition.

FIGURE 6.39

(b)

The infiltrate in the follicle is CD3 dominant (a) and composed primarily of CD4+ T cells (b).

Case Vignette 5

The CD7 preparation shows a loss of CD7 expression.

FIGURE 6.41

TCR beta Panel A Block A Gaussian distribution (V-J) - polyclonal Size standards

TCR beta Panel C Block B Gaussian distribution (D2-J2) - polyclonal Gaussian distribution (D1-J1) - polyclonal

FIGURE 6.42 Polyclonal molecular profile. (Molecular gel and diagnostic interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory at Roswall Park Cancer Institute.)

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CASE VIGNETTE 6

The patient is a 75 year old man who developed a generalized skin rash. He also has a history of an inflammatory process involving his lung, although a specific diagnosis was not established. Diagnosis: Adnexotropic T cell dyscrasia with prominent follicular and eccrine involvement likely representing syringotropic T cell lymphoma (Figures 6.43–6.46). Although this case likely is one of fully evolved lymphoma and this chapter in essence emphasizes the prelymphomatous dyscrasias, a diagnosis of lymphoma was not rendered by any of the referring institutions. The reaction in the eccrine coil was held to be unusual. The point about illustrating this case in Chapter 6 as opposed to Chapter 14 is to emphasize the architectural changes that occur in the follicle and eccrine coil inherent to the group of disorders that fall under the rubric of adnexotropic T cell dyscrasia including overt lymphoma.

This photomicrograph depicts the classic changes encountered in a spectrum of adnexotropic T cell dyscrasias, namely syringolymphoid hyperplasia with alopecia, syringotropic T cell lymphoma, and alopecia mucinosa, including the socalled mucin poor variant also falling under the alternative appellation of follicular lymphocytosis and finally pilotropic mycosis fungoides. Specifically, there is migration of lymphocytes into the outer root sheath epithelium with attendant striking follicular hyperkeratosis.

FIGURE 6.43

FIGURE 6.44 A higher power magnification showing the atypicality of the lymphocytes permeating the outer root sheath epithelium.

Case Vignette 6

(a)

(b)

There is hyperplastic alteration of the straight eccrine duct. The hyperplasia is accompanied by lymphocyte migration around and within the eccrine ductular and glandular epithelium. Virtually identical changes occur in patients with the prelymphomatous dyscrasia of syringolymphoid hyperplasia with alopecia. Unlike this patient, such patients present with isolated patches of alopecia with accompanying anhidrosis.

FIGURE 6.45

FIGURE 6.46 The patient developed the same lymphoepitheliotropic process in the lung which antedated the skin lesions by a few years.

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CASE VIGNETTE 7

The patient is a 15 year old African American girl with a several year history of progressively enlarging plaque on the anterior chest. The lesion currently measures approximately 10 × 15 centimeters. Diagnosis: Cell poor alopecia mucinosa/incipient pilotropic T cell dyscrasia (Figures 6.47 and 6.48).

FIGURE 6.47 Intermediate power examination reveals focal infiltration of the outer root sheath epithelium by lymphocytes with accompanying slight spongiosis.

(a)

(b)

Examination under oil reveals an atypical lymphocytic cytomorphology. The cells are predominantly small in size however they exhibit significant nuclear contour irregularity with cells having a cerebriform appearance.

FIGURE 6.48

Case Vignette 8

CASE VIGNETTE 8

125

The patient is a 42 year old female with recurrent atypical lymphocytic lobular panniculitis commencing at age 17. Diagnosis: Atypical lymphocytic lobular panniculitis (Figures 6.49–6.51).

Patchy perivascular and interstitial lymphocytic and histiocytic infiltrate within the panniculus.

FIGURE 6.49

(a)

FIGURE 6.50 Higher power examination reveals a small dominant lymphocytic cell population with slight lymphocytic atypia.

(b)

FIGURE 6.51 Within the dermis there are scattered singly disposed plump histiocytes, some of which manifest erythrocyte phagocytosis.

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES TCR beta Panel A

Peak 259

TCR beta Panel B minimal product

TCR beta Panel C Peak 186

FIGURE 6.52 A 6 year old girl was diagnosed with clonally restricted endogenous epitheliotropic T cell dyscrasia manifesting a CD4+ CD7+ focally CD62L-negative phenotype consistent with pityriasis lichenoides chronica. The molecular studies show a clonal population of T lymphocytes. The dominant T cell populations included one population at 259 bp and another at 186 bp. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

Additional Molecular and Cytogenetic Studies

127

TCR beta Panel B Block A

Peak 260 bp

TCR beta Panel B Block B

Peak 259 bp

TCR beta Panel B Block C Peak 258 bp

(a) FIGURE 6.53 A 55 year old woman with pityriasis lichenoides over 15 years was diagnosed with cutaneous lymphoid dyscrasia. The molecular studies show that three blocks (A1, B1, and C1) are quite similar and show restricted T cell repertoire with one to four slightly dominant peaks in each multiplex panel. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

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Peaks 182, 189 & 196 bp

TCR beta Panel C Block A Peaks 296 & 302 bp

Peaks 171, 176, 182 & 189 bp

TCR beta Panel C Block B

Peaks 171, 182, 189 & 194 bp

TCR beta Panel C Block C

(b) FIGURE 6.53

(Continued)

Peaks 298 & 302 bp

Additional Molecular and Cytogenetic Studies

TCR beta panel C Results: clonal peaks

Peak 298 bp (Jb1.X)

129

Peak 306 bp (Jb2.X)

TCR beta panel C Results: clonal peaks Peak 298 bp (Jb1.X)

Peak 306 bp (Jb2.X)

(a)

TCR beta panel B Results: restricted repertoire

TCR beta panel B Results: restricted repertoire

(b) FIGURE 6.54 A 14 year old girl was diagnosed with pigmented purpuric dermatosis. The molecular studies show an emerging clonal population of T-lymphocytes in a polyclonal background. The molecular study results from both blocks, representing different biopsy sites procured at different time periods, are very similar with respect to each of the pair of panels. Panel A shows minimal PCR products. Panel B does not show any peaks while panel C shows dominant T cell populations at 298 bp and 306 bp. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

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TCR beta panel A Results: minimal PCR product

TCR beta panel A Results: minimal PCR product

(c) FIGURE 6.54

(Continued)

Clonal peak at 183 bp Block B1 TCR beta Panel C

(a)

TCR beta Panel C

restricted repertoire = multiple distinct peaks, the significance of which can only be established by comparison to additional specimens from same patient

(b)

FIGURE 6.55 A 15 year old girl with a longstanding history of eczema and now with widespread hypopigmented patches was diagnosed with hypopigmented large plaque parapsoriasis. (a) The molecular studies show, on panel C, a peak at 183 bp. (b) The molecular studies show multiple distinct peaks on blocks A and C, classified as a restricted repertoire. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

Additional Molecular and Cytogenetic Studies

Block A1 Multiplex panel B

Block C1 Multiplex panel B

131

Dominant peaks 259 & 265 bp

Dominant peaks 259 & 265 bp

FIGURE 6.56 A 68 year old man with a history of hypertension and achalasia was diagnosed with idiopathic erythroderma. The molecular studies show oligoclonal peaks on blocks A and C. On panel B, peaks are present at 259 bp and 265 bp. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

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Peak 189 bp

block A TCR beta tube C

block B TCR beta tube C Peak 189 bp

block C TCR beta tube C Peak 189 bp

A 35-year-old man was diagnosed with large plaque parapsoriasis. The molecular studies show, on all three blocks of panel C, peaks at 189 bp. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

FIGURE 6.57

Additional Molecular and Cytogenetic Studies

133

Panel A − whole sections - polyclonal

Panel A − LCM - monoclonal

Panel C − whole sections - polyclonal

Panel C − LCM - monoclonal

A 49 year old woman with an isolated lesion on the left upper arm was diagnosed with large plaque parapsoriasis. TCR-β gene rearrangement of whole sections shows that panels A and C have a polyclonal pattern while, LCM (laser capture microdissection) reveals the same panels with monoclonal peaks. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

FIGURE 6.58

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Panel A

peak 258

Panel B

peak 272 Minimal polyclonal background

Panel C

peak 178

Minimal polyclonal background

A 73 year old man with alopecia mucinosa. The molecular studies show a monoclonal peak at 258 bp on panel A, and on panels B and C at 272 bp and 178 bp, respectively. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostic Laboratory of Roswall Park Cancer Institute.)

FIGURE 6.59

Additional Molecular and Cytogenetic Studies

06/22/2005 TCR beta Panel C

CH frozen 1/16/2004 Block A2 TCR beta Panel C

135

Single dominant peak at 187 bp

Definitely polyclonal but largest peak at 187 bp

06/22/2005 TCR beta Panel B

Single small peak at 257 bp

CH frozen 1/16/2004 Block A2 TCR beta Panel B

Definitely polyclonal but largest peak at 257 bp

FIGURE 6.60 The patient is a 6 year old boy with a 1 year history of waxing and waning subcutaneous nodules, who was diagnosed with atypical lymphocytic lobular panniculitis. The biopsy showed a very striking lymphocytic infiltrate with focal loss of CD5, and CD7. The lymphocytes were composed of a mixture of CD4 and CD8 cells. The patient felt well. An outside consultant raised diagnostic considerations of subcutaneous anaplastic large cell lymphoma and gamma-delta panniculitis-like T cell lymphoma. The patient was categorized as having atypical lymphocytic lobular panniculitis over one of panniculitis-like T cell lymphoma. The TCR-β test shows dominant peaks at 187 bp for panel C and 257 bp for panel B. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostics Laboratory of Roswall Park Cancer Institute.) Two biopsies were obtained over 18 months showing quantitative progression of a constant T cell clonotype to eventuate into a true monoclonal profile.

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9/9/2003 TCR beta Panel C

Peak 189 bp

9/15/2004 TCR beta Panel C Peak 189 bp

6/2/2005 TCR beta Panel C

Peak 189 bp

A 46 year old man was diagnosed with pigmentary purpura. The TCR-β test shows monoclonal peaks at 189 bp for all three biopsies on panel C. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostics Laboratory of Roswall Park Cancer Institute.)

FIGURE 6.61

Additional Molecular and Cytogenetic Studies

137

TCR beta Block A1 Panel A Peak 254 bp

TCR beta Block B1 Panel A

Peak 254 bp

TCR beta Block A1 Panel C Peaks 185 & 303 bp

TCR beta Block B1 Panel C Peaks 185 & 303 bp

FIGURE 6.62 A 36-year-old man with nodules in the right thigh and leg was diagnosed with atypical lymphocytic lobular panniculitis. The molecular studies show similar results for two biopsies. Both of the TCR-β results from the two biopsies on panel A show a peak at 254 bp. On panel C, oligoclonal peaks are present at 185 bp and 303 bp. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of the Molecular Diagnostics Laboratory of Roswall Park Cancer Institute.)

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CHAPTER SEVEN

MARGINAL ZONE LYMPHOMA AND OTHER LOW-GRADE B CELL LYMPHOPROLIFERATIVE DISORDERS OF THE SKIN Cynthia M. Magro and A. Neil Crowson

Marginal Zone Lymphoma Clinical Features Low-grade B cell lymphoma of mucosa-associated lymphoid tissue was first recognized in 1983 as a distinct type of lymphoma (Isaacson and Wright, 1983) (Cavalli F, 2004). Marginal zone lymphomas constitute 25% of all primary cutaneous B cell lymphomas (Baldassano et al., 1999). Characteristically, these lymphomas arise in a background of reactive lymphoid hyperplasia. Marginal zone lymphomas of the skin also fall under the alternative designation of mucosal associated lymphoma (MALT)-like lymphoma of the skin (i.e., MALTOMAS) and skin associated lymphoid tissue lymphoma (SALTOMA) (Salama, 2000). Marginal zone lymphoma has emerged as a distinctive clinical and pathological entity recognized in the new World Health Organization–European Organization for Research and Treatment of Cancer (WHO–EORTC) classification scheme for cutaneous lymphoma (Slater, 2005).

Marginal zone lymphoma is most common in middle aged women. However it has also been described in the pediatric population (Bailey et al., 1996; Cerroni et al., 1997a; Servitje et al., 2002; Santucci and Pimpinelli, 2004; Hoefnagel et al., 2005; Sroa and Magro, 2005), where in our reported case an association with chronic antihistamine use was made. Antihistamines have been previously implicated as being causal of atypical reactive lymphoid hyperplasia (Magro and Crowson, 1995; Crowson and Magro, 1995; Slater, 2005; Sroa and Magro, 2005). Other antigenic triggers have been proposed including antidepressant therapy Borrelia burgdorferi and hepatitis C virus infection. It would therefore appear that iatrogenic and endogenous immune dysregulation play a role in the propagation of marginal zone lymphoma and other related B cell lymphomas (Cerroni et al., 1997b; Goodlad et al., 2000; Roggero et al., 2000; Viguier et al., 2002; Lic 2003; Breza and Magro 2006). The MALT-like lymphomas of the skin may present as (1) a primary lymphoma unassociated with extracutaneous disease; (2) with concurrent

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disease involving other extracutaneous sites (i.e. breast, orbit, and lung) or (3) a secondary lymphoma if it is previously established that the patient has MALT-like lymphoma elsewhere (typically of the gastrointestinal tract, orbit, breast, lung, or parotid). In all three groups, there is a significant risk of relapse. Nonetheless the disease process appears to be indolent with only rare cases progressing to a higher grade of lymphoma. Most patients with primary cutaneous marginal zone lymphoma do not develop extracutaneous disease. The most common expression of cutaneous marginal zone lymphoma is in the context of representing primary as opposed to secondary involvement of the skin (Cerroni et al., 1997a; Tomaszewski et al., 2000; Servitje et al., 2002). There are many series indicating that patients with marginal zone lymphoma have an excellent prognosis (>95% 5-year survival rate). In general, the patients have disease limited to local cutaneous recurrences while dissemination to internal organs is rare. Prognostically cutaneous marginal zone lymphoma is likely similar to follicle center cell lymphoma while certain other forms of primary cutaneous B cell lymphoma are associated with a variably more aggressive clinical course (Bailey et al., 1996; Cerroni et al., 1997a, b; Servitje et al., 2002; Santucci and Pimpinelli, 2004; Hoefnagel et al., 2005). (Lietal 2003). The relapse rate is highest in those patients who present with concurrent or previous marginal zone lymphoma involving extracutaneous organ sites and lowest in those with isolated lesions confined to the skin, specifically to the dermis, without evidence of extracutaneous organ involvement. Patients receiving local therapy as opposed to systemic treatment may have a higher incidence of recurrence. It is not uncommon for the recurrent lesions to manifest persistent site localization (Breza and Magro, 2006). The entity of immunocytoma is in essence a form of marginal zone lymphoma in which there is a significant component of neoplastic light chain restricted plasmacytoid cells. An alternative designation of plasmacytic marginal zone lymphoma has been used. The original definition as proposed by the Kiel classification was one of a low-grade B cell neoplasm of lymphocytes intermingled with immunoblasts and some plasmacytoid or atypical plasma cells as apposed to a monomorphous sheetlike proliferation of plasma cells, the latter defining plasmacytoma. The typical clinical presentation is in the context of grouped papular lesions with extremity localization (Figure 7.1) (Magro et al., 2004). Although primary cutaneous immunocytoma is usually unaccompanied by extracutaneous disease, patients in whom serologic studies revealed an underlying

Marginal zone lymphoma/immunocytoma. Classic clinical morphology of immunocytoma characterized by grouped coalescing erythematous to violaceous papules and plaques.

FIGURE 7.1

paraproteinemia of IgM isotype compatible with Waldenstrom’s macroglobulinemia have been de¨ scribed (Duncan and Leboit 1997; Andriko et al., 2001; Magro et al., 2004). (LeBoit et al., 1994). When there is localized disease, conservative treatment in the context of excision and/or radiotherapy seems adequate. For disseminated disease and/or disease that includes both extracutaneous and cutaneous lymphoma, systemic chemotherapy is indicated (See Table 7.1) (Kerl et al., 2004; Hoefnagel et al., 2005). Treatment options are discussed in greater detail in Chapter 2. Pathology The morphological hallmarks are pandermal diffuse and nodular infiltrate of lymphocytes with a heterogeneous composition including centrocyte-like cells (small slightly irregularly contoured lymphocytes with cleaves/grooves traversing the nucleus), small rounded cells (i.e., similar for chronic lymphocytic leukemia), and monocytoid and/or plasmacytoid cells (see Figures 7.3, 7.4, 7.8–7.10, 7.14, 7.15, 7.26, 7.29–7.33, 7.35, and 7.36). The monocytoid cells exhibit rounded nuclei with clear cytoplasms and sharp cytoplasmic membranes. The plasmacytoid component typically shows κ or λ light chain restriction Figures 7.20a and 7.20b; they may represent fully differentiated plasma cells with dysplastic features or small mature lymphocytes with nuclear and cytoplasmic features suggesting early plasmacytic differentiation. The atypical plasma cells exhibit binucleation, a finely dispersed chromatin, nuclear contour irregularity, and Dutcher body formation. Dutcher bodies are pseudoinclusions representing immunoglobulin-rich cytoplasmic invaginations superimposed on the nucleus (Figures 7.27, 7.28, 7.33).

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TABLE 7.1 Marginal Zone Lymphoma Clinical Adults (predilection for middle aged women) Rarely children (chronic antihistamine use has been described) Solitary or grouped papules/nodules Upper extremities, trunk Immune dysregulation, iatrogenic or endogenous, is common Associations include hepatitis C infection, antidepressant and antihistamine therapy, and Borrelia infection Subcategories Primary versus secondary Potential triggers Infection hepatitis C, Epstein–Barr virus (as part of post-transplant lymphoproliferative disease), Borrelia Drug (fluoxetine and antihistamines) Underlying collagen vascular disease(Sjogren’s syndrome/rheumatoid arthritis) Histomorphology Patchy, nodular or diffuse infiltrates Heterogeneous small lymphocytes: round, cleaved, and monocytoid Dysplastic plasma cells Adnexal accentuation is typical with frank epitheliotropism Deeper seated accentuation compared to the intensity of infiltration superficially Subcutaneous involvement in secondary marginal zone lymphoma Reactive germinal centers are common Immunophenotype CD20, CD79a+ (CD20− following rituximab) CD5, CD10, Bcl-6; predominantly negative; however, CD5+ cases described CD43+/− CD23− (occasionally CD23+) clg+ (monoclonal) Cell of Origin Postgerminal center B cell Genetics Trisomy 3 T(11:18)(q:21 q:21) resulting in the fusion of apoptosis inhibitor gene to a novel gene at 18q21 MALT. Fusion product designated as AP12-MALT1 T(14:18) (q32;q21) involving the MALT1 and IgH genes Therapy Excision of solitary lesions; systemic steroids, radiotherapy; interferon-α and anti-CD20 antibody (rituximab) Antibiotic treatment effective in some B. burgdorferi induced (European) cases; systemic chemotherapy if extracutaneous spread. Cessation of potential implicated drugs (i.e. antidepressants)

The plasma cell plasmacytoid aggregates may be found in apposition to the eccrine coil and epidermis. Reactive germinal centers are identified in 75% of cases of marginal zone lymphoma (Figures 7.7, 7.13, 7.17, 7.23a, 7.24). In our experience, a background of reactive lymphoid hyperplasia is seen in most cases of marginal zone lymphoma. Colonization of the germinal centers by the small neoplastic cell population is typical. Infiltration of the eccrine ductular and follicular epithelium by B lymphocytes is a helpful clue, which, if present, is a strong indicator of marginal zone lymphoma. Subcutaneous involvement is more typical of patients who have secondary MALT lymphoma or subsequently develop marginal zone lymphoma at extracutaneous sites. (Bailey et al.,

1996; Cerroni et al., 1997a; Baldassano et al., 1999; Arai et al., 2005). (See Case Vignettes 1–4.) In those marginal zone lymphomas categorized as immunocytoma, the infiltrates typically show perivascular and periadnexal accentuation and are associated with better preservation of the dermal architecture compared to classic marginal zone lymphoma. Although there is a small lymphocytic component identical to that encountered in marginal zone lymphoma, there are many more admixed neoplastic plasmacytoid cells, a finding that is conspicuous around venules (Magro et al., 2004). The plasma cells exhibit dysplastic features. Among these are nuclear shape irregularity, a less condensed chromatin,

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multinucleation, and anisonucleosis with an overall larger cell size. Marginal zone lymphomas may undergo blastic transformation, a feature that may herald a more aggressive clinical course. The blasts have a finely dispersed chromatin, prominent nucleoli, and a moderate amount of clear cytoplasm that expresses CD19, CD20, and IgM but not CD10 or CD23. To render a diagnosis of blastic transformation implies the emergence of a large cell lymphoma in a preexisting MALT lymphoma. There must be sheets or aggregates of transformed lymphocytes. Scattered larger centroblasts and/or immunoblasts admixed with the small lymphoid populace do not qualify as blastic transformation. In the later scenario the large cells interspersed with the small lymphocytic infiltrate are characteristically CD30 positive. We have also encountered unusual sclerosing morphologic variant of MALT-like lymphoma. Ofcourse Paraneoplastic sclerosis, is usually in the context of a monoclonal gammopathy of undetermined significance or with other forms of extracutaneous plasma cell dyscrasia. The classic scenarios are scleromyxedema and POEMS syndrome. We recently encountered a case that was best categorized as a form of sclerosing immunocytoma, in which the biopsy showed a morphology indistinguishable from scleromyxedema with a supervening λ light chain restricted plasmacytoid infiltrate (Figure 7.2) (See Case Vignette 5.) Phenotype The infiltrate is dominated by cells exhibiting expression of pan B cell markers such as CD20 and CD79; the small lymphoid cells are typically CD23 negative and show variable CD21 expression (see Figures 7.6, 7.7, 7.12, 7.13, 7.17–7.21, 7.23, 7.25, 7.34, and 7.37–7.39). They are bcl-2 positive and at least 40% of cases will manifest CD43 coexpression. The neoplastic small lymphocytic component usually does not demonstrate coexpression of CD5 or CD10. There are scattered germinal centers that may be permeated by the neoplastic small lymphocytic infiltrate (Yang, 2000). The germinal centers exhibit a reactive phenotype with an organized CD21and CD23-positive dendritic network and contain small and large cleaved centrocytes and centroblasts. The centrocytes and centroblasts are CD21- and CD23-negative, manifest CD20 positivity, and show moderately intense CD10 expression (see Figures 7.7, 7.13, 7.17, and 7.23). The centrocytes and centroblasts within the germinal centers do not demonstrate bcl-2 positivity, but the small reactive lymphocytes permeating the germinal centers are bcl-2 positive

FIGURE 7.2 Sclerosing immunocytoma (scleromyxedemalike) mimicking eruptive dermatofibromas. The patient was a healthy weight lifter who developed multiple indurated pink papules, raising diagnostic consideration to eruptive dermatofibroma. The biopsy showed an unusual pattern of multinodular sclerosis very reminiscent of scleromyxedema. The molecular studies revealed a clonally restricted B cell population while the phenotypic studies exhibited a λ light chain restricted plasmacytic infiltrate. A diagnosis of a sclerosing variant plasmacytic marginal zone lymphoma/immunocytoma was made. (Also see molecular gels 7.40 and 7.41.)

(see Figure 7.25). Scattered macrophages are noted within the germinal centers. The integrin a4b7, a for MAdCAM-1, a homing receptor found in high endothelial venules of gastrointestinal mucosa, has been identified within the vascular endothelium of cutaneous marginal zone lymphomas, providing further support to potential pathogenetic commonality between marginal zone lymphomas of the skin and its extracutaneous counterpart (Baldassano et al., 1999). The tumor cells typically express IgM and less often IgA or IgG (Chimenti et al., 1996; Gronbaek et al., 2000; Tomaszewski et al., 2000; de Leval et al., 2001). Although marginal zone lymphomas are characteristically CD23 negative, we have recently reported CD23 expression in marginal zone lymphoma of the skin associated with recurrent disease and in one case of a marginal zone lymphoma that underwent blastic transformation (Magro CM, 2006). The expression of CD23 was mainly localized to large transformed cells but was seen as well in small neoplastic lymphocytes. Normally, CD23 is expressed on na¨ıve B cells, monocytes, and follicular dendritic cells and commonly on B chronic lymphocytic leukemia cells. In human tonsillar tissue, CD23 is a precentroblast marker, expressed on na¨ıve B cells both in the mantle zone and early germinal center phase. It is upregulated in the

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early stages of B cell activation by interleukin-4 and functions as an IgE receptor and lymphocyte growth factor (Bonnefoy et al., 1997). In particular it enhances IgE production, and augments B cell proliferation. CD23 has been linked to receptor–ligand interactions between T and B cells with effects on the CD40–CD40L pathway, whereby CD23 is induced after B cell signaling through CD40 and may confer a lymphocyte survival advantage (Magro CM, 2006). Human B lymphocytes induced from a resting state to one of blastic transformation demonstrate CD23 expression, albeit at low levels, and half of the cells express CD5 (Wheeler and Gordon, 1996). Those transitional B cells that exhibit CD23 expression have a tendency to localize to splenic follicles and to proliferate vigorously in response to various antigenic stimuli compared to those that are CD23 negative (James et al., 1990). In a recent study, two of four cases of splenic marginal zone lymphoma that lacked a 7q31 deletion had an atypical immunophenotype because they were partially CD23 positive (Boonstra et al., 2003). Apoptosis regular B cell lymphoma 10 (BCL 10) has been reported in up to 36% at primary cutaneous marginal zone lymphoma and has been linked with a tendency toward extracutaneous dissemination (Gallardo F et al., 2006). The immunocytomas comprise plasma cells that typically do not show CD20 expression although the neoplastic small lymphocytic component is CD20 positive. The plasma cells may exhibit CD56 positivity. The infiltrates demonstrate light chain restriction, which is disproportionately more often λ positive compared to other B cell lymphomas. The small lymphocytic component appears phenotypically abnormal (Magro et al., 2004); the small lymphoid cells characteristically show a marginal zone lymphoma profile, expressing CD20 and CD79, but none of CD5, CD10, or CD23. There may or may not be coexpression of CD43 (i.e., suggesting a postgerminal center cell origin) (Magro et al., 2004). On rare occasions the phenotype may be one that mimics chronic lymphocytic leukemia/small lymphocytic lymphoma, with cells of B cell lineage expressing CD5 (Ferry et al., 1996; Batstone et al., 2003). The cells are truly of marginal zone origin and lack the t(11:14) translocation seen in mantle cell lymphoma and trisomy 12 characteristic of small lymphocytic lymphoma (Batstone et al., 2003). If the patient has been receiving rituximab therapy, the recurrent tumors often show loss of CD20 expression, reflecting a reduction in mRNA synthesis of the CD20 molecule. The small lymphocytic component is CD20 positive, but the plasma cells are usually CD20 negative and may express CD56.

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We have now encountered one case of EBERpositive immunocytoma in a renal transplant patient, suggesting that rare cases of plasmacytic marginal zone lymphoma are forms of monomorphic posttransplant lymphoproliferative disease. The clinical and pathologic spectrum of EBV-associated B cell lymphoproliferative lesions is discussed elsewhere (Chapter 20) (Verma et al., 2005). It would be our recommendation to evaluate any immunocytoma/marginal zone lymphoma for expression of EBER (hence indicative of at least latent and potentially lytic EBV infection) in the clinical setting of solid organ transplantation. It should also be emphasized that a number of reactive T cells may be present; however, the diagnosis becomes apparent with the combination of in situ hybridization studies showing a light chain restricted infiltrate and the heavy chain immunoglobulin rearrangement assay, which demonstrates a clonally restricted B cell infiltrate. (Kamarashev J, 2001). Molecular Studies Heavy chain immunoglobulin rearrangement studies typically show a clonal restriction (Yang et al., 2000), but the incidence of false-negative cases is much higher compared to that encountered in T cell lymphoma. This assay is not as sensitive as either the TCR-γ or TCR-β gene rearrangement assays, but is much more specific; a heavy chain immunoglobulin rearrangement strongly supports a low-grade B cell lymphoproliferative process. The far greater number of false-negative cases reflects the fact that a significant percentage of the infiltrate is reactive. In our hands automated Ventana mRNA analysis typically shows κ or λ light chain restriction in plasmacytic forms including differentiated plasma cells or plasmacytoid small lymphocytes (7.20a and b 7.34a 7.40–7.43). Pathogenesis Mutation analysis of the rearranged immunoglobulin (Ig) genes provides information on the differentiation stage of normal and neoplastic B cells. As such, three levels of peripheral B cell maturation can be recognized. Before antigen exposure, mature but naive B cells display unmutated rearranged Ig genes. On encounter with antigen, affinity maturation of the B cells takes place in the microenvironment of the germinal center. The B cells proliferate, acquire somatic mutations, and undergo isotype switching. Those B cells with the best fit for the antigen are selected and differentiate into plasma cells or memory B cells on leaving the germinal center. B cell neoplasms can therefore be classified into

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three categories: pregerminal center cell, germinal center cell, and postgerminal center cell origin. Thus, follicular lymphoma displays highly mutated Ig genes and on-going mutations consistent with its germinal center cell origin. In contrast, mantle cell lymphomas typically, but not always, have rearranged Ig genes with or without few somatic mutations, which is consistent with its derivation from naive B cells. Finally, lymphomas with Ig gene somatic mutations but lack of ongoing mutations are thought to have a postgerminal center cell origin and are best exemplified by marginal zone lymphoma (Coupland SE, 1999). (Aarts et al., 1998; Kamarashev et al., 2001; Servitje et al., 2002; Smith et al., 2004). The phenotypic profile also supports that the cell of origin in marginal zone is not the marginal zone lymphocyte. Firstly the benign marginal zone counterpart exhibits CD23 positivity without coexpression of CD43. Secondly, κ light chain-expressing plasmacytic cells are a characteristic feature of marginal zone lymphoma. The typical reactive marginal zone lymphocyte, in fact, does not undergo progressive plasmacellular differentiation. In summation the phenotype most closely resembles the postgerminal center memory B cells by virtue of the absence of CD23 expression and the presence of light chain restricted plasmacytic cells (Yang et al., 2000; Servitje et al., 2002; Santucci and Pimpinelli, 2004). There is no normal lymphoid tissue of B cell phenotype within the skin that could give rise to this tumor, thus a preexisting state of B-cell-rich benign lymphoid hyperplasia presumably exists. Borrelia burgdorferi has been associated with low-grade lymphomas including marginal zone lymphoma. Cerroni and co-workers (1997b) identified Borrelia burgdorferi antigen through polymerase chain reaction and Southern blot hybridization studies in primary cutaneous B cell lymphomas including marginal zone lymphomas, immunocytoma, and diffuse large cell B cell lymphoma. In one study, 50 cases of primary cutaneous B cell lymphoma were assessed for specific DNA sequences for Borrelia burgdorferi; such sequences were identified in 18% of cases including those patients with marginal zone lymphoma and immunocytoma. As previously mentioned, we have encountered a single case of EBV-associated marginal zone lymphoma in a renal transplant patient. Hepatitis C virus infection with concomitant monoclonal cryoglobulinemia has been associated with low-grade extracutaneous B cell lymphomas including Waldenstrom’s macroglobulinemia, immunocytomas, and ¨ marginal zone lymphomas at various sites (Silvestri et al., 1997). We and others have reported an association between hepatitis C virus infection and both

classic marginal zone lymphoma and immunocytoma (Viguier et al., 2002; Magro et al., 2004). In our case, subsequent follow-up demonstrated tumoral regression associated with a reduction in viral load (as discussed with Dr. David Wright, Tucson, AZ). In both reported cases, the RT in situ PCR analysis was negative for hepatitis C viral RNA (Crowson et al., 2003). Although it is well established that the virus is tropic to B lymphocytes, it is possible that the virus is not directly oncogenic but rather induces chronic B cell lymphoproliferation through antigenic stimulation. We have encountered cases of marginal zone lymphoma developing in the setting of immune dysregulatory therapy, primarily in the context of antidepressant and antihistamine therapy. We were able to show suppression of T cell proliferation using an in vitro system; live T cells were exposed to physiologic concentrations of fluoxetine and phytohemagglutinin. Not all antidepressants evoked this suppressive response. It was observed only with amitriptyline and fluoxetine, both of which are antidepressants associated with the development of cutaneous pseudolymphomata (Magro and Crowson, 1995; Crowson and Magro, 1995) (Magro and Breza 2006). A suppressive response on T cell function was not observed with bupropion nor have we established an association between marginal zone lymphoma and bupropion administration (Breza and Magro, 2006). This information is of interest both from a pathogenetic perspective and in regard to alternative therapeutic options for those patients who develop atypical lymphocytic infiltrates in the setting of antidepressant therapy. Regarding the plasmacytic variant of marginal zone lymphoma, the majority of the patients had underlying immune dysregulatory states, the spectrum comprising hepatitis C infection, drug therapy in the setting of methotrexate and cyclosporin treatment, other forms of lymphoma, collagen vascular disease including Sjogren’s syndrome and rheumatoid ¨ arthritis, ulcerative colitis, and autoimmune thyroid disease. (Table 7.2) (Magro et al., 2004). We speculate that an antigenic trigger precipitates the immune response due to defects in T cell regulation. The result is reactive lymphoid hyperplasia followed by the emergence of clones responding to specific antigens with a subsequent transforming oncogenic hit. Cytogenetic Abnormalities and Oncogenes Trisomy 3 is found in 60% of cases of marginal zone lymphoma and t(11:18) (q21:q21) has been observed in 25–50% of the cases (Wotherspoon et al., 1995; Brynes et al., 1996; Gazzo et al., 2003).

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TABLE 7.2 Immunocytoma Clinical Adults, elderly Solitary or grouped plaques or tumors Lower extremities most often Endogenous and iatrogenic immune dysregulation is very common Rare IgM paraproteinemia Basically a plasmacytic variant of marginal zone lymphoma Histomorphology Can be very subtle being defined by angiocentric infiltrates of small mature lymphocytes and plasma cells, the latter showing dysplastic features Dutcher bodies frequent Occasionally, the more effacing and nodular growth pattern typical for classic forms of marginal zone or follicle center cell lymphoma can be seen Immunology CD20, CD79a+ CD5− usually (rarely CD5+) CD10−, Bcl-6 − CD43+/− clg+ (monoclonal) In situ hybridization studies show light chain restriction frequently of λ subtype Genetics Monoclonal rearrangement of the JH gene in most Trisomy 3; t(11:18) (q21:q21) Therapy Radiotherapy Surgical excision of solitary lesions Antibiotic treatment effective in some Withdrawal of immune dysregulating drug

Analysis of the t(11:18) breakpoint has shown fusion of the apoptosis-inhibitor gene API2 to a novel gene at 18q21 designated as the MALT1 gene to produce the API2- MALT1 fusion protein. Acquired cytogenetic abnormalities including the loss of 3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of marginal zone lymphoma (Mao et al., 2002). It is hypothesized that trisomy 3q may account for the indolent behavior of marginal zone lymphoma while the loss of this acquired abnormality may explain the development of blastic tumors (Martinez-Climent et al., 2003). Other cytogenetic abnormalities have been isolated including a translocation at roughly the same locus as the IgG-Bcl-2 translocation, namely, t (14:18) (q32;q21). However, it involves the MALT1 and IgH genes (Streubel et al., 2003). One study showed the MALT1 translocation in a small percentage of primary cutaneous marginal zone lymphomas, while it was absent in another study (Espinet et al., 2004). Other studies have assessed for translocations within the IGH, MYC, Bcl-6, and MALT1 loci in cutaneous marginal zone lymphoma and failed to show consistently positive

results (Mao et al., 2002; Espinet et al., 2004; Hallermann et al., 2004). Differential Diagnosis The main differential diagnosis is with reactive cutaneous lymphoid hyperplasia. Among the morphologic features favoring lymphoma are greater density of infiltration toward the base of the biopsy, permeation of the subcutaneous fat by lymphocytes, and plasmacellular atypia, features of which are bi- and trinucleation of plasmacytic cells, irregular nuclear contours, finely distributed chromatin, and significant size variability that is characteristic for marginal zone lymphomas. Perhaps more useful are phenotypic features. (Leimweber et al., 2004). The following supports a reactive etiology: a B to T cell ratio that is less than or equal to 3:1, a relative preservation of CD23 amid the small lymphocytic infiltrate, a κ to λ ratio of less than 4:1, and the presence throughout the lesions of nodules of lymphocytes with a reactive germinal center cell phenotype as characterized by modest CD10 positivity and a preserved CD21 and CD23 dendritic network with absent bcl-2 expression by centroblasts and centrocytes. In marginal zone lymphoma, the

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plasmacytoid cells will show light chain restriction whereby if this kappa restricted the ratio is in excess of 5:1. The small lymphocytes will not express CD23. Some of the germinal centers will demonstrate lysis of the CD23 and CD21 network. The disintegration of the CD23 and CD21 network reflects infiltration of the germinal centers by small neoplastic marginal zone lymphocytes (Leinweber et al., 2004; Arai et al., 2005). The very strong CD10 staining seen in nodal follicular lymphomas and the complete absence of CD10 expression seen in some primary cutaneous follicular lymphomas are not seen in marginal zone lymphoma lesions outside the setting of a composite lymphoma. The differential diagnosis of immunocytoma would encompass those reactive and neoplastic entities in which there is a significant component of plasmacytic infiltration, namely, plasmacytoma and reactive conditions rich in perivascular plasma cells including chronic infections such as secondary syphilis and certain connective tissue disease syndromes such as morphea and lichen sclerosus. Immunocytomas can be deceptively bland because the low power architecture mimics a reactive process as defined by moderately dense angiocentric infiltrates, which surround and permeate vessels, oftentimes with superficial localization. Demonstration of light chain restriction in the plasma cells would clearly rule out a reactive process. The lesions of immunocytoma are frequently λ light chain restricted. The expression of λ should never exceed that of κ in a reactive process; even a codominance of λ and κ may suggest an emerging light chain restricted infiltrate. In contrast to plasma-cell-rich variants of marginal zone lymphoma (i.e., immunocytoma), plasmacytomas are malignant neoplasms that comprise a monomorphous population of plasma cells without a background population of atypical small lymphocytes or lymphoplasmacytic cells (Magro et al., 2004).

Castleman’s Disease Castleman’s disease defines a B cell lymphoproliferative state that classically presents as a solitary mediastinal mass reflecting a lymph node-based proliferation, formerly termed giant follicular lymphoid hyperplasia (Castleman et al., 1956). (See Case Vignette 7.) Ninety percent of cases of Castleman’s disease present in the context of unicentric lymph node disease. The patients are usually asymptomatic and treatment is complete excision. On occasion, the distinctive pathology that defines this condition presents outside the mediastinum and can involve the mesenteric, perinephric, and retroperitoneal lymph

nodes and even extranodal sites including, rarely, the skin. The less common form of Castleman’s disease is the multicentric form, which corresponds to two morphologic variants, namely, the plasma cell and mixed variants, the latter showing overlap features between the classic unicentric hyaline vascular type and the plasma cell form (see Figure 7.46) (Xojima et al., 2003). It is the multicentric one that is more likely to be associated with skin manifestations. Multicentric Castleman’s disease is not a malignancy per se but has a high incidence of concurrent or ensuing malignancy including B cell lymphoma, leukemia, and multiorgan Kaposi’s sarcoma. The condition is associated with considerable morbidity and mortality due to profound wasting and a high incidence of infection. There are a number of serologic abnormalities including a high C reactive protein, polyclonal hypergammaglobulinemia, thrombocythemia, and a monoclonal gammopathy. Additional features of the multicentric form are splenomegaly and lymphadenopathy and serous effusions. The thrombophilic tendency is usually attributable to thrombocythemia (Jackson and Burton, 1990). In contradistinction, unicentric Castleman’s disease is typically asymptomatic (Kingsmore et al., 1993). Patients with multicentric Castleman’s disease may have other clinical stigmata that would fulfill clinical criteria to warrant the designation of POEMS syndrome. POEMS syndrome is an acronym for polyneuropathy, osteosclerotic bone lesions, endocrinopathy, monoclonal gammopathy, and skin lesions. Eleven to thirty percent of patients with POEMS syndrome have Castleman’s disease (Adelman et al., 1994). The remaining patients have a more indolent form of multiple myeloma associated with osteosclerotic bone lesions, where the extent of neoplastic plasma cell infiltration of the marrow is significantly less than that encountered in classic Castleman’s disease. (Lipsker D et al., 2003). Human herpesvirus 8 (HHV8) and interleukin6 have been implicated in multicentric Castleman’s disease; viral interleukin-6 production may be upregulated by HHV8 and may in turn result in the acceleration of human interleukin-6 production. Interleukin-6 has pleiotropic biologic effects, among which are the terminal differentiation of B cells into plasma cells and the enhancement of vascular endothelial cell growth factor. Among the various skin lesions are erythematous and violaceous nodules and plaques without scaling. Many of the skin manifestations seen in patients with Castleman’s disease are paraneoplastic sequela, the classic example being paraneoplastic pemphigus.

Marginal Zone Lymphoma and Other Low-Grade B Cell Lymphoproliferative Disorders of the Skin

Light Microscopic Findings The skin lesions associated with Castleman’s disease are described mainly in the context of POEMS syndrome and are defined by unusual vasoformative proliferations. They have fallen under various designations such as glomeruloid hemangiomas defining a morphology reminiscent of reactive angioendotheliomatosis (Chan et al., 1990; Judge et al., 1993; Del Rio et al., 1994). In our experience, the lesions frequently have an infiltrative quality, resembling an infiltrative hemangioma/microvenular hemangioma (Del Rio et al., 1994). Another paraneoplastic cutaneous feature is a sclerodermoid tissue reaction. In addition, however, a morphology recapitulating that seen in the lymph nodes has been described in the skin (Sleater and Mullins, 1995; Klein et al., 2004); thus, the biopsy will show atrophic germinal centers containing prominent hyalinized vessels (see Figures 7.44 and 7.45) (Keller et al., 1972) and a proliferation of plasma cells that may assume a sheet-like effacing pattern. Localization of changes to the subcutaneous tissue has been described (Sleater and Mullins, 1995). The infiltrates may or may not show evidence of light chain restriction. Subcutaneous plasmacytomas have been described in patients with POEMS syndrome (Lipsker et al., 2003). Phenotyping In the plasmacellular variant, the population is typically polyclonal. If the biopsy does show an ensuing light chain restricted plasmacytic population, then recategorization as a lymphoma arising in a background of multicentric Castleman’s disease must be considered. Pathogenesis Patients with multicentric Castleman’s disease have significantly elevated antibodies to HHV8 and in situ hybridization studies may demonstrate the virus in tissue. These patients have markedly elevated levels of vascular endothelial cell growth factor in their serum, which clearly plays a role in the pathogenesis of other aspects of their clinical presentation, namely, the concomitant atypical vasoformative lesions that develop. The source of vascular endothelial cell growth factor has been a source of debate but it may derive from plasma cells. Interleukin-6 is responsible for many of the other symptoms including the fatigue and wasting. Because of the role of interleukin-6 in inducing B cell differentiation, therapy with antiinterleukin-6 has shown promising results (Mandler et al., 1992; Murata et al., 2000), with most

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patients experiencing an improvement in lymphadenopathy and constitutional symptoms. HHV8 infection results in viral interleukin-6 gene transcription. Viral interleukin-6, in turn, is a transducer of gp130 that stimulates human interleukin-6 production.

Primary Cutaneous Plasmacytoma Cutaneous dissemination in the setting of known multiple myeloma portends a poor prognosis and is typically associated with advanced disease (Requena et al., 2003; Ortin et al., 2004; Alexandrescu et al., 2005), where an association with immunomodulatory therapy with thalidomide has been described. Extramedullary plasmacytoma most commonly affects the upper nasal passages; patients typically die within months of cutaneous dissemination (Requena et al., 2003). However, plasmacytoma also defines a rare form of primary cutaneous B cell neoplasia. Among the therapeutic interventions are radiation for localized disease and combined radiotherapy and chemotherapy for disseminated disease. There is one report of disseminated cutaneous plasmocytoma responsive to total skin radiotherapy and bortemzomib chemotherapy; the lesions underwent complete regression (Floyd et al., 2005). A specific trigger has been postulated in those cases of cutaneous plasmacytoma manifesting labial localization; cases of primary mucosal and/or cutaneous plasmacytoma localized to the lip may be temporally associated with recurrent herpes labialis infection. One patient developed cutaneous plasmacytosis after 13 years of recurrent labial herpes (Zendri et al., 2005). An association with Epstein–Barr virus infection and solid organ transplantation has been described with approximately six cases reported in the literature. As with other forms of primary cutaneous post-transplantation lymphoproliferative disease, the skin lesions occur several years after transplantation (Carbonelle et al., 2004; Buffet et al., 2004; Tessari et al., 2004; Fabbian et al., 2004). In one citation describing two cases, the lesions occurred 7 years and 8 years after transplantation and manifested, respectively, leg and thigh localization (Buffet et al., 2004). Most of the reports have been in the context of renal transplantation. From a demographic perspective, it is a disease of the elderly with a mean age of presentation being 60 years and a male sex predilection (see Table 7.3). Fifty percent of patients demonstrate disease progression with extracutaneous dissemination. Some studies have suggested a disease-associated mortality of approximately 40%. Factors adversely affecting prognosis include the extent of disease and

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TABLE 7.3 Plasmacytoma Clinical Elderly Males > females Solitary, grouped, or multifocal plaques and tumours Head, trunk most often Histomorphology Nodular and/or diffuse infiltrates, mature and immature plasma cells Immunophenotype CD45(LCA), CD20− CD38, CD138+ CD79a+/− CD56+ Genetics Monoclonal rearrangement of the JH gene detected in most. Therapy Radiotherapy Excision of solitary lesions Systemic chemotherapy for generalized disease

whether or not the neoplastic cells elaborate IgA. Some cases of cutaneous plasmacytoma may be associated with multiple myeloma; features suggesting concurrent multiple myeloma include osteolytic bone lesions, a urine or plasma paraprotein, and marrow plasmacytosis. The identification of a monoclonal paraprotein is not diagnostic of multiple myeloma but should prompt careful clinical evaluation to exclude the diagnosis. Twenty-five percent of patients with extramedullary plasmacytosis have a monoclonal paraprotein (Bayer-Garner et al., 2003). Light Microscopic Findings There is a sheet-like infiltrate of plasma cells, sometimes with accentuation around vessels and adnexal structures. The cells appear well differentiated but have dysplastic features that include size variation, bi- and trinucleation, Dutcher bodies, and less condensed chromatin. Some cells show a finely dispersed chromatin without the characteristic regular coarse peripheral clumping that defines a benign plasma cell (Kazakov et al., 2002).

Phenotyping The cells are typically CD20 negative but express CD79 and CD138, epithelial membrane antigen, CD43, and CD117 (Bayer-Garner et al., 2003). There may be focal CD56 positivity. In situ hybridization studies show κ or λ light chain restriction (BayerGarner et al., 2004). While 30% of all marrow-based myelomas are lysozyme positive, lysozyme is not expressed by cutaneous plasmacytomas. Molecular Studies Heavy chain immunoglobulin gene rearrangement is variable and has been reported to be negative. Pathogenesis An association between recurrent herpes labialis and primary mucosal/paramucosal plasmacytoma is of interest from a pathogenetic perspective (Zendri et al., 2005). It has been postulated by some authors that keratinocytes have functional Toll-like receptors. The virus, by interacting with keratinocyte-based Toll-like receptors, may lead to the transcription of the gene that encodes interleukin-6, an important stimulant for plasma cell differentiation via the induction of maturation of mature B cells into plasma cells. Interleukin-6 may also have some oncogenic effects via enhancement of C-MYC and is antiapoptotic. Differential Diagnosis Plasmacytic infiltrates are common in reactive lesions. Among the most exuberant of these are those plasmacytic infiltrates that can accompany primary cutaneous epithelial malignancies. We frequently stain such cases for κ or λ to rule out the possible colonization of a primary epithelial tumor with a neoplastic plasmacytic disorder. There are also a number of infections that can be associated with an exuberant plasmacytic infiltrate. These include Borrelia burgdorferi, syphilis, and primary viral infections, especially herpes. The most simple approach to establishing a diagnosis of reactive plasmacytosis over one of neoplastic derivation is via immunohistochemistry or an in situ hybridization assay to assess for κ or λ light chain restriction.

Case Vignette 1

CASE VIGNETTES CASE VIGNETTE 1

The patient is a 75 year old woman with a history of orbital marginal zone lymphoma who now presents with multiple cutaneous nodules. A skin biopsy was performed. Also available for examination is the orbital biopsy. Diagnosis: Marginal zone lymphoma secondarily involving the skin (Figures 7.3–7.13).

Under 10× objective magnification one can see that the infiltrate is predominated by small monomorphous appearing mature lymphocytes. Dispersed throughout the lesion are reactive germinal centers as characterized by nodules containing centroblastic cells with admixed tingible body macrophages.

FIGURE 7.3 One of the skin nodules demonstrates a massive nodular lymphoid infiltrate, which effaces the dermal architecture.

FIGURE 7.4

Higher power magnification reveals the infiltrate to be composed of small mature lymphocytes.

FIGURE 7.6

FIGURE 7.5

A CD3 preparation shows only a smattering of T lymphocytes suggesting that the dominant lymphoid popular is one of B cells.

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CASE VIGNETTE 1

(Continued)

FIGURE 7.7 A CD23 preparation highlights the reactive germinal centers and also shows the irregular nature of the dendritic network due to infiltration of the germinal center by small marginal zone lymphocytes.

FIGURE 7.8 The patient presented initially with an orbital mass. There is extensive infiltration of the orbital soft tissue by a diffuse nodular lymphocytic infiltrate.

The infiltrate is predominated by small mature lymphocytes in the 7–9 µm size range.

FIGURE 7.10 Under 40× one can see that the dominant cytomorphology is a small lymphocyte; however, there is some element of cytomorphologic heterogeneity. Specifically, some of the cells have a small cleaved appearance while other cells appear more plasmacytoid, demonstrating a closely condensed heterochromatin and a peripheral nuclear disposition. A few plasma cells are also noted.

FIGURE 7.9

Case Vignette 1

Under 100× objective magnification, the heterogeneous nature of the cytomorphology is further exemplified. Specifically, there are cells with a small lymphoplasmacytoid appearance as characterized by a peripheral condensation of chromatin to the nuclear membranes with conspicuous centrally located nucleoli with variable eccentric disposition of the nucleus and somewhat amphophilic cytoplasm. As well, there are small cleaved lymphocytes with angulated and irregularly contoured nuclear profiles. These cells are roughly the same size as the adjacent red cells (i.e., in the 7–9 µm size range). FIGURE 7.11

Immunohistochemical stains reveal that the infiltrate is predominated by CD20 positive B lymphocyte (20×).

FIGURE 7.12

A CD23 preparation highlights germinal center-like foci although it shows extensive lytic alteration of the germinal centers by virtue of infiltration of the germinal center-like foci by small lymphocytes. As well, the small lymphocytes are noticeably CD23 negative. FIGURE 7.13

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CASE VIGNETTE 2

The patient is a 75 year old man with a longstanding history of multiple skin nodules, which have followed a waxing and waning course previously diagnosed as marginal zone lymphoma. A recent lesion was biopsied. Diagnosis: Classic cutaneous marginal zone lymphoma (Figures 7.14–7.28).

FIGURE 7.14

Low power examination under 2× objective magnification reveals a dense nodular infiltrate that focally effaces the dermal architecture.

FIGURE 7.15

Higher power magnification shows that the dominant infiltrate is one of a small mature lymphocytes with hyperchromasia and slight nuclear angulation. As well, there are scattered large centroblastic cells with vesicular chromatin and multiple chromocenters.

FIGURE 7.17 A CD21 preparation highlights reactive germinal centers (20× objective magnification). Nevertheless, there is some irregularity in the dendritic staining pattern with significant areas of dendritic cell lysis due to infiltration of the germinal center-like foci by neoplastic small lymphocytes.

FIGURE 7.16

Higher power magnification shows that the infiltrate is predominated by small mature lymphocytes.

Case Vignette 2

FIGURE 7.18 There is positive staining of B lymphocytes with the pan T cell marker CD43.

(a)

Higher power magnification shows intense staining of the cells for CD20.

FIGURE 7.19

(b)

In situ hybridization studies do not reveal any of the staining of the infiltrate for lambda (a), although there is extensive staining for kappa (b).

FIGURE 7.20

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CASE VIGNETTE 2

(Continued)

FIGURE 7.21 The biopsy demonstrates a striking multinodular lymphocytic infiltrate involving the entire sampled thickness of the dermis with a narrow grenz zone of uninvolved dermis separating the infiltrate from the overlying epidermis.

(a)

FIGURE 7.22 Higher power magnification reveals an infiltrate comprising small and intermediate sized lymphocytes.

(b)

FIGURE 7.23 The CD21 preparation highlights a dendritic antigen presenting cell network within the reactive germinal centers. (a) The findings are in contradistinction to those encountered in neoplastic germinal centers, whereby there is significant dendritic cell lysis due to penetration of the germinal center by neoplastic small lymphocytes. (b).

Case Vignette 2

A CD10 preparation shows weak staining of the germinal center-like foci (20× objective magnification.)

FIGURE 7.24

A bcl-2 preparation shows positive staining amid the centroblastic and immunoblastic cells of the germinal center-like foci. The two possibilities are those of infiltration of the germinal center by neoplastic marginal zone lymphoma cells versus incipient neoplastic transformation of follicles. It is well established that composite lymphomas, combining overlap features of marginal zone lymphoma and follicular lymphoma, may exist. FIGURE 7.25

The biopsy shows a band-like and nodular lymphocytic infiltrate lying in intimate apposition involving the superficial dermis. While the pattern might be more reminiscent of a T cell lymphoproliferative process, higher power magnification reveals an atypical plasmacytic infiltrate, as depicted in Figure 7.27.

FIGURE 7.26

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Higher power magnification reveals significant plasma cell dysplasia including intranuclear inclusions compatible with Dutcher body formation.

FIGURE 7.27

FIGURE 7.28 Higher power magnification reveals significant plasma cell atypia. The cells exhibit binucleation and trinucleation.

Case Vignette 3

CASE VIGNETTE 3

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The patient is a 73 year old woman with a longstanding history of rheumatoid arthritis who presents with multiple nodules on the upper back. Diagnosis: Primary cutaneous marginal zone lymphoma (Figures 7.29–7.34).

(a)

(b)

(c)

The biopsy shows a superficial and deep nodular infiltrate, which assumes a heavier pattern of infiltration as the base is approached.

FIGURE 7.29

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CASE VIGNETTE 3

(Continued)

The infiltrate has a heterogeneous composition comprising small, mature lymphocytes and an admixture of plasma cells. FIGURE 7.30

FIGURE 7.31 The biopsy shows a dense lymphocytic and plasmacytic infiltrate lying in close apposition to the eccrine coil. Frank permeation of the eccrine duct and glands by B lymphocytes would define an important morphologic clue pointing toward lymphoma.

The infiltrate also shows accentuation around the hair follicle. FIGURE 7.32

Case Vignette 3

(a)

(b)

The plasma cells appear atypical. Some appear binucleated and there is variation in nuclear size and shape. Instead of the classic clockface chromatin encountered in the mature plasma cell, the cells have a finely dispersed heterochromatin.

FIGURE 7.33

(a)

FIGURE 7.34

very high.

(b)

In situ hybridization studies for (a) κ and (b) λ reveal a striking dominance of κ over λ. The ratio is

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CASE VIGNETTE 4

The patient is a 73 year old man who presented with a lesion on the lower cheek. Diagnosis: Classic primary cutaneous marginal zone lymphoma (Figures 7.35–7.39)

(a)

(b)

(c)

(d)

The biopsy shows a striking pandermal nodular infiltrate with extension into the subcutaneous fat. The infiltrate manifests accentuation around adnexal structures. FIGURE 7.35

Case Vignette 4

FIGURE 7.36 Higher power magnification reveals a mixture of small mature lymphocytes and atypical appearing plasma cells. The small lymphoid populace includes cells with nuclear irregularity and a finely dispersed heterochromatin. The plasma cells have less than mature-appearing chromatin.

(a) FIGURE 7.37

ratio is high.

(b)

The phenotypic profile reveals a dominance of CD20 cells (b) over those of the CD3 subset (a). The

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CASE VIGNETTE 4

(Continued)

(a) FIGURE 7.38

(b)

The CD23 stain highlights reactive germinal centers.

(a) k

(b) l

FIGURE 7.39 The in situ hybridization studies for κ and λ reveal an overwhelming dominance of κ staining cells over those of the λ subset. The ratio is high.

Case Vignette 5

CASE VIGNETTE 5

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The patient is a 45 year old man who was preoperatively diagnosed with eruptive dermatofibroma (Figures 7.40 and 7.41).

8/6/2005

330 bp

8/19/2005 A

328 bp

330 bp

8/19/2005 B Additional peaks not identified in other specimens

328 bp 330 bp

lgH FR1 FIGURE 7.40 The molecular studies show identical monoclonal B cell populations with polyclonal background on the separate biopsies (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM Pathology Core Facility, Roswall Park Cancer Institute.)

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CASE VIGNETTE 5

(Continued)

94 bp

102 bp 102 bp

9/6/2005

8/19/2005 A

94 bp 102 bp

8/19/2005 B 102 bp 94 bp

lgH FR3 FIGURE 7.41 The molecular studies show oligoclonal peaks with polyclonal background on the three different samples. On all three biopsies, peaks are present at 94 bp and 102 bp. The patient has a sclerosing variant of marginal zone lymphoma. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM Pathology Core Facility, Roswall Park Cancer Institute.)

Case Vignette 6

CASE VIGNETTE 6

The patient is a 27 year old man with a 2-year history of marginal zone lymphoma two new erythematous papules were biopsied (Figures 7.42 and 7.43).

lgH gene rearrangement block B Multiplex panel B

Single peak at 258 base pairs

Minimal to no polyclonal background

lgH gene rearrangement block A Multiplex panel B

Peak at 258 base pairs

Prominent polyclonal background

FIGURE 7.42 IgH gene rearrangement shows monoclonal peaks at 258 bp with minimal to no polyclonal background on two separate biopsies from this one patient. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM Pathology Core Facility, Roswall Park Cancer Institute.)

Peak 289 base pairs

FIGURE 7.43

Another biopsy shows a dominant B cell population at 289 bp.

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CASE VIGNETTE 7

The case is one of subcutaneous Castleman’s disease (Figures 7.44 and 7.45).

The typical changes of the hyaline vascular variant are seen. The case is very unusual not only in the context of representing subcutaneous Castleman’s disease but dendritic cell sarcoma arose in this background atypical lymphoproliferative lesion. The slide is from Dr. Saul Suster’s teaching collection. FIGURE 7.44

(a)

(b)

A higher power magnification shows the atrophic nature of the germinal center. Most of the germinal center comprises small lymphocytes. Only occasional larger cleaved lymphocytes and/or centroblasts are seen. The vessel permeating the germinal center has a hyalinized appearance and defines a conspicuous component of this diminutive germinal center.

FIGURE 7.45

Case Vignette 8

CASE VIGNETTE 8

This patient had classic clinical features of POEMS syndrome (Figure 7.46).

The patient also had areas of extensive plasma cell infiltration amid atrophic germinal centers, hence defining a mixed variant of Castleman’s disease.

FIGURE 7.46

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CHAPTER EIGHT

PRIMARY CUTANEOUS FOLLICLE CENTER CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Clinical Features The European Organization for Research and Treatment of Cancer (EORTC) REAL cutaneous lymphoma project group recognizes primary cutaneous follicle center cell lymphoma as a separate entity. Prognostically, primary follicle center cell lymphoma of the skin is an indolent tumor in contradistinction to the more aggressive clinical course in lymph nodebased follicle center cell lymphoma. As with other forms of cutaneous lymphoma, this diagnosis is rendered when, there is no evidence of extracutaneous dissemination at the time of diagnosis (Cerroni and Kerl, 2001; Willemze et al., 2005). Primary cutaneous follicle center cell lymphoma has a better prognosis than morphologically similar lesions secondarily involving the skin in the context of disseminated lymphoma of primary lymph node origin, or those primary cutaneous lymphomas categorized as diffuse large B cell lymphoma of leg type (Cerroni et al., 2000; Bergmen et al., 2001; Ceroni and Kerl, 2001; Franco et al., 2001; Goodlad et al., 2002). The estimated 5 year survival in patients with primary cutaneous follicle center cell lymphomas is greater than 95%. Primary cutaneous follicle center cell lymphoma accounts for approximately 35% of all cutaneous B cell lymphomas (Hoetnagel et al., 2003). While it is primarily a disease

of older adults with a slight male predilection, cases in the pediatric population have been reported (see Table 8.1) (Ghislanzoni et al., 2005). Primary cutaneous follicle center cell lymphoma must be distinguished from B cell dominant cutaneous pseudolymphoma and non-Hodgkin lymphoma of B cell phenotype with secondary cutaneous involvement. Primary cutaneous follicle center cell lymphoma containing small focal areas of diffuse large cell infiltration do not fall under the rubric of primary cutaneous diffuse large B cell lymphoma (Bogle et al., 2005). However those cases that are dominated by large cells and in which there is mainly a diffuse pattern of infiltration are designated as forms of diffuse large cell B cell lymphoma. They are discussed in Chapter 9. (Goodlad et al., 2003). Patients receiving local therapy, be it in the context of complete surgical excision and/or radiation, have a relatively high incidence of relapse compared to those who receive a more aggressive therapeutic intervention, validating the role of multimodal chemotherapy in those cases presenting with multicentric cutaneous disease (Wong and Weller, 1998; Sabroe et al., 2000; Ferrer et al., 2001; Franco et al., 2001; Mirza et al., 2002; Piccinno et al., 2003; Sah et al., 2004).

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 173

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TABLE 8.1 Follicle Center Cell Lymphoma Clinical Older adults with a slight male predilection Solitary or grouped papules, patches, plaques and tumors Scalp and back most commonly, but any site possible Histomorphology Nodular and/or diffuse infiltrates of centroblasts and centrocytes Accentuation around adnexae with infiltration of follicular and ductular epithelium It may be small cell dominant or mixed Neoplastic and reactive germinal centers are present If a large cell population dominates and the pattern is diffuse, the lesions are recategorized as diffuse large cell B cell lymphoma Grade 1: <5 centroblasts per HPF Grade 2: 6 to 15 centroblasts per HPF Grade 3: >15 centroblasts per HPF Immunophenotype CD20 ± (may be negative following rituximab) CD79 ± CD10 ± Bcl-6 + CD5 − CD43 ± Bcl-2 ±(>40% are bcl-2+) CD23 and CD21, dendritic cell lysis The classic nodal phenotypic profile of CD10 and bcl2 positivity is infrequent. Genetics t(14;18)(q32;q21) absent in 60% as opposed to its detection in over 70% of cases of nodal-based follicular lymphoma Therapy Radiotherapy, excision of solitary lesions, interferon-α, anti-CD20 antibody; systemic chemotherapy is reserved for generalized lesions and/or extracutaneous spread.

Pathology These lymphomas characteristically can exhibit a nodular or a combined, nodular and diffuse pattern of growth (See Case Vignettes 1–4.) The infiltrate is superficial and deep with variable extension into the subcutaneous fat (see Figures 8.1, 8.2, 8.11, 8.20–8.22, and 8.29). There is no dissipation in the intensity of infiltration as the lesional base is approached and, in fact, the infiltrate often becomes more dense in the depths of the lesion; there is usually a narrow grenz zone of separation from the overlying epidermis. As the base of the biopsy is approached, the nodular areas may exhibit an expansile morphology (see Figures 8.12 and 8.29). In contradistinction, the maximum intensity of infiltration in pseudolymphomata is typically in the superficial dermis. We have encountered rare cases of pseudolymphoma localized to the subcutaneous fat, sometimes in the context of several skin lesions with associated lymphadenopathy. In primary cutaneous follicle center cell lymphoma, there is little or no epitheliotropism and angioinvasion is uncommon

but can be seen, especially in mixed cell and large cell dominant forms; concomitant vasculitic changes are rare. That said, any B cell angiotropic process would be a morphologic finding most suggestive of B cell lymphoma. In contrast, the finding of angiotropism in a T cell infiltrate cannot be considered evidence of a neoplastic process, as angiotropism is a morphologic hallmark of many reactive T cell dominant conditions (Wong and Weller, 1998; Sabroe et al., 2000; Ferrer et al., 2001; Franco et al., 2001; Mirza et al., 2002; Leinweber et al., 2004; Sah et al., 2004). While the nodular pattern may predominate, in many cases there are also concomitant areas of diffuse infiltration, and in some cases the pattern is mainly diffuse (see Figures 8.11, 8.20, 8.21 and 8.22). Cases showing a diffuse pattern must be composed of either small lymphocytes or an admixture of small and intermediate sized lymphocytes. If the pattern is diffuse and the infiltrate is large cell dominant, the cases are categorized as representing diffuse large cell

Primary Cutaneous Follicle Center Cell Lymphoma

lymphoma (Goodlad et al., 2003). These lymphomas are discussed in Chapter 9. There can be a background of reactive lymphoid hyperplasia, a distinguishing feature from nodal follicle center cell lymphoma secondarily involving the skin (see Figures 8.15, 8.16 and 8.17). The nodules manifest a variable composition of smaller cleaved lymphocytes with a finely dispersed chromatin and larger centroblasts (see Figure 8.3). The latter have nuclei in the 15–18 µm size range with round or oval profiles, smooth contours, and open chromatin patterns containing 1–3 nucleoli that are often adherent to the chromatinic rim. The atypia of the neoplastic centroblasts far exceed that normally encountered in reactive germinal center centroblasts. While there are scattered reactive germinal centers amid the tumor pointing to the common precursor lesion, namely, lymphocytoma cutis, the neoplastic lymphoid nodules are typically devoid of tingible body macrophages (see Figure 8.3). Characteristically, a diffuse, reactive small lymphocytic infiltrate is present in the background and is focally permeative of the nodules. The infiltrate manifests accentuation around vessels and adnexal structures (see Figure 8.21). There may be permeation of the outer root sheath epithelium by the neoplastic cells but epidermotropism is rare; the identification of intraepidermal and/or intraepithelial adnexal B lymphocytes is highly suggestive of B cell lymphoma. It should be emphasized that this phenomenon of adnexal tropic epitheliotropism is more commonly observed in marginal zone lymphoma. While angiotropism can be seen, there is no accompanying vessel wall necrosis and/or luminal fibrin deposition. In addition, there are rare cases described whereby the tumor is localized to the subcutaneous fat in the absence of known extracutaneous follicle center cell lymphoma (Kazakov et al., 2002). As with lymph node-based follicular lymphoma, there are two main cell types that comprise the neoplastic populace: a small to medium sized cell in the 7–9 µm size range with angulated, twisted, or cleaved nuclei and inconspicuous nucleoli, referred to as centrocytes or cleaved follicle center cells. The adjective cleaved is used to emphasize the nuclear irregularity in this populace; these cells exhibit indentations, deep groves, and linear indentations traversing the long axis of the nucleus. At times the cells may demonstrate a cerebriform configuration reminiscent of the cells encountered in mycosis fungoides. The second cell type is a large transformed cell manifesting a round to oval nucleus with an open chromatin pattern and 1–3 peripherally disposed nucleoli. These cells are referred to, just as

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in the reactive germinal center, as centroblasts. Centroblasts must be distinguished from large cleaved centrocytes, the latter manifesting a more condensed nuclear chromatin, inconspicuous nucleoli, and linear indentations. Only noncleaved large cells are considered in the grading subclassification of these follicular lymphomas (Franco et al., 2001; Sah et al., 2004). (See Figures 8.13 and 8.14). A designation as small cell dominant, mixed, and/or large cell dominant can be made based on the number of centroblasts identified. Hence a small cell dominant lymphoma has 1–5 centroblasts per high power field (grade I), a mixed lymphoma exhibits 6–15 centroblasts per high power field (grade II), and a large cell lymphoma manifests greater than 15 centroblasts per high power field (grade III). In the latter scenario, it is important that a nodular pattern of growth is maintained. If the pattern is diffuse, then such cases predominated by large cells are categorized as diffuse large B cell lymphomas. Grade I small cell dominant follicle center cell lymphomas and grade II mixed follicle center cell lymphomas can show a nodular, diffuse and nodular, or diffuse pattern of growth (see Figures 8.4, 8.5, 8.13, 8.14, and 8.23) (Cerroni et al., 2000; Bergman et al., 2001). The percentage of centroblasts also determines the grade of the lymphoma. The grading scheme assigned for nodal follicular lymphomas, can be applied to primary cutaneous follicle center cell lymphomas and mirrors the aforesaid small, mixed and large cell designations based on large cell numbers. Grade I lymphomas exhibit less than 25% centroblasts per high power field, grade II lymphomas demonstrate between 25%–50% centroblasts per high power field, while a grade III lesion shows greater than 50% centroblasts per high power field (see Figures 8.4, 8.13, and 8.14). There may be variation in the grade in a given tumor and such variation should be commented upon within the pathology report. In cases manifesting a heteromerous grade, the percentage of the lymphoma manifesting a particular grade should be designated. In such instances one can estimate the percentage of the lymphoma demonstrating grade I, grade II, and grade III areas. Unlike node-based lymphoma, the presence of large cells in the context of representing the morphologic equivalent of a grade II or grade III lymphoma is likely not prognostically important. Phenotypic Profile In most cases, the cells within the neoplastic nodules show heterogeneous CD10 expression ranging from an increased or normal expression to one

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that is completely absent, the latter indicative of a CD10 deletion (see Figures 8.7, 8.10, 8.25 and 8.32). While CD10 deletions are common, bcl-6 expression is almost invariably maintained by the neoplastic B lymphocytes (see Figures 8.26 and 8.31) (Bergman et al., 2001; Hoefnagel et al., 2005). As with any reactive germinal center cell, the cells typically do not manifest CD23 or CD21 positivity, but this finding is not an indication of an aberrant phenotype. More important is the pattern of CD21 and CD23 dendritic staining (see Figure 8.15, 8.16, 8.27 and 8.28). Rather than manifesting the typical laminated organized network of a reactive germinal center, there are foci of dendritic cell disruption, with discrete foci within the nodules relatively devoid of CD21 and CD23 expression. The most extreme expression of this abnormal diminished dendritic staining pattern is the failure of the nodules to manifest CD23 or CD21 expression, reflecting the disappearance and/or replacement of the dendritic cell populace by the autonomous proliferation of neoplastic germinal center cells. In addition, the neoplastic cells show variable CD43 and bcl-2 expression; in many cases of primary cutaneous follicle center cell B cell lymphoma, bcl-2 expression by the neoplastic centrocytes and centroblasts is not observed. In addition, MUM1 is characteristically negative (Goodlad et al., 2002). In summation, the phenotypic hallmarks are nodules manifesting a heterogeneous phenotype characterized by variable CD10 expression (i.e., from increased to normal to absent). There may be T cell lineage infidelity with highlighting of centrocytic and/or centroblastic cells with CD43 and bcl-2 expression amid a few larger centroblastic cells (typically not uniformly positive with the majority not staining for bcl-2), and lysis of the CD23 and CD21 dendritic network (see Figures 8.6–8.10, 8.15–8.19, 8.24, 8.26, 8.28, 8.31, 8.32, 8.33, and 8.34) (Hoefnagel et al., 2005). It would appear that these tumors are derived from germinal center cells. While showing aberrant differentiation they are for the most part unrelated histogenetically to those neoplastic follicle center cells that have undergone the classic 14:18 translocation seen in nodal follicular lymphoma. Even in those cases that express CD10, there may not be bcl-2 expression and/or there is CD43 expression, a phenotypic profile at variance with nodal follicular lymphoma (see Figures 8.19 and 8.32). Occasionally, phenotypic studies will reveal a cell of origin cognate to our concept of classic ‘‘follicular’’ lymphoma: neoplastic B cells will exhibit strong CD10 expression in the context of overexpression of bcl-2 without any coexpression of CD43; cytogenetic analysis will reveal the classic 14:18 translocation as discussed

later. (Frances R, 2001; Goodlad JR, 2002; Hoefnagel, 2003). Molecular Studies The automated Ventana mRNA κ and λ light chain assay shows κ light chain restriction characterized by weak staining for κ in nonplasmacytic cells. The κ stain may also highlight presumably neoplastic cells with plasmacytic features, implying in some cases a true composite lymphoma with both marginal zone and follicle center cell features. In some cases of follicular lymphoma, there may not be any significant κ or λ expression, reflecting the lack of plasmacytic differentiation. Expression, if present, is characteristically diffuse, weak, and cytoplasmic. While the in situ κ and λ studies may fail to detect a light chain restricted cell population, polymerase chain reaction studies typically show a rearrangement of the heavy chain immunoglobulin gene (Goodlad et al., 2002). Pathogenesis Phenotypic and genotypic evidence suggests that lesions designated as primary cutaneous follicle center cell lymphomas are in most instances pathogenetically unrelated to primary nodal follicular lymphomas. This difference from a pathogenetic perspective is reflected in a different clinical course. While both groups of patients demonstrate a similar propensity to relapse, the ability to achieve complete remission was significantly better compared to nodal lymphoma as was the long-term prognosis. In the context of skin lymphomas, the term follicle center cell lymphoma was initially derived based on the pattern of growth, namely one of nodular infiltration of the dermis and subcutis. Unlike primary nodal follicular lymphomas phenotypically, many of these lymphomas do not manifest either an overexpression of CD10 or bcl-2 (Pimpinelli et al., 1997). Some lymphomas manifest an overlapping morphologic and phenotypic profile with both marginal zone lymphoma and follicular lymphoma. Such cases may be designated composite lymphoma. Although primary cutaneous follicle center cell may or may not express bcl-2, virtually 100% of secondary follicular lymphomas in the skin do. As a point of reiteration, the 14:18 translocation is seen in a lesser number of cases of primary cutaneous follicle center cell lymphoma cases (range at 30% to 41%) as opposed to 71% of secondary follicular lymphoma cases (Aguilera et al., 2001). (Kim et al., 2005; Volkenandt M, 1992). (See Figure 8.35). One study found very similar phenotypic and molecular features in extranodal follicular lymphomas involving extracutaneous sites, suggesting

Primary Cutaneous Follicle Center Cell Lymphoma

commonality in regard to the biological course in all types of extranodal follicular lymphomas. As with cutaneous follicle center cell lymphomas, these patients also experienced a high relapse rate, although ultimately the biological course proved to be relatively indolent and certainly the long-term prognosis is significantly more favorable compared to nodal follicular lymphoma (Wong and Weller, 1998). Most of these lymphomas arise in a background of reactive lymphoid hyperplasia. It should be emphasized that B-cell-rich lymphocytoma cutis is associated with a state of iatrogenic and/or endogenous immune dysregulation, the latter including underlying collagen vascular disease such as Sjogren’s syndrome and rheumatoid arthritis, or with hepatitis C virus infection. Iatrogenic causes reflect therapy with immune dysregulating agents. We have recently implicated antidepressants pathogenetically in some cases of primary cutaneous B cell lymphoma. Cytogenetics To investigate whether or not primary cutaneous follicle center cell lymphoma is indeed pathogenetically related to nodal follicular lymphoma, studies have assessed for 14:18 translocation in primary cutaneous follicle center cell lymphoma.

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The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas and in a lower percentage of systemic high grade diffuse large B cell lymphomas. The translocation results in the juxtaposition of the Bcl-2 gene on chromosome 18 with the immunoglobulin heavy chain joining region on chromosome 14. Bcl-2 protein prevents apoptosis and the translocation leads to over expression of a functionally normal bcl-2 protein that prevents apoptosis of neoplastic cells (Jsujimoto et al., 1985). Although there are discrepancies in regard to the frequency and/or existence of this translocation in primary cutaneous follicle center cell lymphoma, what can be stated with reasonable certainty is that many cases are unrelated to a 14:18 translocation (see Figure 8.35) (Kim et al., 2005). In another study, an assessment was made of various translocations involving the chromosomal breakpoints of IgG, MYC, BCL6, and MALT1 genes. In classic follicle center cell lymphoma and marginal zone lymphoma of the skin, there were no chromosomal translocations, but primary cutaneous diffuse large cell lymphoma of the leg showed breakpoints in least one of the loci including those of follicle center cell origin. (Hallermann et al., 2004).

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 50 year old man who presents with a violaceous plaque involving the left upper back. A biopsy was performed. Diagnosis: Follicle center cell lymphoma of mixed cell type (Figures 8.1–8.10).

FIGURE 8.1 There is a striking superficial and deep nodular lymphocytic infiltrate. The lesion acquires a greater density of infiltration toward the tissue base with focal permeation of the fat by lymphocytes.

FIGURE 8.2 There is extensive infiltration of the interstitial spaces of the fat by lymphocytes, a finding that may be an important architectural clue to the diagnosis of malignant lymphoma.

FIGURE 8.3 The follicular quality of this neoplasm is appreciated under higher power magnification, where one can see an arrangement of lymphocytes that recapitulates the germinal center. Specifically, the central portion of the nodule is composed of a mixture of cleaved centrocytes and larger centroblastic cells with an accompanying peripheral demarcating concentric rim of small mantle cell-like lymphocytes.

FIGURE 8.4

Higher power magnification reveals that the dominant composition of the germinal center is one comprising small cleaved lymphocytes with only a minor population of immunoblastic and centroblastic cells. (Small cell dominant grade I.)

Case Vignette 1

FIGURE 8.5 Under oil immersion (1000× magnifications) the small cleaved atypical morphology of the lymphocytes is better appreciated.

A CD20 preparation shows striking immunoreactivity of the majority of the lymphocytes for CD20.

A CD10 preparation highlights the germinal center-like foci.

FIGURE 8.8 A CD23 preparation highlights the germinal center-like foci. There is positive staining of the dendritic cells. However, there is considerable irregularity in the dendritic network with zones of significant dendritic cell lysis, the apparent sequela of neoplastic lymphocyte infiltration.

FIGURE 8.7

FIGURE 8.6

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CASE VIGNETTE 1

(Continued)

A bcl-2 preparation demonstrates positive staining of the germinal center-like foci for bcl-2.

FIGURE 8.9

A CD21 stain shows significant dendritic cell lysis recapitulating the morphology captured in Figure 8.8. FIGURE 8.10

Case Vignette 2

CASE VIGNETTE 2

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The patient is a 73 year old woman who developed a few violaceous nodules on the upper trunk. Diagnosis: Primary cutaneous follicle center cell lymphoma (Figures 8.11–8.19).

FIGURE 8.11 Sections show a prominent pandermal diffuse and nodular lymphocytic infiltrate that extends into the subcutaneous fat.

FIGURE 8.12 One can appreciate the follicle-like nature of this process by virtue of the presence of discrete nodules with centroblastic appearing cells surrounded by a mantle-like rim of small mature lymphocytes.

Higher power magnification shows that the composition of the nodule is one comprising atypical centroblastic cells along with smaller centrocytic cells. The larger cell elements show significant cellular atypia, characterized by nuclear contour irregularity and multiple irregular nucleoli. There is also significant mitotic activity. The differential diagnosis of this nodule is one of follicular lymphoma versus a highly activated germinal center. (Mixed/grade II.)

FIGURE 8.14 This is a nodule showing a similar composition dominated by pleomorphic large centroblastic elements. (Large cell dominant/grade III.)

FIGURE 8.13

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CASE VIGNETTE 2

(Continued)

FIGURE 8.15 As these forms of lymphoma usually arise in a background of reactive lymphoid hyperplasia, CD23 and CD21 stains are useful diagnostic adjuncts for highlighting reactive germinal centers. In this photomicrograph, one sees a dendritic staining pattern within a germinal center focus likely representing a reactive follicle.

In this image a CD23 preparation again highlights a reactive germinal center. In contrast, the neoplastic follicles show either irregularity of staining with zones of dendritic cell lysis or complete absence of CD23 staining.

FIGURE 8.16

FIGURE 8.17 One notes positivity for CD79 amid small reactive B lymphocytes; however, the germinal center foci are largely devoid of CD79a staining, compatible with a CD79 deletion.

Case Vignette 2

CASE VIGNETTE 2

(Continued)

FIGURE 8.18 In contrast, the CD20 preparation shows extensive staining of the germinal center foci. Further corroborative evidence of the neoplastic nature of this follicular structure is the virtual absence of CD10 immunoreactivity amid the germinal center-like foci.

FIGURE 8.19 Further corroborative evidence of the neoplastic nature of the process is the complete absence of CD10 staining in the germinal center-like foci, reflecting a CD10 deletion. A lack of staining of CD10 in the setting of BCL6 expression is characteristic for primary cutaneous follicle center cell lymphoma and is an important diagnostic discriminator from nodal follicular lymphoma secondarily involving the skin.

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CASE VIGNETTE 3

The patient is a 58 year old man who presented with a nodule on the face. A biopsy was performed. Diagnosis: Primary cutaneous follicle center cell lymphoma (Figures 8.20–8.28).

(a) FIGURE 8.20

(b)

The biopsy shows a striking deep-seated infiltrate involving the deeper dermis with extension into

the subcutis.

A dominant component of the infiltrate is in apposition to the eccrine coil. Involvement of the adventitial dermis does not define a discriminating feature separating marginal zone lymphoma from follicular lymphoma and vice versa.

FIGURE 8.21

FIGURE 8.22 The infiltrate extends deep, abutting on skeletal muscle.

Case Vignette 3

(a)

(b)

FIGURE 8.23 The infiltrate is composed of a mixture of small cleaved and larger atypical cells without any interposed histiocytes.

(a)

(b)

Phenotypic studies show a dominance of CD20-positive B lymphocytes (a) over those of the CD3 subset (b). Normally reactive infiltrates are of T cell lineage; hence, any dominance of B cells over T cells is abnormal and a ratio of B to T in excess of 3:1 would be most suggestive of B cell lymphoma.

FIGURE 8.24

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CASE VIGNETTE 3

(Continued)

FIGURE 8.25 While the cells are BCL6 positive, there is no expression of CD10. Illustrated is CD10.

FIGURE 8.26

FIGURE 8.27 The CD23 highlights germinal centerlike foci; however, unlike a reactive germinal center, there are significant zones of dendritic cell lysis.

FIGURE 8.28

The cells are BCL6 positive.

The germinal center like nodular foci are largely CD21 negative with only focal staining of the residual CD21 dendritic network. The failure for a structure resembling a germinal center to stain with CD21 is highly suggestive of lymphoma.

Case Vignette 4

CASE VIGNETTE 4

The patient is a 79 year old woman who presented with a purplish appearing nodule. The site of biopsy procurement was undesignated. Diagnosis: Primary cutaneous follicle center cell lymphoma (Figures 8.29–8.35).

(a)

(b)

FIGURE 8.29 The biopsy reveals a nodular infiltrate localized to the subcutaneous fat. The nodules resemble germinal centers; however, they are permeated by lymphocytes and focally the borders become ill defined and the infiltrate assumes a more diffuse pattern.

(a)

(b)

FIGURE 8.30 Higher power magnification reveals its composition being one of small and large lymphocytes without any interposed histiocytes. The smaller cells are centrocytes, while the larger cells have a centroblastic and immunoblastic morphology. The centroblasts typically have peripherally disposed nucleoli lying in apposition to the nuclear membrane. This particular morphology is well exemplified in (b).

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CASE VIGNETTE 4

(Continued)

The nodular foci are BCL6 positive, indicative that the cells are of follicular origin.

FIGURE 8.31

Although the cells are Bcl-6 positive, they fail to show immuno reactivity with CD10. FIGURE 8.32

Unlike classic nodal follicular lymphoma, the cells are bcl-2 negative; note the adjacent rim of small mature bcl-2-positive lymphocytes. In any reactive T-cell component, bcl-2 expression will be observed.

FIGURE 8.33

Case Vignette 4

(a)

(b)

FIGURE 8.34 There is a predominance of CD20-positive lymphocytes over those of the CD3 subset. In reactive infiltrates, almost invariably there is a dominance of (a) CD3 over (b) CD20. Seeing a predominance of CD20 over CD3 is an important point suggesting a diagnosis of B cell lymphoma.

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FIGURE 8.35 The cytogenetic profile shows a t(14;18)(q32;q21),which is primarily associated with primary nodal follicular lymphoma. This translocation is seen in 30 to 40% of primary cutaneous follicle center cell lymphomas.

References

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REFERENCES AGUILERA NS, TOMASZEWSKI MM, MOAD JC, et al. Cutaneous follicle center lymphoma: a clinicopathologic study of 19 cases. Mod Pathol. 2001; 14(9):828–835. BELJAARDS R, VAN BEEK P, WILLEMZE R. Relation between expression of adhesion molecules and clinical behavior in cutaneous follicle center cell lymphomas. J Am Acad Dermatol. 1997; 37: 34–40. BERGMAN R, KURTIN PJ, GIBSON LE, et al. Clinicopathologic, immunophenotypic, and molecular characterization of primary cutaneous follicular B-cell lymphoma. Arch Dermatol. 2001;137(4): 432–439. BOGLE MA, RIDDLE CC, TRIANA EM, JONES D, DUVIC M. Primary cutaneous B-cell lymphoma. J Am Acad Dermatol. 2005; 53(3):479–484. CERRONI L, KERL H. Primary cutaneous follicle center cell lymphoma. Review. Leuk Lymphoma. 2001; 42(5):891–900. CERRONI L, ARZBERGER E, PUTZ B, et al. Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Blood. 2000; 95(12):3922–3928. FERRER A, LOPEZ-GUILLERMO A, MONTOTO S, et al. Successful treatment of isolated cutaneous relapse of follicular lymphoma with rituximab. Ann Hematol. 2001; 80(8):479–481. FRANCO R, FERNANDEZ-VAZQUEZ A, MOLLEJO M, et al. Cutaneous presentation of follicular lymphomas. Mod Pathol. 2001; 14(9):913–919. FRANCO R, FERNANDEZ-VAZQUEZ A, RODRIGUEZ-PERALTO JL, et al. Cutaneous follicular B-cell lymphoma: description of a series of 18 cases. Am J Surg Pathol. 2001; 25(7):875–883. GHISLANZONI M, GAMBINI D, PERRONE T, ALESSI E, BERTI E. Primary cutaneous follicular center cell lymphoma of the nose with maxillary sinus involvement in a pediatric patient. J Am Acad Dermatol. 2005; 52(5 Suppl 1): S73–75. GOODLAD JR, KRAJEWSKI AS, BATSTONE PJ, et al. Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity. Am J Surg Pathol. 2002; 26(6):733–741. GOODLAD JR, KRAJEWSKI AS, BATSTONE PJ, et al. Primary cutaneous diffuse large B-cell lymphoma: prognostic significance of clinicopathological subtypes. Am J Surg Pathol. 2003; 27(12):1538–1545. HALLERMANN C, KAUNE KM, GESK S, et al. Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol. 2004; 123(1):213–219.

HOEFNAGEL JJ, VERMEER MH, JANSEN PM, FLEUREN GJ, MEIJER CJ, WILLEMZE R. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol. 2003; 149(6):1183–1191. KAZAKOV DV, BURG G, DUMMER R, KEMPF W. Cutaneous lymphomas and pseudolymphomas: newly described entities. Recent Results Cancer Res. 2002; 160:283–293. KIM BK, SURTI U, PANDYA A, COHEN J, RABKIN MS, SWERDLOW SH. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol. 2005; 29(1):69–82. LEINWEBER B, COLLI C, CHOTT A, KERL H, CERRONI L. Differential diagnosis of cutaneous infiltrates of B lymphocytes with follicular growth pattern. Am J Dermatopathol. 2004; 26(1):4–13. MIRZA I, MACPHERSON N, PAPROSKI S, et al. Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol. 2002; 20(3):647–655. PICCINNO R, CACCIALANZA M, BERTI E. Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol. 2003; 13(1):49–52. PIMPINELLI N, SANTUCCI M, MORI M, et al. Primary cutaneous B-cell lymphoma: a clinically homogeneous entity. J Am Acad Dermatol. 1997; 37:1012–1016. SABROE RA, CHILD FJ, WOOLFORD AJ, et al. Rituximab in cutaneous B-cell lymphoma: a report of two cases. Br J Dermatol. 2000; 143(1):157–161. SAH A, BARRANS SL, PARAPIA LA, JACK AS, OWEN RG. Cutaneous B-cell lymphoma: pathological spectrum and clinical outcome in 51 consecutive patients. Am J Hematol. 2004; 75(4):195–199. TSUJIMOTO Y, COSSMAN J, JAFFE E, CROCE CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228:1440–1443. VOLKENANDT M, CERRONI L, RIEGER E, et al. Analysis of the 14:18 translocation in cutaneous lymphomas using the polymerase chain reaction. J Cutan Pathol. 1992; 19:353–356. WILLEMZE R, JAFFE ES, BURG G, et al. WHO–EORTC classification for cutaneous lymphomas. Blood. 2005; 105(10):3768–3785. WONG KC, WELLER PA. Primary cutaneous B cell lymphoma: outcomes and treatment. Australas J Dermatol. 1998; 39(4):261–264.

CHAPTER NINE

PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA AND PRECURSOR LYMPHOBLASTIC LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Primary Cutaneous Diffuse Large B-Cell Lymphoma Primary cutaneous diffuse large B-cell lymphoma has a variable prognosis that relates to specific factors including site localization, extent of disease, and phenotypic profile (Pandolfino et al., 2000). Those patients who present with lesions primarily involving the lower extremities appear to have a worse prognosis than those patients with localization of similar neoplasms at other sites (Vermeer et al., 1996). Nevertheless, some patients with lesions located outside the leg may have an aggressive clinical course (Bekkenk et al., 1999; Grange et al., 2000 2001; Santucci and Pimpinelli, 2004). The molecular profile of cutaneous diffuse large B cell lymphoma may be similar, independent of anatomic site (Wiesner et al., 2005). It would appear that the phenotypic profile is the single most important objective parameter that predicts the biologic differences between lymphomas designated as being of ‘‘leg type’’ versus the remainder which encompasses a those of primary cutaneous

follicle center cell origin, and a third group which does not fulfill criteria to be designated as either leg type or follicle center cell origin. The large B cell lymphomas of the leg typically are Bcl-2 and MUM-1/IRF4 positive while the other 2 groups are characteristically Bcl-2 negative and MUM-1/IRF4 negative. (Geelen et al., 1998). The designation now for any primary cutaneous large B cell lymphoma showing Bcl-2 and MUM-1 positivity is that of diffuse large B cell lymphoma, leg type independent of the anatomic site (Grange et al., 2000, 2001, 2004; Santucci and Pimpinelli, 2004). As with other forms of cutaneous lymphoma, the extent of disease influences prognosis. Patients who present with solitary or few lesions have a much better prognosis than those who present with multiple lesions. In general, patients with lower leg lymphomas have multiple lesions (see Figure 9.1); in contrast, when there is involvement of the upper trunk and head, the clinical presentation is usually in the context of one or a few lesions (see figure 9.2).

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 192

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TABLE 9.1 Primary Cutaneous Large B-cell Lymphoma, Figure 9.1 Clinical Elderly; Female 3: male 1. Solitary or clustered tumors. May ulcerate. (More aggressive variants) Lower leg lesions may behave more aggressively however an aggressive clinical course may occur elsewhere; such cases are designated as ‘‘leg’’ type. Three main groups, leg type, follicle center cell diffuse large cell variant and other. Histomorphology Dense diffuse infiltrates with dominant large cell population of centroblasts +/− immunoblasts. Immunophenotype 1. CD20, 79a +/− (loss of CD20 may occur with rituximab therapy) 2. slg (clg) + (monoclonal) 3. Bcl-2+/− 4. Bcl-6+/− 5. MUM1 +/− 6. ∗ Oct2+/− 7. Fox P1 +/− 8. CD138 and CD5− Cases of leg type are typically Bcl-2+, Oct2+ and MUM1+ and Bcl-6−. Conversely, diffuse large cell follicle center cell lymphoma are Bcl-6+, Bcl-2−, MUM1−, Oct2−, Fox P1− Cytogenetics Gains of chromosomes 12, 7, 3, 18q, 11 and x; losses of genes encoding P53. Therapy Radiotherapy and/or surgical excision for solitary lesions. Chemotherapy, rituximab for multiple lesions

The reported 5 year survival rate is variable but has been reported as low as 51% in the leg type lymphoma group versus 95% for the other forms of diffuse large

Primary cutaneous large cell lymphoma, leg type. The patient developed violaceous plaques on the lower extremities. A biopsy was performed and held to be compatible with a diagnosis of primary cutaneous large cell lymphoma, leg type.

FIGURE 9.1

B-cell lymphoma (Fernandez-Vazquez et al., 2001; Brogan et al., 2003; Grange et al., 2004). In the original classification scheme proposed by the European Organization for Research and Treatment of Cancer (EORTC), the large cell lymphomas of the leg were recognized as a separate entity while the World Health Organization (WHO) considered them collectively under diffuse large B cell lymphoma. The joint revised WHO–EORTC classification of cutaneous lymphoid neoplasms subdivides them into three main groups: 1. primary cutaneous large cell B cell lymphoma, leg type manifesting Bcl-2 and MUM-1/IRF4 positivity, 2. primary cutaneous follicle center lymphoma, diffuse large cell type which is Bcl2 and MUM-1 negative but manifests Bcl-6 positivity and 3. a miscellaneous other group for those which are Bcl-2, MUM-1, and Bcl-6 negative (Willemze R 2005; Amo et al., 2000; Aboulafia, 2001; Cerroni and Kerl, 2001; Fernandez-Vazquez et al., 2001; Fink-Puches et al., 2002; Goodlad et al., 2003; Brogan et al., 2003). From a histogenetic perspective, it is likely that most diffuse large B-cell lymphomas of the skin (see Figures 9.1 and 9.2), irrespective of their site of origin, derive primarily from germinal center B cells (Gellrich et al., 2001; Uherova et al., 2001; Hoefnagel et al., 2003).

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(a)

(b)

Diffuse large B-cell lymphoma (follicle center cell type (group 2)). The patient is a 70 year old man who developed a progressively enlarging fungating mass on the upper back over a 4 year period. He was otherwise feeling well. The biopsy was diagnostic of a Bcl-2 negative Bcl-6 positive diffuse large cell lymphoma consistent with a diffuse large cell variant of primary cutaneous follicle center cell lymphoma. (Courtesy of Dr. Kelly Gallina, The Ohio State University.)

FIGURE 9.2

In one study, however three patients with marginal zone lymphoma had skin tumors that transformed into diffuse large B-cell lymphoma in subsequent relapses, suggesting that, at least in some cases, a post germinal center cell appeared to be the cell of origin (Koyama et al., 2000; Camacho et al., 2001). Distinct cytogenetic events are involved in tumor progression. As with other forms of primary cutaneous B cell lymphoma, these tumors have a tendency for recurrence. In one study, only 18% of all cases of diffuse large B cell lymphoma localized to the head and neck area recurred, while the lower extremity lesions manifested a recurrence rate of over 50% during a median follow-up of 72 months (Hembury et al., 2002). The values in regard to recurrences for the lower extremity cases may not be representative, as the numbers in this study were low (i.e., four patients with lower leg lymphomas). Diffuse large B cell lymphoma has been reported to recur as an angiotropic large B cell lymphoma (Kamath et al., 2001). Evolution of the Classification Scheme The WHO scheme recognizes diffuse large B cell lymphoma independent of site and follicular lymphoma primarily in the context of its occurrence in

lymph nodes. The original WHO scheme does not specifically recognize primary cutaneous B cell lymphoma per se. In contrast, the EORTC defines three forms of primary cutaneous B cell lymphoma: follicle center cell lymphoma, immunocytoma/marginal zone lymphoma, and large B cell lymphoma of the leg. A potential deficiency of the EORTC scheme is this: not all large B cell lymphomas are of follicle center cell origin and not all aggressive primary cutaneous large B cell lymphomas occur in the leg. Diffuse large cell lymphoma of the skin has emerged as a distinctive entity with a biological behavior based on the anatomic site and specific aspects of the phenotypic profile. The new scheme, an interplay between the EORTC and WHO systems, divides diffuse large B cell lymphoma of the skin into three different groups: ‘‘leg type’’, primary cutaneous follicle center cell lymphoma, large cell type and other when the lymphoma does not conform to the other two categories (Pimpinelli et al., 1997; Yap et al., 2003; Hsi, 2004; Slater, 2005; Willemze et al., 2005). Pathology A dominant diffuse pandermal infiltrate effacing the dermal architecture is characteristic, although zones of nodular infiltration may also be seen (see Figures 9.6, 9.9, and 9.17). Mitotic activity is brisk

Primary Cutaneous Diffuse Large B-Cell Lymphoma and Precursor Lymphoblastic Lymphoma

and there are numerous apoptotic cells. The infiltrate is either composed of a mixture of small and large cells, with at least 50% of the infiltrate being of large cell type, or almost entirely comprises large cells. If the infiltrate contains a higher proportion of small cells, consideration should be given to alternative categories of primary cutaneous B cell lymphoma, such as follicle center cell lymphoma or marginal zone lymphoma. The large cells include centroblasts, immunoblasts, and pleomorphic large lymphocytes; all three cell types are in the 15–18 µm size range. Perhaps the commonest cell type is the pleomorphic large cell (see Figures 9.8 and 9.18). The small cells exhibit nuclear contour irregularity and finely dispersed chromatin, recapitulating the morphology of a small centrocyte. It is not uncommon to see well differentiated, small hyperchromatic lymphocytes. These cells are frequently of T cell lineage and part of an immune response to the neoplastic B cell populace. In extreme cases, the reactive T cells may obscure the neoplastic B cells, defining the entity of T-cellrich B cell lymphoma (personal observations; Grange et al., 2000; Kamarashev et al., 2000; Li et al., 2001; Hembury et al., 2002; Watabe et al., 2002; Brogan et al., 2003). As some of these tumors are of post germinal center cell origin, plasma cells and/or lymphoplasmacytic forms with atypical nuclear features can be seen. These atypical features include more open chromatin than the mature clock face heterochromatin encountered in benign plasma cells, nuclear irregularity, multinucleation, nuclear size variation, and Dutcher bodies (intranuclear inclusions representing cytoplasmic invaginations containing intracellular immunoglobulin). These atypical plasmacytoid cells are usually light chain restricted. Some cases of diffuse large B-cell lymphoma of the leg show a paucicellular necrobiotic process demarcated by sheets and nodules of neoplastic cells, a pattern reminiscent of necrobiosis lipoidica that may account for the annular appearance of lesions in some patients (see Figure 9.9) (personal observations). Especially in those cases exhibiting a significant reactive T cell infiltrate, there may be scattered epithelioid granulomata, reflecting a local paraneoplastic granulomatous diathesis. Angioinvasion can be seen; (Figure 9.7) epitheliotropism, typical of the small cell neoplastic B cell lymphoma counterparts, is unusual. In both primary cutaneous follicle center cell lymphoma and marginal zone lymphoma, germinal center-like foci are common. In the setting of follicle center cell lymphoma they can be neoplastic or reactive, while in marginal zone lymphoma they are typically reactive, excluding rare

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cases of composite lymphoma. In contrast, seeing reactive or neoplastic germinal centers in lesions of diffuse large B cell lymphoma are unusual (Gogstetter et al., 2000; Kamarashev et al., 2000; Watabe et al., 2002). Phenotype Supporting a diagnosis of B cell lymphoma is a dominance of CD20-positive B cells over those lymphocytes of T cell lineage; the B to T cell ratio is greater than 1:1 with a ratio in excess of 3:1 being most suggestive of B cell lymphoma (see Figures 9.10 and 9.19). An important exclusion are those cases of T-cell-rich B cell lymphoma. In most primary cutaneous B cell lymphomas, the infiltrate is CD20 and CD79 positive (see Figures 9.10, 9.14 and 9.19). However, there may be variation in the expression of these two markers. For example, loss of CD79 is a phenotypic feature supportive of the classification of a B cell dominant infiltrate as a form of lymphoma. In those patients with recurrent tumors treated with rituximab, diminution in CD20 expression compared to pre-treatment biopsies may be observed (Brogan et al., 2003; Hoefnagel et al., 2003; Rawal et al., 2005). In one study that further assessed the histogenesis of diffuse large B-cell lymphoma of the leg, the authors found that all cases demonstrated positivity for Bcl-2 and MUM1 and did not show any significant immunoreactivity with CD10 and CD138 (Paulli et al., 2002). In another study, Bcl-6 and MUM1 expression were inversely correlated. Specifically, lymphomas of the leg were characteristically MUM1 positive and Bcl-6 negative while lymphomas of the upper trunk were MUM1 negative and Bcl-6 positive (Sundram et al., 2005), the letter defining a diffuse large cell variant of follicle center cell origin. Bcl-6 expression may be an independant favorable prognostic variable (Figure 9.20b). Oct2 expression may also be associated with a worse prognosis (Hoefnagel, 2006). Bcl-2 expression has been demonstrated in most primary cutaneous B cell lymphomas of the leg in the absence of a 14:18 translocation. It has been suggested that Bcl-2 expression is of prognostic value and in some way contributes to the more aggressive clinical course observed in patients with primary cutaneous B cell lymphoma of the legs (Grange et al., 2004). Corroborative of this hypothesis is the fact that all lymphomas, independent of site, show a similar prognosis if they express Bcl-2 (see Figure 9.13) (Grange et al., 2004). The molecular and phenotypic profiles of diffuse large B cell lymphoma, like most primary cutaneous

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B cell lymphomas at other sites, do not show the classic nodal follicle center cell phenotypic profile. At further variance with the nodal follicular lymphoma phenotype is the expression of CD43 in many cases (Hoefnagel et al., 2003). (Figure 9.11) These tumors are characteristically CD21 CD23 negative and CD5 expression is usually not seen. A small percentage express CD30. It has been our experience that CD30-positive large B cell lymphomas may be associated with underlying iatrogenic and/or endogenous immune dysregulation. In particular, some of these lymphomas are established to be EBER positive and have arisen in the setting of cyclosporine and/or methotrexate therapy (Verma et al., 2005; Herrera et al., 2002; Magro et al., 2006a). Diffuse large B cell lymphomas independent of site are characteristically CD20 and CD79 positive although there may be some diminution in expression of the latter marker. CD10 and CD138 may be negative. Bcl-6 is positive in the ‘‘follicle center cell variants’’ while it is usually negative in those lymphomas falling under the ‘‘leg type’’ designation (Sundram et al., 2005). Other B cell markers that are typically negative include CD21 and CD23. Aberrant coexpression of CD43 can be seen while CD5 positivity is rare (see Figure 9.21 and 9.22). Most important in prognosticating these tumors is the Bcl-2 and MUM1 profile being positive in the more aggressive leg type lymphomas and negative in those lymphomas falling under the designation of ‘‘diffuse large cell variant of primary cutaneous follicle center cell lymphoma and so called other.’’ Molecular Studies We find the in situ hybridization assays to assess for light chain restriction useful for detection of clonality (see Figures 9.15, 9.16, and 9.23). This is especially true in those neoplasms showing plasmacytic differentiation and/or large cell lymphomas; in the latter, the cytoplasmic RNA expression for either κ or λ is characteristically weak but weak expression does not invalidate the potential usefulness of this assay (Magro et al., 2003). Heavy chain immunoglobulin rearrangement is typically present (Cook et al., 2003). Cytogenetics In one study, an interphase fluorescence in situ hybridization technique was employed to assess for structural aberrations of the genes Bcl-2, Bcl-6, and cMYC, and numerical abnormalities of chromosomes 3, 7, 8, 11, 12, 13, 17, 18q, RB1, and p53. Genetic anomalies were observed in 76% of cases. The most frequent numerical aberrations were gains of

chromosome 12, 7, 3, 18q, 11, and X while losses of genes encoding p53 were observed very infrequently. Bcl-2, c-MYC, and Bcl-6 were rearranged with the IgH gene either in a very small number of cases or not at all. The most significant genetic difference separating diffuse large B cell lymphoma of the skin from the nodal counterpart and extracutaneous diffuse large B cell lymphoma was the absence of Bcl-6 rearrangement in contrast to its identification in 30% of nodal diffuse large B cell lymphomas and 15% of nodal follicular lymphomas (Wiesner et al., 2005). Overall the cytogenetic abnormalities were uniform among all cases of diffuse large B cell lymphoma of the skin independent of site and of Bcl-2 expression (Wiesner et al., 2005). In one series of transformation of marginal zone lymphoma into diffuse large B cell lymphoma, there was a significant 7q deletion—a genetic event that may be involved in the inactivation of the p53 and p16INK4a pathway, thereby promoting transformation (Camacho et al., 2001). Wiesner and co-workers suggested that a gain of chromosome 7 might be associated with a worse prognosis. These cases were diffuse large B cell lymphomas of the so called other subtype, being Bcl-2 and Bcl-6 negative (Wiesner et al., 2005). In a recent study, significant differences using array-based comparative genomic hybridization were established between primary cutaneous follicle center cell lymphomas and diffuse large B cell lymphomas of leg type. The most recurrent alterations in primary cutaneous follicle center cell lymphoma were highlevel DNA amplifications at 2p16.1 and deletion of chromosome 14q32.33 (Dijkman et al., 2005) FISH analysis demonstrated c-REL amplification in patients with gains at 2p16.1. In primary cutaneous large B cell lymphoma leg type, the most striking abnormalities were characterized by a high-level DNA amplification of 18q21.31-q21.33 to include the Bcl-2 and MALT1 genes; as well, deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes were detected. Homozygous deletion of 9p21.3 was detected in almost 50% of patients with diffuse large B cell lymphomas of leg type but in none of the patients with primary cutaneous follicle center cell lymphoma. Complete methylation of the promoter region of the CDKN2A gene was demonstrated only in the leg type B cell lymphomas. Pathogenesis In diffuse large B cell lymphoma, regardless of site, the cells are either of germinal center cell or post germinal center cell origin. They are unlikely to be derived from naive B cells. It is possible that primary

Primary Cutaneous Diffuse Large B-Cell Lymphoma and Precursor Lymphoblastic Lymphoma

cutaneous diffuse large B cell lymphomas arise in a background of reactive lymphoid hyperplasia and/or from a better differentiated primary cutaneous B cell lymphoma. For example, the diagnosis of primary cutaneous large B cell lymphoma may be made in the setting of a recurrent lesion whereby the prior biopsies may have been more consonant with a diagnosis of follicle center cell lymphoma or marginal zone lymphoma. In our recent series on post-transplant B cell lymphoproliferative disease of the skin, we described one patient with classic immunocytoma of the skin who subsequently developed a large B-cell lymphoma (Verma et al., 2005). The nature of the cell of origin can be gleaned from the phenotypic profile. For example, if the cells express Bcl-6 and/or CD10, then it is likely that the lymphoma is of secondary follicle center cell origin since Bcl-6 is expressed in the light and dark zone of secondary follicles. Conversely, those neoplasms without Bcl-6 expression but showing MUM1 expression may be germinal center cells at a later stage of differentiation. The lack of CD138 (syndecan-1) expression does not support a true post germinal center cell origin for many primary cutaneous diffuse large cell lymphomas. From a molecular perspective studies showing hypermutation of the IgG gene clearly suggest that at least in some cases these tumors are of follicle center cell origin (Aarts et al., 1998). In one study assessing six cases of diffuse large B cell lymphoma of leg type, the neoplastic population in all carried hypermutation of Ig genes, and all but one case also harbored mutations of the Bcl-6 gene (Paulli et al., 2002). In another study, none of the cases of primary cutaneous diffuse large B cell lymphoma showed a (14:18) translocation (Geelen et al., 1998; Kim et al., 2003). The expression of MUM1/IRF4 protein is a feature of lower leg lymphoma in contrast with the observed negativity at other sites where prognosis is better (Paulli et al., 2002). MUM1 is expressed at a later stage of B cell differentiation in germinal centers and is involved in the progression of a germinal center to a plasma cell; acquisition of MUM1 staining is associated with loss of Bcl-6 staining. DNA tissue microarray studies have shown increased expression of genes associated with B cell activation, namely, the proto-oncogenes PIM-1, PIM-2 and c-MYC, and the transcription factors MUM1/IRF4 and Oct-2 in lower leg lymphomas in contradistinction to either primary cutaneous follicle center cell lymphoma or diffuse large cell lymphoma at other sites. Primary cutaneous follicle center cell lymphoma shows high expression of SPINK2 (Hoefnagal et al., 2005; Wiesner et al., 2005). The results suggest that different pathogenetic

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mechanisms are involved in the development of primary cutaneous follicle center cell lymphoma and primary cutaneous large B cell lymphoma of the leg and provide molecular support for the subdivision used in the EORTC classification. There are other molecular features of diffuse large B cell lymphoma of the skin that growth potential and features that are, from a genetic perspective, similar to diffuse large B cell lymphoma at other anatomical sites. For example, deletion or promoter region hypermethylation of the p16INK4a gene, and a higher level of retinoblastoma protein expression are evident in diffuse large B cell lymphoma of the skin (>50%) compared to marginal zone lymphoma or follicular lymphoma (<10%) (Grange et al., 2000). Nevertheless, only those tumors of the leg type are associated with an intermediate prognosis while the other forms of diffuse large B cell lymphoma, despite these adverse molecular and genetic markers, have a relatively indolent clinical course. The location-dependent difference in prognosis has been a source of investigation by many authors, although now there is more of a trend to consider these neoplasms from a phenotypic as opposed to a site-specific perspective. In one study, ICAM-1 and LFA-1 were expressed in a high percentage of primary cutaneous large cell lymphomas of the head and neck as opposed to those tumors of the leg (Beljaards et al., 1997) that had significantly lower levels of expression of these adhesion molecules. Dissemination of disease and death directly attributed to the lymphoma only occurred in those patients whose tumors lacked expression of the adhesion markers ICAM-1 and LFA-1 (Beljaards et al., 1997). In patients whose tumors expressed ICAM-1 and LFA-1, death directly attributable to their lymphoma was not documented (Beljaards et al., 1997). Tissuespecific migration is mediated by the interaction of adhesion molecules on the lymphocyte surface (i.e., lymphocyte homing receptors) and endothelial cell ligands. Hence, the difference in expression of adhesion molecules may be of importance in determining clinical behavior (Beljaards et al., 1997; Panizzon and Burg, 1997). Differential integrin expression may also be of pathogenetic importance (Lair et al., 2000). Differential Diagnosis Because of the effacing nature of the infiltrate and striking atypia of the neoplastic population, only on rare occasions would it not be apparent to the pathologist that the process represents a malignant hematopoietic neoplasm. The differential diagnosis would encompass anaplastic large cell lymphoma, leukemia cutis, and secondary lymphoma

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involving the skin in the context of Stage IV disease. Some intravascular B cell lymphomas present on the lower legs, defining either a primary or secondary manifestation of the disease process. As with any other primary cutaneous lymphoma, careful evaluation for extracutaneous lymphoma is needed before rendering a diagnosis of primary cutaneous large B-cell lymphoma.

Cutaneous Precursor B Cell Lymphoblastic Lymphoma/Lymphoblastic Leukemia (Precursor B Cell Acute Lymphoblastic Leukemia Clinical Features The B cell lymphoblastic neoplasms fall under two broad categories: lymphoblastic lymphoma and lymphoblastic leukemia. The biological commonality is clear, as both are malignancies derived from pre-B cell lymphoblasts. The patient is held to have leukemia if there is extensive marrow and peripheral blood involvement at the time of presentation, or to have lymphoma when disease mainly involves the lymph nodes, skin, soft tissue, spleen, and/or liver at presentation. Although peripheral blood and bone marrow involvement is seen, it is not of the same magnitude as that observed in the setting of leukemia. Less than 25% of the marrow cellularity is on the basis of lymphoblastic infiltration and less than 10% of the nucleated elements circulating in the peripheral blood are blasts. Both B cell lymphoblastic lymphoma and lymphoblastic leukemia typically affect patients under 18 years of age and in the setting of lymphoblastic leukemia, 75% are under 6 years of age. The age range of affected patients is from 1 month to 84 years, with a mean age of 17 years. There is a male to female ratio of 2.5:1. Unlike T cell lymphoblastic lymphoma, mediastinal masses are infrequent. Most patients with B cell acute lymphoblastic leukemia present with bone marrow failure. In the context of B cell lymphoblastic lymphoma, the most common clinical presentation is one of multiple cutaneous nodules, reflecting an unusual and distinctive predilection to involve the skin (Koehler et al., 1993; Dommann et al., 1997; Chimenti et al., 1999). In a recent series, the patients were able to achieve long-term remission following aggressive chemotherapeutic intervention. The clinical features of the uncommon B cell lymphoblastic lymphomas are not well characterized, but the tumor usually presents in the skin or lymph nodes with relative sparing of the bone marrow and mediastinum, the latter being characteristically involved in T cell lymphoblastic lymphoma (Sander et al., 1991; Liu et al., 2000; Maitra et al., 2001).

Cutaneous lymphoblastic lymphoma of the B cell subtype typically involves the head and neck area like other forms of cutaneous B cell lymphoma (see Figure 9.3). All patients presenting with primary cutaneous B cell lymphoblastic lymphoma are treated with a multidrug chemotherapeutic regimen. In children, approximately 3.5–7% of all lymphomas involving the skin are of this subtype. Patients with B cell lymphoblastic lymphoma may be found to have generalized lymphoma during their work-up, but there are cases where the tumor is confined to the skin (Sander et al., 1991; Schmitt et al., 1997; Maitra et al., 2001). Although it was once held that cutaneous involvement in the setting of B cell lymphoblastic lymphoma was an adverse prognostic factor, it now appears that cutaneous disease does not discriminate between standardand high-risk acute lymphoblastic lymphoma (Millot et al., 1997). Cases presenting almost exclusively with skin involvement in children usually manifest an immature phenotype. Pathology Skin involvement manifests as extensive pandermal infiltration with involvement of the panniculus. Typically, the infiltrates are deep seated and lack epitheliotropism (see Figures 9.24 and 9.25).

Primary cutaneous B cell lymphoblastic lymphoma. The child presented at 6 weeks of age with a large infiltrative violaceous plaque involving the eye. The biopsy was compatible with primary cutaneous B cell lymphoblastic lymphoma. (Courtesy of Dr. Kawash, Children’s Hospital, Columbus, Ohio.)

FIGURE 9.3

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TABLE 9.2 Precursor B-lymphoblastic Leukemia-Lymphoblastic Lymphoma Clinical Children Localized or generalized skin and subcutaneous tumors, classically involving the scalp. The T cell counterpart rarely involves the skin; its presentation is one of mediastinal involvement. Histomorphology Monomorphous medium-sized cells, with round or convoluted nuclei, finely dispersed chromatin, sparse cytoplasm. Immunophenotype CD20 +/− CD79 +/− CD1a, 3, 7− TδT +/− CD10+/− CD34 +(−) CD99+ ∗ very early forms may be CD20 negative while transitional variants may be CD10 and CD99 negative. Granulocytic sarcoma can show TdT and CD99 positivity Molecular profile Heavy chain immunoglobulin rearrangement. Cytogenetics Hyperdiploidy: better prognosis; hypodiploidy: poor prognosis; translocations: t(9:22), t (4:11) and t(1:19): poor prognosis

We have observed a pattern of angiocentricity unaccompanied by destructive vessel wall alterations. A diffuse and nodular pattern of infiltration may be seen. In most cases, the cells have a monomorphous appearance, being intermediate in size (i.e., in the 9–12 µm size range), with round to oval nuclei containing inconspicuous nucleoli; the nuclear membranes are distinct and the chromatin is finely dispersed. Cytoplasm is sparse. There are two main cell types: one with a round, smooth-contoured nucleus and one with a convoluted nucleus. A larger cell size can be seen in the convoluted variant. Mitoses are frequent. In some cases the cells may be larger with more abundant cytoplasms. In these larger cells, nucleoli may also be prominent, although never of the magnitude that one encounters in immunoblastic lymphoma (see Figures 9.26 and 9.27). The smaller cell variants may cause diagnostic confusion with small round cell carcinoma and metastatic small cell carcinoma, but appropriate phenotypic studies should allow easy distinction (Liu et al., 2000; Kahwash and Qualman, 2002). Immunophenotype The lymphoblasts are terminal deoxynucleoltidyl transferase (TdT) positive and typically express CD10, CD19, and CD79. They are frequently CD24 negative. There is variable expression of CD22 and CD20 while CD45 expression may be absent.

The myeloid associated antigens CD13 and CD33 may be present. Precursor B cell lymphoblastic lymphomas express a whole range of cellular maturity with the most immature of the lymphoblastic lymphomas expressing CD34 and other myeloid markers and lacking mature B cell antigens such as CD20. At the opposite end of the spectrum are more mature B cells that are typically CD34 and TdT negative and express mature B cell markers, including surface immunoglobulin (Soslow RA et al., 1997). It should be emphasized that CD20 is expressed relatively late in the course of B cell differentiation. Cases manifesting surface immunoglobulin expression have been described. To our knowledge six previously reported cases of lymphoblastic B cell lymphoma with surface immunoglobulin expression are reported. If a lymphoblastic lymphoma shows evidence of surface immunoglobulin expression, then the cells are classified as transitional pre-B cells. Such lesions may have a better prognosis (Koehler et al., 1993). CD99 is also commonly seen (see Figures 9.28–9.30) (Link et al., 1983; Schmitt et al., 1997). There is an apparent zonation pattern concerning the phenotypic profile. The cells in intimate apposition to the microvasculature show enhanced CD79 and CD20 staining, while the cells in a more peripheral disposition may be negative. Nevertheless, the entire infiltrate, both the angiocentric and interstitial components, demonstrates TdT and CD10

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positivity. This differential distribution of marker expression may reflect heterogeneity in the state of maturation, with those cells lying in closest apposition to blood vessels expressing CD20 being the most mature. One can view the partial loss of expression of certain pan B cell markers as being indicative of neoplasia. We have explored cutaneous lymphocyte antigen (CLA) expression on these neoplasms and have found that they are almost invariably positive (Figure 9.30). In one case there was a zonation pattern that paralleled the expression pattern found with CD20. CLA initiates skin homing by mediating E-selectindependent tethering and rolling within cutaneous venules. Expression of CLA on a subpopulation of human memory T cells helps to direct homing to the skin. T cells and some B cells in the peripheral blood express CLA, but the pathophysiologic role of CLA-expressing B cells has not yet been clarified. Expression of CLA on class-switched memory B cells in the peripheral blood and tonsils has been revealed by flow cytometry, while expression of CLA by precursor B cells is not described to our knowledge. In one study, CLA on B cells bound to Eselectin transfectants; E-selectin was detected on some of the high endothelial venules in the monocytoid B-cell-rich lymph nodes. An inherent anomaly of the neoplastic precursor B cells may lead to this aberrant expression (Yoshino et al., 1999; Kantele et al., 2003). CD10 is a neutral endopeptidase first discovered on the surface of acute lymphoblastic leukemia cells and originally held to be a tumor-specific antigen (Chubachi et al., 1994; Conde-Sterling et al., 2000). However, it has become increasingly apparent that normal cells at certain stages of maturation or function can demonstrate CD10 expression. Hence, CD10 expression is not a phenotypic sine que non of lymphoblastic lymphoma (Conde-Sterling et al., 2000). It has since been described in other forms of hematologic dyscrasia including angioimmunoblastic lymphadenopathy, Burkitt’s lymphoma, and unspecified peripheral T cell lymphomas (Goerdt et al., 1996; Attygalle et al., 2002, 2004). CD10 is expressed by immature T and B cells, centroblasts and centrocytes within germinal centers of lymphoid follicles, and benign mature T cells undergoing apoptosis. There is a growing body of literature suggesting that CD10 expression may be related to apoptosis. Cells procured from continuous T cell lines that did not normally express CD10 became CD10 positive when

induced into apoptosis by human immunodeficiency virus (HIV) infection and/or with exposure to CD95 monoclonal antibody, etoposide, or staurosporin. In contrast, addition of inhibitors of caspases blocked apoptosis and attenuated CD10 expression (Cutrona et al., 1999; Cutrona and Ferrarini, 2001). Both subsets of T cells (i.e., CD4 positive versus CD8 positive) exhibit CD10 expression upon induction of apoptosis. A characteristic feature of Burkitt’s lymphoma is apoptosis of strongly expressing CD10 positive B cells. Neutral endopeptidase activity results in the cleavage of proteins with inflammatory or proinflammatory activity released by dying lymphocytes; CD10, while not directly triggering apoptosis, represents a control mechanism to reduce the impact of the inflammatory milieu triggered by the apoptotic environment. Cytogenetics The cytogenetic abnormalities in precursor B acute lymphoblastic lymphoma are numerous; however, they can be broadly categorized as follows: hypodiploid, hyperdiploid >50, translocations, and pseudodiploid (see Figures 9.35–9.40). Among those cytogenetic abnormalities associated with a better prognosis are hyperdiploidy between 51 and 65 chromosomes and a t(12;21)(p12;q22), the result of the fusion of the ETV6 gene at 12p13 with the transcription factor encoding the RUNX1 gene at 21q22 (see Figures 9.35 and 9.37). There are three main translocations associated with a poor prognosis: (1). t(9;22) that results from fusion of BCR at 22q11:2 and the cytoplasmic tyrosinase kinase gene Figure 9.38; (2) t(4;11) due to fusion of the MLL gene at 11q23 with AF4 at 4q21 (see Figure 9.36); and (3) t(1;19) translocation fusing the transcription factor encoding gene E2A at 19p13.3 with PBX at 1q23 (see Figure 9.40). Hypodiploidy denotes a worse prognosis (see Figure 9.39) (Perkins, 2000; Cook et al., 2003; Hoefnagal et al., 2005). Differential Diagnosis The differential diagnosis is mainly with T lymphoblastic lymphoma. In one comprehensive study of skin involvement in lymphoblastic lymphoma, the majority of the tumors were of B cell lineage. With respect to T lymphoblastic lymphoma, however, the histomorphology regardless of the subtype of lymphoma was virtually identical. The morphologic hallmarks included a dense, diffuse, monomorphous infiltrate located in the entire dermis and subcutaneous fat and a prominent ‘‘starry sky’’ pattern. The neoplastic

Primary Cutaneous Diffuse Large B-Cell Lymphoma and Precursor Lymphoblastic Lymphoma

cells are characteristically arranged in a mosaic pattern with round or convoluted nuclei, inconspicuous nucleoli, and scant cytoplasms. T cell lymphoblastic lymphomas show CD3, CD10, and TdT positivity. In most cases there will be expression of both CD4 and CD8. T cell receptor gene rearrangement is usually seen but we have encountered cases with concomitant heavy chain immunoglobulin rearrangement. A second case was reported in which a 19 year old man presented with cutaneous, mediastinal, and intrapleural localization of a T lymphoblastic non-Hodgkin’s lymphoma (NHL) of immature phenotype. We have encountered a recent case in which a patient presented with greenish skin lesions that were interpreted as representing granulocytic sarcoma. He was subsequently established to have a large mediastinal mass. The mediastinal lesion was initially interpreted as representing lymphoblastic lymphoma based on CD99 and TdT positivity along with a heavy chain immunoglobulin rearrangement. It was, however, subsequently recategorized as a granulocytic sarcoma showing extensive CD68 and Leder positivity. The important message is that the diagnosis must be correlated with all aspects of the pathology, cytogenetics, and molecular profile. Both CD99 and TdT positivity can be seen in myeloid tumors and should not be considered markers defining lymphoblastic lymphoma (see Figures 9.4, 9.5, and 9.31–9.34) (Robertson et al., 1997).

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Granulocytic sarcoma. The patient developed many greenish grey appearing nodules on the upper back. An initial impression was that of lymphoblastic lymphoma. The case is illustrated in Case Vignette 4. The greenish color, characteristic for granulocytic sarcoma. Interestingly, the biopsy showed a heavy chain immunoglobulin gene rearrangement. (Courtesy of Dr. Mohamad Diab, Department of Dermatology, The Ohio State University.)

FIGURE 9.4

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(a)

(b)

Granulocytic sarcoma. A 27 year old man presented with granulocytic sarcoma extensively involving the mediastinum and the skin on the chest. Computerized tomography shows a large heterogeneously attenuating mediastinal mass with an area of necrosis within it, thickening of the pleura bilaterally, and thickening of the pericardium, which is nodular and multifocal. FIGURE 9.5

Case Vignette 1

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 77 year old woman who presented with an infiltrative plaque on the left calf. Her past medical history was remarkable for rheumatoid arthritis. Diagnosis: Primary cutaneous large cell lymphoma, leg type (Figures 9.6–9.16).

(a)

(b)

Low power examination reveals a nodular infiltrate that involves the superficial and deep dermis with extension into the panniculus. There is no gradation in the intensity of infiltration as the tissue base is approached, an important clue to the diagnosis of endogenous lymphoproliferative disease.

FIGURE 9.6

FIGURE 9.7 The infiltrate manifests angiocentricity. Angiotropic patterns of infiltration are not unique to T cell infiltrates. When angiotropism is established to be a B cell dominant process, the findings are very suspicious for B cell neoplasia.

Higher power magnification shows the cytomorphology of the infiltrate, namely, one predominated by large immunoblastic cells in the 15–20 µm size range manifesting central large eosinophilic nucleoli and a rim of clearish to eosinophilic cytoplasm. FIGURE 9.8

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CASE VIGNETTE 1

(Continued)

FIGURE 9.9 The infiltrate may assume a geographic coalescing pattern with interposed zones of altered collagen in a fashion almost reminiscent of necrobiosis lipoidica. This pattern of growth may account for the frequent clinical presentation, which is one resembling necrobiosis lipoidica, reflecting the potentially annular nature of the lesions clinically.

FIGURE 9.10

A CD20 preparation highlights the perivascular mantles of immunoblastic appearing cells.

FIGURE 9.11 A CD43 preparation shows prominent cytoplasmic membrane staining of the highly atypical lymphoid elements, corroborative of T cell lineage infidelity.

FIGURE 9.12

The MIB-1 proliferation index in this tumor is very high, a finding that may correlate with a more aggressive clinical course. Gene profiling does show an hyperproliferative activated B cell profile.

Case Vignette 1

FIGURE 9.13 The large atypical cells are also Bcl-2 positive, a finding that has been correlated with a more aggressive course clinically and is the critical phenotypic determinant in rendering a diagnosis of diffuse large cell lymphoma leg type; other markers correlating with the aggressive leg type phenotype are MUM, and Oct2 (‘‘activated’’ B cell profile).

FIGURE 9.14 A CD79a preparation shows focal staining of the immunoblastic cells. However, the majority of cells are CD79a negative. This is compatible with a relative CD79a deletion.

In situ hybridization for kappa shows weak cytoplasmic staining of the nodular angiocentric aggregates. Intense staining for kappa and or lambda would only be seen in cells showing fully evolved plasmacytic differentiation. The cell of origin in many leg type lymphomas is a germinal center cell in a later stage of differentiation.

FIGURE 9.16 A comparable staining pattern is not seen with λ. There is essentially no staining with λ. The combined κ and λ results would be indicative of a κ light chain restricted infiltrate.

FIGURE 9.15

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CASE VIGNETTE 2

The patient is a 76 year old woman who presented with an extensive indurated and violaceous plaque on the foot. Diagnosis: Diffuse large cell B cell lymphoma, follicle center cell origin (2nd group) (Figures 9.17–9.23). (Note: not illustrated is Bcl-2, which is negative.)

(a)

(b)

FIGURE 9.17

(c)

The biopsy shows an extensive lymphoid infiltrate effacing the dermis and involving the panniculus.

(a)

(b)

Regarding the cytomorphology, the cells are in the 20–30 µm size range. The nuclei are round to oval with a vesicular chromatin; nucleoli are conspicuous, showing a peripheral disposition to the nuclear membrane compatible with a centroblastic morphology. The cytoplasms are modest and eosinophilic in quality.

FIGURE 9.18

Case Vignette 2

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Phenotypic studies show that the cells are of B cell lineage as revealed by CD79 positivity (a). A lesser number of cells are CD20 positive compatible with a partial CD20 deletion (b). Only a few reactive CD3-positive T cells are present (c).

FIGURE 9.19

( a)

( b)

The tumor cells appear to be of follicle center cell origin based on Bcl-6 (b) positivity despite what appears to be lack of CD10 expression (a).

FIGURE 9.20

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CASE VIGNETTE 2

(Continued)

FIGURE 9.21 The cells also co express CD43, consistent with T cell lineage infidelity. CD2 and CD3 preparations highlight a few reactive T cells.

(a)

FIGURE 9.22

The tumor cells show a high prolifera-

tion index.

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In situ hybridization studies to assess for κ and λ light chain restriction show a predominance of κ staining cells (a) over those of λ subtype (b).

FIGURE 9.23

Case Vignette 3

CASE VIGNETTE 3

209

The patient is a 6 year old boy presenting with a nodular lesion on the scalp. Diagnosis: Primary cutaneous lymphoblastic lymphoma (Figures 9.24–9.30). (Case courtesy of Dr. Samir Kahwash at Children’s Hospital).

FIGURE 9.24 There is an extensive dermal infiltrate of large cells. The infiltrate assumes a nodular and diffuse pattern of growth within the dermis.

FIGURE 9.25

Higher power magnification shows that the cells are of intermediate size, manifesting a delicate finely dispersed heterochromatin with inconspicuous nucleoli and a narrow rim of cytoplasm.

FIGURE 9.27 Oil examination shows that the cells are relatively monomorphous in appearance, exhibiting round to oval nuclei with inconspicuous nucleoli and a narrow rim of lightly eosinophilic cytoplasm.

FIGURE 9.26

Higher power magnification reveals that the cells, although monomorphous, manifest fully evolved cytologic criteria of malignancy.

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CASE VIGNETTE 3

(Continued)

(a)

(b)

CD10 preparation shows sharp cytoplasmic membrane staining of the tumor cells (a). Also important in rendering a diagnosis, although not present in every case, is TdT positivity. The cells are strongly TdT positive. Note the nuclear staining pattern (b). FIGURE 9.28

The cells are CD20 positive. Note that the CD20 staining pattern shows a zonation phenomenon with the most intensely staining cells found in close apposition to blood vessels.

FIGURE 9.29

The cells also stain for cutaneous lymphocyte antigen manifesting an unusual dot-like pattern of positivity.

FIGURE 9.30

Case Vignette 4

CASE VIGNETTE 4

211

An important differential diagnosis of lymphoblastic lymphoma is one granulocytic sarcoma with monocytoid features, as these tumors can show CD99 and TdT positivity. This patient presented with a sudden onset of multiple nodules on his back. The lesions had a greenish hue (illustrated in Figure 9.4). The skin biopsy was interpreted as representing monocytic leukemia cutis based on a characteristic phenotype and the positive Leder stain. Subsequently, the patient developed dyspnea, which led to a mediastinal biopsy that was interpreted at least initially as representing lymphoblastic lymphoma based on CD99 and TdT positivity. Diagnosis: Granulocytic sarcoma with skin and mediastinal disease (Figures 9.31–9.34).

(a)

(b)

In these photographs one can see that the cells are larger than what one would expect in lymphoblastic lymphoma and the chromatin is more open. Another important distinguishing feature is the abundant eosinophilic cytoplasm.

FIGURE 9.31

The cells were weakly CD99 positive. CD99 positivity can be seen in granulocytic sarcomas.

FIGURE 9.32

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CASE VIGNETTE 4

(Continued)

The cells were also weakly positive for TdT. TdT positivity can be seen in granulocytic sarcoma.

FIGURE 9.33

FIGURE 9.34 The cells are strongly Leder positive. Leder is a chloracetate esterase stain and is positive in granulocytic sarcoma.

Additional Molecular and Cytogenetic Studies

213

ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES Cutaneous B cell lymphoblastic Lymphoma (Figures 9.35–9.40)

Among those cytogenetic abnormalities associated with a better prognosis is a t(12:21)(p13;q22), the result of the fusion of the TEL gene at 12p13 with the transcription factor encoding the AML1 gene at 21q22. (Cytogenetics performed and interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

FIGURE 9.35

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FIGURE 9.36 A classic translocation associated with a poor prognosis is t(4:11) due to fusion of the MLL gene at 11q23 with AF4 at 4q21. (Cytogenetics performed and interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

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FIGURE 9.37

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FIGURE 9.38 Another cytogenetic abnormality associated with a poor prognosis is t(9:22) that results from fusion of BCR at 22q11:2 and the cytoplasmic tyrosinase kinase gene on chromosome 9. (Cytogenetics performed and interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.) Hypodiploid ALL Cell

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FIGURE 9.39 Hypodiploidy denotes a worse prognosis. (Cytogenetics performed and interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

Additional Molecular and Cytogenetic Studies

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46,XX,der(19)t(1:19)(q23;p(13)

FIGURE 9.40 This is an image of an acute lymphoblastic leukemia showing der(19)t(1;19). (Cytogenetics performed and interpreted by Dr. Andrew Carroll at the University of Alabama at Birmingham.)

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CHAPTER TEN

INTRAVASCULAR LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Clinical Features Intravascular lymphoma is an aggressive and usually disseminated disease that mainly affects the elderly; B symptoms, anemia, and elevated serum lactate dehydrogenase levels are not uncommon (Willemze et al., 1987; Wick and Rocamora, 1988; Eros et al., 2002; Ferreri et al., 2004). The older terminology for this condition was malignant angioendotheliomatosis; the neoplastic cells were held to be of endothelial cell derivation (Schnyder et al., 1971). The second reported case was that of Kauh and co-workers (1980), who described a 48 year old man with fever and generalized asymptomatic erythematous telangiectatic plaques and patches. It was not until 1985 when it was first proposed that malignant angioendotheliomatosis may represent an angiotropic lymphoma (Wrotnowski et al., 1985). In 1988, Wick and Rocamora distinguished malignant angioendotheliomatosis from reactive angioendotheliomatosis, the former a malignancy of lymphoid origin and the latter defining a form of reactive neovascularization (Wick and Rocamora, 1988). The term malignant angioendotheliomatosis has since been supplanted by the term intravascular large cell lymphoma. It is exclusively a disease of adults; the rare reports of reactive angioendotheliomatosis occurring in infancy reflect a lesion of proliferating endothelia (Brazzelli et al., 1999). This rare neoplasm is characterized by an intravascular proliferation of lymphoma cells, typically of B cell derivation (Bhawan, 1987; Brazzelli et al., 1999; Eros et al., 2002). There is a predilection to

involve the skin and central nervous system (Eros et al., 2002; Ferreri et al., 2004b). Although fever may be a presenting symptom (Kuvliev et al., 1999), the clinical symptoms largely reflect the ischemic sequelae of vascular occlusion associated with the proliferating intravascular tumor cells. While the brain and skin are the most common sites of disease, hepatosplenic (26%) and bone marrow infiltration (32%) are also found to be common. Lymph node disease is seen in only 11% of cases (Ferreri et al., 2004b). When patients present with disease confined exclusively to the skin, that is, the so-called cutaneous variant, they fair much better than do those who present with skin disease in the setting of multiorgan involvement. These patients have a normal platelet count (Demirer et al., 1994; Bogomolski-Yahalom et al., 1998; Ferreri et al., 2004b). B cell intravascular lymphoma can be complicated by hemophagocytic syndrome, but the degree of cytopenia, coagulopathy, and liver dysfunction is less severe compared to that seen in patients with panniculitis-like T cell lymphoma in whom hemophagocytic syndrome develops. This variant typically occurs in patients of Asiatic descent; the Asian variant of intravascular lymphoma manifests pancytopenia and hepatosplenomegaly but usually lacks any neurological abnormality or skin lesions, typical of classical intravascular lymphoma (Murase and Nakamura, 1999; Takahashi et al., 1999).

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 219

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Intravascular lymphoma has been observed in the setting of states of immune dysregulation including lymphopenia of the CD4-positive T cell subset, acquired immunodeficiency syndrome, rheumatoid arthritis, and Sjogren’s syndrome (Chakravarty et al., 1993). Intravascular lymphoma has occurred following a diagnosis of extravascular B and T cell lymphomas of the lung (Tomasini et al., 2004). The cutaneous presentation is one of telangiectatic lesions, panniculitis, erythematous plaques, and tender nodules (Ozguroglu et al., 1997; Wolter et al., 2002; Dedic et al., 2003; Ferreri et al., 2004b). There are reports of hemangiomas and angiolipomas being involved by intravascular lymphoma (Chakravarty et al., 1993; Ozguroglu et al., 1997; Suh et al., 1997; Rubin et al., 1997; Smith et al., 2001; Wolter et al., 2002; Cerroni et al., 2004; Tomasini et al., 2004; Nixon et al., 2005). Fever as the only presenting sign has been described (Kuvliev et al., 1999). Those cases of intravascular lymphoma of T cell phenotype are clearly rare, and their presentation clinically may deviate from classic intravascular lymphoma by virtue of lung involvement in the absence of skin and central nervous system disease (Au et al., 1997; Suh et al., 1997; Hsiao et al., 1999). Treatment is addressed in Chapter 2. Briefly, systemic chemotherapy is warranted including anthracycline and CHOP therapy in concert with granulocyte colony stimulating factor and/or autologous bone marrow transplantation (Koizumi et al., 2001; Ferreri

et al., 2004a, b). Rituximab has also been used (Han et al., 2003). Despite advances in the treatment, this is still considered an aggressive lymphoma with a poor prognosis. Light Microscopic Findings There is intravascular localization of tumor; the affected vessels are of small caliber and include capillaries, small arteries, and venules. The vessels are ectatic and typically distended by intravascular nodular cellular aggregates; there is prominent localization to involve the superficial and mid-dermis. The tumor cells are typically intermediate to large sized lymphocytes with blastic nuclear features and prominent nucleoli. While there can be intravascular fibrin deposition, there are no concomitant vasculitic changes, nor is there extension of neoplastic lymphocytes into the surrounding tissue. Admixed cellular elements such as histiocytes or plasma cells are usually not seen. Cases showing dominant localization within the subcutaneous fat have been described (Wick and Rocomora, 1988; Kanda et al., 1999; Eros et al., 2002; Dedic et al., 2003). Phenotypic Profile The majority of these lymphomas are of B cell phenotype and therefore express pan-B cell markers such as CD79a and CD20. In some cases the critical cells express CD5 while others are CD10 positive. In situ hybridization studies fail to detect EBV in

TABLE 10.1 Intravascular Lymphoma Clinical Elderly Solitary or multiple indurated patches and plaques, often with superimposed petechiae and sometimes mimicking panniculitis Trunk and thighs most often Central nervous system commonly affected as well Hemophagocytic syndrome in Asian variant Primary cutaneous form better prognosis Associated with Sjogren’s syndrome, lymphopenia, HIV disease Rare T cell variants show lung involvement without skin or CNS disease Histomorphology Intravascular aggregates of large atypical lymphoid cells Immunophenotype CD20, 79a + (rare intravascular lymphomas are of T-cell phenotype) CD5 +/− slg + (monoclonal) Rarely T cell variants Genetics Monoclonal rearrangement of the JH gene Therapy Systemic chemotherapy

Intravascular Lymphoma

those intravascular lymphomas of B cell derivation. In contrast, EBV latent protein expression has been demonstrated in the nuclei of intravascular T cell lymphoma cases (Perniciaro et al., 1995; Suh et al., 1997; Khalidi et al., 1998; Hsiao et al., 1999; Kanda et al., 1999; Yegappan et al., 2001). Pathogenesis The purported basis for intravascular lymphomatosis has been held to reflect cytokine interaction between the neoplastic lymphoid cells, the endothelium, and the extravascular compartment. The question arises regarding the mechanism(s) by which the neoplastic B cells demonstrates intravascular localization. Immunohistochemical studies have shown, using formalin-fixed tissue, the localization of lymphocytes to endothelium via specific markers including CD29 (beta 1 integrin subunit) and CD54. These two markers are noticeably not present in these

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tumors. Both CD29 and CD54 are critical to the egress of lymphocytes from their intravascular location into the extravascular tissue; the absence of these markers may account for the intravascular localization of the neoplasm. In another study the intravascular lymphoma cells expressed CD49d (VLA-4), while endothelial cells expressed CD106 (CD49d ligand). Interaction between these adhesion molecules might contribute to the intravascular localization of these lymphomas (Kanda et al., 1999; Panzoni et al., 2000). With respect to the T cell variant, a memory T cell phenotype has been demonstrated. Lymphocyte function-associated antigen-1s, CD11a and CD18, and intercellular adhesion molecule-1 have been demonstrated on the tumor cells and vascular walls in the lesions. The data suggest that the intravascular localization of the tumor is really a function of tumor–endothelial cell interactions (Au et al., 1997; Suh et al., 1997).

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CASE VIGNETTE CASE VIGNETTE 1

The patient presented with a generalized petechial skin rash with supervening livedo. Diagnosis: Intravascular lymphoma (Figures 10.1–10.5).

The ectatic vessels contain intraluminal aggregates of lymphoid cells; there is mural fibrin deposition.

FIGURE 10.1

The lymphoid cells are monomorphous and large, with nuclei in the 20–25 µm size range.

FIGURE 10.2

The large monomorphous lymphoid cells manifest coarse chromatin and prominent, generally solitary nuclei.

FIGURE 10.3

References

A CD20 preparation decorates the intravascular tumor cells as B cells.

FIGURE 10.4

FIGURE 10.5 A CD3 preparation decorates the reactive perivascular T lymphocytes but not the angiotropic neoplastic B cells.

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REFERENCES AU WY, SHEK WH, NICHOLLS J, et al. T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein–Barr viral infection. Histopathology. 1997; 31(6):563–567. BHAWAN J. Angioendotheliomatosis proliferans systemisata: an angiotropic neoplasm of lymphoid origin. Semin Diagn Pathol. 1987; 4(1):18–27. BOGOMOLSKI-YAHALOM V, LOSSOS IS, OKUN E, et al. Intravascular lymphomatosis—an indolent or aggressive entity? Leuk Lymphoma. 1998; 29(5–6):585–593. BRAZZELLI V, BALDINI F, VASSALLO C, et al. Reactive angioendotheliomatosis in an infant. Am J Dermatopathol. 1999; 21(1):42–45. CERRONI L, ZALAUDEK I, KERL H. Intravascular large Bcell lymphoma colonizing cutaneous hemangiomas. Dermatology. 2004; 209(2):132–134. CHAKRAVARTY K, GOYAL M, SCOTT DG, MCCANN BG. Malignant ‘‘angioendotheliomatosis’’ (intravascular lymphomatosis)—an unusual cutaneous lymphoma in rheumatoid arthritis. Br J Rheumatol. 1993; 32(10):932–934. DEDIC K, BELADA D, ZAK P, NOZICKA Z. Intravascular large B-cell lymphoma presenting as cutaneous panniculitis. Acta Medica (Hradec Kralove). 2003; 6(3):121–123. DEMIRER T, DAIL DH, ABOULAFIA DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer. 1994; 73(6):1738–1745. EROS N, KAROLYI Z, KOVACS A, TAKACS I, RADVANYI G, KELENYI G. Intravascular B-cell lymphoma. J Am Acad Dermatol. 2002; 47(5 Suppl):S260–262. FERRERI AJ, CAMPO E, AMBROSETTI A, et al. Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma. Ann Oncol. 2004a; 15(8):1215–1221. FERRERI AJ, CAMPO E, SEYMOUR JF, et al. International Extranodal Lymphoma Study Group (IELSG). Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘‘cutaneous variant.’’ Br J Haematol. 2004b; 127(2):173–183. HAN K, HALEY JC, CARLSON K, PINTER-BROWN L, SORIANO T. Regression of cutaneous intravascular lymphoma with rituximab. Cutis. 2003; 72(2):137–140. HSIAO CH, SU IJ, HSIEH SW, et al. Epstein–Barr virusassociated intravascular lymphomatosis within Kaposi’s sarcoma in an AIDS patient. Am J Surg Pathol. 1999; 23(4):482–487. KAUH YC, MCFARLAND JP, CARNABUCI GG, LUSCOMBE HA. Malignant proliferating angioendotheliomatosis. 5. Arch Dermatol. 1980;116(7):803–806. KANDA M, SUZUMIYA J, OHSHIMA K, TAMURA K, KIKUCHI M. Intravascular large cell lymphoma: clinicopathological, immuno-histochemical and molecular genetic studies. Leuk Lymphoma. 1999; 34(5–6):569–580. KOIZUMI M, NISHIMURA M, YOKOTA A, MUNEKATA S, KOBAYASHI T, SAITO Y. Successful treatment of intravascular malignant lymphomatosis with highdose chemotherapy and autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2001;27(10):1101–1103. KHALIDI HS, BRYNES RK, BROWNE P, et al. Intravascular large B-cell lymphoma: the CD5 antigen is

expressed by a subset of cases. Mod Pathol. 1998; 11(10):983–988. KUVLIEV E, GLAMOUR T, SHEKAR R, WEST BC. Angiotropic large cell lymphoma presenting as fever of unknown origin. Am J Med Sci. 1999; 317(4):266–268. MUNAKATA S, HIRANO S, YOSHIYAMA Y, KOIZUMI M, KOBAYASI T, HATTORI T. [Beneficial effects of CHOP therapy in a case of intravascular large B-cell lymphoma diagnosed by skin biopsy] 16: Rinsho Shinkeigaku. 2000 May;40(5):476–9. MURASE T, NAKAMURA S. An Asian variant of intravascular lymphomatosis: an updated review of malignant histiocytosis-like B-cell lymphoma. Review. Leuk Lymphoma. 1999; 33(5–6):459–473. NARIMATSU H, MORISHITA Y, SAITO S, SHIMADA K, OZEKI K, KOHNO A, KATO Y, NAGASAKA T. Usefulness of bone marrow aspiration for definite diagnosis of Asian variant of intravascular lymphoma: four autopsied cases. Leuk Lymphoma 45(8):1611–6, 2004 Aug. NIXON BK, KUSSICK SJ, CARLON MJ, RUBIN BP. Intravascular large B-cell lymphoma involving hemangiomas: an unusual presentation of a rare neoplasm. Mod Pathol. 2005; 18(8):1121–1126. OZGUROGLU E, BUYULBABANI N, OZGUROGLU M, BAYKAL C. Generalized telangiectasia as the major manifestation of angiotropic (intravascular) lymphoma. Br J Dermatol. 1997; 137(3):422–425. PERNICIARO C, WINKELMANN RK, DAOUD MS, SU WP. Malignant angioendotheliomatosis is an angiotropic intravascular lymphoma. Immunohistochemical, ultrastructural, and molecular genetics studies. Am J Dermatopathol. 1995; 17(3):242–248. PANZONI M, ARRIGONI G, GOULD VE, et al. Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol. 2000; 31(2):220–226. RUBIN MA, COSSMAN J, FRETER CE, AZUMI N. Intravascular large cell lymphoma coexisting within hemangiomas of the skin. Am J Surg Pathol. 1997; 21(7): 860–864. SCHNYDER UW, MULLER H, JUNG EG. [Malignant angioendotheliomatosis of the nose.] Ann Dermatol Syphiligr (Paris). 1971;98(4):404–405. SMITH ME, STAMATAKOS MD, NEUHAUSER TS. Intravascular lymphomatosis presenting within angiolipomas. Ann Diagn Pathol. 2001; 5(2):103–106. SUH CH, KIM SK, SHIN DH, CHUNG KY, KIM SK. Intravascular lymphomatosis of the T cell type presenting as interstitial lung disease—a case report. J Korean Med Sci. 1997; 12(5):457–460. TAKAHASHI N, CHUBACHI A, MIURA I, et al. Lymphomaassociated hemophagocytic syndrome in Japan. Rinsho Ketsueki 1999; 40(7):542–549. TOMASINI C, NOVELLI M, PONTI R, PIPPIONE M, BERNENGO MG. Cutaneous intravascular lymphoma following extravascular lymphoma of the lung. Dermatology. 2004; 208(2):158–163. WILLEMZE R, KRUYSWIJK MR, DE BRUIN CD, MEIJER CJ, VAN BERKEL W. Angiotropic (intravascular) large cell lymphoma of the skin previously classified as malignant angioendotheliomatosis. Br J Dermatol. 1987;116(3):393–399.

References

WICK MR, ROCAMORA A. Reactive and malignant ‘‘angioendotheliomatosis’’: a discriminant clinicopathological study. J Cutan Pathol. 1988; 15(5):260–271. WOLTER M, BADOUAL C, WECHSLER J, et al. Intravascular large cell lymphoma revealed by diffuse telangiectasia and cauda equina syndrome. Ann Dermatol Venereol. 2002; 129(3):320–324.

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WROTNOWSKI U, MILLS SE, COOPER PH. Malignant angioendotheliomatosis. An angiotropic lymphoma? Am J Clin Pathol. 1985;83(2):244–248. YEGAPPAN S, COUPLAND R, ARBER DA, et al. Angiotropic lymphoma: an immunophenotypically and clinically heterogeneous lymphoma. Mod Pathol. 2001; 14(11):1147–1156.

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CHRONIC LYMPHOCYTIC LEUKEMIA OF B CELL AND T CELL PHENOTYPE (T CELL PROLYMPHOCYTIC LEUKEMIA) Cynthia M. Magro and A. Neil Crowson

B Cell Chronic Lymphocytic Leukemia Clinical Features The specific skin infiltrates in patients with B cell chronic lymphocytic leukemia (B-CLL) are varied and include localized or generalized erythematous papules, plaques, nodules, and large tumors. Ulceration is uncommon. In some cases the lesions are confined to sites typical for Borrelia burgdorferi infection, and at scars from previous herpes zoster, or at sites of herpes simplex eruptions (Pujol et al., 1990; Cerroni et al., 1996, 2002; Broustet and Merlio, 1997; Cerroni and Kerl, 1997; Varkonyi et al., 2000; Porter et al., 2001; Agnew et al., 2004; Kakagia et al., 2005). Commonly observed are leukemic infiltrates in primary excision and reexcision specimens of unrelated skin tumors (Smoller and Warnke, 1998; Agnew et al., 2004). Another rare presentation has been that of fingertip hypertrophy, namely, symmetrical tumorous lesions of the distal finger pads with biopsies confirmatory of chronic lymphocytic leukemia. Similar infiltrates have been reported in patients with striking nail bed and nail plate changes (Yagci et al.,

2001; Frieman et al., 2002). Although the presence of leukemia cutis in the setting of CLL is not considered to represent an independent adverse prognostic variable, certain light microscopic features in biopsy material may correlate with outcome (Cerroni et al., 1996; Kaddu et al., 1996). While seemingly counterintuitive, it has been suggested that involvement of the skin may in fact be associated with a better prognosis (Colburn et al., 2002) (see Table 11.1). Chronic lymphocytic leukemia may be associated with a number of paraneoplastic dermatoses including pemphigus, eosinophilic folliculitis, folliculocentric herpes, granulomatous inflammatory processes such as atypical granuloma annulare, and cyclic T cell rich lymphocytic vasculitis (Pujol et al., 1990; Van Mook et al., 2001; Smith et al., 2002; Cabuk et al., 2004). Morphology Histologically, three main architectural patterns are recognized: (1) patchy perivascular and periadnexal, (2) nodular and diffuse, and (3) bandlike (Cerroni et al., 1996; Kaddu et al., 1996). (See Case

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 226

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TABLE 11.1 B Cell Chronic Lymphocytic Leukemia Clinical Elderly adults Infiltrates can be found as an incidental finding in the context of surgery for primary epithelial malignancy Skin involvement does not portend a worse prognosis and may confer a survival advantage Histomorphology Patchy or nodular infiltrates of small lymphocytes Larger cells usually represent proliferation centers and do not denote Richter’s transformation Immunophenotype CD20+ CD5+ CD43+ CD23+ slg+ (monoclonal) Genetics Monoclonal rearrangement of the JH gene in most Cytogenetics are important in prognosticating CLL Trisomy of chromosome 12; 17p deletion deletion of the P53 locus, 11q deletion, poor survival Chromosome 13 deletion: improved survival Deletions in chromosome 7: multidrug resistance to doxoruhicin, vinplastine and colchicine Therapy Therapy is guided by systemic symptoms and extent of peripheral blood involvement, not skin involvement

Vignettes 1–3.) Cytologically, the infiltrates comprise monomorphous lymphocytes in the 7–9 µm size range with generally round nuclei that, compared to normal small B lymphocytes, may show some irregularity of contour and more fine dispersal of chromatin. There is a variable admixture of large cells, plasma cells, and eosinophils (see Figures 11.6, 11.7 11.1–11.9, 11.13, and 11.14). Studies have suggested that certain morphologic parameters may have prognostic significance. For example, cases showing significant epidermal changes such as hyperplasia, an admixture of other inflammatory cell elements, greater than 5% large atypical cells, and a dense infiltrate in a diffuse and pandermal distribution are associated with a worse prognosis (Kaddu et al., 1996). Aggregates of prolymphocytes and paraimmunoblasts compatible with proliferation centers may be observed, but do not appear to adversely affect prognosis (Cerroni et al., 1996; Kaddu et al., 1996). Phenotype Neoplastic B lymphocytes show an aberrant phenotype in paraffin-embedded sections, expressing CD20, CD23, CD5, and CD43 (see Figures 11.6,

11.7, 11.10–11.12 and 11.15). In cryostat sections, coexpression of CD19 and CD5 with immunoglobulin light chain restriction may be demonstrated (see Figures 11.10–11.12) (Hanson et al., 1999; Kurtin et al., 1999). Molecular Studies Polymerase chain reaction studies performed on paraffin-embedded tissues using appropriate consensus primers show immunoglobulin heavy chain gene rearrangement. Cytogenetics Clonal chromosomal abnormalities in leukemic cells are detected in almost half of patients with B-cell CLL using cytogenetic analysis. One-third of these patients have trisomy 12, with or without additional changes. However, the most common abnormalities involve the long arm of chromosome 13, the majority of which are in the form of deletions of 13q14.3. In one study of 325 CLL patients, 55% were found to have this 13q deletion (Dohner et al., 1999; Dohner, 2000). This region, represented by D13S319, is the most commonly deleted region in CLL and is involved in greater than 40% of cases; it seems

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likely that this region contains a tumor suppressor gene relevant to pathogenesis (Dohner et al., 1999; Wolf et al., 2001). The cytogenetic profile has been utilized as a prognostic variable in several studies. In the study by Dohner and co-workers, patients with a 17p deletion faired the worst, followed by those with an 11q deletion and 12q trisomy. Mehes et coworkers also found that the deletion of the p53 locus (17p13) was the strongest predictor for aggressive behavior and early death (Mehes G, 2005). Deletions in chromosome 7 is associated with drug resistance (Karnolsky) Patients with 13q deletion as their sole abnormality had the longest estimated survival times, even longer than those with no genetic abnormality (Dohner et al., 1999; Wolf et al., 2001). Separate studies have confirmed that 13q abnormalities are associated with a better prognosis (Juliusson and Merup, 1998). It would be interesting to see if the majority of patients presenting with cutaneous infiltrates in the setting of CLL have a 13q deletion in light of the concept that skin involvement may be associated with a better prognosis (Khandelwal et al., 2006). Pathogenesis CD5-positive B lymphocytes represent the neoplastic in cell populace in small lymphocytic lymphoma and CLL. B cells with self-reactivity produce natural autoantibodies at low levels in healthy adults and are principally of CD5 phenotype; these antibodies are primarily of IgM subtype in contrast to the IgG autoantibodies typically associated with autoimmune disease. They are often directed against tumors, viruses, and bacteria and hence are apparently important in immune surveillance, although isotype switching of benign or neoplastic lymphocytes can occur (Dighiero, 1993, 1996). When this occurs, antibodies of IgG subtype are produced which are associated with stigmata of autoimmunity. It is not surprising that there are a larger number of circulating CD5-positive B lymphocytes in patients with Sjogren’s syndrome and rheumatoid arthritis (Pers ¨ et al., 1999; Youinou and Lydyard, 2001). Patients with CLL may therefore manifest signs and symptoms of autoimmune disease, including a positive rheumatoid factor assay and thrombocytopenia (Dighiero, 1996; Jonsson et al., 1996). The expansion and proliferation of CD5-positive B lymphocytes requires T helper cell interaction, the latter defining the potential basis of the granulomatous infiltrates seen in the setting of CLL (Tretter et al., 1998). An anti-thymocyte autoantibody is produced by CD5-positive B cells (Kaneko et al., 1999; Hardy and Hayakawa, 2005). This antibody is directed against a surface glycoprotein expressed on

thymocytes and a fraction of mature T cells and may contribute to the inherent T cell dysregulation that can be seen in patients with CLL, among the consequences of which are exaggerated responses to arthropod bites and possibly an increased incidence of peripheral T cell lymphomas (Davis et al., 1998; Martin-Subero et al., 2001; Volk et al., 2002).

T Cell Prolymphocytic Leukemia T cell prolymphocytic leukemia is a distinctive form of leukemia derived from T cells at an intermediate stage of differentiation between a cortical thymocyte and a mature peripheral blood T cell (Galton et al., 1974). It accounts for less than 2% of all cases of small lymphocytic leukemias in adults over the age of 30 (Toyota et al., 2005). Although T cell prolymphocytic leukemia was formerly considered to be the T cell counterpart of typically insidious B-CLL, the aggressive clinical course that defines most cases prompted reclassification by the World Health Organization (WHO). One of the characteristic features of T cell prolymphocytic leukemia is cutaneous involvement, the reported incidence of which is between 25% and 30% (Mallett et al., 1995). From a clinical perspective, prominent involvement of the face, with or without associated swelling, was seen in our cases and has been described in other reports (Levine et al., 1981; Volk et al., 1983; Mallett et al., 1995; Magro et al., 2006). In our recently published series no patient had erythroderma, consonant with other descriptions that have emphasized the relative infrequency of an erythrodermic cutaneous presentation, especially when compared to other forms of primary cutaneous T cell lymphoma (Magro et al., 2006). Also characteristic is the petechial and/or purpuric quality of the lesions due to red cell extravasation (Magro et al., 2006). Other features encountered in our patients and in other reported series include a linear and symmetrical distribution of lesions and an annular morphology (see Table 11.1) (Levine et al., 1981; Volk et al., 1983; Logan and Smith, 1988; Magro et al., 2006). Skin involvement is common at some point in the course of T cell prolymphocytic leukemia. (Serra et al., 1998; Beltran Fernandez et al., 2002; Magro et al., 2006). In the largest reported series, 28% of patients with T cell prolymphocytic leukemia had cutaneous involvement; in this subset 23 out of 26 patients had concurrent presentations of skin and peripheral blood involvement (Mallett et al., 1995). Other clinical features include marked peripheral blood involvement, accompanying anemia and thrombocytopenia, lymphadenopathy, bone marrow involvement, and

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TABLE 11.2 T Cell Prolymphocytic Leukemia Clinical Older adults, poor prognosis Petechial rash with facial involvement symmetry Concurrent systemic disease with extensive peripheral blood and bone marrow involvement Histomorphology Dominant angiocentric lymphocytic infiltrates with hemorrhage, minimal epidermotropism. Cells have round to reniform nuclei, single nucleolus Immunophenotype CD3, CD4, CD5, in the majority of cases Dual expression of CD4 and CD8 in 25% of cases CD8: +25% CD4+CD8+: small percentage CD52+, CD7+, BF1+ TCL1 oncogene antibody+ Genetics Monoclonal rearrangement of the T cell receptor gene(s) Inversion of chromosome 14 with breakpoints at q11 and q32 resulting in the activation of the TCL-1 oncogene Trisomy 8 and c-myc overamplification 11q 23 breakpoints Therapy Systemic chemotherapy; Campath

hepatosplenomegaly (Matutes et al., 1986; Hoyer et al., 1995). Other series have described a slight male preponderance. The mean age at presentation is 69 years (Matutes et al., 1991). Pleural effusions, ascites, and/or central nervous system involvement are frequent occurrences at some point in the clinical course (Levine et al., 1981; Matutes et al., 1991; Magro et al., 2006) (see Table 11.2). Campath has emerged as an important treatment option recognizing the high level of CD52 expression on the tumor cells (Ginaldi et al., 1998; Lundin et al., 2002).

Pathologic Abnormalities/Light Microscopic Findings The infiltrates are mainly dermal based and often assume a band-like disposition superficially with grenz zone of separation from the overlying epidermis (Magro et al., 2006). (See Case Vignettes 3–5.) Epitheliotropism is not prominent, although it is seen in most cases and is localized to the acrosyringes. The dominant site of infiltration is around blood vessels; changes compatible with necrotizing vasculitis are not seen but there is prominent red cell extravasation, which translates clinically into petechiae (See Figures 11.16, 11.17 and 11.22).

The cytomorphology of T cell prolymphocytic leukemia is defined by small to intermediate sized cells with a fine chromatin and a small single nucleolus, centrally positioned. The nuclei are frequently indented and/or have irregular profiles; the cytoplasms are conspicuous, agranular, and eosinophilic in quality (Volk et al., 1983; Garand et al., 1998; Magro et al., 2006). Cytoplasmic protrusions or blebs held to be characteristic of T prolymphocytic leukemia are best appreciated on peripheral blood smears. In more indolent cases, the infiltrates are composed of small, well-differentiated lymphocytes. Those cases with a more aggressive clinical course show a larger cell type with greater nuclear atypia (See Figures 11.17, 11.20, and 11.22).

Phenotypic Abnormalities The main T cell subset is that of CD4-positive cells with preservation of CD7 and CD62L (Matutes et al., 1991; Matutes, 1998; Magro et al., 2006). A CD4-positive, CD8-negative phenotype is seen in two-thirds of cases while CD4 and CD8 are coexpressed in 25% of cases; a CD4-negative, CD8positive phenotype is rare (Matutes et al., 1998) (Figure 11.21). Twenty percent of cases of prolymphocytic leukemia do not express surface CD3, although

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there is preservation of CD7 expression within the cytoplasm (Figures 11.18, 11.23) similar to that encountered in T cell acute lymphoblastic lymphoma (Ginaldi et al., 1996). Those cases of prolymphocytic leukemia that are CD8 positive do not usually express cytotoxic proteins such as granzyme or TIA (Richaud-Patin et al., 2003; Nakajima et al., 2004). CD52 is expressed at fairly high levels compared to other types of T cell lymphoma and may explain the excellent treatment response to the anti-CD52 antibody Campath (Ginaldi et al., 1998; Lundin et al., 2002) (25 a). We have been able to demonstrate CD52 using paraffin-embedded tissue but are not aware of other studies that have assessed CD52 expression in fixed tissue. We have found TCL-1 oncogene antibody positivity to be specific for T cell prolymphocytic leukemia (Magro et al., 2006). Cytogenetics Chromosome abnormalities are detected in most cases of T cell prolymphocytic leukemia with the most consistent chromosomal abnormality being an inverted chromosome 14, a cytogenetic abnormality detected in two-thirds of cases (Isobe et al., 1988; Mossafa et al., 1994). Tandem translocations between both chromosomes 14 have also been described in some cases (Brito-Babpulle and Catovsky, 1991). It has been suggested that the 14q inversion results in the juxtaposition of a putative oncogene, TCL-1, located at the 14q32.1 region centromeric to the immunoglobulin heavy chain locus, with the gene encoding for the TCR-α chain at 14q11.2 leading to the expression and activation of TCL-1 (Pekarsky et al., 2001). TCL-1 is not normally expressed in T cells; it is implicated in B cell proliferation and therefore is present in both normal and neoplastic B lymphocytes. It is not expressed in differentiated B cells and therefore is not present in those lymphomas associated with terminal B cell differentiation such as marginal zone lymphoma or multiple myeloma. The juxtaposition to the gene encoding the TCR results in an expected activation and promotion of T cell proliferation. Identical abnormalities of chromosome 14 have been identified in lymphocytes from patients who have ataxia telangiectasia. These patients have an increased risk of developing leukemias, particularly T cell prolymphocytic leukemia (Brito-Babpulle and Catovsky, 1991; Taylor et al., 1996). In addition, the 1.3 kb tcl-1 transcript has been expressed in cases of ataxia telangiectasia with lymphocytosis or in patients who have developed a T cell leukemia (Thick et al., 1996). When the leukemia develops in ataxia telangiectasia, additional abnormalities are always documented (Brito-Babpulle, Catovsky 1991;

Taylor et al. 1996). Trisomy 8 and iso8q are found in 55% of cases of T cell prolymphocytic leukemia; abnormalities of the short arm of chromosome 8 occur less frequently (Mossafa et al., 1994). Although rearrangement of CMYC has not been demonstrated, cells from T cell prolymphocytic leukemia cases with trisomy 8 or iso8q over express the c-myc protein as estimated by flow cytometry analysis, suggesting that a high expression of c-myc plays a role in disease progression as a secondary event (Maljaie et al., 1995). In the one case in our series that showed the most aggressive clinical course there were multiple copies of chromosome 8 and an overexpression of CMYC. Abnormalities involving chromosome 11, including 11q23 breakpoints where the ataxia telangiectasia-mutated gene is located, have also been reported in T cell prolymphocytic leukemia (see Table 11.2) (Monni and Knuutila, 2001). A single case described a nonreported cytogenetic abnormality, namely, one of a t(6;6) (Maljaie et al., 1995). Differential Diagnosis The differential diagnosis of T cell prolymphocytic leukemia is mainly with those other T cell lymphoproliferative lesions associated with peripheral blood involvement and would encompass S´ezary syndrome, adult T cell leukemia lymphoma, and large granular lymphocyte leukemia (Fouchard et al., 1998; Nicot, 2005). In adult T cell leukemia lymphoma, hypercalcemia, HTLV-1 positivity, and a chronic clinical course at least in some cases are characteristic. From a pathologic perspective, there is epidermotropism, the cells exhibit a floret appearance and are CD7 negative. In large granular cell leukemia, skin involvement does not occur and the course is indolent. From a cytomorphologic perspective, the cells are large with abundant granular cytoplasms, are typically CD8, CD16, and CD57 positive, and express a variety of cytotoxic granule protein markers including TIA and perforin. While skin infiltration is common, erythroderma is not seen. In T cell acute lymphoblastic lymphoma, the patients are typically young and mediastinal involvement is characteristic; skin disease is uncommon. From a phenotypic perspective, the cells are CD10 and TdT positive. The expression of CD4, CD8, and/or both CD4 and CD8 are variable. In S´ezary syndrome, patients manifest erythroderma, which is distinctly uncommon in T cell prolymphocytic leukemia, and the cells are characteristically CD7 negative. S´ezary cell leukemia manifests peripheral blood involvement analogous to S´ezary syndrome in the absence of skin disease (Lee et al., 2003).

Case Vignette 1

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The patient is a 58 year old woman with a well established history of chronic lymphocytic leukemia who presented with a 5 day history of subcutaneous nodules on the lower extremities. Diagnosis: Primary infiltration of the skin with chronic lymphocytic leukemia (Figures 11.1–11.7).

The lower power view of a skin biopsy that was done on a patient suspect for recurrent chronic lymphocytic leukemia. The salient observations are a lymphocytic infiltrate in the dermis and subcutis, which is very focal and, at least in the dermis, assumes a dominant angiocentric disposition. Low power examination reveals a pattern that could easily be mistaken for a nonspecific reactive process without knowledge of the clinical history of chronic lymphocytic leukemia. FIGURE 11.1

(a)

(b)

FIGURE 11.2 Higher power magnification reveals that the infiltrate is predominated by small lymphocytes that are roughly in the same size range as erythrocytes. They form a loose perivascular cuff and merge imperceptibly into the interstitium of the reticular dermis. Higher power magnification discloses some element of nuclear atypicality; nevertheless it is not obvious at this power that the process is a neoplastic one.

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(Continued)

FIGURE 11.3 There is a fairly tight cuff of lymphocytes around blood vessels, although unassociated with effacement of the dermal architecture and hence mimicking a reactive dermatosis, specifically one in the context of either collagen vascular disease or a delayed type dermal hypersensitivity reaction.

The process mimics collagen vascular disease. At this power there is the suggestion of possible interstitial mucin deposition. As well, the lymphocytes are found in apposition to the straight eccrine duct, blood vessels, and eccrine coil. This constellation of findings resembles those morphologic features encountered in lupus erythematosus and some incipient presclerotic lesions of morphea. FIGURE 11.4

The key in making the diagnosis is the abnormal cytomorphology best appreciated under oil immersion microscopy. First, one can see that the nuclei have a finely dispersed chromatin as opposed to the more closely condensed heterochromatin of mature, reactive T lymphocytes. Second, the nuclei are round to oval. In contrast, the T lymphocytes of reactive dermatoses have intrinsic nuclear contour irregularity. Third, there are conspicuous although not prominent nucleoli, another feature of at variance with a reactive T lymphocyte. Finally, in some instances there are chromocenters that assume a clock face pattern of disposition to the nuclear membrane, defining a lymphoplasmacytoid cell, another morphologic finding that would be exceptional in a T-cell-dominant reactive infiltrate. FIGURE 11.5

Case Vignette 1

FIGURE 11.6 The hallmark of the neoplastic nature of the process, of course, is the fact that the cells are of B cell lineage as revealed by staining of the dermal lymphoid population for CD20. In contradistiction, most reactive cutaneous lymphoid infiltrates are of T cell lineage.

A CD23 preparation discloses positivity of the B lymphocytes, corroborative of a diagnosis of chronic lymphocytic leukemia of B cell type.

FIGURE 11.7

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CASE VIGNETTE 2

The patient underwent a re-excision of a squamous cell carcinoma. No other medical history was indicated on the requisition. Subsequently, it was established that the patient had a longstanding history of chronic lymphocytic leukemia after a letter was sent regarding the supervening abnormal lymphocytic infiltrate noted within the re-excision specimen. Diagnosis: Chronic lymphocytic leukemia coincidently involving the skin in the setting of squamous cell carcinoma (Figures 11.8–11.12).

(a)

(b) FIGURE 11.8

(c)

Amid this squamous cell carcinoma are nodular perivenular aggregates of lymphocytes.

Case Vignette 2

Higher power magnification highlights the monomorphic nature of the infiltrate. The cells are in the 7 µm size range. Under 100× objective examination, the cells have finely dispersed chromatin with inconspicuous nucleoli. FIGURE 11.9

FIGURE 11.11

positive.

The cells are also intensely CD23

A CD20 preparation highlights many of the cells in a perivenular array.

FIGURE 11.10

FIGURE 11.12 A CD5 preparation shows immunoreactivity of the perivascular B lymphocytes.

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CASE VIGNETTE 3

The patient is an 88 year old woman who underwent re-excision of a basal cell carcinoma. The patient has a known history of chronic lymphocytic leukemia. Diagnosis: Incidental involvement of the skin with chronic lymphocytic leukemic infiltrates (Figures 11.13–11.15).

(a)

(b)

(c)

FIGURE 11.13 The biopsy shows a residual basal cell carcinoma. However, in addition there is a background of lymphocytic infiltration. The cells are arranged mainly around vessels.

Case Vignette 3

Higher power magnification reveals a small mature lymphocytic infiltrate. The cells have a round to slightly irregular nuclear contour. The chromatin is mature and evenly dispersed, manifesting a peripheral condensation. Nucleoli are present but not conspicuous.

FIGURE 11.14

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CASE VIGNETTE 3

Chronic Lymphocytic Leukemia of B Cell and T Cell Phenotype (T Cell Prolymphocytic Leukemia)

(Continued)

(a)

(b)

(c)

(d)

FIGURE 11.15 The cells are CD20 positive (a), CD23 positive (b), CD5 positive (c). CD3 is useful as it clearly outlines the few T cells; hence, the large number of cells manifesting CD5 positivity are not of T cell lineage but rather represent an excessive expansion of CD5-positive B cells (d).

Case Vignette 4

CASE VIGNETTE 4

239

The patient is a 60 year old woman who presented with a petechial eruption involving the face and new onset pleural effusions. Investigations revealed a prominent peripheral blood lymphocytosis. Diagnosis: T cell prolymphocytic leukemia (Figures 11.16–11.18).

FIGURE 11.16 The biopsy shows a striking angiocentric lymphocytic infiltrate involving the superficial dermis. There is a narrow grenz zone separating the infiltrate from the overlying epidermis. In addition to this band-like pattern noted superficially, the remainder of the dermis is remarkable for an angiocentric pattern of lymphocytic infiltration. The cells surround and permeate the vessels although there are no frank vasculitic changes. Extensive red cell extravasation is noted.

(a)

(b)

FIGURE 11.17 Higher power magnification reveals that the cells are relatively small and manifest round to reniform, eccentrically disposed nuclei and a rim of eosinophilic cytoplasm.

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CASE VIGNETTE 4

Chronic Lymphocytic Leukemia of B Cell and T Cell Phenotype (T Cell Prolymphocytic Leukemia)

(Continued)

FIGURE 11.18 From a phenotypic perspective, the cells are CD3, CD7, and CD8 positive. Overall, the combined clinical, light microscopic, and phenotypic profile is most compatible with T cell prolymphocytic leukemia. Illustrated is CD7.

Case Vignette 5

CASE VIGNETTE 5

241

The patient has a well established history of T cell prolymphocytic leukemia. She presented with a symmetrical petechial skin rash. She died within 6 months of the development of this distinctive cutaneous eruption. Diagnosis: T cell prolymphocytic leukemia involving the skin (Figures 11.19–11.21).

FIGURE 11.19 A skin biopsy shows a dominant angiocentric disposition of the infiltrate. There is associated red cell extravasation.

FIGURE 11.20 Higher power magnification discloses the nature of the infiltrate, namely, one of small to intermediate sized lymphocytes with round to reniform shaped nuclei manifesting an eccentric disposition. The cytoplasm is eosinophilic in quality.

FIGURE 11.21 The cells are CD4 positive. The majority of cases of T cell prolymphocytic leukemia are CD4 positive.

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CASE VIGNETTE 6

The last patient in this series of T cell prolymphocytic leukemia had a prior history of non-Hodgkin’s lymphoma. He presented with a petechial skin rash and fatigue. He was discovered to have peripheral blood lymphocytosis. Approximately 3 months later he died of multiorgan dissemination with leukemic infiltrates. Diagnosis: T cell prolymphocytic leukemia (Figures 11.22–11.25).

(a)

(b)

FIGURE 11.22 The biopsy reveals a very atypical angiocentric infiltrate with attendant red cell extravasation. The cells are intermediate in size, manifesting an eccentrically disposed nucleus with abundant eosinophilic cytoplasm.

From a phenotypic perspective, the cells show both CD4 and CD8 positivity. They were also CD7 positive. In 25% of cases these tumors will coexpress both antigens. Illustrated is CD4. FIGURE 11.23

This FISH study shows multiple copies of chromosome 8 (green probe) along with overexpression of c-myc (red probe).

FIGURE 11.24

Case Vignette 6

(a)

(b)

FIGURE 11.25 (a) The cells are CD52 positive. Despite the CD52 positivity, the patient did not respond to Campath. This lymphoma continues to be an aggressive neoplasm with poor survival. (b) There is TCL1, oncogene antibody expression a finding very specific for T cell prolymphocytic leukemia.

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES

1

2

6

3

7

14

13

19

8

4

9

10

15

16

20

21

5

11

12

17

18

22

X

Y

FIGURE 11.26 Cytogenetics was performed on a peripheral blood sample for Case Vignette 6, using a PHA stimulated culture. An abnormal karyotype was demonstrated and included a translocation between chromosome 1 and 7, a loss of chromosome 11 and 13, an abnormal 12p, and an inverted chromosome 14. This cytogenetic profile is typical for T cell prolymphocytic leukemia. (Cytogenetic studies and interpretation by Dr. Nyla Hereema, Director of Cytogenetics, The Ohio State University.)

1

2

3

6

7

8

13

14

15

19

20

9

10

16

21

22

4

5

11

12

17

18

X

Y

The patient is a 73 year old man who developed a skin lesion on his right cheek that was biopsied in April 2003 and interpreted as representing a basal cell carcinoma. A subsequent reexcision revealed residual tumor along with a monomorphic small cell infiltrate compatible with chronic lymphocytic leukemia based on phenotypic studies. The patient had no known history of chronic lymphocytic leukemia. Subsequent investigations revealed a mild peripheral blood lymphocytosis. Cytogenetic studies of his peripheral blood showed an abnormal clone manifesting a translocation between chromosome 1 and 13 with a breakpoint at 13q14. Chromosome 10 also appeared abnormal with additional breakpoints at 10q22 and 10q24. (Cytogenetic studies and interpretation by Dr. Nyla Hereema, Director of Cytogenetics, The Ohio State University.) FIGURE 11.27

Additional Molecular and Cytogenetic Studies

FIGURE 11.28 Fluorescent in situ hybridization study conducted on peripheral blood on another patient with CLL using probes for chromosome 12 centromere (green) and D13S319, which localizes to 13q14.3 (red), appears normal (i.e., there are two green and two red signals). (Cytogenetic studies and interpretation by Dr. Nyla Hereema, Director of Cytogenetics, The Ohio State University.)

245

FIGURE 11.29 Fluorescent in situ hybridization study was conducted on peripheral blood using probes for chromosome 12 centromere (green) and D13S319, which localizes to 13q14.3 (red). A deletion for 13q14.3 is detected as there is only one red signal. (Cytogenetic studies and interpretation by Dr. Nyla Hereema, Director of Cytogenetics, The Ohio State University.)

Single peak at 296 bp Not in expected size range and excluded

The patient is a 75 year old man who presented with fatigue and a petechial skin rash. There was striking peripheral blood lymphocytosis. A diagnosis of T cell prolymphocytic leukemia was made. The molecular profile from his skin biopsy shows findings typical for T cell lymphoma/leukemia involving the skin in the context of disseminated multiorgan disease. The characteristic polyclonal background that may be seen with mycosis fungoides is not seen. The biopsy is composed almost exclusively of a single monoclonal population of T cells. (Molecular gel and interpretation provided by Dr. Carl Morrison, Director of Molecular Diagnostics Laboratory, The Roswall Park Buffalo, NY.)

FIGURE 11.30

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GARAND R, GOASGUEN J, BRIZARD A, et al. Indolent course as a relatively frequent presentation in T-prolymphocytic leukaemia. Groupe Francais d’Hematologie Cellulaire. Br J Haematol. 1998; 103:488–494. MEHES G. Chromosome abnormalities with pragnostic impact in B cell chronic lymphocytic leukemia. Pathol Oncol Res. 2005; 11:205–210. GINALDI L, MATUTES E, FARAHAT N, DE MARTINIS M, MORILLA R, CATVOSKY D. Differential expression of CD3 and CD7 in T-cell malignancies: a quantitative study by flow cytometry. Br J Haematol. 1996; 93:921–927. GINALDI L, DE MARTINIS M, MATUTES E, et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. Leuk Res. 1998; 22:185–191. HANSON CA, KURTIN PJ, KATZMANN JA, et al. Immunophenotypic analysis of peripheral blood and bone marrow in the staging of B-cell malignant lymphoma. Blood. 1999; 94(11):3889–3896. HARDY RR, HAYAKAWA K. Development of B cells producing natural autoantibodies to thymocytes and senescent erythrocytes. Springer Semin Immunopathol. 2005; 26(4):363–375. HOYER JD, ROSS CW, LI CY, et al. True T-cell chronic lymphocytic leukemia: a morphologic and immunophenotypic study of 25 cases. Blood. 1995; 86:1163–1169. ISOBE M, RUSSO G, HALUSKA FG, CORCE CM. Cloning of the gene encoding the delta subunit of the human T-cell receptor reveals its physical organization within the alpha-subunit locus and its involvement in chromosome translocations in T-cell malignancy. Proc Natl Acad Sci USA. 1988; 85:3933–3937. JONSSON V, SVENDSEN B, VORSTRUP S, et al. Multiple autoimmune manifestations in monoclonal gammopathy of undetermined significance and chronic lymphocytic leukemia. Leukemia. 1996; 10(2):327–332. JULIUSSON G, MERUP M. Cytogenetics in chronic lymphocytic leukemia (review). Semin Oncol. 1998; 25(1):19–26. KADDU S, SMOLLE J, CERRONI L, KERL H. Prognostic evaluation of specific cutaneous infiltrates in B-chronic lymphocytic leukemia. J Cutan Pathol. 1996; 23(6):487–494. KAKAGIA D, TAMIOLAKIS D, LAMBROPOULOU M, KAKAGIA A, GREKOU A, PAPADOPOULOS N. Systemic B-cell chronic lymphocytic leukemia first presenting as a cutaneous infiltrate arising at the site of a herpes simplex scar. Minerva Stomatol. 2005; 54(3):161–163. KANEKO T, HARA Y, YOSHIMURA A, KATO I. Induction of anti-thymocyte/T lymphocyte antibodies in mice injected with lipopolysaccharides from periodontopathic bacteria. J Periodontal Res. 1999; 34(2):105–112. KARNOLSKY IN. Cytogenetic abnormalities in chronic lymphocytic leukemia. Med (Plovdiv). 2000; 42:5–10. KHANDELWAL A, SEILSTAD KH, BYRD J, MAGRO CM. Subclinical chronic lymphocytic leukemia associated with a 13Q deletion presenting initially in the skin: apropos of a case. J Cutan. Pathol. 2006; 33:256–259. KURTIN PJ, HOBDAY KS, ZIESMER S, CARON BL. Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol. 1999; 112(3):319–329. LEE HJ, IM JG, GOO JM, et al. Peripheral T-cell lymphoma: spectrum of imaging findings with clinical and

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CHAPTER TWELVE

CUTANEOUS MANTLE CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Clinical Features Mantle cell lymphoma is a mature B cell lymphoma manifesting a characteristic morphology, phenotype, and molecular profile; it is an aggressive form of B cell lymphoma, accounting for 3–10% of all cases of non-Hodgkin lymphoma (Banks et al., 1992; Campo et al., 1999) (see Table 12.1). Weisenburger and co-workers first recognized the entity using the designation of diffuse intermediate lymphocytic lymphoma (Weisenberger (1981)). Mantle cell lymphoma is associated with a poor prognosis and has remained incurable with current chemotherapeutic approaches; although patients often have an initial response to chemotherapy, most develop progressive disease and succumb to it. The median survival is only 3 years with more protracted survivals being uncommon. As with many forms of non-Hodgkin lymphoma, the disease primarily affects Caucasians and is uncommon in patients of African descent. The mean age at presentation is 60 years and there is a male predominance of 4:1. Disease is often widespread at initial presentation with lymph node, spleen, liver, and/or bone marrow involvement. Peripheral blood lymphocytosis is found in at least one-quarter of cases. When progressive dissemination occurs, the gastrointestinal tract and Waldeyer’s ring are preferential sites of involvement. Most cases of intestinal lymphomatosis

represent mantle cell lymphoma; the gross morphology is characterized by multiple sized polyps affecting any segment of the gastrointestinal tract (Campo et al., 1999; Swerdlow and Williams, 2002). Although this is mainly a nodal lymphoma, there are rare cases where the lesions are confined to the skin or initially present in the skin; in the vast majority of patients, mantle cell lymphoma involving the skin reflects Stage IV disease (Bertero et al., 1994; Geerts and Busschots, 1994; Sarikaya et al., 2000; Moody et al., 2001; Hisatake et al., 2002; Sen et al., 2002). There are reports of mantle cell lymphoma initially presenting in the skin, but concurrent work-up in such cases usually reveals systemic disease. There are too few cases of primary mantle cell lymphoma of the skin to make any definite conclusion regarding prognosis; in one reported case the disease process remained confined to the skin at 30 months of follow-up (Sen et al., 2002). In another reported case, a patient developed multiple skin nodules involving the chest, upper arms, and face; the tumor cells showed a characteristic phenotypic and cytogenetic profile consistent with mantle cell lymphoma (Hisatake et al., 2002). The patient received eight courses of THP-COP therapy and went into complete remission. Based on the limited literature precedent, it is possible that primary cutaneous mantle cell lymphoma behaves in a more indolent fashion analogous to other forms of primary cutaneous B cell

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 248

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lymphoma (Hisatake et al., 2002). Mantle cell lymphoma secondarily involving the skin, may herald a blastoid transformation. Light Microscopic Findings Critical to understanding the skin findings is an understanding of the classic morphology seen in the lymph node (see Figures 12.1–12.4, 12.9, and 12.10 and 12.11). The pattern of lymph node involvement is diffuse versus nodular, and there are essentially four different patterns: mantle zone, large nodular, small nodular, and diffuse. In the so-called mantle zone pattern the lymph node manifests expansion of the perifollicular mantle zone by a monomorphous population of cells, which, while showing striking cellular uniformity in a given case, ranges in morphology between cases (Yatabe et al., 2001). In the large nodular pattern, these areas are large circumscribed expansile foci without discernible germinal centers. The small nodular pattern comprises small neoplastic nodules without germinal centers. The diffuse pattern shows significant zones of architectural effacement. The main cell types include a small mature lymphocytic morphology identical to that encountered in small lymphocytic lymphoma and chronic lymphocytic leukemia, a small-cleaved centrocyte, a monocytoid cell, and a classic mantle zone lymphocyte. The latter has an intermediate appearance between a small round lymphocyte and a cleaved lymphocyte. The monocytoid cells resemble those encountered in nodal marginal zone lymphoma whereby the cells exhibit rounded nuclei and abundant clear cytoplasms (see Figures 12.3, 12.4, and 12.10 and 12.11–12.12). Regardless of the cell type (i.e., small lymphocytic, cleaved, classic mantle, or monocytoid), the chromatin is finely dispersed and nucleoli are indistinct (Harris and Bhan, 1985; Ott et al., 1998). Plasma cells may be seen in the small noncleaved lymphocytic variant and are typically nonneoplastic in nature. The germinal centers are usually atrophic and/or disrupted by infiltrating neoplastic small lymphocytes, imparting an appearance compatible with progressive transformation (Campo et al., 1999; Yatabe et al., 2001; Swerdlow and Williams, 2002). In cases showing reactive plasma cells in concert with atrophic germinal centers, the pattern may resemble Castleman’s disease. Only rarely have plasmacytic neoplasms been described concurrently with mantle cell lymphoma. In the skin the morphology and immunohistochemical profile may closely mirror that encountered in the lymph node (Geerts and Buschotts, 1994; Marti et al., 2001). However, the classic presentation is one manifesting a blastoid morphology. In this regard the concept of blastoid mantle cell lymphoma must be

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addressed. When there is a significant proliferation of blastoid cells, the designation blastic mantle cell lymphoma is used (see Figures 12.3, 12.4, and 12.12). Case Vignettes 1 and 3 are examples of blastoid mantle cell lymphoma secondarily involving the skin. The morphologic features of a blastoid mantle cell lymphoma include larger cell size, enhanced nuclear pleomorphism, and increased mitotic activity. Some authors have recognized two cytologic variants: one resembling a lymphoblast and one characterized by enhanced pleomorphism. Blastic transformation may be the defining morphology in those tumors that recur in the skin, and evolution to a blastic morphology usually portends an aggressive clinical course (Decaudin et al., 1997; Singleton et al., 1999). A grade is not given for mantle cell lymphoma irrespective of the site of involvement, but if blastoid areas are observed this is commented upon in the report. In cases of mantle cell lymphoma involving the skin in the context of Stage IV disease, the dominant localization of the infiltrate may be within the fat. A cutaneous eruption simulating insect bites has been repeatedly described in association with chronic lymphocytic leukemia. The hallmarks are those defined by florid delayed hypersensitivity. There are eczematoid changes in the epidermis in concert with a superficial and deep angiocentric and perifollicular T-cell-rich lymphocytic and eosinophilic infiltrate. The process is clearly reactive in nature. In our experience, most of these cases have been accompanied by an eosinophilic pustular follicular reaction cognate to eosinophilic folliculitis. Similar changes of dysregulated type IV hypersensitivity have also been described in the setting of mantle cell lymphoma (Dodiuk-Gad et al., 2004; Shigekiyo et al., 2004; Khamaysi et al., 2005). Phenotypic Profile The tumor cells have a characteristic phenotype: they are CD10 and CD23 negative but express CD5, CD19, CD20, FMC7, IgM, cyclin D1, and bcl-1, and exhibit light chain restriction (see Figures 12.5–12.8, 12.13, and 12.14) (Barista et al., 2001). CD5 is normally present on T cells. There are other small CD5-positive B cell malignancies, namely, chronic lymphocytic leukemia and small lymphocytic lymphoma. In this regard the CD23 stain is useful as it is positive in small lymphocytic lymphoma/chronic lymphocytic leukemia and negative in mantle cell lymphoma. The cells usually coexpress CD43 (Campo et al., 1999; Moody et al., 2001; Swerdlow and Williams, 2002). Although one of the hallmarks of mantle cell lymphoma is CD5 positivity, on rare occasions the tumor cells are CD5 negative (Bell et al., 1998;

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Cutaneous Mantle Cell Lymphoma

Morice et al., 2004). It is felt, at least by some authors, that CD5 negativity may be associated with a better prognosis. Some cases showing loss of CD5 will demonstrate CD10 expression (Morice, 2004). Regardless of whether CD5 is present or not, the ultimate diagnosis must rest on a careful integration of light microscopic, molecular, and phenotypic features rather than on any one specific parameter. It should also be emphasized that cyclin D1 is not unique to mantle cell lymphoma, as cyclin D1 expression is described in plasma cell myeloma, Hodgkin lymphoma, and anaplastic large cell lymphoma (Yatabe et al., 2001). Conversely cyclin D1 negative mantle cell lymphomas are reported. They lack the t(11:14) (q13:q32) by FISH and may express cyclin D2 and cyclin D3 (Jueta 2005; Yatabe et al., 2001; Fu et al., 2005). There are cases of mantle cell lymphoma that have demonstrated an aberrant phenotype in regard to expression of certain T cell markers. Specifically, in one case of cutaneous blastoid mantle cell lymphoma, the cells expressed CD8 and α/β chains in the absence of other T cell markers with expression of the cytotoxic proteins perforin and granzyme (Schroers et al., 2005). CD8 is expressed on B cells in 1% of all B cell chronic lymphocytic leukemia cases, but usually in the context of CD8 α/α (Schroers et al., 2005). Cutaneous lymphocyte-associated antigen is a lymphocyte homing receptor expressed selectively by T cells of the cutaneous immune system and their malignant counterpart, cutaneous T cell lymphomas. It is not expressed by the vast majority of B cell lymphomas. It was described in one case of blastoid mantle cell lymphoma secondarily involving the skin, leading the authors to postulate that its expression on the tumor cells may have resulted in preferential cutaneous migration (Marti et al., 2001). Molecular Studies A dual genotype manifested by rearrangement of the immunoglobulin heavy chain gene (IgH) and T cell receptor-γ gene rearrangements has been observed in mantle cell lymphoma (see Table 12.1) (Vergier et al., 2002). Cytogenetic Profile At a cytogenetic level, the translocation (11;14)(q13;q32) can be detected in two-thirds of mantle cell lymphomas; the translocation juxtaposes an immunoglobulin heavy chain transcriptional enhancer on chromosome 14q32 to the proto-oncogene cyclin D1 on chromosome 11q13 (bcl-1/PRAD-1) involving an area of at least 220 kb, resulting in an overexpression of cyclin D1 messenger RNA (see

TABLE 12.1 Mantle Cell Lymphoma Clinical Adults. Most often multiple tumors Typically in the context of nodal disease and hence represents Stage IV disease; rare cases of primary cutaneous mantle cell lymphoma Histomorphology Monomorphous small to medium sized lymphocytic proliferation Characteristically, in the skin a blastic morphology is seen Immunophenotype CD20+ CD5+ (rare cases are CD5−) Cyclin-D1/bcl-1+ (occasionally negative including blastoid areas) CD23− CD10− CD8 positivity (rarely) Genetics t(11;14)(q13;q32) del 11 q 22.3-923.1. del 13 q Therapy Systemic chemotherapy Bone marrow transplantation

Figure 12.15) (Campo et al., 1999; Bertz et al., 2000; Dubus et al., 2002; Swerdlow and Williams, 2002). Cyclin D1 belongs to the family of G1 cyclins and plays an important role in G1/S transition of the cell cycle. In particular, high levels of cyclin D1 have been shown to bind p27, and hence the inhibitory effect of p27 on cyclin E, an important cell cycle regulator, is significantly attenuated (Swerdlow and Williams, 2002; Soslow et al., 1997; Zukerberg et al., 1996). Approximately 60% of all bcl-1 breakpoints can be detected by Southern blot analysis; the detection rate by polymerase chain reaction is 40%. Fluorescence in situ hybridization is the best method to detect the chromosomal breakpoints characteristic of mantle cell lymphoma (see Figure 12.16) (Espinet et al., 1999; Belaud-Rotureau et al., 2002; Sun et al., 2003). Another common genomic abnormality in mantle cell lymphoma is a deletion involving 11q22.3–923.1; this region is approximately 2–3 Mb in size and contains the genes encoding the ataxia telangiectasia mutated protein (Schaffner et al., 2000; Fernandez et al., 2005), which is critical for DNA repair. The level of expression of this protein is intimately associated with specific subsets of lymphocytes, being negative or expressed at low levels in immature B cells in bone marrow and immature T cells of the

Cutaneous Mantle Cell Lymphoma

thymic cortex. T cells of thymic medulla and peripheral tissues strongly express ataxia telangiectasia mutated protein as do B lymphocytes of the mantle zone and plasma cells, while the majority of germinal center B cells are negative or only weakly labeled. In contradistinction, many mantle cell lymphomas do not express the protein (Schaffner et al., 2000; Swerdlow and Williams, 2002; Starczynski et al., 2003). Other aberrations that have been associated with disease progression include complex karyotypes and tetraploid chromosome clones (Ott et al., 1997; Fernandez et al., 2005), 17p/p53 abnormalities, and INK4a/ARF deletions. Genomic aberrations similar to chronic lymphocytic leukemia have been described including a high frequency of deletions in 13q (Dreyling et al., 1997; Pinyol et al., 1997; Bentz et al., 2000; Rosenwald et al., 2003).

251

Pathogenesis The cell of origin has been suggested to be at a pregerminal center stage of development based on the presence of an unmutated VH status. However, other studies have shown a mutated VH gene in a proportion of mantle cell lymphoma cases. A similar subdivision has been described in CLL patients where these differences are held to be prognostically significant. Mutated VH genes have been detected in 29% of all cases of mantle cell lymphoma patients in one series, but as regards other features of B cell maturation, there is no evidence for class switch recombination or bcl-6 expression. Mutation of the VH gene does not appear to be a variable influencing survival. Deregulation of cell cycle control following overexpression of cyclin D1 may be a determinant of survival (Kienle et al., 2003).

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 53 year old man with a longstanding history of mantle cell lymphoma who developed right inner thigh lesions compatible with recurrent mantle cell lymphoma with blastoid features (i.e., recurrent blastoid mantle cell lymphoma) (Figures 12.1–12.8).

FIGURE 12.2 Intermediate power examination reveals extensive infiltration of the dermis by lymphocytes with splaying of the collagen fibers and effacement of the dermal architecture.

There is a striking pandermal infiltrate that penetrates into subcutaneous fat. There is effacement of the dermal architecture.

FIGURE 12.1

FIGURE 12.3 Higher power magnification reveals a proliferation of intermediate sized and larger lymphocytes with nuclear hyperchromasia and nuclear contour irregularity.

Higher power magnification shows intermediate sized lymphocytes with nuclear contour irregularity and a finely dispersed chromatin with conspicuous, although not unusually prominent, nucleoli. In addition, there are larger atypical cells typical of blastoid mantle cell lymphoma.

FIGURE 12.4

Case Vignette 1

FIGURE 12.5 A bcl-1 preparation shows intense nuclear staining of many of the lymphocytes, corroborative of a diagnosis of mantle cell lymphoma.

FIGURE 12.6

A CD5 preparation reveals focal staining of the infiltrate. Some of the positive staining cells are larger abnormal lymphocytes. In contradistinction, the CD23 preparation is characteristically negative.

FIGURE 12.7 A CD79a preparation shows extensive staining of the infiltrate.

FIGURE 12.8

In contrast, there is a striking CD20 deletion that likely reflects a rituximab effect.

253

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CASE VIGNETTE 2

The patient is a 70 year old man with widespread mantle cell lymphoma involving lymph nodes, bone marrow, and pharynx. Illustrated is a pharyngeal biopsy (Figures 12.9–12.10 and 12.11).

FIGURE 12.9

There is a diffuse infiltrate within the

corium.

FIGURE 12.10 and 12.11 Higher power magnification reveals a relatively monomorphic small to intermediate sized population. The cells range in quality from a round to irregularly contoured and/or marginally angulated nucleus with a finely divided chromatin and small chromocenters. There is minimal necrosis and no mitotic activity. The cytomorphology is typical of mantle cell lymphoma and is in contradistinction to the enhanced blastoid atypia demonstrated in Case Vignettes 1 and 3.

Case Vignette 3

CASE VIGNETTE 3

255

The patient is a 52 year old man who was diagnosed with blastoid mantle cell lymphoma in 2005; he had a response to chemotherapeutic intervention. He now presents with cutaneous nodules although is otherwise asymptomatic (Figures 12.12–12.14).

The biopsy shows an extensive diffuse and nodular infiltrate with accentuation around the eccrine coil. The cells exhibit the classic appearance of blastoid mantle cell lymphoma. They are intermediate to large in size with a finely dispersed chromatin and conspicuous eosinophilic nucleoli.

FIGURE 12.12

FIGURE 12.13

The phenotypic studies show bcl-1

positivity.

FIGURE 12.14 There is focal staining of the tumor cells for CD5; however, many of the tumor cells are negative.

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES

1

2

6

7

14

13

19

3

20

8

4

9

10

15

16

21

22

5

11

12

17

18

X

Y

Cytogenetic studies conducted on a lymph node sample. A t(11:14)(q13;q32) can be detected in two-thirds of mantle cell lymphomas; the translocation juxtaposes an immunoglobulin heavy chain transcriptional enhancer on chromosome 14q32 to the proto-oncogene cyclin D1 on chromosome 11q13 (bcl-1/PRAD-1) involving an area of at least 220 kb, resulting in an overexpression of cyclin D1 messenger RNA. (Cytogenetic studies performed and interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

FIGURE 12.15

(a)

(b)

FIGURE 12.16 A 56 year old man was diagnosed with blastoid mantle cell lymphoma. (a) The image shows the reactive lymph node with IgH CCND (cyclin D1) fusion probe. Note the absence of orange-green fusions. (b) In the patient there are orange green fusions reflective of the juxtaposition of the immunoglobulin heavy chain enhancer and the proto-oncogene cyclin D1. (Study and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

References

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REFERENCES BANKS PM, CHAN J, CLEARY ML, et al. Mantle cell lymphoma. A proposal for unification of moprhologic immunologic and molecular data. Am J Surg Pathol. 1992; 16:637–640. BARISTA I, ROMAGUERA JE, CABANILLAS F. Mantle cell lymphoma. Lancet Oncol. 2001; 2:141–148. BELAUD-ROTUREAU MA, PARRENS M, DUBUS P, et al. A comparative analysis of FISH, RT-PCR, PCR, and immunohistochemistry for the diagnosis of mantle cell lymphomas. Mod Pathol. 2002; 15(5):517–525. BELL ND, KING JA, KUSYK C, NELSON BP, SENDELBACH KM. CD5 negative diffuse mantle cell lymphoma with splenomegaly and bone marrow involvement. South Med J. 1998; 198:171–180. BENTZ M, PLESCH A, BULLINGER L, et al. t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2000; 27:285–294. BERTERO M, NOVELLI M, FIERRO MT, BERNENGO MG. Mantle zone lymphoma: an immunohistologic study of skin lesions. J Am Acad Dermatol. 1994; 30(1):23–30. CAMPO E, RAFFELD M, JAFFE ES. Mantle-cell lymphoma. Review. Semin Hematol. 1999; 36(2):115–127. DECAUDIN D, BOSQ J, MUNCK JN, et al. Mantle cell lymphomas: characteristics, natural history and prognostic factors of 45 cases. Leuk Lymphoma. 1997; 26(5–6):539–550. DODIUK-GAD RP, DANN EJ, BERGMAN R. Insect bite-like reaction associated with mantle cell lymphoma: a report of two cases and review of the literature. Int J Dermatol. 2004; 43(10):754–758. DREYLING MH, BULLINGER L, OTT G, et al. Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res. 1997; 57:4608–4614. DUBUS P, YOUNG P, BEYLOT-BARRY M, et al. Value of interphase FISH for the diagnosis of t(11:14)(q13;q32) on skin lesions of mantle cell lymphoma. Am J Clin Pathol. 2002; 118(6):832–841. ESPINET B, SOLE F, WOESSNER S, et al. Translocation (11;14)(q13;q32) and preferential involvement of chromosomes 1, 2, 9, 13, and 17 in mantle cell lymphoma. Cancer Genet Cytogenet. 1999; 111(1): 92–98. FERNANDEZ V, HARTMANN E, OTT G, CAMPO E, ROSENWALD A. Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol. 2005; 23(26):6364–6369. FU K, WEISENBURGER DD, GREINER TL et al. Cyclin D1 negative mantle cell lymphoma: a clinicopathologic study based on gene expressing profiling. Blood 2005; 106:4315–4321. GEERTS ML, BUSSCHOTS AM. Mantle-cell lymphomas of the skin. Review. Dermatol Clin. 1994; 12(2):409–417. HARRIS NL, BHAN AK. Mantle zone lymphoma. A pattern produced by lymphomas of more than one cell type. Am J Surg Pathol. 1985; 9:872–882. HISATAKE J, KAWAKAMI K, NAKAMAKI T, et al. Primary subcutaneous mantle cell lymphoma treated successfully with THP-COP therapy. Rinsho Ketsueki. 2002; 43(5):384–388. KHAMAYSI Z, DODIUK-GAD RP, WELTFRIEND S, et al. Insect bite-like reaction associated with mantle cell lymphoma:

clinicopathological, immunopathological, and molecular studies. Am J Dermatopathol. 2005; 27(4):290–295. KIENLE D, KROBER A, KATZENBERGER T, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma. Correlation with genomic aberrations, clinical chracteristics and outcome. Blood. 2003; 102:3003–3009. MARTI RM, CAMPO E, BOSCH F, et al. Cutaneous lymphocyteassociated antigen (CLA) expression in a lymphoblastoid mantle cell lymphoma presenting with skin lesions. Comparison with other clinicopathologic presentations of mantle cell lymphoma. J Cutan Pathol. 2001; 28(5):256–264. MOODY BR, BARTLETT NL, GEORGE DW, et al. Cyclin D1 as an aid in the diagnosis of mantle cell lymphoma in skin biopsies: a case report. Am J Dermatopathol. 2001; 23(5):470–476. MORICE WG, HODNEFIELD JM, KURTIN PJ, HANSON CA. An unusual case of leukemic mantle cell lymphoma with a blastoid component showing loss of CD5 and aberrant expression of CD10. Am J Clin Pathol. 2004; 122(1):122–127. OTT G, KALLA J, OTT MM, et al. Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. Blood. 1997; 89(4):1421–1429. OTT G, KALLA J, HANKE A, et al. The cytomorphological spectrum of mantle cell lymphoma is reflected by distinct biological features. Leuk Lymphoma. 1998; 32(1–2):55–63. PINYOL M, HERNANDEZ L, CAZORLA M, et al. Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. Blood. 1997; 89:272–280. ROSENWALD A, WRIGHT G, WIESTNER A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003; 3:185–197. SARIKAYA I, PATEL M, HOLDER L. Cutaneous mantle cell lymphoma detected with Ga-67 citrate. Clin Nucl Med. 2000; 25(10):849–851. SCHAFFNER C, IDLER I, STILGENBAUER S, DOHNER H, LICHTER P. Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc Natl Acad Sci USA. 2000; 97(6):2773–2778. SCHROERS R, HILDEBRANDT Y, STEFFENS R, et al. Immunophenotypic and genetic characterization of a CD8 positive mantle cell lymphoma in a patient with concomitant mycosis fungoides. Eur J Haematol 2005; 75: 78–84. SEN F, MEDEIROS LJ, LU D, et al. Mantle cell lymphoma involving skin: cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cytologic features. Am J Surg. Pathol. 2002; 26(10):1312–1318. SHIGEKIYO T, OHMORI H, et al. Unusual skin reactions after mosquito bites and Epstein–Barr virus reactivation in a patient with mantle cell lymphoma. Intern Med. 2004; 43(10):986–989. SINGLETON TP, ANDERSON MM, ROSS CW, SCHNITZER B. Leukemic phase of mantle cell lymphoma, blastoid variant. Am J Clin Pathol. 1999; 111(4):495–500.

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SOSLOW RA, ZUKERBERG LR, HARRIS NL, WARNKE RA. bcl1 (PRAD-1/cyclin D-1) overexpression distinguishes the blastoid variant of mantle cell lymphoma from B-lineage lymphoblastic lymphoma. Mod Pathol. 1997; 10(8):810–817. STARCZYNSKI J, SIMMONS W, FLAVELL JR, et al. Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias. Am J Pathol. 2003; 163(2):423–432. SUN T, NORDBERG ML, COTELINGAM JD, VEILLON DM, RYDER J. Fluorescence in situ hybridization: method of choice for a definitive diagnosis of mantle cell lymphoma. Am J Hematol. 2003; 74(1):78–84. SWERDLOW SH, WILLIAMS ME. From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Hum Pathol. 2002; 33(1):7–20.

VERGIER B, DUBUS P, KUTSCHMAR A, et al. Combined analysis of T cell receptor gamma and immunoglobulin heavy chain gene rearrangements at the single-cell level in lymphomas with dual genotype. J Pathol. 2002; 198(2):171–180. WEISEN BURGER DD, NATHWANI BN, DIAMOND LW, WINBERG CD, RAPPAPORT H. Malignant lymphoma, intermediate lymphocytic type: a clinicopathologic study of 42 cases. Cancer. 1981; 48(6):1415–1425. YATABE Y, SUZUKI R, MATSUNO Y, et al. Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases. Pathol Int. 2001; 51(10):747–761. ZUKERBERG LR, BENEDICT WF, ARNOLD A, DYSON N, HARLOW E, HARRIS NL. Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1. Blood. 1996; 88(1):268–276.

CHAPTER THIRTEEN

PRIMARY CUTANEOUS γ δ T CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

INTRODUCTION The T cell receptor (TCR) consists of either the γ δ or the αβ heterodimer expressed in association with the CD3 complex of proteins on the cell surface of T lymphocytes. The majority of mature T cells express an αβ TCR over one of γ δ subtype. Less than 5% of all lymphocytes are of the γ δ subtype (Bluestone et al., 1995; Toro et al., 2003). Despite the relatively small number of γ δ T cells, neoplastic proliferations of this cell type have been described, defining an unusually aggressive form of post-thymic T cell lymphoma with a propensity to involve extranodal organs, especially the skin, liver, spleen, and intestine. The best known are the hepatosplenic lymphoma (Figures 13.1–13.3), enteropathy type T cell lymphoma (Figures 13.4–13.6), and primary cutaneous γ δ T cell lymphoma including panniculitislike T cell lymphoma (Nosari et al., 1999; Yamaguchi et al., 1999; Belhadj et al., 2003). Among the rarest forms from this group of lymphoid neoplasms are the T cell lymphoblastic lymphomas of γ δ subtype (Biondi et al., 1989; Ralfkiaer et al., 1992). Clinical Features Primary cutaneous γ δ T cell lymphoma has a characteristic clinical presentation, being one of ulcerative nodules involving the extremities and

associated with an aggressive clinical course (see Table 13.1). Concurrent extracutaneous involvement is characteristic (Berti et al., 1991; Toro et al., 2000, 2003; Jones et al., 2002). A clinical presentation reminiscent of disseminated pagetoid reticulosis has been described (Massone et al., 2004). Some patients have developed hemophagocytic syndrome. These lymphomas are often resistant to multiagent chemotherapy and rapidly manifest widespread, multiorgan dissemination. Patients with concomitant salivary gland and skin involvement have been described, suggesting selective organ involvement as in marginal zone lymphoma (Lima et al., 2003). Cutaneous γ δ T cell lymphoma may have a dominantly subcutaneous presentation, resembling the αβ variant of panniculitis-like T cell lymphoma but with a more aggressive clinical course (Avinoach et al., 1994). Some authors restrict the designation of panniculitis like-T cell lymphoma to those cases derived from T cells of the αβ subset. In cases of γ δ T cell lymphoma involving the subcutis, if there is significant dermal involvement apart from deep-seated eccrine involvement, the diagnosis of panniculitis-like T cell lymphoma should not be made (Massone et al., 2004). The term panniculitis-like T cell lymphoma should only be applied to those cases manifesting dominant localization to the subcutis.

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 259

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Hepatosplenic T cell lymphoma. The sinusoids are distended with a monotonous population of small to medium sized lymphoid forms. Portal triads are spared, as is the white pulp of the spleen.

FIGURE 13.1

Hepatosplenic T cell lymphoma. The small to medium sized lymphoid forms percolate the sinusoids.

Hepatosplenic T cell lymphoma. Under oil immersion (100 × objective) magnification the medium sized lymphocytes have a thin rim of pale cytoplasm; the nuclei contain dispersed chromatin and indistinct nucleoli. One neoplastic lymphocyte with a C-shaped nucleus has cytotoxic azurophilic granules in its cytosol. FIGURE 13.3

FIGURE 13.2

In those tumors there are CD56 positive, there may be an association with Epstein–Barr virus (EBV) infection. In a recent study of the prognostic significance of TCR γ δ expression in cutaneous lymphomas (Toro et al., 2003), the authors assessed a number of parameters for potential association with survival including T cell subtype, hemophagocytosis, histologic profile, age, sex, and the presence or absence of adenopathy. There was a significant survival advantage for patients with αβ cutaneous T cell lymphoma versus patients with γ δ cutaneous T cell lymphoma. There was also a statistically significant decrease in survival among patients who had subcutaneous

FIGURE 13.4 Enteropathy type T cell lymphoma. There is slight blunting of the small bowel villi by a monotonous population of small to intermediate lymphoid forms.

involvement compared with patients who had epidermotropic and/or dermal involvement (Berti et al., 1999; Toro et al., 2000, 2003; Slater, 2005). In one study of 50 patients with peripheral T cell lymphomas involving the skin, eight cases represented γ δ variants, six of whom had disease first confined to the skin while two had concurrent extracutaneous disease (Massone et al., 2004). Even in patients with initial skin-confined disease, the clinical course was aggressive with death occurring within 1–50 months of presentation. The cells did not express

Introduction

FIGURE 13.5 Enteropathy type T cell lymphoma. A monotonous population of small to intermediate lymphoid forms dissects through the collagen and smooth muscle bundles through the full thickness of the small bowel.

FIGURE 13.6 Enteropathy type T cell lymphoma. A monotonous population of small to intermediate lymphoid forms show lobate or indented nuclei and open chromatin patterns. This CD3-expressing population of CD4-positive and CD56-negative cells showed clonal restriction when T cell receptor gene rearrangement was analyzed by polymerase chain reaction. This phenotype is somewhat atypical for the entity as most cases express neither CD4 nor CD8. (The case is courtesy of Dr. L.R. Johnson of Regional Medical Laboratory, Tulsa, OK.)

either CD4 or CD8; most were CD56 positive and expressed the cytotoxic T cell intracellular antigen 1. Most of these γ δ lymphomas were natural killerlike (NK-like) T cell lymphomas. There is clearly an overlap clinically and pathologically between cutaneous γ δ T cell lymphoma and NK-like T cell lymphoma. True NK lymphomas do not show either

261

TCR-β or TCR-γ rearrangement (Massone et al., 2004). The greatest literature precedent is not in the context of primary cutaneous γ δ T cell lymphoma but rather extracutaneous γ δ T cell lymphoma, specifically enteropathy type T cell lymphoma and hepatosplenic T cell lymphoma. Enteropathy type T cell lymphoma is strongly associated with celiac disease; the constant state of lymphocyte proliferation responding to endogenous gut antigen is postulated to eventuate in a neoplastic process in a small percentage of patients affected with this malabsorption syndrome. The patients typically have a prodromal period whereby their celiac disease becomes refractory to all therapeutic interventions. The patients have an identical haplotype to that encountered in patients with celiac disease. From a morphologic perspective the most common presentation is one of a large cell dominant transmural lymphoma accompanied by tissue eosinophilia. In some instances a small cell pattern dominates. The adjacent mucosa shows classic changes of an atrophying enteropathy with marked villus attenuation (see Figures 13.4–13.6) (Long-Muritano et al., 2002; Meijer et al., 2004; Doran et al., 2005; Hervonen et al., 2005). Hepatosplenic T cell lymphoma is characterized by marked infiltration of the hepatic sinusoids, bone marrow, and spleen. Lymph node involvement is rare. These lymphomas have been linked with underlying immunosuppression and are characteristically seen in the setting of solid organ transplantation. From a cytogenetic perspective, they may show isochrome 7 or trisomy 8, the latter potentially associated with an overamplification of c-myc (see Figures 13.1–13.3) (Cooke et al., 1996; Nosari et al., 1999; Belhadj et al., 2003; Thayu et al., 2005; Wei et al., 2005; Moleti et al., 2006). Morphology The biopsies show a striking diffuse and/or nodular infiltrate that usually spans the entire thickness of the dermis with frequent extension into fat. There may be a narrow grenz zone that separates the infiltrate from the overlying epidermis. Epidermotropism is variable and in some series is infrequent (Toro et al., 2000; Jones et al., 2002). If there is epidermotropism, it is similar to other forms of epitheliotropic T cell lymphoma with basilar colonization and Pautrier’s-like microabscess formation. In some cases, the morphology resembles pagetoid reticulosis whereby the neoplastic cells are confined almost exclusively to the epidermis (Berti et al., 1991). Angiotropism, in our experience,

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TABLE 13.1 Cutaneous γ δ T-cell Lymphoma Clinical Adults; rare in children. Disseminated plaques and tumors Often ulcerated Aggressive course Hemophagocytic syndrome Classic extracutaneous variants: enteropathic and hepatosplenic More aggressive course among patients with subcutaneous involvement compared to those with dermal and/or epidermotropic lymphomas Aggressive variants of panniculitis-like T cell lymphoma may represent the γ δ variant Histomorphology Nodular or diffuse infiltrate of small- to medium- or large-sized pleomorphic cells Epidermotropism Subcutaneous involvement is very common Immunophenotype CD3+ δ1+ βF1 − CD4, 30 − CD8 − (+) (most commonly double negative for CD4 and CD8) CD5 −/+, CD7, CD62L CD30 − granzyme + perforin + (majority of cases) TIA−1+ (majority of cases) CD56 +/− (some cases will represent true NK like T cell lymphomas) EBER −/+ (+ in those cases which are CD56+) Genetics Monoclonal rearrangement of the T-cell Receptor gene gamma(s); germline configuration for TCR beta Isochrome 7q and trisomy 8 Therapy Systemic chemotherapy.

is common; there may be mural and luminal fibrin deposition with associated ischemic necrosis of the epidermis (see Figures 13.7 and 13.8). Adnexotropism is a frequent finding (Massone et al., 2004). There are reports of predominantly subcutaneous involvement with minimal involvement of the overlying skin. Such cases follow an aggressive clinical course with ensuing hemophagocytic syndrome and death from pancytopenia. Some authors have recognized these cases as a distinctive form of panniculitis-like T cell lymphoma, namely, of the γ δ subtype (see Figures 13.9 and 13.10) (Guizzardi et al., 2003). The tumor cells are intermediate in size with significant nuclear irregularity; the chromatin is coarse and aggregated and nuclear membranes are thick and irregular. The closely condensed chromatin that typifies the neoplastic lymphocytes of mycosis fungoides is not seen. Nucleoli are conspicuous; there

may be multiple chromocenters. The degree of atypia exceeds that observed in mycosis fungoides. The larger cells may demonstrate a more blastic, rounded appearance with finely dispersed chromatin (Fujita et al., 1993; Toro et al., 2003). Phenotype The cells usually manifest a double negative phenotype (Jones et al., 2002), although in a small percentage of cases the cells are CD8 positive. There is variable deletion of pan T cell markers such as CD2, CD5, CD7, and CD62L. In addition, there is typically expression of T cell intracellular antigen, perforin, and granzyme B. CD56 and CD16, distinctive for NK cell lymphomas, may be positive (Ascani et al., 1994; Toro et al., 2000; Guizzardi et al., 2003). In some instances, however, the neoplastic γ δ T cells do not appear to express any cytotoxic or NK cell features (Lima et al., 2003).

Introduction

Ultrastructural Analysis Electron microscopy shows the γ δ T lymphocytes to have prominent villi containing dense and multivesicular bodies and to form close contacts with the surrounding keratinocytes, suggesting that these cells play a role in the skin-associated lymphoid tissue system (Ascani et al., 1994).

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Molecular Studies All cases exhibit gene rearrangement of the TCR-γ by either Southern blot or polymerase chain reaction. Studies assessing for TCR-β gene rearrangement show a germline configuration.

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CASE VIGNETTE CASE VIGNETTE 1

The patient was diagnosed with primary cutaneous γ δ T cell lymphoma. The tumor cells are CD4 and CD8 negative. However, a TCR-γ gene rearrangement was observed. The cells are also extensively CD56 and TIA1 positive. TIA positive (Figures 13.7 and 13.8).

(a)

(b)

FIGURE 13.7 A 75 year old man presented with nodular plaques on the trunk and extremities. The biopsy shows an effacing dermal infiltrate of intermediate to large pleomorphic cells.

(a) FIGURE 13.8

tumor cells.

(b)

There is striking angioinvasion. In particular, there is extensive permeation of the blood vessels by

Case Vignette 2

CASE VIGNETTE 2

265

The patient is a 36 year old man who presented with a several-month history of waxing and waning plaques who was diagnosed with panniculitis-like T cell lymphoma of the γ δ variant. The tumor cells are CD8 positive β F1 negative, and show a TCR-γ gene rearrangement. As well, there is staining for granzyme B and T-cell intracellular antigen 1 (Figures 13.9 and 13.10).

The biopsy shows extensive permeation of the interstitial spaces of the fat by atypical lymphocytes.

FIGURE 13.9

The characteristic internal cytoplasmic rimming at adipocytes by atypical lymphocytes.

FIGURE 13.10

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Primary Cutaneous γ δ T Cell Lymphoma

REFERENCES ASCANI S, LEONI P, FRATERNALI ORCIONI G, et al. Gamma/delta T-cell lymphoma involving the subcutaneous tissue and associated with a hemophagocytic syndrome. Am J Dermatopathol. 1994; 16(4):426–433. AVINOACH I, HALEVY S, ARGOV S, SACKS M. Gamma/delta T-cell lymphoma involving the subcutaneous tissue and associated with a hemophagocytic syndrome (review). Am J Dermatopathol. 1994; 16(4):426–433. BELHADJ K, REYES F, FARCET JP, et al. Hepatosplenic gamma delta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients (review). Blood. 2003; 102(13):4261–4269. Epub 2003 Aug 7. BERTI E, CERRI A, CAVICCHINI S, et al. Primary cutaneous gamma/delta T-cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol. 1991; 96(5):718–23. BERTI E, TOMASINI D, VERMEER MH, et al. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol. 1999; 155:483–492. BIONDI A, CHAMPAGNE E, ROSSI V, et al. T-cell receptor delta gene rearrangement in childhood T-cell acute lymphoblastic leukemia. Blood. 1989; 73(8):2133–2138 BLUESTONE JA, TANG Q. Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci USA. 2004; 101 (Suppl 2):14622–14626. Epub 2004 Aug 20. BLUESTONE JA, KHATTRI R, SCIAMMAS R, SPERLING AI. TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol. 1995; 11:307–353. COOKE CB, KRENACS L, STETLER-STEVENSON M, et al. Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin. Blood. 1996; 88(11):4265–4274. DORAN M, DU PLESSIS DG, LARNER AJ. Disseminated enteropathy-type T-cell lymphoma: a cauda equina syndrome complicating coeliac disease. Clin Neurol Neurosurg. 2005; 107(6): 517–520. EVENS AM, GARTENHAUS RB. Molecular etiology of mature T-cell non-Hodgkin’s lymphomas. Front Biosci. 2003; 8:d156–175. FUJITA M, MIYACHI Y, FURUKAWA F, et al. A case of cutaneous T-cell lymphoma expressing gamma delta T-cell receptors. J Am Acad Dermatol. 1993; 28(2 Pt 2):355–360. GUIZZARDI M, HENDRICKX IA, MANCINI LL, MONTI M. Cytotoxic gamma/delta subcutaneous panniculitis-like T-cell lymphoma: report of a case with pulmonary involvement unresponsive to therapy. J Eur Acad Dermatol Venereol. 2003; 17(2):219–222. HERVONEN K, VORNANEN M, KAUTIAINEN H, COLLIN P, REUNALA T. Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives. Br J Dermatol. 2005; 152(1):82–86. ISOMOTO H, MAEDA T, AKASHI T, et al. Multiple lymphomatous polyposis of the colon originating from T-cells: a case report. Dig Liver Dis. 2004; 36(3):218–221. JONES D, VEGA F, SARRIS AH, MEDEIROS LJ. CD4−CD8−’’double-negative’’ cutaneous T-cell

lymphomas share common histologic features and an aggressive clinical course. Am J Surg Pathol. 2002; 26(2):225–231. LANG-MURITANO M, MOLINARI L, DOMMANN-SCHERRER C, SCHUELER G, SCHOENLE EJ. Incidence of enteropathyassociated T-cell lymphoma in celiac disease: implications for children and adolescents with type 1 diabetes. Pediatr Diabetes. 2002; 3(1):42–45. LIMA M, CANELHAS A, SANTOS C, et al. Non-cytotoxic gamma-delta peripheral T-cell lymphoma affecting the mandibular and parotidal lymph nodes and the skin. Leuk Lymphoma. 2003; 44(3):525–529. MASSONE C, CHOTT A, DIETER M, et al. Subcutaneous blastic natural killer NK/T-cell and other cytotoxic lymphomas of the skin: amorphologic immunophenotypic and molecular study of 50 patients. Am J Surg Pathol. 2004; 28: 719–735. MEIJER JW, MULDER CJ, GOERRES MG, BOOT H, SCHWEIZER JJ. Coeliac disease and (extra)intestinal T-cell lymphomas: definition, diagnosis and treatment (review). Scand J Gastroenterol Suppl. 2004; 241:78–84. MOLETI ML, TESTI AM, GIONA F, et al. Gamma-delta hepatosplenic T-cell lymphoma. Description of a case with immunophenotypic and molecular follow-up successfully treated with chemotherapy alone. Leuk Lymphoma. 2006; 47(2):333–336. NOSARI A, ORESTE PL, BIONDI A, et al. Hepato-splenic gammadelta T-cell lymphoma: a rare entity mimicking the hemophagocytic syndrome. Am J Hematol. 1999; 60(1):61–65. RALFKIAER E, WOLLF-SNEEDORFF A, THOMSEN K, GEISLER C, VEJLSGAARD GL. T-cell receptor gamma delta-positive peripheral T-cell lymphomas presenting in the skin: a clinical, histological and immunophenotypic study. Exp Dermatol. 1992; 1(1):31–36. SLATER DN. The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005; 153(5): 874–880. THAYU M, MARKOWITZ JE, MAMULA P, RUSSO PA, MUINOS WI, BALDASSANO RN. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr. 2005; 40(2):220–222. No abstract available. TORO JR, BEATY M, SORBARA L, et al. Gamma delta Tcell lymphoma of the skin: a clinical, microscopic, and molecular study. Arch Dermatol. 2000; 136(8): 1024–1032. TORO JR, LIEWEHR DJ, PABBY N, et al. Gamma-delta Tcell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 2003; 101(9):3407–3412. WEI SZ, LIU TH, WANG DT, CAO JL, LUO YF, LIANG ZY. Hepatosplenic gammadelta T-cell lymphoma. World J Gastroenterol. 2005; 11(24):3729–3734. YAMAGUCHI M, OHNO T, NAKAMINE H, et al. Gamma delta T-cell lymphoma: a clinicopathologic study of 6 cases including extrahepatosplenic type. Int J Hematol. 1999; 69(3):186–195.

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MYCOSIS FUNGOIDES Cynthia M. Magro, Martin C. Mihm, and A. Neil Crowson

DEFINITION Mycosis fungoides is a T cell lymphoma of mature T cells typically at the CD4 subset and represents the most common type of cutaneous lymphoma. Cumulatively, it accounts for no more than 0.5% of all cases of non-Hodgkin’s lymphoma. Over 4342 articles had been published on mycosis fungoides between November 1949 and December 2006, making it the most commonly discussed form of cutaneous lymphoma in the medical literature.

HISTORICAL PERSPECTIVE Jean-Louis Alibert is credited with the first description of mycosis fungoides in 1806, though in fact earlier citations described what we now recognize as mycosis fungoides of the Alibert type. This distinctive form of T cell lymphoma was first identified in the 1970s as a disease of T lymphocyte derivation through the use of the sheep red blood cell rosetting technique (Zucker-Franklin 1974).

from 1973 to 1992, indicated an incidence rate of 0.3 per 105 person years (Weinstock and Gardstein, 1999). The highest incidence rate was shown to be in the United States in African-Americans, where the least frequently affected group was the Asian population. In all ethnic groups, men were more often affected than women. Mycosis fungoides typically occurs in adulthood; most patients present between the ages of 50 and 65 years with a chronic, recalcitrant, slowly progressive dermatitis of several years’ duration. The fatality rate was found to be 0.064 per 105 person years in the SEER data. The incidence of death among men was almost twice that of women. In both the SEER study and in a Swedish study, a decline in the death rate by as much as 22% has been shown (Swanbeck et al., 1994). This decline in the death rate is probably due to better diagnosis and therapy, but may also reflects earlier diagnosis in a refractory disease with slow progression. These studies also suggest that onset in later life and in persons of African-American extraction were two factors that augured for a poorer prognosis.

DEMOGRAPHICS

CLINICAL PRESENTATION

A study of data from various cancer registries was undertaken as part of the Surveillance, Epidemiology and End Results (SEER) program. This data, gathered

Mycosis fungoides has a heterogeneous clinical presentation that may include patches, plaques, tumors, and erythroderma (Figures 14.1–14.4). Each

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(a)

(b)

(c)

The patient had erythroderma and circulating S´ezary cells in concert with a very high CD4 to CD8 peripheral blood ratio. A diagnosis was made of S´ezary syndrome. This patient had a background of B cell small lymphocytic lymphoma. He had an unusually aggressive clinical course, developing large cell T cell infiltrates in his lymph nodes. FIGURE 14.1

phase has its own distinctive clinical morphology and histological features. The most common presentation is one of patches and plaques. Untreated patients may undergo a slow evolutionary progression of their disease from patch to plaque to tumor stage mycosis fungoides; in some cases, despite the absence of any therapeutic intervention, the clinical course may be stable not progressing beyond plaque stage mycosis fungoides and death may ensue in a fashion attributable to other causes. The length of time for progression from the onset of clinical disease to

the development of diagnostic cutaneous lesions of mycosis fungoides ranges from months to five or six decades; the average length of time is 4–6 years (Dummer et al., 2000, 2003).

Patch Stage In the initial patch stage of mycosis fungoides, the clinical presentation is one of scaly patches and macules of varying sizes that typically manifest well defined borders. Salmon-colored to reddish tan

Clinical Presentation

(a)

(b)

(c)

(d)

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FIGURE 14.2 (a-d) The images are all examples of follicular mycosis fungoides. The hallmarks are a somewhat ill-defined plaque with supervening raised prominent follicular orifices.

(a)

(b)

FIGURE 14.3 The patient had a longstanding history of follicular mycosis fungoides. She developed progressive infiltration and induration. The biopsy was compatible tumor stage mycosis fungoides.

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(a)

(b)

Follicular mycosis fungoides. (a) Prior to treatment the patient had extensive nodular lesions on the face. (b) Following treatment the nodularity is no longer apparent although there is extensive pigmentary changes. Folliculotropic MF is the one form of MF where there is facial predilection. Photographs provided by Kelly Gallina. FIGURE 14.4

or red, the lesions are usually intensely pruritic. When no pruritus is present, the lesions are often found at routine examination of a patient who was previously unaware of their presence. The trunk is the most commonly affected site, and in some patients, lesions are limited to the bathing trunk area. Both the pruritus and the scaliness reflect the prominent epitheliotropism of lymphocytes into the epidermis. This phase of the disease may have a long, insidious course that may be present for decades, with patients reporting a longstanding history of chronic eczema or psoriasis that has proved refractory to treatment. The Mycosis Fungoides Study Group reported that 77% of patients had a prior history of a skin condition diagnosed as a reactive dermatitis in almost one-third of cases (Lamberg and Bunn, 1979b). This study emphasizes the importance of performing appropriate and often sequential biopsies in patients with an established history of dermatitis (Bunn and Lamberg, 1979; Lamberg and Bunn, 1979a, b).

Plaque Stage The plaque stage of the disease typically emanates from the antecedent patch stage but may arise de novo. Plaques are variably indurated and violaceous in color. The borders are pronounced and may exhibit a serpiginous, arcuate, or annular morphology. In

both the patch and plaque stage there may be areas of variable hyperpigmentation and hypopigmentation along with focal atrophy and telangiectasia, resulting in a poikilodermatous appearance. Coalescing infiltrative facial plaques may impart a leonine appearance, usually a sign of advanced disease. A rare clinical presentation is one of persistent, chronic pruritus unaccompanied by any discernible skin lesions (Lamberg and Bunn, 1979a, b).

Tumor Stage The emergence of tumor stage mycosis fungoides is usually characterized by the development of skin nodules superimposed on a background of longstanding plaques and patches, which are typically seen in combination with tumor lesions. On occasion, tumors are seen in the absence of other lesion types. Tumors can be solitary but are more often multifocal and may involve unusual sites such as mucosal regions. When progression to tumor stage occurs, there may be dissemination to other organ sites such as lymph nodes, bone marrow, central nervous system, and peripheral blood. Tumor stage lesions can occur anywhere but have a predilection for the face and body folds: the axillae, groin, and antecubital fossae, and in women the inframammary areas. Tumors often surmount previously existing plaques. Tumor nodules can be

Clinical Variants

associated with ulceration (see Figures 14.3 and 14.4) (Lamberg and Bunn, 1979a, b).

Extracutaneous Dissemination The time course from inception of disease to extracutaneous dissemination is usually one of several years. The development of extracutaneous involvement by mycosis fungoides is related to the extent of the disease. Patients with patches or patches and plaques rarely go on to systemic involvement, while those with tumors and/or erythroderma are more susceptible (Dummer et al., 2000). There is a usually stereotypic pattern of progression with the regional nodes being first involved, followed by the viscera, and only rarely the bone marrow. The lungs, liver, and spleen are the most frequently affected visceral organs but diagnostic lesions may appear anywhere (Bunn and Lamberg, 1979; Lamberg and Bunn, 1979a, b; de Conick et al., 2001).

CLINICAL VARIANTS Several clinical variants of mycosis fungoides have been described. Some are sufficiently common to merit a recognition as distinct clinicopathological entity while others represent isolated case reports of peculiar forms of skin involvement. For example, digital palmar and plantar mycosis fungoides has been described (Stasko et al., 1982). Others include a variant of mycosis fungoides that manifests dominant tropism of lymphocytes to adnexal structures and thus falls under the appellation of syringotropic and/or pilotropic cutaneous T cell lymphoma (see Table 14.1 and Figures 14.2–14.4). Rare patients, particularly those with plaque stage lesions, manifest a bullous form of the disease that in other respects has a course similar to that of the nonbullous forms.

TABLE 14.1 Variants of Mycosis Fungoides Bullous/spongiotic Erythrodermic Adnexotropic: pilotropic (follicular) and syringotropic Granulomatous including granulomatous slack skin Hypopigmented Pagetoid reticulosis (Woringer–Kolopp type) Papular Pigmented purpura-like Papular erythroderma of Ofuji

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Papuloerythroderma Patients in the plaque or tumor stage may develop erythroderma, a finding that heralds systemic involvement. However there is a distinctive form of erythroderma termed papuloerythroderma of Ofuji (Ofuji et al., 1984) that in some patients reflects a form of cutaneous T cell lymphoma including follicular mycosis fungoides (Shimauchi et al., 2006; Shah et al., 1995; Bech-Thomsen and Thomsen, 1998; Hur et al., 2002; Martinez-Barranca et al., 2005). The process designated as papuloerythroderma appears to encompass several different neoplastic conditions and nonneoplastic dermatoses (Table 14.2). Characteristically sparing the creases of the skin (e.g., the antecubital, popliteal, and axillary areas), patients manifest erythroderma accentuated on the trunk and extensor aspects of the extremities with superimposed lichenoid papules (Ofuji et al., 1984). There is striking tissue eosinophilia as well as prominent peripheral blood eosinophilia with an elevated CD4 to CD8 ratio. The patients do not fulfill criteria for S´ezary syndrome in light of the absence of peripheral blood CD4+ CD7− lymphocytosis and/or circulating atypical cerebriform lymphocytes in the peripheral blood (see below). Indeed, many patients with papuloerythroderma do not have cutaneous T cell lymphoma (Nazzari et al., 1992) but rather an underlying immune-dysregulating process such as atopy, visceral malignancy, such as, gastric carcinoma, non-Hodgkin lymphoma, myeloid leukemia, or an infective process (Lonnee et al., 1996; Nazzari and Sabattini, 1999; De Vries et al., 2002). With respect to the latter, Ofuji’s papuloerythroderma has been described in the setting human immunodeficiency virus infection hepatitis C infection, bacterial cholangitis, strongyloidosis and fungal infection (Tay et al., 1994; Azon-Masoliver et al., 1998; Ota et al., 2005).

Mycosis Fungoides in Childhood Mycosis fungoides is rare in childhood, representing 0.5–5% of all cases. In childhood the process presents in a very early stage, namely, as patches and plaques without evidence of peripheral blood or lymph node involvement (Pabsch et al., 2002). Hypopigmented mycosis fungoides is a form of cutaneous T cell lymphoma, which appears more commonly among younger patients, especially those of African-American extraction (El-Shabrawi-Caelen, et al. 2002). Tumors and nodules are rarely present. Some children with mycosis fungoides have a concurrent and/or prior history of skin lesions compatible with pityriasis lichenoides chronica (Garzon, 1999;

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TABLE 14.2 Papular Erythroderma of Ofuji Clinical features Elderly patients with relapsing, coalescent, papular dermatosis with sparing of the skin fold areas (deck chair sign) A protracted course of repeated relapses without known precipitating factors Some cases may be associated with mycosis fungoides Other etiologies including atopy and a paraneoplastic process in the setting of solid visceral malignancy Peripheral blood eosinophilia; high levels of IgE Histomorphology Perivascular infiltration of mononuclear cells containing varying populations of eosinophils in the upper dermis In those cases that represent true dyscrasias there will be lymphoid atypia

Thomson et al., 1999). In our experience, patients in the latter setting manifest an indolent clinical course.

Adnexotropic Mycosis Fungoides The adnexotropic forms of mycosis fungoides have clinical manifestations that flow from a selected pattern of adnexal involvement in which the infiltrate of atypical cells is dominantly confined to the hair follicle or the eccrine apparatus. The first form of adnexotropic mycosis fungoides falls under the designation of folliculotropic mycosis fungoides/pilotropic mycosis fungoides (Kossard et al., 1995; Vergier et al., 1996; Beylot-Barry and Vergier, 1998; Peris et al., 1999; Van Doorn et al., 2002); the preferred designation according to the revised WHO–EORTC classification of cutaneous lymphoma is folliculotropic mycosis fungoides. The follicular based lesions precede, develop concurrently with, or occur subsequent to lesions of more typical mycosis fungoides (Pereyo et al., 1997). One study suggested that the folliculotropic variant of mycosis fungoides appeared to have a more aggressive clinical course compared to classic mycosis fungoides, possibly reflecting the deeper seated nature of tumor infiltration due to the inherent depth of the intrafollicular infiltrate. Unilesional variants are described (see Figures 14.2–14.4) (Marzano et al., 1999). The presentation of follicular mycosis fungoides can be as striking nodular tumors on the scalp and face stippled with comedo-like hyperkeratotic follicular lesions on the head and trunk (Klemke et al., 1999) (Figure 14.4). The appearance on the scalp may resemble a dissecting cellulitus associated with progressive alopecia (Gilliam et al., 1997). Another characteristic presentation is one of alopecia mucinosa as defined by mottled hairless patches, located preferentially on the head and neck and sometimes accompanied by grouped follicular papules, comedones, and cysts (Fraser-Andrews et al., 1999; Bonta et al., 2000; DeBloom et al., 2001; Flaig et al., 2001; Francis et al., 2001; Campanati et al., 2002; Cerroni et al., 2002). Lesions outside the head and neck, such

as on the lower extremities, are nonetheless typically associated with hair loss (Pestarino et al., 2001). Some cases of folliculotropic mycosis fungoides are not associated with mucinosis of the involved follicular apparatus and in that setting the plaques have alopecia without the formation of boggy plaques (Ozdemir et al., 2002). Patients with follicular mycosis fungoides may respond to combination therapy such as electron beam irradiation, extracorporeal photopheresis, and interferon-α therapy. The second adnexotropic variant involves the eccrine apparatus, where there may be almost exclusive involvement of the eccrine coil. This lesion presents clinically as multiple papules with associated anhidrosis (Zelger et al., 1994; Haller et al., 2001). The designation of syringotropic cutaneous T cell lymphoma has been used for such cases. An alternative proposed appellation is one of syringolymphoid hyperplasia with alopecia. However, we consider syringolymphoid hyperplasia with alopecia as a form of cutaneous lymphoid dyscrasia, which may presage overt eccrinotropic T cell lymphoma. The cutaneous lymphoid dyscrasias are discussed in detail in Chapter 6.

Woringer–Kolopp Disease (Pagetoid Reticulosis) Mycosis fungoides may present as a solitary lesion. The unilesional variant of mycosis fungoides falls under the designation of Woringer–Kolopp disease, named after the two authors who first reported the entity (Woringer and Kolopp, 1939). In the original article, the authors described a patient with a solitary lesion in which light microscopic examination revealed a hyperplastic epidermis with pagetoid invasion by atypical mononuclear cells. The disease process behaves in an indolent fashion in that the lesion remains localized to the skin without additional cutaneous lesions and/or extracutaneous dissemination. This process has a predilection for young adults with approximately 20% of cases occurring in patients

Clinical Variants

less than 15 years of age. The lesions have a propensity to involve acral sites and may undergo evolution from indurated plaques to those that manifest a verrucous surface or ulcerate. The basis for categorizing this process as a form of mycosis fungoides is the cumulative morphologic, immunophenotypic, and molecular evidence: the pattern of intraepidermal growth is one cognate to that observed in mycosis fungoides but with almost exclusive localization to the epidermis; the phenotypic profile is that defined by a striking preponderance of CD4-positive lymphocytes demonstrating a loss of CD7 and CD62L hence recapitulating the phenotypic profile encountered in classical mycosis fungoides. A T cell receptor gene rearrangement is often determined through standard molecular studies (Wood et al., 1988). In two cases described by us, a clear association with a prior spider bite and molecular evidence of polyclonality argued that, at least in some patients, Woringer–Kolopp disease is a form of lymphomatoid hypersensitivity reaction (Crowson and Magro, 1994). A subcategory of Woringer–Kolopp disease has been designated as the disseminated type, often referred to as pagetoid reticulosis or the Ketron–Goodman variant (Nakada et al., 2002). This variant is demographically similar to classical mycosis fungoides and occurs in older adults. In addition, there is a tendency for a more aggressive clinical course not only in regard to lesional recurrence but also in the context of transformation into a more aggressive lymphoma, specifically CD30positive anaplastic large cell lymphoma and CD30negative large cell lymphoma. In our view, the Ketron–Goodman variant should be considered an epidermotropic variant of mycosis fungoides rather than a disseminated form of Woringer–Kolopp disease. The latter term should be reserved, in our view, for unilesional, dominantly epidermotropic mycosis fungoides associated with an indolent clinical course. There are also cases of Ketron–Goodman/pagetoid reticulosis that represent primary cutaneous aggressive cytotoxic CD8 lymphoma.

Granulomatous Slack Skin/Granulomatous Mycosis Fungoides In the original EORTC classification of cutaneous T cell lymphoma (CTCL), granulomatous slack skin was considered a provisional entity. The diagnosis of granulomatous slack skin is made based on an integration of characteristic clinical features with distinctive light microscopic findings, which are alluded to below. In this variant, the patients develop large areas of loose skin with a predilection to involve intertriginous areas and other regions of the

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body with relatively redundant skin. Of interest is the similarity of this condition clinically and light microscopically to the interstitial granulomatous drug reaction. In the setting of CTCL, drug modulation has no effect on disease progression. In those cases of mycosis fungoides where there is a diffuse pattern within the dermis exactly recapitulating the morphology encountered in granulomatous slack skin but with typical clinical features of mycosis fungoides, we use the designation granulomatous mycosis fungoides. We consider granulomatous slack skin a distinctive form of granulomatous mycosis fungoides with highly characteristic clinical features. (See Figures 14.5–14.7).

Sezary Syndrome This disorder is characterized by the triad of erythroderma, lymphadenopathy, and abnormal T cells, so-called S´ezary cells, in the peripheral blood, the lymph nodes, and the skin (Table 14.3). In some cases the erythroderma and the syndrome appear in a patient with a stable form of patch or plaque stage mycosis fungoides while in other cases the disease

Granulomatous MF. The patient presented with infiltrative plaques temporally associated with calcium channel blocker therapy. An initial diagnosis was rendered of granulomatous drug reaction. However, over the ensuing months her skin rash became very extensive with progressive hardening of the skin despite drug cessation; one year after discontinuing her drug she continues with progressive disease. A diagnosis was made of granulomatous mycosis fungoides possibly arising in a background of interstitial granulomatous drug reaction. The biopsy shows a diffuse pattern of infiltration. An important clue to the diagnosis is the basilar colonization unaccompanied by destructive epithelial changes and the narrow grenz zone separating this subtle intraepidermal component from the overlying epidermis.

FIGURE 14.5

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Granulomatous MF. Higher power magnification shows cerebriform lymphocytes colonizing the epidermis.

FIGURE 14.6

appears de novo or arises in a background of adiopathic erythroderma. The erythroderma is associated with severe pruritus. Hence, there is marked scaling, lichenification, alopecia, and even nail dystrophy. In this variant the palms are hyperkeratotic and oftentimes fissured and there may be an ectropion. The presence of a band-like infiltrate of cells with or without epidermotropism is characteristic. Unlike classic mycosis fungoides where the 5 year survival rate approaches 90%, the 5 year survival for S´ezary syndrome ranges in different studies from 11% to 33% with an overall average 5 year survival of 24% (Willemze et al., 2005). Most patients succumb to opportunistic infections (see Figure 14.1).

(a)

The authors of the 2005 WHO–EORTC classification for cutaneous lymphoma suggested that there must be an absolute criterion, which is one of established T cell clonality in the peripheral blood and skin, ideally demonstrating the same T cell clone (Willemze et al., 2005). The authors proposed two additional criteria of which at least one must be present; the first is both cytomorphologic and quantitative, requiring a count of 1000 or more S´ezary cells per square millimeter in the peripheral blood. The second criterion is an immunophenotypic one: the CD4 to CD8 T lymphocyte ratio in the peripheral blood must be in excess of 10:1 with a concomitant loss of certain pan T cell markers such as CD2, CD3, CD7 and CD5 (Willemze et al., 2005). The International Society for Cutaneous Lymphoma suggested that any patient with erythroderma with molecular evidence of T cell clonality would be designated as having S´ezary syndrome (Vonderheid et al., 2002). We and others feel that the emergence of T cell clonality, while a feature that suggests a lymphoid dyscrasia, should not be equated with malignancy. From a phenotypic perspective, the killer receptor p140/KIR3DL2 (KIR) has been identified in malignant cell lines isolated from the skin and blood of patients with transformed mycosis fungoides and S´ezary syndrome. One study examined the in vivo expression of this receptor in various CTCL subtypes, which constituted a heterogeneous group. The large transformed cells diffusely expressed KIR in S´ezary syndrome, in lymphomatoid papulosis (LyP), and in CD4-positive/CD30-positive as well as CD8-positive large cell pleomorphic CTCL (Wechsler et al., 2003).

(b)

FIGURE 14.7 Lichenoid variant of MF. Significant zones of superficial colloid body formation are noted, compatible with a lichenoid tissue reaction. At variance with lichen planus is the degree of cytologic atypia and significant areas with passive migration of lymphocytes.

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´ TABLE 14.3 Sezary Syndrome Clinical Elderly adults Pruritic erythroderma May be preceded by idiopathic erythroderma Generalized lymphadenopathy Poor prognosis Absolute criterion T cell gene rearrangement in peripheral blood and potentially other sites including skin and lymph node Along with Two of the Following Additional Criteria Peripheral blood CD4+/CD8+ ratio > 10 Increased numbers of circulating CD4+CD7 − lymphocytes ´ Circulating Sezary cells in peripheral blood greater than 1000 per square millimeter Conversion to a CD4/CD25 regulatory cell phenotype associated with supervening profound immunosuppression Histomorphology Small pleomorphic cerebriform cells infiltrate epidermis and dermis Phenotype of Circulating Cells CD2, CD3, CD4, CD5+ CD7, CD8,CD62− Molecular studies Monoclonal rearrangement of the T cell receptor gene(s)

In contrast, the infiltrating lymphocytes did not express KIR in mycosis fungoides at the patch/plaque stage or in CD4-positive/CD30-negative large cell pleomorphic CTCL, except for scattered small cells. KIR is not typically seen in inflammatory lesions excluding a few scattered positive staining cells in the setting of lichen planus.

TABLE 14.4 Clinical Staging of Mycosis Fungoides Stage I

Stage II Stage III

Prognosis The single most critical predictor of survival is the extent of clinical disease as defined by the stage (Table 14.4). Early cutaneous disease (Stage I) is divided into Stage I T1 when less than 10% of the entire body surface is involved versus Stage I T2 when more than 10% of the body surface is affected. Early stage mycosis fungoides may progress to T3 and T4 with the advent of tumor development and erythrodermic mycosis fungoides, respectively. Patients with limited disease have an excellent 5 year survival, no different from the general population, while those patients with more advanced disease, especially in the context of extracutaneous dissemination, have a more ominous prognosis. As a terminal event, transformation to large cell T cell lymphoma is seen. S´ezary syndrome is considered an aggressive form of peripheral T cell lymphoma with a 5 year survival rate in the 10–30% range. A comprehensive study regarding prognosis and treatment was performed by the Dutch lymphoma group. At the

Stage IV

Disease confined to the skin either with limited patches/plaques (Stage Ia); disseminated patches/plaques (Stage Ib); or skin tumors (Stage Ic) Lymph nodes enlarged but uninvolved histologically Lymph node involvement documented by histology Visceral dissemination

time of presentation, over 90% of patients with mycosis fungoides initially had skin disease only and less than 10% presented with concurrent nodal or visceral involvement. An important predictor of enhanced survival was entry into complete remission following initial treatment. The disease-related and overall survival for patients with mycosis fangoides was 89% and 80%, respectively, at 5 years and 75% and 57% at 10 years (Van Doorn et al., 2000). Patients with tumor stage mycosis fungoides but without evidence of concurrent extracutaneous disease have a 5 year survival of approximately 70–80%. Another factor predictive of worse prognosis is the presence of follicular mucinosis (14.33). In those patients where the biopsy showed follicular mucinosis, the disease-related survival was 81% and 36% at 5 and

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10 years and the overall survival was 75% and 21%, respectively (Van Doorn et al., 2000). Bone marrow biopsy is more desirable for staging compared to bone marrow aspirate. The detection rate of bone marrow involvement at initial staging varies from 6% to 21.7% for cutaneous T cell lymphoma. However, bone marrow involvement is relatively uncommon at the inception of the disease process. Morphology/Light Microscopic Findings Particularly vexing for the pathologist is rendering a diagnosis of mycosis fungoides in its incipient phase, whereby discrimination from inflammatory dermatoses including reactive lymphoid hyperplasia may be problematic (Table 14.5). The diagnosis of mycosis fungoides should only be made after careful integration of the histologic and immunophenotypic profile with other aspects of the clinical presentation. Histologically, most cases represent patch stage/early plaque stage mycosis fungoides and are characterized by a superficial band like lymphocytic infiltrate with variable epitheliotropism (see Figures 14.8 and 14.9). A prominent angiocentric component is not seen. The infiltrate in the dermis has a tendency to exhibit a band-like pattern and/or to infiltrate the interstitium. In the earlier phases of mycosis fungoides, the dermal component may assume a pattern of superficial perivascular infiltration without any tendency for band-like lymphocytic infiltration. The epidermis is of variable thickness with zones of hyperplasia alternating with zones of attenuation. In the realm of patch and plaque stage mycosis fungoides, significant deep dermal perivascular extension is unusual. In areas of dermal infiltration, oftentimes one observes laminated dermal fibroplasia.

One of the characteristic clues to a diagnosis of mycosis fungoides is the intraepidermal architectural disposition of the infiltrate (Figures 14.10–14.14). Apparent under low to intermediate magnification is a single cell and clustered intraepidermal proliferation of atypical lymphocytes separated from a subjacent band-like dermal infiltrate by a narrow rim of uninvolved papillary dermal collagen and an intact basal layer of epidermal keratinocytes. Typically, this infiltrate is disposed continuously across the breadth of a punch or shave biopsy specimen (Nickoloff, 1988). For this reason, in the diagnosis of patch and plaque stage mycosis fungoides, a shave biopsy is preferable to a punch biopsy. The inverse is true for assessment of tumor stage mycosis fungoides for reasons which will be presently discussed. The pattern of intraepidermal lymphocytic infiltration is one characterized by haphazardly disposed single cells permeating the mid- and upper spinous layers of the epidermis. Second, there may be collections of cerebriform cells within the epidermis without concomitant Langerhans’ cells or intercellular edema, hence defining a characteristic morphologic hallmark, the Pautrier’s microabscess (Figures 14.15–14.17). Colonization of the basal layer of the epidermis unaccompanied by any true vacuolar change or keratinocyte necrosis is characteristic. The presence of lymphocytes percolating an otherwise nonreactive and nonspongiotic epidermis and without any propensity for specific localization such as the acrosyringia or the suprapapillary plates is characteristic (Figures 14.9–14.14, 14.18, and 14.19). In lymphomatoid drug reactions, in contrast, the observation of lymphocytes around necrotic keratinocytes indicates that their presence within the epidermis reflects a cellular cytotoxic event; their localization to epidermal sites of antigen processing

TABLE 14.5 Histopathological Features of Early Mycosis Fungoides Epidermis Small cohesive intraepidermal collections of lymphocytes (Pautrier’s microabscesses) Lymphocytes aligned along the basal layer at the dermal–epidermal junction in a continuous array without degenerative epithelial changes Intraepidermal lymphocytes often larger than the lymphocytes in the dermis Epidermotropism of lymphocytes with only slight spongiosis and typically no vesiculation Intraepidermal lymphocytes surrounded by a clear ‘‘halo’’ Oil immersion high-power microscopy shows cerebriform nuclear contours Dermis Papillary dermis expanded by band-like lymphoid infiltrate (especially in plaque stage) and often with fibrosis comprising coarse, horizontally disposed ‘‘wiry’’ bundles of collagen Plasma cells and eosinophils Phenotypic profile: CD4+ in most cases; CD8 variant recognized CD7 − CD62L− Molecular profile: restricted repertoire or small clonal population amid a polyclonal profile

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(a)

(b)

(c)

Architecture of plaque stage mycosis fungoides. In each biopsy there is a band-like lymphocytic infiltrate lying in close apposition to the epidermis, although unaccompanied by frank destructive changes of the epidermis. There is supervening haphazard migration of lymphocytes involving the upper layers of the epidermis. This particular pattern of band-like infiltration without true interface change, with a grenz zone of uninvolved papillary dermis, and supervening haphazard epitheliotropism is a characteristic of mycosis fungoides. FIGURE 14.8

is characteristic. Distinctive lacunar spaces surround the aberrant intraepidermal cells (Smaller et al., 1998), whether they are disposed either singly or in small clusters; this is a valuable clue even though these halo-like spaces are not, in our experience, pathognomonic of mycosis fungoides as they can be seen under other circumstances including certain benign dermatoses (see Figures 14.10). There is a disparity between the degree and pattern of epidermal infiltration and the lack of keratinocyte injury. Papillary dermal edema, basilar vacuolopathic change, and eosinophilic spongiosis, although exceptional findings, are seen in a minority of cases of mycosis fungoides. In addition, some cases show a pattern

of band-like lymphocytic infiltration that defines a lichenoid tissue reaction, whereby there is destruction of basal layer keratinocytes in a fashion that mimics lichen planus. Such cases have fallen under the designation lichenoid mycosis fungoides (Figures 14.7 and 14.20–14.24). Distinction from lichen planus is made through the observation of other zones more typical of mycosis fungoides as characterized by lymphocytic epitheliotropism, especially by atypical lymphocytes. In one study the authors highlighted lymphoid atypia, plasmacytic infiltration, and tissue eosinophilia as the features separating lichenoid mycosis fungoides from lichen planus (Guitart et al., 1997).

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Architecture of MF. This is another photomicrograph depicting plaque stage mycosis fungoides. The critical question is why this biopsy is consistent with lymphoma as opposed to a reactive lichenoid process. The key is the narrow grenz zone of uninvolved papillary dermis that separates the band-like lymphocytic infiltrate from the overlying epidermis, albeit in the context of focal basilar lymphocyte colonization unaccompanied by destructive epithelial changes.

FIGURE 14.9

Epidermotropism. There is infiltration of the epidermis by small atypical hyperchromatic lymphocytes. The lymphocytes are closely aggregated without any intervening inflammatory cell elements such as histiocytes or eosinophils and assume a quiescent disposition in the epidermis amid coalescing large vacuous spaces.

FIGURE 14.10

Cytologically, the neoplastic lymphoid cells manifest a characteristic cerebriform or gyrate nuclear contour. The cells within the epidermis typically show greater nuclear contour irregularity and hyperchromasia as well as larger nuclear diameters when compared to lymphocytes within the dermis

FIGURE 14.11 Epidermotropism. The biopsy shows colonization of the basal layer by very atypical cerebriform lymphocytes. The cells are noticeably more atypical than lymphocytes in the dermis. Unlike a true immunologically mediated interface dermatitis, there is no significant epithelial injury.

(Figures 14.25–14.30). The assessment of nuclear atypia is performed at high power magnification, preferably under oil immersion (100× objective) magnification, where the undulating complexity of the nuclear contour is best appreciated. It should be emphasized that small cerebriform lymphocytes, even those with rather complex contours, are a feature of reactive states and hence their presence is not as significant as the demonstration of the intermediate and larger lymphocytes. Regarding adnexal involvement, significant follicular infiltration has been described in 57% of cases (Rongioletti and Smoller, 2000). Eccrine involvement has been reported in 30% of cases. Follicular mucinosis was detected in 8.4% of cases. With respect to the designation of patch versus plaque versus tumor stage, the following morphologic features are characteristic for the three main forms of mycosis fungoides. In early patch stage the infiltrate is superficial and oftentimes perivascular, while the epidermis is variably hyperplastic and there is invariably basilar colonization and/or singly disposed epidermotropic lymphocytes in the spinous layer, typically with minimal spongiosis and without vesiculation. At this phase dermal fibrosis and poikilodermatous changes may be noted. There is a variable admixture of eosinophils and plasma cells, but these are typically sparse or absent in early lesions of mycosis fungoides. The defining cytology in mycosis fungoides is that of atypical intraepidermal

Clinical Variants

(a)

279

(b)

Epidermotropism. Those photomicrographs demonstrates the phenomenon of passive intraepidermal lymphocyte migration unaccompanied by significant epithelial destruction. Note the arrangement of lymphocytes along the basal layer of the epidermis without supervening destructive epithelial changes and the grenz zone of uninvolved superficial papillary dermis.

FIGURE 14.12

one is a higher density of infiltration in the superficial dermis, defined by a band-like pattern, and the second is the presence of Pautrier’s microabscesses in the epidermis. When progression to tumor stage has occurred, one or more of these light microscopic features becomes apparent : (1) there may be dermal effacement with variable extension of the infiltrate into fat; (2) a prominent nodular deep-seated angiocentric component is present; or (3) there is prominence of large S´ezary cells and lymphoid blasts

Epidermotropism. This photomicrograph represents early plaque–patch stage mycosis fungoides. Even at this power the findings are characteristic for CTCL. First, there are discontiguous foci of basilar colonization by lymphocytes unaccompanied by significant destructive epithelial changes. The pattern of migration that emanates from the basilar foci is one that we equate with an infiltrative pattern. In addition, there is haphazard migration of lymphocytes to involve the upper layers of the epidermis, with relative sparing of the midportions of the spinous layer of the epidermis. Overall, the pattern of intraepidermal lymphoid infiltration is an irregular one and does not conform to the more orderly pattern that one associates with true immunologically mediated intraepidermal reactions. Please refer to Chapters 4 and 5.

FIGURE 14.13

lymphocytes of intermediate to large size (i.e., in the 11–15 µm size range). Progression to plaque stage mycosis fungoides is heralded by two typical morphologic findings:

FIGURE 14.14 Epidermotropism. This photomicrograph shows striking colonization of the epidermis by atypical lymphocytes. There is some degree of spongiosis, however, significant destructive epithelial changes are not observed.

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FIGURE 14.15 Pautrier’s microabscess. This photomicrograph shows the classic features of a Pautrier’s microabscess. The cells are all of lymphoid derivation, manifesting a closely aggregated arrangement in the epidermis without any supervening component of true vesiculation. Specifically, there is no supervening spongiosis nor are there any discernible Langerhans’ cells.

FIGURE 14.16 Pautrier’s microabscess. This photomicrograph shows a classic Pautrier’s microabscess, defined by the presence of collections of atypical cells, many with a cerebriform appearance, within the epidermis.

with primitive chromatin representing in excess of 30% of the infiltrate (Figures 14.31, 14.32, 14.40–14.43). The pagetoid reticulosis variants exhibit striking infiltration of the epidermis by atypical lymphocytes with only minimal involvement of the dermis. Establishing a morphological diagnosis of mycosis fungoides can be difficult, in part due to the inherent subjectivity regarding the assessment of cytologic and architectural atypia. A number of studies

Pautrier’s microabscess. While the dermis does have a number of admixed histiocytes, the intraepidermal component is characterized by collections of small atypical lymphocytes. FIGURE 14.17

FIGURE 14.18 Architecture of MF. This morphology can be confused with psoriasis based on the pattern of hyperplasia and parakeratosis. However, careful inspection does reveal haphazard migration of a low density epitheliotropic lymphocytic infiltrate in the epidermis, including small foci of colonization of the basal layer unaccompanied by true destructive epithelial changes. It is a difficult case and part of the lack of greater lymphocytic infiltration may reflect prior and concurrent treatment with targretin.

have attempted to isolate a reproducible approach to morphologic diagnosis (Guitart et al., 2001). In one such study, the morphologic parameters assessed included the density of infiltration, the degree of epidermotropism, and the degree of cytologic atypia. The authors found that a dense pattern of infiltration was an important diagnostic clue, as was epidermotropism, being identified in 75–100% of cases with the presence of Pautrier’s microabscesses, while

Clinical Variants

FIGURE 14.19 Architecture of MF. Further inspection of the epidermis revealed small Pautrier microabscesses, clearly confirmatory of recurrent MF following treatment.

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FIGURE 14.21 Partially treated MF mimicking lichenoid MF. There are prominent regressive stromal changes with conspicuous pigment incontinence. The epidermis is attenuated. Overall the findings are compatible with a largely regressed plaque of mycosis fungoides in the setting of PUVA intervention.

Partially treated MF mimicking lichenoid MF. This photomicrograph shows partially treated MF. Note the regressive fibroplasias and marked epithelial attenuation. The patient had received PUVA therapy.

FIGURE 14.20

Lichenoid MF. The findings would raise consideration to a regressed inflammatory lichenoid reaction. There are no specific clues in this case, as there are additional features that one would associate with an immunologically mediated process primarily in the context of keratinocyte necrosis. Higher magnification, however, does reveal significant lymphoid atypia amid the residual lymphoid populace, and clonality was identified in all specimens examined, showing the same T cell clone.

FIGURE 14.22

highly specific for the diagnosis, being seen in a minority. The key to recognizing a Pautrier’s microabscess is the noticeable absence of other inflammatory cells including Langerhans’ cells and eosinophils. ‘‘Wiry’’ thickening of papillary and upper reticular dermal collagen fibers, comprising bundles of dense collagen arranged in a reticulated or horizontal pattern, was considered a minor criterion. There are many incipient cases of mycosis fungoides in which the density of infiltration is low, but in which other clues, such as epidermotropism of atypical lymphocytes without similar cells in the dermis, loss of the retiform pattern, or wiry sclerosis of the collagen table, prompt the diagnosis. Conversely,

there are many dermatoses such as lichen planus, lichenoid connective tissue disease syndromes, and lichenoid and lymphomatoid drug reactions that are characterized by striking, high-density lymphoid infiltration. Regarding wiry sclerosis of the collagen table, any resolving lichenoid infiltrate may evoke

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FIGURE 14.23 Lichenoid MF. This higher power view shows a low density small lymphocytic infiltrate without significant atypia in concert with prominent colloid body formation in the superficial dermis. The differential diagnosis is with a resolving lichenoid dermatitis. For the reasons stated under Figure 14.20, the case was interpreted as representing lichenoid mycosis fungoides.

FIGURE 14.24 Lichenoid MF. There is a marked reduction in CD62L expression, a phenotypic finding characteristic of mycosis fungoides.

this pattern of laminated fibrosis, and the criterion is therefore not, in isolation, diagnostic of mycosis fungoides. Among the rare histologic variants are pustular mycosis fungoides, bullous mycosis fungoides, mycosis fungoides with spongiotic vesiculation, mycosis fungoides with mostly dermal infiltrates, mycosis fungoides with prominent dermal mucin deposition, acanthosis nigricans-like mycosis fungoides, interstitial or granuloma annulare-like mycosis fungoides (Su et al., 2002), and lesions of mycosis fungoides where there is a dominant angiotropic pattern.

Cytomorphology of MF. There is marked dermal and intraepidermal lymphoid atypia. Many of the cells within the epidermis exceed the degree of dermal atypia. The cells have a noticeably pleomorphic appearance. The cells are focally closely aggregated in the epidermis, defining a Pautrier’s microabscess.

FIGURE 14.25

FIGURE 14.26 Cytomorphology of MF. The cells exhibit prominent nuclear contour irregularity, whereby the gyrate, cerebriform outlines are particularly conspicuous. Nucleolation is conspicuous although not unusually prominent.

Part of the staging procedure involves the assessment of lymph nodes (Scarisbrick, 2006). The grading system that is utilized recognizes five degrees of paracortical infiltration in lymph node biopsies from patients with mycosis fungoides. LN-0 through LN3 defines dermatopathic lymphadenopathy, while in LN-4 there is partial or total effacement and this is synonymous with mycosis fungoides. The LN grade was then assigned according to the number of atypical lymphocytes present in dermatopathic

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FIGURE 14.27

Cytomorphology of MF. The cytomorphology that typifies MF is well exemplified by this photomicrograph. The cells are small to intermediate in size and manifest irregular nuclear outlines, with discrete halos demarcating the cells from adjacent keratinocytes.

FIGURE 14.29

Cytomorphology of MF. In this same case (see Figure 14.28) cells with a classic gyrate cerebriform appearance are noted in the dermis. Cerebriform lymphocytes are seen in reactive conditions, but the degree of hyperconvolution is less than in classic MF.

FIGURE 14.28 Cytomorphology of MF. The cells colonize the epidermis; they exhibit a cerebriform appearance with discrete halos.

FIGURE 14.30

foci under high dry (60× objective) magnification. If the lymph node grade varies in a given lymph node, the highest grade is assigned. Cases were categorized as unclassifiable when neither of mycosis fungoides-type lymphomatous involvement or the paracortical changes of dermatopathic lymphadenitis were recognized. A grade of LN-1 was assigned if only occasional isolated atypical lymphocytes were identified while a grade of LN-2 was assigned when the atypical lymphocytes occurred in small clusters of three or more cells. A grade of LN-3 was assigned

if atypical lymphoid aggregates were present but did not efface the nodal architecture (Colby et al., 1981). The histologic features of adnexotropic mycosis fungoides include the presence of cerebriform lymphocytes in close apposition to the outer root sheath epithelium with permeation of the wall by lymphocytes. There may be associated attenuation of the outer root sheath epithelium and follicular plugging. The cytomorphology of the lymphoid population includes small and intermediate sized cerebriform lymphocytes (Figures 14.33 and 14.34). There may

Cytomorphology of MF. A lower power shows a small cell dominant monotype infiltrate. Note the passive pattern of epitheliotropism.

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FIGURE 14.31 Tumor stage MF. The infiltrate, while lying in close apposition to the epidermis, is not permeative of the epidermis. With progression to tumor stage mycosis fungoides, the transformed cell population is no longer dependent on intraepidermal cytokines for maintenance of growth and proliferation.

FIGURE 14.32 Tumor stage MF. Higher power magnification reveals that the infiltrate is composed of large atypical cells in the 15–20 µm size range. The cells have a blastic appearance manifesting a finely dispersed chromatin with prominent nucleoli.

be a paucity of other inflammatory cell elements. Careful assessment of the interfollicular compartment reveals low density haphazard infiltration of the epidermis by atypical lymphocytes (Pereyo et al., 1997). Follicular mucinosis along with interfollicular mucin deposition is observed to varying degrees in most cases (Flaig et al., 2001). Based on the degree of follicular and interfollicular mucin deposition, Flaig et al. (2001) proposed the designation of mycosis fungoides-associated follicular mucinosis over one of

FIGURE 14.33 Follicular involvement in MF. At variance with classic mycosis fungoides is the striking follicular involvement whereby there is supervening spongiosis and an apparent admixture of Langerhans’ cells. However, the supervening mucinosis and the presence of multinucleated giant cells are important clues that serve to distinguish this atypical pilotropic reaction from follicular eczema.

Follicular MF. This is an important image, namely, one showing follicular tropism of atypical lymphocytes; note the passive pattern of migration and the close aggregation/apposition of the atypical hyperchromatic cells. In isolation, this finding is not diagnostic of lymphoma but suggests at least a pilotropic T cell dyscrasia, as in the context of a precursor lesion such as alopecia mucinosa, over frank mycosis fungoides.

FIGURE 14.34

follicular mycosis fungoides. In our experience, the degree of mucin deposition is variable and in some cases is minimal or absent. Others have described cases of follicular mycosis fungoides where mucin deposition is absent (Kossard and Rubel, 2000; Ozdemir et al., 2002). It is nonetheless important to recognize

Extracutaneous Involvement in Mycosis Fungoides

that follicular mucin deposition is observed in mycosis fungoides and that its presence should always prompt consideration of the diagnosis. Regarding syringotropic variants of mycosis fungoides, there may be significant hyperplasia of the eccrine ducts and glands whereby these adnexal structures are surrounded and permeated by lymphocytes. Hyperplasia of the follicular epithelium may be seen, specifically in the context of follicular based basaloid proliferative islands infiltrated by lymphocytes. The term used for this phenomenon when in the context of pilotropic mycosis fungoides is folliculolymphoid hyperplasia. Biopsies from clinically uninvolved skin in patients with mycosis fungoides have been assessed. Surprisingly, it was established that in 33% of biopsies of nearby skin and in 22% of biopsies from distant skin a diffuse band-like and epidermotropic lymphocytic infiltrate could be detected (Braverman et al., 1987).

EXTRACUTANEOUS INVOLVEMENT IN MYCOSIS FUNGOIDES The presence of extracutaneous, extranodal involvement by CTCL has been reported in several publications (Long and Mihm 1974; Brigham et al., 1982; Stokar et al., 1985; Sirois et al., 1993; van’t Veen et al., 1994). Most often, involvement is suspected by clinical history, by physical examination, or by abnormalities found in screening tests. The most common clinical findings associated with dissemination included fever, loss of weight, widespread lymphadenopathy including that of the hilar lymph nodes, hepatoand splenomegaly, and peripheral blood abnormalities including lymphocytosis and eosinophilia (Long and Mihm, 1974). Autopsy studies of patients with mycosis fungoides reveal much more extensive involvement than would be suspected on the basis of clinical symptomatology; involvement of practically every organ system has been recorded. Once visceral involvement has been documented, no further staging needs to be performed, although other organ sites are often biopsied if clinical symptoms suggest involvement. The morphology of involvement principally consists of diffuse infiltrates of tissue, although nodular infiltrates are also observed. Symptoms vary and depend on the actual pattern of tumor spread. Involvement of the lungs is found at autopsy in 40–60% of cutaneous T cell lymphoma patients but is usually

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asymptomatic. Chest x-ray shows nodular densities, diffuse or patchy infiltration, as well as patchy areas of consolidation and bilateral hilar adenopathy. The most common pathologic abnormality of the lungs comprises bilateral nodular infiltrates composed of extensive aggregates of malignant lymphoid cells with poorly defined borders. They are invariably associated with histologically diffuse infiltration, at least around the immediate involved zone of nodularity. Patchy areas of interstitial infiltration are often noted. Some patients manifest a pleural effusion that results in pleuritic symptomatology. Thoracocentesis will reveal the abnormal lymphoid cells often admixed with eosinophils. Gastrointestinal involvement is often associated with diffuse involvement of the mucosa and submucosa by the malignant infiltrate, while some patients manifest nodules that extend through the muscularis propria. Perforation can result from the tumors but can also reflect lymphomatous infiltration of an artery leading to thrombosis and ischemia. Diffuse involvement may result in ascites or diarrhea, sometimes in association with diffuse involvement of liver parenchyma. Jaundice can occur due to obstruction of the bile duct secondary to lymphadenopathy. The gallbladder mucosa has also been shown to manifest diffuse mucosal and submucosal infiltration. Nodules, often ulcerated, can affect the oral cavity, pharynx, and larynx and can lead to hoarseness and in some instances dysphagia, especially if extension into the esophagus is present. The cardiovascular system is commonly involved by patchy infiltration that may be subendocardial, intramuscular, or pericardial, often with symptoms of pericarditis. Infiltration of the conducting system can lead to arrhythmia, while more diffuse myocardial involvement may result in congestive heart failure. Renal involvement includes diffuse interstitial infiltration, particularly of the renal pelvis. Nodular subcapsular or parenchymal or renal pelvic infiltrates may occur and these can lead to renal failure. Both the peripheral and central nervous systems may be involved. The leptomeninges are infiltrated diffusely but rarely exhibit nodular masses. The brain itself may be involved by large tumefactions or diffuse infiltrates, which may lead to cerebral hemorrhage or multifocal leukoencephalopathy. Involvement of the spinal cord and peripheral nerves can result in peripheral neuropathy. A lumbar puncture can be useful in evaluating for S´ezary cells to confirm involvement. Imaging is also an important tool (Tien et al., 1992). Extraocular and intraocular structures may manifest involvement. The retina, choroid, and optic nerve may be affected; conjunctival infiltration

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can affect the palpebrae leading to ulcerated nodules or infiltrated plaques. The bulbar conjunctiva may be infiltrated, sometimes in association with corneal opacification. Bone marrow involvement is uncommon early in the disease but in advanced stages there may be nodular or diffuse infiltration. In 11of 15 cases autopsied, bone marrow infiltration was noted (Long and Mihm, 1974). Skeletal involvement, as in other organ systems, can be associated with diffuse infiltration leading to widespread osteoporosis and osteolysis. Diffuse intra-articular involvement has been shown to be associated with arthritis, whereby synovial involvement may result in effusions; the pannus of rheumatoid arthritis does not develop. Arthrotomy will reveal atypical lymphoid cells usually with admixed plasma cells and eosinophils. Regarding the autopsy findings of mycosis fungoides, in none of 15 reported cases in one series did the lymphoma change in histology in extracutaneous sites; the morphology was characteristic of mycosis fungoides (Long and Mihm, 1974).

FIGURE 14.35 Phenotypic profile of MF. The cells are noticeably CD7 negative. The cells are arranged in a cohesive array within the epidermis defining a Pautrier’s microabscess.

Phenotypic Profile The neoplastic lymphoid cells in mycosis fungoides are typically CD3+/CD4+/CD45 RO+; the larger cells may express CD30. There is usually a prominent diminution in the quantitative degree of CD7 and CD62 expression (typically less than 10% of the infiltrate will be CD7 positive while less than 30% of the infiltrate will be CD62 positive). Diminution of pan T cell marker CD7 and CD62 expression is considered significant when less than 30% and 50% of the cells express the antigen respectively (Figure 14.36). As well, the larger atypical cells in the epidermis may be CD5 negative (Figures 14.35–14.39). CD16, the cutaneous lymphocyte homing receptor, is expressed in cases exhibiting a high degree of epidermotropism. CD103, the epithelial lymphocyte homing receptor, is expressed on epidermotropic cells and, to a lesser extent, on dermal infiltrating cells. There is also prominent expression of cutaneous lymphocyte antigen (CLA). Progression of mycosis fungoides from the plaque stage to the tumor stage has been associated with the acquisition of cytotoxic molecule expression, namely, of granzyme B and TIA in lymphocytes defining the emergence of a cytotoxic CD4 phenotype (Vermeer et al., 1999, 2001a, b). In this regard more than 10% of the neoplastic cells show granular cytoplasmic staining for granzyme B and/or TIA1. Tumor cells expressing TIA-1 and/or granzyme B include neoplastic T cells with cerebriform nuclei and blast cells; expression of TIA-1 is more frequent than

FIGURE 14.36 Phenotypic profile showing loss of CD7. One can see that the intraepidermal lymphoid population shows no immunoreactivity with CD7 in this lesion of plaque stage mycosis fungoides. This pattern of profound loss of CD7 expression is characteristic of mycosis fungoides. While a reduction in CD7 can be seen in reactive conditions, the degree of loss of this marker is not as profound as that observed in the setting of mycosis fungoides.

granzyme B. Once progression to tumor stage mycosis fungoides has occurred, at least 75% of the cells express TIA-1 and granzyme (Figure 14.37). There is variable expression of CD30 (Figures 14.43–14.45). The question obviously arises as to why the enhanced expression of granzyme and TIA by the neoplastic cells is associated with tumor progression. It has been suggested that these tumor cells may have the capacity to induce apoptosis in antitumor immune

Extracutaneous Involvement in Mycosis Fungoides

FIGURE 14.37 Phenotypic profile showing loss of CD5. This CD5 stain shows that the most atypical cells in the epidermis are CD5 negative. The loss of CD5 would be considered a definite marker of phenotypic aberration, while the loss of CD7 is not specific for a dyscrasia per se. Perhaps the one exception is lupus erythematosus profundus, which can show a reduction in CD5 expression.

Phenotypic profile showing CD4 positivity. Mycosis fungoides is a malignancy of CD4 lymphocytes in the majority of cases, although there are uncommon examples of CD8 variants of mycosis fungoides. This CD4 stain does highlight a number of positive staining cells in the epidermis and dermis.

FIGURE 14.38

cells and so aid the escape from immune control. This hypothesis could explain the gradual reduction in the numbers of CD8-positive T cells and the worsening prognosis observed during disease progression. In one study, the first diagnostic biopsies showing patch and/or plaque stage mycosis fungoides did not show any clinical difference between those cases in which cytotoxic proteins were expressed versus those in

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The tumor cells are strongly lymphocyte common antigen positive. Most primary cutaneous lymphomas are cutaneous lymphocyte antigen positive. In contrast, aggressive T cell lymphomas that commonly involve the skin but in the context of disseminated multiorgan disease may be cutaneous lymphocyte antigen negative. Another interesting feature that we have seen is the loss of cutaneous lymphocyte antigen expression with disease progression in lesions of mycosis fungoides (unpublished observations).

FIGURE 14.39

which cytotoxic protein expression was not observed (Vermeer et al., 1999, 2001b). Although the vast majority of cases of mycosis fungoides are of the CD4 subset, a small percentage of cases will be of the CD8 subset (Figure 14.38). This is particularly the case in hypopigmented mycosis fungoides, a relatively indolent form of mycosis fungoides. Nevertheless it is possible that the CD8 lymphocytes in fact are reactive and if their higher numbers may account for a lack of disease progression (El Shabrawi-Caelen et al., 2002). CD25 is frequently assessed. However, it should be emphasized that while 50% of cases of mycosis fungoides manifest variable membrane and intracytoplasmic CD25 expression, when membrane staining is assessed only a small percentage of cells show immunoreactivity. The recognition of this information is important in light of a potential role for therapy with the chimeric fusion protein DAB48 Il-2. A recent study showed that a small percentage of cases of mycosis fungoides (<10%) showed an unusual phenotype characterized by CD45 RA expression. CD45 RA is usually seen in NK and CD8 lymphomas, which are traditionally associated with a more aggressive clinical course. Further phenotyping showed that the CD45 RA neoplastic cells belonged to a minority component displaying a CD62-negative, CD11a-positive and CD29-positive phenotype. Most cases showed an aberrant phenotype with loss of

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T cell lineage markers and expression of cytotoxic molecules; there was a rearrangement of the γ δ chain of the T cell receptor (Fierro et al., 2001). Despite the aberrant nature of the phenotype within this subcategory of mycosis fungoides, the clinical course was relatively indolent. (Fierro et al., 2001). There is also a difference in the phenotypic profile of patients with mycosis fungoides and S´ezary syndrome. Specifically, a type I cytokine production profile consisting of IL-2 and interferon-γ production is common in mycosis fungoides, while a type II cytokine profile is characteristic of S´ezary syndrome. The type II cytokine profile is associated with interleukin-4 production, which could partly explain the peripheral blood eosinophilia seen in S´ezary syndrome and the tissue eosinophilia of tumor phase mycosis fungoides (Shohat et al., 2001).

Molecular Profile Molecular studies in early lesions of mycosis fungoides may be negative. One study examined T cell receptor gene rearrangement by polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis in archival specimens and found an overall clonal restriction rate of 75%. PCR is preferred over Southern blot because of greater sensitivity; clonality is detected in 59% of cases of mycosis fungioides examined by Southern blot analysis versus over 75% of cases by PCR. In either assay, both molecular weight and nucleotide sequence are assessed. With respect to PCR, 1% of the entire T cell infiltrate must be clonal for a discrete band to be detected. T cells express receptors of either the αβ or the γ δ type. The vast majority of T cell lymphomas express the αβ type of T cell receptor. The α and β chains contain numerous variable (V) segments, making it difficult to amplify the unique CDR3. All αβ TCR-positive T cells contain one rearranged allele of the γ chain gene. The γ chain contains only a very limited number of V segments. Hence, PCR to detect T cell clonality typically utilizes primers directed at the V segments of the γ chain gene. There are two possible PCR techniques to amplify the CDR3 region of the TCR-γ chain gene. One group uses a pair of consensus primers annealing to the V segment between nucleotides 272 and 290 and J segment between nucleotides 45 and 62. Other groups use specific primers for all known V and J segments, which are combined in two primer groups (Klemke et al., 2002). In our experience, using capillary size fragment analysis, clonality is characteristic and it appears that the same clonal populations are maintained over time 14(46-51); we have observed the identical molecular profiles over a several year period in some patients.

A retroviral pathogenesis has been postulated in mycosis fungoide but it is generally regarded as unproven. The human T lymphotropic retrovirus (HTLV-1) genes Tax and/or Pol have been detected in 30–90% of patients in the United States with mycosis fungoides, but none of these patients have PCR positivity with respect to structural proteins of HTLV-1 (Lessin et al., 1994).

Cytogenetics A recent study has a shown a relatively high rate of loss of heterozygosity on 10q23-24 (23%) and microsatellite instability (27%) in mycosis fungoides. In addition, loss of heterozygosity of chromosome 10q appears to be associated with disease progression in mycosis fungoides. The candidate tumor suppressor gene PTEN demonstrated a homozygous deletion in 20% of patients, with loss of heterozygosity of chromosome 10q (Scarisbrick et al., 2001).

Pathogenesis There are three main systems involved in the regulation of apoptosis: FAS, the bax/bcl-2 system, and p53. It is well established that indolent forms of lymphoma are more frequently related to an accumulation of nonproliferating lymphocytes that have defective apoptotic mechanisms leading to enhanced cell longevity. Mycosis fungoides is a lymphoma characterized by an indolent course with slow progression over years and sometimes even decades. Presumably, an accumulation of apoptotically defective antigenresponsive T cells could be the basis of the clinical lesions of mycosis fungoides. There have been prior studies that have assessed apoptosis in lesions of mycosis fungoides with indeterminate results. In one study, six point mutations of the coding sequence of the FAS gene were uncovered in 13% of patients with the disease. In this study, there was no relationship between the clinical and/or histologic pattern of lesions and the profile of mutations (Dereure et al., 2002). The authors hypothesized that defective apoptosis of chronically antigen-stimulated T cells is involved in some cases of mycosis fungoides through alterations of regulators of this apoptotic process; clearly, defective apoptosis does not appear to contribute to the pathogenesis of all cases (Dereure et al., 2000, 2002). The effectiveness of PUVA in the initial phases of CTCL presumably reflects the upregulation of apoptosis rather than the reduction in the proliferation rate of T cell growth. Abnormal expression of FAS or bax has been reported in other human hematologic malignancies, specifically myeloma. An acquired defect in apoptosis in a subset of activated epidermotropic

Extracutaneous Involvement in Mycosis Fungoides

T cells may be pathogenetically important at the inception of some cases of mycosis fungoides. Perhaps the most common mutation of tumor suppressor genes in human cancers is that of p53, which has been reported in a number of noncutaneous tumors including colorectal carcinoma. Mutations of p53 have only been reported in more aggressive cases, which have undergone transformation into tumor stage mycosis fungoides (Kapur et al., 2001), the only form in which consistent expression of p53 is seen. p53 is noticeably absent in the setting of plaque and patch stage mycosis fungoides (Kanavaros et al., 2001). 17p chromosomal loss has been detected in a subset of S´ezary syndrome patients. Whittaker and co-workers isolated p53 gene mutations in 40% of patients with tumor stage mycosis fungoides that were noticeably absent in patients with early stage disease (Whittaker et al., 2001). These findings correlated with p53 protein expression in tissue. These investigators postulated that prior phototherapy may have played a role in the induction of this genetic event as the mutation spectrum they observed was consistent with UVB-induced mutations (McGregor et al., 1999; Mao et al., 2002). A number of their patients had received previous phototherapy. Another study of large cell transformation in mycosis fungoides identified overexpression of p53 in the absence of a p53 mutation (Li et al., 1998). p53 gene inactivation is associated with treatment resistance in nonHodgkin’s lymphoma. Upregulation of intercellular adhesion molecule1 expression on follicular epithelium adjacent to lymphocyte function-associated antigen-1-positive folliculotropic lymphoma cells suggests a potential

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mechanism involved in lymphocyte homing mechanisms (Gilliam et al., 1997); similar expression is not observed in nonneoplastic folliculotropic inflammatory processes. It is unclear whether the expression of the intercellular adhesion molecule occurs as a sequela of the folliculotropic inflammation or is a critical event leading to the infiltration of follicular structures by lymphocytes. The mechanical obstruction of the follicle by tumor cells leads to subsequent hyperkeratosis and cyst formation. Chromosomal amplification of JUNB, a member of the activating protein-1 (AP-1) transcription factor complex involved in cell proliferation and T-helper-2 (Th2) cytokine expression by T cells, has been identified in patients with S´ezary syndrome (Mao et al., 2002). Genomic microarray analysis in the setting of mycosis fungoides and S´ezary syndrome reveals similar profiles pointing toward a common pathogenesis. The majority of cases will show gains of JUNB, RAF1, CTSB, PAK1, FGFR1, PTPN, and BCR. The overexpression of JUNB was consistently detected in primary cutaneous anaplastic large cell lymphoma, mycosis fungoides, and S´ezary syndrome. Through the AP-1 transcription factor complex, the JUNB protein helps to promote Th2 lymphocyte differentiation through upregulation of interleukin-4 (Il-4). JUNB appears to promote apoptosis and to inhibit tumor cell proliferation in cutaneous T cell lymphoma. This is in turn a reflection of the constitutive activation of transcription factor NF-κB, which controls the activation of JUNB. Apart from JUNB, other oncogenes such as RAF1, CTSB, and PAK1 are also frequently identified in mycosis fungoides and S´ezary syndrome.

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CASE VIGNETTES CASE VIGNETTE 1

The patient has a well established history of cutaneous T cell lymphoma and now presents with progressive tumor nodules. The clinical impression is one of progression to tumor stage mycosis fungoides. Diagnosis: Progression to tumor stage mycosis fungoides (Figures 14.40–14.45).

FIGURE 14.40 This photomicrograph shows the epitheliotropism typical for mycosis fungoides. However, unlike classic MF, the neoplastic populace includes many transformed cellular elements.

FIGURE 14.41 A higher power magnification shows a number of large transformed cellular elements. The key in recognizing tumor transformation is one of cells showing more abundant cytoplasm, a finely dispersed heterochromatin, and conspicuous eosinophilic nucleoli.

There is extensive permeation of the interstitial spaces of the fat in a fashion reminiscent of panniculitis-like T cell lymphoma.

FIGURE 14.43

FIGURE 14.42

Many of the cells are CD30 positive.

Case Vignette 1

There is a loss of cutaneous lymphocyte antigen expression.

FIGURE 14.44

Acquisition of a cytotoxic phenotype is also highly characteristic and may play a role in tumor progression. It is possible that the tumor cells acquire the ability to kill immunosurveillance regulatory CD8 cells. Granzyme expression is illustrated. FIGURE 14.45

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES TCR beta Block A Multiplex panel B

Dominant peak at 263 base pairs Polyclonal background

TCR beta Block B Multiplex panel B

Dominant peak at 263 base pairs

Polyclonal background

FIGURE 14.46 A 58 year old woman has a history of mycosis fungoides. Note the dominant T cell population at 263 bp. Two different samples show an identical clonal population of T cells at a base pair size of 263. (Molecular gel and interpretation provided by Carl D. Morrison, Roswall Park, Buffalo, New York.)

Additional Molecular and Cytogenetic Studies

1/26/2005 panel C

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Monoclonal peak 264 bp

1/26/2005 panel A

Clonal peak 254 bp Polyclonal background

7/1/2002 panel A

Clonal peak 254 bp

FIGURE 14.47 The patient has an established history of mycosis fungoides. A biopsy performed in January 2005 shows a monoclonal T cell population at 264 and 254 bp in panels C and A, respectively. A biopsy performed 6 months later shows a dominant T cell population with an identical base pair size.

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Multiplex panel A Block C

Single peak 236 bp

Single peak 205 bp

Multiplex panel C Block C

Multiplex panel A Block D Single peak 236 bp

Single peak 205 bp

Multiplex panel C Block D

FIGURE 14.48 A 51 year old man was diagnosed with mycosis fungoides. The molecular studies show a monoclonal population of T lymphocytes in both specimens. Blocks C1 and D1 both have single peaks at 236 bp on panel A and 205 bp on panel C. (Molecular gel and interpretation provided by Carl D. Morrison, MD, Roswall Park, Buffalo, New York.)

Additional Molecular and Cytogenetic Studies

295

S9/9/2003 TCR beta Panel A Peak 264 bp

9/15/2004 TCR beta Panel A Peak 264 bp

6/2/2005 TCR beta Panel A Minimal product

The patient had a biopsy compatible with large plaque parapsoriasis in September 2003. There was a monoclonal population of T cells. The identical T cell clone is seen 1 year later, at which point his biopsy was compatible with mycosis fungoides.

FIGURE 14.49

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9/9/2003 TCR beta Panel C

Mycosis Fungoides

Peak 189 bp

9/15/2004 TCR beta Panel C Peak 189 bp

6/2/2005 TCR beta Panel C

Peak 189 bp

FIGURE 14.50 The patient has a history of a recalcitrant dermatitis. A biopsy in 2003 was suspicious for an evolving T cell dyscrasia. Molecular studies show a prominent T cell population that is maintained over time. His most recent biopsy in June 2005 was consistent with fully evolved mycosis fungoides. The dominant T cell population is even more prominent at this point compared to earlier biopsies.

References

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CHAPTER FIFTEEN

PRIMARY CUTANEOUS PLEOMORPHIC SMALL/MEDIUM SIZED T-CELL LYMPHOMA AND PERIPHERAL T-CELL LYMPHOMA, UNSPECIFIED, PRESENTING IN THE SKIN (CD30-NEGATIVE LARGE CELL T CELL LYMPHOMA) Cynthia M. Magro and A. Neil Crowson

Clinical Features Primary cutaneous T cell lymphoma (CTCL) comprises a spectrum of entities that vary clinically and histologically from a molecular, phenotypic, and cytogenetic perspective. It is true that the vast majority of primary cutaneous T cell lymphomas are represented by mycosis fungoides and those that fall under the rubric of CD30-positive lymphoproliferative disease. However, there is a distinctive subtype of cutaneous T cell lymphoma that, while representing only roughly 10% of cases, defines the third most common form of CTCL after mycosis fungoides and CD30-positive anaplastic-large cell lymphoma (Beljaards et al., 1994; Kerl and Cerroni, 2000). The WHO

recognizes these lesions under the designation of peripheral T-cell lymphoma, unspecified while the EORTC has used the designation primary cutaneous pleomorphic small/medium sized T cell lymphoma (provisional entity) and CD30-negative large cell T cell lymphoma (Slater, 2005). There appears to be considerable heterogeneity of clinical outcome, a phenomenon that may relate to the morphologic, phenotypic, and genomic heterogeneity, although the latter has yet to be elucidated. Based on the recent joint classification scheme for primary cutaneous lymphoma offered by the EORTC and WHO, the current nomenclature adopts the EORTC designation of primary cutaneous

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 300

Primary Cutaneous Pleomorphic Small/Medium Sized T-Cell Lymphoma and Peripheral T-Cell Lymphoma

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TABLE 15.1 Peripheral T Cell Lymphoma, Unspecified/CD30-Negative Cutaneous Large T Cell Lymphoma Clinical Adults Solitary, localized, or disseminated plaques and tumors Sometimes ulcerated Aggressive course Formerly categorized as d’emblee mycosis fungoides Histomorphology Nodular or diffuse infiltrates characterized by medium and large sized pleomorphic cells or immunoblasts Immunophenotype CD2+/− CD3+/− CD5+/− CD7−/+ (those cases that are CD7+ may be CD2−) CD62L− CD4+(−) βF1+ CD30− CD8+/− These are aggressive lymphomas and it is not uncommon to see deletions of standard pan T cell markers including CD2,CD3, and CD5 although there may be preservation of CD7 Genetics Rearrangement of the T cell receptor gene(s)

(a)

(b)

FIGURE 15.1 The patient is an 82 year old woman with a 3 year history of nodules and plaques on her legs and arms. Her biopsy was compatible with a pleomorphic small/medium sized T cell lymphoma.

pleomorphic small/medium sized T cell lymphoma CD30-negative large cell T cell lymphoma falls under the designation of peripheral T cell lymphoma, unspecified. (Table 15.1) (Willemze et al., 1994, 2005; Nagasawa et al., 2000; Chang et al., 2003). Lymphomas that fall under the designation of primary cutaneous pleomorphic small/medium

sized T-cell lymphoma have an estimated 5 year survival between 60 and 80%, with the best prognosis seen in those cases presenting as solitary lesions. When the disease is confined to one area, the preferred method of treatment is one of surgical excision or radiotherapy. In those cases with more generalized disease, treatment regimes that

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The patient presented with a sudden onset of infiltrative nodular lesions on her arms. She had concurrent orbital disease. She died 6 months later. She had a CD30negative large cell periperhal T cell lymphoma presenting in the skin. FIGURE 15.2

incorporate cyclophosphamide and interferon-α have been effective (Figure 15.1). The therapeutic approach is discussed in greater detail in Chapter 2 (Bekkenk et al., 2003). Patients whose lymphomas fall under the designation of CD30-negative large cell T cell lymphoma present with solitary, localized, or generalized cutaneous disease without any specific site predilection. Some of these cases were formerly considered under the appellation of d’emblee mycosis fungoides, a term used to describe mycosis fungoides presenting in its inception as a solitary tumor or plaque. Since the first described case in 1950, the few reported examples of this variant of mycosis fungoides suggested a clinical course different from classic mycosis fungoides as, at least in some patients, there was a rapidly progressive clinical course with death occurring within months of diagnosis (Figure 15.2) (Sanyal et al., 1980; Coulson and Sanderson, 1985). At one point it was held that a patient who presented with localized disease might follow an indolent clinical course, analogous to those with a localized cutaneous presentation of large cell B cell lymphoma. It has since been established that the initial clinical presentation be it in the context of localized or multicentric disease may have no bearing on 5 year survival; survival rates are less than 20%, including those patients who present with localized disease. One of the cases illustrated clinically in this chapter exemplifies this concept. At the time the clinical photograph was taken, the patient was clinically asymptomatic without constitutional

symptoms. Within less than 6 months she died of disseminated multiorgan lymphoma. Because of the potential for an aggressive clinical course, patients should be treated with multiagent chemotherapy (O’Quinn et al., 2000; Joly et al., 1995). Those primary cutaneous peripheral T cell lymphomas that are CD30 positive are prognostically different from those that are CD30 negative. They tend to have a more indolent course and are considered under the topic of CD30-positive lymphoproliferative disease. The designation for such cases is anaplastic large cell lymphoma. Unlike mycosis fungoides, in primary cutaneous pleomorphic T cell lymphoma there is no prior eczematous or other precursor lesion (Figures 15.1 and 15.2). There is no evidence of extracutaneous disease at the time of presentation, especially in the context of nodal disease. Like other forms of primary CTCL, it tends to occur in older patients, but there are reports of this entity occurring in patients as young as 16 years of age. It accounts for approximately 30% of all primary cutaneous T cell lymphomas. In primary cutaneous pleomorphic T cell lymphoma, the lesions consist of plaques, papules, or tumors, some of which show central ulceration typically without scaling. While the classic presentation is as tumor nodules, some patients have presented with leonine facies prior to the development of peripheral blood and bone marrow involvement (Vocks et al., 2000). Pruritus, which is common in mycosis fungoides, is usually not observed in patients with primary cutaneous pleomorphic T cell lymphoma (Friedmann et al., 1995). When the skin lesions are localized, the prognosis is excellent and the patients respond very well to limited treatment (Bekkenk et al., 2003). If presenting as a solitary tumor, treatment should comprise complete excision with or without subsequent radiation. When the disease presents with disseminated skin lesions, a more aggressive therapeutic approach is warranted because of a worse prognosis, with earlier series reporting deaths attributable to disease. Those patients with the generalized cutaneous form of the disease typically have a relapsing course (Bekkenk et al., 2003) with complete remission being exceptional (Joly et al., 1995). In one study of 11 patients with disseminated skin lesions, three died and eight had a chronic relapsing course with only one patient achieving complete remission; patients who presented with localized disease had a very good prognosis with most achieving complete remission (Friedmann et al., 1995). The morphologic spectrum encompasses small

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cell dominant, and mixed small/medium sized cells (Kim and Vandersteen, 2001). An interesting phenotypic variant that may be of prognostic significance is seen in those cases of pleomorphic T cell lymphoma composed of T cells of the αβ subtype, whereby there is expression of T cell intracellular antigen and other cytotoxic proteins, a finding that may portend an aggressive clinical course. These patients would appear to be appropriately designated as pleomorphic T cell lymphoma based on CD56 negativity and the fact that the cells are not of the γ δ subtype. These patients may behave like those with natural killer (NK) cell and NK-like T cell lymphoma and primary cutaneous cytotoxic CD8-positive epidermotropic T cell lymphoma (Massone et al., 2004). There is no pathogenetic role for any specific virus including Epstein–Barr virus, human herpes virus types 7 and 8, and HTLV-1 in the development and maintenance of cutaneous malignant lymphomas of this subtype (Anagnostopoulos et al., 1996; Nagore et al., 2000). There is one prior report of pleomorphic T cell lymphoma arising in a background of Sjogren’s syndrome. It may be that reactive lymphoid hyperplasia in the setting of iatrogenic or endogenous immune dysregulation, including collagen vascular disease, may be an initiating event in lymphomagenesis (van der Valk et al., 1989). There is a growing body of literature describing this association. There are rare reports of patients with both myelodysplastic syndrome and primary cutaneous pleomorphic T cell lymphoma including the concomitant presentation of both hematologic diseases with subsequent evolution into acute myelogenous leukemia (Breccia et al., 2002). Studies have shown clonality in lymphocytes in 7–22% of patients with myelodysplastic syndrome; cytogenetic abnormalities have been identified in lymphocytes of myelodysplastic syndrome patients including monosomy 7 and trisomy 8, suggesting a cytogenetic basis for the association. The coexistence of myeloid dyscrasias with other forms of CTCL has been described previously, including acute myelogenous leukemia occurring subsequent to a diagnosis of S´ezary syndrome (Carrozza et al., 2002). Although circulating clonal T cells is a phenomenon that one associates with S´ezary syndrome, one study using a highly sensitive polymerase chain reaction (PCR) assay for T cell receptor-γ gene rearrangement found that 10 of 13 patients with pleomorphic CTCL had circulating clonal T cells.

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Such findings underscore the importance of recognizing primary cutaneous pleomorphic T cell lymphoma as a systemic disease process (Muhe et al., 1997). Pathology/Light Microscopic Findings In early lesions, a zonal pattern of dermal infiltration may be seen, whereby the lymphocytes cells surround and permeate nerves, pilosebaceous units, and blood vessels. In a minority of cases, the infiltrate is intimately apposed to the dermoepidermal junction, whereby the superficial aspect of the infiltrate coalesces to produce a band-like pattern. Despite the heavy dermal infiltrate, there is usually only minimal epidermotropism, although at times it may be prominent (see Figures 15.3, 15.9, 15.16, 15.20, 15.22 and 15.26) (Friedmann et al., 1995). Even in the latter cases, the most useful feature is the massive extent of dermal involvement in the context of a small cell dominant process, a phenomenon that would not be observed in patch or plaque stage mycosis fungoides. A lesion of mycosis fungoides with such heavy and deep-seated involvement has usually progressed to tumor stage; the dominant cytomorphology would then be larger cells admixed with a background population of small cerebriform lymphocytes, eosinophils, and plasma cells. In contrast, there is invariably deep dermal involvement in the initial phase of the primary cutaneous pleomorphic T cell lymphoma, often with extension into the subcutaneous fat (see Figures 15.3, 15.9, 15.12, 15.16, 15.22 and 15.24). In mycosis fungoides, the lesions are usually confined to the epidermis and superficial dermis for years before a deep dermal infiltrate develops. Histologically, the characteristic cerebriform cells of mycosis fungoides are uncommon in primary cutaneous pleomorphic T cell lymphoma. In contrast the lymphoid nuclei are heterogeneous and show multilobation, angulation, transverse grooves, and irregular blebs (see Figures 15.5, 15.13, 15.18 and 15.25). The chromatin is less coarse than that of the neoplastic cell of mycosis fungoides. Nucleoli are not prominent except in the large atypical cells, where they may be multiple (Friedmann et al., 1995). There may be an admixture of eosinophils, plasma cells, and epithelioid histiocytes, the latter sometimes so striking as to warrant designation as primary cutaneous Lennert’s lymphoma or to lead to diagnostic misinterpretation as a reactive process (see Figure 15.4) (Kiesewetter et al., 1989; Bhushan et al., 2000; Scarabello et al., 2002). Classification of pleomorphic T cell lymphoma is based on the dominant cytomorphology, categorizing the lesions as small cell dominant, mixed, or large

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TABLE 15.2 Pleomorphic Small/Medium T Cell Lymphoma Clinical Adults and elderly Localized or multiple tumors Head and neck, upper trunk most often ´ Good 5 year survival although not as good as classical mycosis fungoides (excluding Sezary syndrome) Histomorphology Small to medium sized pleomorphic cells Immunophenotype CD3− CD4+/− (majority of cases are CD4+) βF1+ CD8/30−/+ CD7− CD2+/− CD5+/− Molecular profile Monoclonal rearrangement of the T cell receptor gene(s)

cell dominant. The validation for this is based on the biological behavior; those patients who die from their disease appear to have biopsies that manifest a large cell cytomorphology. Pleomorphic T cell lymphoma of small cell/medium cell type appears to represent a low-grade lymphoma (Table 15.2) (see Figures 15.3–15.6, 15.9–15.12, 15.16–15.19 and 15.26–15.27) (Bekkenk et al., 2003). The small cells are in the 7–9 µm range, intermediate cells are in the 9–11 µm range, and large cells are greater than 11 µm (see Figure 15.3). The distinction between low grade small/medium pleomorphic T cell lymphoma versus CD30-negative large cell peripheral T cell lymphoma unspecified is based on the percentage of large cells; an infiltrate comprising more than 30% large cells defines the latter while one with less than 30% is compatible with the former. If one examines the specimen under 40× objective magnification, the large cell variant would manifest greater than 15 large cells per high power field (see Figures 15.18, 15.25, 15.28, and 15.30). The large cells have an open nucleus with large eosinophilic nucleoli that can be multiple; the nuclear contours are variable, ranging in quality from monomorphous and oval to those that show considerable irregularity. Years ago some cases of CD30-negative large cell peripheral T cell lymphoma were designated as primary cutaneous multilobated T cell lymphoma (Toonstra et al., 1983). (Goldman et al., 1991). While the differential diagnosis of any neoplastic epitheliotropic lymphocytic process includes S´ezary syndrome and mycosis fungoides, the cerebriform lymphocytes that define the dominant cytomorphology in either of these conditions are not

observed in primary cutaneous pleomorphic T cell lymphoma. As noted earlier, the concept of d’emblee mycosis fungoides (i.e., mycosis fungoides initially presenting in tumor stage) is now discredited; today such cases would be categorized as CD30-negative large cell peripheral T cell lymphoma unspecified (Marzano et al., 1997). Phenotypic Profile Immunophenotypic studies have shown that the primary cutaneous pleomorphic T cell lymphoma has a mature T cell phenotype, being negative for TDT in the majority of cases. In 70% of cases, the neoplastic cells are CD4 positive; the remainder manifests a CD8positive phenotype. As with any T cell neoplasm, the tumor cells will show loss of pan T cell markers such as CD2, CD5, CD62, and CD7 (see Figures 15.7, 15.8, 15.14, and 15.15). It has been our experience that the degree of CD7 deletion is much more variable relative to mycosis fungoides, as some cases show only modest reduction in CD7 expression while other cases show a profound reduction. A reduction in CD5 expression not uncommon. Characteristically, those cases manifesting preservation of CD7 expression will show a significant reduction in CD2 expression (Beljaards et al., 1994). There are cases that may not show CD4 or CD8 expression and/or be CD8 positive, where there is cytotoxic protein expression by virtue of T cell intracellular antigen positivity, a finding of great prognostic significance. These patients may have an aggressive clinical course (Massone et al., 2004).

Primary Cutaneous Pleomorphic Small/Medium Sized T-Cell Lymphoma and Peripheral T-Cell Lymphoma

Rarely, lesions that either have the clinical and morphologic features of unspecified peripheral T cell lymphoma or primary cutaneous pleomorphic small/medium sized T cell lymphoma contain CD30positive cells (Gianotti et al., 1991; Marzano et al., 1997). Gianotti and co-workers described an elderly female patient who presented with a solitary lesion on the upper back (Gianotti et al., 1991), which mainly comprised medium to large cells that focally expressed CD30 but not CD25. The lesion was excised and the patient is apparently alive and well. The critical differential diagnosis in this case is one of anaplastic large cell lymphoma. In our experience, the CD30-positive express primary cutaneous pleomorphic T cell lymphomas comprise mainly small and medium sized cells with admixed CD30 positive large cells. Patients have an indolent course and a tendency toward spontaneous regression, hence recapitulating the biological course of the classic CD30-positive lymphoproliferative lesions. There are insufficient large cells to use the designation of anaplastic large cell lymphoma and the plaque-like morphology of the lesions clinically precludes designation as lymphomatoid papulosis (see Figures 15.15–15.21) albeit one patient in our series had lesions of lymphomatoid papulosis. Cytogenetics Little is known about the cytogenetic abnormalities in this subtype of lymphoma. In one reported case of CD30-negative large cell T cell lymphoma, gene expression profiling using complementary DNA microarrays indicated significantly increased expression of genes encoding an apoptosis-inhibitory protein and certain cyokines and cytokine receptors (e.g., MCP-1, MCP-2, IP-10, and IL-2Rγ ) in the tumor-bearing skin (see Figure 15.31) (Murakami et al., 2001). Differential Diagnosis The differential diagnosis of primary cutaneous pleomorphic T cell lymphoma is with peripheral T cell lymphomas secondarily involving the skin. Peripheral T cell lymphomas are post-thymic T cell lymphomas that generally present initially in a lymph node or other lymphoid organs such as the spleen and Waldeyer’s ring. Most patients with nodal peripheral T cell lymphoma present with generalized lymphadenopathy and have Stage IV disease by virtue of involvement of the skin (50%), liver (50%), peripheral blood (30%), and lungs or pleura or both (20%). No patient has peripheral blood involvement without skin involvement. According to the Working Formulation, the cases are of mixed cell type or large cell predominant. Peripheral T cell lymphomas account for 15% of all diffuse

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aggressive lymphomas in the United States. The large cells of peripheral T cell lymphoma are variable in appearance, with some cells resembling the mononuclear cell variants of Reed–Sternberg cells by virtue of large, open nuclei with prominent eosinophilic nucleoli. The mirror image binucleated morphology of the classic Reed–Sternberg cell is not identified, however (Mourad et al., 2003). Mitotic activity is marked. Multinucleation and lobulation are typical. When the multilobated morphology is striking, the term multilobed peripheral T cell lymphoma is used. Inflammatory cells are usually present in the background and include eosinophils, plasma cells, and epithelioid histiocytes. When the latter are dominant, the appellation of Lennert’s lymphoma has been used (van der Putte et al., 1982a,b). Folliculotropic mycosis fungoides may be very difficult to distinguish from primary cutaneous pleomorphic T cell lymphoma but there usually is prominent epidermotropism, Pautrier’s microabscesses are present, and the cells have a characteristic cerebriform appearance. Patients often have a waxing and waning course over years and there may be other lesions typical of classic mycosis fungoides. Critical to the accepted definition of either primary cutaneous pleomorphic small/medium T cell lymphoma and the peripheral unspecified variant is the absence of extensive CD30 expression, recognizing those rare variants that do manifest focal CD30 expression. The cases are either completely negative, or the CD30 antigen is expressed by less than 30% of neoplastic cells, or expression is weak. Such cases differ from anaplastic large cell lymphoma by virtue of a smaller cell diameter and a more monomorphous cytomorphology. The distinction from the small cell variant of anaplastic lymphoma may be difficult because CD30 expression may be very focal in this variant of anaplastic large cell lymphoma. However, in primary cutaneous pleomorphic T cell lymphoma, the small and intermediate cells show the typical cytomorphology with nuclear hyperchromasia and significant nuclear contour irregularity, including irregular blebs and transverse grooves; the cells have sparse cytoplasmic volumes. In contrast, the small cell variant of anaplastic Ki-1 lymphoma manifests cells with round to oval nuclear contours with a finely dispersed primitive (blast-like) chromatin and prominent nucleoli and a distinct rim of eosinophilic cytoplasm. Perhaps more important in the distinction is the expression of cytotoxic proteins TIA-1 and granzyme in cases of anaplastic Ki-1 lymphoma amid the CD30 populace; these cytotoxic makers are not usually expressed in cutaneous pleomorphic T cell lymphoma (Kummer et al., 1997; Kinney and Kadin, 1999).

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 41 year old man with a large cutaneous nodule site undesignated, which erupted over a several week period. Diagnosis: Primary cutaneous pleomorphic small/medium sized T cell lymphoma (Figures 15.3–15.8).

FIGURE 15.3 There is a massive dermal infiltrate that manifests a pushing nodular border at the tissue base with extension into the subcutaneous fat.

FIGURE 15.4 Intermediate power examination reveals an admixture of epithelioid histiocytes, many of which are arranged in cohesive epithelioid granulomata. The degree of histiocytic infiltration would define this lesion as a form of granulomatous peripheral T cell lymphoma/Lennert’s lymphoma.

Higher power magnification reveals that the lymphocytes are in the 7–9 µm size range, manifesting nuclear contour irregularity, although cells with a frankly cerebriform/S´ezary appearance are not identified.

FIGURE 15.6 The majority of the lymphocytes show CD2 immunoreactivity.

FIGURE 15.5

Case Vignette 1

FIGURE 15.7 Higher power magnification reveals that in fact many of the larger atypical cells are CD2 negative. It is not uncommon to see deletions of the pan T cell markers in the setting of peripheral mature post-thymic T cell lymphomas.

A CD7 preparation shows a striking diminution in CD7 expression amid the lymphocytes with many of the cells not manifesting any CD7 immunoreactivity. Nucleolar staining is a common artefact.

FIGURE 15.8

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CASE VIGNETTE 2

The patient is a 43 year old woman with a plaque-like lesion on the lower leg. Diagnosis: Primary cutaneous pleomorphic small/medium sized T cell lymphoma (Figures 15.9–15.15).

FIGURE 15.9

Low power examination reveals a massive dermal infiltrate with a narrow grenz zone of uninvolved papillary dermis.

FIGURE 15.10 The pattern of infiltration is diffuse with prominent involvement of the interstitium associated with focal effacement of the dermal architecture.

The infiltrate is predominated by small mature lymphocytes with nuclear contour irregularity, although cells with a conspicuous cerebriform appearance are not observed. As well, there are admixed epithelioid histiocytes.

FIGURE 15.12

FIGURE 15.11

There is extensive involvement of the subcutaneous fat with lymphocytes permeating and widening the interstitial spaces of the fat.

Case Vignette 2

Examination under 100× objective magnification reveals that the lymphocytes have irregular polylobated nuclear contours.

FIGURE 15.13

FIGURE 15.14 Immunohistochemistry reveals a striking reduction in CD7 expression.

There is also a reduction in CD5 expression, although not to the same magnitude as that observed for CD7.

FIGURE 15.15

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CASE VIGNETTE 3

The patient is a 42 year old man with a several year history of multiple nodular lesions on the extremities and trunk. He also had concurrent lesions of classic lymphomatoid papulosis. Diagnosis: Primary cutaneous pleomorphic small/medium sized T cell lymphoma with CD30 positivity (Figures 15.16–15.21).

The infiltrate surrounds and permeates nerves and blood vessels. There is conspicuous tissue eosinophilia.

FIGURE 15.16

There is a striking pandermal diffuse and nodular lymphocytic infiltrate.

FIGURE 15.17

Higher power (100× objective) magnification shows nuclear contour irregularity, although cells with a frankly cerebriform appearance are not seen.

FIGURE 15.19 A CD30 preparation highlights the larger atypical cells. Nevertheless, the findings are not within the clinical spectrum of lymphomatoid papulosis nor do they fulfill morphologic criteria of anaplastic large cell lymphoma.

FIGURE 15.18

Case Vignette 3

(a)

(b)

FIGURE 15.20 The patient did, however, have lesions compatible with lymphomatoid papulosis, as demonstrated in these images which show psoriasiform hyperplasia with spongiform pustulation associated with a superficial and mid-dermal mixed inflammatory cell infiltrate without dermal effacement.

FIGURE 15.21 A CD30 preparation highlights the superficially disposed aberrant cell population. This patient has an unusual form of primary cutaneous pleomorphic small/medium sized T cell lymphoma, namely, one associated with focal CD30 positivity and in this case with concomitant lesions of lymphomatoid papulosis.

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CASE VIGNETTE 4

The patient exhibited a sudden onset of a cutaneous nodule, clinically held to represent an arthropod bite reaction. Diagnosis: Peripheral T cell lymphoma, unspecified (CD30-negative large cell T cell lymphoma) (Figures 15.22–15.25).

One can see a striking lymphomatoid vascular reaction with obliteration of the vascular architecture undoubtedly resulting in ischemic sequelae as manifested by ulceration with epidermal and dermal necrosis (20× objective magnification).

FIGURE 15.22 There may be prominent angioinvasion leading to extensive epithelial and dermal necrosis, as noted here. This lesion was clinically thought to represent an arthropod bite reaction. However, such cases are to be distinguished from primary cutaneous epidermotropic cytotoxic CD8 lymphoma and NK T cell lymphoma, which does indeed manifest prominent angiotropism.

FIGURE 15.23

An important clue to diagnosing this case as lymphoma is the marked involvement of the subcutaneous fat.

FIGURE 15.25

FIGURE 15.24

Examination under 100× objective magnification highlights the nuclear contour irregularity. However, the cells have polylobated pleomorphic nuclear outlines rather than being distinctively cerebriform, the latter defining the characteristic cytomorphology of mycosis fungoides.

Case Vignette 5

CASE VIGNETTE 5

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The patient is a 63 year old man with a history of cutaneous T cell lymphoma. He has had a relatively indolent course. While he had persistent nodular lesions (Figures 15.26–15.28), he also had other smaller ulcerative papular lesions that underwent a waxing and waning course typical of lymphomatoid papulosis. Diagnosis: Primary cutaneous pleomorphic small/medium sized lymphoma with focal CD30 positivity, possibly representing a more indolent variant of pleomorphic T cell lymphoma (please refer to text for further discussion).

(a)

(b)

FIGURE 15.26 All biopsies appeared similar, showing a superficial and deep angiocentric and periadnexal lymphocytic infiltrate.

The cytomorphology is dominated by a mixture of small and intermediate sized lymphocytes with a finely condensed chromatin and nuclear contour irregularity. Cells with a significant cerebriform S´ezary morphology are not seen. There is also a minor large cell component. With respect to the latter cell populace, the cells are in the 15–20 µm size range, manifesting a vesicular chromatin with conspicuous nucleoli; these cells are CD30 positive. As well, there are admixed plasma cells and eosinophils. Foci of granulomatous inflammation are noted. FIGURE 15.27

FIGURE 15.28 Phenotypic studies were conducted revealing that the infiltrate was CD2, CD3, and CD5 positive. In addition, the CD4 to CD8 ratio was in excess of 4:1 with a substantial deletion of CD7 with less than 10% of the infiltrate manifesting CD7 positivity. Phenotypic studies revealed approximately 20% of the infiltrate to be CD30 positive.

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CASE VIGNETTE 6

The patient is a 40 year old woman who presented with a localized eruption involving the extremity (illustrated in Figure 15.2). Shortly after she developed orbital proptosis and bowel infarction. She died within 6 months of diagnosis. Diagnosis: CD30-negative large T cell lymphoma/peripheral T cell lymphoma, unspecified.

(a)

(b)

The biopsy shows a striking nodular infiltrate spanning the entire sampled dermis and extending into the subcutaneous fat. Unlike classic panniculitis-like T cell lymphoma, there is prominent involvement of the overlying skin by a lymphomatous infiltrate. In classic panniculitis-like T cell lymphoma, there is prominent involvement of the eccrine coil with relative sparing of the overlying superficial dermis and epidermis.

FIGURE 15.29

FIGURE 15.30 Higher power magnification shows large pleomorphic cells. The cells were CD2,CD4, and CD10 positive and failed to show reactivity with CD30.

Additional Molecular and Cytogenetic Study

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FIGURE 15.31 Unlike certain hematologic malignancies, especially those of B cell derivation, from a cytogenetic perspective there are no consistent abnormalities found in patients with primary cutaneous pleomorphic small/medium sized and/or primary cutaneous CD30-negative large T cell lymphoma. Complex karyotypes such as the one exemplified here have been described, especially in patients with malignant lymphoma with a more aggressive clinical course. Among the many abnormalities illustrated in this karyotype is a 6q deletion, which has been observed in more aggressive forms of cutaneous T cell lymphoma. (Cytogenetics interpreted by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

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Primary Cutaneous Pleomorphic Small/Medium Sized T-Cell Lymphoma and Peripheral T-Cell Lymphoma

REFERENCES ANAGNOSTOPOULOS I, HUMMEL M, KAUDEWITZ P, KORBJUHN P, LEONCINI L, STEIN H. Low incidence of Epstein–Barr virus presence in primary cutaneous T-cell lymphoproliferations. Br J Dermatol. 1996; 134(2):276–281. BEKKENK MW, VERMEER MH, JANSEN PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003; 102(6): 2213–2219. BELJAARDS RC, MEIJER CJ, VAN DER PUTTE SC, et al. Primary cutaneous T-cell lymphoma: clinicopathological features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma. J Pathol. 1994; 172(1):53–60. BHUSHAN M, CRAVEN NM, ARMSTRONG GR, CHALMERS RJ. Lymphoepithelioid cell lymphoma (Lennert’s lymphoma) presenting as atypical granuloma annulare. Br J Dermatol. 2000; 142(4):776–780. BRECCIA M, PETTI MC, D’ELIA GM, D’ANDREA M, CARMOSINO I, ALIMENA G. Cutaneous pleomorphic T-cell lymphoma coexisting with myelodysplastic syndrome transforming into acute myeloid leukemia: successful treatment with a fludarabine-containing regimen. Eur J Haematol. 2002; 68(1):1–3. CARROZZA PM, KEMPF W, KAZAKOV DV, DUMMER R, BURG G. A case of S´ezary’s syndrome associated with granulomatous lesions, myelodysplastic syndrome and transformation into CD30-positive large-cell pleomorphic lymphoma. Br J Dermatol. 2002; 147(3):582–586. CHANG SE, JEE MS, KIM KJ, et al. Relative frequency of the different types of cutaneous T cell and natural killer cell lymphomas in Korea based on the proposed WHO classification and the EORTC classification. J Dermatol. 2003; 30(1):42–47. COULSON IW, SANDERSON KV. F cell lymphoma presenting as tumour d‘emblee mycosis fungoides associated with coeliac disease. J R Soc Med. 1985; 78(Suppl 11): 23–24. FRIEDMANN D, WECHSLER J, DELFAU MH, et al. Primary cutaneous pleomorphic small T-cell lymphoma. A review of 11 cases. The French Study Group on Cutaneous Lymphomas. Arch Dermatol. 1995; 131(9):1009–1015. GIANOTTI R, ALESSI E, CAVICCHINI S, BERTI E. Primary cutaneous pleomorphic T-cell lymphoma expressing CD30 antigen. Am J Dermatopathol. 1991; 13(5):503–508. GOLDMAN BD, BARI M, KANTOR GR, KADIN ME, MICAILY B, VONDERHEID EC. Cutaneous multilobated T-cell lymphoma with aggressive course. J Am Acad Dermatol. 1991; 25(2 Pt 2):345–349. JOLY P, VASSEUR E, ESTEVE E, et al. Primary cutaneous medium and large cell lymphomas other than mycosis fungoides. An immunohistological and follow-up study on 54 cases. French Study Group for Cutaneous Lymphomas. Br J Dermatol. 1995; 132(4):506–512. KERL H, CERRONI L. Controversies in cutaneous lymphomas. Semin Cutan Med Surg. 2000; 19(2):157–160. KIESEWETTER F, HANEKE E, LENNERT K, et al. Cutaneous lymphoepithelioid lymphoma (Lennert’s lymphoma). Combined immunohistological, ultrastructural, and DNA-flow-cytometric analysis. Am J Dermatopathol. 1989; 11(6):549–554. KIM YC, VANDERSTEEN DP. Primary cutaneous pleomorphic small/medium-sized T-cell lymphoma in a young man. Br J Dermatol. 2001; 144(4):903–905.

KINNEY MC, KADIN ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol. 1999; 111(1 Suppl 1):S56–67. KUMMER JA, VERMEER MH, DUKERS D, MEIJER CJ, WILLEMZE R. Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype. J Invest Dermatol. 1997; 109(5):636–640. MARZANO AV, ALESSI E, BERTI E. CD30-positive multilobated peripheral T-cell lymphoma primarily involving the subcutaneous tissue. Am J Dermatopathol. 1997; 19(3):284–288. MASSONE C, CHOTT A, METZE D, et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. 2004; 28(6):719–735. MOURAD WA, AL NAZER M, TULBAH A. Cytomorphologic differentiation of Hodgkin’s lymphoma and Ki-1+ anaplastic large cell lymphoma in fine needle aspirates. Acta Cytol. 2003; 47(5):744–748. MUHE JM, LUKOWSKY A, ASADULLAH K, GELLRICH S, STERRY W. Demonstration of frequent occurrence of clonal T cells in the peripheral blood of patients with primary cutaneous T-cell lymphoma. Blood. 1997; 90(4):1636–1642. MURAKAMI T, FUKASAWA T, FUKAYAMA M, USUI K, OHTSUKI M, NAKAGAWA H. Gene expression profile in a case of primary cutaneous CD30-negative large T-cell lymphoma with a blastic phenotype. Clin Exp Dermatol. 2001; 26(2):201–204. NAGASAWA TB, MIWA H, NAKATSUKA S, ITAMI S, YOSHIKAWA K, AOZASA K. Characteristics of cutaneous lymphomas in Osaka, Japan (1988–1999) based on the European Organization for Research and Treatment of Cancer classification. Am J Dermatopathol. 2000; 22(6): 510–514. NAGORE E, LEDESMA E, COLLADO C, OLIVER V, PEREZPEREZ A, ALIAGA A. Detection of Epstein–Barr virus and human herpesvirus 7 and 8 genomes in primary cutaneous T- and B-cell lymphomas. Br J Dermatol. 2000; 143(2):320–323. O’QUINN RP, ZIC JA, BOYD AS. Department of Medicine (Dermatology), Mycosis fungoides d’emblee: CD30negative cutaneous large T-cell lymphoma. J Am Acad Dermatol. 2000; 43 (5 Pt 1):861–863. SANYAL B, MATHWIA V, GUPTA IM, GUPTA OP. Mycosis fungoides (d’emblee type) of the paranasal sinules. Ear Nose Throat J. 1980; 59(12): 499–501. SCARABELLO A, LEINWEBER B, ARDIGO M, et al. Cutaneous lymphomas with prominent granulomatous reaction: a potential pitfall in the histopathologic diagnosis of cutaneous T- and B-cell lymphomas. Am J Surg Pathol. 2002; 26(10):1259–1268. SLATER DN. The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005; 153(5):874–880. TOONSTRA J, VAN DER PUTTE SC, KALSBEEK GL. Multilobated cutaneous T cell lymphoma. Report of two cases resembling Crosti’s reticulosis. Dermatologica. 1983; 166(3):128–135.

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PUTTE SC, TOONSTRA J, DE WEGER RA, VAN JA. Cutaneous T-cell lymphoma, multilobated type. Histopathology 1982a; 6(1):35–54. VAN DER PUTTE SC, SCHUURMAN HJ, TOONSTRA J. Cutaneous T-cell lymphoma, multilobated type, expressing membrane differentiation antigens of precursor T-lymphocytes. Br J Dermatol. 1982b; 107(3): 293–300. VAN DER VALK PG, HOLLEMA H, VAN VOORST VANDER PC, BRINKER MG, POPPEMA S. Sjogren’s syndrome with specific cutaneous manifestations and multifocal clonal T-cell populations progressing to a cutaneous

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pleomorphic T-cell lymphoma. Am J Clin Pathol. 1989; 92(3):357–361. VOCKS E, HERTENBERGER B, WORRET WI, KAUDEWITZ P, FELLBAUM C, RING J. An unusual cutaneous T cell lymphoma presenting as leonine facies. Eur J Dermatol. 2000; 10(4):309–312. WILLEMZE R, BELJAARDS RC, MEIJER CJ. Classification of primary cutaneous T-cell lymphomas. Histopathology. 1994; 24(5):405–415. WILLEMZE R, JAFFE ES, BURG G, et al. WHO–EORTC classification for cutaneous lymphomas. Blood. 2005; 105(10):3768–3785. Epub 2005 Feb 3.

CHAPTER SIXTEEN

ADULT T CELL LEUKEMIA/LYMPHOMA Cynthia M. Magro

Clinical Features Adult T cell leukemia/lymphoma was first detailed in 1977 representing a (Uchiyama et al., 1977) (Table 16.1). Neoplasm of mature helper CD4 T lymphocytes for which human T cell lymphotropic virus type 1 (HTLV-1) is the proven etiologic agent (Uchiyama et al., 1977; Fujihara et al., 1997). There is a high seroprevalence of HTLV-1 in Japan, the Caribbean, and parts of central Africa, corresponding to the regions where adult T cell leukemia/lymphoma is most common. In the United States the prevalence rate is highest among prostitutes and intravenous drug users in specific regions of the country, such as Newark, New Jersey. The virus is endemic in the southeastern United States (Di Caudo et al., 1996). The neurological disorder tropical spastic paraparesis or HTLV-1-associated myelopathy is the other major disease associated with HTLV-1 infection (Setoyama et al.,1999; Lee et al., 2004; Jeang, 2005; Nicot, 2005). Although HTLV-1 has been implicated in up to 50% of cases of non-Hodgkin lymphoma in the West Indies, it is an uncommon cause of lymphoma in the United States (Wood et al., 1996). HTLV-1 Viral infection may occur early in life, but the disease has a long period of latency. Among the modes of transmission are sexual intercourse, sharing of contaminated intravenous needles, breast

milk, and exposure to blood and blood products (Fujihara et al., 1997; Sharata et al., 1997). It cannot be transmitted using fresh frozen plasma (Okochi et al., 1984). The estimated prevalence rate of adult T cell leukemia/lymphoma in patients infected with the virus is approximately 2.5%. Infection is a long-term process throughout the duration of a patient’s life. Sporadic cases occur in adults in the United States; the average age at which a diagnosis of lymphoma is made is 55 years. The male to female ratio is approximately 1.5:1 (Di Caudo et al., 1996; Taylor and Matsuoka, 2005). There are two broad categories of presentation, namely, as an acute process and as one characterized by a more insidious clinical course (Gning et al., 2003) (Table 16.1). As regards the former, patients present with a sudden onset of fever, lymphadenopathy, hypercalcemia, and peripheral blood involvement; the mortality rate is high (Table 16.2). There is a variant of acute adult T cell leukemia/lymphoma falling under the designation of lymphomatous adult T cell leukemia/lymphoma in which the clinical picture comprises pronounced lymphadenopathy without peripheral blood involvement (i.e., less than 1% abnormal T lymphocytes in the circulation). In this variant, hypercalcemia is uncommon (Setoyama et al., 1997). Median survival in the lymphomatous form of acute adult T cell leukemia/lymphoma is

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 318

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TABLE 16.1 Adult T Cell Leukemia/Lymphoma Clinical Adults Acute: acute leukemic, lymphomatous Insidious: smoldering (<5% circulating neoplastic cells) and chronic types (peripheral blood lymphocytosis); primary skin involvement may be seen Acute features including skin rash, hypercalcemia, lymphadenopathy, hepatosplenomegaly, and peripheral blood involvement Histomorphology Epidermotropic features similar to those observed in mycosis fungoides; however, the cells have a florette polylobated appearance; rare cerebriform variants are described Keratinocyte necrosis may be prominent Deeper seated perivascular lymphocytic infiltrates Granulomatous inflammation in some cases Immunophenotype CD3, CD4 + CD8 − CD62L + CD7 − (rare positive cases) FoxP3 tumor cells are positive Cutaneous lymphocyte antigen positive Genetics Monoclonal integration of HTLV-1 DNA Therapy PUVA for cases restricted to the skin Systemic chemotherapy

TABLE 16.2 Acute Adult T Cell Leukemia/Lymphoma Clinical Features Leukemia Hypercalcemia Lytic bone lesions Hepatosplenomegaly Skin lesions Lymphadenopathy Stage IV Bone marrow

At Presentation (%) 62 73 36 61 61 61 100 58

approximately 10 months. The classic skin lesions seen in acute adult T cell leukemia/lymphoma are purpuric and papulonodular in nature, whereby purpura reflects angioinvasion with associated vascular compromise. In the acute cases, considerable skin disease may be seen at presentation. Vesicular lesions can occasionally develop, reflecting the rapidity of lesional onset along with marked epidermotropism (Uchiyama et al., 1977). The second presentation is a chronic one that in turn is subcategorized into chronic adult T cell leukemia/lymphoma and smoldering adult T cell

leukemia/lymphoma (Table 16.3) (Yamaguchi et al., 1983). The smoldering variant follows an indolent course for decades (Setoyama et al., 1999; Germain et al., 2000). Circulating neoplastic cells comprise less than 5% of nucleated cells in the peripheral blood. Hypercalcemia is not seen. In chronic adult T cell leukemia/lymphoma, skin involvement is prominent, but in addition there is peripheral blood lymphocytosis. Compared to the acute form, circulating abnormal cells are less numerous and hypercalcemia is absent. Regardless of the subtype of adult T cell leukemia, an endogenous state of immune suppression is seen in patients with adult T cell leukemia/lymphoma, as manifested by cutaneous anergy, impaired cellular immune responses, and opportunistic infection (Yamaguchi et al., 1983; Nakasone et al., 1992). Pathology Skin biopsies in adult T cell leukemia/lymphoma resemble those of mycosis fungoides including in the context of a superficial band-like infiltrate with prominent epidermotropism and intraepidermal Pautrier’s-like microabscesses (see Figures 16.1–16.3). At variance with mycosis fungoides is prominent epithelial necrosis and a deep-seated angiocentric

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TABLE 16.3 Smoldering and Chronic Adult T Cell Leukemia/Lymphoma Smoldering Adult T Cell Leukemia/Lymphoma

Chronic Adult T Cell Leukemia/Lymphoma

Normal WBC Blood ATLL <5% No lymphadenopathy Skin rash Normal LDH Survival >2 years No hepatosplenomegaly

Increased WBC Blood ATLL >10% Mild lymphadenopathy Skin rash is variable LDH slightly elevated Survival >2 years Slight hepatosplenomegaly

infiltrate oftentimes accompanied by pronounced angioinvasion (Di Caudo et al., 1996; Yamaguchi et al., 2005). The nuclei of the neoplastic lymphocytes demonstrate a multilobated contour with lobations that impart a floret or flower-like appearance; there is hyperchromasia and prominent nucleolation (see Figures 16.9–16.12) (Fujihara et al., 1997; Setoyama et al., 1998). The cytoplasms may be rather abundant, manifesting a basophilic granular quality with Giemsa staining. While acute adult T cell leukemia/lymphoma is often associated with an epidermis of normal thickness, the typical biopsy from a lesion of chronic smoldering adult T cell leukemia/lymphoma may show prominent acanthosis analogous to the pattern of epidermal hyperplasia that can be seen in mycosis fungoides. Some cases have shown granulomatous inflammation in a fashion reminiscent of Lennert’s lymphoma (Setoyama et al., 1997), while others have reported a pattern of granulomatous inflammation mimicking annular elastolytic granuloma (Kuramoto et al., 1990). The smoldering chronic variants may exhibit only low grade atypia, best appreciated under oil immersion (100 × objective) magnification (Germain et al., 2000). Occasionally, a giant cell morphology may be seen (Sakuma et al., 1988). Especially in the chronic variant, cerebriform lymphocytes indistinguishable from those encountered in mycosis fungoides can be observed (Weisenberger et al., 1982). Although the infiltrate is typically dominated by a combination of small and intermediate sized lymphocytes, occasional larger cells may be observed. In the lymph node, the larger cells may be of B cell lineage and appear to be infected with Epstein–Barr virus. They are held to represent the sequelae of diminished immune surveillance due to the underlying lymphoma and are not considered to be neoplastic per se. True neoplastic blasts may also be observed, however, including those that express CD30 (Lee et al., 1997; Nakamura et al., 2002).

Phenotypic Studies The neoplastic cells express CD2, CD3, CD4, and CD5; a CD7 deletion is often noted. Rarely, a CD8positive phenotype is seen (see Figures 16.4–16.6). The cells can manifest increased expression of the interleukin-2 receptor, best evaluated by an antibody to CD25 (Matsushita et al., 1994; Nakase et al., 1994; Lorand-Metze and Pombo-de-Oliviera, 1996). Unlike mycosis fungoides, which typically exhibits a loss of the selectin CD62L, there is no diminution in CD62L expression; in fact, it is expressed at relatively high levels (Tanaka et al., 1997; Magro et al., 2005). There is no expression of cytotoxic proteins TIA-1 and granzyme B (Kikuchi 1997; Kato et al., 2001). Rare cases may exhibit expression of CD30 in the large cells of adult T cell leukemia/lymphoma (Lee et al., 1997). Cutaneous lymphocyte associated antigen (CLA) is expressed at higher levels in peripheral adult T cell leukemia/lymphoma cells from patients with skin involvement compared to cells from those without (see Figure 16.7) (Tanaka et al., 1997). Beta 7 is particularly highly expressed on peripheral adult T cell leukemia/lymphoma cells from patients with gastrointestinal involvement and is expressed at lower levels in those patients with skin involvement only (Tanaka et al., 1997). Selective migration of T cell subsets into peripheral lymph nodes, skin, and gastrointestinal tract mucosa may be determined by heterogeneity of adhesion molecule expression (Tanaka et al., 1997). Pathogenesis In situ hybridization studies reveal expression of HTLV-1 RNA by the neoplastic lymphocytes (see Figure 16.13) (Setoyama et al., 1998). HTLV-1 infects other cell types including B cells and synovial cells, suggesting a more ubiquitous level of expression for its receptor, recently identified as glucose transporter type 1 (Manel et al., 2003). It has been held that HTLV-1 is only integrated into transcription units of

Adult T Cell Leukemia/Lymphoma

dividing cells in contradistinction to HIV, which can infect nondividing cells (Wu et al., 2003). Increasing the level of expression of the receptor with TGF-β or mitogen may enhance infectivity (Jones et al., 2005). HTLV-1 has been shown to induce T cell activation and proliferation mediated by interleukin-2 (Bex and Gaynor, 1998; Hatta and Koeffler, 2002), which in turn is due to the pleiotropic action of tax, one of the HTLV1 viral proteins. Hence, the direct sequel of HTLV-1 infection is the propagation of clonal populations of infected T cells. These clonal populations are detected during the carrier state and do not necessarily manifest malignant transformation. Additional genetic events likely occur that result in the evolution of some of these T cell clones into the hematologic malignancy we know as adult T cell leukemia/lymphoma. The clonal populations are controlled by immune-based cytotoxic T cells, which in turn are stimulated by Tax. Neoplastic evolution is associated with the loss of Tax expression by the cells (Johnson et al., 2001). Tax production can be impaired by genetic changes of Tax, specifically deletion of the 5′ long terminal repeat, and with DNA methylation. Deletion of the 5′ long term repeat, the promoter enhancer for viral gene transcription, is associated with disease progression. Methylation results in silencing of viral gene transcription. By loss of Tax expression the cells may escape immune surveillance mechanisms (Tamiya et al., 1996; Koiwa et al., 2002; Takeda et al., 2004). Additional genetic events that eventuate in neoplastic transformation and/or define genomic characteristics of adult T cell leukemia/lymphoma by virtue of loss or overexpression are those involving p16, p53, TCL1, MEL1S, and EGR3. TCL1, located at the 14q32.1 region, was found to be overexpressed in adult T cell leukemia, indicating that this gene may play an important role in the pathogenesis of this disease (Narducci et al., 1997; Ariyama et al., 1999). The TCL1 locus on chromosome 14 band q32.1 has been implicated in various T cell lymphomas including T prolymphocytic leukemias, acute and chronic leukemias associated with the immunodeficiency syndrome and ataxia-telangiectasia, and adult T cell leukemia. All breakpoints cloned in this area have been mapped to 14q32.1, an area distant by 10,000 kb from the immunoglobulin heavy chain gene locus on chromosome 14q band 32.3 (Virgilio et al., 1993; Ariyama et al., 1999; Johnson et al., 2001; Hatta and Koeffler, 2002; Kwon et al., 2005). p53 mutations and p16 deletions are associated with a poor prognosis (Yamada et al., 1997). Tumor suppressor lung cancer 1 gene (TSLC1) is unregulated in adult T cell leukemia/lymphoma cells; it was originally

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described in lung cancer cells, where loss of its expression was associated with invasive properties of lung cancer cells (Kuramochi et al., 2001). Aberrant expression of MEL1S gene through DNA hypomethylation makes the cells resistant to TGF-β while lack of expression of EGR3 results in inadequate Fas ligand production, hence preventing the cell from dying via activation-induced cell death (Mittelstadt and Ashwell 1998; Tanaka, 2001; Krueger et al., 2003). Recent studies suggest that adult T cell leukemia/ lymphoma cells are likely of T regulatory cell origin (Kohno et al., 2005), a unique cell type known to exhibit an activated helper/inducer T cell phenotype (see Figure 16.14). The expression levels of the T regulatory cell marker Foxp3 and glucocorticoid-induced tumor necrosis factor receptor family related protein (GITR) have been shown to be significantly higher in adult T cell leukemia/lymphoma patients compared to healthy adults. In addition, the same authors showed that the adult T cell leukemia/lymphoma cells are unresponsive in vitro to concanavalin A stimulation and suppress the proliferation of normal T cells. GITR can be induced by HTLV-1 protein tax (Matsubara et al., 2005). The production of chemokines and cytokines by the neoplastic cells has been assessed by ELISA and reverse transcription–polymerase chain reaction after cultivation for 96 hours in the presence or absence of anti-CD3/CD28 monoclonal antibodies. The critical cells express the Th2 chemokine receptor but not necessarily a Th2 cytokine profile. The tumor cells also express thymus and activation-regulated chemokine and macrophage-derived chemokine, which is associated with tumor formation (Shimauchi et al., 2005). Hypercalcemia is a significant feature of adult T cell leukemia/lymphoma and is present in at least 50% of patients at some point during their clinical course. The mechanism of hypercalcemia might be mediated by the expression of parathyroid hormonerelated protein gene in cooperation with IL-1 and TGF-β via the tax protein (Johnson et al., 2001). Concerning a role for HTLV-1 in other lymphomas, a standard polymerase chain reaction/ Southern blot assay showed expression of HTLV-1 proviral pX, POL and ENV genes in the lesional skin of 10% of American patients with mycosis fungoides. With a subsequent modification of the standard assay to destroy low level contamination, only a very small number of cases were positive. The modified UV polymerase chain reaction/Southern blot assay to test an additional 28 cases failed to detect HTLV-1. The consensus is that HTLV-1 is not involved in the pathogenesis of mycosis fungoides (Pancake et al., 1996; Wood et al., 1996, 1997; Zucker-Franklin et al., 2001).

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CASE VIGNETTES CASE VIGNETTE 1

This patient was diagnosed with chronic adult T cell leukemia/lymphoma (chronic smoldering variant) (Figures 16.1–16.7).

There is a band-like lymphocytic infiltrate in intimate apposition to an epidermis showing conspicuous keratinocyte necrosis. The low power pattern resembles a lichen planus-like reaction.

FIGURE 16.1

(a)

Higher power (40× objective) magnification reveals prominent migration of small mature lymphocytes into the epidermis. There is lymphocyte satellitosis around necrotic keratinocytes, a morphologic finding that could be confused with being indicative of an immunologically mediated process.

FIGURE 16.2

(b)

FIGURE 16.3 The infiltrate in the epidermis and dermis is predominated by small mature lymphocytes. The cells have a slightly atypical nuclear contour with irregular lobation; however, a distinctive S´ezary/cerebriform morphology is not present.

Case Vignette 1

FIGURE 16.4

Phenotypic studies were conducted and reveal that the infiltrate is dominated by CD4-positive lymphocytes.

FIGURE 16.5 A CD2 preparation highlights positive staining cells in the dermis and epidermis. However, there are many epitheliotropic lymphocytes in the epidermis that are CD2 negative. This deletion of CD2 is characteristic for more aggressive forms of post-thymic T cell lymphoma.

FIGURE 16.6 Many of the cells within both the epidermis and dermis show intense cytoplasmic immunoreactivity with a monoclonal antibody to CD7. This is one of the rare cases where there is CD2 diminution but maintenance of CD7 expression.

As with many primary epitheliotropic T cell lymphomas, the cells are intensely cutaneous lymphocyte antigen (CLA) positive. FIGURE 16.7

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CASE VIGNETTE 2

The patient is a 24 year old woman who presented with generalized lymphadenopathy, skin rash, and severe peripheral blood lymphocytosis. Diagnosis: Acute adult T cell leukemia and lymphoma (Figures 16.8–16.10).

FIGURE 16.8 The lymph node architecture is effaced. As with many post-thymic T cell malignancies, there is neovascularization.

(a)

FIGURE 16.9 A population of pleomorphic smaller and intermediate sized lymphocytes is observed.

(b)

FIGURE 16.10 The nuclei are polylobated. The excessive degree of nuclear infoldings and nuclear surface irregularities, imparts a granulocyte appearance to the cells.

Case Vignette 3

CASE VIGNETTE 3

The patient presented with classic features of acute adult T cell leukemia/lymphoma with prominent peripheral blood involvement. Diagnosis: Acute adult T cell leukemia/lymphoma (Figures 16.11–16.14).

The marrow aspirate contains a number of hyperlobated atypical lymphoid forms.

FIGURE 16.11

(a)

(b)

FIGURE 16.12 The peripheral blood shows atypical lymphocytes characteristic of acute adult T cell leukemia/lymphoma. The 16.12b is provided by Dr. Wayne Tam, Weill Medical College of Cornell University.

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(Continued)

RT in situ hybridization for HTLV-1 shows positive staining of many of the lymphocytes. (Image provided by Dr. Gerard Nuova) FIGURE 16.13

FIGURE 16.14 The cells are positive for Fox P3, a marker of T regulatory cells. Adult T cell leukemia/lymphoma is now considered a neoplastic disorder of T regulatory cells.

References

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ANGIOIMMUNOBLASTIC LYMPHADENOPATHY (AILD)/ANGIOIMMUNOBLASTIC T CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Clinical Features The term angioimmunoblastic lymphadenopathy with dysproteinemia was coined by Frizzera, Moran, and Rappaport in 1974 (Frizzera et al., 1974). This is a rare acute systemic disorder characterized by marked constitutional symptoms, fever, polyclonal hypergammaglobulinemia, Coombs-positive hemolytic anemia, and generalized tender lymphadenopathy; hepatosplenomegaly is common (Table 17.1) (Sallah and Gagnon, 1998; Sallah et al., 2000; Ferry, 2002). The majority of patients with angioimmunoblastic lymphadenopathy are middle aged or elderly, but it has been reported in children (Schotte et al., 1992). The syndrome is usually precipitated by drug ingestion; among the most commonly implicated agents are penicillin, doxycycline, sulfonamide, dilantin, macrolides, allopurinol, and halothane (Irino et al., 1981; Sasaki and Sumida, 2000; Batinac et al., 2003). Patients may have an established history of drug hypersensitivity. It has also been described in patients with other forms of hematologic dyscrasia (Gaulier et al., 2000). Initially, the disorder was thought to

be a reactive immune response to an unknown stimulus with a high potential for malignant transformation. It is now evident that angioimmunoblastic lymphadenopathy follows an aggressive course in 80% or more of cases, with a median survival of less than 3 years, especially if complete response with chemotherapy is not achieved. The WHO has recognized this distinctive condition as a form of peripheral T cell lymphoma and thus the new terminology: angioimmunoblastic T cell lymphoma. Most patients succumb to infection (Frizzera et al., 1974; Jaffe, 1995; Siegert et al., 1995; Sallah and Gagnon 1998; Mihaljevic et al., 1999; Sallah et al., 2000; Ferry, 2002). Originally thought to be a disease of B cell derivation, immunologic and molecular studies have since shown most cases to be T cell clonal disorders with the majority of cases manifesting rearrangement of the T cell receptor gene (Vrsalovic 2004, Smith 2000). However, cytogenetic and molecular studies have consistently shown chromosomal abnormalities and monoclonal or oligoclonal B cell populations

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 329

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TABLE 17.1 Angioimmunoblastic T Cell Lymphoma Clinical Adults Acute systemic disorder Marked constitutional symptoms, fever, polyclonal hypergammaglobulinemia, Coombs-positive hemolytic anemia, and tender generalized lymphadenopathy Hepatosplenomegaly is common Sudden onset macular/papular skin rash Positive autoimmune serologies are common Temporally associated with drug therapy: penicillin, doxycycline, sulfonamide, dilantin, macrolides, allopurinol, or halothane Histomorphology Small to medium sized pleomorphic lymphocytes, plasma cells, eosinophils, histiocytes, and immunoblasts The infiltrate can be superficially confined Neovascularization Histology may resemble a lymphomatoid hypersensitivity reaction Immunophenotype CD3+, CD4+, CD5+ CD8− CD10+ CD7− and CD62L− EBV+/CD20+ cells (non neoplastic component) CD21+ antigen presenting dendritic cells in clusters (nonneoplastic component) Genetics Monoclonal rearrangement of the T cell receptor gene(s) and potentially an IgH rearrangement as well Therapy Systemic steroids, interferon-α, chemotherapy

(Brauninger et al., 2001) with one study reporting an incidence of 16.6% (Vrsalovic 2004). Only 25% of patients achieve complete and sustained remission when combined chemotherapy agents are used; therapeutic options in addition to multiagent chemotherapy include glucocorticoids and interferon-α (Jaffe, 1995; Pautier et al., 1999). It seems likely that angioimmunoblastic lymphadenopathy develops in a multistep fashion (Figure 17.1). Patients have evidence of T cell dysfunction characterized by anergy to a variety of stimuli that would normally evoke a cell-mediated immune reaction. Corroborative of underlying immune dysregulation are features of an autoimmune diathesis such as systemic antineutrophilic cytoplasmic antibody-associated necrotizing vasculitis or cutaneous confined vasculitis, including IgA-associated vasculitis (Arlet et al., 1982; Garcia Bragado et al., 1983; Simon et al., 1983; Hamidou et al., 2001; Sugaya et al., 2001), dermatomyositis (Hashefi et al., 2000), cold agglutinins (Papineschi J et al., 1984) and cryoglobulins (Molina Boix et al., 1984), circulating immune complexes, smooth muscle antibodies, a positive rheumatoid factor, and antinuclear antibodies (Siegert et al., 1995). Kaposi’s sarcoma has also been

reported. (Tosi et al., 1979; Suster et al., 1987; Cazzola et al., 1982). Subsequent antigenic exposure in the context of drug therapy or viral infection that provokes an excessive T cell response could then theoretically lead to the emergence of clonal T cell infiltrates at various organ sites. Epstein–Barr virus (EBV) has been detected in several cases studied, although the dominant localization appears to be in B cells instead of T cells (Brown et al., 2001). Other implicated viruses include HTLV-1 and cytomegalovirus (Kozuru et al., 1996; Yu AM et al., 1992). Given the abnormalities in T cell suppressor function, there may be an aberrant and excessive T cell immunologic response to a few EBV-infected B cells. A second mutagenic ‘‘hit’’ then might lead to the selection and oncogenic transformation of a specific T cell clone. Early intervention with corticosteroids seems a logical step if downregulation of the hyperimmune response might then inhibit the progression of the monoclonal phase of the disease. The prelymphomatous phase is likely reflected in those cases that are either oligoclonal or polyclonal by polymerase chain reaction. Despite a trigger that clearly provokes a reactive process ab initio, the prognosis at best is guarded with a median

Angioimmunoblastic Lymphadenopathy (AILD)/Angioimmunoblastic T Cell Lymphoma

survival of 23 months after diagnosis. The commonest cause of death is one related to sepsis (Jaffe, 1995). Skin rashes occur in 50% of cases and include a macular and/or papular eruption and a generalized petechial rash (Bernstein et al., 1979; Seehafer et al., 1980; Schotte et al., 1992; Mahendran et al., 2001; Murakami et al., 2001; Cerroni et al., 2004). The more common morbilliform rash closely resembles a viralor drug-induced exanthem (Table 17.1) (Yoon et al., 2003). Light Microscopic Findings The lymph node changes are characteristic. There is expansion of the paracortex by an arborizing network of hyalinized postcapillary venules in concert with a pleomorphic mixed infiltrate of small mature lymphocytes, plasma cells, and transformed lymphocytes with a variable admixture of eosinophils. Recognizing that this process represents, at its inception, an aberrant immune reaction, it is not surprising that hyperplastic germinal centers are present in lymph node biopsies in some patients (Frizzera et al., 1974; Jaffe, 1995, Ree et al., 1998, 1999; Kojima et al., 2001). One considers a diagnosis of angioimmunoblastic T-cell lymphoma when there are sheets of immunoblasts that are at least 200 µm in diameter. In addition, there is a striking hyperplasia of dendritic cells as highlighted by a CD21 preparation. Characteristically, sprouts of CD21-positive follicular dendritic cells extend beyond the confines of the germinal centers and occasionally envelop small blood vessels to generate a concentric array around proliferating postcapillary venules; some have postulated that these CD21-positive cells are fibroblasts overexpressing CD21 (Jones et al., 1998). Grading of angioimmunoblastic lymphadenopathy is generally not performed. An increase in immunoblasts may be observed over time (see Figures 17.7–17.9 and 17.13–17.15). The skin findings are those of a nonepidermotropic ‘‘lymphomatoid’’ vascular reaction. Specifically, there is a mixture of small lymphocytes and atypical large lymphocytes including cells with an immunoblastic and centroblastic morphology, which are found in close apposition to blood vessels (see Figures 17.2 and 17.11) (Martel et al., 2000). The endothelial cells appear proplastic, manifesting hyperplasia and enlargement. Scattered eosinophils and plasma cells are present. There may be increased vascularity and/or concomitant injurious vascular changes characterized by mural fibrin deposition and erythrocyte extravasation (see Figures 17.11) (Martel et al., 2000; Brown et al., 2001; Murakami et al., 2001). The proliferation index may be high (see Figure 17.12).

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In biopsies procured at an early stage in development, the changes are often subtle; typically, the differential diagnosis in those cases is one of a delayed dermal hypersensitivity reaction (see Figure 17.2) (Schmuth et al., 1997; Huang et al., 2004). In more advanced cases the infiltrate may assume a diffuse pattern (see Figure 17.10). Primary cutaneous B cell lymphoma has been described in the setting of angioimmunoblastic lymphadenopathy (Viraben et al., 1998). Unusual presentations include scleromyxedematous lesions with a concomitant serum monoclonal gammopathy and Grover’s disease (Rahmani et al., 1983; Zelickson et al., 1989). Phenotypic Profile The infiltrates in both the skin and lymph node are predominated by mature T cells, primarily of CD4 phenotype (see Figures 17.3 and 17.5); characteristic is the presence of CD10 positivity amid the neoplastic T cells. Loss of other pan T cell markers such as CD7 and CD62L is common (see Figure 17.4). However there can be variation in the extent of CD4 expressions (Lee SS et al., 2003). The CD10 positive staining cells are those with clear cytoplasms (see Figures 17.3 and 17.5) (Attygalle et al., 2002). The expression of CD10 is of interest not only in terms of devising potential treatment strategies but also sheds light on pathogenesis. CD10 is a 100 kDa integral membrane protein with neutral endopeptidase activity originally discovered on the surface of acute lymphoblastic leukemia cells. It is apparent that normal cells at certain stages of maturation or function can demonstrate CD10 expression (Conde-Sterling et al., 2000). In hematopoietic cells, CD10 has been described in immature T and B cells, B cells of the germinal centers of lymphoid follicles, granulocytes, and the cells of select lymphoid malignancies, specifically angioimmunoblastic lymphadenopathy and lymphoblastic lymphoma (Cutrona et al., 1999; Bladon and Taylor, 2000; Conde-Sterling et al., 2000; Cutrona and Ferrarini, 2001; Attygalle et al., 2002, 2004; Morabito et al., 2003). A growing body of literature on the pathophysiologic significance of CD10 expression suggests that it relates to apoptosis as opposed to being a marker of stage of differentiation. For example it is found only in those cells within germinal centers that are undergoing apoptosis (Cutrona et al., 1999; Bladon and Taylor, 2000; Cutrona and Ferrarini, 2001; Morabito et al., 2003). A characteristic feature of Burkitt’s lymphoma cells is apoptosis; not surprisingly, this tumor expresses abundant CD10 (Cutrona et al., 1995). B cells induced into apoptosis by human immunodeficiency virus (HIV) infection in vitro express CD10. Similarly

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A 31 year old man with angioimmunoblastic lymphoma had chest computerized tomography that showed new right axillary lymphadenopathy and stable mediastinal lymphadenopathy.

FIGURE 17.1

mature T cells induced to undergo apoptosis also express CD10. The neutral endopeptidase activity results in the cleavage of proteins with inflammatory or proinflammatory activity released by dying T cells. Thus CD10, while not directly triggering apoptosis, represents an inhibitor of the inflammatory milieu triggered by the apoptotic environment. CD10 may also degrade cytokines that would normally inhibit T cell apoptosis, thereby potentiating an alternative pathway to promote apoptosis (Cutrona et al., 1999). Another characteristic feature of angioimmunoblastic lymphadenopathy is prominent interfollicular dendritic cell hyperplasia. An invariable accompaniment are scattered desmin-expressing dendritic reticulum cells that manifest long, attenuated cytoplasmic processes. Such cells are not seen in other forms of peripheral T cell lymphoma, at least to the degree encountered in patients with angioimmunoblastic lymphadenopathy (Jones et al., 1998). This dendritic cell populace is highlighted by the CD21 stain (see Figure 17.9). Some authors have suggested that these cells are fibroblasts overexpressing CD21. Recently described in patients with angioimmunoblastic lymphadenopathy are circulating peripheral blood lymphocytes that manifest intracellular CD3 expression in the absence of surface CD3. These cells are of the CD4 subset and do not express CD7 or CD2. It has been hypothesized that these circulating cells are the malignant peripheral blood

counterpart of the tissue infiltrates in patients with angioimmunoblastic lymphadenopathy (Serke et al., 2000). With respect to EBV expression, one characteristically observes a few transformed B cells expressing EBV latent proteins but such cells are not held to be neoplastic in nature. One case report indicates that the neoplastic and/or prelymphomatous T cell infiltrate can show EBV expression in roughly 50% of the cells in a given skin biopsy (Brown et al., 2001); this study emphasized the heterogeneity in expression, with some biopsies showing few positive staining cells in skin biopsies procured at an earlier time. Molecular Studies Genotypic studies are variable. There may be an absence of clonality, or clonal restriction of B or T cells, or both together; prior clones can disappear and new ones may appear (Gaulier et al., 2000; Smith et al., 2000; Willenbrock et al., 2001). Patients who have rearrangements of both the T cell receptor and heavy immunoglobulin chain genes have a worse prognosis. In prelymphomatous angioimmunoblastic lymphadenopathy, oligoclonality may be observed rather than a monoclonal pattern (Lipford et al., 1987; Suzuki et al., 1987). In the study by Lipford and co-workers, lymph nodes and peripheral blood from patients were found to contain clones of lymphoid cells harboring either immunoglobulin or T cell receptor gene rearrangements that could regress

Angioimmunoblastic Lymphadenopathy (AILD)/Angioimmunoblastic T Cell Lymphoma

during the course of disease (Lipford et al., 1987). In the study by O’Connor and co-workers (1986) of 25 cases of angioimmunoblastic lymphadenopathy, 19 cases showed a rearrangement of the T cell receptor β chain, and one case showed a clonal rearrangement of the immunoglobulin gene (O’Connor et al., 1986). In another report the concomitant heavy chain immunoglobulin rearrangement was attributable to a supervening low grade B cell lymphoproliferative disorder (Christopoulos et al., 2001). Pathogenesis Transformation into lymphoma likely occurs when the overly reactive clone, responding to an antigen, becomes susceptible to genetic errors such as chromosomal translocations and deregulation of oncogenes during cell divisions (Schlegelberger et al., 1996). This situation may be analogous to rare cases of clonally restricted T cell infiltrates temporally associated with drug therapy that subsequently evolve into lymphoma. One could surmise that treatment in a prelymphomatous phase might prevent or hinder progression to angioimmunoblastic T cell lymphoma. The exact inciting trigger leading to evolution into lymphoma is unclear. One could postulate a role for EBV infection but in point of fact the majority of the EBV-infected cells, at least in this setting, are of B cell derivation and unrelated to the neoplastic populace. In particular, most EBV-infected cells carry mutated immunoglobulin genes, indicating that in angioimmunoblastic lymphadenopathy EBV preferentially resides in memory and/or germinal center B cells (Brauninger et al., 2001). In one study on B immunoblastic lymphoma developing in a background of angioimmunoblastic lymphadenopathy, clonal EBV integration was observed (Brauninger et al., 2001; Zettl et al., 2002).

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Human herpesvirus-8 (HHV-8) DNA sequences have been reported to be strictly associated not only with various forms of Kaposi’s sarcoma but also with an unusual subgroup of acquired immunodeficiency syndrome (AIDS)-related B cell lymphomas. A putative association with Castleman’s disease has also been made. HHV-8 and HHV-6 DNA sequences have been detected in lymphoid tissues of patients with angioimmunoblastic lymphadenopathy. In reactive lymphadenopathies, the HHV-6 late antigenexpressing cells include plasma cells, histiocytes, and rare granulocytes in interfollicular areas and within cells that neither have an atypical cytomorphology nor appear transformed. Such findings argue against a major pathogenetic role for the virus in lymphomagenesis (Luppi et al., 1996, 1998; Vrsalovic et al., 2004). A recent study used complementary DNA microarrays to reveal significant expression of chemokines including macrophage inhibitory protein and tumor necrosis factor β (TNF-β). There is overexpression of certain cytokines including TNF-α, TNF-β, interleukin-6 (IL-6), and IL-1b (Yamuguchi et al., 2000). Expression of certain cytokines such as macrophage inflammatory protein, an apoptosis inhibitory protein, and IL-16 could be associated with a more aggressive clinical course (Murakami et al., 2001). The proliferation of arborizing postcapillary venules in angioimmunoblastic lymphadenopathy may reflect the elaboration of a vascular growth factor. Mast cells may also play a role in angiogenesis. They are of high density in biopsies of angioimmunoblastic lymphadenopathy and it has been shown that mast cells exhibit expression of vascular endothelial cell growth factor at higher levels, accounting for the potential synergy between mast cell count and vascular density (Jones et al., 2000; Fukushima et al., 2001).

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CASE VIGNETTES CASE VIGNETTE 1

A 32 year old man presented with clinical features of angioimmunoblastic lymphadenopathy including lymphadenopathy, hemolytic anemia, and positive Epstein–Barr virus serology. The lymph node from the patient illustrated in Figures 17.2–17.5 shows typical changes of angioimmunoblastic lymphadenopathy. (see Figures 17.6–17.9)

There is a superficial perivascular mononuclear cell infiltrate that would raise consideration to a form of lymphomatoid hypersensitivity. Careful inspection under oil immersion (100× objective) magnification reveals a polymorphous and pleomorphic mononuclear cell infiltrate, which obscures the vascular architecture. As well, there is focal tissue eosinophilia.

FIGURE 17.2

FIGURE 17.4 There is a substantial diminution in pan T cell marker expression. This illustration shows a reduction in CD7 expression.

FIGURE 17.3

The infiltrate is a CD3-dominant T cell

infiltrate.

The infiltrate is composed primarily of cells of the CD4 subset.

FIGURE 17.5

Case Vignette 1

FIGURE 17.6 The germinal centers are atrophic. The paracortex shows numerous small blood vessels. Unlike the case illustrated in Case Vignette 3, the immunoblastic cell populace is less conspicuous. This case truly has features of so-called angioimmunoblastic lymphadenopathy as opposed to frank lymphoma, although it is now recognized that even these earlier, less severe morphologic expressions of the disease process are associated with an equally grave prognosis.

FIGURE 17.7 The germinal center has features reminiscent of Castleman’s disease, namely those of a sclerosing, atrophic germinal center with hyalinizing neovascularization.

Higher power magnification reveals a proliferation of small capillaries in concert with scattered large atypical immunoblastic forms.

FIGURE 17.8

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(Continued)

(a)

(b)

A CD21 preparation reveals a very distinctive pattern, namely, one of extensive paracortical dendritic cell hyperplasia. A comparable phenomenon may be observed in skin biopsies of patients with angioimmunoblastic lymphadenopathy.

FIGURE 17.9

Case Vignette 2

CASE VIGNETTE 2

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This patient was diagnosed with angioimmunoblastic lymphoma involving skin and lymph nodes (Figures 17.10–17.12).

FIGURE 17.10

There are diffuse dermal sheets of cells.

Angioimmunoblastic lymphoma: surrounding high endothelial venules in this richlyvascular dermal stroma is a polymorphous infiltrate of immunoblasts, plasma cells, histiocytes, and small lymphoid forms.

FIGURE 17.11

FIGURE 17.12 Angioimmunoblastic lymphoma: lymphoid blasts, some in mitosis, are evident. This CD3expressing population showed clonal restriction.

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CASE VIGNETTE 3

The patient has classic angioimmunoblastic lymphadenopathy with extensive lymph node involvement (Figures 17.13–17.15).

FIGURE 17.13 The lymph node shows architectural effacement. There is a diffuse lymphocytic infiltrate with supervening arborizing small blood vessels noted throughout the lymph node.

FIGURE 17.14 Higher power magnification highlights the larger atypical immunoblastic cell populace amid small lymphocytes. The small blood vessels are conspicuous.

FIGURE 17.15 The neoplastic cells have a large rounded blastic appearance, exhibiting a finely divided chromatin.

Case Vignette 4

CASE VIGNETTE 4

The patient has lymph node biopsy-proven angioimmunoblastic lymphadenopathy and presented with a skin rash and concurrent lymph node enlargement (Figures 17.16–17.18).

FIGURE 17.16 A moderately dense angiocentric lymphocytic infiltrate involving the superficial and middermis.

FIGURE 17.17 The infiltrate is composed of mononuclear cells with supervening neovascularization.

FIGURE 17.18 Higher power magnification showed a dominance of small mature lymphocytes with only mild atypia. This case serves to emphasize that the skin findings may at times be nonspecific and resemble a lymphomatoid hypersensitivity reaction. The increased vascularity in areas of lymphocytic infiltration recapitulates the paracortical neovascularization seen in the lymph node of patients with AILD.

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Angioimmunoblastic Lymphadenopathy (AILD)/Angioimmunoblastic T Cell Lymphoma

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CHAPTER EIGHTEEN

CD8 T CELL LYMPHOPROLIFERATIVE DISEASE OF THE SKIN Cynthia M. Magro and A. Neil Crowson

INTRODUCTION In this chapter we review those primary cutaneous lymphoproliferative lesions that derive from CD8 lymphocytes, including neoplastic disorders of CD8 lymphocytes which are primary to the skin and those in which secondary skin involvement is not uncommon. Among these neoplastic conditions are 1. classic primary cutaneous T cell lymphomas representing mycosis fungoides, primary cutaneous pleomorphic T cell lymphoma of the CD8 subset, and/or CD30-negative large cell T cell lymphoma, 2. primary cutaneous cytotoxic aggressive epidermotropic CD8 lymphoma, 3. CD8-positive variants of prolymphocytic leukemia, 4. CD8-positive lymphomatoid papulosis The CD8 variants of γ δ T cell lymphoma, CD8 variant of hydroa-vacciniforme like T cell lymphoma, and CD8 anaplastic large cell lymphoma are considered in different chapters. In addition, we address those infiltrates in which there is an exuberant T cell infiltrate whereby the dominant cell populace is of CD8 lineage and there is accompanying lymphoid atypia but the

process represents a pseudolymphoma. The two main entities that fall under this category are CD8-positive pseudolymphoma related to underlying HIV disease and drug-induced lymphomatoid reactions, which we refer to as reversible T cell dyscrasia. Panniculitislike T cell lymphoma, also of CD8 T cell derivation, primarily involves the subcutis. In this regard, it is considered in a separate chapter.

Primary Cutaneous CD8 Lymphoma The World Health Organization and the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group proposed a classification scheme for primary cutaneous T cell lymphomas (Willemze, 2005) whereby the vast majority comprised resting or activated CD4-positive memory T cells. Nevertheless, there are cases of classic primary cutaneous T cell lymphomas in which the neoplastic cell populace is of the CD8 subtype; these lymphomas include entities that clinically and morphologically are indistinguishable from mycosis fungoides, follicular mycosis fungoides, pagetoid reticulosis, and S´ezary syndrome. In addition, there are specific forms of cutaneous and subcutaneous T cell lymphoma where the CD8 phenotype is a defining hallmark. Due to the heterogeneous presentation of cases published to date, CD8 lymphomas are not included as a separate group by the WHO–EORTC

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 343

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excluding primary cutaneous aggressive epidermotropic CD8 T-cell lymphoma and panniculitis like T cell lymphoma (Berti et al., 1999; Willemze et al., 2005). Many of the primary lymphomas of the skin, which are CD8 positive, manifest cytotoxic features (i.e., they express perforin, TIA, and granzyme) and hence are held to represent the malignant counterpart of cytotoxic CD8 T lymphocytes. There are additional types of cytotoxic lymphocytes, which may define the cell of origin for other types of lymphomas. The three main subsets of cytotoxic lymphocytes are CD8 cytotoxic T cells, natural killer(NK)/NK-like T cells, and CD4-positive cytotoxic T cells. All of these lymphoid lesions manifest cytotoxic protein expression. Perforin is a pore-forming protein that has similarities to the complement fraction C9, expression of which is limited to cytotoxic lymphocytes. Pores are formed in the membranes of the target cells and effector molecules, such as granzyme A and B or T-cell-restricted intracellular antigen (TIA), enter the cytoplasm through the pores and then activate caspases such as CPP32. The perforin/granzyme route and the Fas/Fas ligand system are the two major pathways that mediate the effector functions of cytotoxic lymphocytes. While neoplastic CD8- and CD4-positive T cells show a T cell receptor (TCR) gene rearrangement, true neoplastic NK cells are typically CD3 negative and CD56 positive and do not show TCR gene rearrangement. On rare occasions, NK-like T cells are CD8 positive and will, if clonally restricted, show a TCR gene rearrangement (Nieda M, 2005 and Santucci M et al., 2003). There are no true NK cells that are CD8 positive. The classic lymphomas/leukemias that demonstrate cytotoxic granule expression include large granular lymphocytic leukemia (Osuji et al., 2005 and Sun et al., 1992), enteropathy-associated T cell lymphoma (Kanavaros et al., 2000), hepatosplenic γ δ T cell lymphoma (Kanavaros et al., 2000), nasal and nasal type NK/and NK-like T cell lymphoma (Kanavaros et al., 2000), panniculitis-like T cell lymphoma (Yung et al., 2001), anaplastic large cell lymphoma (Kanavaros et al., 2000), and the related CD30-positive lymphoproliferative disorders, tumor stage mycosis fungoides and a minority of classic Hodgkin lymphoma cases (Asano O 2006). While all of the aforesaid lymphomas may express cytotoxic granules, there is considerable heterogeneity with respect to the cell of origin. The main CD4-positive cytotoxic lymphoproliferative syndromes are primary cutaneous CD30-positive (anaplastic large cell) lymphomas, borderline CD30-positive lymphoproliferative disease (type C lymphomatoid papulosis),

and lymphomatoid papulosis; these lymphoproliferative lesions also express granzyme B and TIA-1 (Boulland et al., 2000). In addition, the progression of plaque to tumor stage mycosis fungoides, a neoplasm typically derived from CD4 lymphocytes, is heralded by the acquisition of cytotoxic properties by the neoplastic CD4 cell population; the acquisition of cytotoxic granule expression may induce apoptosis of anti-tumor immune cells, hence contributing to tumor progression (Vermeer et al., 1999). The NK and NK-like T cell lymphomas have a phenotype characterized by CD56 positivity and are usually CD4 and CD8 negative. They are subcategorized into nasal, nasal type, and aggressive. The NK-like T cell lymphomas are frequently of the γ δ subtype (Santucci, 2003; Liu and McKee, 2002). The topics of mycosis fungoides, NK and NK-like T cell lymphoma, panniculitis-like T cell lymphoma, anaplastic large cell lymphoma, and related CD30-positive lymphoproliferative disease along with Hodgkin lymphoma are considered in other chapters. CD8-positive peripheral T cell lymphomas account for less than 14% of all peripheral T cell lymphomas and have a propensity to involve extranodal sites such as skin, subcutaneous tissue, intestine, lung, soft tissue, orbit, and central nervous system. CD8-positive peripheral T cell lymphomas are derived either from mature CD8-positive αβ T cells with cytotoxic function clearly distinguishable from NK cells or from CD8-positive γ δ T cells. Most γ δ T cells are neither CD4 nor CD8 positive (Toro et al., 2000, 2003). The small percentage that are CD8 positive respond to stimuli with lymphokine production and proliferation and are not simply precursors to αβ T cells. There does not appear to be any association of CD8-positive lymphomas with Epstein–Barr virus infection. Among the distinctive CD8-positive peripheral T cell lymphomas are enteropathy-associated lymphoma, panniculitis-like T cell lymphoma, and primary cutaneous aggressive epidermotropic CD8

TABLE 18.1 Common forms of CTCL Potentially Manifesting a CD8 Profile ∗ Mycosis

fungoides Primary cutaneous pleomorphic T cell lymphoma Anaplastic large cell lymphoma CD30 negative large cell lymphoma Overall the clinical course does not differ from the more common CD4 variants of these forms of CTCL *rare CD8 variants of MF exhibiting CD56 positivity; Clinical course is indolent.

Introduction

T cell lymphoma (Table 18.1). Enteropathy-associated lymphoma is almost invariably associated with celiac disease (Kumar et al., 2001). It is not uncommon for these patients to present simultaneously with both malabsorption attributable to celiac disease and features one associates with lymphoma in the context of abdominal pain and perforation. While there are no reports of enteropathy-associated lymphoma involving the skin, dermatitis herpetiformis could be an associated cutaneous manifestation in this setting. Among our proposed criteria for inclusion as a primary cutaneous CD8 lymphoma regardless of subtype are the following: (1) presentation with skin lesions with no evidence of extracutaneous disease at the time of diagnosis; (2) expression of CD8 antigen along with other T-cell-associated antigens by the neoplastic T cell population. There are two main clinical subgroups of primary cutaneous CD8 T cell lymphoma, one with an aggressive clinical course and the other with a course resembling other more common forms of CTCL such as mycosis fungoides, Woringer–Kolopp disease, and primary cutaneous pleomorphic T cell lymphoma, (Agnarsson et al., 1990; Alaibac and Chu, 1996; Whittam et al., 2000; Dummer et al., 2002) (Table 18.1). The cases that follow an aggressive clinical course have fallen under the designation of primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphoma (Urrutia et al., 1990; Berti et al., 1999). In the seminal paper by Berti and co-workers (1990), nine cases of cytoxic CD8 lymphoma were characterized by a distinctive set of clinicopathological and immunophenotypical features uncharacteristic of other types of CTCL. Among the clinical features was a sudden onset of patches, plaques, and nodules (Berti et al., 1999). Extracutaneous disease was common with characteristic sites of involvement including the lung, testes, central nervous system, and oral cavity, the latter occurring in almost 50% of cases. There was noticeable sparing of lymph nodes. The median survival in these cases was only 32 months (Berti et al., 1999) and the disease was refractory to chemotherapy (Berti et al., 1999; Felgar et al., 1999; Vermeer et al., 1999) (see Table 18.2). As CD8-positive lymphocytes define the reactive lymphocyte population that functions in the normal immunosurveillance of lesions of CD4+ cutaneous lymphoma, some studies have correlated the intensity of the reactive CD8 response to an improved clinical outcome. Hence, a potential diagnostic pitfall lies in those cases of mycosis fungoides in which there may be an exuberant reactive CD8 populace; such cases may be erroneously interpreted as representing a

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TABLE 18.2 Primary Cutaneous Aggressive CD8+ Epidermotropic cell Lymphoma Clinical features Explosive onset of skin lesions Plaques and nodules Extracutanesus dissemination involoving the lung, testes, oral cavity and central nervous system. Median Survival of 32 months Histopathology Prominent epidermotropism Angiocentric infiltrates of markedly atypical cells with cutaneous necrosis Frequent extension into fat Phenotypic profile CD8+, Th1 cytokine profile Granzyme +, Perforin +, TIA + CD7(+/−) Molecular profile Alpha beta or gamma delta

CD8 subtype of cutaneous T cell lymphoma. (Koubek, 1990; Jones et al., 2004). A Th2 dominant cytokine milieu predominates in the setting of CD4-positive malignancies and hence therapies that augment Th1 responses, like retinoids and interferons, may have a beneficial effect on these conditions. In contrast, neoplasms of CD8 derivation produce a Th1-like cytokine profile with enhanced production of IL-2 and interferon-γ , and it is therefore held that treatment with Th1-augmenting regimens could result in a deterioration in clinical status due to promotion of tumor cell growth (Bargetzi et al., 2003). Histomorphology In those cases that clinically resemble mycosis fungoides, including the unilesional variant, the infiltrate is relatively superficial. Epidermotropism may be striking. The dominant cells are intermediate sized lymphocytes in the 9–11 µm size range with convoluted/cerebriform nuclei morphologically indistinguishable from those seen in CD4-positive mycosis fungoides (see Figure 18.17) (Agnarsson et al., 1990). There is a tendency for colonization of the basal layer and prominent pagetoid infiltration. Pautrier’s microabscesses are frequent and there is infiltration of the epidermis by singly disposed tumor cells; perinuclear halos imparting a pagetoid appearance are frequent (see Figure 18.42–18.44). Significant epithelial injury, despite the cytotoxic properties of the cells, is not a feature. Those cases resembling CD4 variants of primary cutaneous pleomorphic T cell

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lymphoma have a superficial and deep perivascular and periadnexal lymphocytic infiltrate with prominent infiltration of the outer root sheath epithelium by lymphocytes. There is only minimal epidermotropism but there can be prominent infiltration of hair follicles by lymphocytes. Unlike mycosis fungoides, the dominant cell population comprises small and intermediate sized lymphocytes with polylobated, noncerebriform nuclei (see Figure 18.4). There are also cases dominated by large cells falling under the designation of CD30-negative large cell T cell lymphoma type unspecified (see Figures 18.39–18.41). In the aggressive variant, there may be acanthosis and pseudoepitheliomatous hyperplasia of the epidermis with epidermotropism in excess of that encountered in typical mycosis fungoides cases, often associated with prominent keratinocyte necrosis and sometimes with subepidermal bulla formation (see Figures 18.1–18.3, 18.10–18.12, 18.14, and 18.15). The infiltrate shows angiocentricity, often with an angioinvasive component resembling a grade III angioimmunoproliferative lesion; deep dermal and subcuticular involvement may be seen. Adnexal tropism with infiltration of the eccrine coil and hair follicle may be striking and has been likened to the morphology of the lymphoepithelial lesion encountered in Sjogren’s syndrome (see Figure 18.10). Some cases show numerous large neoplastic cells with prominent nucleoli. The cytology does not deviate from that of primary mixed and large cell dominant forms of primary cutaneous pleomorphic T cell lymphoma (see Figures 18.4 and 18.12). In cases with subcutaneous involvement, the differential diagnosis is primarily with panniculitis-like T cell lymphoma, but distinction can be made in light of prominent involvement of the dermis and, at times, of the epidermis (Avinoach et al., 1994). Phenotype The cases that clinically and morphologically resemble mycosis fungoides and primary cutaneous pleomorphic T cell lymphoma are characteristically CD2 positive and CD7 negative while the aggressive cases may be CD2 negative with relative preservation of CD7. In our own experience, we have found a CD7 deletion in most of the aggressive variants as well (see Figures 18.6, 18.7, and 18.17) (Berti et al., 1999). Almost all of these lymphomas are CD3 positive (see Figure 18.5). There is a significant reduction in CD62L expression in both aggressive and indolent forms (Magro et al., 2005). In those lymphomas labeled as primary aggressive CD8 cytotoxic lymphoma, the expression of CD45 Ro is typically not seen and the cells are infrequently

granzyme positive (see Figures 18.8, 18.9, 18.13, and 18.16) (Berti et al., 1999). On rare occasions, CD8 lymphomas of the skin will show coexpression of CD20 and/or B cell clonal restriction. There are a limited number of prior citations alluding to the aberrant expression of CD79a and CD20 in peripheral T cell lymphomas (Quintanilla-Martinez et al., 1994; Warzynski et al., 1994; Takami et al., 1998; Blakolmer et al., 2000; Mohrmann and Arber, 2000; Yao et al., 2001). One case that pursued an aggressive clinical course revealed a CD3, CD8, CD43, TIA-1, CD20, CD56, and CD79a-positive phenotype. A second study investigated CD79a and CD20 reactivity in 94 extranodal non-B-cell lymphomas (enteropathy-type intestinal T-cell lymphoma [n = 52], nasal NK/T cell lymphoma [n = 11], and primary cutaneous peripheral T cell lymphoma [n = 31]) and in 17 cases of nodal peripheral T cell lymphoma, type unspecified. One cutaneous peripheral T cell lymphoma had a CD20-positive phenotype while three enteropathy-associated lymphomas and one NK-like T cell lymphoma showed CD79 positivity although in the absence of CD20 expression. All five B cell marker-positive extranodal lymphomas had a CD8 phenotype, similar to our recently reported case (Magro et al., 2006).

CD8 Variant of Lymphomatoid Papulosis and Other Related CD30-Positive T Cell Lymphoproliferative Disorders of CD8 Subtype Lymphomatoid papulosis has a cytomorphology, phenotype, and molecular profile suggesting a malignant neoplastic process but a clinical course that is typical of benign disease, being one of spontaneous regression (see Figures 18.25–18.29) (Kadin, 1986; Karp and Horn, 1994). The basis of its categorization as a form of neoplasia lies in the identification of clonality, features of an aberrant phenotype as defined by a significant diminution in CD7 and CD62L expression, and the identification of a single T cell clone at multiple sites in cutaneous lesions of lymphomatoid papulosis in patients with coexistent primary cutaneous anaplastic large cell lymphoma (Table 18.3) and Hodgkin lymphoma. We have encountered cases of lymphomatoid papulosis that have manifested a CD8 phenotype; in all, the lesions followed a clinical course characteristic for lymphomatoid papulosis. From a clinical perspective, there appears to be a predilection to involve younger men with an onset in childhood (Magro et al., 2006).

Introduction

TABLE 18.3 CD8 Lymphomatoid Papulosis Clinical features Male dominance Younger onset in childhood Clinical course: waxing and waning; No different from other forms of lymphomatoid papulosis Histopathology Lymphocytic and granulomatous eccrinotropic hidradenitis Lack of other inflammatory cell elements such as neutrophils and eosinophils suggesting a different cytokine milieu than classic LYP Phenotypic profile CD8+; rarely with co-expression of CD56. CD30+, granzyme+

Light Microscopic Findings There are four cardinal morphologic clues that may favor the CD8-positive variant of lymphomatoid papulosis over the conventional CD4-positive subtype of lymphomatoid papulosis. First, eosinophils and neutrophils characteristic of classic lesions of lymphomatoid papulosis are not common in the CD8positive variant. Second, striking vasculitic changes are common, the basis of which may be one reflective of the cytokine milieu (see Figure 18.25). Third, cases may show granulomatous inflammation and a dominance of small mature lymphocytes, defining a subtype of lymphomatoid papulosis we refer to as lymphocytic and granulomatous eccrinotropic lymphomatoid papulosis (see Figures 18.26–18.28) (Crowson et al., 2003). Finally, the excessive pleomorphism encountered in type A CD4-positive lymphomatoid papulosis is a less constant feature of CD8 lymphomatoid papulosis (Magro et al., 2006). In CD8 forms of lymphomatoid papulosis, the cytokine milieu associated with the CD8 cell may be the basis for both the composition of the infiltrate and the presence of vascular injury. Specifically, CD8-positive T cells can be classified into at least two functional subsets of CD8 lymphocytes: those producing, high amounts of interferon (IFN)-γ designated as Tc1 and those associated with interleukin (IL)-4, -5 and low IFNγ designated as Tc2. (Willemze et al., 2005). (Delfs et al., 2001; Fischbein et al., 2002; Crowson et al., 2003; Raisky et al., 2003; Schnickel et al., 2004). The granulomatous inflammation and paucity of neutrophils noted in our cases define the expected cytokine milieu if the neoplastic cells are of the Tc1 subset. The differential diagnosis of this variant is one of primary cutaneous aggressive epidermotropic

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CD8-positive T cell lymphoma. Among the differentiating features from cytotoxic CD8 lymphoma is the clinical presentation, which is typical of lymphomatoid papulosis and distinct from aggressive CD8 lymphoma. Furthermore, CD30 positivity is rare in cases of primary cytotoxic CD8 lymphoma. The concomitant granulomatous inflammation with perieccrine coil accentuation, most unusual in CD8 lymphomas, is characteristic for the lymphocytic and granulomatous eccrinotropic form of lymphomatoid papulosis (see Figure 18.29) (Crowson et al., 2003). There is very limited literature precedent on CD8 variants of lymphomatoid papulosis. There are a total of 9 reported cases. Among these cases were a 15 year old girl in whom the lesions developed over 2 weeks (Aoki et al., 2003; Magro et al., 2006), a 40 year old woman with a waxing and waning course over 20 years (Wu and Tsai, 2004), a 4 year old boy, and 4 other cases who were men in their thirties whose clinical course was of years duration without evidence of progression, whereby the lesions responded well to methotrexate. From a morphologic perspective, severe angiodestruction, led the authors to initially consider a form of aggressive angiocentric CD8 lymphoma.

CD8 Prolymphocytic Leukemia T cell chronic lymphocytic leukemia (T-CLL) has recently been reclassified under the heading of T cell prolymphocytic leukemia (T-PLL) because of its unfavorable clinical course, independent of morphologic features (Absi et al., 2005). (See Case Vignettes 4 and 5.) This rare neoplasm usually shows a CD4+/CD8− phenotype. However, there are rare reports describing CD8 expression. (Ascani et al., 1999; Zinzani et al., 1999). Histopathology There are prominent superficial and deep angiocentric lymphocytic infiltrates in the absence of significant epitheliotropism. The infiltrates surround and permeate the cutaneous vasculature although there are no vasculitic alterations (see Figures 18.18, 18.19, 18.22, and 18.23). The cells have a characteristic morphology that allows their easy identification as being prolymphocytic in nature; the cells are small to intermediate in size, exhibit a finely dispersed chromatin with inconspicuous nucleoli, and have eccentrically disposed nuclei with moderate amounts of eosinophilic cytoplasm (see Figure 18.20).

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CD8 Pseudolymphoma Related to Underlying HIV Disease Patients with human immunodeficiency virus (HIV) infection can develop a characteristic skin eruption characterized by massive infiltration of the epidermis and dermis by CD8 lymphocytes, presumably representing a response to HIV-associated viral antigen. (See Case Vignette 7.) After primary HIV infection, there is oligoclonal expansion of HIV-specific cutaneous T lymphocytes within the peripheral blood (see Figures 18.30–18.32). Studies have documented a cutaneous T cell lymphocyte response against viral peptides derived from structural or regulatory HIV proteins in the blood and lymphoid organs. In the same way lymphocytic infiltrates related to immunologically driven responses to viral antigen are the presumptive basis of HIV-associated lymphocytic alveolitis and skin eruptions in simian immunodeficiency virus infected rhesus monkeys (Bachelez et al., 1998; Schwartz, 2003). Of interest, HIV-specific cutaneous T lymphocytes are identified in HIV patients within lesions of lymphocytic alveolitis and the splenic pulp in the setting of splenomegaly and thrombocytopenia (Roos et al., 1994; Hofman et al., 2000). Light Microscopic Findings There is a dense pandermal lymphocytic infiltrate that effaces the architecture and is accentuated around the nerves and the eccrine coil. Prominent exocytosis is seen. The infiltrate has a polymorphous admixture of small to intermediate sized lymphocytes and transformed cells that is concerning for possible lymphoma because of its extensive nature and dermal obliteration (see Figures 18.30 and 18.31).

Phenotypic Studies The infiltrate is of T cell lineage as revealed by expression of CD3 (see Figure 18.33). A normal phenotype is reported. However we have observed a significant diminution in CD7 expression, although with relative preservation of CD62L expression (see Figure 18.34). The main infiltrating T lymphocyte is of CD8 subtype. Molecular Studies Oligoclonality is observed. In one study, the authors described the redundant use of CDR3 amino acid sequences within the BV2, BV6, BV8, and V16 subsets, being highly suggestive of an antigen-driven expansion of CD8 lymphocytes as well as arguing against superantigen stimulation (Bachelez et al., 1998).

CD8 Cytotoxic Pseudolymphoma Related to Drug Therapy We have encountered a number of cases of skin eruptions clinically, histologically, and phenotypically resembling lymphoma, whereby drugs are the implicated trigger (see Figures 18.35–18.38). Such cases fall under the designation of reversible T cell dyscrasias. The majority of these infiltrates are either composed of a mixture of B and T cells and/or are defined by a CD4-dominant T cell infiltrate. However, we have also encountered cases of drug associated pseudolymphomatous infiltrates in which the dominant infiltrate is of CD8 subtype falling under the designation of a CD8 cytotoxic lymphomatoid hypersensitivity reaction.

Case Vignette 1

CASE VIGNETTES CASE VIGNETTE 1

The patient is a 76 year old man with a nodule on the foot. Diagnosis: Primary cutaneous CD8-positive epidermotropic cytotoxic lymphoma (Figures 18.1–18.9).

Sections show psoriasiform hyperplasia of the epidermis with an associated superficial band-like and perivascular lymphocytic infiltrate accompanied by moderate spongiosis. The low power impression of the process may be a reactive dermatosis because of the degree of spongiosis and associated perivascular infiltrate in the sampled dermis.

FIGURE 18.1

FIGURE 18.2 The pattern of infiltration of the epidermis is an epidermotropic one, whereby there are atypical lymphocytes permeating all layers of the epidermis with colonization of the basal layer. This process is largely unaccompanied by significant degenerative epithelial changes excluding some degree of spongiosis.

FIGURE 18.3 The cells are surrounded by discrete halos. There is a tendency for intraepithelial clustering to produce intraepithelial foci reminiscent of a Pautrier’s microabscess; however, the cells, while pleomorphic, are not typical for those encountered in mycosis fungoides.

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CD8 T Cell Lymphoproliferative Disease of the Skin

(Continued)

(a)

(b)

FIGURE 18.4 Higher power magnification (100× objective) shows significant nuclear contour irregularity, whereby many of the cells have prominent atypia. The cells are in the 20 µm size range, manifesting excessive nuclear contour irregularity.

A CD3 preparation reveals that the infiltrate is primarily of T cell derivation.

FIGURE 18.5

The large atypical cells within the epidermis are CD2 negative.

FIGURE 18.6

Case Vignette 1

There is virtually no staining of the infiltrate for CD7.

FIGURE 18.7

A CD8 preparation highlights many of the large atypical cells within the epidermis.

FIGURE 18.8

FIGURE 18.9 Many of these large atypical cells are also granzyme positive, compatible with a cytotoxic CD8 phenotype.

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CASE VIGNETTE 2

The patient is a 43 year old man who presented with a papular lesion on the right lateral aspect of the proximal thigh in May 2004. The case was interpreted as an anaplastic large cell lymphoma due to concomitant CD30 staining within the tumor cells. He had a staging CT scan, which showed increased activity in both testicles and a small lymph node near the midline of the right hemipelvis. The patient was started on CHOP therapy; after four cycles he developed a lesion in the axillary region. Although the patient was initially asymptomatic, he had progressive disease and died 12 months after presentation. Diagnosis: Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphoma (Figures 18.10–18.16).

(a)

(b)

FIGURE 18.10 Low power examination of the thigh lesion reveals a striking infiltrate that spans the entire thickness of the dermis with accentuation around the eccrine coil and hair follicles. There is massive infiltration of the epidermis with attendant surface ulceration. Aggressive cutaneous T cell lymphomas typically show this pattern of pandermal nodular infiltration with angiotropism and adnexotropism, the latter being demonstrated in (b) as well (i.e., there is prominent follicular involvement).

There is striking nodular accentuation around the eccrine coil.

FIGURE 18.11

Higher power magnification reveals excessive pleomorphism of the cells. The cells are intermediate to large in size, manifesting hyperchromasia and nuclear contour irregularity. Although the cells are clearly malignant, there is an element of monomorphism to this infiltrate; in addition, the cells are mononuclear as opposed to being either binucleated or multinucleated, the latter being typical for anaplastic large cell lymphoma.

FIGURE 18.12

Case Vignette 2

(a)

(b)

(c)

(d)

(e) FIGURE 18.13 Phenotypic studies reveal a CD8-positive T cell infiltrate (e) with granzyme expression (c,d), compatible with a cytotoxic phenotype, and as well the cells are CD30 positive (a,b).

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(Continued)

A second biopsy was performed on this patient, showing the epitheliotropic nature of this lymphoma, although accompanied by deeper seated extension of the infiltrate relative to that observed in patch and plaques stages of mycosis fungoides. This purely epidermotropic pattern is reminiscent of Woringer–Kolopp disease.

FIGURE 18.14

Lymphocytes

Higher power magnification (400×) reveals that the dominant epitheliotropic cell populace is a monomorphic one in the 15 µm size range, exhibiting eccentrically disposed reniform nuclei (noncerebriform), identical to the cytomorphology of the cells captured on the earlier biopsy. The degree of epitheliotropism is typically prominent and as noted here the distinction between keratinocytes and infiltrating neoplastic lymphocytes is difficult because of the extensive colonization of the epidermis by atypical cells. The cells lack a cerebriform appearance. FIGURE 18.15

FIGURE 18.16 The majority of the cells in the epidermis and dermis are CD8 positive.

Case Vignette 3

CASE VIGNETTE 3

The patient is a 61 year old woman with a longstanding history of chronic recalcitrant eczematous plaques. The clinical question was one of mycosis fungoides. Diagnosis: CD8 variant of mycosis fungoides (Figure 18.17).

A biopsy shows a superficial bandlike lymphocytic infiltrate with prominent epitheliotropism. The epidermis manifests of attenuation with an overlying hyperkeratotic scale. The degree of epitheliotropism is very striking and exceeds that seen in classic mycosis fungoides. However unlike primary cutaneous CD8 positive epidermotropic cytotoxic T cell lymphoma the cells are cerebriform. The findings were interpreted as representing a CD8 variant of mycosis fungoides. The importance of illustrating this case is to emphasize that a small percentage of cases of MF will be of the CD8 subset and that such staining does not portend a worse prognosis.

FIGURE 18.17

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CASE VIGNETTE 4

The patient is a 68 year old woman who presented with a petechial skin rash. She had a striking peripheral blood lymphocytosis. Subsequent bone marrow examination was also positive for a lymphoproliferative syndrome. Diagnosis: CD8 variant of T cell prolymphocytic leukemia (Figures 18.18–18.21).

Examination under 4× objective magnification reveals a narrow grenz zone of uninvolved papillary dermis with a concomitant dense pandermal interstitial and angiocentric lymphocytic infiltrate.

FIGURE 18.18

FIGURE 18.20 Examination under 40× objective manification reveals that the infiltrate is relatively monomorphic, transgressing the vessel wall although not associated with any vasculitic changes despite red cell extravasation. The cells have features characteristic for a prolymphocytic T cell. In particular, the cells are slightly larger than a red cell (approximately 9 µm in diameter) with a finely dispersed chromatin, reniform to oval, eccentrically disposed nuclei, and abundant homogeneous eosinophilic cytoplasm.

Another biopsy from this same patient shows the dominant angiocentric nature of the infiltrate. Note the grenz zone of uninvolved papillary dermis. Low power examination reveals a pattern of infiltration with concomitant dermal edema that would be characteristic for a reactive process.

FIGURE 18.19

FIGURE 18.21 Oil immersion (100× objective magnification) examination highlights the cytoplasmic staining for CD7. Most post-thymic T cell lymphomas demonstrate a characteristic CD7 deletion. Preservation of CD7 is a feature of prolymphocytic leukemia.

Case Vignette 5

CASE VIGNETTE 5

357

This patient had an unusually aggressive clinical course. A 47 year old man presented in November 2003 with a nonpruritic skin rash. He also complained of fatigue, diaphoresis with athletic participation, dizziness, and headaches. His past medical history was remarkable for lymphoma diagnosed 14 years previously at age 33. His cutaneous examination revealed scattered discrete petechial lesions in a linear array involving the upper back and axilla bilaterally along with purplish discoloration of his face. He then had a rapid downhill course, with a markedly elevated white blood cell count at 399 × 103 /µL. Flow cytometric studies revealed that 99% of the cells were T cells that expressed CD3+,CD5+,CD7+,CD4+,CD8+, and CD52+. He died of multiorgan lymphomatous dissemination. Diagnosis: T cell prolymphocytic leukemia showing coexpression of CD4 and CD8 (Figures 18.22–18.24).

FIGURE 18.22 The biopsy shows the characteristic morphology of T cell prolymphocytic leukemia, which is one of a nodular angiocentric cuff of lymphocytes that surround and permeate the vessels with red cell extravasation.

The cells coexpressed both CD4 and CD8. We have encountered cases that are exclusively CD8 positive. Illustrated is CD4. FIGURE 18.23

FIGURE 18.24 The cells also show coexpression with CD8. This interesting biphenotypic profile is seen in 25% of cases of T cell prolymphocytic leukemia. It is possible that these cases are more closely related to cortical thymocytes than to mature peripheral blood T lymphocytes. Illustrated is CD8.

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CASE VIGNETTE 6

The patient is a 35 year old man with a 2 year history of recurrent papular nodular lesions that first commenced within a few weeks of recurrent infectious mononucleosis. Diagnosis: CD8 variant of lymphomatoid papulosis (Figures 18.25–18.29).

One of the critical aspects is the nodular expansion of the eccrine coil by a mononuclear cell infiltrate manifesting variable atypia. In the CD8 variant other inflammatory cell elements, specifically in the context of neutrophils and eosinophils, may be absent, a sequela of the cytokine milieu associated with the neoplastic CD8 cell populace (please see text).

FIGURE 18.25

Low power examination reveals a necrotizing vascular reaction characterized by angiocentric infiltrates of lymphocytes and histiocytic forms with mural fibrin deposition. Necrotizing vasculitic changes are a characteristic finding in the CD8 variant of lymphomatoid papulosis. An important clue to the diagnosis is pandermal extension of the infiltrate with nodular distortion of the eccrine coil apparent at this magnification. This unusual bottleneck deformity pattern of infiltration is quite characteristic for the eccrinotropic variant of lymphomatoid papulosis.

FIGURE 18.26

Accentuation around the eccrine coil is typical and there may be accompanying granulomatous inflammation. This photomicrograph shows both vasculitis and granulomatous infiltrates.

FIGURE 18.28 Because of the accentuation of inflammation around the eccrine coil, granulomatous infiltrates, and vasculitis, such cases can be misinterpreted as representing a reactive process, especially of infectious based etiology. However, careful inspection will reveal scattered atypical large hematopoietic cells.

FIGURE 18.27

Case Vignette 6

FIGURE 18.29 The phenotypic profile reveals that the atypical cell populace is CD30 and CD8 positive with coexpression of granzyme. Illustrated is CD8.

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CASE VIGNETTE 7

The patient is a 35 year old man with a history of HIV disease who presented with multiple skin nodules. Diagnosis: HIV-associated CD8 pseudolymphoma (Figures 18.30–18.34).

FIGURE 18.30 There is a massive effacing pandermal infiltrate that assumes a nodular configuration as the base is approached. The low power architecture is very concerning for lymphoma.

FIGURE 18.31 There is prominent epitheliotropism with effacement of the dermal–epidermal junction. Prominent migration of lymphocytes into the epidermis is observed.

Higher power examination reveals that the infiltrate represents a mixture of small, intermediate sized and larger lymphocytes with variation in nuclear contours, albeit the cells are not overtly malignant.

FIGURE 18.33

FIGURE 18.32

Phenotypic studies reveal a predominance of CD2- and CD3-positive T lymphocytes of the CD8 subset. Illustrated is CD3.

Case Vignette 7

(a)

(b)

The cells show a loss of CD7. CD7 deletion can be observed in the setting of lymphomatoid hypersensitivity in patients with underlying immune dysregulatory states. Patients with HIV disease have higher numbers of circulating CD7-negative memory T cells. The key in establishing the diagnosis in this case is the extensive CD8 positivity, which is illustrated in (b). FIGURE 18.34

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CASE VIGNETTE 8

The patient is a 55 year old man who presented with infiltrative plaques involving the face and forearms, basically in a photodistribution and temporally associated with ranitidine ingestion. Diagnosis: CD8 variant of drug-associated lymphomatoid hypersensitivity triggered by antihistamine therapy (Figures 18.35–18.38).

The clinical diagnosis was a photoallergic drug reaction versus discoid lupus erythematosus. Low-power examination reveals a dense band-like and perivascular lymphocytic infiltrate involving the superficial and mid-dermis. There is relative sparing of the deeper dermis.

FIGURE 18.35

A critical clue to categorization as a pseudolymphoma is the presence of Langerhans-cellrich vesicles within the epidermis compatible with features of eczematoid hypersensitivity. Please compare these to the Pautrier’s microabscesses illustrated in Chapter 14.

FIGURE 18.36 Examination under 40× objective magnification reveals a dense lymphocytic infiltrate. The adjective ‘‘lymphomatoid’’ is used to describe this process because of the density of infiltration along with supervening lymphoid atypia. The latter is defined by a mixed population of lymphocytes including large immunoblastic forms and smaller lymphoid elements demonstrating nuclear contour irregularity.

FIGURE 18.37

The infiltrate is dominated by CD8positive lymphocytes.

FIGURE 18.38

Case Vignette 9

CASE VIGNETTE 9

363

The patient is a 65 year old woman who first presented in 2001 with a left posterior thigh pea-sized nodule, which initially resembled a mosquito bite and then continued to increase in size. Because the patient was asymptomatic and without evidence of extracutaneous disease, it was decided to treat her with radiation. There was complete regression of the tumor. The left thigh tumor then relapsed in September 2003. The tumor recurred and despite chemotherapeutic intervention has still followed a recurrent course with no evidence of extracutaneous dissemination. She has had a sustained response to Ontak (Figures 18.39–18.41). Diagnosis: Peripheral T cell lymphoma type unspecified (CD30-negative large cell lymphoma) with CD8 positivity typifying the concept that a certain percentage of cutaneous CD8 lymphomas of the skin will represent classic forms of CTCL.

There is a massive dermal infiltrate effacing the architecture, associated with significant epidermotropism.

FIGURE 18.39

FIGURE 18.41

The cells exhibit a monomorphous appearance comprising large lymphoid forms in the 20–30 µm size range, manifesting a vesicular chromatin with thin nuclear membranes and conspicuous nucleoli. FIGURE 18.40

The cells are CD8 positive.

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FISCHBEIN MP, YUN J, LAKS H, et al. Role of CD8+ lymphocytes in chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg. 2002; 123:803–809. JONES D, IBRAHIM S, PATEL K, LUTHRA R, DUVIC M, MEDEIROS LJ. Degree of CD25 expression in T-cell lymphoma is dependent on tissue site: implications for targeted therapy. Clin Cancer Res. 2004; 10(16):5587–5594. KADIN ME. Characteristic immunologic profile of large atypical cells in lymphomatoid papulosis. Possible implications for histogenesis and relationship to other diseases. Arch Dermatol. 1986; 122:1388–1390. KANAVAROS P, BOULLAND ML, PETIT B, ARNULF B, GAULARD P. Expression of cytotoxic proteins in peripheral Tcell and natural killer-cell (NK) lymphomas: association with extranodal site, NK or T gamma delta phenotype, anaplastic morphology and CD30 expression. Leuk Lymphoma. 2000; 38(3–4):317–326. KARP DL, HORN TD. Lymphomatoid papulosis. J Am Acad Dermatol. 1994; 30:379–395. KOUBEK K. [Immunologic classification of lymphoid cells based on the detection of membrane phenotype using monoclonal antibodies in patients with T-lymphoproliferative diseases.] Vnitr Lek. 1990; 36(8):746–752. KUMAR V, RAJADHYAKSHA M, WORTSMAN J. Celiac diseaseassociated autoimmune endocrinopathies. Clin Diagn Lab Immunol. 2001; 8(4):678–685. LIU V, MCKEE PH. Cutaneous T-cell lymphoproliferative disorders: approach for the surgical pathologist: recent advances and clarification of confused issues. Adv Anat Pathol. 2002; 9(2):79–100. MAGRO CM, SACHDEVA MP, COWSON AN, BARUSEVICIUS A, BARAN PN, KOVATICH AJ. The application of a monoclonal antibody to CD62L on paraffin-embedded tissue samples in the assessment of the cutaneous T-cell infiltrates. J Cutan Pathol. 2005; 32(1):12–20. MAGRO CM, CROWSON AN, MORRISON C, MERATI K, PORCU P, WRIGHT D. CD8+ lymphomatoid papulosis and its differential diagnosis. Am J Clin Pathol. 2006; 125:490–501. MOHRMANN RL, ARBER DA. CD20-positive peripheral Tcell lymphoma: report of a case after nodular sclerosis Hodgkin’s disease and review of the literature. Mod Pathol. 2000; 13:1244–1252. NIEDA M. Cytotoxic T lymphocytes Nippor Rinsho 2005; 63:142–148. OSUJI N, MATUTES E, CATOVSKY D, LAMPERT I, WOTHERSPOON A. Histopathology of the spleen in T-cell large granular lymphocyte leukemia and T-cell prolymphocytic leukemia: a comparative review. Am J Surg Pathol. 2005; 29(7):935–941. QUINTANILLA-MARTINEZ L, PREFFER F, RUBIN D, et al. CD20+ T-cell lymphoma. Neoplastic transformation of a normal T-cell subset. Am J Clinical Pathol. 1994; 102:483–489. RAISKY O, SPRIEWALD BM, MORRISON KJ, et al. CD8(+) T cells induce graft vascular occlusion in a CD40 knockout donor/recipient combination. J Heart Lung Transplant. 2003; 22:177–183. ROOS MT, DE LEEUW NA, CLAESSEN FA, et al. Viroimmunological studies in acute HIV-1 infection. AIDS 1994; 8(11):1533–1538.

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WHITTAM LR, CALONJE E, ORCHARD G, FRASER-ANDREWS EA, WOOLFORD A, RUSSELL-JONES R. CD8-positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases. Br J Dermatol. 2000; 143(6):1199–1204. WILLEMZE R, BELJAARDS RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol. 1993; 28(6):973–980. WILLEMZE R, MEIJER CJ. EORTC classification for primary cutaneous lymphomas: the best guide to good clinical management. European Organization for Research and Treatment of Cancer. Am J Dermatopathol. 1999; 21:265–273. WILLEMZE R, JAFFE ES, BURG B, et al. WHO–EORTC classification for cutaneous lymphoma. Blood. 2005; 105:3768–3785. WU WM, TSAI HJ. Lymphomatoid papulosis histopathologically simulating angiocentric and cytotoxic T-cell lymphoma: a case report. Am J Dermatopathol. 2004; 26:133–135. YAO X, TERUYA-FELDSTEIN J, RAFFELD M, et al. Peripheral T-cell lymphoma with aberrant expression of CD79a and CD20: a diagnostic pitfall. Mod Pathol. 2001; 14: 105–110. YUNG A, SNOW J, JARRETT P. Subcutaneous panniculitic Tcell lymphoma and cytophagic histiocytic panniculitis. Australas J Dermatol. 2001; 42(3):183–187. ASANO N, OSHIRE A, NATSUO K, et al. Prognostic significance of T-cell or cytotoxic molecules phenotype in classical Hodgkin’s lymphoma: a clinicopathologic study. J Clin Oncol. 2006; 24:4626–4633.

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SUBCUTANEOUS PANNICULITIS-LIKE T CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

Clinical Features Subcutaneous panniculitis-like T cell lymphoma was first described by Gonzalez and co-workers in 1991. Other cases of panniculitis-like T cell lymphoma antedated this first description, but fell under different designations such as histiocytic cytophagic panniculitis and Weber–Christian disease (Nemesanszky et al., 1976; Achten et al., 1977; Kosztovics et al., 1977; Aronson et al., 1985a,b; Craig et al., 1998; Malaviya et al., 1998). In 1985, Aronson and co-workers described a 36 year old woman with a 6 year history of recurrent panniculitis followed by a sudden worsening of her condition with skin infiltration by malignant lymphocytes and concomitant hemophagocytic syndrome, designating the process as fatal panniculitis. In retrospect, this clinical vignette was characteristic for some cases of panniculitis-like T cell lymphoma (Aronson et al., 1985a). Panniculitislike T cell lymphoma is a form of primary cutaneous T cell lymphoma that shows dominant localization within the fat. It has a predilection for adults in the third to fourth decades of life. The early descriptions emphasize an aggressive clinical course (Burg et al., 1991; Gonzalez et al., 1991; Slater 1993; von den Driesch et al., 1997). There is a slight female predominance, but in our experience the more rapidly progressive and ultimately fatal cases occur more often in men (unpublished observations). In the revised

WHO–EORTC classification, the term subcutaneous T cell lymphoma has been supplanted by subcutaneous panniculitis-like T cell lymphoma. Patients typically present with indurated violaceous plaques most commonly involving the upper arms and thighs (see Figure 19.1). There is an overlap with enigmatic conditions such as lupus erythematosus profundus (also termed lupus profundus), atypical lymphocytic lobular panniculitis, Weber–Christian disease, and histiocytic cytophagic panniculitis. Among the many similarities to lupus profundus are a reproducible tendency to involve the proximal extremities or trunk, exacerbation during pregnancy, accompanying systemic connective tissue disease symptoms such as fever, anorexia, and leukopenia, and, of course, the pathology and molecular findings. Specifically, clonality has been demonstrated in both lupus profundus and panniculitis-like T cell lymphoma (Magro 2001). Some cases of panniculitis-like T cell lymphoma have sufficient clinical and morphologic overlap with lupus profundus that they are initially diagnosed as the latter entity; in one case report, for example, the patient’s biopsies were interpreted by an international lymphoma expert as representing lupus profundus in the face of progressive disease and significant ensuing constitutional symptoms; the patient eventually

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 366

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(a)

(b)

Panniculitis-like T cell lymphoma. The patient had a several year history of plaques and nodules involving the upper thigh and upper arms. In 2003 a biopsy was sent for dermatopathology consultation by an outside lab because of the progressive nature of her lesions. A diagnosis of lupus profundus was made. Eventually, she was seen at a tertiary care center for further assessment. Retrospective review of the earlier biopsy and her more recent one showed classic changes of panniculitis-like T cell lymphoma. There was progressive undermining of the surgical site following biopsy. FIGURE 19.1

succumbed to panniculitis-like T cell lymphoma (Ma et al., 2005). The diagnosis of lupus profundus becomes questionable in such cases when there is lack of responsiveness to traditional therapies such as Plaquenil. In our own experience, constitutional symptoms are uncommon in most cases of lupus profundus and atypical lymphocytic lobular panniculitis and should be an important clinical clue to a diagnosis of panniculitis-like T cell lymphoma. Although it is usually seen in adults, panniculitis-like T cell

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lymphoma is described in children (Ali et al., 2000; Fink-Puches et al., 2004), and there are reports of what we believe to be a precursor lesion, namely that of atypical lymphocytic lobular panniculitis, in children as young as 6 years of age (Magro et al., 2005). While sustained remission has been achieved with chemotherapy, there are still patients with panniculitis-like T cell lymphoma who die of the disease (Au et al., 2000; Wollina et al., 2001). The cause of death is often attributable to hemophagocytic syndrome, the basis of which is the production of a phagocytosis-inducing factor by neoplastic T lymphocytes and where the terminal event typically relates to bacterial or fungal sepsis (Romero et al., 1996; Huilgol et al., 1998). Dissemination to other organ sites is very uncommon. Some, but not all, cases of what was originally termed histiocytic cytophagic panniculitis likely represent subcutaneous panniculitis-like T cell lymphoma. Such cases are ascribed to infection and develop following bone marrow transplantation or represent the rare syndrome of familial erythrophagocytosis (Craig et al., 1998; Yung et al., 2001). The main microbial pathogens implicated in nonneoplastic hemophagocytic syndrome are Epstein–Barr virus, adenovirus, and herpesvirus. Dissemination to lymph nodes and other organs is very uncommon. (Avinoach et al., 1994; Munn et al., 1996; Wang et al., 1996) and usually occurs late in the course of panniculitis-like T cell lymphoma. There are sporadic reports of lung involvement (Guizzardi et al., 2003; Wells et al., 2004; Ma et al., 2005). In one reported case, a patient presenting with dyspnea underwent an open lung biopsy showing changes of bronchiolitis obliterans, which did not remit with prednisone (Wells et al., 2004). The extent of the lung involvement paralleled the skin disease (Wells et al., 2004). An association with capillary leak syndrome has been made (Takimoto et al., 1998). Another uncommon clinical manifestation includes alopecia (Torok and Kirschner, 2002). There are two broad categories of panniculitislike T cell lymphoma, which differ prognostically (Table 19.1). The majority of cases are of the αβ subgroup, while a small subset, representing approximately 25% of cases, are of the γ δ variant (Kumar et al., 1998; Salhany et al., 1998). According to the recent WHO–EORTC classification of cutaneous lymphoma the authors propose restricting the designation of subcutaneous panniculitis like T cell lymphoma to those cases exclusively of the alpha beta T cell phenotype. This chapter primarily focuses on the αβ subtype, while the γ δ form of panniculitislike T cell lymphoma is considered under the topic

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TABLE 19.1 Subcutaneous Panniculitis-like T Cell Lymphoma Clinical Adults, with erythematous plaques and tumors arising preferentially on buttocks and thighs In some a waxing and waning prodrome (possibly representing the entity of atypical lymphocytic lobular panniculitis) and a protracted course In some hemophagocytic syndrome develops; more common in the γ δ variant Two main variants: αβ, which has a more indolent course, and γ δ, which occurs more commonly in males and has an aggressive clinical course including the development of hemophagocytic syndrome (this variant is also considered in Chapters 13 and 21). WHO–EORTC suggests reserving the term subcutaneous panniculitis like T cell lymphoma for the alpha beta variants Histomorphology Nodular and/or diffuse infiltrates within subcutaneous fat; circumferential rimming of adipocytes by neoplastic lymphocytes Cytomorphology: small to medium sized and large pleomorphic cells admixed with variable numbers of macrophages showing erythrophagocytosis Necrosis prominent Small vessel intraluminal and mural fibrin deposition Lower to mid dermal extension characteristically involving the eccrine coil Permeation of the interstition of the dermis by plump rounded histiocytes Immunophenotype CD2− CD3−/+ (the more atypical cells may be CD3−) CD8+ (most cases) βF1+ (majority of cases)/βF1−in γ δ variants CD30− CD56−/+ (majority are negative/CD56+ in γ δ variants) TIA-1+, granzyme +, perforin + CD4−CD8−, small percentage of cases CD4+CD8+, small percentage of cases CD7−,CD62L−, and CD5− (variable loss of these markers) Genetics Monoclonal rearrangement of the T cell receptor gene(s) (αβ vs. γ δ) Therapy Oral steroids; systemic chemotherapy; radiotherapy.

of γ δ T cell lymphoma in Chapter 13. The latter is frequently a form of natural killer-like (NK-like) T cell lymphoma by virtue of CD56 positivity. Characteristically, the patients who have a more indolent waxing and waning course, and achieve remission with combination chemotherapy, have a tumor of the αβ subtype (Go and Wester, 2004). Their disease may be localized to the upper arms and thighs. Typically, the γ δ variant subtype of panniculitis-like T cell lymphoma has an aggressive course with most patients dying within 2 years of presentation (Avinoach et al., 1994; Przybylski et al., 2000; Toro et al., 2000; Hoque et al., 2003). They have widespread lesions with truncal involvement. Those who die characteristically develop hemophagocytic syndrome (Avinoch et al., 1994; Gonzalez 1991; Huilgol 1998). In regard to the waxing and waning course that may presage the αβ variant of panniculitis-like T cell

lymphoma, it is likely that such patients have a preneoplastic indeterminate lymphocytic panniculitis, falling under the designation of atypical lymphocytic lobular panniculitis (Magro et al., 2001) (Magro et al., 2004). It is not uncommon to see foci reminiscent of atypical lymphocytic lobular panniculitis amid an architecture otherwise characteristic for panniculitislike T cell lymphoma. We view atypical lymphocytic lobular panniculitis as the subcuticular equivalent of cutaneous lymphoid dyscrasias which may presage mycosis fungoides such as large plaque parapsoriasis, pityriasis lichenoides, and atypical pigmentary purpura. The topic of atypical lymphocytic lobular panniculitis is given full consideration in Chapter 6. Among the treatment options for panniculitislike T cell lymphoma are multidrug chemotherapy, autologous and allogeneic bone marrow transplantation, and, in more refractory cases, limb amputation

Subcutaneous Panniculitis-Like T Cell Lymphoma

(Haycox et al., 1997; Leonard et al., 2003). The use of allogenic bone marrow transplantation defines a recent advent; in one reported case, a patient underwent a sibling matched allogeneic transplantation using total body irradiation as induction therapy (Leonard et al., 2003). The various chemotherapeutic regimens have included denileukin diftitox, fludarabine, mitoxantrone, and dexamethasone. Morphology Panniculitis-like T cell lymphoma exhibits a variable admixture of pleomorphic small, medium, or large lymphocytes and histiocytes infiltrating the subcutis in a lobular pattern (see Figures 19.2, 19.7, 19.10, 19.11, 19.16 and 19.17). Erythrophagocytosis is a frequent and distinctive finding that defines an important diagnostic clue but is of variable expression from case to case; in some patients it is striking while in other cases the erythrophagocytosis is apparent only after careful analysis. Karyorrhexis and fat necrosis are present in most cases (see Figure 19.2b and 19.3) (Mehregan et al., 1994; Marzano et al., 2000). The fat necrosis is an ischemic sequel of the obliterative vasculopathy seen in most cases; in this regard the pattern can resemble lipomembranous fat necrosis, the classic morphologic expression of subcutaneous anoxia, although more commonly it is a fibrinoid acellular mummification (Ohtake et al., 1998; Weenig et al., 2001). The vasculopathic changes range from a pauci-inflammatory thrombogenic vasculopathy to one characterized by prominent lymphocytic angioinvasion with variable mural and luminal fibrin deposition, defining a lymphomatoid vasculitis (see Figure 19.4). Lymphocytic angioinvasion is particularly striking in the γ δ variants (Munn et al., 1996; Salhany et al., 1998). With respect to cytomorphology, the cells exhibit pleomorphic nuclear contours with many cells showing irregular nuclear blebs and polylobulation (see Figures 19.5, 19.12, and 19.19). The cytoplasms are sightly eosinophilic in quality and show discrete, small vacuoles appreciable only under oil immersion (100× objective magnification), likely reflecting intracytoplasmic cytotoxic granules. There is typically extension into the overlying lower dermis, whereby the dominant infiltrate is localized mainly to the eccrine coil; adventitial dermal infiltration can be striking (see Figure 19.6). Extensive superficial dermal involvement and prominent epidermotropism would not be supportive of a diagnosis of panniculitis-like T cell lymphoma and would be more characteristic for other and more aggressive forms of peripheral T cell lymphoma including any of the NK or NK-like T cell lymphomas, primary cutaneous γ δ T cell lymphoma,

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or primary cutaneous CD8-positive cytotoxic epidermotropic T cell lymphoma, all of which can also show deep dermal and subcutaneous involvement. The more superficial aspects of the dermis are remarkable for a subtle single cell histiocytic infiltrate. There is usually a low-density epitheliotropic infiltrate of atypical lymphocytes within the epidermis but a grenz zone of relatively uninvolved papillary and superficial reticular dermis may be seen. This low density intraepidermal lymphoid populace is likely reactive. The rimming of lymphocytes around individual adipocytes is an almost ubiquitous feature. Characteristically, the cells assume an internal disposition to the adipocyte cytoplasmic membrane as opposed to an extracellular pattern of infiltration within the fat lobule. However, the internal rimming can be seen in other forms of lymphoma involving the fat, lupus profundus and atypical lymphocytic lobular panniculitis. Thus, we do not advocate its use as a specific criterion per se, although it is more common to see this phenomenon of internalization of lymphocytes in cases of panniculitis-like T cell lymphoma (see Figures 19.11 and 19.18) (Salhany et al., 1998; Magro et al., 2004; Lozzi GP et al., 2006). Initially interpreting a case of panniculitis-like T cell lymphoma as representing lupus profundus or the converse may occur. The most important clues to distinguish panniculitis-like T cell lymphoma from lupus profundus include erythrocyte phagocytosis and the absence of both a destructive atrophying interface dermatitis and of reactive germinal centers (see Figure 19.8). The ‘‘bean bag histiocyte’’ is seen with great regularity in both panniculitislike T cell lymphoma and lupus profundus and reflects the phagocytosis of debris by this populace (Haycox et al., 1997; Ikeda et al., 2000). We have encountered lesions of panniculitis-like T cell lymphoma and atypical lymphocytic lobular panniculitis where there is dermal mucin deposition, but in such cases an accompanying destructive interface dermatitis is generally absent and (Mehregan et al., 1994; Marzano et al., 2000; Ma et al., 2005) there are no other clinical features suggestive of lupus erythematosus. Atypical lymphocytic lobular panniculitis is, in our view, a preneoplastic subcutaneous lymphoid dyscrasia in which the density of infiltration and the degree of fat necrosis are much less than that seen in lupus profundus or panniculitis-like T cell lymphoma (Magro et al., 2001, 2004). The degree of cytologic lymphoid atypia is also less than in panniculitis-like T cell lymphoma. While erythrocyte phagocytosis may

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be seen, it is not of the degree seen in panniculitislike T cell lymphoma. The obliterative vasculopathy with angiocentric and intraluminal fibrin deposition seen in both lupus profundus and panniculitislike T cell lymphoma is not seen (Magro et al., 2004). Phenotype Cells often express CD3 and CD8 along with cytotoxic proteins, such as granzyme B, T cell intracellular antigen 1 (TIA-1), and perforin (Kumar et al., 1998; Salhany et al., 1998; Dargent et al., 2001), but are typically CD56 and CD57 negative (see Figures 19.7 and 19.8) (Kumar et al., 1998; Liu and McKee 2002). Ultrastructural studies have confirmed the presence of cytoplasmic granules and active cellular and matrix interactions resembling those encountered in benign cytotoxic CD8 T lymphocytes (Munn et al., 1996; Wang et al., 1996; Dargent et al., 1998; Marzano et al., 2000; Yamazaki, 2002). The cells frequently manifest a deletion of CD5 and CD7 with variable diminution in CD3 expression (see Figures 19.9 and 19.13) (Magro et al., 2004). The nonneoplastic counterpart is a cytotoxic CD8 T cell. The prominent tissue necrosis is likely a combination of ischemia in concert with the inherent destructive properties of the cytotoxic CD8 lymphocytes (Sen et al., 2002). Tumor cell apoptosis is also typical and likely reflects enhanced constitutive expression of the Fas ligand, a member of the tumor necrosis factor (TNF) family. The Ki-67 proliferation index is intermediate to high. Approximately 11% of panniculitis-like T cell lymphomas are of CD4 phenotype, reflecting the neoplastic counterpart of the benign cytotoxic CD4-positive T cell. These cells are known to express Fas ligand but not cytotoxic proteins such as granzyme or TIA. All these armed effector T cells express adhesion molecules such as selectins, addressins, and integrins that allow interactions with ligands expressed on certain cell subsets, leading to specific homing events, possibly explaining the localization of the neoplastic cells to the subcutaneous fat (Go and Wester, 2004). We have encountered two cases of panniculitislike T cell lymphoma associated with hepatitis C infection in which the cells, while manifesting cytotoxic properties, appeared to be of null phenotype in one case as revealed by lack of expression of both CD4 and CD8 and expressed both CD4 and CD8 in another (see Figures 19.14 and 19.15). Both patients were middle aged to elderly women and had a relatively indolent clinical course of lesions over a duration of several years. TCR-β rearrangements were present, suggesting that the neoplastic cell of origin was of the αβ subset. The literature

precedent regarding cytotoxic panniculitis-like T cell lymphomas of the null phenotype is limited. Kumar and co-workers found that all cases of panniculitislike T cell lymphoma showed cytotoxic protein expression as revealed by extensive expression of TIA and granzyme; 3 of 16 cases failed to show significant CD4 or CD8 expression, suggesting a derivation from cytotoxic T cells of the null phenotype (Kumar et al., 1998; Go and Wester, 2004). Molecular Studies Critical to the designation of panniculitis-like T cell lymphoma of the αβ subset is the documentation of a TCR-β rearrangement and/or expression of βF1 by the neoplastic cells (Munn et al., 1996). There is no compelling evidence pointing to a role for Epstein–Barr virus (EBV) genome in the propagation of lesions of panniculitis-like T cell lymphoma (Kumar et al., 1998). Most cases represent neoplasms of T cells expressing the αβ receptor while 25% represent T cells exhibiting the γ δ TCR (Salhany et al., 1998). In general, the γ δ variants, especially those that manifest CD56 expression, follow an aggressive clinical course. Differential Diagnosis Weber–Christian disease is a nebulous condition that in many cases likely represents the recently described form of subcuticular T cell dyscrasia designated indeterminate lymphocytic lobular panniculitis/atypical lymphocytic lobular panniculitis or panniculitis-like T cell lymphoma (White and Winkelmann, 1998; Rehman et al., 2002; Magro et al., 2004). Two other conditions morphologically resembling subcutaneous panniculitis-like T cell lymphoma are atypical lymphocytic lobular panniculitis and lupus profundus (Magro et al., 2004). In our construction, atypical lymphocytic lobular panniculitis likely represents the preneoplastic phase of panniculitis-like T cell lymphoma. There is a morphologic, phenotypic, and genotypic similarity with panniculitis-like T cell lymphoma. The patients typically present with a several year history of plaques and nodules located over the thighs and arms, which follow a waxing and waning course in the setting of an otherwise unremarkable medical history (Figure 19.16). The pathology of atypical lymphocytic lobular panniculitis has common features with panniculitis-like T cell lymphoma that include lymphocytic infiltration of the panniculus, lymphoid atypia, erythrocyte phagocytosis, variable CD5 and CD7 deletion, increased numbers of CD8 lymphocytes, and clonal restriction (see Figure 19.16–19.21). A diagnosis of panniculitislike T cell lymphoma is not rendered in light of the

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absence of constitutional symptoms, the tendency for spontaneous resolution, and the absence of cytopenia. As well there are some distinguishing morphological features including the absence of greater density of infiltration, the lack of ‘‘malignant’’ lymphoid atypia and inconspicuous or absent erythrocyte phagocytosis. Phenotypically, the Ki-67 proliferation index is low and the infiltrate contains a significant number of CD4 lymphocytes; cytotoxic protein granules are not expressed. Infiltration of the dermis and subcutis by plump histiocytes showing erythrocyte phagocytosis is nonetheless common. In addition, interstitial mucin deposition is characteristic, present usually in areas of deeper seated interstitial histiocytic infiltration (Magro et al., 2004). With respect to lupus profundus, this condition also presents with waxing and waning plaques and nodules; however, there are either overlying skin changes diagnostic of lupus erythematosus and/or the patient has a known history of lupus erythematosus. Discriminating light microscopic features include an atrophying interface dermatitis, dermal mucinosis, plasmacellular infiltration, germinal center formation, a positive lupus band test, the absence of red cell phagocytosis, a dominance of CD4 lymphocytes, and the absence of cytotoxic protein granule expression amidst the dominant lymphoid population. There can be significant lymphoid atypia and, from a phenotypic perspective, deletion of CD5, CD7, and CD62L can be seen although not to the same degree as that encountered in panniculitis-like T cell lymphoma. Clonal restriction can be seen in lupus profundus, but more common is the finding of oligoclonality and/or the emergence of a small T cell clone in a polyclonal background. In contrast, in panniculitis-like T cell lymphoma the clonal infiltrate is typically in the context of a minimal polyclonal background (personal observations). The molecular profiles encountered in atypical lymphocytic lobular panniculitis, and lupus profundus are illustrated in Chapters 5 and 6. (Magro et al., 2004).

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Another consideration diagnostically is the NK and NK-like T cell lymphomas involving the subcutis. Both panniculitis-like T cell lymphoma and NK lymphoma may demonstrate prominent involvement of the fat lobule, tissue necrosis, and an admixture of pleomorphic lymphocytes that express TIA. In NK and NK-like T cell lymphoma, the patients present with Stage IV disease with significant extracutaneous dissemination and show extensive dermal involvement, in contrast to the relative confinement of dermal involvement to the adventitia of the eccrine coil in cases of panniculitis-like T cell lymphoma. In addition, most cases of NK lymphoma exhibit EBV positivity, which is distinctly uncommon in panniculitis-like T cell lymphoma. NK lymphomas fail to show T cell receptor gene rearrangement, unlike panniculitis-like T cell lymphoma and NK-like T cell lymphomas. In NK-like T cell lymphoma, there is no expression of CD4 or CD8, while most cases of panniculitis-like T cell lymphoma are composed of CD8 cytotoxic T lymphocytes; as mentioned, a null phenotype is rare in the setting of panniculitis-like T cell lymphoma. Other forms of peripheral T cell lymphomas including those which originate in the skin such as anaplastic large cell lymphoma and primary cutaneous pleomorphic T cell lymphoma can extensively involve the fat. Subcutaneous lymphoid hyperplasia at sites of ethnic scarification has been described and held to simulate panniculitis-like T cell lymphoma (Dargent et al., 2001; Dargent and DeWolf-Peeters, 2004). The authors reported a case of a 40 year old black man who developed a tumoral lymphoid hyperplasia mimicking subcutaneous panniculitis-like T cell lymphoma, arising at a site of tribal scarifications. The authors emphasized that only after careful immunohistochemical and molecular studies was a definitive diagnosis established of panniculitic pseudolymphoma.

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 23 year old man with a prior history waxing and waning plaques. This episode was the most severe and did not spontaneously resolve. There were accompanying fevers. Diagnosis: Subcutaneous panniculitis like T cell lymphoma (Figures 19.2–19.9).

(a)

(b)

There is extensive infiltration of the interstitial spaces of the fat by lymphocytes. Also, these foci of lymphocytic infiltration are associated with zones of fat necrosis with extensive deposition of fibrin. (a) The histiocytes demonstrate phagocytosis of cellular debris and red blood cells. (b)

FIGURE 19.2

At higher power magnification the dichotomous pattern of lymphocytic infiltration of the fat juxtaposed to zones of fat necrosis is observed.

FIGURE 19.3

Case Vignette 1

FIGURE 19.4

The vessels show a thrombogenic vas-

culopathy.

FIGURE 19.6 Although there is relative sparing of the epidermis and superficial dermis, striking infiltration of the eccrine coil can be observed. In these areas of dermal involvement, the infiltrate may be predominated by small mature lymphocytes without significant nuclear contour irregularity.

Higher power magnification reveals that the lymphocytes are small and intermediate in size and show significant nuclear contour irregularity with hyperchromasia, irregular transverse nuclear grooves, and conspicuous nucleoli. Cells with a classic cerebriform and/or polylobated morphology are not typical.

FIGURE 19.5

FIGURE 19.7 A CD3 preparation shows scattered positive tumor cells. However, there is a significant diminution in CD3 expression, with many of the atypical cells devoid of staining.

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FIGURE 19.8

phenotype.

Subcutaneous Panniculitis-Like T Cell Lymphoma

(Continued)

These lymphomas are primarily of CD8

FIGURE 19.9

expression.

There is a significant reduction in CD7

Case Vignette 2

CASE VIGNETTE 2

The patient is a 53 year old woman with a history of hepatitis C who had a waxing and waning course over 10 years of subcutaneous nodules, primarily involving the upper thigh. More recently, however, the lesions have persisted and have not undergone spontaneous resolution. She had no cytopenia. Diagnosis: Panniculitis-like T cell lymphoma (Figures 19.10–19.15).

(a) FIGURE 19.10

(b)

There is an extensive infiltrate in the fat with associated fat necrosis.

FIGURE 19.11 The lymphocytes are internalized within the adipocytes, lying in intimate apposition to the cytoplasmic membrane.

FIGURE 19.12 The cytomorphology is one characterized by small and intermediate sized lymphocytes with significant nuclear contour irregularity.

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CASE VIGNETTE 2

FIGURE 19.13

expression.

Subcutaneous Panniculitis-Like T Cell Lymphoma

(Continued)

Phenotypic studies show a loss of CD5

The cells show both CD4 and CD8 expression. Depicted is the CD8 stain. This photomicrograph shows localization of the lymphocytes to the interior of the adipocyte.

FIGURE 19.14

FIGURE 19.15 While the CD4 and CD8 stains were difficult to interpret because of extensive staining with both markers, the tumor cells were granzyme and T cell intracellular antigen positive. We have encountered cases of relatively indolent αβ panniculitislike T cell lymphoma whereby the cells did not show significant expression of either CD4 or CD8 and/or showed immunoreactivity with both markers. Illustrated is granzyme.

Case Vignette 3

CASE VIGNETTE 3

The patient is a 13 year old boy with recurrent subcutaneous nodules accompanied by thrombocytopenia and splenomegaly. The clinical concern was panniculitis-like T cell lymphoma versus Weber–Christian disease. Diagnosis: Atypical lymphocytic lobular panniculitis (Figures 19.16–19.21).

(a)

(b) FIGURE 19.16 Examination reveals infiltration of the interstitium of the fat lobule by mononuclear cells. However, note the preservation of the fat architecture without any accompanying fat necrosis.

The interstitial spaces are widened by a moderately intense lymphocytic infiltrate accompanied by red cell extravasation.

FIGURE 19.17

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(Continued)

FIGURE 19.18 There is an accompanying histiocytic infiltrate. The macrophages show focal erythrocyte phagocytosis.

FIGURE 19.19

There is a CD7 deletion.

FIGURE 19.21

FIGURE 19.20

Oil-Immersion (100× objective magnification) examination highlights the cytomorphology of the infiltrate, which is one predominated by small and intermediate-sized lymphocytes with condensed chromatin and nuclear contour irregularity.

There is a CD5 deletion.

References

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involvement unresponsive to therapy. J Eur Acad Dermatol Venereol. 2003; 17(2):219–222. HAYCOX CL, BACK AL, RAUGI GJ, PIEPKORN M. Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation. J Am Acad Dermatol. 1997; 37(5 Pt 2):832–835. HOQUE SR, CHILD FJ, WHITTAKER SJ, et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol. 2003; 148(3):516–525. HUILGOL SC, FENTON D, PAMBAKIAN H, et al. Fatal cytophagic panniculitis and haemophagocytic syndrome. Clin Exp Dermatol. 1998; 23(2):51–55. IKEDA E, ENDO M, UCHIGASAKI S, et al. Phagocytized apoptotic cells in subcutaneous panniculitis-like Tcell lymphoma. J Eur Acad Dermatol Venereol. 2000; 15(2):159–162. KOSZTOVICS A, BEDI J, EGEDY S. [A case of systemic Pfeiffer–Weber–Christian syndrome complicated by DIC (author’s transl).] Klin Wochenschr. 1977; 55(1): 41–42. KUMAR S, KRENACS L, MEDEIROS J, et al. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes. Hum Pathol. 1998; 29(4):397–403. LEONARD GD, HEGDE U, BUTMAN J, JAFFE ES, WILSON WH. Extraocular muscle palsies in subcutaneous panniculitis-like T-cell lymphoma. J Clin Oncol. 2003; 21(15):2993–2995. LIU V, MCKEE PH. Cutaneous T-cell lymphoproliferative disorders: approach for the surgical pathologist: recent advances and clarification of confused issues. Adv Anat Pathol. 2002; 9(2):79–100. LOZZI GP, MASSONE L, CITARELLA L. Rimming of adipocytes by neoplastic lymphocytes a histopathogen feature not restricted to subcutaneous T cell lymphoma. Am J Dermatopathol. 2006; 28:9–12. MA L, BANDARCHI B, GLUSAC EJ. Fatal subcutaneous panniculitis-like T-cell lymphoma with interface change and dermal mucin, a dead ringer for lupus erythematosus. J Cutan Pathol. 2005; 32(5):360–365. MAGRO CM, CROWSON AN, KOVATICH AJ, BURNS F. Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T-cell lymphoma: a spectrum of subcuticular T-cell lymphoid dyscrasia. J Cutan Pathol. 2001; 28(5):235–247. MAGRO CM, CROWSON AN, BYRD JC, SOLEYMANI AD, SHENDRIK I. Atypical lymphocytic lobular panniculitis. J Cutan Pathol. 2004; 31(4):300–306. MALAVIYA AN, HUSSAIN MA, ABDEEN S, CHERIAN S, RASHID W. Cytophagic histiocytic panniculitis: a rare catastrophic form of systemic panniculitis. Br J Rheumatol. 1998; 37(7):799–800. MARZANO AV, BERTI E, PAULLI M, CAPUTO R. Cytophagic histiocytic panniculitis and subcutaneous panniculitislike T-cell lymphoma: report of 7 cases. Arch Dermatol. 2000; 136(7):889–896. MEHREGAN DA, SU WP, KURTIN PJ. Subcutaneous T-cell lymphoma: a clinical, histopathologic, and immunohistochemical study of six cases. J Cutan Pathol. 1994; 21(2):110–117. MUNN SE, MCGREGOR JM, JONES A, et al. Clinical and pathological heterogeneity in cutaneous gamma-delta

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T-cell lymphoma: a report of three cases and a review of the literature. Br J Dermatol. 1996; 135(6):976–981. NEMESANSZKY E, KOSZTOVICS A, BEDI J, VEGH M. [Changes in serum enzymes in severe liver damage in Pfeifer–Weber–Christian syndrome with fatal outcome.] Orv Hetil. 1976; 117(33):2011–2013. OHTAKE N, SHIMADA S, MIZOGUCHI S, et al. Membranocystic lesions in a patient with cytophagic histiocytic panniculitis associated with subcutaneous T-cell lymphoma. Am J Dermatopathol. 1998; 20(3):276–280. PRZYBYLSKI GK, WU H, MACON WR, et al. Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell lymphomas are derived from different Vdelta subsets of gamma/delta T lymphocytes. J Mol Diagn. 2000; 2(1):11–19. REHMAN F, HARTH M, SPOUGE AR. Weber–Christian disease with severe polyarthritis and polyosteitis. J Rheumatol. 2002; 29(5):1102–1103. ROMERO LS, GOLTZ RW, NAGI C, et al. Subcutaneous T-cell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation. J Am Acad Dermatol. 1996; 34(5 Pt 2):904–910. SALHANY KE, MACON WR, CHOI JK, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol. 1998; 22(7):881–893. SEN F, RASSIDAKIS GZ, JONES D, MEDEIROS LJ. Apoptosis and proliferation in subcutaneous panniculitis-like T-cell lymphoma. Mod Pathol. 2002; 15(6):625–631. SLATER DN. Subcutaneous T-cell lymphoma with florid granulomatous panniculitis. Histopathology. 1993; 22(1):95. TAKIMOTO Y, IMANAKA F, SASAKI N, et al. Gamma/delta T cell lymphoma presenting in the subcutaneous tissue and small intestine in a patient with capillary leak syndrome. J Am Acad Dermatol. 1998; 39(5 Pt 1):721–736.

THOMSON AB, MCKENZIE KJ, JACKSON R, WALLACE WH. Subcutaneous panniculitic T-cell lymphoma in childhood: successful response to chemotherapy. Med Pediatr Oncol. 2001; 37(6):549–552. TORO JR, BEATY M, SORBARA L, et al. Gamma delta T-cell lymphoma of the skin: a clinical, microscopic, and molecular study. Arch Dermatol. 2000; 136(8):1024–1032. TOROK L, KIRSCHNER A. Panniculitis-like T-cell lymphoma clinically manifested as alopecia. Br J Dermatol. 2002; 147(4):785–788. VON DEN DRIESCH P, STAIB G, SIMON M Jr, STERRY W. Subcutaneous T-cell lymphoma. J Am Acad Dermatol. 1997; 36(2 Pt 2):285–289. WANG CY, SU WP, KURTIN PJ. Subcutaneous panniculitic T-cell lymphoma. Int J Dermatol. 1996; 35(1):1–8. WEENIG RH, NG CS, PERNICIARO C. Subcutaneous panniculitis-like T-cell lymphoma: an elusive case presenting as lipomembranous panniculitis and a review of 72 cases in the literature. Am J Dermatopathol. 2001; 23(3):206–215. WELLS J. KOSKY CA, SCDYER RA et al. Unusual case of subcutaneous panniculitis-like T-cell lymphoma. Australas J Dermatol. 2004; 45:114–118. WHITE JW Jr, WINKELMANN RK. Weber–Christian panniculitis: a review of 30 cases with this diagnosis. J Am Acad Dermatol. 1998; 39(1):56–62. WOLLINA U, LOOKS A, MEYER J, et al. Treatment of stage II cutaneous T-cell lymphoma with interferon alfa-2a and extracorporeal photochemotherapy: a prospective controlled trial. J Am Acad Dermatol. 2001; 44(2):253–260. YAMAZAKI K. An ultrastructural study of cutaneous panniculitis-like T-cell lymphoma: cytoplasmic granules and active cellular and cell-to-matrix interaction mimic cytotoxic T-cells. Ultrastruct Pathol. 2002; 26(3):185–190. YUNG A, SNOW J, JARRETT P. Subcutaneous panniculitic T-cell lymphoma and cytophagic histiocytic panniculitis. Australas J Dermatol. 2001; 42(3):183–187.

CHAPTER TWENTY

EPSTEIN–BARR VIRUS-ASSOCIATED LYMPHOPROLIFERATIVE DISEASE Cynthia M. Magro and A. Neil Crowson

INTRODUCTION Epstein–Barr virus (EBV) is a member of the Lymphocryptovirus genus and is a member of the gamma herpesvirus family of viruses that manifest considerable structural and genomic overlap and contain linear, double-stranded DNA. The main method of transmission of EBV is via oropharyngeal secretions from infectious mononucleosis patients; it is also seen in secretions from immunosuppressed patients and, at lower levels, from healthy EBV-seropositive individuals. It is most commonly associated with an acute infection characterized by coryza, fatigue, and generalized lymphadenopathy defining the syndromic complex of infectious mononucleosis (Andersson, 1996; Balfour HH, et al., 2005). Under normal immunologic surveillance mechanisms, there is a suppression of proliferation of EBV-infected cells by HLA-restricted cytotoxic T cells. With latent or chronic infections, the viral agent becomes incorporated into the human genome. Viral agents capable of integration into the host’s genetic material are particularly dangerous as they may seize control of the host cell’s ability to regulate normal cell growth and proliferation. Cell growth and proliferation may be enhanced by viral interference with tumor suppressor gene function (p53 and pRb). Viruses may also

act as vectors for mutated proto-oncogenes. Overexpression of these oncogenes in viral-infected cells interferes with normal cell function and is hence permissive to dysregulated cell growth and proliferation, which may lead to malignant transformation and tumor formation (Iwatsuki et al., 1997, 2000; Kimura H, 2006). Infection with EBV has been implicated in select cutaneous lymphoproliferative syndromes (Hanto et al., 1985; Wagner et al., 1998; Ishihara et al., 2000; Iwatsuki et al., 2000; Harris et al., 2001). Among these are: • B cell lymphoma in the setting of immunosuppressive therapy encompassing post-transplant lymphoproliferative disorder and methotrexateassociated lymphoproliferative disease • Primary cutaneous Hodgkin lymphoma (Chapter 24) • Angioimmunoblastic lymphadenopathy-like T cell lymphoma (Chapter 16) • Natural killer (NK) and NK-like T cell lymphoma (Chapter 21) • Lymphomatoid granulomatosis (Chapter 22) In the majority of cutaneous lymphomas there is no defined role for EBV in propagation of cutaneous

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 381

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lymphoproliferative disease (Astopoulos et al., 1996). The role of EBV is well described for two subgroups of lymphoma: (1) NK and NK-like T cell lymphomas, including those that show dominant localization to the subcutaneous fat, and (2) B cell lymphoma developing in the setting of iatrogenic immune dysregulation. This latter group of patients comprises solid organ transplant recipients receiving immunosuppressive agents and patients with underlying collagen vascular disease who take methotrexate (Kamel et al., 1994; Schwend et al., 1994; Iwatsuki et al., 1997, 2000; Chai et al., 1999; Fam et al., 2000; Ikediobi and Tyring, 2002; Bekkenk et al., 2003; Verma et al., 2005). These EBV-associated large cell B cell lymphomas may be CD30 positive although they are not considered under the rubric of anaplastic large cell lymphomas (Hellier et al., 2001; Hirose et al., 2003; Oguz et al., 2003; Kim et al., 2004) of interest there have been reports of anaplastic large cell lymphoma not associated with known immunosuppression where EBV transcripts have been identified (Shimura et al., 2001; Shimauchi et al., 2004). The majority of anaplastic large cell (CD30-positive) lymphomas of the skin are unassociated with EBV infection (Hellier et al., 2001); hence the significance of EBV in these anecdotal case reports remains questionable. There are reports of post-transplantation anaplastic large cell lymphoma of T or null cell phenotype; however, unlike posttransplant B cell lymphoproliferative disease, these cases are mainly unassociated with EBV infection. There are forms of lymphoid proliferation whereby EBV is likely a critical inciting trigger but where the lesions are in an indeterminate category. These lesions have been attributed to excessive and aberrant hypersensitivity to mosquito bites while others clinically resemble hydroa vacciniforme (Chen et al., 2002), including their exacerbation with ultraviolet exposure, falling under the rubric of hydroa vacciniforme-like EBV-associated lymphoproliferative disease. Some of these cases, however, eventuate into classic NK and NK-like T cell lymphomas (Cho et al., 1997, 2001; Chai et al., 1999; Ishihara et al., 2000). Our discussions in this chapter focus on (1) hydroa vacciniforme-like EBV-associated lymphoproliferative disease and (2) EBV-associated B cell lymphoproliferative disease related to iatrogenic immune dysregulation (Cho et al., 1997). Many of the other entities where EBV has been implicated are considered in separate chapters as outlined above.

Hydroa Vacciniforme-Like EBV-Associated T Cell Lymphoproliferative Disease/ Mosquito Bite Hypersensitivity Clinical Features An unusual expression of EBV-associated lymphoproliferative disease has been encountered in young patients from Asia and Latin America who develop a vesiculopustular eruption (Cho et al., 1997, 2001; Iwatsuki et al., 1999; Ishihara et al., 2000). This condition is now recognized as a distinctive clinical pathological entity and has fallen under alternative names including hydroa-like lymphoma and edematous and scarring vasculitic panniculitis. The lesions may follow a waxing and waning course over several years. There is a predilection to involve the face and scalp. Although primarily localized to the head and neck area with dominant facial involvement, the eruption may extend to involve sun-protected skin (Isoda et al., 1998; Magana et al., 1998; Tokura et al., 1998; Iwatsuki et al., 1999; Jung et al., 1999). There may be an association with sun exposure and skin lesions may resolve with avoidance of sun exposure. Some cases have no association with sun exposure (Heo et al., 2003). Skin lesions manifest an evolutionary course characterized by erythema, vesiculation, necrosis, ulceration, and crusting. Although specific exacerbation with sunlight is not always documented, the lesions most closely resemble severe hydroa vacciniforme, hence accounting for the specific appellation of hydroa vacciniforme-like eruptions. Lesions that follow a recurrent course are typically characterized by their necrotic morphology and localization to the face (Magana et al., 1998; Jung et al., 1999). Some patients have an underlying increased susceptibility to bacterial infections. One patient suffering from recurrent vesicular papular lesions resembling hydroa vacciniforme but also involving sun-protected areas developed repeated bacterial infections and ultimately died of sepsis (Yoon et al., 2001). The role for EBV in lesional propagation as determined through in situ hybridization studies suggests a clonal expansion of EBV infected NK cells. In some cases there is progression to lymphoma (Isoda et al., 1998; Magana et al., 1998; Ishihara et al., 2000; Cho et al., 2001, 2005; Chen et al., 2002). Hemophagocytic syndrome may develop in such patients. The term ‘‘angiocentric cutaneous T cell lymphoma of childhood’’ has been applied to those cases that develop in children (Isoda et al., 1998). Progression to large granular cell leukemia has been documented, the latter representing a low

Introduction

grade peripheral blood malignancy of cytotoxic CD8 lymphocytes (Cho et al., 1997). Many of these patients manifest a striking lymphomatoid hypersensitivity reaction to mosquito bites (Ishihara et al., 2000); in the original description this phenomenon was seen in patients in the first two decades of life (Tokura et al., 1998). Among the hallmarks are bullous lesions developing into necrosis, a subsequent onset of high temperature, and general malaise following the mosquito bite. Some patients went on to experience lymphadenopathy and hepatosplenomegaly with supervening hepatic necrosis. It was subsequently established that these patients had chronic EBV infection, whereby the virus colonized natural killer cells. The natural killer cell, infected with monoclonal (or oligoclonal) EBV, seems to be involved in the pathogenesis of the hypersensitivity. Half of the patients reported died of hemophagocytic syndrome, granular lymphocyte proliferative disorder, or lymphoma. Mosquito bite-related lymphomatoid hypersensitivity is mediated through prior immortalization of NK cells by EBV with subsequent proliferation of these infected cells in response to mosquito mouth part antigens (Tsuge et al., 1999; Ishihara et al., 2000; Asada et al., 2005; Cho et al., 2005; Tokura et al., 2005). Light Microscopic Findings In the lesions that resemble hydroa vacciniforme, light microscopic examination of the preneoplastic phase reveals a picture not dissimilar to lymphomatoid papulosis. In particular, there are dense angiotropic and periadnexal atypical mononuclear cell infiltrates associated with variable tissue eosinophilia. The vessels are surrounded and permeated by the infiltrate and show accompanying mural and/or luminal fibrin deposition, defining a lymphomatoid vasculitis (Chai et al., 1999; Ishihara et al., 2000; Cho et al., 2001). The degree of tissue eosinophilia encountered in Type A lymphomatoid papulosis is not typically seen. In cases progressing to lymphoma, the dominant angiocentric infiltrate is one with an immunoblastic morphology and an even greater density of angiocentric infiltration, resulting in luminal obliteration (Isoda et al., 1998). Foci of supervening effacing infiltration of the interstitium may be observed. There may be prominent involvement of the subcutaneous fat. Differentiating these lesions from panniculitis-like T cell lymphoma is the extensive involvement of the dermis, whereby in most cases only a narrow grenz zone separates the infiltrate from the overlying epidermis. In contrast, in subcutaneous panniculitis-like

383

T cell lymphoma, the dermal infiltrate is largely in an eccrinotropic array, and there is little involvement of the superficial and mid-dermal aspects of the overlying skin (Magana et al., 1998; Cho et al., 2001, 2005). Phenotypic Profile The infiltrate is composed of T cells, as revealed by CD2 expression. There may be focal expression of CD30 within the transformed cells. The small-nuclearRNA(EBER) stain will show positivity amid variable numbers of cells compatible with latent infection. We are not aware of evaluation of lytic infection via thymidine kinase expression. The infiltrate includes many NK cells and NK like T cells and therefore TCR-β and TCR-γ rearrangements may not be seen; the cells may express cytoplasmic CD3 but will fail to show immunoreactivity with CD4 or CD8 (Cho et al., 2004, 2005). In a recent study, lymphocytes isolated from the peripheral blood and skin of patients with hydroa vacciniforme-like eruptions also manifested NK features suggesting a form of NK cell by virtue of a germ line configuration for the T cell receptor and expression of CD56 and CD16. There is one report of a hydroa vacciniforme-like T cell lymphoma with CD8 expression (Chen et al., 2002). Molecular Profile As the cells may manifest NK properties, the T cell receptor may show a germ line configuration; nevertheless, clonality is inferred through analysis of EBV terminal repeats. In another study, cutaneous lesions of all patients with typical hydroa vacciniforme lesions were found to contain EBER-positive cells in 3–10% of the infiltrate. There was subsequent confirmation using polymerase chain reaction amplification, whereby EBV DNA sequences were detected in the majority of cases (Cho et al., 1997, 2001). Cytogenetic Profile One study described the cytological and cytogenetic features of six EBV-infected NK cell clones. Three of the cell clones were derived from patients with nasal T/NK cell lymphomas; two cell clones were isolated from patients with chronic active EBV infection (CAEBV) and the third clone was derived from a patient with hydroa vacciniforme-like eruptions. An analysis of the number of EBV terminal repeats revealed monoclonal EBV genomes along with evidence of type II latency of EBV infection in all six clones. Cytogenetic analysis detected deletions in chromosome 6q in five out of the six NK cell clones, while 6q was not deleted in four control cell lines of T cell lineage, suggesting that 6q deletion is a

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characteristic feature of EBV-positive NK cells, which proliferated in the diseased individuals whether they had malignant or nonmalignant lymphoproliferative disease (Tien et al., 1993; Tsuge et al., 1999). Pathogenesis EBV is a B cell lymphotropic virus gaining access into B cells via the complement receptor (CR2/CD21), which in turn is the receptor for C3d. B cell activation occurs when there is crosslinking of CD21. The viral genome is incorporated into the nucleus, resulting in the encoding of a variety of latent genes. The products include six nuclear antigens (EBNAs 1, 2, 3A, 3B and 3C and EBNA-LP) and three latent membrane proteins (LMPs 1, 2A, and 2B), which play varying roles in B cell immortalization (Flaitz and Hicks, 1998). Latent membrane protein 1 is an EBVencoded oncogene of the tumor necrosis factor family that plays a key role in transforming keratinocytes and B lymphocytes in vitro. This transformation is through the signal transduction pathway, which activates nuclear factor κβ and inhibits apoptosis. One of the important antiapoptotic mechanisms has been attributed to the inhibition of bcl2-associated protein X (bax), a potent proapoptotic protein (Grimm et al., 2005). Latent membrane protein (LMP1) is an integral protein essential for cell transformation. It contains 386 amino acid sequences and is encoded by the EBV BNFL1 gene. A deleted variant of LMP1 is very effective in inducing cell immortalization. The 30 bp deletion is associated with a variety of EBV-related hematologic malignancies and has been described in most cases of Hodgkin’s lymphoma and certain cases of peripheral T cell lymphomas according to the Danish study group (Sandvej et al., 1994). Although the 30 bp deletion is usually seen in patients with cutaneous lymphoproliferative disease, a similar frequency of this deletion is observed in the throat washings of healthy donors.

Epstein–Barr Virus-Associated B Cell Lymphoproliferative Disease in the Setting of Iatrogenic Immune Dysregulation Most patients who develop EBV-associated B cell lymphoproliferative disease have underlying iatrogenic and/or endogenous immune dysregulation. A serious complication in solid organ transplant recipients is the development of secondary hematologic malignancies. Among the broad categories of EBV-associated lymphoproliferative disease are post-transplant lymphoproliferative disease (PTLD), lymphoproliferative disease in patients with acquired immunodeficiency syndrome (AIDS) and lymphomas

developing in the setting of methotrexate therapy, typically in patients with underlying rheumatoid arthritis (Knowles et al., 1995; Cerroni et al., 2004). Post-transplant lymphoproliferative disease is the most frequently reported hematologic dyscrasia in the setting of immune dysregulation; the incidence varies depending on the organ transplanted and the degree to which the patient is immunosuppressed (Tanner et al., 2001; Soler et al., 2003). Among the predisposing risk factors are younger recipient age, higher numbers of rejection episodes, and high-dose cyclosporine immunosuppression (Table 20.1). The reason to suspect a role for EBV in the propagation of PTLD is multifactorial and comprises a higher incidence of primary or reactivated EBV infection in patients with PTLD compared to the general transplant population, a high level of EBV DNA in the blood of affected patients, and the detection of EBV protein, DNA, or RNA in the tissue of PTLD biopsies, at least those of B cell lineage (Johannessen and Crawford, 1999; Beynet et al., 2004). The presumptive basis is one related to iatrogenic immune dysregulation. In addition to its role in the evolution of PTLD, there are many cases of EBVassociated lymphoproliferative disease in the setting of low-dose methotrexate therapy as will be alluded to presently (Viraben et al., 1996; Theate et al., 2002, 2003). While EBV-associated lymphoproliferative disease of the immunosuppressed is well described, only rarely does the disease first manifest itself in the skin (Beynet et al., 2004). The categories of PTLD include early lesions comprising reactive plasmacytic hyperplasia, polymorphic PTLD, monomorphic B cell PTLD, and T cell neoplasms. In most instances, the cell of origin is derived from the host, whereby the infected host cells have clearly escaped normal immunosurveillance, likely reflecting the inherent state of immune dysregulation in these patients. In rare instances, the cell of origin in fact is donor; this scenario is most commonly observed in the setting of lung and liver transplantation and occurs mainly in the allografted tissue. The exception, where the dominant neoplastic cell is of donor origin, is in the marrow transplant recipient since a successful allograft would manifest as an immune system almost exclusively of donor origin (Ng et al., 2000; Verschuuren et al., 2001; Au et al., 2002; Bielorai et al., 2003; Wang et al., 2005). While most monomorphic and polymorphic PTLD cases arise within 1–2 years following transplantation, the majority of cases of cutaneous PTLD arise several years after the initiation of immunosuppressive therapy (Iwatsuki et al., 2000; Verma et al., 2005). All of the categories of PTLD will be described

Introduction

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TABLE 20.1 Post-transplant Lymphoproliferative Disorder Clinical Children and adults Onset of skin lesions within several years from organ transplantation in contrast to a shorter temporal passage with extracutaneous LPD Plasmacytic hyperplasia, polymorphic or monomorphic post-transplant lymphoproliferative disorder are the main subdivisions Histomorphology Mature polyclonal plasma cells in plasmacytic hyperplasia Plasma cells, immunoblasts, intermediate cells in polymorphic type Overt lymphoma, usually large B cell or plasmablastic, in monomorphic type T cell variants are usually in the context of anaplastic large cell lymphoma Immunophenotype CD20+, 79a+, CD30+ (large cell monomorphic variants) LMP-1+ EBER-1+ (excluding T cell LPD, i.e., anaplastic large cell lymphoma) In one series, Thymidine kinase + in up to 50% of cases indicative of lytic infection (Verma et al., 2005) CD3−/+, CD5 −/+ (rare cases are of T cell derivation, usually EBER negative) Genetics Monoclonal rearrangement of JH gene in polymorphic and monomorphic types; dual rearrangement in anaplastic large cell lymphoma (personal observations) (also refer to Chapter 23)

with the major emphasis being given to the monomorphic variant, which is the most common cutaneous expression of PTLD. Plasmacytic Hyperplasia This phenomenon occurs only rarely in the skin where the hallmark is relative preservation of the involved tissue with an infiltrate of polyclonal plasma cells and B cell immunoblasts in a T-cell-rich inflammatory background (Beynet et al., 2004). A prominent angiocentric growth pattern can be seen. Most cases of plasmacytic hyperplasia involve lymph nodes and tonsillar tissue and this phenomenon in other organ sites is uncommon (Dunphy et al., 2002). There is a predilection to involve children and young adults. The natural course is one of spontaneous regression temporally associated with a reduction in the immunosuppressive regimen. However there are cases where plasmacytic hyperplasia presaged plasmacytic malignancy (Beynet et al., 2004; Dunphy CH et al., 2002). Polymorphic PTLD In polymorphic PTLD there is tissue effacement of both nodal and extranodal organs. The infiltrate is polymorphous, as the name suggests, comprising a range of B cell morphologies including small mature B lymphocytes, plasma cells, and plasmacytoid immunoblasts. There is considerable necrosis and

an admixture of bizarre immunoblasts is seen. At one time some of the cases were designated as polymorphic B cell lymphomas when the number of atypical immunoblastic cells was high. That distinction is no longer made and all of these cases fall under the designation of polymorphic PTLD, although there likely is a continuum in regard to polymorphic PTLD and overt B cell lymphoma. As with plasmacytic hyperplasia, the lesions regress when there is a reduction in the immunosuppressive regimen. The designation of lymphoma is not used because of the absence of both B cell clonality and of phenotypic aberrations. Polymorphic PTLD represents a precursor lesion to the monomorphic variant (Tanner et al., 2001; Soler et al., 2003; Beynet et al., 2004). Monomorphic Post-transplant Lymphoproliferative Disorder Numerous reported PTLD primary cutaneous EBV-positive B cell lymphomas can be found in the literature (McGregor et al., 1993; Joseph et al., 1994; Tanner et al., 2001; Soler et al., 2003). Primary cutaneous EBV-associated B cell lymphoma in the setting of solid organ transplantation may follow a more indolent course compared to its extracutaneous counterpart. In one series comprising 673 renal allograft patients with B cell PTLD, four patients were diagnosed as having primary cutaneous lymphoma;

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the lymphomas were of B and T cell lineage in three patients and one patient, respectively. EBV DNA was identified by polymerase chain reaction in all of the B cell lymphomas and was absent in the T cell lymphoma. The patients with cutaneous B cell lymphoma were treated with surgery or radiotherapy for the primary lesion, remaining free of the disease for an average duration of 3.9 years (Tanner et al., 2001; Soler et al., 2003). We recently reported as a series of 6 patients with post-transplant B cell lymphoma (Verma et al., 2005). As with other reported series, all patients underwent a reduction in their immunosuppressive regimen, which in three of the six cases was associated with lesional regression. However, in two cases progressive extracutaneous disease necessitated chemotherapy, while in one case recurrence of skin lesions led to the use of external beam radiation, which was successful in achieving lesional resolution. Among the monomorphic PTLDs we encountered in our recent series were primary cutaneous plasmablastic lymphoma, marginal zone lymphoma, and diffuse large B cell lymphoma. All patients were receiving immunosuppressive agents for several years prior to the development of the lymphoma rather than the more brief time course of less than one year following transplantation seen in extracutaneous EBV-associated lymphoproliferative disease. In half of the cases, simple withdrawal of immunosuppression led to complete lesional regression without recurrence. Another aspect of the treatment regimen was antiviral therapy; two patients developed recurrent disease after reducing their antiviral therapy. The question obviously arises as to why antiviral therapy would play any role in treating lymphomas, which are presumably the basis of latent EBV infection. We showed lytic infection by virtue of thymidine kinase positivity in 50% of cases of primary cutaneous EBV-associated PTLD studied. Lytic infection has therapeutic implications in regards to the use of antiviral therapy in the treatment of this form of lymphoproliferative disease (Harris et al., 2001; Verma et al., 2005).

Plasmablastic Lymphoma as a Form of Monomorphic PTLD. Despite the prevalence of PTLD among transplant recipients, plasmacytic lesions in this setting are uncommon (McGregor et al., 1993; Joseph et al., 1994; Ojanguren et al., 2003; Cioc et al., 2004). There are two reports of an extramedullary plasmacytoma following cardiac transplantation (Rees et al., 1998; Ibe et al., 1999). We have recently reported cutaneous plasmablastic lymphoma in the setting of solid organ transplantation

(see Figures 20.1–20.6, 20.12, 20.13, and 20.14) (Verma et al., 2005). Prior reports of plasmablastic lymphoma have been almost exclusively in AIDS patients, mainly in the context of oral disease (Figures 20.12–20.14) (Nguyen et al., 2003). These tumors have also fallen under the alternative designation of anaplastic plasmacytoma and are characterized by a confluent proliferation of differentiated although highly atypical plasma cells. This lymphoma was first described in the oral cavity in the setting of HIV disease with other sites of involvement including stomach, nasal cavity, and an origin in sacrococcygeal cysts (Chetty et al., 2003; Ojanguren et al., 2003). The lesions follow an aggressive clinical course with death following multiorgan dissemination in an average of 6 months. The demonstration of human herpes virus (HHV8) is recently described in plasmablastic lymphoma. HHV8 expresses polypeptides which enhance cell proliferation and produces viral interleukin-6, a promoter of B cell and plasma cell proliferation (Cioc and Nuovo, 2002; Watabe et al., 2002; Oguz et al., 2003). It is possible that the significant elevation in circulating IL-6 levels in EBV-associated PTLD may be attributable to not only EBV (Nagore et al., 2000) but in some cases to HHV8 infection as well. EBV-infected patients with PTLD have a tenfold or greater elevation in circulating IL-6 levels (Matsushima et al., 1999; Cannan M, Cesarman E, 2000). Among the conditions where HHV8 has been described are Kaposi’s sarcoma, primary-effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and plasmablastic lymphoma (Cioc et al., 2002). Dual infection with EBV and HHV8 has been demonstrated in only a few malignancies, including PEL, MCD, and oral plasmablastic lymphoma in AIDS patients (Cioc et al., 2002; Theate et al., 2003). As with EBV, the exact role played by HHV8 in the development of lymphoma is unclear. HHV8 expresses polypeptides homologous to the oncogenic protein products cyclin-D and bcl-2. D-type cyclins promote exit from G0/G1 and thus enhance cell proliferation, contributing to the oncogenic potential of this virus (Feigal, 1999; Watabe et al., 2002; Oguz et al., 2003). The association of EBV/HHV8 with plasmablastic lymphoma could indicate that iatrogenic and/or endogenous suppression of T cell immunity combined with a dual cellular coinfection with both HHV8 and EBV may be critical to the genesis of plasmablastic lymphoma (Papadaki et al., 2000). The immunosuppression associated with organ transplantation in immunosuppression in concert with both EBV and HHV8 predisposes patients to the more aggressive plasmablastic lymphoma. The

Introduction

poor prognosis relates to the failure to have recognized the additional role of HHV8 in lesional propagation. FDA-approved treatment for HHV8 does not include acyclovir. Alternative agents including daunorubicin, paclitaxel, interferon α, and alitretinoin are other therapeutic options (Vander Straten et al., 2000).

Plasmacytic Marginal Zone Lymphoma as a Form of Monomorphic PTLD. Plasmacytic marginal zone lymphoma represents another novel type of monomorphic PTLD rarely encountered (See Figures 20.7–20.9). The architecture and phenotypic profile of marginal zone lymphoma are seen; however, a preponderance of light chain restricted neoplastic plasma cells and greater accentuation around blood vessels are characteristic. Previously recognized infective triggers have included hepatitis C virus as well as Borrelia burgdorferi (Abd-el-Baki et al., 1998; Patriarca et al., 2001). While the skin lesions in the case that we encountered responded to a reduction in the immunosuppressive regimen, the patient later developed a disseminated multiorgan plasmablastic large cell lymphoma that was also EBV positive. Diffuse Large B Cell Lymphoma as a Form of Monomorphic PTLD. Diffuse large B cell lymphoma is perhaps the most common morphologic expression of PTLD in the skin; in our experience there may be concomitant coexpression of CD30. Large B cell lymphoma expressing CD30 is a well described phenomenon, with the majority of lesions occurring in extranodal sites including the lung, gastrointestinal tract, and brain; their association with EBV infection has been previously made (Shimakage et al., 1997; Shimura et al., 2001). There are two prior reported cases of primary cutaneous CD30-positive B cell lymphoma including one in the setting of EBV infection (see Figures 20.10 and 20.11) (Oguz et al., 2003). T Cell Post-transplant Lymphoproliferative Disorders. There are an increasing number of reports of cutaneous T cell lymphoma arising in the setting of solid organ transplantation. Unlike the post-transplant B cell disorders, EBV expression in the lymphoma cells has not been consistently demonstrated. There are approximately 23 cases of post-transplant T cell lymphoproliferative disorder in the literature at the present time. While the majority of these do represent CD30-positive lymphoproliferative disease, mainly in the context of anaplastic large cell lymphoma, there are other less

387

frequent forms of post-transplant T cell lymphoproliferative disease including mycosis fungoides, S´ezary syndrome, panniculitis-like T cell lymphoma, and primary cutaneous pleomorphic T cell lymphoma (Tomson et al., 1991; Pascual et al., 1992; Euvrard et al., 1992; Kaplan et al., 1993; McGregor et al., 1993; Schuneman et al., 1998; Lye, 2000; Guz et al., 2000; Hoshida et al., 2001; McMullan et al., 2001; Seckin et al., 2001; Ward et al., 2002; Cooper et al., 2003; Defossez-Tribout et al., 2003; Coyne et al., 2004; Kim et al., 2004; Lucioni et al., 2004; Rajakariar et al., 2004; Bregman et al., 2005; De Nisi et al., 2005; Salama, 2005). As with the B cell lymphoproliferative conditions, these tumors develop at least a few years after the solid organ transplant. Since most of the reported cases are EBV negative, one would have to surmise that events other than those related to EBV infection might be implicated. It has been postulated that drugs, specifically cyclosporine, by inhibiting interleukin-2 production, will attenuate T regulatory cells, interfering with the elimination of emerging clones of T cells (Hess, 1982; Kahan et al., 1989). Post-transplant CD30-positive lymphoproliferative disease in childhood seems to be associated with a good prognosis, with most patients experiencing spontaneous regression (Katugampola et al., 2005). HTLV-1-associated post-transplant adult T cell leukemia has been described among renal transplant patients in Japan. The authors attributed the disorder to HTLV-1 infection during hemodialysis (Hoshida et al., 2001). In three patients with S´ezary syndrome-like presentations, two patients had an aggressive and lethal clinical course, while the other patient achieved remission with prednisone and chlorambucil (Pascual et al., 1992). The most common of the T cell lymphoproliferative disorders is anaplastic large cell lymphoma; the prognosis is variable. Patients can have an aggressive clinical course while others have achieved remission (Kaplan et al., 1993; Cooper et al., 2003; Coyne et al., 2004; Lucioni et al., 2004; Rajakariar et al., 2004; Salama, 2005; Katugampola et al., 2005; De Nisi et al., 2005). In our own experience, one patient achieved remission while another patient died shortly after diagnosis of unrelated causes. In contradistinction, primary cutaneous anaplastic large cell lymphoma not associated with solid organ transplantation has a very favorable prognosis (Bekkenk et al., 2000). Overall, while the literature precedent is limited, it would appear that T cell lymphoproliferative disease in the setting of solid organ transplantation does follow a more aggressive clinical course compared to the T cell counterpart in the nontransplanted host. There is no difference light microscopically or phenotypically with the specific subtypes of T cell lymphoma in

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the nontransplanted patient. In two cases of anaplastic large cell lymphoma we encountered, the cells expressed a CD3-, CD4-positive phenotype and manifested a dual heavy chain and TCR-β rearrangement. Methotrexate-Associated Lymphoproliferative Disease We have encountered a few cases of primary cutaneous B cell lymphoma in the setting of methotrexate therapy. Patients had underlying rheumatoid arthritis and a similar pathology, namely, a diffuse large B cell lymphoma manifesting CD30 positivity. Methotrexate-associated B cell lymphoproliferative disease has been recognized for two decades, and while many cases of EBV-positive lymphoma in patients treated with methotrexate are reported, there are only rare reports of methotrexate/EBV-associated primary cutaneous B cell lymphoma (Chai et al., 1999; Fam et al., 2000; Tournadre et al., 2001). The most common lymphoproliferative disease associated with methotrexate therapy is diffuse large B cell lymphoma. One study reported that 33% of lymphomas developing in patients with rheumatoid arthritis or dermatomyositis contained the EBV genome, while only 4% of lymphomas in the general population show molecular evidence of EBV infection (Kamel et al., 1994). Conversely, in this autoimmune population, 83% of the lymphoid lesions that were associated with EBV occurred in patients treated with immunosuppressive therapy, most commonly methotrexate (Kamel et al., 1994). Partial regression and/or spontaneous resolution of lymphoma after withdrawal of the immunosuppression is commonly reported, again signifying a role for methotrexate in tumor formation (Theate et al., 2002). Patients with rheumatoid arthritis have also developed lymphoma in the setting of cyclosporine and penicillamine therapy (Kamel et al., 1994).

Pathogenetic Link Between EBV-Associated B Cell Lymphoma and Iatrogenic Immune Dysregulation Related to Either Methotrexate or Cyclosporine. EBV-infected B cells express a host of EBV-related components including six EBV nuclear antigens (EBNAs), two EBV-encoded RNAs (EBERs), and three latent membrane proteins (LMPs) (Tanner et al., 2001; Holmes and Sokol, 2002; Soler et al., 2003). Two latent proteins, EBNA-2 and LMP-1, are target antigens for cytotoxic T lymphocytes and hence are important for viral clearance (Tanner et al., 2001; Holmes and Sokol, 2002; Soler et al., 2003). Even in perfectly healthy persons, small numbers of EBV-infected B cells remain infected, albeit in a latent state. Reactivation at a later time can occur; the exact mechanisms leading to reactivation

are unclear. One of the consequences of latent infection is progressive B cell immortalization (Tanner et al., 2001). The mechanisms of immortalization have more or less been elucidated. Studies have shown that LMP-1 augments B cell proliferation and is also antiapoptotic (Johannessen and Crawford, 1999; Holmes and Sokol, 2002). B cell transformation occurs via transcriptional transactivation of viral and cellular genes by EBV. Transformed lymphocytes are more susceptible than are resting lymphocytes to other genetic mutations, including proto-oncogene and onco-suppressor mutations (Chetty et al., 2003; Verma et al., 2005). It would appear that the ability of EBV to induce B cell proliferation and subsequent oncogenic transformation is associated with immunosuppressive therapy. One of the consequences of such therapy is attenuation of cytotoxic T lymphocyte responses directed against viral antigen. The decrement in T cell immunosurveillance results in unsuppressed growth of the aforementioned emerging infected B cell clones (Hanto et al., 1985; Berg et al., 1992; Scheinfeld et al., 1997). The adoptive transfer of EBV-specific autologous cytotoxic T lymphocytes suggests a critical role for endogenous CD8-positive T cells in controlling PTLD. Cyclosporin A promotes antiapoptotic gene expression and induces chromosomal breaks (Bird et al., 1981; Tanner et al., 2001; Latipova and Aliavi, 2002). EBV-encoded viral thymidine kinase (vTK) is expressed only during the lytic form of infection. Studies have shown evidence of lytic infection in the setting of post transplant lymphoproliferative disease (Porcu et al., 2002; Verma et al., 2005). EBV can infect cells in the context of a latent infection or in lytic form. In cells containing the lytic type of EBV polymerase, the viral genome is replicated though a virally encoded DNA polymerase and virally encoded kinases will phosphorylate ganciclovir into its active cytotoxic form. In contrast, in cells that are latently infected the virus is replicated by the host cell DNA polymerase; only a small subset of viral genes are transcribed, and ganciclovir cannot be converted into its active form. Phosphorylated ganciclovir inhibits not only the virally encoded DNA polymerase but also the host cell DNA polymerase and is thus cytotoxic (Furman and Barry, 1988; Andersson, 1996). Hence, in cases showing evidence of lytic infection, there would be a logical role for agents such as ganciclovir (Feng et al., 2004). A novel therapy for EBV-associated PTLD is one of intentional induction of the lytic form of EBV infection. In this study the authors discovered that gemcitabine

Introduction

and doxorubicin induce lytic EBV infection in EBVtransformed B cells in vitro and in vivo (Feng et al., 2004). Gemcitabine and doxorubicin both activate transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBVnegative B cells. The addition of gancyclovir would

389

be expected to enhance cell killing by gemcitabine or doxorubicin in lymphocytes infected with wild type EBV given the induction of lytic infection by these two chemotherapeutic drugs and the cytotoxic efficacy of gancyclovir only in cells with features of lytic infection.

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 38 year old woman who had a renal transplant 4 years previously and was on long-term cyclosporine. She developed a nodular lesion on her lower extremity that was thought to represent a pyogenic granuloma. Diagnosis: EBV and HHV8 associated plasmablastic lymphoma (Figures 20.1–20.6).

(a)

(b)

FIGURE 20.1 There is a striking infiltrate within the dermis of atypical plasma cells, which effaces the dermal architecture. There is a pseudoalveolar-like lobulated architectural growth pattern due to intersecting vascular septa coursing through the neoplasm.

(a)

(b)

FIGURE 20.2 The cells have a plasmacytoid appearance. Specifically, there is eccentric disposition of the nucleus with nucleolar prominence and a clock-face condensation of the heterochromatin. However, the cells exhibit considerable pleomorphism; in addition, cells with a rounded, more blastic appearance are also noted.

Case Vignette 1

FIGURE 20.3 A feature of plasma cell neoplasms is membrane staining of the neoplastic cells for CD56.

FIGURE 20.4

Higher power magnification shows a large cell morphology, although with plasmacytoid features.

FIGURE 20.6 An in situ hybridization assay for EBER demonstrates positivity.

FIGURE 20.5

An additional biopsy reveals nodular distortion of the dermis by this vary atypical infiltrate.

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CASE VIGNETTE 2

The patient is a 53 year old man who had a postcadaveric renal transplant in 1992 and presented in May 2002 with a 1 year history of non tender, nonpruritic neck and back lesions. Diagnosis: Post-transplant lymphoproliferative disorder with initial presentation in the skin as marginal zone lymphoma followed by subsequent evolution to large cell lymphoma involving lymph nodes (Figures 20.7–20.11). Plasmacytic marginal zone lymphoma is illustrated in Figures 20.7–20.9.

(a)

(b)

FIGURE 20.7 A skin biopsy reveals a nodular perivascular and periadnexal atypical lymphocytic and plasmacellular infiltrate.

The infiltrate is positive for CD79 and CD56 with λ light chain restriction. Illustrated is the λ stain.

FIGURE 20.8

FIGURE 20.9 EBER analysis shows striking nuclear expression in virtually all tumor cells.

Case Vignette 2

Shortly after, the patient developed a neck mass, which was biopsied and was diagnostic of a large cell lymphoma involving the cervical lymph nodes.

FIGURE 20.10

The EBER stain is strongly positive. The patient died shortly after developing nodal large cell lymphoma.

FIGURE 20.11

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CASE VIGNETTE 3

An HIV patient presented with a large intraoral mass, which was biopsied and held to be characteristic for plasmablastic lymphoma (Figures 20.12–20.14).

High power magnification captures the pleomorphic plasmacytoid appearance of the cells.

FIGURE 20.12

FIGURE 20.13 An HHV8 immunohistochemical stain shows extensive decoration of the tumor cells.

An EBV in situ hybridization assay for latent protein expression shows numerous positive cells.

FIGURE 20.14

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IWATSUKI K, XU Z, TAKATA M, et al. The association of latent Epstein–Barr virus infection with hydroa vacciniforme. Br J Dermatol. 1999; 140(4):715–721. IWATSUKI K, XU Z, OHTSUKA M, KANEKO F. Cutaneous lymphoproliferative disorders associated with Epstein–Barr virus infection: a clinical overview. J Dermatol Sci. 2000; 22(3):181–195. JOHANNESSEN J, CRAWFORD DH. In vivo models for Epstein–Barr virus (EBV)-associated B cell lymphoproliferative disease (BLPD). Rev Med Virol. 1999; 9:263–277. JOSEPH G, BARKER RL, YUAN B, MARTIN A, MEDEIROS J, PEIPER SC. Posttransplantation plasma cell dyscrasias. Cancer. 1994; 74:1959–1964. JUNG DY, KIM JW, LEE SK, LEE WW. Epstein–Barr virusassociated lymphoproliferative skin lesion with recurrent necrotic papulovesicles of the face. J Dermatol. 1999; 26(7):448–451, 1999 Jul. KAHAN A, GERFAUX J, KAHAN A, JORET AM, MENKES CJ, AMOR B. Increased proto-oncogene expression in peripheral blood T lymphocytes from patients with systemic sclerosis. Arthritis Rheum. 1989; 32(4):430–436. KAMEL OW, VAN DE RIJN M, LEBRUN DP, WESS LM, WARNKE RA, DORFMAN RF. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein–Barr virus and other features associated with immunosuppression. Hum Pathol. 1994; 25:638–643. KAPLAN MA, JACOBSON JO, FERRY JA, HARRIS NL. T-cell lymphoma of the vulva in a renal allograft recipient with associated hemophagocytosis. Am J Surg Pathol. 1993; 17(8):842–849. KATUGAMPOLA RP, FINLAY AY, HARPER JI, DOJCINOV S, MAUGHAN TS. Primary cutaneous CD30+ T-cell lymphoproliferative disorder following cardiac transplantation in a 15-year-old boy with Netherton’s syndrome. Br J Dermatol. 2005; 153(5):1041–1046. KIM HK, JIN SY, LEE NS, WON JH, PARK HS, YANG WI. Posttransplant primary cutaneous Ki-1 (CD30)+/CD56+ anaplastic large cell lymphoma. Arch Pathol Lab Med. 2004; 128(8):e96–99. KIMURA H. Pathogenesis of chronic active Epstein–Barr virus infection: Is this an infections disease, lymphoproliferative disorder or immunodeficiency. Red Med Virol. 2006; 16:251–261. KNOWLES DM, CESARMAN E, CHADBURN A, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood. 1995; 85:552–565. LATIPOVA NS, ALIAVI AL. [Chromosomal aberrations in lymphocytes of patients with systemic lupus erythematosus during cytostatic therapy.] Ter Arkh. 2002; 74(5):35–38. LUCIONI M, IPPOLITI G, CAMPANA C, et al. EBV positive primary cutaneous CD30+ large T-cell lymphoma in a heart transplanted patient: case report. Am J Transplant. 2004; 4(11):1915–1920. LYE WC. Successful treatment of Epstein–Barr virusassociated T-cell cutaneous lymphoma in a renal allograft recipient: case report and review of the literature. Transplant Proc. 2000; 32(7): 1988–1989. MAGANA M, SANGUEZA P, GIL-BERISTAIN J, et al. Angiocentric cutaneous T-cell lymphoma of childhood (hydroalike lymphoma): a distinctive type of cutaneous T-cell lymphoma. J Am Acad Dermatol. 1998; 38(4):574–579. MATSUSHIMA AY, STRAUCHEN JA, LEE G, et al. Posttransplantation plasmacytic proliferations related to Kaposi’s

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CHAPTER TWENTY-ONE

NASAL AND RELATED EXTRANODAL NATURAL KILLER CELL/T CELL LYMPHOMAS Cynthia M. Magro and A. Neil Crowson

INTRODUCTION The Natural Killer (NK) and NK-like T cell lymphomas, collectively now designated as NK/T cell lymphomas, are aggressive lymphomas. They are included in the revised European–American (REAL) classification of lymphoid neoplasms, the World Health Organization (WHO) classification schemes (Harris et al., 1994; Jaffe et al., 1997, 2000), and in the most recent joint EORTC and WHO classification scheme for cutaneous hematologic malignancies (Willemze et al., 2005). These lymphomas usually have an extranodal presentation, where characteristic sites of initial involvement are the gastrointestinal tract, skin, and nasal cavities. Bone marrow involvement at initial presentation is uncommon (Wong et al., 2001; Jaffe E et al., 1997). The NK/T cell lymphomas have been categorized as nasal versus nonnasal (Chan et al., 1993; Jaffe et al., 1997; Aviles et al., 2000; Chan et al., 2000; Greer et al., 2001). Most of the NK cell lymphomas present with nasopharyngeal involvement, with the majority of cases being reported from Asia; the most common form of NK cell lymphoma is thus of the sinonasal/nasal subtype (Figure 21.1). In the

nonnasal category, the main categories of lymphoma are nasal type, aggressive, and blastoid (Figure 21.2) (Natkunam et al., 1999). Nasal type is a confusing term as it suggests an initial presentation in the sinonasal region, when in fact this tumor does not present initially in the sinonasal area but instead in extranasal sites. Nevertheless, the light microscopic, phenotypic, and molecular profiles closely parallel those of the so-called nasal NK/T cell lymphoma, hence the designation ‘‘nasal type’’ (Hirakawa et al., 1999; Cho et al., 2000; Santucci et al., 2003). As regards the blastoid form of NK cell lymphoma, this rare neoplasm is now considered to derive from plasmacytoid monocytes and is not considered a lymphoma per se (Noguchi et al., 1997; Petrella et al., 2002, 2004, 2005). Nevertheless, we consider it in detail in this chapter along with a tumor it closely mimics namely a CD4 variant of NK like T cell lymphoma. There is a male predominance, whereby the median age at presentation varies from 43 to 64 years (Aviles et al., 2000). In those lymphomas categorized as representing NK cell lymphomas as opposed to NK-like T cell lymphomas, there is a frequent association with Epstein–Barr virus (EBV)

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 399

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An 85 year old woman with nasal NK cell lymphoma. Computerized tomography shows a lesion extending from the maxillary sinus through the nasal cavity and filling most of the ethmoid sinuses.

FIGURE 21.1

FIGURE 21.2 A 20 year old man with aggressive NK cell lymphoma. Chest computerized tomography shows extensive lymphadenopathy involving the left supraclavicular, bilateral hilar, and mediastinal lymph nodes.

infection, particularly in Asian patients and less often in Caucasians (Jaffe et al., 1997; Chang et al., 2000, 2002a; Greer et al., 2001; Gaal et al., 2002; Siu et al., 2002). Familial cases linked with pesticide exposure have been described (Kojya et al., 2001). The NK cell and NK-like T cell lymphomas typically follow an aggressive clinical course with death occurring

within 12 months after presentation. Although NK T cell lymphoma can initially present in the skin, secondary cutaneous involvement in the context of known extracutaneous disease usually heralds an aggressive clinical course with refractoriness to chemotherapeutic and other intervention (Jaffe et al., 1997; Miyamoto et al., 1998).

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(a)

401

(b)

FIGURE 21.3 The patient is a 63 year old man who was diagnosed as having acute myelogenous leukemia. He presented concurrently with skin, bone marrow, and peripheral blood involvement. He was later established to have hematodermic neoplasm, which is illustrated in Figures 21.22–21.25.

The phenotypic profile includes CD2 and CD56 positivity. The distinction between an NK cell lymphoma versus an NK-like T cell lymphoma relates to the presence or absence of a T cell receptor (TCR) gene rearrangement and the expression of CD3. Those lymphomas that lack surface CD3 expression and TCR-β or TCR-γ gene rearrangements are considered to represent NK lymphomas, while those lymphomas that manifest surface CD3 expression and TCR-β or TCRγ gene rearrangement are considered to represent NK-like T cell lymphomas (Chan et al., 1993; Jaffe et al., 1997; Santucci et al., 2003). NK cell lymphomas typically do not express either CD4 or CD8. Those lymphomas that fall under the designation of an NKlike T cell lymphoma can on rare occasion be CD8 positive, and/or CD4 positive, although the majority exhibit a null phenotype (Chan et al., 1993; Jaffe et al., 1997). Rare cases of apparently CD3-negative, CD8-positive NK-like T cell lymphoma have been described (Kamarashev et al., 2001; Tao et al., 2002). The CD4-positive, CD56-positive hematodermic neoplasm is a distinctive hematologic dyscrasia that does not exhibit a TCR gene rearrangement or surface or cytoplasmic CD3 expression (Noguchi et al., 1997; Petrella et al., 2002, 2005). These tumors are of monocytic derivation and were formerly designated blastic NK cell lymphoma (Figure 21.3) (see Table 21.1). We first consider the biology of NK cells and T cells with NK cell properties and then discuss in more detail this unique subgroup of lymphomas, addressing both the clinical and pathologic features.

TABLE 21.1 Categorization of NK/T cell lymphoproliferative syndromes Nasal Nasal type Aggressive Panniculitis-like T cell lymphoma of the γ δ variant CD4+ NK/T cell lymphoma (not to be confused with hematodermic neoplasm) Chronic granular lymphocytosis/large granular cell leukemia

BIOLOGY OF NK AND NK-LIKE T CELLS Natural killer (NK) cell lymphomas are so designated because the neoplasms derive from a cell whose normal phenotypic counterpart is the NK cell. NK cells, also referred to as Tγ lymphocytes, differentiate from immature thymocytes to acquire characteristic phenotypic and genotypic characteristics and exhibit cytotoxic properties without prior sensitization (Hallett and Murphy, 2004; Farag and Caligiuri, 2005). They are not major histocompatibility complex (MHC) antigen restricted in their function and hence belong to the innate immune system. These cells recognize and kill certain target cells, especially tumor and virally infected cells with altered expression of class I MHC antigens. NK-like T cells perform a similar function and share with true NK cells CD56 and cytoplasmic CD3 positivity; however,

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they demonstrate a rearrangement of TCR and express CD3 on the surface. Collectively, both NK and NK-like T cells account for 2–5% of peripheral blood lymphocytes. From a cytomorphologic perspective, these cells demonstrate high cytoplasmic to nuclear ratios and have cytoplasms that contain prominent azurophilic granules in Giemsa stained smears. The NK cells express receptors for both the Fc portion of IgG and sheep erythrocytes. NK cells contain truncated cytoplasmic CD3, usually the ξ chain of CD3. However, they are without surface CD3 expression (Jaffe et al., 1997). The CD3 intracellular localization can only be reliably detected in paraffinembedded tissue using the technique of antigen retrieval with the CD3ξ antibody (Greer et al., 2001). Otherwise the routine polyclonal CD3 antibody may be negative. The cells also express CD2 but neither CD4 nor CD8. They are CD56 positive. CD56 is a neural cell adhesion molecule also designated NCAM. Other markers of NK cells such as CD11b, CD1c, CD16, and CD57 are positive (Hallett and Murphy, 2004; Farag and Caligiuri, 2005). The cells do not express TCR BF1 (αβ receptor) and TCR delta 1 (γ δ receptor) and hence fail to demonstrate rearrangement of either the TCR-β or TCR-γ chains. Clonality can be demonstrated with EBV terminal repeat probes (Canioni et al., 2001; Ling et al., 2002). Both NK cells and NK-like cytotoxic T lymphocytes are phenotypically mature lymphocytes whose cytoplasmic granules contain cytotoxic proteins that are capable of mediating cellular lysis in vitro. Among the cytolytic proteins are perforin (cytolysin), granzyme, Fas ligand (CD95L), and T cell intracellular antigen (TIA-1). TIA-1 is structurally related to the tumor necrosis factor receptor family that induces apoptosis when introduced into target cells (Hallet and Murphy, 2004; Farag and Caligiuri, 2005). It should be emphasized that NK cells and NKlike T cells are not the only cells that express cytotoxic proteins. Among cells with cytotoxic properties are NK cells and cytotoxic αβ and γ δ T lymphocytes. There is variation in the expression of cytotoxic proteins. The most ubiquitous is TIA-1; it is detected on virtually all cytotoxic cells. However, granzyme B and perforin expression are largely confined to activated cytotoxic cells. The various lymphoproliferative syndromes derived from hematopoietic cells with cytotoxic properties include NK/T cell lymphoma, γ δ T cell lymphomas, tumor stage mycosis fungoides, CD30-positive lymphoproliferative disease, and primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphoma. Most extranodal T and NK-cell non-Hodgkin lymphomas are activated cytotoxic lymphomas, except hepatosplenic lymphoma,

which is derived from nonactivated cytotoxic cells (Felgar et al., 1997; Kato et al., 1999; Natkunum et al., 1999; Kanavaros P, 2000).

NK/T-Cell Lymphoma The NK/NK-like T cell lymphomas are considered aggressive lymphomas and are typically resistant to standard chemotherapy (Jaffe et al., 1997; Natkunam et al., 1999; Aviles et al., 2000; Cheung et al., 2002). Even high dose chemotherapy with peripheral blood stem cell transplantation has not improved survival in this group of lymphomas (Takenaka et al., 2001). The presentation is usually of relatively rapid onset. Rarely, there may be a preceding phase of chronic peripheral blood NK cell lymphocytosis associated with neutropenia (De Lord et al., 1998). Skin involvement is variable. When it occurs outside the context of primary cutaneous NK cell lymphoma, it usually portends a poor prognosis (Aviles et al., 2000). Although these neoplasms do follow an aggressive clinical course, bone marrow involvement at the time of clinical presentation is uncommon (Wong et al., 1992). The three main subtypes of NK cell and NK-like T cell malignancies are each considered separately: nasal, nasal type that encompasses primary cutaneous NK and NK-like T cell lymphoma, and aggressive NK-cell lymphoma. As for hematodermic neoplasm, it is not a tumor of NK-like T cells or NK cells; nevertheless, it is discussed since it was formerly considered a form of NK-cell lymphoma falling under the designation of blastic NK-cell lymphoma. Brief mention is given to a very rare form of NK-cell lymphoma derived from NK-like CD4 T lymphocytes. Consideration is also given to chronic NK-cell peripheral blood lymphocytosis, which may precede the development of some of the more evolved NK cell and NK-like T cell malignancies, a condition that has also been termed large granular cell leukemia (Chan et al., 1993; Loughran, 1993; Jaffe et al., 1997; Chang et al., 2000; Takahashi et al., 2001). Finally, panniculitis-like T cell lymphoma is recognized as a distinctive form of peripheral T cell lymphoma and a small percentage of these cases will represent NK/T-cell lymphomas frequently of the γ δ subtype. We have considered this form of lymphoma in the panniculitis-like T cell lymphoma chapter (Chapter 19) and in the chapter on cutaneous γ δ T cell lymphoma (Chapter 13).

Nasal NK/T-Cell Lymphoma This lymphoma presents as a destructive midline facial lesion (see Figures 21.1, 21.4–21.12 and 21.13–21.16) (Chan et al., 1993; Jaffe et al., 1997;

Biology of NK and NK-like T Cells

Gaal et al., 2000; Cheung et al., 2002; Kwong, 2005). The 5 year survival is approximately 30%. It also falls under the designation of lethal midline granuloma and sinonasal lymphoma and can present with palatal destruction, orbital swelling, and erythema (Yamazaki et al., 2000; Hon et al., 2002). The initial clinical presentation may be localized to the aerodigestive tract, but this aggressive neoplasm tends to disseminate to various extranodal sites, although bone marrow involvement is uncommon. Among the classic sites of tumor dissemination are skin, gastrointestinal tract, testis, and cervical lymph nodes (Miyamoto et al., 1998; Chang et al., 2000; Cho et al., 2000; Takahashi et al., 2001; Cheung et al., 2002). The skin lesions are oftentimes ulcerated. Intestinal involvement presents with perforation (Lei et al., 1997; Cheung et al., 2002). The clinical course may be complicated by hemophagocytic syndrome (see Figure 21.1) (Takahashi et al., 2001) (see Figures 21.30–21.35).

Nasal Type NK/T Cell Lymphoma These tumors present with extranodal and extranasal disease with the skin, gastrointestinal tract, spleen, soft tissues, and testis being the commonest sites of involvement. The patients typically have systemic complaints. The skin lesions are polymorphous, ranging from a generalized erythematous macular and papular rash to distinctive subcutaneous nodules that may ulcerate. The survival rate is 10%. Because of striking angiocentricity, a secondary ischemic alteration with ulceration is common. These forms of lymphoma are common in Asia and occur rarely in the United States and Europe (Jaffe et al., 1997; Miyamoto et al., 1998; Natkunam et al., 1999; Mraz-Gernhard et al., 2001). There is an association with EBV infection in over 90% of those cases that represent true NK lymphomas. Morphologically, phenotypically, and genotypically, the cases are identical to nasal NK lymphoma (see Table 21.2). The most common site of involvement is the skin; in one series, 34 of 49 cases showed cutaneous involvement (Kanavaros et al., 2000). In regard to primary cutaneous NK cell and NK-like T cell lymphoma of the nasal type, it would appear that males are involved more frequently than females, with elderly individuals affected preferentially. However, this lymphoma may develop in children, especially in those cases preceded by EBV-associated hydroa-vacciniforme-like lesions/mosquito bite hypersensitivity. The majority of the cases will eventuate with extracutaneous disease within weeks to a few months from the initial skin presentation (Ansai et al., 1997; Miyamoto et al., 1998; Natkunam et al., 1999; Mraz-Gernhard et al.,

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2001). The designation of primary cutaneous NK cell and NK-like T cell lymphoma is used even if there is extracutaneous dissemination within less than 6 months from initial presentation. Involvement of the fat is common and the designation of panniculitislike T cell lymphoma is only used for those cases that show dominant localization of tumor within the subcutis (see Figures 21.30–21.35) (Kumar et al., 1998; Chang et al., 2000).

Aggressive NK Cell Lymphoma The aggressive NK cell lymphoma predominantly affects young patients with a male preponderance. (See Case Vignette 3.) (See Figures 21.2 and 21.17–21.20). Some patients present with hemophagocytic syndrome. There is generalized lymphadenopathy in concert with hepatosplenomegaly (De Lord et al., 1998; Tao et al., 2002; Lima et al., 2003). There is typically significant bone marrow and blood involvement, anemia, leukopenia, thrombocytopenia, and hepatosplenomegaly, but skin involvement is relatively uncommon although we have encountered it and others have reported it (Lima et al., 2003). Circulating large granular lymphocytes are observed. Most patients die of a fulminant process with multiorgan failure and coagulopathy (see Table 21.3) (Hamaguchi et al., 2001; Tao et al., 2002; Murdock et al., 2004). When it does occur, the patients present with an extensive cutaneous eruption characterized by multiple erythematous macules, papules, and plaques on the trunk and extremities. Pathology In the nasal, and nasal type, forms of NK cell and NK-like T cell lymphoma, epitheliotropism, angioinvasion, and subcuticular extension are typical (Wong et al., 1992). The degree of dermal involvement exceeds that seen in the epidermis and the process often extends into the subcutis. The angiocentric infiltrates cause luminal attenuation that induces local tissue ischemia with secondary necrosis. There may also be extensive involvement of the adventitial dermis of the eccrine coil (see Figures 21.4–21.7, 21.9, and 21.30–21.35). In true NK cell lymphomas, cytoplasmic granularity may be seen (Wong et al., 1992). The atypical cells of either the NK cell or NK-like T cell lymphomas are usually medium sized and larger cells with significant nuclear contour irregularity (Wong et al., 1992). The chromatin is arranged in large coarse aggregates within the nucleus as opposed to the closely condensed chromatin that gives a hyperchromatic appearance to nuclei in lesions of mycosis fungoides or pleomorphic T cell lymphoma. The nuclei are usually

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TABLE 21.2 Extranodal NK/T Cell Lymphoma, Nasal Type Clinical Adults Solitary, localized or disseminated plaques and tumors, sometimes ulcerated. Aggressive course due to ensuing extracutaneous dissemination Histomorphology Nodular or diffuse infiltrates characterized by small-, medium- or large-sized pleomorphic cells Immunophenotype CD2, 3ε (cytoplasmic), CD56+ CD3 (surface) − CD30− CD4, usually−; there are rare forms of NK-like T cell lymphoma of the CD4 subset CD8+/− Granzyme+ TIA-1+ EBER-1+ (true NK, less commonly in NK-like T cell lymphoma) Beta F1−/+ γ δ+/− Genetics T cell receptor gene(s) in germ line configuration in true NK lymphomas; however, a TCR-β or TCR-γ δ rearrangement in NK-like T cell lymphomas Therapy Systemic chemotherapy

TABLE 21.3 Aggressive NK Lymphoma Predominantly affects young patients Preponderance of males over females Hemophagocytic syndrome Generalized lymphadenopathy in concert with hepatosplenomegaly Significant bone marrow and blood involvement, anemia, leukopenia, and thrombocytopenia Skin involvement is uncommon Most patients die of a fulminant process with multiorgan failure and coagulopathy

too atypical to warrant consideration of a reactive process. Mitotic activity and individual cell necrosis may be prominent. Cells with a cerebriform appearance are uncommon (see Figure 21.10). While in most cases the cytologic atypia is striking, there are some cases of NK cell and NK-like T cell lymphoma in which the cytology is bland (Chinen et al., 2002). While the infiltrates in nasal and nasal type NK/T cell lymphoma are striking and dense, the biopsy findings in cases of aggressive NK cell lymphoma involving the skin may be subtle (see Figures 21.17–21.21). Skin involvement is uncommon and when it occurs it is usually in the context of a macular skin rash. In our experience, the infiltrates are modest and are mainly in a perivascular array,

typically confined to the superficial dermis. High power magnification reveals marked cytologic atypia. The cells have abundant granular to finely vacuolated cytoplasms. The phenotypic studies will of course be confirmatory. In the one case we examined, EBVencoded RNA (EBER) was focally positive. One study by Kojima and co-workers (2000) assessed the clinicopathological features of five Japanese patients with CD56-positive primary cutaneous lymphomas and found that angiocentric proliferation was more prominent in EBER-1-positive patients than those in whom biopsies were EBER negative. Phenotypic Profile The cells typically express CD56; other markers of mature benign NK cells such as CD16 and CD57 are frequently negative (see Figures 21.10 and 21.20) (Mori et al., 2001). For example, in one study assessing sinonasal NK/T cell lymphoma in the United States, none of 14 cases were positive for CD16 or CD57 (Gaal et al., 2000). The cells may express some T cell associated antigens, most notably CD2 and CD5 (Chan et al., 1986; Jiang et al., 2003). In those cases which are true NK lymphomas there is a lack of expression of BF1 or of TCR-γ or TCR-β rearrangement. Only the cytoplasmic ξ CD3 antigen is reliably positive while staining with polyclonal anti-CD3 may reveal

Biology of NK and NK-like T Cells

negative results. Regarding CD3 staining, many laboratories use a polyclonal CD3, which is directed against the whole CD3 complex being composed of six polypeptides using four different transmembrane CD3 chains including γ , δ, ε, and ζ , there are three different dimers that constitute the CD3 complex: γ ε, γ ε, and ζ ζ . The presence of the entire complex is not needed for staining. In our experience, most NK lymphomas will show some staining for polyclonal CD3, and therefore the gold standard for distinguishing between a true NK cell and NK-like T cell is to establish a germ line configuration for the TCR. EBER staining will usually reveal a few positive neoplastic cells while immunohistochemical stains may be negative. In contrast, the NK-like T cell lymphoma does show surface expression of CD3 and shows TCR-γ or TCR-β rearrangement (Jaffe et al., 1997; Mori et al., 2001). The coexpression of CD56 and CD30 by tumor cells has been associated with a survival advantage compared with those that are CD30 negative (Natkunam et al., 2000). CD43 positivity is common (Takeshita et al., 2000). Expression of TIA and granzyme is variable (see Figures 21.15 and 21.22) (Yamashita et al., 1998). In one study from Japan, the heterogeneity of the phenotypic profile was demonstrated in 88 cases of NK/T cell lymphoma; the tumor cells expressed CD3 ξ , CD5, and CD56 in 88%, 64%, and 28% of cases, respectively. CD57 expression was not seen (Jiang et al., 2003) for either NK or NK-like T cell lymphoma. The cells are typically CD4 and CD8 negative. However, in a minority of cases, the cells are CD8 positive (Case Vignette 2) (see Figure 21.16). The killer cell inhibitory receptor, has been isolated on normal NK lymphocytes, a minor subpopulation of CD8 lymphocytes, and, recently, on neoplastic T lymphocytes in patients with mycosis fungoides and S´ezary syndrome; it is notably absent on nonneoplastic CD4 lymphocytes (Dukers et al., 2001). This new class of molecules has been discovered recently and can modulate the cytotoxic activity of NK and T cells. Two groups of killer inhibitory receptors are known: the immunoglobulin superfamily-like receptors that specifically recognize MHC antigens B and C, and the lectin-like receptors that recognize MHC peptides (Dukers et al., 2001). It has been shown that while both CD8- and CD56-positive NK and NKlike T cell lymphomas expressed TIA, perforin, and granzyme, there is a difference in the pattern of killer cell inhibitory receptor expression (Felgar et al., 1997; Takakuwa et al., 2002). Cytotoxic CD8 lymphomas have a tendency to express many of the killer inhibitory receptors including p58, p70, p140, NKG2, and leukocyte immunoglobulin-like receptor, while the CD56-positive lymphomas only express one of the

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inhibitory receptors, specifically LIR-1. Conversely, the CD8 lymphomas may only express one or two of the cytotoxic proteins as opposed to the expression of many of them in CD56-positive lymphomas (Lei et al., 1997; Foss et al., 2000; Kamarashev et al., 2001). Expression of cutaneous lymphocyte associated antigen has been associated with a poor outcome in cases of nasal type lymphoma (Yoshino et al., 2002). Molecular Studies As true nasal lymphomas represent NK cell lymphomas, the tumors do not show clonal TCR-β rearrangement. Although clonality cannot be detected by TCR gene studies, the detection of a single circularized episome form of EBV in the neoplasm and/or molecular demonstration of X chromosome inactivation in female patients with NK cell lymphoma provides evidence for clonal restriction (Gaal et al., 2000; Siu et al., 2000). Cytogenetics Sakajiri and co-workers (2001) studied the expression profile of the Rb, p53, p15INK4B, p16INK4A, and p14ARF genes in NK/T cell lymphomas. In this study, amplification of the p53 gene was shown in one nasal NK cell lymphoma, and point mutations of the p53 gene in one blastic NK cell lymphoma/leukemia and one chronic NK cell lymphocytosis. Homozygous deletions of p15, p16, and p14 genes were detected in 5 of 31 samples representing 3 cases of nasal NK cell lymphoma and 2 cases of blastic NK cell lymphoma/leukemia. Hemizygous deletion of the Rb gene was shown in one blastic NK cell lymphoma. In other cell lines, complete loss and an aberrant migration of Rb protein expression were observed (Sakajiri et al., 2001). The same group of workers analyzed various oncogenes including NRAS, K-RAS, H-RAS, C-MYC, N-MYC and MDM2 by Southern blot, PCR-SSCP, Western blot analysis, and immunohistochemical staining. They found no point mutations of the RAS family genes, C-MYC and NMYC genes. No overexpression of c-myc protein was detected by Western blot analysis. They found high expression of mdm2 protein in some cases by Western blot analysis. Via immunohistochemical staining another group of authors found overexpression of mdm2 protein in 93% of cases of NK lymphoma excluding chronic NK lymphocytosis (Sugimoto et al., 2002). Other cytogenetic and molecular analyses have shown DNA losses at chromosomes 6q, 11q, 13q, and 17p to be recurrent aberrations in NK cell malignancies (Figure 21.36). Frequent DNA gains are also found in chromosomes 1p, 6p, 11q, 12q, 17q, 19p, and 20q. In the study by Quintanilla-Martinez and coworkers (2001), p53 mutations were associated with

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advanced disease in patients with nasal NK/T cell lymphoma (see Figure 21.36). A complex karyotype has been associated with an aggressive clinical course (Lima et al., 2001). Differential Diagnosis Other extracutaneous lymphomas, which are now considered to be subsets of NK-like T cell lymphomas, include intestinal T cell lymphoma and hepatosplenic T cell lymphoma, but these rarely involve the skin. CD56-positive lymphoblastic lymphoma has been described; its main distinguishing feature is TdT expression. These tumors will manifest mediastinal and nasal involvement (Amo et al., 2000). There are reactive conditions that can be associated with CD56 expression within nonneoplastic T cells (Eksioglu-Demiralp et al., 1999; Kim et al., 1999).

ROLE OF EPSTEIN–BARR VIRUS IN THE EVOLUTION OF NK/T CELL LYMPHOMAS Epstein–Barr virus (EBV) has been detected in mature extracutaneous NK/NK-like T cell neoplasms but not in myeloid/NK cell precursor acute leukemia. Identification of EBV does not have specific prognostic significance, but its role in the propagation of disease is evidenced by the presence of EBV-associated DNA, EBV-encoded nuclear RNA, and clonality of EBV-DNA fragments containing the terminal repeats (Gaal et al., 2002). There are nine latency associated viral proteins comprising six EBNAs and three LMPs (Nagata et al., 2001a, b; Stadlmann et al., 2001). The differences in the patterns of EBV gene transcription are determined by cell phenotypes and the usage of gene promoters. In latency I, EBV-infected cells express only EBNA-1, which is essential for episomal replication. In latency II, the EBNA-1, LMP-1, and LMP-2 genes but not other EBNA genes are transcribed. In addition to latency associated genes, EBV encodes proteins that modulate the host’s immune system and inhibit apoptosis designated BHRF1 and BARF1 (Stadlmann et al., 2001). The latent membrane proteins and EBV-associated nuclear antigens may play an important role in EBV-induced cell transformation (Xu et al., 2001). The latency II pattern of viral gene transcript in the nasal type NK/T cell lymphoma is distinct from that identified in the B cell system and consistent with that observed in nasopharyngeal carcinoma. The expression of viral IL-10 and bcl-2 homologue might be responsible for tumor progression by interference with the host immune system and

apoptosis, respectively. The restricted expression of the latency associated EBV genes and the production of IL-10 and bcl-2 may favor tumor growth, promoting evasion of host immune surveillance (Gaal et al., 2002; Imashuku, 2002; Cheung et al., 2003). Necrosis is a characteristic feature of these neoplasms and may reflect angiocentricity or perhaps a role for enhanced expression of tumor necrosis factor α and nuclear factor κ-B as demonstrated by Northern blot analysis in EBV-positive angiocentric lymphoma cells (Takeshita et al., 2000).

Blastic/Blastoid NK Cell Lymphoma/Agranular CD4-positive CD56-positive Hematodermic Neoplasm Blastic NK cell lymphoma has emerged as a distinctive form of hematologic malignancy with a propensity to involve the skin early in its course (DiGiuseppe et al., 1997; Ko et al., 1998; Ginarte et al., 2000; Aoyama et al., 2001; Rakozy et al., 2001; DuBois et al., 2002). The skin lesions have a violaceous hue and a predilection to involve the trunk, the extremities, and the neck. These tumors are described in non-Asians, typically elderly individuals; the mean age is 59 years. In addition to skin, lymph node and bone marrow involvement is common. Lesions are typically resistant to chemotherapy and most patients die within less than 3 years of diagnosis (Petrella et al., 2005). While the cells are CD56 positive, this hematopoietic malignancy can be easily distinguished from the NK/T cell lymphomas of the nasal type and from the aggressive type. The differences are indicated by the blastoid appearance of the neoplastic cell populace, the lack of EBV association, and a highly characteristic immunophenotypic profile, including CD4 CLA, BDCA-2, TCL-1 and CD123 expression and characteristically absent CD2 and CD3 expression (see Figures 21.37–21.42). However, we have seen CD2 expression in monocytes differentiating along dendritic cell lines has been described (Di Pucchio et al., 2003; Khoury et al., 2002; Petrella et al., 2002; Jay et al., 2006). Gene rearrangement studies will reveal a germ line configuration (see Table 21.4). It has now been established that these neoplasms, in fact, are not of lymphoid derivation; the cell of origin is a plasmacyoid dendritic monocyte (Uchiyama et al., 1998; Gniadecki et al., 2004; Petrella et al., 2004, 2005).

Panniculitis-like T Cell Lymphoma Showing CD56 Positivity Those cases of NK cell and NK-like T cell lymphoma that primarily involve the subcutaneous fat may

Role of Epstein–Barr Virus in the Evolution of NK/T Cell Lymphomas

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TABLE 21.4 Hematodermic Neoplasm Clinical Elderly adults Localized or multifocal violaceous plaques and tumors Lesions located near drainage area of affected lymph nodes Extensive multiorgan disease with bone marrow involvement and/or peripheral blood involvement Rare cases exclusively involving the skin may have a better prognosis with a lesser tendency for extracutaneous spread Histomorphology Monomorphous infiltrate of medium sized cells in dermis and subcutis with epidermal sparing; cells are plasmacytoid dendritic cells of monocytic derivation. Older terminology was blastic NK-like lymphoma, the latter being a misnomer although it is still commonly referred to as blastic NK cell lymphoma; it is not a neoplasm of lymphoid derivation Immunology CD4+ CD56+ CD123+ TIA-1− CD3, CD5, CD20, CD57− CD68, TdT+/− CD7, CD2+/− Genetics Germ line configuration of T cell receptor gene(s) and JH genes Epstein–Barr virus infection has not been implicated Therapy Systemic chemotherapy

be difficult to distinguish from other forms of panniculitis-like T cell lymphoma (Gniadecki et al., 2004; Chattopadhyay et al., 2005). CD56 positivity is seen in less than 10% of cases of panniculitis-like T cell lymphoma. In most cases of CD56-positive panniculitis-like T cell lymphoma, the tumor is not a true NK cell lymphoma, as the cells manifest surface CD3 positivity along with rearrangement of the TCR gene. Both CD56 variants of panniculitis-like T cell lymphoma and other forms of panniculitislike T cell lymphoma will exhibit localization of the infiltrate within the subcutis along with a characteristic rimming of adipocytes by lymphoma cells, often with angiocentricity (Takeshita et al., 1995; Yamashita et al., 1999). The distinction is based on the phenotypic profile and the clinical features. Disseminated multiorgan disease is characteristic for NK/T cell lymphoma including those with dominant localization to the fat; as well, hemophagocytic syndrome is not uncommon.

Chronic Granular Lymphocytosis/Large Granular Cell Leukemia The lymphoproliferative disease of granular lymphocytes (LDGLs) is due to the proliferation of granular lymphocytes (GLs) manifesting a CD8 cytotoxic phenotype with or without CD3 expression; the terms

chronic granular lymphocytosis and large granular cell leukemia are applied interchangeably (Sun et al., 1992). It is considered briefly in the differential diagnosis of NK cell disorders despite a lack of tropism to the skin. Because of the profound immune dysregulation inherent to this disorder, patients can develop cutaneous disease including vasculitis, and this disorder may presage overt NK/T cell lymphoma. The exact definition is one of a granular lymphocytosis greater than 2000/ µL lasting for more than 6 months. In one recent study, the mean age of patients with chronic granular lymphocytosis was 60 years and the mean duration of disease was 59 months. Of interest was an association with recurrent bacterial infection in the majority of these patients and the fact that over 50% of them had classic autoimmune stigmata, underlying solid visceral malignancy or other causes of immune dysfunction. Reported associated disorders include rheumatoid arthritis, pure red blood cell aplasia, HIV infection, and ovarian cancer. While splenomegaly was frequent, other clinical stigmata including lymphadenopathy, skin involvement and type B symptoms were uncommon (Chan et al., 1986; Loughran and Starkebaum, 1987; Semanzato et al., 1987; Rabbani et al., 1999). Frequent hematologic abnormalities included neutropenia and anemia, and in less than half of cases, significant peripheral blood lymphocytosis. Antinuclear cytoplasmic antibodies,

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antinuclear antibodies, and polyclonal hypergammaglobulinemia were among the frequent serologic abnormalities. Molecular studies clearly show the expansion of a clone of T cells that typically express CD8, CD16, CD56, and CD57. Clonality is important to the diagnosis and management but does not, in isolation, establish the diagnosis (Loughran and Starkebaum, 1987; Semenzato et al., 1987; Oshimi, 1988; Sun et al., 1992). To reiterate, there are no specific cutaneous lesions per se. In light of the association with autoimmune disease, malignancy, and recurrent infection, these patients can develop cutaneous lesions such as livedoid vasculopathy, urticarial vasculitis, and recurrent aphthous stomatitis unrelated to their inherent chronic NK-cell lymphocytosis.

Natural Killer-like T Cell Lymphoma of the CD4 Subset: A Rare Variant of Natural Killer Cell Lymphoma to Be Distinguished from the Hematodermic Neoplasm Over 95% of all NK and NK-like T cell lymphomas are either of the null phenotype or are CD8 malignancies. (See Case Vignettes 4 and 5.) Virtually all CD4/CD56positive malignancies involving solid organs do so in the context of the hematodermic neoplasm, a tumor that is now established to be of monocytic lineage. However, there may be an additional form of NK-like T cell lymphoma that does appear to represent the malignant transformation of a well recognized benign CD4/CD56-positive T cell counterpart. Clinical Features We recently encountered two cases that were initially assumed to represent hematodermic neoplasms based on an apparently characteristic phenotypic profile; however, subsequent biopsies revealed that in each case, the tumor was best categorized as a form of true NK-like T cell lymphoma derived from T cells of the CD4 subset. Specifically, the neoplastic cell populace was CD4 and CD56 positive. Subsequent TCR-β studies revealed clonal restriction confirmatory of a T cell neoplasm. The clinical presentation and light microscopic profile were similar to the hematodermic neoplasm from a demographic perspective, with the index cases being a 63 year old man and a 76 year old man. There was a history of myelofibrosis in one patient, which has also been described in patients with hematodermic neoplasm. The younger patient’s presentation was heralded by a distinctive cutaneous presentation of enlarging ulcerative tumor nodules involving the head and neck area, chest, shoulders, and upper back. Staging disclosed bone marrow involvement. His lymphoma

proved to be relatively refractory to a standard cytotoxic chemotherapeutic regimen. The second patient was apparently previously healthy and in this patient we were able to establish a role for EBV in lesional propagation (see Figure 21.29). Both patients died within less than 12 months from presentation. Regarding the literature precedent on CD4 variants of NK cell lymphoma, in one report of two cases, the authors describe two disparate clinical courses, benign in one and aggressive in the second. In another case report the patient showed extensive infiltration of multiple organs including lymph node, peripheral blood, bone marrow, skin, lungs, liver, spleen, and peritoneal cavity by neoplastic T cells manifesting a characteristic phenotype, namely, CD4, CD3, and CD56 positive (Hofbauer et al., 2001; Rakozy et al., 2001). In both of these citations the authors commented on the distinct granular nature of the neoplasm, which was a morphologic feature absent in our cases. There was a fourth case reported in 2004 characterized by an NK cell blastic morphology and phenotypic profile, however, the molecular studies did show a TCR gene rearrangement; the reported case was an adolescent girl who presented with isolated disease involving the skin and without subsequent extracutaneous dissemination (Liu et al., 2004). Light Microscopic Findings The infiltrates assume an effacing pattern with pandermal involvement and a distinct grenz zone of papillary dermal sparing with an uninvolved epidermis. Involvement of the subcutis is characteristic. From a cytologic perspective, the cells have a lymphoblastic appearance, exhibiting round to oval nuclei with inconspicuous nucleoli and relatively abundant vacuolated cytoplasm (see Figures 21.26, 21.27, and 21.30–21.32). Phenotypic Studies The cells show strong CD2, CD3, CD4, and CD56 positivity; they are CD8 and granzyme negative (see Figures 21.25 and 21.28). The CD30 preparation is characteristically negative. Of interest is the identification of a new class of antibodies designated as killer cell inhibitory receptors (KIRs), which were initially found on a subset of NK cells. Subsequent studies have revealed that in addition to NK cells, KIRs can also be detected on a subset of CD8 and on transformed neoplastic CD4-positive lymphocytes. These cells may not manifest cytotoxic granule protein expression in the context of granzyme or TIA as was exemplified by our cases. We did not assess our cases for KIR expression. However one would speculate that these tumors may express killer inhibitor receptors.

Role of Epstein–Barr Virus in the Evolution of NK/T Cell Lymphomas

Molecular Studies Since this is a T cell lymphoma, not surprisingly the TCR-β studies will show clonal restriction. Cell of Origin Despite the rarity of this distinctive neoplasm, with only four previously reported cases, there is a reasonable body of literature describing the benign cellular counterpart, including peripheral blood CD4/CD56-positive lymphocytosis, and reports describing infiltration of tissue by reactive CD4/CD56positive T lymphocytes. In regard to the latter, there is one prior report of an ulcerative lesion of herpes involving the nasopharynx, whereby the massive extent of lymphocytic infiltration raised consideration to a diagnosis of nasal type lymphoma (TaddesseHeath et al., 2003). Subsequent phenotyping revealed an infiltrate that was CD3, CD4, CD5, and CD56 positive; TCR-β studies failed to disclose a monoclonal T cell infiltrate. There were classic herpetic cytopathic changes. The authors postulated that the CD4/CD56positive T cells represented a unique viral response associated with mucocutaneous herpes infection. In a second citation, the authors described an interesting subset of T cells in patients with Behcet’s disease, which were CD4/CD56 positive (Eksioglu-Demiralp et al., 1999). Other autoimmune conditions and/or disease states, such as rheumatoid arthritis, are associated with an increase in the number of peripheral blood CD4/CD56-positive T lymphocytes (Kim et al., 1999). Dysregulation of the FAS/FASL apoptotic pathway may play some role in the association of the expansion

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of a distinctive subtype of T cell with autoimmune disease. In another paper, the authors describe an association between a pleural mesothelioma and an unusual form of large granular proliferation of CD3/CD4/CD56-positive cells lacking CD8 expression (Claudpierre et al., 1998). In addition to reactive expansion, there is a growing body of literature in regard to clonal persistent granular lymphocytosis/leukemia derived from this rare subset of CD56positive granular T lymphocytes (Eksioglu-Demiralp et al., 1999). One study of ten patients with T cell large granular lymphocytic leukemia showed that in those cases that did not express CD16, the lymphocytes were more likely to be of the CD4 subset. In addition, TCR-β studies disclosed clonality confirming a T lymphocytic as opposed to a monocytic derivation. In 2003, Lima and co-workers further expanded our recognition of CD4-positive T cell large cell granular leukemia. They described monoclonal expansions of CD4-positive T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of such cells in a series of 34 consecutive cases of this indolent process (Lima et al., 2003). The main distinguishing feature from CD8-positive T-large granular cell leukemia was the absence of cytopenia and autoimmune phenomena and the frequent presence of concomitant neoplasia. The phenotypic profile showed typical cytotoxic properties including granzyme, CD56, and CD57 expression; the subtype of CD4 T cells was that associated with a Th1 cytokine profile defined by the production of interferon-γ , tumor necrosis factor-α, and interleukin-2.

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CASE VIGNETTES CASE VIGNETTE 1

The patient is an 85 year old woman with a recent diagnosis of sinonasal natural killer cell lymphoma who developed skin nodules. Diagnosis: Nasal NK cell lymphoma secondarily involving the skin. There was no T cell gene receptor rearrangement (Figures 21.4–21.12). Her radiographic imaging studies are illustrated in Figure 21.1.

FIGURE 21.4

There is a striking nodular pandermal infiltrate that involves the subcutaneous fat.

FIGURE 21.5

There is extensive involvement of the subcutaneous fat with expansion of the interstitium by atypical lymphocytes, although largely unaccompanied by significant fat necrosis.

FIGURE 21.6 The infiltrate within the fat closely mimics panniculitis-like T cell lymphoma. The most useful distinguishing feature is the presence of striking overlying dermal involvement.

FIGURE 21.7

Within the dermis the nodular aggregates of severely atypical lymphocytes manifest a characteristic predilection for venules and small arteries with expansion of the vessel wall by lymphocytes. Although there is prominent infiltration of the vessel wall and perivascular connective tissue by neoplastic lymphocytes, there is no frank necrotizing alteration of the vessel wall.

Case Vignette 1

(a)

(b)

FIGURE 21.8 Prominent angioinvasion is noted. At disparity with the infiltration of the vessel wall is a lack of luminal and/or mural fibrin deposition.

(a)

(b)

FIGURE 21.9 High power (100× objective) magnification reveals the atypical cytomorphology. The cells are a mixture of small and intermediate sized lymphocytes that demonstrate a finely dispersed chromatin with multiple chromocenters and conspicuous, although not unusually prominent, nucleoli. The cytoplasm is abundant and eosinophilic in quality. Although nuclear contour irregularity is observed, a significant cerebriform/S´ezary cell component is not seen.

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(Continued)

FIGURE 21.10 This is a CD56 preparation, which shows extensive staining of the tumor cells with prominent cytoplasmic membrane staining.

In this immunohistochemical preparation for granzyme there is granular cytoplasmic staining. Note the characteristic dot-like staining pattern.

FIGURE 21.11

This immunohistochemical preparation for polyclonal CD3 shows intracytoplasmic staining with perinuclear accentuation. In general, the assessment regarding CD3 staining (i.e., cytoplasmic versus cytoplasmic and membrane) cannot be reliably made on paraffin-embedded tissue. CD3 epsilon, which is not illustrated, stains exclusively the cytoplasmic portion of the CD3 molecule; it is positive in NK cell lymphomas. If a polyclonal preparation for CD3 is used, many true NK cell lymphomas are positive since staining does not require an intact and complete CD3 molecule to manifest a positive reaction. The gold standard for separating NK and NK-like T cell lymphomas is still based on demonstrating a germ line configuration of the T cell receptor gene in the setting of NK cell lymphoma.

FIGURE 21.12

Case Vignette 2

CASE VIGNETTE 2

The patient is a 45 year old woman who presented with an intranasal mass. Diagnosis: Nasal NK-like T cell lymphoma (Figures 21.13–21.16).

FIGURE 21.13 Sections show a diffuse infiltrate of atypical lymphocytes with by discrete perinuclear halos.

FIGURE 21.14 The cells appear small and well differentiated. The most conspicuous abnormality is one of a fine condensed chromatin and nuclear contour irregularity with discrete pericellular halos.

FIGURE 21.15 The cells are diffusely granzyme positive. They were also positive for CD56.

FIGURE 21.16 The cells express CD8. Given the presence of a TCR-γ rearrangement, however, the tumor is clearly an NK-like T cell lymphoma. While most NK-like T cell lymphomas are of null phenotype, in a small percentage of cases the cells will be of the CD8 subset.

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CASE VIGNETTE 3

The patient is a 23 year old man, previously well, who developed profound respiratory failure, a macular and papular skin rash, hepatosplenomegaly, and coagulopathy. Peripheral blood studies revealed a clonally restricted CD8+ CD56+ lymphocytosis with high EBV titer. Diagnosis: Aggressive NK-like T cell lymphoma/leukemia. The patient died (Figures 21.17–21.21). His radiographic imaging studies are shown in figure 21.2.

Low power examination shows a relatively banal appearing infiltrate. There is a modest perivenular lymphocytic infiltrate with focal permeation of the interstitium. Skin disease is uncommon in this variant of NK cell lymphoma and when it occurs the findings are usually in the context of a modest perivascular lymphocytic infiltrate as illustrated here. Nevertheless, closer inspection of the infiltrate along with phenotypic studies suggest a CD8 natural killer cell disorder.

FIGURE 21.17

FIGURE 21.18 Higher power magnification shows the pleomorphism of this angiocentric population. The lymphocytes are small, intermediate, and larger forms in the 7–20 µm size range with significant nuclear hyperchromasia and nuclear contour irregularity.

Phenotypic studies reveal that many of the large atypical cells are of CD8 subtype.

FIGURE 21.19

Case Vignette 3

FIGURE 21.20 The cells were CD56 positive (illustrated) and stained focally with EBER (not illustrated).

The cells manifest cytotoxic properties by virtue of prominent granzyme B positivity.

FIGURE 21.21

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CASE VIGNETTE 4

The patient is a 63 year old man with a fulminant clinical course. The patient presented with multiple skin nodules in concert with fatigue and night sweats. Investigations revealed multiorgan disease. He died within 6 months. Diagnosis: NK-like T cell lymphoma of the CD4 subset as a simulator of hematodermic neoplasm (Figures 21.22–21.25).

(a)

(b)

(c)

(d)

FIGURE 21.22 The biopsy shows a striking pandermal nodular infiltrate assuming an interstitial, perivascular, and periadnexal disposition with dermal effacement. There is extension into the subcutis.

Case Vignette 4

FIGURE 21.23

The infiltrate is largely nonepider-

motropic.

Higher power magnification reveals that the cells are intermediate in size, manifesting a markedly atypical but monomorphic appearance. The cells have round to oval nuclei, which are eccentrically disposed and are associated with a perinuclear hof.

FIGURE 21.24

417

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(Continued)

(a)

(b)

(c)

The cells are CD56, CD43, and CD4 positive. The obvious diagnosis from a clinical, light microscopic, and phenotypic perspective, of course, is one of hematodermic neoplasm. However, molecular studies confirmed the presence of a T cell receptor gene rearrangement (a) CD56; (b) CD43; (c) CD4.

FIGURE 21.25

Case Vignette 5

CASE VIGNETTE 5

The patient is a 76 year old man with cutaneous nodules, fatigue, peripheral blood lymphocytosis and lymphadenopathy. Diagnosis: NK-like T cell lymphoma of the CD4 subset (Figures 21.26–21.29).

A skin biopsy is remarkable for a superficial and mid-dermal effacing infiltrate that was non epidermotropic. FIGURE 21.26

(a)

(b)

(c)

Higher power magnification reveals a mixed population of cells comprising small, intermediate, and larger forms with nuclei ranging in quality from being round to oval to those with irregular contours. In addition, the cytoplasm is abundant with villous projections.

FIGURE 21.27

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(Continued)

(a)

(b)

(c)

The cells are CD3 (a), CD4 (b), and CD56 (c) positive and the TCR studies show a TCR-β rearrangement.

FIGURE 21.28

FIGURE 21.29

The cells are focally EBER positive.

Case Vignette 6

CASE VIGNETTE 6

The patient experienced sudden onset of multiple violaceous nodules on the trunk and subsequently developed lymph node and lung involvement. Diagnosis: Primary cutaneous nasal type NK cell lymphoma (Figures 21.30–21.36).

FIGURE 21.30 Sections show a striking diffuse large cell pleomorphic infiltrate associated with tumor cell necrosis.

FIGURE 21.31 Higher power magnification shows extensive tumor cell necrosis.

FIGURE 21.32 There is angioinvasion with infiltration of the vessel wall by tumor cells with associated mural necrosis.

FIGURE 21.33

There are sheets of macrophages manifesting erythrocyte phagocytosis, another feature of natural killer lymphomas. The clinical correlate of this finding is one of hemophagocytic syndrome.

421

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(Continued)

A monoclonal CD3 preparation fails to show significant immunoreactivity of the tumor cells for CD3, corroborative of a diagnosis of a natural killer cell lymphoma.

FIGURE 21.35 The cells show a striking proliferation index with more than 70% of the cells demonstrating nuclear staining for Ki-67.

FIGURE 21.34

1

2

3

6

7

8

13

14

15

19

20

4

9

10

16

21

22

5

11

12

17

18

X

Y

46,XY,del(6)(q13q15)

FIGURE 21.36 A chromosome 6q deletion has been described in natural killer cell and natural killer-like T cell lymphomas. (Cytogenetics interpreted and prepared by Dr. Nylan Heerema, Director of Cytogenetics, The Ohio State University).

Case Vignette 7

CASE VIGNETTE 7

423

The patient presented with multiple skin nodules and peripheral blood and bone marrow involvement. The patient had an established diagnosis of acute myelogenous leukemia. Diagnosis: Hematodermic neoplasm (Figures 21.37–21.40).

(a) FIGURE 21.37

(b)

The biopsy shows a striking mononuclear cell infiltrate that effaces the dermal architecture.

(a)

(b)

Higher power magnification reveals intermediate to large cells with a finely dispersed chromatin and abundant eosinophilic cytoplasm.

FIGURE 21.38

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(Continued)

The cells do not show any pan T cell marker immunoreactivity. They are CD4 positive.

FIGURE 21.39

FIGURE 21.40

The cells are CD56 positive.

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CHAPTER TWENTY-TWO

LYMPHOMATOID GRANULOMATOSIS (LYG) Cynthia M. Magro and A. Neil Crowson

INTRODUCTION Lymphomatoid granulomatosis (LYG) typifies the concept of progressive lymphogenesis generated by the combination of a lymphotropic viral trigger in concert with underlying immune dysregulation. This distinctive entity was first described in the medical literature by Liebow and co-workers 34 years ago (Liebow et al., 1972). The authors identified patients with angiocentric and angiodestructive lesions involving the lungs and other extranodal sites, in whom it was initially unclear as to whether the disease process was neoplastic or inflammatory. It was recognized, however, that there was a clinical course analogous to a high-grade hematopoietic malignancy even though the histomorphology raised consideration to a reactive process. In particular, the latter was suggested by virtue of a destructive necrotizing vasculitis with a polymorphous infiltrate that included many inflammatory cells. In an act of foresight, the authors indicated that a search for antibodies to Epstein–Barr virus (EBV) or for the virus itself might be critical in establishing the etiology. The first documentation in the literature that established a potential association between EBV and LYG was by Veltri and co-workers (1982). The authors encountered a case of LYG in which lymphoid cells in a patient with antibodies to EBV expressed EBV-encoded antigens

(Veltri et al., 1982). It has since been established that the process is one of a dysregulated CD4 T cell response to EBV-infected B cells (Medeiros et al., 1992; Peiper, 1993). The combination of an inadequate host response in concert with EBV-associated B cell immortalization creates a milieu conducive to malignant transformation into a large B cell lymphoma (Guinee et al., 1994). Lymphomatoid granulomatosis shares some features with other forms of angiocentric T cell lymphoma and natural killer cell lymphomas, namely, disease localization to extranodal sites and an angioinvasive and destructive tendency (Guinee et al., 1994; Lin, 1999). In fact, this category of lymphoproliferative disease has been designated as angiocentric immunoproliferative lesion (AIL) and encompasses LYG and other forms of lymphoma manifesting striking angiocentricity, and angiodestruction. Included in the category of non-LYG angioimmunoproliferative dyscrasias are natural killer cell lymphoma and natural killer-like T cell lymphoma (Jaffe et al., 1996; Jaffe and Wilson, 1997). The latter frequently manifest sinonasal localization and have previously fallen under the alternative appellations of lethal midline granuloma and polymorphic reticulosis (Lipford et al., 1988). While all of these lymphomas are types of angioimmunoproliferative disorders, they are histogenetically distinct.

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 429

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This chapter focuses exclusively on LYG. The term LYG is a misnomer as the lesion is not granulomatous morphologically. The name stems from the combination of multiple radiographic nodules resembling pulmonary granulomatous disease such as mycobacterial infection or Wegener’s granulomatosis in concert with a low power microscopic appearance of nodular zones of tissue necrosis accompanied by a palisade of mononuclear cells. Unlike benign reactive necrotizing granulomatous disorders, these lesions exhibit a dominant pattern of infiltration of blood vessels, leading to ischemic necrosis. The infiltrating cell is predominantly of lymphocytic derivation rather than representing a histiocyte (McNiff et al., 1996; Guinee et al., 1998), although varying numbers of histiocytes are also seen. Clinical Features (See Table 22.1) The clinical presentation is an extranodal one with a tendency to involve the upper and lower respiratory tracts, central and peripheral nervous system, kidney, and skin (Liebow et al., 1972). In most patients the initial clinical presentation is predominantly referable to the lungs; the cardinal manifestations are those of cough, dyspnea, and/or chest pain. In 20% of cases, however, the initial manifestation is one of a peripheral neuropathy in concert with skin disease (Figure 22.1). Patients of all ages can be affected including children (Lipford et al., 1988; Guven and Baskin, 2001). Approximately 20% of patients have leukopenia and/or lymphopenia or, rarely, lymphocytosis (Angel et al., 1994; Magro et al., 1994; Beaty et al., 2001). Untreated, the median survival tends to be under 2 years. Survival is inversely proportional to the grade of the lesions. Immune dysregulation is a critical aspect of the clinical presentation of LYG; the disease has thus been described in diverse settings including Sjogren’s ¨ syndrome, Wiskott–Aldrich syndrome (Ilowite et al., 1986), rheumatoid arthritis, hepatitis C and human immunodeficiency virus infection, and solid organ transplantation (Peiper 1993; Haque et al., 1998; Tas et al., 2000; Sebire et al., 2003). In regard to the latter, LYG has now been recognized as a distinct form of post-transplant lymphoproliferative disorder as exemplified by one transplant recipient who developed a diffuse large cell B cell lymphoma with features of LYG (Saxena et al., 2002). There are cases described of primary cutaneous LYG (Angel et al., 1994; Tawfik et al., 1994; Sebire et al., 2003). Histopathology Three grades of LYG are recognized (Lipford et al., 1988; Jaffe and Wilson, 1997). Grade I lesions

The patient presented with concurrent lung and skin nodules. As with many hematologic dyscrasias, the lesions manifest as raised nodular plaques with a deep violaceous color. A diagnosis was made of lymphomatoid granulomatosis.

FIGURE 22.1

manifest a lymphomatoid vascular reaction (see Table 22.2) characterized by angiocentric nodular cuffs of lymphocytes and histiocytes that surround and permeate blood vessels. The caliber and types of affected vessels are mainly venules, arterioles, and small arteries. This may result in obliteration of the vascular architecture. Luminal attenuation may lead to ischemic necrosis. Immunophenotypically, the infiltrate is composed of a mixture of T cells and histiocytes. There is striking dominance of CD4-positive lymphocytes over those of CD8 phenotype (see Figures 22.2, 22.3, 22.5, and 22.6). There are a few scattered large immunoblastic B cells. In grade II lesions, the number of large atypical B immunoblasts is increased, but without confluent nodular or sheet like foci. In grade III lesions, there is a sheet-like proliferation of transformed pleomorphic B cells. The malignant infiltrate may assume a nodular, diffuse, or predominantly angiocentric pattern. In situ reverse polymerase chain reaction studies almost invariably demonstrate localization of EBV transcripts to the large atypical B cell population in all grades of LYG (see Figures 22.7 and 22.8). The lymphoma that develops in these patients is a form of EBV-related large B cell lymphoma (see Figure 22.9) (Katzenstein et al., 1979; Medeiros et al., 1992; Myers et al., 1995; Jaffe and Wilson, 1997; Haque et al., 1998), as revealed by staining of the neoplastic cells for latent membrane protein. In early lesions of LYG, the vascular pathology can assume two dominant patterns: one is characterized by extensive infiltration of the vessel by CD4-positive lymphocytes unaccompanied by vessel wall injury (see Figures 22.3, 22.5, and 22.6).

Introduction

431

TABLE 22.1 Lymphomatoid Granulomatosis Clinical Adults Skin lesions in the setting of multiple pulmonary nodules and central nervous system involvement Histomorphology Grade 1 : angio-obliterative panmural vascular infiltrates dominated by small reactive CD4 lymphocytes with only few EBV positive large B cells with attendant ischemic necrosis Grade 3 : large cell B cell lymphoma, typically EBER positive, arising in a background of a reactive T cell rich lymphomatoid vascular reaction. Of interest the malignant B cells may show inherent angiocentricity at variance with classic large B cell lymphoma Immunophenotype CD20+ (large B lymphocytes) CD3, 4+ (reactive small lymphocytes) EBV+ (large B lymphocytes) Very few CD8 lymphocytes reflecting an inherent deficiency of this cell population which allows unrepressed growth of the EBV infected B cells Genetics Monoclonal rearrangement of the JH gene; potentially may see a restricted T cell repertoire amidst the florid lymphomatoid reactive T cell populace Therapy Systemic chemotherapy; interferon-α

TABLE 22.2 Primary Cutaneous Lymphomatoid Vascular Reactions Neoplastic Conditions: Natural killer (NK) and NK like T cell lymphomas Primary cutaneous CD8 positive epidermotropic Cytotoxic T cell lymphoma Lymphomatoid papulosis Grade III lymphomatoid granulomatosis Reactive conditions in the setting of iatrogenic Immune dysregulation Reversible T cell dyscrasia induced by drug therapy Polymorphic post transplant lymphoproliferative disease Reactive conditions in the setting of endogenous immune dysregulation Collagen vascular disease Reactive conditions in the setting of viral infection Hydroa vacciniforme like eruptions related to EBV infection Human immunodeficiency virus infection Hepatitis C Grade I and II lymphomatoid granulomatosis

Due to the inherent immune dysregulation present in patients with LYG, the reactive T cell infiltrate may exhibit atypical cytomorphologic (in essence pseudolymphomatous) features defining a form of lymphomatoid hypersensitivity (Liebow et al., 1972;

Guinee et al., 1994). The second pattern is one characterized by fibrinoid necrosis of the vessel wall. The vascular damage may be mediated by the chemokines IP-10 and Mig, which are overexpressed in involved tissues. The basis for the upregulation of these chemokines likely reflects latent EBV infection within the neoplastic cells. EBV latent membrane protein can cause upregulation of both IP-10 and Mig, which have been shown to cause endothelial and vascular damage including fibrinoid necrosis (Teruya-Feldstein et al., 1997). Striking involvement of subcutaneous fat may cause a resemblance to panniculitis-like T cell lymphoma (Baselga et al., 1997); however, the dominant infiltrate is of CD4 subset and does not exhibit the characteristic cytotoxic CD8 profile that is observed in most cases of panniculitis-like T cell lymphoma. In summation, LYG in its inceptive and intermediary stages is an immune dysregulatory disorder of angiocentrically disposed reactive T cells triggered by EBV-infected B cells. The tissue destruction is attributable to the reactive T cells and/or neoplastic B cells, the latter defining its oncogenic endpoint. Histogenesis EBV infection lies at the heart of LYG and is intrinsically linked to all aspects of its pathogenesis and pathophysiology (Veltri et al., 1982; Medeiros et al., 1992; Myers et al., 1995; Nicolson et al., 1996; Jaffe and Wilson, 1997). The initial lesions

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of LYG comprise a reactive T cell infiltrate with a variable admixture of plasma cells, histiocytes, and rare transformed cells. This initial low grade lesion is likely reflective of an abnormal immune response to a small number of EBV-infected B cells consistent with a viral associated lymphomatoid hypersensitivity reaction in the setting of underlying systemic immune dysregulation. If the normal T cell defense mechanisms fail to suppress this clone (as might be expected in patients with intrinsic T cell dysfunction), neoplastic transformation is postulated to ensue when the transformed lymphocytes are exposed to additional oncogenic hits to culminate in a large B cell lymphoma. Of interest, the role of EBV in the propagation of the skin lesions is less consistent. Angel and co-workers (1994) evaluated 10 biopsies from 7 cases of primary cutaneous lymphomatoid granulomatosis using in situ hybridization for the presence of EBV-encoded RNAs (EBER-1 and EBER-2). Only one case showed EBER expression. Clonality Studies In NK and NK-like T cell lymphoma, EBV detected by molecular hybridization studies has been localized to T lymphocytes, in contrast to the dominant EBV B cell localization in the setting of LYG (Jaffe et al., 1996; Jaffe and Wilson, 1997). The EBV-associated genome has a uniform configuration consistent with a clonal process. Sixty percent of cases exhibit B cell clonality, representing in most cases higher grade lesions (grade II/III). In addition, different B cell clones may be isolated at different sites in a given patient with LYG. TCR-β and TCR-γ rearrangements can also occur since overexpansion of an epitope-specific T cell clone or a few T cell clones (i.e., a restricted repertoire) may occur in the setting of endogenous immune dysregulation, the latter defining the inherent immunologic milieu that is associated with LYG. Differential Diagnosis (See Table 22.2) The differential diagnosis encompasses those states in which atypical lymphoid infiltrates manifest prominent angiocentricity. These states can be broadly categorized into (1) reactive conditions such as lymphomatoid vasculitis as a sequel of viral infection including in the context of polymorphic post-transplant lymphoproliferative disorder, connective tissue disease, and drug-induced immune dysregulation, and (2) endogenous angiocentric T cell dyscrasias (Magro et al., 1994, 1997). The latter encompass natural killer cell and natural killer-like T cell lymphomas, which are considered in detail

in Chapter 21 (Jaffe et al., 1996; Kim et al., 1998; Uchiyama et al., 1998), primary cutaneous CD8positive epidermotropic cytotoxic T cell lymphoma, discussed in Chapter 18, as well as lymphomatoid papulosis (Chapter 23) (see Table 22.2). Viral infections including those associated with human immunodeficiency virus infection can mimic the histomorphology of the angioimmunoproliferative lesion and, if there is superimposed EBV infection, progression to true T-cell-rich angiocentric B cell lymphoma can ensue (Gold et al., 1990). LYG is closely linked with post-transplant lymphoproliferative disease (PTLD). Both are EBV-mediated processes, whereby the aberrant cell with neoplastic potential is of B cell lineage and there is a background population of reactive T cells. In fact, LYG has not been included as part of the clinical and morphologic spectrum of PTLD; there are cases of LYG developing in the post-transplant setting (Tas, et al. 2000). Much of the tissue destruction observed in these settings of immune dysregulation and low level EBV infectivity is mediated by a reactive CD4-positive T cell infiltrate. It would be reasonable to state that in polymorphic PTLD and grade I and grade II lesions of LYG the dominant basis of the inflammatory cell infiltrate is a reactive, albeit potentially oligoclonal one, responding to a viral epitope found within a minor cell population of EBV-infected B cells (Guinee et al., 1994; Savoia et al., 1994; Weschler et al., 1998; Morice et al., 2002). The sequence of oncogenic events leading to ensuing malignant B cell transformation, therefore defining grade III LYG or monomorphic variants of PTLD, is complex. While the T cell infiltrate in both lymphomatoid papulosis and LYG is largely of the CD4 subset, the neoplastic cell in the former disorder manifests CD30 positivity and cytotoxic features. It is uncommon in LYG to see supervening tissue eosinophilia in contrast to its frequent observation in lesions of lymphomatoid papulosis. The angiocentric T cell and natural killer cell lymphomas are malignant angiodestructive processes and contrast with the reactive polyclonal and oligoclonal patterns observed in grade I and grade II LYG. In regard to grade I and grade II LYG, there is indeed striking morphologic and even phenotypic overlap between LYG and the reactive lymphomatoid vasculitic responses seen in the setting of viral infection and collagen vascular disease (Magro C, 1996). The hallmark of natural killer cell lymphomas is a germ line configuration of the T cell receptor and cytoplasmic confinement of CD3 expression without concomitant surface expression and CD56 positivity. The T cells are either double negative or express CD8.

Introduction

These cells frequently express cytotoxic proteins such as TIA, granzyme, and perforin (Jaffe et al., 1996). In contradistinction, only in a minority of cases will LYG progress to lymphoma and then it is one of B cell lineage; most patients die as a consequence of the immunosuppression inherent to this condition. The T cells that are, in essence, reactive are primarily of the CD4 subset and basically ineffectual as a cytotoxic viral defense. Treatment Treatment modalities have included corticosteroids for early minimal disease, but for more advanced lesions, cyclophosphamide and aggressive combination chemotherapy are indicated.

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Interferon-α 2b, because of its antiviral, antiproliferative, and immunomodulatory effects, has also been suggested (Wilson et al., 1996). Dosing regimens have included cyclophosphamide at 100 mg and prednisone at 40 mg daily. Among the more recent therapeutic strategies are a reduction in immunosuppression and single agent therapy with rituximab; it is thought that early therapeutic intervention in patients presenting with disease limited to the skin may on occasion lead to lesional resolution (Tong et al., 1992). When skin disease occurs in the setting of known pulmonary involvement, the prognosis is not altered. In contrast, patients with neurologic involvement have a grave prognosis (Katzstenstein et al., 1979; Jaffe and Wilson, 1997).

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CASE VIGNETTE CASE VIGNETTE 1

The patient is a 79 year old woman who simultaneously presented with multiple pulmonary and skin nodules. Diagnosis: Lymphomatoid granulomatosis with features of EBV-associated large cell B cell lymphoma arising from a CD4-dominant lymphomatoid vascular reaction (Figures 22.2–22.9).

There is intraparenchymal necrosis, which reflects an ischemic sequela of the lymphomatoid vascular reaction. There are two forms of lymphomatoid vascular reactions, one representing a T-cell-driven lymphomatoid vasculitis as a (Figures 22.3–22.6) type IV immune reaction to virally infected cells and the other being that of frank B cell lymphoma transgressing the vessel walls (Figures 22.7–22.9). Both forms of vascular reaction have been illustrated and lead to parenchymal nodules of infarcted tissue.

FIGURE 22.2

(a)

(b)

There is a striking angiocentric infiltrate of atypical small lymphocytes and admixed histiocytic forms transgressing the vessel wall with associated segmental mural fibrin deposition and concomitant ischemic necrosis of the surrounding tissue.

FIGURE 22.3

Case Vignette 1

(a)

(b)

Oil immersion (100× objective) magnification reveals that the infiltrate is composed of twisted serpentine histiocytic forms with admixed smaller lymphocytes. It should be emphasized that in lymphomatoid vasculitis the majority of cells within the vessel wall are in fact not neoplastic but rather are of T cell and histiocytic derivation, responding to a few EBV-infected cells.

FIGURE 22.4

These T cells are also mainly of the CD4 phenotype, indicative of a relative CD8 deficiency. The expected T cell responding to a viral infection would be one of CD8 lineage.

FIGURE 22.5

In contrast, the CD8 preparation is virtually negative.

FIGURE 22.6

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Lymphomatoid Granulomatosis (LYG)

(Continued)

(a)

(b)

FIGURE 22.7 In other areas there is a sheet-like proliferation of transformed pleomorphic immunoblastic cells. The same pleomorphic infiltrate also shows striking transgression through vessel walls. Note the significant difference in cytomorphology between this overtly malignant large B cell lymphoma and the T-cell-rich lymphomatoid vascular reaction depicted in earlier figures.

FIGURE 22.8 A CD20 preparation decorates the pleomorphic large cell population.

In situ hybridization studies for Epstein–Barr virus reveal nuclear localization to the neoplastic large cell B cell population.

FIGURE 22.9

References

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MAGRO CM, CROWSON AN, HARRIST TJ. Atypical lymphoid infiltrates in cutaneous lesions of connective tissue disease. Am J Dermatopathol. 1997; 19(5):446–455. MCNIFF JM, COOPER D, HOWE G, et al. Lymphomatoid granulomatosis of the skin and lung. An angiocentric T-cell-rich B-cell lymphoproliferative disorder. Arch Dermatol. 1996; 132(12):1464–1470. MEDEIROS LJ, JAFFE ES, CHEN YY, WEISS LM. Localization of Epstein–Barr viral genomes in angiocentric immunoproliferative lesions. Am J Surg Pathol. 1992; 16(5):439–447. MORICE WG, KURTIN PJ, MYERS JL. Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol. 2002; 118(3):391–398. MYERS JL, KURTIN PJ, KATZENSTEIN AL, et al. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein–Barr virus infection. Am J Surg Pathol. 1995; 19(11):1300–1312. NICHOLSON AG, WOTHERSPOON AC, DISS TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein–Barr virus-associated B-cell lymphoma. Histopathology. 1996; 29:317–324. PEIPER S. Angiocentric lymphoproliferative disorders of the respiratory system: incrimination of Epstein–Barr virus in pathogenesis. Blood. 1993; 82(3):687–689. SAVOIA P, NOVELLI M, BERTERO M, BERNENGO MG. Adhesion molecules in lymphomatoid granulomatosis. Dermatology. 1994; 189(1):9–15. SAXENA A, DYKER KM, ANGEL S, MOSHYNSKA O, DHARAMPAUL S, COCKROFT DW. Posttransplant diffuse large B-cell lymphoma of ‘‘lymphomatoid granulomatosis’’ type. Virchows Arch. 2002; 441(6):622–628. SEBIRE NJ, HASELDEN S, MALONE M, DAVIES EG, RAMSAY AD. Isolated EBV lymphoproliferative disease in a child with Wiskott–Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol. 2003; 56(7): 555–557. TAS S, SIMONART T, DARGENT J, et al. [Primary and isolated cutaneous lymphomatoid granulomatosis following heart–lung transplantation.] Ann Dermatol Venereol. 2000; 127(5):488–491. TAWFIK N, MAGRO CM, CROWSON AN, et al. Lymphomatoid granulomatosis presenting as a solitary cutaneous nodules. Int J Dermatol. 1994; 33(3):188–189. TERUYA-FELDSTEIN J, JAFFE ES, BURD PR, et al. The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein–Barr virus-positive lymphoproliferative disease. Blood. 1997; 90(10):4099–4105. TONG MM, COOKE B, BARNETSON RS. Lymphomatoid granulomatosis. J Am Acad Dermatol. 1992; 27(5 Pt 2):872–876. UCHIYAMA N, ITO K, KAWAI K, et al. CD2−, CD4+, CD56+ agranular natural killer cell lymphoma of the skin. Am J Dermatopathol. 1998; 20(5):513–517. VELTRI RW, RAICH PC, MCCLUNG JE, SHAH SH, SPRINKLE PM. Lymphomatoid granulomatosis and Epstein–Barr virus. Cancer. 1982; 50:1513.

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CHAPTER TWENTY-THREE

CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDERS INCLUDING LYMPHOMATOID PAPULOSIS, BORDERLINE CD30-POSITIVE LYMPHOPROLIFERATIVE DISEASE, ANAPLASTIC LARGE CELL LYMPHOMA, AND T-CELL-RICH CD30-POSITIVE LARGE B CELL LYMPHOMA Cynthia M. Magro and A. Neil Crowson

INTRODUCTION The spectrum of CD30-positive lymphoproliferative disorders encompasses lymphomatoid papulosis (LYP), primary cutaneous and secondary anaplastic

Ki-1 large cell lymphoma (ALCL), borderline CD30positive lymphoproliferative disorder, Hodgkin lymphoma either primarily or secondarily involving the skin, and CD30-positive large B cell lymphoma (Louvet et al., 1996). In one study that addressed the

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 439

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spectrum of CD30-positive cutaneous lymphoproliferative lesions, ALCL comprised 45% of cases, LYP 17% of cases, borderline lesions 16% of cases, non-Hodgkin lymphoma of the nonanaplastic subtype 20% of cases, and Hodgkin lymphoma 1% of cases (Paulli et al., 1995). Lymphomatoid hypersensitivity reactions including persistent arthropod bite reactions, cutaneous herpes infections, and certain chemotherapy reactions may also be associated with reactive CD30-positive hematopoietic infiltrates (Nathan and Belsito, 1998; Hwong et al., 2001; Gallardo et al., 2002). Leinweber et al., 2006). The diverse spectrum of cutaneous lesions associated with CD30 expression reflects the nature of the CD30 molecule and the various cell types that can express it, including mitotically active cells of monocytic, B cell, or T cell lineage. CD30 expression does not equate to a neoplastic event and can be identified in a minority of reactive T or B lymphocytes and in lymphocytes exposed to transforming viruses such as Epstein–Barr virus (EBV) and HTLV-1 (Stein et al., 1985). The CD30 antigen was first detected on Reed–Sternberg cells of Hodgkin lymphoma but has since been described in stimulated or transformed peripheral blood T or B cells, T cell and B cell lymphoma lines, and myeloid cell lines (Stein et al., 1985; Chiarle et al., 1999). In paraffin embedded tissue, an epitope of the CD30 molecule which is preserved following formalin fixation is detected with the BerH2 antibody (Schwarting et al., 1989). Ki-1 is an antibody that detects a much greater proportion of the CD30 molecule on frozen tissue and hence is a more sensitive assay for CD30 expression. A monoclonal antibody raised against a Hodgkin disease cell line in 1982 (Stein et al., 1985, 2000), Ki-1 was subsequently shown to be expressed not only by the malignant cells in Hodgkin disease but also by a small percentage of lymphoid cells in the parafollicular regions of normal lymph nodes (Stein et al., 1985). The Ki-1 antigen, subsequently designated the CD30 cluster, was identified as an activation antigen that could be expressed even on activated histiocytes (Stein et al., 2000). It is part of the growth factor tumor necrosis factor family. The gene encoding the CD30 molecule is found on chromosome 1p36 (Fonatsch et al., 1992; Gruss et al., 1996).

a benign clinical course but a malignant-appearing histology (Macaulay et al., 1968). In that original paper the waxing and waning nature of the eruption with the tendency for spontaneous resolution and subsequent recurrence was emphasized. Our understanding of LYP has been refined over the years and we now consider this condition a form of endogenous cutaneous lymphoid neoplasia that in most cases has a clinical course that is self-limited. Clinical criteria currently used to diagnose LYP are: (1) multiple papules or nodules; (2) spontaneous regression or waxing and waning of lesions that often heal with a scar; (3) no evidence of progression to a diameter in excess of 3 centimeters during 3 months of observation without treatment; and (4) absence of lymphadenopathy (Figure 23.1) (Karp and Horn, 1994). Significant advances in the understanding of this disorder have been made over the last decade. Willemze first recognized that there were two distinct variants: type A and type B (Willemze et al., 1983) and we have now expanded our morphologic spectrum to encompass type C LYP as will be discussed presently (Figure 23.2) (Willemze and Beljaards, 1993; El Shabrawi-Caelen et al., 2004). There is a general consensus that LYP is associated with the concurrent or subsequent development of lymphoma in a minority of cases. The incidence of progression to lymphoma is variable but estimated to range between 4% and 20% (Varga et al., 1990; Beljaards and Willemze, 1992; Kadin et al., 2001; Kempf et al., 2002; Steinhoff et al., 2002). Although a variety of associated lymphomas are described in the setting of LYP, including mycosis fungoides, anaplastic large cell lymphoma, and Hodgkin lymphoma (Terao et al., 2000), in our experience the most common is anaplastic large cell lymphoma, typically arising in

Lymphomatoid Papulosis Clinical Features Lymphomatoid papulosis is recognized in the classification schemes of both the WHO and EORTC (Willemze et al., 2005; Slater, 2005). Macaulay (1968) first described this distinctive entity characterized by a recrudescent eruption of nodules or papules with

FIGURE 23.1 Classic lesions of lymphomatoid papulosis. The patient had been developing ulcerative papulo-nodular lesions that underwent spontaneous regression.

Introduction

FIGURE 23.2 In a background of well established LYP, the patient developed a larger lesion, which eventually regressed over a period of a few weeks. The biopsy resembled anaplastic large cell lymphoma. A diagnosis of type C LYP was made. The absolute distinction between type C LYP and anaplastic large cell lymphoma is difficult.

a background of type A or type C LYP (Willemze et al., 1983; Harrington et al., 1989; Kaudewitz et al., 1990, Beljaards and Willemze, 1992; Chott et al., 1996; Basarab et al., 1998; Silva et al., 1998; Wang et al., 1999; Aoki et al., 2001; El Shabrawi-Caelen et al., 2004; Gallardo et al., 2004). Our experience is in contrast to that of El Shabrawi-Caelen and co-workers (2004), who assessed the clinicopathologic features of 85 cases of LYP and found that the majority of patients presented with only one histologic subtype of LYP. Eight of the 85 patients in this series had lymphoma. Of interest, the most frequent subtypes of lymphoma were Hodgkin disease and mycosis fungoides, and not anaplastic large cell lymphoma. These authors also described ‘‘regional’’ LYP. (El-Shabrawi-Caelen 2004). In regard to the morphologic subtypes of LYP, we recognize three variants of LYP based on the architecture and cytomorphologic composition: types A, B, and C (see Table 23.1) (El Shabrawi-Caelen et al., 2004). The least common type is type B LYP, and one would question whether or not such cases may actually represent pityriasis lichenoides. It should also be emphasized that integral to the diagnosis of type C LYP and more specifically its separation from anaplastic large cell lymphoma is the clinical presentation; the clinical picture should not deviate from classic LYP being one of relatively small lesions that undergo spontaneous regression. In classic LYP lesions, whereby the presumptive cell of origin is one of CD4 cytotoxic phenotype, the lesions manifest no

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sex predilection and can occur at any age from infancy to the eighth decade with the median age being in the fourth or fifth decades (Wang et al., 1992; Kadin et al., 2001; Van Neer et al., 2001). This is in contrast to the CD8 variant, where there is a clear predilection to involve young males; in our own series the eruption typically commences in adolescence (Magro et al., 2006). The incidence of LYP ranges from 1.2 to 1.9 per million in New England (Wang et al., 1992). The overall prognosis in those patients who have LYP and then develop lymphoma relates to the presence or absence of extracutaneous lymphoma; those patients with extracutaneous lymphoma have a worse prognosis (Beljaards and Willemze, 1992). Patients with LYP can develop lymphoma or may have concurrent lymphoma. Those patients who have or subsequently develop mycosis fungoides may have type B LYP while those patients with anaplastic large cell lymphoma or Hodgkin lymphoma who have LYP usually have the type A variant (Beljaards and Willemze, 1992; Basarab et al., 1998; Zackheim et al., 2003; Gallardo et al., 2004). It appears that progression of LYP to malignant lymphoma is more frequent in males (Beljaards and Willemze, 1992; Basarab et al., 1998). While most think of LYP in the context of cutaneous disease, there can be intraoral involvement (Chimenti, et al. 2001). In fact, most cases of what is reported as so-called eosinophilic ulcer of the tongue represent LYP (Ficarra et al., 1997); the clinical features are similar to those of LYP, namely, spontaneously regressing lesions with a tendency toward recurrence (Ficarra et al., 1997; Chimenti et al., 2001). From a histomorphologic perspective, the cases resemble either type A or type C LYP. Pathology In classic type A LYP, the dominant low power pattern is that of superficial and deep perivascular, perineural, and eccrinotropic infiltrates associated with variable epidermal hyperplasia (see Figures 23.17, 23.18, 23.21, 23.24, 23.25, 23.27, and 23.31). The hyperplastic changes within the epidermis can be striking and are typically accompanied by prominent infiltration of the epidermis by neutrophils (Cespedes et al., 2000; Scarisbrick et al., 2001; El Shabrawi-Caelen et al., 2004). The infiltrate typically assumes a greater density toward the base of the biopsy as opposed to the classic wedge-shaped morphology that one expects in classic lymphomatoid hypersensitivity reactions. In regard to the angiocentric infiltrates, there is marked expansion and permeation of the vessel by inflammatory cells with

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TABLE 23.1 Lymphomatoid Papulosis Clinical Young adults with recurrent crops of papules and nodules <1 cm that heal within 2–6 weeks without treatment to yield scars Excellent prognosis Histomorphology Four histopathological types: Type A: large, atypical, CD30+ cells in a perivascular array with eccrinotropic accentuation and numerous eosinophils and neutrophils Type B: wedge-shaped or band-like infiltrate of small to medium sized atypical cells with epidermotropism; CD30± Type C: sheets of atypical large cells mimicking anaplastic large cell lymphoma, sometimes with involvement of the subcutis; critical distinction is based on clinical presentation including size of lesion(s) Granulomatous eccrinotropic: nodular expansion of the eccrine coil with sarcoidal granulomas; may be a feature of the CD8 subtype of LYP Immunophenotype CD4, majority of cases CD30+ CD15− CD8−(+) (a small percentage of cases are of the CD8 subtype) Granzyme + CD56 −(+) Fascin + Cytogenetics T(2;5) uncommon, up to 10% of cases in some series

luminal attenuation. It is not uncommon to see supervening mural and/or luminal fibrin deposition. Such necrotizing vasculitic changes are often accentuated in the deeper aspects of the biopsy. Ischemic alterations of the overlying epidermis may be seen. The composition of the infiltrate is mixed, comprising small reactive lymphocytes, larger atypical cells, and eosinophils (El Shabrawi-Caelen et al., 2004). Neutrophils are characteristically observed more superficially and show dominant localization within the epidermis. Granulomatous inflammation can be seen, usually around the blood vessels and the eccrine coil; we coined the term granulomatous eccrinotropic lymphomatoid papulosis for cases showing conspicuous nodular distortion of the eccrine coil with superimposed granulomatous inflammation (see Figure 23.24) (Crowson et al., 2003). Having once identified these distinctive features in LYP, we now recognize it more frequently. The large atypical component ranges in the degree of atypia. In lesions containing a number of small reactive lymphocytes and only a few other inflammatory cell elements, the cells are mononuclear, with a prominent basophilic nucleolus, and nuclear irregularity can be prominent. While most of the cells are mononuclear, occasional binucleated cells can be seen. In some cases there is hypereosinophilia of the cytoplasm with senescent alteration of the nucleus

resulting in a morphology reminiscent of the mummified cell of Hodgkin lymphoma (see Figures 23.19, 23.22). Mitoses are frequent. In cases showing numerous eosinophils and neutrophils, this atypical large cell populace may become more conspicuous both cytologically and quantitatively. The CD8 variant will be discussed in detail, but it differs from the more common form of LYP by virtue of the relative lack of other inflammatory cell elements, the frequent presence of granulomatous foci, and frank vasculitis—a constellation of changes that we attribute to the cytokine milieu associated with this specific T cell subset (Magro et al., 2006). Although we have emphasized the infiltration of the eccrine coil, there may be involvement of the hair follicle (El Shabrawi-Caelen et al., 2004) Case Vignette 2. The cases showing prominent follicular involvement are problematic in their distinction from lymphomatoid variants of eosinophilic folliculitis and pilotropic mycosis fungoides. The greatest dermal infiltration is seen in lesions that are of 2–3 weeks of age. The fully developed type A lesion that is of 2–3 weeks of age frequently contains numerous histiocytes, neutrophils, and eosinophils, with the granulocytic component forming sheets in the superficial dermis and frequently manifesting exocytosis, eventuating in epidermal necrosis, ulceration, and formation of a neutrophil-containing scale-crust (Willemze et al., 1983). Neutrophils may pack the

Introduction

blood vessels. Fibrinoid necrosis of blood vessels and erythrocyte extravasation may be seen at this stage (Willemze et al., 1983) and fibrosis ensues. The so-called type B lesions more closely mimic mycosis fungoides histologically, with band-like infiltrates of small, irregularly contoured lymphoid forms in close apposition to the undersurface of the epidermis. Pautrier’s microabscesses are unusual in both types of lesion and their presence should raise consideration of mycosis fungoides. Some forms of LYP contain clusters and sheets of large atypical mononuclear cells, histologically reminiscent of CD30-positive anaplastic large cell lymphoma, but generally sparing the subcutis. Such cases, which are dominated by large atypical cells, fall under the designation of type C/borderline LYP (see Figures 23.17 and 23.18). Critical to making the diagnosis of type C LYP over one of anaplastic large cell lymphoma are the clinical findings. As noted above, there is a variant of LYP characterized by a prominent nodular lymphocytic and granulomatous infiltrate in apposition to the eccrine coil, whereby the number of neoplastic cells may be few (Crowson et al., 2003). Because of the nature of this infiltrate, the possibility of a reactive process such as secondary syphilis, Lyme disease, a postherpetic eruption, and even collagen vascular disease is raised. As we have already emphasized, it is quite likely that inflammation around the eccrine coil is very common in LYP; it is an important morphologic clue to the diagnosis. For example, in lymphomatoid reactions triggered by exogenous antigen (excluding an arthropod assault where there may be prominent accetuation around the eccrine coil), superficially confined CD30-positive lymphocytic infiltrates with relative sparing of the deep dermis are present, a constellation of findings which would be uncommon in LYP. Conversely, deep-seated collections of CD30-positive cells favor a diagnosis of LYP over lymphomatoid hypersensitivity. It is possible that this form of LYP may be more common in those cases showing a CD8 phenotype as will be discussed later (see Figures 23.23 and 23.29) (Magro et al., 2006). Phenotypic and Molecular Studies It is established that LYP is a lymphoproliferative disorder (Wood et al., 1986; Steinhoff et al., 2002). In patients with LYP uncomplicated by lymphoma, polymerase chain reaction (PCR) amplification analysis revealed a single Vβ7 transcript of identical size in each lesion in any one patient with LYP. In addition, the dominant band from each lesion was excised, reamplified, and directly sequenced, confirming that monoclonality from multiple lesions of patients with

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LYP is derived from a single transformed T cell. This study also showed, through the method of semiquantitative PCR and DNA sequencing, that the atypical lymphocytes in lesions of LYP and lymphoma were identical (Chott et al., 1996). Our own work using the multiplex PCR technique reveals identical T cell clones in lesions of LYP (see Figures 23.47–23.49) (Chott et al., 1996). The large atypical lymphocytes of both type A and type B LYP exhibit pan T cell antigen expression for CD3, CD5, and CD2. The cells are characteristically of the CD4 subtype (Kummer et al., 1997; Kadin M, 1986; Kadin M, 1985). Both the large atypical cells of type A LYP and the large cerebriform cells of type B LYP show positivity for activation markers HLADR, TAC (the antigen for the interleukin-2 receptor), transferrin receptor (T9), and Ki-67. Phenotypic abnormalities are revealed in both subtypes of LYP by virtue of diminished expression of the pan T cell antigens CD62L and/or CD7 (Magro et al., 2005). The cells show variable positivity for CD30 with frequent lack of expression in those cases designated as type B LYP. Although the cells show a cytotoxic phenotype by virtue of prominent granzyme and TIA expression, the cells are CD56 negative and other markers indicative of natural killer cell differentiation are also usually negative (Boulland et al., 2000; Harvell et al., 2002). Nevertheless, there are rare reports of CD56 positivity in lesions of LYP. The phenotypic profile is demonstrated in Figures 23.20a and b, and 23.23 (Bekkenk et al., 2001; Wu and Tsai, 2004). The expression of fascin has also been assessed in patients with LYP and other forms of CD30positive lymphoproliferative disease (Kempf et al., 2002). Fascin is part of a family of actin binding proteins that cause aggregation of filaments into bundles in vitro and may be involved in the migration of tumor cells (Goncharuk et al., 2002; Hashimoto et al., 2005). Fascin is not normally expressed in B or T lymphocytes. However, it has been demonstrated in Reed–Sternberg (RS) cells and in malignant cells of anaplastic large cell lymphoma (Pinkus et al., 1997; Fan et al., 2003). Because there is a similarity between the morphology and appearance of the cells in LYP and anaplastic large cell lymphoma, it would only be logical that fascin is expressed in LYP. Hence, in one study, the expression of fascin was explored. Fascin could be found in cases of LYP; however, overall the detection rate was less compared to systemic lymphoma and anaplastic large cell lymphoma (Kempf et al., 2002). The expression was primarily cytoplasmic in nature. Of interest is the expression of fascin in the CD30-negative cerebriform lymphocytes of type

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B LYP. The greatest degree of fascin expression was encountered in cases of type C LYP. Cytogenetics A characteristic feature of lymph node based anaplastic large cell lymphoma is a distinctive translocation involving the short and long arms, respectively, of chromosomes 2 and 5 (t(2;5) (p23;q35)), detected in up to 65% of cases using a reverse transcription–polymerase chain reaction (RT-PCR) assay to detect the NPM/ALK fusion transcript (LeBeau et al., 1989; Wellmann et al., 1995; DeCoteau et al., 1996; Wood, 1998). The result of the translocation is the expression of a protein designated anaplastic lymphoma kinase (ALK); its expression is intimately associated with and determined by the promoter for nucleophosmin (Wood, 1998). Anaplastic lymphoma kinase is absent in normal lymphocytes. It was postulated that this distinctive translocation might also be seen in other CD30-positive lymphoproliferative disorders including LYP, but studies that have assessed for it and the expression of its product have shown only 10% of cases to manifest this distinctive translocation (Beylot-Barry et al., 1996; Wood et al., 1996; Wood, 1998) (Kadin ME, Morris SW 1998).

CD8 Lymphomatoid Papulosis Although the majority of cases of LYP are of the CD4 subset, a CD8 variant has been recognized. (See Case Vignettes 7 and 8.) We have recently described four such cases and there is a literature precedent in the context of earlier reported cases as well (Berti et al., 1999; Wu and Tsai, 2004; Magro et al., 2006). From a clinical perspective, the cases are similar to other forms of LYP, manifesting a waxing and waning course. Most patients are younger men, suggesting an age and sex predilection. As with other forms of LYP, the lesions show an excellent response to methotrexate. These cases are typically misdiagnosed as representing primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T cell lymphoma, but the clinical course of the latter is one of extracutaneous dissemination and death, usually within less than 3 years from diagnosis (Urrutia et al., 1990; Berti et al., 1999). Light Microscopic Findings There are four cardinal morphologic clues that may favor CD8 LYP over one of the more characteristic CD4 subtypes of LYP. First, eosinophils and neutrophils characteristic of classic lesions of LYP are not seen in this variant (Magro et al., 2006). Second, striking vasculitic changes are common, the basis

of which may be one reflective of the cytokine milieu. Third, there is granulomatous inflammation. In all cases, the large cells had a monotypic appearance, closely resembling the morphology of a large activated histiocyte. The excessive pleomorphism encountered in type A CD4-positive LYP may not be seen. (Figure 21.22). Histogenesis In CD8-positive forms of LYP, the cytokine milieu associated with the specific subtype of CD8 cell may be responsible for the unique composition of the infiltrate and the presence of vascular injury. Specifically, CD8-positive T cells can be classified into at least two functional subsets: Tc1, producing high amounts of interferon (IFN)-γ and Tc2, producing interleukin (IL)-4, -5, -10, and -13 and low levels of IFN-γ (Willemze et al., 2005). Studies have implicated CD8 cells of the Tc1, high IFN-γ subset as an effector cell populace contributing to active vasculopathy in the setting of transplant rejection (Delfs et al., 2001; Fischbein et al., 2002; Crowsen et al., 2003; Raisky et al., 2003; Schnickel et al., 2004). If indeed the neoplastic CD8 lymphocytes are of this Tc1 subset, the other features, namely, granulomatous inflammation and a dearth of neutrophils, would be the expected morphologic expression of this cytokine milieu. Differential Diagnosis The differential diagnosis of this variant of LYP is one of primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T cell lymphoma, as there are many overlapping features with this entity. These features consist of large numbers of markedly atypical lymphocytes along with their dominant angiocentric growth pattern with marked vessel wall destruction. In addition, the expression of CD8 and granzyme and deletion of certain pan T cell markers in the neoplastic cells are the phenotypic profile commonly seen in cytotoxic CD8 lymphoma. However, the most critical differentiating point that allows its distinction from cytotoxic CD8 lymphoma is the clinical presentation, which is typical of LYP and not at all characteristic of aggressive CD8 lymphoma. Furthermore, CD30 positivity is very uncommon in the setting of primary cytotoxic CD8 lymphoma, although it does occur (as demonstrated in Case Vignette 4). The concomitant granulomatous inflammation with eccrine coil accentuation while characteristic of some cases of LYP (i.e., eccrinotropic LYP) is uncommon in aggressive CD8 lymphomas of LYP (Crowson et al., 2003).

Introduction

Borderline CD30-Positive Lymphoproliferative Disorders (Type C LYP) (Case Vignette 9) Such cases manifest borderline features morphologically between anaplastic large cell lymphoma and LYP; however, clinically the lesions are most compatible with LYP. It is very likely that there is a greater incidence of progression of type C LYP into primary cutaneous anaplastic large cell lymphoma (Wu and Tsai, 2004). Light Microscopic Findings The characteristic hallmarks on light microscopy are defined by a morphology that is more reminiscent of anaplastic large cell lymphoma than of LYP. In particular, there is a striking and dense infiltrate of large atypical cells defining the dominant cell populace. The overlying epidermis characteristically shows hyperplastic changes with foci of spongiform pustulation. At a light microscopic level, independent of the clinical presentation, a potential clue would be a tendency for angiocentricity as opposed to the dense effacing infiltrate typical of anaplastic large cell lymphoma. There is often relative sparing of the subcutaneous fat. In general, the absolute distinction between anaplastic large cell lymphoma and LYP can be difficult and thus the rubric borderline CD30positive lymphoproliferative disease. (Figure 23.31 and 23.32) Phenotypic Features The phenotypic profile resembles anaplastic large cell lymphoma and type A LYP (Varga et al., 1990). Hence, the abnormal cell demonstrates limited cytotoxic properties primarily in the context of granzyme and TIA expression. The cells are typically CD3 and CD4 positive. In contrast, there are a significant number of anaplastic large cell lymphoma cases that are CD3 negative, defining a null phenotype. Fascin expression more closely resembles that encountered in anaplastic large cell lymphoma (Kempf et al., 2002); the majority of cells are positive. (Figure 23.33) Treatment Methotrexate appears to be the treatment of choice for severe cases of LYP (Christensen et al., 1994; Vonderheid et al., 1996; Yazawa et al., 2001; Wu and Tsai, 2004). The effectiveness of methotrexate relates either to its inhibitory effect on DNA synthesis, its anti-inflammatory effects, or both. The atypical lymphocytes seen in LYP and anaplastic large cell (Ki1-positive) lymphoma manifest high mitotic activity,

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and hence it would seem likely that methotrexate significantly inhibits the proliferation of these cells especially during the initial phase of lesional development. The recommended dosage is 10–25 mg given every 1 to 4 weeks (Vonderheid al., 1996). The major side effect is hepatic fibrosis. Liver biopsies with guidelines similar to that implemented for patients receiving methotrexate for psoriasis should be used (Vonderheid et al., 1996).

Cutaneous Anaplastic Large Cell Lymphoma At the other end of the spectrum of CD30-positive lymphoproliferative disorders is anaplastic large cell lymphoma (Table 23.1). Stein and co-workers (1985) recognized a distinctive large cell hematopoietic neoplasm associated with extensive lymph node effacement manifesting sinusoidal accentuation; the neoplastic cell population is typically of T cell or null cell phenotype expressing the CD30 or Ki-1 antigen. There is heterogeneity in terms of the morphologic spectrum of the lesion, with cells ranging from small forms to large highly atypical sarcomatoid variants. There are five main variants: the common type (classic), giant cell rich, small cell, lymphohistiocytic, and Hodgkin disease-like (Table 23.2) (Stein et al., 2000). However, Hodgkin disease-like anaplastic large cell lymphoma may represent ‘‘tumor-cellrich’’ classic Hodgkin disease, ALK(+) or ALK(−) anaplastic large cell lymphoma (Stein et al., 2000). There are other unusual variants including neutrophil rich, eosinophil rich, sarcomatoid, and signet ring (Chan et al., 1990; Le Tourneau et al., 1990; Falini et al., 1997; McCluggage et al., 1998; Suzuki et al., 2001; Cepeda et al., 2003; Ogose et al., 2003). Although one recognizes these morphologic variants, there is no clear-cut clinical difference between the various morphologic subtypes except with respect to the small cell variant (Kinney et al., 1993). Specifically, the small cell subtype of anaplastic Ki1 lymphoma may be associated with a leukemic picture and hence has a more aggressive clinical course (Kinney et al., 1993; Kinney and Kadin, 1999). An alternative classification scheme is according to the anaplastic lymphoma kinase result (see Table 23.3). Specifically, the lymphomas are now categorized according to the presence or absence of ALK expression (Kinney and Kadin, 1999). The vast majority of primary cutaneous anaplastic large cell lymphomas are ALK negative (DeCoteau et al., 1996; Su et al., 1997; Wood, 1998). However, in the context of extracutaneous anaplastic large cell lymphoma, ALK-negative lesions tend to occur in older individuals; the prognosis is much worse compared to

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TABLE 23.2 Anaplastic Large Cell Lymphoma Subtypes 1. Primary cutaneous without known lymphoma elsewhere. Patients may have a history of LYP especially the type C (borderline variant) 2. Nodal anaplastic large cell lymphoma secondarily involving the skin 3. Anaplastic large cell lymphoma in the setting of other known lymphomas most commonly mycosis fungoides and Hodgkin lymphoma

TABLE 23.3 Anaplastic Large Cell Lymphoma Clinical Adults most often Solitary or regionally localized tumors, often ulcerated, some >2 cm in diameter Favorable prognosis in the context of primary anaplastic large cell lymphoma Small cell anaplastic lymphoma may be associated with an aggressive clinical course due to a high incidence of bone marrow and peripheral blood involvement Histomorphology Nodular and diffuse infiltrates characterized by cohesive sheets of large CD30+ cells; extends into subcutis Cytomorphology: large anaplastic cells; large pleomorphic cells or immunoblasts; small/medium and signet-ring cell morphology may be observed Admixed neutrophils and eosinophils with prominent infiltration of a hyperplastic epidermis by neutrophils Cytomorphologic variants: classic, sarcomatoid, giant cell, small cell, and Hodgkin disease-like Immunophenotype CD2+ CD3, frequently negative ZAP70− CD30+ CD4+ (majority of cases) CD8−/+ (rare CD8 variants) CD15, EMA− TIA-1(+) CD56−(+) ALK-1−/+ (most primary cutaneous cases are negative) CD56− (rare positive cases) Clusterin + Cytogenetics and molecular studies Usually absence of t(2;5) in primary cutaneous variants Monoclonal rearrangement of the T-cell receptor gene(s) despite lack of expression of TCR-β on surface Rare cases of both T and B cell rearrangement in the post-transplant setting Therapy Solitary or localized lesions: surgical excision and/or radiotherapy Systemic chemotherapy only if patients have extracutaneous involvement

ALK-positive forms (Willemze and Beljaards, 1993; Nakamura et al., 1997; Wood, 1998; Bekkenk et al., 2000; Stein et al., 2000). Anaplastic large cell lymphomas of the skin can be categorized as those that are primary in the skin in the absence of prior lymphoma, those that secondarily involve the skin in the setting of primary nodal Ki-1 positive lymphoma, and those developing in the setting of known lymphoma. The spectrum of

the latter encompasses Hodgkin lymphoma, mycosis fungoides, and other forms of post-thymic T cell lymphoma (Kinney and Kadin, 1999; Aoki et al., 2001; Kang et al., 2002). Perhaps the most common form of anaplastic large cell lymphoma involving the skin is in the context of primary cutaneous anaplastic large cell lymphoma; the median age at presentation is 60 years. The lesions usually present as solitary tumors

Introduction

manifesting variable ulceration; however, at times there may be multicentricity (Figure 23.3) (Krishnan et al., 1993). Patients with more disseminated disease benefit from systemic polychemotherapy. Approximately 25% of patients with anaplastic large cell lymphoma show regression of their lesions. The absolute distinction between anaplastic large cell lymphoma and LYP may be difficult. Furthermore, there are cases of primary cutaneous anaplastic large cell lymphoma that are associated with a concurrent and/or a prior history of LYP, pointing to a common cell of origin (Aoki et al., 2001). In our own experience, we have found that such cases are more commonly associated with type C LYP/borderline CD30-positive lymphoproliferative disease. However, in LYP the lesions are multiple and small with a tendency for spontaneous regression, and extracutaneous spread does not occur. In contrast, in primary cutaneous anaplastic large cell lymphoma, the lesions may be solitary and may not regress, and there is the possibility of extracutaneous dissemination. Secondary anaplastic large cell lymphoma reflects tumor progression when it develops in other settings including peripheral T cell lymphoma, mycosis fungoides, and Hodgkin lymphoma. It is the general consensus that the subsequent acquisition of CD30 expression in a previously CD30-negative lymphoma does not necessarily denote a better prognosis (Krishnan et al., 1993; Paulli et al., 1995). Another category of anaplastic large cell lymphoma of the skin is in the context of a distinctive form of post-transplant T cell lymphoproliferative disorder. In our own experience, we have not found EBER positivity and molecular studies have shown both a B and T cell rearrangement despite a phenotypic profile that would warrant categorization as a form of T cell lymphoma (see Figures 23.50 and 23.51) (Kim et al., 2004; Salama, 2005; unpublished observations). Clinically, the distinction of anaplastic large cell lymphoma from LYP is important. Some authors note that the presence of a solitary lesion greater than 3 centimeters, persistence without spontaneous regression, and the presence of significant lymphadenopathy are probably indicative of malignant lymphoma and/or a progression of lesions of LYP into anaplastic large cell lymphoma. Such criteria might be construed as rather stringent in that there are published series addressing the clinical features of anaplastic Ki-1 lymphoma whereby lesions smaller than 2 centimeters occur in over 63% of patients and while 63% had a solitary lesion the remainder did have multiple lesions. Other investigators have used a 2 centimeter cutoff as distinguishing lymphoma from LYP. Regression is not a helpful feature as it is seen in both conditions, with

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FIGURE 23.3 The patient presented with a persistent large ulcerative nodule that did not undergo spontaneous regression. The biopsy findings were compatible with anaplastic large cell lymphoma.

well-documented cases of CD30-positive lymphoma undergoing spontaneous regression (Demierre et al., 1997). The cases that most frequently undergo regression are the so-called borderline cases that manifest overlap features between CD30-positive lymphoma and LYP (Paulli et al., 1995; Slater, 2005). We have seen spontaneous regression in lesions of unequivocal primary cutaneous anaplastic large cell lymphoma (Figure 23.3) Light microscopic Findings Pathologically, anaplastic large cell lymphoma differs from LYP by virtue of a predominance of CD30-expressing cells, in excess of 75%. In contrast, in LYP the CD30-positive cells are noted amid a polymorphous inflammatory cell background. Phenotypic and histologic features suggestive of evolution from LYP into CD30-positive lymphoma include a further loss of pan T cell marker expression, extension into the subcutis, and a greater proportion of atypical cells relative to the inflammatory cell background with effacement of the dermal architecture by sheets of atypical cells. In addition to the sheet-like pattern of growth, the infiltrate has a striking angiocentric disposition (see Figures 23.4, 23.8, 23.11, and 23.14). Subcutaneous involvement can be prominent. Two cytologic types are recognized in anaplastic large cell lymphoma (Krishnan et al., 1993; Paulli et al., 1995; Demierre et al., 1997). Type I cells are polygonal forms between 10 and 30 µm in diameter that exhibit a distinct pink-staining cell membrane. Their angulated cell borders impart a squamoid appearance to the cell. The nuclei are usually round

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to oval but can show irregular foldings. The chromatin is dispersed as coarse clumps with areas of clearing. Nucleoli are large and multiple. The cytoplasm is abundant and is pale to amphophilic in quality (see Figures 23.9 and 23.12). The type II cell, measuring 15–50 µm. The nuclei are oval, lobulate, reniform, or horseshoe shaped and may be centrally placed with a prominent paranuclear hof. The chromatin is irregularly clumped and shows less clearing than the type I cell. The cytoplasm is abundant and deeply amphophilic or basophilic. The cells may contain multiple nuclei, often in a wreath-like arrangement or resembling those cells encountered in Hodgkin lymphoma (Figures 23.15 and 23.37). Although pseudoepitheliomatous hyperplasia occurs in up to 20–30% of cases of CD30-positive anaplastic large cell lymphomas, this phenomenon has been reported in lesions of type A LYP (Cespedes et al., 2000; Scarisbrick et al., 2001; El Shabrawi-Caelen et al., 2004). In the small cell variant there are scattered large atypical hallmark cells as described above, but the dominant population comprises abnormal small to intermediate sized lymphocytes (see Figures 23.4–23.6) (Kinney et al., 1993). The cells demonstrate nuclear contour irregularities including cells with polylobated nuclei with a floret-like morphology, clear cytoplasms, and distinct cytoplasmic membranes. The cells can be mistaken for histiocytes but they are usually negative for CD3 and often negative for CD45 Ro; staining for CD30 and ALK is variably positive. Although the literature suggests negative staining for CD30, we have seen cases that are markedly positive (Kinney et al., 1993). CD30-positive examples of small cell anaplastic lymphoma are illustrated in Figures 23.3–23.7. Phenotypic Profile Most cases of anaplastic large cell lymphoma are CD45 positive and exhibit a T cell phenotype, usually of helper cell type, or a null cell phenotype (see Figures 23.7, 23.10, 23.13, and 23.16) (Kummer et al., 1997; Juco et al., 2003). However, it has now been established that a small percentage of cases of anaplastic large cell lymphoma may be of B cell phenotype or represent CD8 variants (see Figures 23.24–23.30) (Magro et al., 2006). In regard to those cases showing an apparent B cell phenotype, the basis of the classification as anaplastic large cell lymphoma was due to coexpression of CD30 and EMA, as well as the demonstration of a t(2;5) translocation (Adam et al., 2003; Rudzki et al., 2005). However, the B cell variant, clearly

representing the least frequent of the immunophenotypic subgroups, is prognostically similar to other forms of large B cell lymphoma; as long as disease is localized, the prognosis is excellent. We designate such cases as CD30-positive large B cell lymphoma. The expression of activation antigens is very common including T9 (transferrin receptor), HLA-DR, CD40, and Tac. They may show an aberrant T cell phenotype by virtue of CD3 negativity. Unlike Hodgkin lymphoma, the cells are leukocyte common antigen positive and are Leu-M1 negative. In addition, there is evidence of cytotoxic potential (Boulland et al., 2000). In nodal Ki-1 positive lymphomas, the cytotoxic characteristics are revealed by the expression of cytotoxic granular protein perforin and TIA-1 (see Figure 23.20). TIA-1 is a 15 kDa cytotoxic granule associated membrane protein expressed in natural killer cells and cytotoxic T lymphocytes (Krenacs et al., 1997). TIA1 was first characterized by Anderson et al. (1990). TIA-1 is expressed in 20–36% of peripheral blood T lymphocytes; strongly by natural killer (NK) cells and CD8-positive cytolytic T cells and less strongly by CD4-activated cells. There is preferential expression in cells possessing cytotoxic potential. Studies have shown the expression of these cytotoxic proteins in a spectrum of lymphoma including NK cell lymphomas, rare cases of Hodgkin lymphoma, anaplastic large cell lymphoma, and certain distinctive forms of peripheral T cell lymphoma including panniculitislike T cell lymphoma and hepatosplenic and intestinal lymphomas. In primary cutaneous Ki-1 positive lymphomas, granzyme B and TIA have been observed while in CD30-negative primary cutaneous large T cell lymphomas, the neoplastic cells usually do not express these proteins (Kumar et al., 1996; Boulland et al., 2000). Only on rare occasions will true natural killer cell properties be demonstrated by virtue of CD56 positivity. The differential diagnosis of such lesions is that of NK cell lymphoma (Chang et al., 2000). In the small cell variant, the small lymphoid cells are typically CD30 negative; nevertheless, there is a clonal loss of one of the pan T cell antigens, especially CD3, and expression of the NPM-ALK protein may be seen (Kinney et al., 1993). In regards to extracutaneous anaplastic large cell lymphoma. ALK expression is seen in only 15% and 30% of the Hodgkin-like and giant cell forms, respectively, while ALK expression is seen in 80–100% of classic small cell and lymphohistiocytic variants (see Figures 23.4–23.7) (Kinney et al., 1993). Regardless of the cytomorphologic variant, most cases of primary cutaneous anaplastic large cell lymphoma are negative.

Introduction

With respect to those anaplastic large cell lymphomas that demonstrate a null cell (i.e., CD3-negative) phenotype, there may still be a demonstrable TCR rearrangement. CD3 transduces the expression of ZAP-70 that integrates costimulatory signals to guide downstream signaling. In addition to the lack of CD3 expression, 70% of cases of anaplastic large cell lymphoma lack ZAP-70 expression. The majority of anaplastic large cell lymphomas do not express either TCR-β or TCR-γ on the surface despite a TCR rearrangement (Bonzheim et al., 2004). In summation, while there is a rearrangement of the TCR there is a lack of true TCRβ protein expression both in the context of CD3 and ZAP-70 expression (Bonzheim, 2004). This lack of expression of TCRβ on the surface of the tumor cell is useful in the distinction between ALK-negative anaplastic large lymphoma and those rare cases of peripheral large T cell lymphoma which are CD30 positive but which do express TCRβ on the surface (Bonzheim, 2004). Six cases of CD8-positive anaplastic large cell lymphoma of the skin are reported in the literature (Kikuchi et al., 1992; Fukunaga et al., 2002). Three of these cases were localized and were disease free after at least a year of follow-up, hence defining a clinical pattern more analogous to classic primary cutaneous anaplastic large cell lymphoma. In the other half, however, recurring disease was noted, one of them demonstrating widespread involvement. One could argue that those cases following a more aggressive clinical course should be categorized as CD30 variants of primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T cell lymphoma (see Figures 23.35–23.38). Clusterin is a marker that is positive in nodal anaplastic Ki lymphoma (Wellmann et al., 2000; Lae et al., 2002; Saffer et al., 2002a,b; Nascimento et al., 2004). Clusterin is an ubiquitous, highly glycoslated protein that comprises an αβ subunit remaining covalently linked by disulfides. Of interest was its identification in the testes, where it was named because of its ability to cause clustering of Sertoli cells (Fritz et al., 1983). It is widely distributed in tissues, plasma, cerebrospinal fluid, breast milk, and semen. Despite an extensive expression in tissue, it is limited to dendritic antigen presenting cells in normal lymphoid tissue. Clusterin has a role in autoimmunity primarily in the context of regulating complement activity and is considered to be an antiapoptotic protein. In regard to anaplastic large cell lymphoma, it was initially thought that clusterin expression could distinguish between primary and secondary anaplastic large cell lymphoma; cutaneous studies have failed to show a significant difference in

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expression (Lae et al., 2002). However, clusterin does exhibit a distinctive pattern of golgi accentuation in anaplastic large cell lymphoma, that is not seen in other forms of hematologic malignancy. Clusterin is seen in other lymphomas, but the staining pattern is diffuse cytoplasmic and/or membrane in distribution (Wellmann et al., 2000; Saffer et al., 2002a,b; Nascimento et al., 2002, 2004). Expression of the lymphocyte homing receptor CD44 and CD44v6 has been linked to unfavorable prognosis in non-Hodgkin lymphoma. In the context of CD30-positive cutaneous lymphoproliferative disease, the expression of this marker is described in up to 50% of cases of both anaplastic large cell lymphoma and LYP; in the realm of cutaneous lymphoproliferative disease, expression of this marker does not appear to correlate with an adverse prognosis (Liang et al., 2002). Cytogenetics Lymph node based CD30-positive large cell lymphomas of either T cell or null cell type manifest a characteristic translocation, namely, t(2;5)(p23;q35), and express the NPM–ALK hybrid protein detected by the antibody ALK1. The chromosomal rearrangement fuses part of the nucleophosmin gene on chromosome 5q35 to a portion of the anaplastic lymphoma kinase gene on chromosome 2p23, generating a chimeric molecule and a unique 80 kDa NPM–ALK fusion protein (see Figure 23.52). The incidence of translocation ranges from 15% to 80%. Furthermore, the translocation has been detected in some peripheral T cell lymphomas other than classical anaplastic large cell lymphoma and some diffuse large B cell lymphomas. In addition, a cryptic abnormality has been detected that is easily recognized using fluorescence in situ hybridization, namely, inv (2)(p23q35). The result is a distinctive ALK protein expression restricted to the cytoplasms of the neoplastic cells. ALK protein expression is held to be an independent prognostic variable predicting good patient outcome. The principal methods of detection of ALK are RT in situ PCR, cytogenetics, and immunohistochemistry. This translocation is present in a minority of cases of LYP and primary cutaneous CD30-positive anaplastic large cell lymphoma (i.e., 10–20% of cases); in contrast, the rate of t(2;5) is higher in nodal CD30positive lymphomas with a prevalence rate of about 40% in such cases, being identified particularly in younger patients (Herbst et al., 1997; Kutok et al., 2002; Kapur et al., 2005). Pathogenesis The pathogenetic basis of the regression that can occur in some cases of anaplastic large cell lymphoma

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is of interest. The question arises as to molecular events that are responsible for the spontaneous regression of some cases of CD30-positive lymphoma and what events lead to lesional progression and ultimately patient demise. Transforming growth factor receptor β designated TBRII, is a multifunctional polypeptide that regulates cell proliferation and differentiation; its main effect is growth inhibition. Cell culture lines derived from anaplastic large cell CD30positive lymphoma may not show any inhibitory growth response to TBRII, due to a point mutation in TBRII, leading to inhibition of the wild-type receptor, hence rendering the cell resistant to the inhibitory effects of TBRII (Knaus et al., 1996; Kadin et al., 2001). Part of tumor progression may reflect increasing resistance to TBRII mediated growth inhibition (Levi, 2000). Bax, a pro apoptotic protein is expressed at high levels in CD30+ lymphoproliferative disease. A higher apoptotic index is seen in LYP relative to ALCL (Greisser 2005). Resistance to CD30 mediated growth inhibition may also play a role in disease progression (Levi et al., 2000).

CD30-Positive Large B Cell Lymphoma Recognized forms of primary cutaneous B cell lymphoma (PCBCL) include marginal zone lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, and follicular lymphoma (Salama, 2000). With the exception of primary B cell lymphomas manifesting lower extremity localization and their analogs, PCBCL follows a relatively indolent course despite a tendency to relapse. Most of these neoplasms arise from a background of reactive lymphoid hyperplasia with germinal center cell formation (i.e., lymphocytoma cutis). The relapse rate is highest in patients with multiple lesions and lowest in those who present with isolated lesions confined to the skin. In our experience the majority of cases are women; in our original series there were seven women and three men ranging in age from 22 years to 95 years (mean age 75.2 years); six patients were over 80 years of age (Nagasawa et al., 2000). The most common presentation was as a solitary nodule without accompanying constitutional symptoms and/or signs of extracutaneous lymphoma. One patient had multiple lesions. Among the more common site localizations were arm, face, upper trunk, and legs. In two cases the lesions developed concurrently with the administration of methotrexate for rheumatoid arthritis. The lesions were excised in six cases with no recurrence, while in four cases the areas were treated with low dose radiation with complete resolution. A systemic work-up, including total body CT scans and bone marrow biopsy, was negative in all cases excluding

one, a 75 year old woman receiving methotrexate for rheumatoid arthritis who presented in February 2002 with many nodules on the skin surface and who was found to have multiple bilateral pulmonary nodules. The patient was treated with rituximab with resolution of all subcutaneous and pulmonary nodules. A recurrence in July 2002 was found to express EBER. Multiagent chemotherapy and acyclovir were introduced and the methotrexate was withheld; she achieved remission. The range of follow-up in the other cases was 2–48 months (mean 23.4 months); all patients are alive and well. Light Microscopic Findings In the majority of cases in our study, the dominant morphology was a diffuse and nodular small lymphocytic infiltrate with focal granulomatous inflammation and scattered reactive germinal centers. There were scattered large atypical cells in the infiltrate disposed singly and in small aggregates; these cells were in the 20–30 µm size range, manifesting oval to irregularly contoured nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. There were four cases in which the biopsies demonstrated a diffuse and angiocentric proliferation of immunoblastlike cells with a dearth of other inflammatory cell elements and no granulomatous inflammation. Two of these patients had received methotrexate for underlying rheumatoid arthritis (see Figures 23.39–23.41 and 23.44). Phenotypic Studies In our experience, the small lymphocytic component is composed of a mixture of T and B cells, whereby the T to B cell ratio ranges from 2:1 to 5:1. The T cells exhibit a normal phenotype. The residual germinal centers show weak CD10 staining; the dendritic network is accentuated by the CD23 and CD21 stains. The large atypical cell population expresses CD30, CD20, CD43, and CD79; bcl-2 positivity is usually not seen. The cells typically do not express CD21, CD23, cyclin D1, CD5, or CD10 (see Figures 23.42, 23.43, 23.45, and 23.46). Differential Diagnosis The differential diagnosis includes anaplastic large cell lymphoma, LYP including the borderline/type C variant (Paulli et al., 1995), and lymphomatoid hypersensitivity reactions including persistent arthropod bite reactions, cutaneous herpes infection, and certain chemotherapy reactions associated with reactive CD30-positive hematopoietic infiltrates (Nathan and Belsito, 1998; El-Asrar et al., 2002; Gallardo et al., 2002). While there are

Introduction

only a few reports describing CD30 expression in primary cutaneous B cell lymphoma, extracutaneous CD30-positive diffuse large B cell lymphoma has been previously described (Noorduyn et al., 1994; Lai et al., 2000). Prognostically, they behave no differently from other forms of large B cell lymphoma (Noorduyn et al., 1994; Lai et al., 2000). In one multicenter study on cutaneous CD30-positive lymphoproliferative disease, only 2 of 17 cases in the CD30-positive non-Hodgkin lymphoma category were of B cell phenotype (Paulli et al., 1995). These uncommon lymphomas were designated as CD30positive non-anaplastic large B cell lymphomas. There are only two other reports of which we are aware

451

describing CD30-positive large B cell lymphoma, one in the context of a case report and the other representing a series of cutaneous lymphomas in the setting of HIV infection (Beylot—Barry et al., 1999; Herrera et al., 2002; Watabe et al., 2002), whereby four cases were associated with EBV infection. In our series the two cases in which there was EBV RNA expression in the lymphoma cells were in the setting of rheumatoid arthritis and methotrexate therapy (Verma et al., 2005). There is literature precedent regarding methotrexate therapy and the subsequent development of an EBV-positive primary cutaneous B cell lymphoma (Fam et al., 1999).

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CASE VIGNETTES CASE VIGNETTE 1

The patient is a 78 year old man with nodal anaplastic large cell lymphoma with bone marrow and peripheral blood involvement who presented with skin lesions. Diagnosis: Small cell variant of anaplastic large cell lymphoma (Figures 23.4–23.7).

FIGURE 23.4

Massive pandermal infiltrate effacing the dermal architecture with infiltration of the epidermis.

FIGURE 23.5

In classic small cell variant there are scattered large atypical hallmark cells as described earlier; however, the dominant cell population is an abnormal small to intermediate sized lymphocyte. In the case illustrated, however, there are no hallmark cells. Instead, all of the cells are small to intermediate in size and have a relatively monomorphic appearance. Cytoplasmic membranes are characteristically distinct and cytoplasm can be clear.

FIGURE 23.7

FIGURE 23.6

There is prominent epitheliotropism of this small cell variant of anaplastic large cell lymphoma. This pattern of epitheliotropism along with the small size of the neoplastic lymphoid populace would raise diagnostic consideration to mycosis fungoides. However, the subjacent extensive infiltrate would be unusual. The distinction from pleomorphic small to medium sized cutaneous T cell lymphoma is difficult.

From a phenotypic perspective, the cells may be negative for CD3 and are often negative for CD45 Ro; staining for CD30 and ALK is variably positive. While the literature suggests negative staining for CD30, in this case there is extensive staining for CD30, defining what is truly a ‘‘small cell’’ CD30-positive lymphoma. Illustrated is CD30.

Case Vignette 2

CASE VIGNETTE 2

The patient was diagnosed with a classic variant of anaplastic large cell lymphoma, although with monomorphic features (Figures 23.8–23.10).

The biopsy shows a pattern manifesting a massive pandermal infiltrate of large atypical cells.

FIGURE 23.8

In contrast with Case Vignette 1, the cells are intermediate to large in size. They have a monomorphic appearance. The cells have uniform, round to oval nuclei; the chromatin shows areas of clearing. The cytoplasm is relatively abundant. This case defines the classic monomorphic variant of anaplastic large cell lymphoma. FIGURE 23.9

FIGURE 23.10 From a phenotypic perspective, the cells are CD3 and CD4 positive and manifest extensive staining for CD30. The illustration is of CD30 positivity.

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CASE VIGNETTE 3

The patient is a 65 year old renal transplant recipient with multiple skin nodules. Diagnosis: Post-transplant anaplastic large cell lymphoma (please refer to Chapter 20 as well) (Figures 23.11–23.13).

The biopsy shows a nodular expansile lesion in the dermis with dermal effacement. There is a grenz zone separating the infiltrate from the overlying epidermis.

FIGURE 23.11

(a)

The cytomorphology is dominated by large mononuclear cells without a significant multinucleated cell component.

FIGURE 23.12

(b)

A definitive diagnosis can be made with the CD30 preparation, which clearly shows extensive intense membrane and perinuclear staining: (a) CD3 preparation; (b) CD30 stain.

FIGURE 23.13

Case Vignette 4

CASE VIGNETTE 4

The patient is a 52 year old renal transplant recipient who developed lower extremity ulcerating plaques. Diagnosis: Post-transplant T cell lymphoproliferative disorder consistent with anaplastic large cell lymphoma (Figures 23.14–23.16). An unusual pattern of dual T and B cell rearrangement.

The biopsy shows a striking infiltrate that effaces the dermal architecture.

FIGURE 23.14

Higher power magnification reveals that the infiltrate is dominated by large highly atypical cells in the 30 µm size range, manifesting multinucleation. Many bizarre mitoses are noted. FIGURE 23.15

FIGURE 23.16 Phenotypic studies reveal CD4 staining without CD2 or CD3 positivity. There is extensive CD30 staining. There is no staining for EBV. Of interest, the tumor showed both TCR-β and IgH rearrangement.

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CASE VIGNETTE 5

The patient is a 33 year old woman with a several year history of papules and nodules that undergo ulceration and then heal, although now one nodule is unresponsive to topical steroids. Diagnosis: Type C LYP (CD30-positive lymphoproliferative disease, borderline lesion) (Figures 23.17–23.20).

The biopsy shows a superficial sheetlike effacing dermal infiltrate associated with hyperplastic epidermal changes.

FIGURE 23.17

There is a band-like lymphocytic infiltrate lying in intimate apposition to the epidermis, the latter showing reactive epithelial hyperplasia. Pseudoepitheliomatous hyperplasia is a characteristic finding within the spectrum of CD30-positive lymphoproliferative disease.

FIGURE 23.18

FIGURE 23.19 Higher power magnification reveals an infiltrate composed almost exclusively of severely atypical mononuclear and multinucleated hematopoietic cellular elements.

Case Vignette 5

(a)

(b)

FIGURE 23.20 The cells are CD30 and granzyme positive. Because of the effacing nature of the infiltrate and a dominance of poorly differentiated large atypical cells, the lesion resembles anaplastic Ki-1 lymphoma. However, the clinical course was ultimately more consonant with a diagnosis of lymphomatoid papulosis and hence this case is categorized as representing CD30 borderline lymphoproliferative disease.

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CASE VIGNETTE 6

The patient is a 60 year old woman with a 1 year history of waxing and waning lesions. Diagnosis: Type A LYP (Figures 23.21–23.23).

FIGURE 23.21

A biopsy shows a nodular angiocentric

infiltrate.

Higher power magnification reveals that the dominant composition is one of larger cells in the 15–20 µm size range with prominent nucleoli. The more prototypic lymphomatoid vascular reaction encountered in LYP is one of a similar pattern of nodular expansion but with a greater admixture of other inflammatory cell elements including eosinophils and neutrophils. FIGURE 23.22

Case Vignette 6

(a)

(b)

(c)

Phenotypic studies reveal T cells of the CD8 subset with striking CD30 positivity. This case is an unusual example of CD8 LYP. (a) CD8; (b) CD30; (c) granzyme.

FIGURE 23.23

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CASE VIGNETTE 7

The patient is a 35 year old man who presented with a 3 year history of ulcerative papular and nodular lesions that underwent spontaneous regression. Diagnosis: CD8 variant of LYP (Figures 23.24–23.26).

FIGURE 23.24 Higher power magnification of the eccrine coil reveals supervening granulomatous inflammation. The presence of deep-seated perineural and eccrinotropic granulomatous inflammation may be misconstrued as being indicative of a reactive process of infectious based etiology. One must always remember that sarcoidal-like granulomatous inflammation may be an important feature of a paraneoplastic process.

FIGURE 23.25 The eccrinotropic nature of the process is once again well exemplified. Note the significant admixture of neutrophils.

Immunohistochemical staining for CD8 decorates the large atypical cells.

FIGURE 23.26

Case Vignette 8

CASE VIGNETTE 8

461

The patient is a 30 year old man with a 15 year history of spontaneously regressing skin lesions. An initial diagnosis was made of primary cutaneous aggressive cytotoxic CD8 lymphoma. It was then reviewed at a tertiary center and held to represent a form of panniculitis-like T cell lymphoma. The patient was perfectly well and his lesions resolved with methotrexate therapy. Diagnosis: CD8 variant of LYP (Figures 23.27–23.30).

FIGURE 23.27 The surface is ulcerated. There is an extensive pandermal infiltrate that extends into the subcutaneous fat. The extension into fat leads to an initial consideration of panniculitis-like T cell lymphoma.

(a)

(b)

Closer inspection reveals atypical large cell infiltrates surrounding and permeating the blood vessels in concert with focal epitheliotropism. An inherent feature of this interesting group of disorders is the presence of significant neutrophilia, which may be dermal based although more commonly is in the context of significant intraepidermal neutrophilia. The marked involvement of the panniculus in this case led to an initial assessment of panniculitis-like T cell lymphoma.

FIGURE 23.28

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(Continued)

(a) FIGURE 23.29

(b)

There are scattered large atypical cells that are (a) CD8 positive and (b) CD30 positive.

FIGURE 23.30 In some cases there may be prominent infiltration of the epidermis and acrosyringium by small lymphocytes in a fashion reminiscent of mycosis fungoides.

Case Vignette 9

CASE VIGNETTE 9

463

The patient is a 57 year old man with a several week history of a 1 × 2 cm nodule in the groin area. It was clinically held to represent a cyst. After the initial surgical procedure, the lesion underwent spontaneous regression. The designation in this case was made of type C LYP because of the clinical course being one of a nodule undergoing spontaneous regression albeit in the context of a dense effacing dermal infiltrate (Figures 23.31–23.34).

There is a dense superficial effacing dermal infiltrate with associated ulceration.

FIGURE 23.31

FIGURE 23.32 The infiltrate is composed of atypical intermediate to large sized hematopoietic elements.

FIGURE 23.33 Phenotypic studies reveal staining of the cells for CD30; note the strong cytoplasmic membrane and perinuclear dot-like staining pattern.

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(Continued)

(a) FIGURE 23.34

The cells are granzyme positive and express CD4.

(b)

Case Vignette 10

CASE VIGNETTE 10

The patient is a 72 year old woman who presented with a nodular lesion involving the eyelid. Diagnosis: CD8 variant of anaplastic large cell lymphoma (Figures 23.35–23.38).

FIGURE 23.35 The biopsy shows a massive dermal infiltrate effacing the dermal architecture. The infiltrate lies in intimate apposition to the epidermis with variable permeation of the epidermis by lymphocytes.

FIGURE 23.37 The infiltrate is predominated by large, severely atypical cells in the 20–30 µm size range. The cells demonstrate areas of chromatinic clearing with prominent nucleoli. The infiltrate exhibits accentuation around the blood vessels.

FIGURE 23.36

There is nodular distortion of the

eccrine coil.

Phenotypic studies demonstrate that the infiltrate is primarily of T cell lineage as revealed by expression of CD3. There is striking staining of the infiltrate for CD30. The bcl2 preparation is negative. The majority of the cells are CD8 positive. The photomicrograph is of CD8.

FIGURE 23.38

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CASE VIGNETTE 11

The patient is a 75 year old woman, previously healthy, who presented with an ulcerative lesion on the scalp. Diagnosis: T-cell-rich CD30-positive large B cell lymphoma (Figures 23.39–23.43).

There is a prominence of small mature lymphocytes along with admixed granulomatous foci.

FIGURE 23.39 There is a striking superficial to middermal nodular infiltrate that effaces the dermal architecture.

FIGURE 23.40

Higher magnification shows a smattering of large atypical cells.

FIGURE 23.42

FIGURE 23.41

The cells are CD30 positive.

FIGURE 23.43 The large atypical cells also show CD20 immunoreactivity.

Case Vignette 12

CASE VIGNETTE 12

467

The patient is a 68 year old woman who presented with a large cheek nodule. She had a history of rheumatoid arthritis and had been receiving methotrexate. Diagnosis: EBV-associated CD30-positive large cell B cell lymphoma in the setting of methotrexate therapy (Figures 23.44–23.46).

FIGURE 23.44

There is a diffuse large cell pleomor-

FIGURE 23.45

phic infiltrate.

FIGURE 23.46

The cells are CD20 positive.

The cells are CD30 positive.

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES

Panel A

peak 254

Panel C

peak 194

FIGURE 23.47 A 44 year old man with a 1 year history of pruritic papules of axilla, upper arms, inferior abdomen, and thighs was diagnosed with type A lymphomatoid papulosis. The molecular studies show a monoclonal population of T lymphocytes with peaks at 254 bp on panel A and 194 bp on panel C. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

Multiplex panel C Single peak 300 bp

FIGURE 23.48 A 24 year old man was diagnosed with lymphomatoid papulosis with granulomatous eccrinotropic features. Molecular studies show a monoclonal population of T lymphocytes with peaks at 300 bp on panel C. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

Additional Molecular and Cytogenetic Studies

Panel C

469

clonal peak at 179 bp

polyclonal background

A 34 year old woman was diagnosed with lymphomatoid papulosis. The molecular studies show a monoclonal population of T lymphocytes amid a strong polyclonal background with peaks at 179 bp and 296 bp on panel C. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

FIGURE 23.49

Block A1 Ig H FR1

Block B1 Ig H FR1

Peak 310 bp

Peak 310 bp

FIGURE 23.50 A 65 year old man with a history of two nodules in the head and neck area composed of a malignant monomorphic T cell infiltrate was diagnosed with anaplastic Ki-1 lymphoma. Molecular studies show both biopsies contain the monoclonal peaks at 310 bp with polyclonal background. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

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TCR beta Panel A

IgH FR1

Post-transplant anaplastic large cell lymphoma (CD4 T cell phenotype) with both T and B cell rearrangement. A 53 year old woman with new onset of lower extremity purpuric patches, upper chest purpura, and medical history of diabetes mellitus, hypertension, and status post liver transplant was diagnosed with anaplastic Ki-1 lymphoma. Molecular studies show a monoclonal peak at 272 bp on TCR beta panel A and a peak at 320 bp on IgH V-D-J tube A. Both of these monoclonal peaks arise in a polyclonal background. This is an example of a post-transplant anaplastic large cell lymphoma. Interestingly, these tumors can be EBV negative. In our experience we have encountered this phenomenon of B cell lineage infidelity in two cases of post-transplant anaplastic large cell lymphoma. In both cases the neoplastic cells showed CD2, CD3, and CD4 positivity. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University).

FIGURE 23.51

1

2

6

3

7

13

14

19

20

4

8

9

10

11

16

15

21

22

5

12

17

18

X

Y

FIGURE 23.52 Lymph-node-based CD30-positive anaplastic large cell lymphomas of either T cell or null cell lineage manifest a very characteristic translocation, namely, t(2;5)(p23;q35), and express the NPM–ALK hybrid protein detected by the antibody ALK1. This chromosomal rearrangement fuses part of the nucleophosmin gene on chromosome 5q35 to a portion of the anaplastic lymphoma kinase gene on chromosome 2p23, generating a chimeric molecule and a unique 80-kDa NPM–ALK fusion protein. This translocation is very uncommon in primary cutaneous anaplastic large cell lymphoma.

References

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CHAPTER TWENTY-FOUR

PRIMARY CUTANEOUS HODGKIN LYMPHOMA Cynthia M. Magro

Clinical Features Hodgkin lymphoma involving the skin is unusual, developing in less than 10% of patients with Hodgkin lymphoma in lymph nodes or other extranodal sites (Tassies et al; 1992; Kumar et al., 1996; Fargnoli et al., 2001; Erkilic et al., 2004; Jurisic et al., 2005). Cutaneous involvement initially involving the skin can occur although is very uncommon. (Kumar et al., 1996; Jurisic et al., 2005). The lack of tropism to the skin is interesting, as there are other CD30-positive lymphoproliferative conditions that characteristically demonstrate prominent skin involvement, specifically in the context of lymphomatoid papulosis and anaplastic large cell lymphoma. Despite the rarity of cutaneous involvement in the setting of Hodgkin lymphoma, lymph node-based disease is common, representing approximately 20–30% of all cases of lymphoma (Erkilic et al., 2004). The existence of primary cutaneous Hodgkin lymphoma is not universally accepted. In our own cumulative experience, we have seen only one case that was likely bone fide primary cutaneous Hodgkin lymphoma. We reported a series of T-cell-rich CD30positive large cell B cell lymphoma including cases that were clearly EBER related, which raised diagnostic consideration of Hodgkin lymphoma but were histogenetically distinctive (Magro et al., 2006). It seems possible that some cases of primary cutaneous

Hodgkin lymphoma reported in the literature represent this distinctive form of B cell lymphoma. In regard to secondary cutaneous Hodgkin lymphoma, most patients with skin involvement have advanced disease (De Grip et al., 1999; Pagliaro and White, 1999; Takagawa et al., 1999). In most instances the cutaneous lesions represent a direct extension from extensive mediastinal disease. To designate a patient as having primary cutaneous Hodgkin lymphoma, there must be no evidence of extracutaneous Hodgkin lymphoma for at least 6 months following diagnosis. It is interesting to note that both primary cutaneous Hodgkin lymphoma and secondary Hodgkin lymphoma most commonly affect the chest although more generalized cutaneous disease has been described. The cutaneous disease may presage lymph node involvement although this event of extracutaneous dissemination is uncommon. The time frame between initial skin presentation and subsequent establishment of lymph node disease in reported cases is said to have a range of 2 months to 6 years (Silverman et al., 1982; Kumar et al., 1996; Guitart and Fretzin, 1998; Jurisic et al., 2005). There are cases of primary cutaneous Hodgkin lymphoma in which long-term follow up showed no extracutaneous dissemination (Davies and Dobbs, 1993; Sioutos et al., 1994; Cerroni

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 475

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et al., 1995; Solomon and Goldman, 1997; DeGrip et al., 1999; Narayanan et al., 1999; Pagliaro and White, 1999; Fargnoli et al., 2001). It has been suggested that primary cutaneous Hodgkin lymphoma and even those cases that develop lymph node disease subsequent to skin involvement may follow a more indolent course (Kadin, 1991; Jurisic et al., 2005). This indolent clinical course mirrors that encountered in other cases of primary cutaneous B cell lymphoproliferative disease. As previously mentioned, some of these cases may represent T-cell-rich CD30-positive large B cell lymphoma. In our series on this distinctive form of primary cutaneous B cell lymphoma, the patients typically followed an indolent course as would be expected in many cases of primary cutaneous B cell lymphoma (Figure 24.1) (Magro et al., 2006). As with other malignancies, the immune status of the host may significantly alter the clinical course. For example, primary cutaneous Hodgkin lymphoma in the setting of HIV disease may follow a rapidly progressive downhill course, eventuating in death (Shaw and Jacobs, 1989). Hodgkin lymphoma is associated with EBV infection in a significant percentage of cases. One study was able to establish EBV as an independent prognostic variable determining survival. In children less than 15 years old, EBV infection was associated with

Hodgkin lymphoma of the skin. The patient had no known history of Hodgkin lymphoma. He presented with a violaceous plaque, in essence morphologically indistinguishable from other forms of cutaneous lymphoma.

FIGURE 24.1

favorable survival while in adults aged 15–44 years, EBV did not affect outcome. In older patients with nodular sclerosing Hodgkin’s lymphoma, EBV positivity was associated with poorer survival (Keegan et al., 2005).

TABLE 24.1 Cutaneous Hodgkin’s Lymphoma Clinical Adults most commonly Solitary, grouped or multifocal papules, plaques and tumors at drainage area of affected lymph nodes or in direct extension to skin from an underlying mediastinal tumor Histomorphology Nodular or diffuse lymphocytic infiltrates with Reed-Sternberg and mummified cells in classic while lacunar cells are seen in lymphocyte predominant. Variable sclerosis Admixed small lymphocytes, histiocytes and eosinophils Immunology CD30+(classic); -(lymphocyte predominant) CD15+ (classic);-(lymphocyte predominant) CD45− (classic);+ (lymphocyte predominant) CD20+/− (classic); + (lymphocyte predominant) EBER+/Fascin+ CD40+ Clusterin− Cytogenetics Very complex no reproducible abnormality from case to case. The complexity to each case is characteristic for Hodgkin lymphoma. Nonclassic Hodgkin lymphoma has higher level of B cell expression compared to classic Hodgkin lymphoma even though both are derived from B cells in most instances Therapy Treatment for underlying disease; radiotherapy of isolated skin tumor

Subtypes of Hodgkin Lymphoma

SUBTYPES OF HODGKIN LYMPHOMA In Hodgkin lymphoma, the neoplastic cell is associated with a variable inflammatory host response comprising lymphocytes, plasma cells, and eosinophils. In many cases, the inherent difficulty in diagnosis reflects the fact that the reactive populace defines the dominant component of the infiltrate and obscures the neoplastic cell populace. Hodgkin lymphoma is divided into five variants—four of which are represented by classic Hodgkin lymphoma while the fifth form is a distinctive clinical and pathological entity (Harris, 1999). These five subtypes are (1) classic Hodgkin lymphoma of nodular sclerosing type, (2) classic Hodgkin lymphoma, mixed cellularity type, (3) classic Hodgkin lymphoma of lymphocyte-rich type, (4) classic Hodgkin lymphoma, lymphocytedepleted forms, and (5) ‘‘nonclassic’’ nodular/diffuse lymphocyte-predominant Hodgkin lymphoma (Harris, 1999). The most common of these is nodular sclerosing Hodgkin lymphoma, while the least common are lymphocyte-depleted and the nonclassic lymphocyte-predominant types (Harris, 1999). In the context of skin disease the cases that we have encountered have been characterized by classic Hodgkin lymphoma cells typically in a polymorphous background not specifically accompanied by any sclerosis and thus resembling node-based classic Hodgkin lymphoma of mixed cellularity type. It is probably not reasonable to subclassify cases of cutaneous Hodgkin lymphoma presenting initially in the skin. In one study comparing secondary skin lesions of Hodgkin lymphoma to their nodal counterparts (Cerroni et al., 1995), all seven patients had nodular sclerosis Hodgkin disease in the lymph nodes with six of the seven cases showing a similar histology in the skin. They concluded that the histologic findings in the cutaneous lesions correlated for the most part with those of the nodal counterpart (Cerroni et al., 1995).

Classic Hodgkin Lymphoma Light Microscopic Findings In classic Hodgkin lymphoma, there is a variable background inflammatory cell infiltrate dominated by reactive T lymphocytes with a smattering of eosinophils (see Figure 24.3) (Jaffe, 1999). The neoplastic cells are large with abundant hypereosinophilic cytoplasms. The nuclei contain large prominent eosinophilic nucleoli. It is common to see mirror image binucleation and other forms of multinucleation (Harris, 1999; Jaffe, 1999). Senescent mummified cells

477

with an effaced chromatin pattern are also seen (see Figure 24.6). When there is concomitant sclerosis, the designation nodular sclerosing is used while the mixed cellularity designation is applied to those cases without fibrosis; the lymphocyte-depleted variants have numerous malignant cells with a relative dearth of inflammatory cells (see Figures 24.2 and 24.4) (Harris, 1999; Jaffe, 1999). Lymphocyte-rich Hodgkin lymphoma has two recognized variants: a diffuse form and a nodular form (Shimabukuro et al., 2005; de Jong et al., 2006). The nodular form is alternatively designated as follicular Hodgkin lymphoma. The classic appearance is one of expanded follicles composed predominantly of mantle zone lymphocytes in the absence of sclerosis. Overall the histomorphology closely resemble nodular lymphocyte predominant Hodgkin lymphoma. Within the expanded mantle zones are scattered Reed Sternberg cells and their variants; these are the clue to the diagnosis. Prognostically, lymphocyte rich forms of Hodgkin lymphoma likely do better than either mixed cellularity or nodular sclerosing variants (Shimabukuro-Vornhagen et al., 2005; de Jong et al., 2006).

Lymphocyte-Predominant Hodgkin lymphoma This distinctive form of lymphoma occurs predominantly in young men with a mean age at presentation in the mid-thirties. The overall 10 year survival rate is in excess of 90% (Feugier et al., 2004). There are two broad categories of lymphocyte-predominant Hodgkin lymphoma: diffuse and nodular, the latter being the classic one (Nogova et al., 2005). The large pleomorphic cells are often described as Reed–Sternberg variants. They are frequently mononuclear but maintain a large size and lie in a vacuous rounded space; thus the designation lacunar cell (see Figure 24.7) (Chang et al., 1995). The chromatin is finely divided with peripherally disposed nucleoli. A variation on the same theme is a cell with a nuclear morphology reminiscent of a piece of popcorn, designated the popcorn cell. The cells have a less distinct nucleolus compared to the classic Reed Sternberg cell. In about 20% of cases of nodular lymphocyte predominant Hodgkin lymphoma there is progressive transformation of germinal centers (Burns et al., 1984). The hallmark is an expanded follicle permeated by mantle zone B-lymphocytes (Burns et al., 1984). The neoplastic cell in this variant has distinct histogenetic profile, being closely related to a germinal center or post germinal center B cell (Chang et al, 1995).

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Molecular and Phenotypic Profiles The molecular and phenotypic profiles for Hodgkin lymphoma are characteristic. The Reed– Sternberg-like cell is typically of B cell derivation (Kuppers et al., 1994; Tamaru et al., 1994; Kanzler et al., 1996; Braeuninger et al., 1997; Kuppers and Rajewsky, 1998; Harris, 1999; Marafioti et al., 2000). Occasionally, a null phenotype exists, and in less than 2% of cases the cell is of T cell derivation (Kadin et al., 2001). The cells are typically EMA negative (Pinkus and Kurtin, 1985). In classic Hodgkin lymphoma, the cells are CD30 and CD15 positive and do not express common leukocyte antigen (CD45) (see Figure 24.8) (Jaffe, 1999). Nevertheless, the neoplastic B lymphocyte in nodular lymphocyte-predominant Hodgkin disease has the immunophenotype and genotype of a postgerminal center B cell; in classic Hodgkin lymphoma the mature B cell antigen demonstrates a lower level of expression (see Figures 24.9 and 24.10) (Tzankov et al., 2003; Buettner et al., 2005). In lymphocyte-predominant Hodgkin lymphoma, the cells are CD45 positive and CD20 positive. There is no CD30 or CD15 immunoreactivity, although the cells do show strong immunoreactivity for epithelial membrane antigen (Chang et al., 1995). The profile is opposite to that observed in the setting of classic Hodgkin lymphoma. Furthermore, it has been shown that the morphologic and immunophenotypic features of lymphocyte-predominant Hodgkin lymphoma are preserved in extranodal sites (Chang et al., 1995). The differential diagnosis of Hodgkin lymphoma is anaplastic large cell lymphoma (Harris, 1999). Clusterin is a useful marker that has been used to discriminate between anaplastic large cell lymphoma and Hodgkin lymphoma (Wellmann et al., 2000; Saffer et al., 2002; Nascimento et al., 2004). Significant clusterin immunoreactivity is seen in lesions of anaplastic large cell lymphoma, while clusterin expression in Hodgkin lymphoma is uncommon, manifesting only cytoplasmic membrane immunoreactivity in rare cells (Nascimento et al., 2004). There are rare cases of Hodgkin lymphoma that are of T cell lineage (Kadin et al., 2001; Willenbrock et al., 2002). Those cases categorized as T cell variants of Hodgkin lymphoma provide an interesting link between Hodgkin lymphoma, lymphomatoid papulosis, and anaplastic large cell lymphoma. Cytogenetics From a pathogenetic perspective, classic Hodgkin lymphoma is quite different from lymphocytepredominant Hodgkin lymphoma. While in both, the

neoplastic cells are of B cell derivation, in classic Hodgkin lymphoma the cells have genetic alterations that prevent somatic mutations. In the lymphocytepredominant forms of Hodgkin lymphoma, the cells undergo somatic hypermutation analogous to follicle center cells exposed to antigen. Hence, the degree of anomalous differentiation encountered in the classic variant is not seen. There are no constant cytogenetic profiles. The reported karyotypes in Hodgkin lymphoma are complex and include polyploidy, chromosome gains or losses, translocations, inversions, and deletions (Kristoffersson et al., 1987). One such complex karyotype is illustrated. In one paper the authors were able to show a Bcl6 breakpoint translocation in cases of nodular lymphocyte-predominant Hodgkin lymphoma using fluorescence in situ hybridization, whereby chromosomal breakpoints in the IgH locus were detected along with an IgH–BCL6 juxtaposition, indicating a t(3; 14)(q27; q32) translocation (see Figure 24.13) (Renne et al., 2005). Histogenesis The neoplastic cell is a large monocytoid cell with frequent binucleation whose histogenesis was questioned for years. It is now established that the neoplastic cell is of B cell derivation and that Hodgkin lymphoma is thus a B cell lymphoma (Kuppers et al., 1994; Tamaru et al., 1994; Kanzler et al., 1996; Braeuninger et al., 1997; Kuppers and Rajewsky, 1998; Harris, 1999; Marafioti et al., 2000). Coexpression of CD15 and CD30 and lack of expression of CD45 are typical for cases of classic Hodgkin lymphoma, while the neoplastic cells in lymphocyte-predominant Hodgkin lymphoma are CD15 negative and CD45 positive (Harris, 1999; Jaffe, 1999). Although Hodgkin lymphoma is usually equated with CD30 expression by the neoplastic cells, in lymphocyte-predominant Hodgkin lymphoma, cells are characteristically CD30 negative. The neoplastic cell is therefore histogenetically distinct from that implicated in classic Hodgkin lymphoma (Harris, 1999). Even though we recognize these tumors to be B cell malignancies, the special stains that indicate B cell derivation may be only weakly positive or the cells may demonstrate a null phenotype, a phenomenon best exemplified in cases of classic Hodgkin lymphoma. In classic Hodgkin disease, no immunoglobulin is produced despite immunoglobulin gene rearrangement and subsequent somatic mutations (see Figure 24.14) (Re et al., 2001; Braeuninger et al., 2005). The basis of this abortive immunoglobulin synthesis is unclear but may relate to dysregulation in transcriptional machinery (Braeuninger et al., 2005). The indolence of the disease may reflect the absence of immunoglobulin expression,

Subtypes of Hodgkin Lymphoma

perhaps placing the neoplastic cell at a growth disadvantage unless other antiapoptotic events take place. Such a survival advantage could occur in the setting of EBV infection and may relate to the poorer survival described in EBV-associated Hodgkin lymphoma (Bechtel et al., 2005; Braeuninger et al., 2005; Keegan et al., 2005). The interplay between EBV infection and promotion of antiapoptotic events has been elucidated (Bechtel et al., 2005; Braeuninger et al., 2005). The role of EBV in the evolution of Hodgkin’s lymphoma is well established (Pallesen et al., 1991; Deacon et al., 1993). In particular, the nuclear proteins of this virus such as EBNA and LMP are detected in 40% of cases of classic Hodgkin lymphoma and are most apparent

479

in the mixed cellularity form (Pallesen et al., 1991; Deacon et al., 1993). The sequela of LMP expression is the induction of bcl-2 expression, allowing the cells to evade apoptotic events. An additional mechanism by which the Reed–Sternberg cells escape apoptosis is likely though the nuclear factor (NF) κβ pathway (Younes et al., 1995). NF κβ represents a group of transcription factors that are important for apoptosis and oncogenesis. NF κβ is upregulated in the Reed–Sternberg cells in classic Hodgkin lymphoma. The CD40 ligand may be involved in the upregulation of NF κβ. Reed–Sternberg cells are characteristically strongly CD40 positive (O’Grady et al., 1994; Younes et al., 1995).

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CASE VIGNETTE CASE VIGNETTE 1

The patient is a 30 year old man who presented with a scalp nodule in 2000. There were no features of ensuing extracutaneous lymphoma. Diagnosis: Primary cutaneous Hodgkin lymphoma (Figures 24.2–24.11).

(a)

(b)

There is a striking nodular mixed inflammatory cell infiltrate. The infiltrate is dense and while lying in close apposition to the epidermis is demarcated from it by a narrow grenz zone of uninvolved dermis.

FIGURE 24.2

(a)

(b)

FIGURE 24.3 Higher power magnification reveals an infiltrate that contains a few scattered large hematopoietic elements typical for those encountered in Hodgkin lymphoma.

Case Vignette 1

(a)

(b)

FIGURE 24.4 There is a nodular infiltrate with sclerosis and conspicuous tissue eosinophilia typical for nodular sclerosing Hodgkin lymphoma.

(a)

(b)

The classic morphology of the Reed–Sternberg cell is illustrated. The cells are large with brightly eosinophilic nucleoli and abundant cytoplasms. Binucleation is characteristic.

FIGURE 24.5

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(Continued)

(a)

(b)

FIGURE 24.6 Senescent change is observed. Such cells are referred to as mummified, an appropriate term when one considers the nature of the cells—basically ones undergoing progressive apoptosis, a point alluded to in greater detail in the chapter.

Typical lacunar cells of lymphocyte predominant Hodgkin lymphoma.

FIGURE 24.7

FIGURE 24.8 The neoplastic cells in classic Hodgkin lymphoma are CD30 positive. The CD30 positivity manifests perinuclear golgi and cytoplasmic membrane staining.

Case Vignette 1

FIGURE 24.9 There is rosetting of CD3-positive T cells around neoplastic Reed–Sternberg cells.

FIGURE 24.11

The cells are weakly bcl6-positive, corroborative of an underlying B cell origin for the neoplastic cell populace.

FIGURE 24.10

The cells are strongly CD40 positive.

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ADDITIONAL MOLECULAR AND CYTOGENETIC STUDIES

FIGURE 24.12 Laser capture microdissection polymerase chain reaction of areas rich in Reed–Sternberg-like cells reveal a heavy chain immunoglobulin rearrangement.

1

2

3

6

7

8

13

14

15

19

20

4

mar

9

21

10

11

5

12

16

17

18

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X

Y

Karyotype in Hodgkin lymphoma is very complex and not reproducible from case to case. Unlike many other lymphoid neoplasms, there is no predictable cytogenetic abnormality. Illustrated is a characteristic Hodgkin lymphoma karyotype. 45,XY,add(1)(p34),add(1)(q42),del(2)(p?16),der(10)t(10;12)(q26;q13),add(11)(q23),-12,-13,add(16)(q2?4), add(19)(q13.1),add(19)(q13.3),+mar. (Cytogenetic interpretation and image provided by Dr. Nyla Heerema, Director of Cytogenetics, The Ohio State University.)

FIGURE 24.13

Additional Molecular and Cytogenetic Studies

Panel A

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Dominant peak 312 bp

Panel B Polyclonal results

Panel C Polyclonal results

A 39 year old woman diagnosed with diffuse lymphocyte-rich classic Hodgkin lymphoma. The IgH(V-D-J) gene rearrangement shows a monoclonal population of B lymphocytes in a polyclonal background in one of three multiplex panels. A peak at 312 bp is present on panel A while panels B and C show polyclonal results. (Molecular gel and interpretation provided by Carl D. Morrison, MD, DVM, Pathology Core Facility, The Ohio State University.)

FIGURE 24.14

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HARRIS N. Hodgkin’s lymphoma: classification, diagnosis and grading. Semin Hematol. 1999; 26:220–232. JAFFE ES. Introduction: Hodgkin’s lymphoma—pathology, pathogenesis, and treatment. Semin Hematol. 1999; 36(3):217–219. JURISIC V, BOGUNOVIC M, COLOVIC N, COLOVIC M. Indolent course of the cutaneous Hodgkin’s disease. J Cutan Pathol. 2005; 32(2):176–178. KADIN ME. Lymphomatoid papulosis, Ki-1+ lymphoma, and primary cutaneous Hodgkin’s disease. Semin Dermatol. 1991; 10(3):164–171. KADIN ME, DREWS R, SAMEL A, et al. Hodgkin’s lymphoma of T-cell type: clonal association with a CD30+ cutaneous lymphoma. Hum Pathol. 2001; 32(11):1269–1272. KANZLER H, KUPPERS R, HANSMANN ML, RAJEWSKY K. Hodgkin and Reed–Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med. 1996;184(4):1495–1505. KEEGAN TW, GLAZER SL, CLARKE CA, et al. Eastein–Barr virus as a marker of Survival after Hodgkin’s lymphoma: a population-based study. J Clin Oncol. 2005; 23(30): 7604–7613. KRISTOFFERSSON U, HEIM S, MANADAHL N, et al. Cytogenetic studies in Hodgkin’s disease. Acta Pathol Microbiol Immunol Scand. 1987; 95:289–295. KUMAR S, KINGMA D, WEISS W, et al. Primary cutaneous Hodgkin’s disease with evolution to systemic disease. Am J Surg Pathol. 1996; 20(6):754–759. KUPPERS R, RAJEWSKY K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin’s disease. Annu Rev Immunol. 1998; 16:471–493. KUPPERS R, RAJEWSKY K, ZHAO M, et al. Hodgkin disease: Hodgkin and Reed–Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA. 1994;91(23):10 962–10966. MAGRO CM, NASH JW, WERLING RW, PORCU P, CROWSON N. Primary cutaneous CD30+ large cell B-cell lymphoma: a series of 10 cases. Appl Immunohistochem Mol Morphol. 2006; 14(1):7–11. MARAFIOTI T, HUMMEL M, FOSS HD, et al. Hodgkin and Reed–Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood. 2000;95(4):1443–1450. NARAYANAN G, REKHA NAIR A, SOMINI KOSHY E, KRISHNAN NAIR M. Cutaneous relapse in Hodgkin’s disease. Acta Oncol. 1999; 38(7):969–970. NASCIMENTO AF, PINKUS JL, PINKUS GS. 3 Clusterin, a marker for anaplastic large cell lymphoma immunohistochemical profile in hematopoietic and nonhematopoietic malignant neoplasms. Am J Clin Pathol. 2004; 121(5):709–717. NOGOVA L, REINEKE T, JOSTING A, et al. Lymphocyte-predominant and classical Hodgkin’s lymphoma—comparison of outcomes. Eur J Haematol Suppl. 2005; 66:106–10.

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O’GRADY J, STEWART S, LOWREY J, et al. CD40 expression in Hodgkin’s disease. Am J Dermatol. 1994; 144:21–26. PAGLIARO JA, WHITE SI. Specific skin lesions occurring in a patient with Hodgkin’s lymphoma. Australas J Dermatol. 1999; 40(1):41–43. PALLESEN G, HAMILTON-DUTOIT SJ, ROWE M, YOUNG LS. Expression of Epstein–Barr virus latent gene products in tumour cells of Hodgkin’s disease. Lancet 1991;337(8737):320–322. PINKUS GS, KURTIN PJ. Epithelial membrane antigen—a diagnostic discriminant in surgical pathology: immunohistochemical profile in epithelial, mesenchymal, and hematopoietic neoplasms using paraffin sections and monoclonal antibodies. Hum Pathol. 1985; 16(9):929–940. RE D, STARATSCHEK-JOX A, HOLTICK U, DIEHL V, WOLF J. Deregulation of immunoglobulin gene transcription in the Hodgkin–Reed–Sternberg cell line L1236. Br J Haematol. 2001; 115(2):326–328. RENNE C, MARTIN-SUBERO JI, HANSMANN ML, SIEBERT R. Molecular cytogenetic analyses of immunoglobulin loci in nodular lymphocyte predominant Hodgkin’s lymphoma reveal a recurrent IGH–BCL6 juxtaposition. J Mol Diagn. 2005; 7(3):352–356. SAFFER H, WAHED A, RASSIDAKIS GZ, MEDEIROS LJ. Clusterin expression in malignant lymphomas: a survey of 266 cases. Mod Pathol. 2002; 15(11):1221–1226. SHAW MT, JACOBS Sr. Cutaneous Hodgkin’s disease in a patient with human immunodeficiency virus infection. Cancer. 1989;64(12):2585–2587. SHIMABUKURO-VORNHAGEN A, HAVERKAMP H, ENGERT A, et al. Lymphocyte-rich classical Hodgkin’s lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin’s Study Group trials. J Clin Oncol. 2005;23(24):5739–5745. SILVERMAN CL, STRAYER DS, WASSERMAN TH. Cutaneous Hodgkin’s disease. Arch Dermatol. 1982; 118(11):918–921.

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SIOUTOS N, KERL H, MURPHY SB, KADIN ME. Primary cutaneous Hodgkin’s disease. Unique clinical, morphologic, and immunophenotypic findings. Am J Dermatopathol. 1994; 16(1):2–8. SOLOMON BA, GOLDMAN RJ. Ulcerated nodules and papules on the neck and chest. Cutaneous Hodgkin disease (HD). Arch Dermatol. 1997; 133(11):1454–1455, 1457–1458. TAKAGAWA S, MARUYAMA R, YOKOZEKI H, et al. Skin invasion of Hodgkin’s disease mimicking scrofuloderma. Dermatology. 1999; 199(3):268–270. TAMARU J, HUMMEL M, ZEMLIN M, KALVELAGE B, STEIN H. Hodgkin’s disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes. Blood. 1994;84(3):708–715. TASSIES D, SIERRA J, MONTSERRAT E, MARTI R, ESTRACH T, ROZMAN C. Specific cutaneous involvement in Hodgkin’s disease. Hematol Oncol. 1992; 10(2):75–79. TZANKOV A, ZIMPFER A, PEHRS AC, et al. Expression of Bcell markers in classical Hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol. 2003; 16(11):1141–1147. WELLMANN A, THIEBLEMONT C, PITTALUGA S, et al. Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood. 2000;96(2):398–404. WHITE RM, PATTERSON JW. Cutaneous involvement in Hodgkin’s disease. Cancer. 1985;55(5):1136–1145. WILLENBROCK K, ICHINOHASAMA R, KADIN ME, et al. Tcell variant of classical Hodgkin’s lymphoma with nodal and cutaneous manifestations demonstrated by single-cell polymerase chain reaction. Lab Invest. 2002; 82(9):1103–1109. YOUNES A, GARG A, AGGARWAL BB. Nuclear transcription factor-kβ in Hodgkin’s disease. Leuk Lymphoma. 1995; 44(6):929–935.

Index

Acquired immunodeficiency syndrome (AIDS), Epstein-Barr virus association, 384–387 Actinic prurigo, polymorphous light eruption, 54 Actinic reticuloid reaction, polymorphous light eruption, 54 Activating protein-1 (AP-1), mycosis fungoides, 289 Activation/proliferation markers: anaplastic large cell lymphoma, 448–449 defined, 10 Acute myelogenous leukemia, nasal/extranodal natural killer cell/T cell lymphomas, 400–401 Adhesion markers, follicle center cell lymphoma, 177 Adnexotropic mycosis fungoides, clinical features, 273, 278–279 Adnexotropic T cell dyscrasia, case study, 122–123 Adult T cell leukemia/lymphoma: case studies, 322–326 chronic/smoldering variant, 319–323 clinical features, 318–319 pathogenesis, 320–321 pathology, 319–320 phenotypic studies, 320 Alibert variant, mycosis fungoides, 267 ALK1 antibody, anaplastic large cell lymphoma, 449 ALK-1 Break apart Probe, defined, 12 Allergic contact dermatitis: clinical features, 33–34 differential diagnosis, 36 histomorphology, 34–35 pathogenesis, 35–36 Allogeneic bone marrow transplantation, cell-poor vacuolar interface

dermatitis, graft-versus-host disease, 43 Allogeneic hematopoietic stem cell transplantation (all-HSCT), cutaneous T cell lymphoma therapy, 20 Alopecia, syringolymphoid hyperplasia with, 103–104 Alopecia mucinosa: case study, 120–121 cell-poor pilotropic T cell dyscrasia, 124 clinical features, 104–106 molecular profile, 134 mucin-poor pilotropic T cell dyscrasia, 118–119 αβT cell subtype: subcutaneous panniculitis-like T cell lymphoma, 367–368 Anaplastic large cell lymphoma, 445 Angiocentric cutaneous T cell lymphoma of childhood, hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 Angiocentric immunoproliferative lesion (AIL), lymphomatoid granulomatosis, 429–433 Angioimmunoblastic lymphadenopathy (AILD): case studies, 334–339 clinical features, 329–331 Epstein-Barr virus, 381 light microscopic findings, 331 molecular studies, 332–333 pathogenesis, 333 phenotypic profile, 331–332 Antibody-dependent cellular immunity, collagen vascular disease, 44–45 Anti endothelial cell antibodies, collagen vascular disease, 44–45

Anti-Ro-associated systemic lupus erythematosus: interface dermatitis and, 45 lichenoid dermatitis, 48–49 AP12 MALT1 Fusion Probe, defined, 12 Atopic eczema, nummular eczema, differential diagnosis, 38 Atrophoderma of Pasini and Pierini, morphea pathogenesis, 57 Atypical lymphocytic lobular panniculitis: case studies, 116–117, 125 clinical features, 106–108 molecular profile, 134–135, 137 subcutaneous panniculitis-like T cell lymphoma and, 368–371 Atypical pigmentary purpura reactions, lymphomatoid tissue reactions, 65–66 Autoimmune progesterone dermatitis, 41–42 Baboon syndrome, allergic eczematous drug reaction, 36 Bacille-Calmette-Gu´erin vaccine, pityriasis rosea, 37 Bacterial infection, hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 bax/bcl-2 system, mycosis fungoides, 288–289 B-cell chronic lymphocytic leukemia (B-CLL) clinical features, 226 cytogenetic studies, 227–228 molecular studies, 227 morphology, 226–227 pathogenesis, 228 phenotype, 227

The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, by Cynthia M. Magro, A. Neil Crowson, and Martin C. Mihm Copyright  2007 John Wiley & Sons, Inc. 489

490

Index

B cell markers, defined, 9–10 Bcl-1 marker: defined, 9 mantle cell lymphoma, 248 bcl-2IgH Fusion probe, defined, 12 Bcl-2 marker: defined, 9–10 diffuse large B cell lymphoma, 192–199 follicle center cell lymphoma BCL-6 protein, defined, 10 BCL-10 marker, defined, 10 Benign disorders: clonality and, 30–31 lymphocytic infiltrates: autoimmune disease, diffuse/nodular infiltrates, 55–59 basic principles, 33 cell-poor vacuolar interface dermatitis, 40–46 diffuse/nodular infiltrates without atypia, 52–55 lichenoid interface dermatitis, 46–52 spongiotic and eczematous dermatitis, 33–378 Bexarotene, cutaneous T cell lymphoma therapy, 17 BF-1 antibody, defined, 8 Blastic/blastoid NK cell lymphoma, epidemiology, 406 Bone marrow involvement, mycosis fungoides, 286 Borderline CD30-positive lymphoproliferative disorders, 445 Borrelia burgdorferi: marginal zone lymphomas, 146 morphea pathogenesis, 58 Capillary electrophoresis, polymerase chain reaction products, 28–29 Cardiovascular system, mycosis fungoides, 285 Carmustine (BCNU), cutaneous T cell lymphoma therapy, 20–21 Castleman disease: cell-poor vacuolar interface dermatitis, 44 defined, 8 lymphomatoid granulomatosis, 430–433, 432–436 lymphomatoid tissue reactions, 68 mycosis fungoides, 267–268, 286–288 agranular CD4-positive CD56-positive hematodermic neoplasm, 406 pityriasis lichenoides chronica, 102–103 T cell prolymphocytic leukemia (T-PLL), 357 CD5 antigen: B-cell chronic lymphocytic leukemia (B-CLL), 228 defined, 8 diffuse large B cell lymphoma, 196 marginal zone lymphoma mycosis fungoides, 286–288

CD7 antigen: CD8 T cell lymphoproliferative disease, 346 cutaneous lymphoid dyscrasia, 94 defined, 8 large plaque parapsoriasis, 95–96 lymphomatoid tissue reactions, 654–668 mycosis fungoides, 286–288 CD8 antigen: allergic contact dermatitis, 34 anaplastic large cell lymphoma, 465 cell-poor vacuolar interface dermatitis, 44 defined, 8–9 γ δ T cell lymphoma, 261–264 lymphomatoid granulomatosis, 430–433 lymphomatoid papulosis, 442–445 mycosis fungoides, 267–268 CD8 varients of lymphoma: 343–345 nasal/extranodal natural killer cell/T cell lymphomas, 401–405 pityriasis lichenoides chronica, 102–103 subcutaneous panniculitis-like T cell lymphoma, 370 CD8 T cell lymphoproliferative disease: basic characteristics, 343–345 case studies, 349–363 CD30-positive disorder, 460–462 drug therapy and, 348 histomorphology, 345–346 lymphomatoid papulosis variants, 346–347 NK/T cell lymphomas, 414–415 phenotypic profile, 346 primary cutaneous lymphoma, 343–345 pseudolymphomas, 348 CD10 antigen: angioimmunoblastic lymphadenopathy, 331–332 defined, 9 diffuse large B cell lymphoma, 196–197 follicle center cell lymphoma, 176 marginal zone lymphomas, 148 precursor B lymphoblastic lymphoma/leukemia, 200 CD15 marker, defined, 10 CD16 marker, defined, 9 CD19 antigen, defined, 9 CD20 antigen: defined, 9 CD21 network: angioimmunoblastic lymphadenopathy, 331–332 follicle center cell lymphoma, 176 marginal zone lymphoma, 148 CD22 antigen, defined, 9 CD23 antigen: mantle cell lymphoma CD23 expression: chronic lymphocytic leukema follicle center cell lymphoma, 176 marginal zone lymphoma, 144–146 differential diagnosis, 147–148 CD25 antigen, defined, 10 CD25-positive cutaneous T cell lymphoma, immunotoxin therapy, 17

CD29 markers, intravascular lymphoma, 221 CD30 antigen: atypical pigmentary purpura reactions, 65–66 cutaneous T cell lymphoma therapy, 14–15 defined, 10 diffuse large B cell lymphoma, 196 lymphomatoid granulomatosis, 432–433 lymphomatoid tissue reactions, 68 CD30-based lymphomas: EORTC classification, 3–6 primary cutaneous Hodgkin lymphoma, 475–479 CD30-negative large cell T cell lymphoma: case studies, 312, 314 clinical features, 300–303 CD30-positive lymphoproliferative disease: borderline disease, 445 case studies, 310–311, 313, 451–470 CD8 lymphomatoid papulosis, 444–445 classification, 300–303 cutaneous anaplastic large cell lymphoma, 445–450 epidemiology, 439–440 large B cell lymphoma, 450–451 lymphomatoid papulosis, 440–445 clinical features, 440–441 cytogenetics, 444 pathology, 441–443 phenotypic and molecular studies, 443–444 molecular and cytogenetic studies, 468–470 type A variant, 458–459 type B variant, 458–459 type C variant, 456–457 CD34 antigen, defined, 10 CD43 antigen: defined, 8, 10 diffuse large B cell lymphoma, 196 CD44 markers, anaplastic large cell lymphoma, 449 CD45 marker: CD8 T cell lymphoproliferative disease, 346 mycosis fungoides, 287–288 CD52 antibody, 9 CD54 markers, intravascular lymphoma, 221 CD56 markers: defined, 9 lymphomatoid granulomatosis, 432–433 nasal/extranodal natural killer cell/T cell lymphomas, 406 CD4 subset, 409 epidemiology, 401–402 subcutaneous panniculitis-like T cell lymphoma, 370 CD62L selectins: defined, 8 CD8 T cell lymphoproliferative disease, 346 cutaneous lymphoid dyscrasia, 94

Index

large plaque parapsoriasis, 95–96 lymphomatoid tissue reactions, 65–68 CD68 marker, defined, 10 CD71 antigen, defined, 10 CD79 marker, diffuse large cell B lymphoma, 195–196 CD123 antigen, defined, 10 CD138 markers, 9 Cell-poor vacuolar interface dermatitis: collagen vascular disease, 44–45 erythema multiforme, 40–42 Gianotti-Crosti syndrome, 42 graft-versus-host disease, 42–44 morbiliform viral exanthum and drug eruption, 44 Centroblasts, follicle center cell lymphoma, 175 Chemotherapy, cutaneous T cell lymphoma, topical therapy, 20–21 Chronic active EBV infection (CAEBV), hydroa vacciniforme-like Epstein-Barr virus associations, 383–384 Chronic lymphocytic leukemia B-cell type, 18 clinical features, 226 cytogenetic studies, 227–228 molecular studies, 227 morphology, 226–227 pathogenesis, 228 phenotype, 227 follicular mucinosis, 85 mantle cell lymphoma, 249 molecular and cytogenetic studies, 244–245 skin infiltration, 231–233, 236–238 squamous cell carcinoma, 234–235 T-cell type: clinical features, 228–229 cytogenetics, 230 differential diagnosis, 230 light microscopic analysis, 229 phenotypic abnormalities, 229–230 prolymphocytic leukemia, 239–240, 242–243 skin involvement, 241 Classification schemes for lymphoma, 1–6 See also specific classification scheme Clonality assessment in prelymphomatous and reactive states collagen vascular disease, 87 lupus erythematosus profundus (LEP), 88 lymphocytoma cutis, 71 lymphomatoid granulomatosis, 432 lymphomatoid tissue reactions, 66–67 dermatitis, 86 drug reactions, 79 polyclonal drug reactions, 80 vascular reactions, 84 pigmented purpuric dermatosis, 100 pityriasis lichenoides chronica, 102–103 polymerase chain reaction: basic principles, 25 design criteria, 27

Clusterin, anaplastic large cell lymphoma, 449 c-MYC oncogene, diffuse large B cell lymphoma and T cell prolymphocytic leukemia, 197 Collagen vascular disease: antibody-dependent cellular immunity and/or anti endothelial cell antibodies, 44–45 clonality assessment, 87 lymphomatoid tissue reactions: lupus erythematosus profundus, 69–70 lymphocytoma cutis, 70–71 lymphomatoid lupus erythematosus, 68–69 pathogenesis, 69 primary cutaneous plasmacytosis, 71–72 viral-associated lymphomatoid dermatitis, 70 Complementary determining region (CDR), immunoglobulin H receptor structure, 26 Complement receptors, hydroa vacciniforme-like Epstein-Barr virus associations, 384 Connective tissue disease, lichenoid syndromes, 48–51 Consensus sequence, immunoglobulin H receptor structure, 26 Coup de sabre lesions, morphea, 57 Cutaneous anaplastic large cell lymphoma, CD30-positive lymphoproliferative disorders, 445–450 Cutaneous lymphocyte antigen (CLA): adult T cell leukemia/lymphoma, 320 cutaneous lymphoid dyscrasia, 94 defined, 9 mantle cell lymphoma, 250 mycosis fungoides, 287–288 precursor B lymphoblastic lymphoma/leukemia, 200 Cutaneous lymphoid dyscrasia (CLD): atypical lobular panniculitis, 106–108 hypopigmented mycosis fungoides, 96–97 idiopathic follicular mucinosis/alopecia mucinosa, 104–106 large plaque parapsoriasis, 94–96 pigmented purpuric dermatosis, 97–100 pityriasis lichenoides chronica, 100–103 precursor lesions, 93–94 syringolymphoid hyperplasia with alopecia, 103–104 Cutaneous mantle cell lymphoma: case studies, 252–256 clinical features, 248–249 cytogenetic profile, 250–251 light microscopic findings, 249 molecular studies, 250 pathogenesis, 251 phenotypic profile, 249–250 Cutaneous T cell lymphoma (CTCL). See also Primary cutaneous lymphomas

491

advanced stage therapeutic goals, 15 basic characteristics, 14–15 CD8 T cell lymphoproliferative disease, 344–345 cytotoxic chemotherapy, 18 diagnostic work-up and staging, 15 epidermotropic cytotoxic lymphoma, 349–354 extracorporeal photopheresis, 15–16 granulomatous slack skin, 273 immunotoxins, 17 interferons, 16 investigational therapies, 18–20 allogeneic hematopoietic stem cell transplantation, 20 histone deacetylase inhibitors, 19–20 monoclonal antibodies, 19 toll-like receptor agonists and cytokines, 19 monoclonal antibodies, 17–18 mycosis fungoides, 285–289 post-transplant lymphoproliferative disease, 387–388 precursor lesions, 93–94 primary small/mixed pleomorphic variant: case studies, 305–314 clinical features, 300–303 cytogenetics, 305, 315 differential diagnosis, 305 molecular profiles, 315 pathology/light microscopic findings, 303–304 phenotypic profile, 304–305 retinoids, 16–17 S´ezary syndrome, 274–285 skin-directed therapies, 20–22 Cyclin D1 IgH Fusion Probe, defined, 12 Cyclosporine, Epstein-Barr virus-associated B cell lymphoma, 388–389 Cytogenetics: anaplastic large cell lymphoma, 449 B-cell chronic lymphocytic leukemia (B-CLL), 227–228 CD30-positive lymphoproliferative disease, 468–470 diffuse large B cell lymphoma, 196 follicle center cell lymphoma, 177, 190 hydroa vacciniforme-like Epstein-Barr virus associations, 383–384 lymphocyte-predominant Hodgkin lymphoma, 478 lymphomatoid papulosis, 444 mantle cell lymphoma, 250–251, 256 marginal zone lymphomas, 147 mycosis fungoides, 288, 292–296 nasal/extranodal natural killer cell/T cell lymphomas, 405–406 precursor B lymphoblastic lymphoma/leukemia, 200, 213–215 primary cutaneous Hodgkin lymphomas, 484–485 primary cutaneous small/medium sized pleomorphic T cell lymphoma, 305, 315

492

Index

Cytogenetics: (Continued) T cell prolymphocytic leukemia (T-PLL), 230, 244–245 Cytokines: angioimmunoblastic lymphadenopathy, 333 cutaneous T cell lymphoma therapy, toll-like receptor agonists, 19 Cytomegalovirus (CMV), cutaneous T cell lymphoma therapy, 18 Cytoplasmic granularity, nasal/extranodal natural killer cell/T cell lymphomas, 403–404 Cytotoxic chemotherapy, cutaneous T cell lymphoma therapy, 18 Cytotoxic molecule expression, mycosis fungoides, 286–288 Cytotoxic protein markers, defined, 9 Cytotoxic pseudolymphoma, CD8 T cell lymphoproliferative disease, 348 Delayed dermal hypersensitivity, allergic contact dermatitis, 35 D’emblee mycosis fungoides, clinical features, 302–303 Denileukin diftitox, cutaneous T cell lymphoma therapy, 17 Dermatomyositis: antibody-dependent cellular immunity, 45–46 erythema multiforme differential diagnoses, 41–42 Dermatophytid, pityriasis rosea, 37 Diffuse histiocytic lymphoma, classification scheme, 1 Diffuse large B cell lymphoma: case studies, 206–208 classification, 194 clinical features, 192–194 cytogenetics, 196 differential diagnosis, 197–198 molecular studies, 196 monomorphic post-transplant lymphoproliferative disease, 387 pathogenesis, 196–197 pathology, 194–195 phenotype, 195–196 Drug reactions: CD8 T cell lymphoproliferative disease, 348 case studies, 362 follicular mucinosis, lymphocytic leukemia, 85 lichen planus, 47–48 hypersensitivity case study, 76–77 lymphocytoma cutis, 75 lymphomatoid tissue: clinical features, 64–65 clonality assessment, 79 endogenous immune dysregulation, 73 histopathology, 65–66 molecule profile, 66–67 pathogenetic basis, 67–68

phenotypic profile, 66 polyclonal drug reactions, 80 morphea histopathology, 57 pityriasis rosea, 37 Dutcher body formation, marginal zone lymphomas, 142–144 Dysproteinemia. See Angioimmunoblastic lymphadenopathy (AILD) Eczematoid purpura of Doucas and Kapetankis, clinical features, 97–99 Eczematous dermatitis: allergic contact dermatitis, 33–37 pathogenesis, 35–36 subacute conditions, 38–40 tissue reactions, 37–38 Enteropathy type T cell lymphoma, clinical features, 260–261 Eosinophilia-myalgia syndrome, morphea histopathology, 57 Epidermotropism: CD8 T cell lymphoproliferative disease, 345, 349–354 mycosis fungoides, 278–279 Epstein-Barr Virus-Associated Latent Small Nuclear RNA (EBER): defined, 11 hydroa vacciniforme-like Epstein-Barr virus associations, 383–384 nasal/extranodal natural killer cell/T cell lymphomas, 404 Epstein-Barr Virus (EBV): CD30-positive large B cell lymphoma, 467 lymphocyte-predominant Hodgkin lymphoma, 479 lymphomatoid granulomatosis, 429–436 lymphoproliferative disease: B cell iatrogenic immune dysregulation, 384–389 case studies, 390–394 epidemiology, 381–382 hydroa vacciniforme variant, 382–384 nasal/extranodal natural killer cell/T cell lymphomas, 399–401, 406–409 blastic/blastoid variants, 406 CD4 subset, 408–409 chronic granular lymphocytosis/large granular cell leukemia, 407–409 panniculitis-like variant, 406–407 plasmablastic lymphoma, 386–387, 390–391 primary cutaneous Hodgkin lymphomas, 476–479 subcutaneous panniculitis-like T cell lymphoma, 370–371 Eruptive dermatofibromas, marginal zone lymphomas: molecular studies, 165–166 phenotypic profiles, 144–145 Erythema annulare centrifugum (EAC): features and pathology, 39–40 perivascular lymphocytic infiltrates, 54 Erythema chronicum migrans: features and pathology, 40

gyrate erythemas, 54–55 Erythema gyratum repens: features and pathology, 40 manifestation, 55 Erythema marginatum: features and pathology, 40 manifestation, 55 Erythema multiforme, clinical features and pathology, 40–42 Erythroderma: mycosis fungoides, clinical features, 267–268 pityriasis lichenoides chronica, 102–103 S´ezary syndrome (SS), 274–285 Erythrophagocytosis, subcutaneous panniculitis-like T cell lymphoma, 369–370 European BIOMED-2 collaborative study: clonality, 25 PCR clonality determination and detection, 29–30 European Organization for the Research and Treatment (EORTC): diffuse large B cell lymphoma, 193–194 lymphoma classification, 2–6 primary cutaneous lymphomas, 173–174 S´ezary syndrome (SS), 274–285 subcutaneous panniculitis-like T cell lymphoma, 366–368 Extracorporal photopheresis (ECP), cutaneous T cell lymphoma therapy, 15–16 skin-directed agents, 22 Extracutaneous dissemination, mycosis fungoides, 271, 285–289 cytogenetic abnormalities, 288 gene rearrangement profile, 288 pathogenesis, 288–289 phenotypic profile, 286–288 Family-specific sequence, immunoglobulin H receptor structure, 26 Fas ligand: mycosis fungoides, 288–289 subcutaneous panniculitis-like T cell lymphoma, 370 Fatal panniculitis, defined, 366–367 Fluorescent in-situ hybridization (FISH), defined, 11–12 Follicle center cell lymphoma. See also Diffuse large B cell lymphoma clinical features, 173–174 cytogenetics, 177, 190 large cell type, 181–183 mixed cell case vignettes, 178–180, 184–189 molecular studies, 176, 190 pathogenesis, 176–177 pathology, 174–175 phenotypic profile, 176 prognosis, 177 Follicular mucinosis: clinical features, 104–106 lymphocytic leukemia, drug reactions, 85 Follicular mycosis fungoides:

Index

cytomorphology, 283–285 patch formation, 268–270 Folliculolymphoid hyperplasia, cytomorphology, 285 Folliculotropic mycosis fungoides, clinical features, 272 Fox P3 antibody, 9 Framework regions (FRs), immunoglobulin H receptor structure, 26 γ δ T cell subtype: case studies, 264–265 clinical features, 259–261 molecular studies, 263 morphology, 261–262 phenotype, 262 subcutaneous panniculitis-like T cell lymphoma, 367–370 ultrastructural analysis, 263 Gastrointestinal involvement, mycosis fungoides, 285 Gemcitabine, cutaneous T cell lymphoma therapy, 18 Gene rearrangement profile, mycosis fungoides, 288 Gianotti-Crosti syndrome: clinical features and pathology, 42 pityriasis rosea differential diagnosis, 36–37 Giant follicular lymphoid hyperplasia, clinical features, 148–149 Glucocorticoid -induced tumor necrosis factor receptor family related protein (GITR), adult T cell leukemia/lymphoma, 321 Gougerot-Blum purpura, 97–99 Graft-versus-host disease: cell-poor vacuolar interface dermatitis, 42–44 lichenoid dermatitis, 51–52 morphea histopathology, 57 Granular lymphocytes (GLs), NK/T cell lymphomas, 407–408 Granulocytic sarcoma, precursor B lymphoblastic lymphoma/leukemia, 200–202, 211–212 Granulomatous eccrinotropic lymphomatoid papulosis, pathology, 442–443 Granulomatous mycosis fungoides, clinical features, 273 Granzyme B: mycosis fungoides, 286–288 primary cutaneous aggressive CD8 epidermotropic T cell lymphoma subcutaneous panniculitis-like T cell lymphoma, 370 Gyrate erythemas, clinical features and pathology, 54–55 Hemophagocytic syndrome, hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 Hepatitis C virus:

marginal zone lymphomas, 146–147 subcutaneous panniculitis-like T cell lymphoma, 370 Hepatobiliary disease, lichenoid dermatitis, 47–48 Hepatosplenic T cell lymphoma, clinical features, 259–261 Hermatodermic neoplasms, nasal/extranodal natural killer cell/T cell lymphomas, 406–409, 416–420, 423 Herpes-associated erythema multiforme, pathogenesis, 42 HTLV-1 detection, basic technique, 11 Histone deacetylase inhibitors (HDACi), cutaneous T cell lymphoma therapy, 19–20 HLA-DR antigen, defined, 10 Hodgkin lymphomas: lymphomatoid papulosis, 442–443 primary cutaneous variants: case studies, 480–483 classic subtypes, 477 clinical features, 475–476 cytogenetics, 478 histogenesis, 478–479 lymphocyte-predominant variant, 477 molecular and phenotype profiles, 478 Human herpesvirus 7 (HHV-7), pityriasis rosea, 36–67 Human herpesvirus 8 (HHV-8): angioimmunoblastic lymphadenopathy, 333 Castleman’s disease, 148–149 plasmablastic lymphoma variant, 386–387, 390–391 Human immunodeficiency virus (HIV), CD8 pseudolymphoma, 348, 360–361 Human T cell lymphotropic retrovirus (HTLV-1) genes: adult T cell leukemia/lymphoma, 318–321 mycosis fungoides, 288 post-transplant lymphoproliferative disease, 387–388 Hydroa vacciniforme: Epstein-Barr virus associations, 382–384 polymorphous light eruption, 54 Hypopigmented epitheliotropic T cell dyscrasia, clinical features, 96–97 Hypopigmented large plaque parapsoriasis: clinical features, 96–97 molecular profile, 130 Hypopigmented mycosis fungoides, clinical features, 96–97 Iatrogenic immune dysregulation EBV-associated B cell lymphoproliferative disease: epidemiology, 384–385 monomorphic PTLD, 385–386 diffuse large B cell lymphoma, 387 plasmablastic lymphoma, 386–387

493

plasmacytic marginal zone lymphoma, 387 plasmacytic hyperplasia, 385 polymorphic PTLD, 385 Idiopathic erythroderma: molecular profile, 131 pityriasis lichenoides chronica, 102–103 Id reaction, 37 Imiquimod, cutaneous T cell lymphoma therapy, 21 Immune reactions, polymorphous light eruptions, 52–54 Immunocytomas, marginal zone lymphomas: clinical features, 142 phenotypic profiles, 144–145 Immunofluorescent analysis: lupus erythematosus profundus, 70 subacute cutaneous lupus erhtyematosis, 50 Immunoglobulin genes: marginal zone lymphomas, 145–146 molecular profiles, 167 molecular diagnostic techniques, basic principles, 25 receptor structure, 26–27 Immunoglobulin heavy (IgH) gene: receptor structure, 26–27 Immunotoxins, cutaneous T cell lymphoma therapy, 17 Incipient pilotropic T cell dyscrasia, light microscopic findings, 105 Intercellular adhesion markers (ICAM): diffuse large B cell lymphoma, 197 follicle center cell lymphoma, 177 mycosis fungoides, 289 Interface dermatitis, cell-poor vacuolar variants, 40–45 Interferon-α, cutaneous T cell lymphoma therapy, 16 Interferon-γ , lymphomatoid papulosis, 444–445 Interleukin-2, cutaneous T cell lymphoma therapy, 17 Interleukin-12, cutaneous T cell lymphoma therapy, 19 International Working Formulation, lymphoma classification, 1–3 Interstitial granulomatous drug reaction, clinical features, 63–65 Intravascular lymphoma: case studies, 222–223 clinical features, 219–220 light microscopy, 220 pathogenesis, 221 phenotypic profiles, 220–221 Investigational therapies, cutaneous T cell lymphoma, 18–20 allogeneic hematopoietic stem cell transplantation, 20 histone deacetylase inhibitors, 19–20 monoclonal antibodies, 19 toll-like receptor agonists and cytokines, 19

494

Index

Jessner’s lymphocytic infiltrate of the skin, clinical features and pathology, 58–59 JUNB amplification, mycosis fungoides, 289 Juvenile springtime eruption, differential diagnosis, 54 Ketron-Goodman mycosis fungoides variant, clinical features, 273 Ki-1 lymphoma, CD30-positive lymphoproliferative disorders, 445–450 Ki-67 antibody: defined, 10 subcutaneous panniculitis-like T cell lymphoma, 370–371 Kiel classification for lymphoma, 1–2 marginal zone lymphomas, 142 Killer inhibitory receptor, nasal/extranodal natural killer cell/T cell lymphomas, 405 Killer receptor p140/KIR3DL2 (KIR), S´ezary syndrome, 274–285 Labial herpes, primary cutaneous plasmacytoma, 149–150 Large cell type follicle center cell lymphoma, 181–183 Large granular cell leukemia, NK/T cell lymphomas, 407–408 Large granular lymphocytic leukemia: cytotoxic granule expression, 344–345 hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 Large plaque parapsoriasis (LPP): differential diagnosis, 96 epidemiology, 94–95 light microscopic findings, 95–96 molecular profile, 132–133 mycosis fungoides, 295 Latent membrane proteins (LMPs), Epstein-Barr virus-associated B cell lymphoma, 388–389 Lichen aureus, clinical features, 97–98 Lichenoid dermatitis: clinical features, 46 connective tissue disease, 48–51 drug reactions, 76–77 graft-versus-host disease, 51–52 hepatobiliary disease, 47–48 histopathology, 47 pathogenesis, 46–47 photoallergic pathology, 37–38 Lichenoid mycosis fungoides, 274–285 Lichen planus, features and pathogenesis, 46–48 Lukes-Collins classification system, lymphoma, 1–2 Lupus erythematosus profundus (LEP): clinical features and pathogenesis, 69–70 subcutaneous nodules, 88 subcutaneous panniculitis-like T cell lymphoma, differential diagnosis, 369–370 Lyme disease, interface dermatitis and, 45

Lymph node assessment: angioimmunoblastic lymphadenopathy, 334–339 mycosis fungoides, 282–285 subcutaneous panniculitis-like T cell lymphoma, 367–368 Lymphocyte-predominant Hodgkin lymphoma, 477–478 Lymphocytic infiltrates: autoimmune disease, diffuse/nodular infiltrates, 55–59 basic principles, 33 cell-poor vacuolar interface dermatitis, 40–45 classification scheme, 34 diffuse/nodular infiltrates without atypia, 52–55 lichenoid interface dermatitis, 46–52 spongiotic and eczematous dermatitis, 33–37 spongiotic and eczematous tissue reactions, 37–38 subacute eczematous dermatitis, 38–40 Lymphocytic leukemia, follicular mucinosis, 85 Lymphocytoma cutis: antidepressant therapy, 75 clinical features, 70–71 drug reactions, T-cell-rich infiltrates, 78 lymphomatoid tissue reactions, 63–66 panniculitis-like T-cell lymphoma, 74 T-cell-rich diffusion, 81–83 Lymphoma classifications: Kiel, Lukes-Collins and working formulation, 1–2 lymphomatoid papulosis features and, 440–441 WHO, REAL, and EORTC classifications, 2–6 Lymphomatoid granulomatosis: clinical features, 430–431 clonality studies, 432 differential diagnosis, 432–433 epidemiology, 429–430 Epstein-Barr virus, 381 histogenesis, 432–433 histopathology, 431–432 Lymphomatoid hypersensitivity reaction: allergic contact dermatitis, 35–36 dermatitis, 86 endogenous immune dysregulation, 73 Lymphomatoid lupus erythematosus, lymphomatoid tissue reactions, 68–69 Lymphomatoid papulosis: CD8 T cell lymphoproliferative disease, 346–347 case study, 358–359 clinical features, 440–441 cytogenetics, 444 pathology, 441–443 phenotypic and molecular studies, 443–444 Lymphomatoid tissue reactions: basic principles, 63–64 collagen vascular disease:

lupus erythematosus profundus, 69–70 lymphocytoma cutis, 70–71 lymphomatoid lupus erythematosus, 68–69 pathogenesis, 69 primary cutaneous plasmacytosis, 71–72 viral-associated lymphomatoid dermatitis, 70 drug eruptions: clinical features, 64–65 histopathology, 65–66 molecule profile, 66–67 pathogenetic basis, 67–68 phenotypic profile, 66 Lymphomatoid vascular reaction, clinical features, 65–66 Lymphoproliferative disease of granular lymphocytes (LDGLs), NK/T cell lymphomas, 407–408 Majocchi’s purpura, clinical features, 97–99 Malignancy, clonality and, 30–31 MALT1 Break apart Probe, defined, 12 MALT1 IgH Fusion Probe, defined, 12 Mantle cell lymphoma: blastoid features, 252–253 case studies, 252–256 chemotherapeutic intervention, 255 clinical features, 248–249 cytogenetic profile, 250–251 diffuse infiltrates, 254 light microscopic findings, 249 molecular studies, 250 pathogenesis, 251 phenotypic profile, 249–250 Marginal zone lymphoma: classical cutaneous involvement, 154–162 clinical features, 141–142 cytogenetic abnormalities, 147 differential diagnosis, 147–148 Epstein-Barr virus, 392–393 molecular studies, 145 monomorphic post-transplant lymphoproliferative disease, 387 pathogenesis, 145–146 pathology, 142–144 phenotypic profile, 144–145 primary cutaneous involvement, 162–163 secondary skin involvement, 151–153 Mast cell (MC) skin density, morphea pathogenesis, 58 Max-Joseph spaces, lichenoid dermatitis, 47 Mechlorethamine, cutaneous T cell lymphoma therapy, 20–21 MEL1S gene, adult T cell leukemia/lymphoma, 321 Methotrexate-associated lymphoproliferative disease: borderline CD30-positive lymphoproliferative disorders, 445, 467 Epstein-Barr virus and, 388–389

Index

8-Methoxypsoralen (8-MOP), cutaneous T cell lymphoma therapy, 15–16 Mixed cell follicle center cell lymphoma, case studies, 178–190 Mixed connective tissue disease (MCTD): lichenoid dermatitis, 49–51 morphea histopathology, 57 Molecular profile: alopecia mucinosa, 134 angioimmunoblastic lymphadenopathy, 332–333 atypical lymphocytic lobular panniculitis, 108, 134–135, 137 B-cell chronic lymphocytic leukemia, 227 CD8 pseudolymphoma, 348 CD30-positive lymphoproliferative disease, 468–470 cutaneous T cell dyscrasias, 126–137 clonally restricted endogenous epitheliotropic manifestation, 126 diffuse large B cell lymphoma, 196 Epstein-Barr virus-associated lymphoproliferative disease, 383 eruptive dermatofibromas, 165–166 follicle center cell lymphoma, 176, 190 follicular mucinosis, 105–106 γ δ T cell lymphoma, 263 hydroa vacciniforme-like Epstein-Barr virus associations, 383 hypopigmented large plaque parapsoriasis, 130 hypopigmented mycosis fungoides, 97 idiopathic erythroderma, 103, 131 large plaque parapsoriasis, 132–133 lymphocyte-predominant Hodgkin lymphoma, 478 lymphomatoid papulosis, 443–444 lymphomatoid tissue reactions, 66–67 lymphoproliferative disorders: basic principles, 25 immunoglobulin receptor structure, 26–27 PCR-based clonality assessment, 27–31 mantle cell lymphoma, 250, 256 marginal zone lymphomas, 145 mycosis fungoides, 292–296 nasal/extranodal natural killer cell/T cell lymphomas, 405 NK/T cell lymphomas, 409 pigmented purpuric dermatosis, 100, 129–130, 136 pityriasis lichenoides chronica (PLC), 127–128 precursor B lymphoblastic lymphoma/leukemia, 213–215 primary cutaneous Hodgkin lymphomas, 484–485 primary cutaneous plasmacytoma, 150 primary cutaneous small/medium sized pleomorphic T cell lymphoma, 315 subcutaneous panniculitis-like T cell lymphoma, 370, 375–376 syringolymphoid hyperplasia with alopecia, 104

T cell prolymphocytic leukemia (T-PLL), 230, 244–245 Monoclonal antibodies: cutaneous T cell lymphoma therapy, 17–18 mycosis fungoides, 294 Monomorphic post-transplant lymphoproliferative disease (PTLD): diffuse large B cell lymphoma, 387 Epstein-Barr virus association, 385–387 marginal zone lymphoma, 387 plasmablastic lymphoma variant, 386–387 Morbilliform viral exanthum and drug eruption, features and pathology, 44 Morphea: clinical features and pathology, 56–57 histopathology, 57 pathogenesis, 57–58 Mosquito bite hypersensitivity, hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 Mucosal associated lymphoma (MALT)-like lymphoma, clinical features, 141–142 Multilobated peripheral T cell lymphoma, differential diagnosis, 305 MUM-1/IRF4 marker, diffuse large B cell lymphoma, 192–199 MUM1 myeloma antigen, follicle center cell lymphoma, and diffuse large cell B cell lymphoma 177 MYC amplification and translocation, trisomy 8, 11–12 MYC Break apart Probe, defined, 12 MYC IgH Fusion Probe, defined, 12 Mycoplasma pneumoniae, erythema multiforme pathogenesis, 42 Mycosis fungoides: architecture of, 277–278, 280–285 case studies, 290–291 CD8 variant, 355 clinical features, 267–271 extracutaneous dissemination, 271 patch stages, 268–270 plaque stage, 270, 277 tumor stage, 270–271 cutaneous T cell lymphoma therapy, 14–15 cytogenetic studies, 292–296 cytomorphology, 282–285 defined, 267 demographics, 267 drug eruptions: clinical features, 64–65 histopathology, 65–66 molecular profile, 66–67 pathogenesis, 67–68 phenotypic profile, 66 extracutaneous involvement, 285–289 cytogenetic abnormalities, 288 gene rearrangement profile, 288 pathogenesis, 288–289 phenotypic profile, 286–288 histopathology, 276–277 historical evolution, 267

495

hypopigmented lesions, 96–97 molecular profiles, 292–296 morphology/light microscopic findings, 276–285 tumor staging, 275, 284–285, 290–291 variants, 271–285 adnexotropic, 272 in childhood, 271–272 granulomatous slack skin, 273 papuloerythroderma, 271 S´ezary syndrome, 273–285 Woringer-Kolopp disease, 272–273 Mycosis fungoides (MF), lymphomatoid tissue reactions, 63–64 Myelodysplastic syndrome, primary pleomorphic T cell lymphoma, 303 Myelomonocytic markers, defined, 10 Narrowband UVB, cutaneous T cell lymphoma therapy, 22 Nasal/extranodal NK cell lymphomas: aggressive variant, 403–406 blastic/blastoid neoplasm, 406 case studies, 410–424 CD4 subset, 408–409 cell biology, 401–406 chronic granular lymphocytosis/large granular cell leukemia, 407–408 epidemiology, 399–401 Epstein-Barr virus, 406–409 panniculitis-like variants, 406–407 Natural killer (NK) cells: CD8 T cell lymphoproliferative disease, 344–345 Epstein-Barr virus, 381 markers, 9 nasal/extranodal NK T cell lymphomas: aggressive variant, 403–406 blastic/blastoid neoplasm, 406 case studies, 410–424 CD4 subset, 408–409 cell biology, 401–406 chronic granular lymphocytosis/large granular cell leukemia, 407–408 epidemiology, 399–401 Epstein-Barr virus, 406–409 panniculitis-like variants, 406–407 subcutaneous panniculitis-like T cell lymphoma, 368–371 Nervous system involvement, mycosis fungoides, 285–286 Nickel allergeis, spongiotic dermatitis, 33–34 Nodular sclerosis, classical Hodgkin lymphoma, 477 Nonscarring discoid lupus erythematosus, clinical features and pathology, 55–56 NPM-ALK hybrid protein, anaplastic large cell lymphoma, 449 Nuclear factor (NF) pathways, lymphocyte-predominant Hodgkin lymphoma, 479

496

Index

Null cell phenotypes, anaplastic large cell lymphoma, 449 Nummular eczema, pathology and diagnosis, 38 Ofuji papuloerythroderma, clinical features, 271–272 Oncogenes, marginal zone lymphomas, 147 ORAL disease, plasmablastic lymphoma variant, 386–387 p53 system, mycosis fungoides, 288–289 Pagetoid reticulosis, clinical features, 272–273, 280–285 Palisading granulomatous drug reaction, clinical features, 64–65 Panniculitis-like T-cell lymphoma: case study, 74 CD56 positivity, 406–407 γ δ T cell lymphoma and, 265 Papuloerythroderma, clinical features, 271–272 Paraffin embedded tissue, classification, 10–11 Parakeratotic scale, allergic contact dermatitis, 34–35 Parapsoriasis: epidemiology, 94–95 hypopigmented large plaque parapsoriasis, 96–97 Parvovirus B19, systemic lupus erythematosus and, 45 Patch formation, mycosis fungoides, 268–270, 278–279 Pathogenesis, hydroa vacciniforme-like Epstein-Barr virus associations, 384 Paucicellular necrobiotic process, diffuse large cell B lymphoma, 195 Pautrier’s microabscess: adult T cell leukemia/lymphoma, 319–320 mycosis fungoides, 280–285 Pediatric variant, mycosis fungoides, 271–272 Peripheral T cell lymphoma: CD8 T cell lymphoproliferative disease, 363 classification, 300–303 Perivascular lymphocytic infiltrates, histopathology, 54 Perry-Romberg syndrome, morphea pathogenesis, 57 Phenotypic profile: adult T cell leukemia/lymphoma, 320 anaplastic large cell lymphoma, 448–449 angioimmunoblastic lymphadenopathy, 331–332 atypical lymphocytic lobular panniculitis, 108 B-cell chronic lymphocytic leukemia (B-CLL), 227 borderline CD30-positive lymphoproliferative disorders, 445

Castleman’s disease, 148 CD8 pseudolymphoma, 348 CD8 T cell lymphoproliferative disease, 346 CD-30 positive large B cell lymphoma, 450 diffuse large cell B lymphoma, 195–196 Epstein-Barr virus-associated lymphoproliferative disease, 383 follicle center cell lymphoma, 176 γ δ T cell lymphoma, 262 hydroa vacciniforme-like Epstein-Barr virus associations, 383 hypopigmented mycosis fungoides, 97 idiopathic erythroderma, 103 intravascular lymphoma, 220–221 lymphocyte-predominant Hodgkin lymphoma, 478 lymphocytoma cutis assessment, 71 lymphomatoid papulosis, 443–444 mantle cell lymphoma, 249–250 marginal zone lymphomas, 144–145 mycosis fungoides, 286–288 nasal/extranodal natural killer cell/T cell lymphomas, 401, 404–405 NK/T cell lymphomas, CD 4 subset, 408 pigmented purpuric dermatosis, 100 pityriasis lichenoides chronica, 102 primary cutaneous plasmacytoma, 150 primary cutaneous small/medium sized pleomorphic T cell lymphoma, 304–305 subcutaneous panniculitis-like T cell lymphoma, 370 syringolymphoid hyperplasia with alopecia, 104 T cell prolymphocytic leukemia (T-PLL), 229–230 Photoallergic lichenoid dermatitis, 37–38 Photodynamic therapy (PDT), cutaneous T cell lymphoma, 22 Phototherapy, cutaneous T cell lymphoma, 21–22 Pigmented purpuric dermatosis (PPD): case study, 112–115 clinical features, 97–100 light microscopic findings, 99–100 molecular profile, 129–130, 136 Pilotropic T cell dyscrasia: 105, 118–119 PIM proto-oncogenes, diffuse large B cell lymphoma, 197 Pityriasis lichenoides chronica (PLC): case study, 109–111 clinical features, 100–103 molecular profile, 127–128 Pityriasis lichenoides et varioliformis acuta (PLEVA), clinical features, 100–103 Pityriasis rosea, pathology and diagnosis, 36–37 Plaque formation, mycosis fungoides, 270, 277–279

Plasmablastic lymphoma, Epstein-Barr virus association, 386–387, 390–391, 394 Plasma cell markers, defined, 9 Plasmacytic hyperplasia, Epstein-Barr virus association, 385, 392–393 Plasmacytic marginal zone lymphoma, monomorphic post-transplant lymphoproliferative disease, 387 Plasmacytoma, primary cutaneous manifestations, 149–150 Platelet-derived growth factor (PDGF), morphea pathogenesis, 58 Pleomorphic small/medium sized T cell lymphoma: case studies, 306–314 classification, 303–304 clinical features, 300–303 cytogenetics, 304 differential diagnosis, 305 phenotypic profile, 304–305 POEMS syndrome (Polyneuropathy, osteosclerotic bone lesions, endocrinopathy, monoclonal gammopathy): case study, 169 Castleman’s disease, 148–149 POL gene, herpes-associated erythema multiforme pathogenesis, 42 Polymerase chain reaction (PCR): clonality determination and detection, 27–31 limitations of, 30–31 results evaluation, 29–30 lymphoproliferative disorders diagnosis, basic principles, 25 mycosis fungoides, 288 pityriasis rosea, 36–37 Polymorphic post-transplant lymphoproliferative disease (PTLD), Epstein-Barr virus association, 385 Polymorphous light eruption (PMLE), type IV immune reaction, 52–54 Popcorn cell morphology, lymphocyte-predominant Hodgkin lymphoma, 477–478 Porphyria cutanea tarda, morphea histopathology, 57 Post-transplant lymphoproliferative disease (PTLD): anaplastic large cell lymphoma, 454–455 Epstein-Barr virus association, 384–387 lymphomatoid granulomatosis, 432–433 T cell disorder, 387–388 Precursor B lymphoblastic lymphoma/leukemia: clinical features, 198–199 cytogenetics, 200 differential diagnosis, 200–202 immunophenotype, 199–200 molecular and cytogenetic studies, 213–215 pathology, 199 Pregnancy, papules of, 39

Index

Primary cutaneous lymphomas: B cell lymphoma, angioimmunoblastic lymphadenopathy, 331–332 diffuse large B cell lymphoma: classification, 194 clinical features, 192–194 cytogenetics, 196 differential diagnosis, 197–198 molecular studies, 196 pathogenesis, 196–197 pathology, 194–195 phenotype, 195–196 EORTC classification, 4–6 epidermotropic cytotoxic lymphoma, 349–354 Epstein-Barr virus, 381 follicle center cell lymphoma: clinical features, 173–174 cytogenetics, 177, 190 large cell type, 181–183 mixed cell case vignettes, 178–180, 184–189 molecular studies, 176, 190 pathogenesis, 176–177 pathology, 174–175 phenotypic profile, 176 prognosis, 177 γ δ T cell lymphoma: case studies, 264–265 clinical features, 259–261 molecular studies, 263 morphology, 261–262 phenotype, 262 ultrastructural analysis, 263 Hodgkin lymphoma: case studies, 480–483 classic subtypes, 477 clinical features, 475–476 cytogenetics, 478 histogenesis, 478–479 lymphocyte-predominant variant, 477 molecular and phenotype profiles, 478 large cell lymphoma, 203–205 CD30-positive B cell variant, 450–451 lymphoblastic lymphoma, 209–210 lymphomatoid granulomatosis, 431–433 NK/T cell lymphomas, 421–422 precursor B lymphoblastic lymphoma/leukemia: clinical features, 198–199 cytogenetics, 200 differential diagnosis, 200–202 immunophenotype, 199–200 pathology, 199 small/medium sized pleomorphic T cell lymphoma: case studies, 306–314 classification, 303–304 clinical features, 300–303 cytogenetics, 304 differential diagnosis, 305 phenotypic profile, 304–305 Primary cutaneous plasmacytoma, clinical features, 149–150

Primary cutaneous plasmacytosis, clinical features, 71–72 Primer design: immunoglobulin H, 27 T-cell receptor-β structure, 27–29 Prolymphocytic leukemia, CD8 T cell lymphoproliferative disease, 347 Pruritic urticarial plaques, features and pathology, 39 Pseudoepitheliomatous hyperplasia, CD8 T cell lymphoproliferative disease, 346 Pseudolymphoma, CD8 T cell lymphoproliferative disease, 348, 360–361 Pseudomycosis fungoides (pseudo-MF), drug eruptions, 64–65 lichenoid features, 76–77 Psoralen plus UVA exposure (PUVA), cutaneous T cell lymphoma therapy, 21–22 Purine analogs, cutaneous T cell lymphoma therapy, 18 Radiation therapy, cutaneous T cell lymphoma, 22 Reactive clonal lymphomatoid dermatitis of memory and activated T cells, lymphomatoid tissue reactions, 68 Recalcitrant dermatitis, mycosis fungoides, 296 Reed-Sternberg cells: lymphocyte-predominant Hodgkin lymphoma, 477–478 lymphomatoid papulosis, 443–444 primary cutaneous Hodgkin lymphomas, molecular and cytogenetic profile, 484–485 Renal involvement, mycosis fungoides, 285 Restricted T cell repertoire, PCR clonality determination and detection, 29–30 Retinoids, cutaneous T cell lymphoma therapy, 16–17 topical agents, 21 Reverse transcriptase in situ hybridization, defined, 11 Reverse transcriptase polymerase chain reaction (RT-PCR): lymphomatoid lupus erythematosus, 69 lymphomatoid papulosis, 444 Reversible lymphoid sycrasia, lymphomatoid tissue reactions, 68 Reversible T cell dyscrasia, lymphomatoid tissue reactions, 63–64 Revised European-American Classification of Lymphoid Neoplasms (REAL) classification: lymphoma classification, 2–6 nasal/extranodal natural killer cell/T cell lymphomas, 399–401

497

Scleroderma, morphea histopathology, 57 Sclerodermatomyositis (SDM), lichenoid dermatitis, 49–51 Sclerosing immunocytoma, marginal zone lymphomas, 144–145 Seborrheic dermatitis, nummular eczema, differential diagnosis, 38 Sensitivity, clonality assessment by PCR, 30–31 S´ezary syndrome (SS): clinical features, 273–285 cutaneous T cell lymphoma, 14 extracorporal photopheresis therapy, 15–16 idiopathic erythroderma, 102–103 morphology/light microscopic findings, 276–285 mycosis fungoides, clinical features, 267–268 phenotypic profiles, 286–288 prognosis, 275–276 staging, 275–276 Single-strand conformation polymorphism (SSCP), lymphomatoid lupus erythematosus, 69 Skin-directed therapies, cutaneous T cell lymphoma, 20–22 Skin disorders: anaplastic large cell lymphoma, 445–450 B cell lymphoproliferative disorder, marginal zone lymphoma: clinical features, 141–142 cytogenetic abnormalities, 147 differential diagnosis, 147–148 molecular studies, 145 pathogenesis, 145–146 pathology, 142–144 phenotypic profile, 144–145 CD8 T cell lymphoproliferative disease: basic characteristics, 343–345 case studies, 349–363 drug therapy and, 348 histomorphology, 345–346 lymphomatoid papulosis variants, 346–347 phenotypic profile, 346 primary cutaneous lymphoma, 343–345 pseudolymphomas, 348 CD30-positive lymphoproliferative disease, 463–464 chronic lymphocytic leukemia: skin infiltration, 231–233, 236–238 T-cell type, 241 cutaneous T cell lymphoma: granulomatous slack skin, 273 skin-directed therapies, 20–22 hydroa vacciniforme-like Epstein-Barr virus associations, 382–384 Jessner’s lymphocytic infiltrate of the skin, 58–59 marginal zone lymphoma, 151–153 mast cell skin density, morphea pathogenesis, 58

498

Index

Skin disorders: (Continued) mycosis fungoides, granulomatous slack skin, 273 NK/T cell lymphomas, 410–412 primary cutaneous Hodgkin lymphomas, 475–479 T cell prolymphocytic leukemia, 241 Sleeve-like morphology: erythema annulare centrifugum, 39–40 polymorphous light eruption, 53–54 Small plaque parapsoriasis, features and pathology, 39 Spiegler-Fendt lymphocytic infiltrate, lymphocytoma cutis, 70–71 Spongiotic reactions: allergic contact dermatitis, 33–37 tissue reactions, 37–38 Squamous cell carcinoma, chronic lymphocytic leukemia, 234–235 Staging evaluation, cutaneous T cell lymphoma, 14 Stevens-Johnson syndrome, erythema multiforme, 41–42 Subacute cutaneous lupus erythematosis (SCLE): lichenoid dermatitis, 48–51 lymphomatoid tissue reactions, 68–69 Subcutaneous panniculitis-like T cell lymphomas: case studies, 372–378 clinical features, 366–369 differential diagnosis, 370–374 molecular studies, 370 morphology, 369–370 phenotype, 370 Suberoylanilide hydroxamic acid (SAHA), cutaneous T cell lymphoma therapy, 20 Surveillance, Epidemiology and End Results (SEER) program, mycosis fungoides demographics, 267 Syphilis, lichen planus eruptions, 48 Syringolymphoid hyperplasia with alopecia (SLHA), clinical features, 103–104 Syringotropic cutaneous T cell lymphoma, clinical features, 272 Systemic lupus erythematosus: antibody-dependent cellular immunity, 45 classification of, 45 erythema multiforme, 41–42 histopathology, 50 lichenoid dermatitis, 49–51 T cell antibodies, classification, 8–9 T cell dyscrasias: adnexotropic manifestation, 122–123 lymphomatoid granulomatosis, 432–433 lymphomatoid tissue reactions, 66 subcutaneous panniculitis-like T cell lymphoma, 370–371 T-cell intracellular antigen 1 (TIA-1): nasal/extranodal natural killer cell/T cell lymphomas, 402

subcutaneous panniculitis-like T cell lymphoma, 370 T cell lymphomas. See also Mycosis fungoides angioimmunoblastic variant: case studies, 334–339 clinical features, 329–331 light microscopic findings, 331 molecular studies, 332–333 pathogenesis, 333 phenotypic profile, 331–332 CD8 T cell lymphoproliferative disease: basic characteristics, 343 case studies, 349–363 drug therapy and, 348 histomorphology, 345–346 lymphomatoid papulosis variants, 346–347 phenotypic profile, 346 primary cutaneous lymphoma, 343–345 pseudolymphomas, 348 γ δ T cell lymphoma: case studies, 264–265 clinical features, 259–261 molecular studies, 263 morphology, 261–262 phenotype, 262 ultrastructural analysis, 263 intravascular lymphoma, 219–223 lymphomatoid tissue reactions, basic principles, 63–64 molecular profile, 66–67 nasal/extranodal NK cell variants: aggressive variant, 403–406 blastic/blastoid neoplasm, 406 case studies, 410–424 CD4 subset, 408–409 cell biology, 401–406 chronic granular lymphocytosis/large granular cell leukemia, 407–408 epidemiology, 399–401 Epstein-Barr virus, 406–409 panniculitis-like variants, 406–407 panniculitis-like T-cell lymphoma, 74 precursor lesions, cutaneous lymphoid dyscrasia, 93–108 subcutaneous panniculitis-like variant: case studies, 372–378 clinical features, 366–369 differential diagnosis, 370–371 molecular studies, 370 morphology, 369–370 phenotype, 370 T cell prolymphocytic leukemia (T-PLL): case studies, 239–240 CD8 T cell lymphoproliferative disease, 347 case study, 356–357 clinical features, 228–229 cutaneous T cell lymphoma therapy, 18 cytogenetic abnormalities, 230 differential diagnosis, 230, 242–243 pathology, 229

phenotypic profiles, 229–230 skin involvement, 241 T-cell receptor-β marker: primer design, 27–28 receptor structure, 27 T-cell receptor-γ marker: defined, 8 T-cell receptors (TCR): anaplastic large cell lymphoma, 448–449 cutaneous T cell lymphoma and rearrangement of, 15 lymphomatoid tissue reactions, 63–64 molecular diagnostic techniques, 25 nasal/extranodal natural killer cell/T cell lymphomas, epidemiology, 401–402 T-cell-restricted intracellular antigen (TIA), CD8 T cell lymphoproliferative disease, 344 TCL-1 oncogene: adult T cell leukemia/lymphoma, 321 T cell prolymphocytic leukemia (T-PLL), 230 TCR-1 antibody, defined, 8 Terminal deoxynucleoltidyl transferase (TdT), precursor B lymphoblastic lymphoma/leukemia, 199–200 Th2 cytokines: CD8 T cell lymphoproliferative disease, 345 cutaneous T cell lymphoma therapy, 14–15 T helper cells, allergic contact dermatitis, 34 Tissue eosinophilia, papuloerythroderma, 271 Tissue growth factor (TGF), morphea pathogenesis, 57–58 Toll-like receptors (TLRs): cutaneous T cell lymphoma therapy, agonists and cytokines, 19 primary cutaneous plasmacytoma, 150 Topical corticosteroids, cutaneous T cell lymphoma therapy, 20 Total skin electron beam (TSEB) therapy, cutaneous T cell lymphoma, 22 Toxic epidermal necrolysis, erythema multiforme pathogenesis, 42 Transforming growth factor-β (TGF-β): anaplastic large cell lymphoma, 450 morphea pathogenesis, 58 Trimetrexate (TMTX), cutaneous T cell lymphoma therapy, 18 Trisomy 3, marginal zone lymphomas, 147 Trisomy 8, MYC amplification and translocation, 11–12 Tumid lupus erythematosus, clinical features and pathology, 55–56 Tumor necrosis factor-α (TNF-α), cell-poor vacuolar interface dermatitis, 44 Tumor staging, mycosis fungoides, 270–271, 283–285, 290–291 Tumor suppressor genes, mycosis fungoides, 289

Index

Ultrastructural analysis, γ δ T cell lymphoma, 263 Variable heavy (VH) segments, immunoglobulin receptor structure, 26–27 Vascular lymphomatoid tissue reactions: clonality assessment, 84 lymphomatoid granulomatosis, 432–436 V-D-J rearrangement, immunoglobulin H Receptor structure, 26–27 Viral-associated lymphomatoid dermatitis, clinical features, 70

Viral thymidine kinase (vTK) assay: defined, 11 Epstein-Barr virus-associated B cell lymphoma, 388–389 Weber-Christian disease, subcutaneous panniculitis-like T cell lymphoma, 370–371, 377–378 WHO classification: diffuse large B cell lymphoma, 193–194 of lymphoma, 2–6

499

nasal/extranodal natural killer cell/T cell lymphomas, 399–401 S´ezary syndrome (SS), 274–285 subcutaneous panniculitis-like T cell lymphoma, 366–368 Woringer-Kolopp disease, clinical features, 272–273 Zoon’s balanitis/vulvitis, primary cutaneous plasmacytosis, 71–72