Progress in Hodgkin's Disease

Progress in Hodgkin’s Disease

G.W. Richter

Department of Pathology, University of Rochester Medical Center, Rochester, New York

Kim Solez

Department of Pathology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

ISSN  0074-7718

Volume 33 • Number Suppl. (C) • 1992

Table of Contents

Cover image

Title page

Editorial Advisory Board

Copyright page

Contributors

Preface

Differential Diagnosis between Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

Publisher Summary

I Introduction

II Low Grade B Cell Lymphoma

III Pleomorphic (Peripheral) T Cell Lymphomas

IV Large Cell Lymphoma and Anaplastic Large Cell Lymphoma

V Conclusions

Diagnosis and Grading of Nodular Sclerosing Hodgkin’s Disease: A Study of 2190 Patients

Publisher Summary

I Introduction

II Patient Population

III Histological Criteria

IV The Clinical Relevance of Grading NS

V Discussion

Acknowledgments

Lymphocyte-Predominance Hodgkin’s Disease

Publisher Summary

I History

II Histology

III Cytology of L&H Type RS Cells

IV Immunophenotype Of L&H Type RS Cells

V Nodular Lymphocyte-Predominance Hodgkin’s Disease Cell Lines

VI Immunophenotype of B Cells

VII Immunophenotype of T Cells

VIII Relation to Progressively Transformed Germinal Centers

IX Large Cell Lymphomas

X Diffuse Variants of Nodular LPHD (Diffuse Paragranuloma)

XI Clinical Features of NLPHD

XII Conclusion

Immunophenotype of Reed—Sternberg Cells

Publisher Summary

I Introduction

II Activation Antigens

III Lymphoid Markers

IV Other Antigens

V Conclusion

The Nature and Function of the Hodgkin’s Cell Lectin and Its Role in Lymphocyte Agglutination

Publisher Summary

I Introduction

II Dual Role of the Hodgkin’s Cell Lectin as Carbohydrate-Binding Protein And Ectosialyltransferase

III Relationship Between The Hodgkin’s Cell Lectin and the Hepatic Asialoglycoprotein Receptor

IV Subcellular Distribution of the Hodgkin’s Cell Lectin

V Hodgkin’s Cell Lectin as a Lymphocyte Agglutinant and Mitogen

VI Expression of the Hodgkin’s Cell Lectin in Disease-Involved Human Tissues

Role of T Cells in the Pathogenesis of Hodgkin’s Disease

Publisher Summary

I Introduction

II Possible Relationship Between Immune Alterations and Pathogenesis of the Disease

IV Pathogenic Hypotheses

Acknowledgments

Gene Analysis and Epstein—Barr Viral Genome Studies of Hodgkin’s Disease

Publisher Summary

I Introduction

II Antigen Receptor Gene Analysis of Hodgkin’s Disease

III Molecular Studies of Epstein-Barr Virus in Hodgkin’s Disease

IV In Situ Hybridization Studies for the Identification of Reed-Sternberg Cell mRNA: Interleukin-5

V Studies on the Molecular Cytogenetics of Hodgkin’S Disease

Hodgkin’s Disease: Analysis of Cell Line Data

Publisher Summary

I Introduction

II The Cell of Origin in Hodgkin’s Disease

III The Cellular Pathogenesis of Hodgkin’s Disease

IV Conclusions

Acknowledgment

Index

Contents of Recent Volumes

Editorial Advisory Board

Robert Kisilevsky,     Kingston, Ontario, Canada

M. Mihatsch,     Basel, Switzerland

Peter C. Nowell,     Philadelphia, Pennsylvania

Steen Olsen,     Aarhus, Denmark

U. Pfeifer,     Bonn, Germany

Sibrand Poppema,     Edmonton, Alberta, Canada

Stephen T. Reeders,     New Haven, Connecticut

Andrew H. Wyllie,     Edinburgh, Scotland

R.M. Zinkernagel,     Zürich, Switzerland

Copyright page

Copyright © 1992 by ACADEMIC PRESS, INC.

All Rights Reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

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United Kingdom Edition published by

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Library of Congress Catalog Number: 62-21145

International Standard Book Number: 0-12-364933-1

PRINTED IN THE UNITED STATES OF AMERICA

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Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

M.H. Bennett,     Department of Pathology, Mount Vernon Hospital, Nortwood, Middlesex, England (27)

Volker Diehl,     Klinik I für Innere Medizin, Universität zu Köln, D-5000 Köln 41, Germany (185)

Nancy L. Harris,     Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 (1)

B. Vaughan Hudson,     U.C.M.S.M., London W 1, England (27)

G. Vaughan Hudson,     U.C.M.S.M., London W 1, England (27)

Judith Hugh

Department of Laboratory Medicine, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada

Department of Pathology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada (81)

Christof v. Kalle,     Klinik I für Innere Medizin, Universität zu Köln, D-5000 Köln 41, Germany (185)

K.A. MacLennan,     Department of Pathology, The Royal Marsden Hospital, London SW3 6S5, England (27)

D. Macchia,     Department of Clinical Immunology, University of Florence, 50134 Florence, Italy (141)

E. Maggi,     Department of Clinical Immunology, University of Florence, 50134 Florence, Italy (141)

Elisabeth Paietta,     Department of Oncology, Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, New York 10467 (115)

P. Parronchi,     Department of Clinical Immunology, University of Florence, 50134 Florence, Italy (141)

M.-P. Piccinni,     Department of Clinical Immunology, University of Florence, 50134 Florence, Italy (141)

Sibrand Poppema

Department of Laborary Medicine, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada

Department of Pathology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada (53, 81)

S. Romagnani,     Department of Clinical Immunology, University of Florence, 50134 Florence, Italy (141)

C. Simonelli,     Department of Clinical Immunology, University of Florence, 50134, Italy (141)

Lawrence M. Weiss,     Department of Surgical Pathology, Division of Anatomical Pathology, City of Hope National Medical Center, Duarte, California 91010 (165)

Preface

Sibrand Poppema

Volume 33 of the International Review of Experimental Pathology summarizes the progress that has been made in the diagnosis and understanding of the pathogenesis of Hodgkin’s disease in the past ten years. This volume provides data that go beyond those covered in current textbooks in pathology and hematology and should be of interest to all pathologists and clinicians dealing with the diagnosis and management of Hodgkin’s disease, as well as to lymphoma researchers.

The first half of this volume deals with diagnostic aspects, whereas the second half focuses on recent developments in the understanding of the pathogenesis of Hodgkin’s disease. The first chapter discusses the differential diagnosis between Hodgkin’s disease and non-Hodgkin’s lymphomas, and provides needed guidelines on how to deal in a practical way with the grey areas between these two groups of diseases. In the second chapter, the criteria for a prognostically relevant histological grading of the most frequent subtype of Hodgkin’s disease, the nodular sclerosis subtype, are described and supported with results from over 2000 patients. The third chapter summarizes data indicating that the nodular lymphocyte predominance subtype of Hodgkin’s disease is a separate entity, different in morphology, immunophenotype, and clinical behavior from the other subtypes of Hodgkin’s disease. The fourth chapter provides a thorough inventory of the various reagents that have been used to try to define the immunophenotype of Reed-Sternberg cells. Also, an attempt is made, for the first time, to correlate the expression of surface markers on Reed-Sternberg cells with clinical behavior.

In the fifth chapter, the focus is on potential mediators of lymphocyte agglutination to Reed-Sternberg cells. Special emphasis is given to a lectin on Reed-Sternberg cells that functions as an ectosialyltransferase and perhaps is a lymphocyte mitogenic factor. The sixth chapter deals with the immunological alterations in Hodgkin’s disease. The findings support a hypothesis that the T cell reaction in Hodgkin’s disease may reflect an autologous mixed leukocyte reaction in vivo. This reaction might be a consequence of an abnormal recognition by T cells of autologous major histocompatibility complex class II determinants. In the seventh chapter, an overview of molecular genetic studies into the pathogenesis of Hodgkin’s disease is presented. Immunoglobulin gene analysis has shown that cases of Hodgkin’s disease with a high percentage of Reed-Sternberg cells frequently have clonal rearrangements. Also, in up to half of the patients with Hodgkin’s disease, Epstein-Barr virus genomes can be demonstrated in the Reed-Sternberg cells by in situ hybridization. These findings suggest that at least in a subgroup of patients, Epstein-Barr virus transformation of B cells may play some role in the pathogenesis of Hodgkin’s disease. The final chapter deals with the results of studies on Hodgkin cell lines. Cell lines have played an important part in Hodgkin’s disease research, mostly because of the scarcity of Reed-Sternberg cells in the involved lymph nodes. Most notably, Hodgkin cell lines have been used as an immunogen to produce antibodies with Reed-Sternberg cell reactivity. Also, Hodgkin cell lines are good models to study the production of cytokines, which may play a role in the complex interactions between Reed-Sternberg cells and the surrounding reactive cells.

I greatly appreciate the effort by all of my collaborators on this volume to provide such a thorough review of their respective fields of interest. I believe that the content of this volume is an appropriate reflection of what has been achieved in the past ten years as a result of experimental pathologic studies into Hodgkin’s disease.

Differential Diagnosis between Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

Nancy L. Harris,     Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Publisher Summary

This chapter discusses the problems and solutions to differential diagnosis between Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). HD differs from NHLs morhophologically, immunologically, and clinically. Morphologically, most tumors consist of a relatively homogenous population of neoplastic cells, whereas HD consists predominantly of reactive cells, with the neoplastic population remaining a small minority of the cells. Immunologically, most NHLs correspond to a recognizable stage of either T or B cell differentiation, permitting them to be classified according to their normal counterpart in the immune system. In HD, there is still no knowledge of the lineage of the malignant cell—T, B or monocyte/macrophage—or whether it is even the same in all cases. For the most part, HD remains a morphologic diagnosis in which distinction from other lymphomas rests on identifying the morphologic features of the characteristic immunologic reaction that defines the disease. The inherent complexity of these disorders, coupled with the relatively primitive understanding of HD and its relationship to the NHLs, inevitably results in some cases in which no combination of morphology, immunophenotyping, and genetic analysis can result in a definitive diagnosis.

I Introduction

II Low-Grade B Cell Lymphoma

A Definitions

B Morphology

C Immunophenotype

D Genotype

III Pleomorphic (Peripheral) T Cell Lymphomas

A Definitions

B Morphology

C Immunophenotype

D Molecular Genetics

IV Large Cell Lymphoma and Anaplastic Large Cell Lymphoma.

A Definitions

B Morphology

C Immunophenotype

D Molecular Genetics

V Conclusions

References

I Introduction

Despite all the advances in immunology and molecular genetics of the last two decades, the diagnosis of Hodgkin’s disease (HD) remains primarily morphologic, based on the appearance of the complex infiltrate on routine, paraffin-embedded, hematoxylin- and eosin-stained sections. Although frustrating to researchers, who regularly offer new diagnostic immunologic or molecular genetic tests for the disease, this is good news for the practicing pathologist, who can usually both diagnose and subclassify this common type of lymphoma with confidence, based on relatively simple and straightforward histologic criteria. This review will focus on specific criteria, most of which are covered in greater detail elsewhere in this volume, that are useful in distinguishing HD from other lymphomas. In most cases, as indicated, morphologic criteria will suffice. Immunophenotypic and, less often, molecular genetic analysis may play a role in confirming the impression based on morphologic examination, and the utility of these techniques in specific situations will be addressed.

No discussion of this differential diagnosis would be complete, however, without recognition of the fact that we still do not know exactly what Hodgkin’s disease is, and what its relationship is with the disorders known as non-Hodgkin’s lymphomas (NHLs). If, as the variety of suggested lineages implies, the neoplastic cell of HD may in some cases be a T lymphocyte, in others a B lymphocyte, and in still others a monocyte/macrophage derivative, then there may be a true borderline between HD and NHL. In some patients, neoplastic transformation of a particular B or T cell might lead to a B or T NHL, but in others, because of a different immunologic makeup of the host, the same neoplastic B or T cell may give rise to the extraordinary, tumorous immunologic reaction that we recognize histologically and clinically as HD. In general, we expect that most difficult cases result from problems in fixation, sectioning, sampling, or lack of experience, but in fact the difficulty in some cases may result from a true overlap between HD and NHL—real borderline cases. Thus we may have to accept the fact that in occasional cases the differential diagnosis cannot be resolved because the disease itself has not decided whether to be HD or NHL in this patient.

There are three major categories of lymphoma that may be confused with various subtypes of Hodgkin’s disease: low-grade B cell lymphomas, so-called peripheral T cell lymphomas, and large cell lymphomas, including the recently described anaplastic type. Each of these entities will be discussed, reviewing morphologic, immunologic, and molecular genetic features that may be useful in the differential diagnosis.

II Low Grade B Cell Lymphoma

A Definitions

Lymphocyte-predominance Hodgkin’s disease (LPHD), by definition, contains a predominance of small, reactive-appearing lymphocytes, with only rare diagnostic Reed-Sternberg (RS) cells, although the characteristic mononuclear variants (L&H cells or the lymphocytic and/or histiocytic cells of Lukes and Butler) may be numerous (Lukes et al., 1966 a,b). The pattern may be either nodular (NLPHD) or diffuse (Fig. 1A and B). These features-predominance of small lymphocytes, rarity of malignant-appearing cells, and occasional follicular pattern-may give rise to a differential diagnosis of non-Hodgkin’s lymphoma (see Tables I and II).

Table I

Lymphocyte-Predominance Hodgkin’s Disease versus Low-Grade B Cell Lymphoma: Morphologic Featuresa

aAbbreviations: LPHD, lymphocyte-predominance Hodgkin’s disease; FCC, follicular center cell; CB/CC, centroblastic/centrocytic lymphomma; B-CLL, B cell chronic lymphocytic leukemia.

Table II

Lymphocyte-Predominance Hodgkin’s Disease versus Low-Grade B Cell Lymphoma: Immunologic and Molecular Genetic Featuresa

aAbbreviations: Ig, immunoglobulin; TCR, T cell receptor; LPHD, lymphocyte-predominance Hodgkin’s disease; CB/CC, centroblastic/centrocytic lymphoma; B-CLL, B cell chronic lymphocytic leukemia; P, polytypic; M, monotypic; G, germline; R, rearranged.

Fig. 1 Hodgkin’s disease, lymphocyte-predominance type, nodular. (A) Note the large, poorly circumscribed nodules, which have a back-to-back arrangement and appear molded to one another. There are numerous pale, epithelioid histiocytes (×31). (B) Same case, higher magnification; note the overall lack of atypia of the background infiltrate, with some admixed centrocytes. The neoplastic cells have irregular nuclei and prominent nucleoli (×500).

B Morphology

1 LPHD versus Small Lymphocytic Lymphoma

The lymphocytic background of LPHD is usually less monotonous than the nodal infiltrate produced by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Fig. 2A and B). The lymphocytes range from small, hyperchromatic cells with clumped chromatin and no nucleoli to slightly irregular, larger cells with indented or cleaved nuclei, resembling follicular center cells (centrocytes). Scattered immunoblasts may be present, but most large mononuclear cells either resemble centroblasts (large noncleaved follicular center cells) or are examples of the so-called L&H cells, with popcorn-shaped, vesicular nuclei and small nucleoli apposed to the nuclear membrane (Burns et al., 1984). In contrast, the lymphocytes of CLL are usually round, have slightly more open chromatin than normal lymphocytes, often with visible nucleoli, and have an extremely monotonous appearance. Even when larger cells are admixed, the entire population looks as though it belongs to a single clone; like islands of maturing erythroid cells in the bone marrow, there is a continuum of morphology between the largest and the smallest cells, in contrast to the heterogeneity of a reactive population. When large cells are present, they resemble immunoblasts, with prominent central nucleoli, rather than the centroblasts and L&H cells of LPHD. In many cases, when large cells are present, they are concentrated in pseudofollicular proliferation centers, visible at low magnification as regularly distributed, pale areas in the darker infiltrate of small lymphocytes (Lennert, 1978).

Fig. 2 Chronic lymphocytic leukemia. (A) At low magnification, there are poorly defined nodular areas, which are paler than the surrounding infiltrate, widely separated, and uniformly distributed within the node (×31). (B) Same case, higher magnification; note monotonous infiltrate of small lymphocytes, admixed with slightly larger cells with prominent nucleoli (prolymphocytes and paraimmunoblasts) (×500).

Other cell types are more numerous in LPHD than in CLL. The presence of large numbers of epithelioid histiocytes should increase suspicion for LPHD; these cells are relatively uncommon in CLL. Finally, a nodular pattern, if present, should suggest HD.

2 NLPHD versus Follicular Lymphoma

The nodular pattern seen in many cases of LPHD may give rise to a differential diagnosis of follicular lymphoma (CB/CC or centroblastic/centrocytic lymphoma). The problem is compounded by the fact that the nodules of LPHD may represent altered follicles, so that they may contain residual follicular center cells (Pinkus and Said, 1988; Poppema et al.,1979a,b; Timmens et al., 1986). It is important to recognize that the background infiltrate in HD may contain lymphoid cells other than small, round lymphocytes, and that the presence of single cells or even aggregates of cells that are identical to follicular center cells (both centrocytes and centroblasts) does not exclude a diagnosis of HD. The nodules in NLPHD are usually very large, relatively poorly demarcated from the surrounding infiltrate, and often have an almost polygonal shape, conforming to the shape of adjacent nodules like puzzle pieces (Fig 1). In follicular lymphomas, the follicles are usually smaller than in LPHD, more regular and uniform in shape, and more sharply delineated from the interfollicular region. In addition, they usually contain exclusively centrocytes and centroblasts, with only a minor admixture of small lymphocytes. In rare cases, the neoplastic centroblasts may be atypical in appearance, with hyperchromatic nuclei and even binucleate forms resembling RS cells (Lennert, 1978); in these cases the other cells will usually be large centrocytes, readily distinguishable from the smaller cells seen in NLPHD (Fig 3A and B).

Fig. 3 Malignant lymphoma, follicular centroblastic/centrocytic (follicular mixed small cleaved and large cell), with sclerosis, resembling Hodgkin’s disease, nodular sclerosis type. (A) At low magnification, well-formed follicles can be seen within the nodules demarcated by the fibrous bands (×31). (B) At high magnification, the background lymphocytes are highly atypical (×500).

C Immunophenotype

Because both follicular lymphomas and the vast majority of SLL/CLL are B-lineage neoplasms expressing monotypic immunoglobulin (Ig), immunophenotyping studies will usually resolve this differential diagnosis if morphologic features are inconclusive. In addition, many low-grade B cell lymphomas express antigens not readily detected on normal nodal or circulating B cells, antigens such as CD5 (B-CLL and centrocytic/intermediate lymphoma) or CD 10 (follicular lymphoma). In LPHD, the infiltrate consists predominantly of polyclonal B cells expressing IgM and IgD, with a lesser admixture of T cells of both subsets; numerous follicular dendritic cells can be found in the B cell areas (Coles et al., 1988; Timmens et al., 1986). The B cells have a normal phenotype and are CD5 and CD 10 negative. In NLPHD, the RS cell variants usually express CD20 antigen and are CD15 negative (Pinkus and Said, 1985, 1988). They are often, but not always, CD30 positive, but this antigen may also be detected in some large cells in follicular lymphomas, particular on frozen sections (Piris et al., 1991). Thus, CD15 and CD30 are not useful in this differential diagnosis.

For practical purposes, if the lymphocytic infiltrate, either nodular or diffuse, expresses monotypic Ig, a diagnosis of non-HD lymphoma is established and HD is excluded. An infiltrate that expresses B-lineage antigens in the absence of Ig expression, particularly if there is coexpression of CD5 or CD 10, should be considered suspicious for B cell NHL.

D Genotype

Clonal rearrangements of T or B cell antigen receptor genes have to date not been detected with the Southern blot technique in cases of LPHD, nor has bcl-2 oncogene rearrangement (Knowles et al., 1986; Said et al., 1991). Detection of one of these rearrangements in a case of suspected LPHD should argue strongly against the diagnosis.

III Pleomorphic (Peripheral) T Cell Lymphomas

A Definitions

Many cases of T cell lymphoma are characterized by a polymorphous proliferation of atypical lymphoid cells of varying size, including small lymphocytes, medium-sized atypical cells, and transformed or bizarre cells, which may resemble Reed-Sternberg cells or their variants, as well as eosinophils and epithelioid histiocytes (Suchi et al., 1987) (Table III). This mixture of cell types may give rise to a differential diagnosis of Hodgkin’s disease of mixed cellularity type, in which numerous mononuclear and binucleate RS cells are present in a background of small lymphocytes, histiocytes, and eosinophils (Fig 4A and B). Classifications of T cell lymphoma are not uniformly agreed upon, but, in general, the tumors that give rise to a differential diagnosis of Hodgkin’s disease, mixed-cellularity type, would fit into the Working Formulation categories of diffuse mixed small and large cell or large cell immunoblastic, pleomorphic subtype. In the new Kiel classification for T cell lymphoma (Suchi et al., 1987), cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) and lymphoepithelioid lymphoma (LEL) cell types, and, less often, pleomorphic, medium-sized and large cell type, are most often confused with mixed-cellularity Hodgkin’s disease (MCHD).

Table III

Mixed-Cellularity Hodgkin’s Disease versus Pleomorphic T