Table Of ContentEditorial 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
International Review of
EXPERIMENTAL
©PATHOLOGY
Volume 33
PROGRESS IN
HODGKIN'S DISEASE
Edited by
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
Guest Editor
Sibrand Poppema
Department of Laboratory Medicine
Cross Cancer Institute
Edmonton, Alberta
Canada
ACADEMIC PRESS, INC.
Harcourt Brace Jovanovich, Publishers
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This book is printed on acid-free paper. ©
Copyright © 1992 by ACADEMIC PRESS, INC.
All Rights Reserved.
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92 93 94 95 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
M. H. Bennett, Department of Pathology, Mount Vernon Hospital, Nort-
wood, 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 Hospi-
tal, 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, and Department of Pathology, Uni-
versity 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 Flor-
ence, 50134 Florence, Italy (141)
Sibrand Poppema, Department of Laborary Medicine, Cross Cancer Insti-
tute, Edmonton, Alberta T6G 1Z2, Canada, and Department of Pathol-
ogy, University of Alberta, Edmonton, Alberta T6G 2R7, Canada (53, 81)
ix
X Contributors
S. Romagnani, Department of Clinical Immunology, University of Flor-
ence, 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
Volume 33 of the International Review of Experimental Pathology summa-
rizes 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 pathol-
ogy and hematology and should be of interest to all pathologists and clini-
cians 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 differen-
tial 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 fre-
quent subtype of Hodgkin's disease, the nodular sclerosis subtype, are de-
scribed and supported with results from over 2000 patients. The third chap-
ter 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 immunopheno-
type 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 ag-
glutination 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 immuno-
logical 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 pre-
sented. Immunoglobulin gene analysis has shown that cases of Hodgkin's
disease with a high percentage of Reed-Sternberg cells frequently have
XI
XÜ Preface
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 no-
tably, Hodgkin cell lines have been used as an immunogen to produce an-
tibodies 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 sur-
rounding 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 be-
lieve 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.
Sibrand Poppema
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
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 immunologie
or molecular genetic tests for the disease, this is good news for the practic-
International Review of Experimental Pathology, Volume 33
Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved. 1
2 Nancy L. Harris
ing pathologist, who can usually both diagnose and subclassify this com-
mon type of lymphoma with confidence, based on relatively simple and
straightforward histologie 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 in-
dicated, morphologic criteria will suffice. Immunophenotypic and, less
often, molecular genetic analysis may play a role in confirming the impres-
sion 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 lin-
eages implies, the neoplastic cell of HD may in some cases be a T lympho-
cyte, 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 immunologie
makeup of the host, the same neoplastic B or T cell may give rise to the ex-
traordinary, tumorous immunologie reaction that we recognize histologi-
cally and clinically as HD. In general, we expect that most "difficult" cases
result from problems in fixation, sectioning, sampling, or lack of experi-
ence, 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 re-
solved 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 dis-
cussed, reviewing morphologic, immunologie, and molecular genetic fea-
tures that may be useful in the differential diagnosis.
II. LOW GRADE B CELL LYMPHOMA
A. Definitions
Lymphocyte-predominance Hodgkin's disease (LPHD), by definition, con-
tains 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
Hodgkin's vs. Non-Hodgkin's: Diagnosis 3
of Lukes and Butler) may be numerous (Lukes etal, 1966 a,b). The pattern
may be either nodular (NLPHD) or diffuse (Fig. 1A and B). These fea-
tures-predominance of small lymphocytes, rarity of malignant-appearing
cells, and occasional follicular pattern-may give rise to a differential diag-
nosis of non-Hodgkin's lymphoma (see Tables I and II).
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 lympho-
cytic 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 non-
cleaved 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 etal, 1984). In contrast, the lymphocytes of CLL
are usually round, have slightly more open chromatin than normal lympho-
cytes, often with visible nucleoli, and have an extremely monotonous ap-
pearance. 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 concen-
trated in pseudofollicular proliferation centers, visible at low magnification
as regularly distributed, pale areas in the darker infiltrate of small lympho-
cytes (Lennert, 1978).
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 pat-
tern, if present, should suggest HD.
2. NLPHD versus Follicular Lymphoma
The nodular pattern seen in many cases of LPHD may give rise to a differ-
ential diagnosis of follicular lymphoma (CB/CC or centroblastic/centro-
cytic lymphoma). The problem is compounded by the fact that the nodules
