Malignant Lymphoma

Malignant Lymphoma This page intentionally left blank Malignant Lymphoma Edited by BW Hancock MD FRCP FRCR Profess...

Author: B. W. Hancock | P. J. Selby | K. MacLennan | J. O. Armitage

69 downloads 1171 Views 47MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

Malignant Lymphoma

This page intentionally left blank

Malignant Lymphoma Edited by

BW Hancock MD FRCP FRCR Professor of Clinical Oncology and YCR Director of Cancer Research, The University of Sheffield, UK

PJ Selby MD FRCP Director, ICRF Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK

K MacLennan DM FRCP Professor of Tumour Pathology, ICRF Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK and

JO Armitage MD Professor and Chairman, Department of Internal Medicine, Section of Oncology and Hematology, University of Nebraska Medical Center, Omaha, Nebraska

A member of the Hodder Headline Group LONDON Co-published in the USA by Oxford University Press Inc., New York

First published in Great Britain in 2000 by Arnold, a member of the Hodder Headline Group, 338 Huston Road, London NW1 3BH http://www.arnoldpublishers.com Co-published in the United States of America by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 2000 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1P 9HE. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authorfs] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies' printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 0 340 74207 0 12345678910 Commissioning Editor: Joanna Koster Project Editor: Sarah de Souza Production Editor: James Rabson Production Controller: Fiona Byrne Project Manager: Marian Haimes Typeset in 10/12 pt Minion by Phoenix Photosetting, Chatham, Kent Printed and bound in Great Britain by The Bath Press, Bath

To the memory of Tim McElwain and Mike Bennett for their major contributions to an understanding of the clinical management and pathology of malignant lymphoma


Contents

Color plates appear between pages 50 and 51 Contributors Preface Foreword

PART 1

1

HISTOPATHOLOGY

4

5

6

7

8

9

3

Hodgkin's disease

KA MacLennan, B Vaughan Hudson, G Vaughan Hudson 3

1

Lymphoma classification KA MacLennan

2

ix xi xiii

9

Follicular lymphoma KA MacLennan

21

Mantle cell lymphoma DD Weisenburger, JO Armitage

27

Diffuse indolent B cell neoplasms KA MacLennan

43

Diffuse aggressive B cell lymphoma KA MacLennan

49

T cell lymphoproliferative disorders AS Jack, SJ Richards, KA MacLennan

55

Extranodal lymphomas PG Isaacson

71

Cytogenetics WG Sanger, BJ Dave, MR Bishop

91

PART 2

PATHOGENESIS

105

10

Hodgkin's disease V Diehl, J Wolf

107

Viruses and malignant lymphoma LM Weiss, KL Chang

115

Molecular biology VI Pappa, BD Young

133

11

12

viii Contents

PART 3

EPIDEMIOLOGY

13

Hodgkin's disease NE Mueller

14

159

161

Non-Hodgkin's lymphoma RA Cartwright

169

PART 4

CLINICAL MANAGEMENT

179

15

Hodgkin's disease: clinical features PWM Johnson, PJ Selby, BW Hancock

16

Imaging of lymphoma K Sandrasegaran, PJ Robinson, A Sprigg

17

421

The way forward BW Hancock, PJ Selby, JO Armitage, KA MacLennan

Index

399

Long-term problems M Henry-Amar

31

385

Infections B Crosse, PJ Selby

30

371

Lymphoma in the elderly PWM Johnson

29

359

Pediatric lymphomas JS Malpas

28

351

Cutaneous lymphomas RT Hoppe, YH Kim

27

331

AIDS-related lymphoma AM Levine

26

325

High-dose therapy PJ Bierman, JM Vose, JO Armitage

25

309

Other low-grade non-Hodgkin's lymphomas JA Radford

24

299

Follicular lymphoma TA Lister, AZS Rohatiner

23

287

Lymphoblastic lymphoma in adults JW Sweeten ham

22

269

Aggressive non-Hodgkin's lymphoma ER Gaynor, Rl Fisher

21

247

Advanced Hodgkin's disease BW Hancock, PJ Selby

20

221

Localized non-Hodgkin's lymphoma SB Sutcliffe, MK Gospodarowicz, MH Robinson

19

205

Localized Hodgkin's disease SB Sutcliffe, AR Timothy, MH Robinson

18

181

437

439

Contributors

James 0 Armitage

Michel Henry-Amar

Department of Internal Medicine, University of Nebraska

Centre Francois-Baclesse, Service de Recherche Clinique,

Medical Center, Omaha, Nebraska, USA

Caen, France

Philip J Bierman

Richard T Hoppe

Department of Internal Medicine, University of Nebraska

Professor of Cancer Biology, Chairman, Department of

Medical Center, Omaha, Nebraska, USA Michael R Bishop National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA

Radiation Oncology, Stanford University Medical Center, Stanford, California, USA PG Isaacson Department of Histopathology, Royal Free and University College London Medical School, University Street, London, UK

Ray A Cartwright Director, Leukaemia Research Fund, Centre for Clinical Epidemiology, University of Leeds, 30-32 Hyde Terrace, Leeds, UK Karen L Chang Department of Pathology, City of Hope National Medical Center, Duarte, California, USA

Andrew S Jack Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Leeds, UK PWM Johnson CRC Department of Medical Oncology, Southampton General Hospital, Southampton, UK Youn H Kim

B Crosse ICRF Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK Bhavana J Dave

Associate Professor of Dermatology, Stanford University Medical Center, Stanford, California, USA Alexandra M Levine Professor of Medicine, University of Southern California

Assistant Professor, Pathology/Microbiology and Pediatrics,

School of Medicine, Norris Cancer Hospital, Los Angeles,

University of Nebraska Medical Center, Omaha, Nebraska, USA

California, USA

V Diehl Department of Internal Medicine I, University of Cologne, Germany

T Andrew Lister Consultant Medical Oncologist, Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, UK

Richard I Fisher

KA MacLennan

Professor of Medicine, Director Division of

Consultant Histopathologist, ICRF Cancer Medicine Research Unit, St James's University Hospital, Beckett Street, Leeds, UK

Hematology/Oncology, Loyola University Medical Center, Maywood, Illinois, USA Ellen R Gaynor Professor of Medicine, Division of Hematology/Oncology, Loyola University Medical Center, Maywood, Illinois, USA

JS Malpas Masters Lodge, Charterhouse Square, London, UK Nancy E Mueller

Mary K Gospodarowicz

Professor of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

Professor of Radiation Oncology, Department of Radiation

VI Pappa

Oncology, University of Toronto, Princess Margaret Hospital,

Second Department of Internal Medicine, Athens University,

Toronto, Ontario, Canada

Evangelismos Hospital, Athens, Greece

Barry W Hancock

JA Radford

YCR Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK

Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, UK

x Contributors SJ Richards

John W Sweetenham

Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Leeds, UK

University of Colorado Health Sciences Center, Division of

Martin H Robinson

Adrian R Timothy

YCRC Department of Clinical Oncology, Weston Park Hospital

St Thomas' Hospital, Lambeth Palace Road, London

Medical Oncology, Denver, Colorado, USA

NHS Trust, Sheffield, UK

B Vaughan Hudson

PJ Robinson

The British National Lymphoma Investigation,

Department of Radiology, St James's University Hospital, Beckett Street, Leeds, UK

UCH/Middlesex Hospital, London, UK G Vaughan Hudson

Ama ZS Rohatiner

The British National Lymphoma Investigation,

Medical Oncology Unit, St Bartholomew's Hospital, West

UCH/Middlesex Hospital, London, UK

Smithfield, London, UK

Dennis D Weisenburger

K Sandrasegaran

Department of Pathology and Microbiology, University of

Department of Radiology, Birmingham Heartlands Hospital,

Nebraska Medical Center, Omaha, Nebraska, USA

Birmingham, UK

Lawrence M Weiss

Warren G Sanger

Chairman, Department of Pathology, City of Hope National Medical Center, Duarte, California, USA

Director, Cytogenetics Laboratories, Professor, Pathology/Microbiology and Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA PJ Selby Director, ICRF Cancer Medicine Research Unit, St James's

Jurgen Wolf Department of Internal Medicine I, University of Cologne, Germany Julie M Vose

University Hospital, Beckett Street, Leeds, UK

University of Nebraska Medical Center, Omaha, Nebraska,

A Sprigg

USA

Department of Radiology, Sheffield Children's Hospital, Western Bank, Sheffield, UK

BD Young Imperial Cancer Research Fund, Medical Oncology

Simon B Sutcliffe Vancouver Cancer Center, Vancouver, Canada

Department, St Bartholomew's Hospital Medical College, London, UK

Preface

This book gives fiilly referenced reviews of the many aspects of malignant lymphoma. It is a field where it is of particular importance that the clinician be aware of the variations in histological structure in the lesions with which he or she deals; we hope that the histopathology chapters are intelligible to the clinician, particularly as the most recent classification (Revised EuropeanAmerican Lymphoma/World Health Organisation) is likely to be universally accepted. An understanding of the pathogenesis (particularly the role of viruses and relevance of molecular biological discoveries) and epidemiology is likely to improve treatment strategies, so these subjects are also covered in depth. However,

clinical management, in all its aspects, comprises the major section of the book since it is towards improving the patient's lot that we all strive. We have invited an international panel of distinguished experts in all fields to contribute chapters in the hope that the book will give you a truly global interpretation of current and possible future strategies in understanding, diagnosing and treating this wide spectrum of diseases known collectively as the malignant lymphomas. Barry Hancock August 2000


Foreword

When the history of oncology research is finally written, the lymphomas will be the tumor group that dominates. As a group these tumors have opened up trails where there were no paths in understanding the biology of cancer, in general, and shown how biology can be effectively linked to cancer management. They have also served as a model for how multidisciplinary teams can coalesce to properly diagnose, stage and treat a group of complex cancers. A number of prominent firsts are associated with lymphomas. Hodgkin's disease was the first hematological malignancy described, followed in a few decades by the lymphocytic lymphomas. They were also the first tumors of a major organ system in adults cured by chemotherapy. Treatments developed for them have led to principles that have had applications in many other cancers as well. For many years, however, the field was plagued by a cacophony of pathology classification systems developed by prominent pathologists the world over. Most relied on empiricism and were not easy to learn and use. Always, it was difficult to match data across systems. A major advance occurred when the Working Formulation was developed because it brought some commonality to the language we used and allowed a more accurate crosscomparison of study results. It was, however, not a very scientific classification. Now we have the Revised European-American

Lymphoma (REAL) classification, which has brought order out of chaos by merging science with clinical practice, and it has brought us this book. The REAL classification was first met with considerable skepticism by lymphoma clinicians who feared it would be too unwieldy for practical use. On the contrary its strong scientific foundation and logical display of the numerous lymphoma subtypes has made it easy to remember and the most efficient lymphoma classification yet devised. So it is appropriate to have a new text on the subject that re-arrays the rich lode of information available to us on lymphomas under the new system. The editors and authors of this text have done just that. The content covers the science well, and distills all the information in a practical way and covers the new entities offered in the REAL classification. It is the judgement of this author that this is the definitive text in the field and, that it will be a necessary and welcome addition to the bookshelf of any physician who sees patients with lymphomas. Now if we can only call them what they are instead of what they are not! Vincent T. DeVita Jr, MD Professor of Medicine and Epidemiology and Public Health Yale University School of Medicine 30 June 2000


PART

Histopathology

Lymphoma classification Hodgkin's disease Follicular lymphoma

3 9 21

Mantle cell lymphoma

27

Diffuse indolent B cell neoplasms

43

Diffuse aggressive B cell lymphoma

49

T cell lymphoproliferative disorders

55

Extranodal lymphomas

71

Cytogenetics

91

1


1 Lymphoma classification KAMACLENNAN

Introduction Rappaport classification Lukes and Collins classification Kiel classification National Cancer Institute sponsored lymphoma classification project

3 3 4

Revised Kiel classification Revised European-American lymphoma classification Lymphoma classification project

4

WHO classification

5 6 6 7

References

8

4

INTRODUCTION The classification of the non-Hodgkin's lymphomas has been the subject of considerable controversy over many decades. Our understanding of the immune system has increased dramatically over recent years and thus our appreciation of the complexity of its neoplasms has been heightened. These factors, together with the introduction of new methodologies for the study of malignant lymphoma has greatly expanded the number of distinct entities that we now can recognize. This has inevitably led to terminological confusion, and many clinicians regard lymphoma classification with apprehension and distaste. The clinical management strategies for the treatment of malignant lymphoma still revolve around the concepts of low-grade lymphoma, which are regarded as indolent but incurable, and high-grade lymphomas, which are aggressive but potentially curable. However, embedded within these clinical groupings are distinctive biological entities that have widely varying clinical behavior. In order to understand how far we have progressed in the difficult field of the classification of the non-Hodgkin's lymphomas, it is of some value to review the history of lymphoma classifications briefly. Although earlier reports of lymphoproliferative disease are available, the first detailed study and documentation that malignant lymphoma was a distinctive entity was provided by Thomas Hodgkin's classical paper describing the disease,1 which Samuel Wilks generously gave the eponymous name Hodgkin's disease.2 This was

based upon macroscopic findings alone. In later years microscopic study of tissue from cases of malignant lymphoma was undertaken and the bewildering complexity of neoplasms of the immune system became apparent.3"5 The first classification of the modern era to gain widespread acceptance was proposed by Henry Rappaport.

RAPPAPORT CLASSIFICATION The Rappaport classification (Table 1.1) was submitted for publication as a fascicle of the Armed Forces Institute of Pathology Atlas of Tumor Pathology in 1959 but was not published until 1966.6 The classification paid particular attention to the architecture of non-Hodgkin's lymphoma, believing that there were nodular and diffuse subtypes of each cytological form. Although lacking any precision in terminology or lineage, the Rappaport classification proved extremely useful clinically and persisted for more than 20 years.

Table 1.1 Original Rappaport classification of 1956

1. 2. 3. 4. 5.

Lymphocytic type, well differentiated Lymphocytic type, poorly differentiated Mixed type (lymphocyticand reticulum cell) Reticulum-cell type Hodgkin's type

4 Lymphoma classification

Table 1.2 Original Lukes and Collins classification of 1974

Table 13 Original Kiel classification of 1974

I U cell (undefined cell) type II T eel I types Mycosis fungoides and Sezary syndrome Convoluted lymphocyte ?lmmunoblastic sarcoma (of T cells) ?Hodgkin's disease III B eel I types Small lymphocyte (chronic lymphocytic leukemia; CLL) Plasmacytoid lymphocyte Follicular center cell (FCC) types (follicular, diffuse, follicular, and diffuse and sclerotic) Small cleaved Large cleaved Small non-cleaved Large non-cleaved Immunoblastic sarcoma (of B cells) IV Histiocytictype V Unclassifiable

Low-grade malignancy Malignant lymphoma- lymphocytic (CLL and others) Malignant lymphoma - lymphoplasmacytoid (immunocytic) Malignant lymphoma - centrocytic Malignant lymphoma - centroblastic-centrocyticfollicular; follicular and diffuse; diffuse; with and without sclerosis High-grade malignancy Malignant lymphoma - centroblastic Malignant lymphoma - lymphoblastic Burkitt type Convoluted-cell type Others Malignant lymphoma - immunoblastic

In the 1970s the development of modern immunological concepts of T and B cell lineage impacted on lymphoma classification.7

LUKES AND COLLINS CLASSIFICATION The Lukes and Collins classification (Table 1.2) was developed based on cell lineage and morphological alterations associated with lymphocyte transformation in response to antigenic stimulus. It introduced new terminology to describe the varied cell morphology of follicle center cells, and terms such as cleaved and non-cleaved became widely accepted. Central to the classification was the belief that experienced hematopathologists could discriminate between B and T cell lineage lymphoma with reliability.7"13 In Europe, a similar ideology was used by Karl Lennert and members of the European Lymphoma Club to formulate the Kiel classification.

KIEL CLASSIFICATION The Kiel classification (Table 1.3) achieved popularity in Europe and as its central tenet was the concept that the cytology of lymphoma cells could be used as a grading system to predict clinical behavior. The presence of numerous transformed or blast cells was indicative of aggressive disease. Important in the structure of the Kiel classification was the belief that the nodular lymphomas proposed by Rappaport were the neoplastic equivalent of germinal center B cells. The Kiel classification introduced new terminology for follicle center B cells. Although originally termed germinoblasts and germinocytes as equivalent to the large non-cleaved and

small cleaved cells of the Lukes and Collins classification, this was subsequently changed as the terms centroblast and centrocyte were introduced.14"17 The Lukes and Collins and the Kiel classifications were the most scientifically appropriate classifications that existed in their day.18 However, four other classifications were also in use in the early 1970s. These were the Dorfman classification,19 World Health Organisation (WHO) classification,20 the British National Lymphoma Investigation classification21'22 and the updated Rappaport classification.23 These employed different terminology and had different criteria for diagnosis. It is therefore no surprise that there was a degree of confusion that pertained during this period and caused extreme difficulties in the comparison of therapeutic trials in malignant lymphoma. In an attempt to resolve these difficulties, the American National Cancer Institute sponsored a comparative study of lymphoma classification.

NATIONAL CANCER INSTITUTE SPONSORED LYMPHOMA CLASSIFICATION PROJECT The National Cancer Institute (NCI) lymphoma classification project studied the reproducibility and clinical value of the six major lymphoma classifications that were used in the 1970s. Six pathologists each representing a particular lymphoma classification and six expert hematopathologists who were to use each classification studied 1175 cases of malignant lymphoma accrued at four major oncology institutions (three Northern American and one European: Stanford University, Tufts-New England Medical Center, University of Minnesota Hospitals and the Milan National Tumour Institute). The prognostic significance and reproducibility of each classification was studied. As it transpired there was no significant difference between any of the six classifications in terms of clinical value and reproducibility. An attempt was made to select one classification for

Revised Kiel classification 5

Table 1.4 Working formulation of non-Hodgkin's lymphomas for clinical usage Low grade A. Small lymphocytic Consistent with CLL; plasmacytoid B. Follicular predominantly small cleaved cell Diffuse areas, sclerosis C. Follicular mixed small cleaved and large cell Diffuse areas, sclerosis Intermediate grade D. Follicular predominantly large cell Diffuse areas, sclerosis E. Diffuse small cleaved cell Sclerosis F. Diffuse mixed, small and large cell Sclerosis; epithelioid cell component G. Diffuse large cell Cleaved cell, non-cleaved cell, sclerosis High grade H. Large cell, immunoblastic Plasmacytoid, clear cell, polymorphous epithelioid cell component I. Lymphoblastic Convoluted, non-convoluted J. Small non-cleaved cell Burkitt's, follicular areas Miscellaneous Composite, mycosis, fungoides, histiocytic, extra medullary, plasmacytoma, unclassifiable, other

use world-wide. This was unsuccessful and so, after analysis of survival data, a working formulation of nonHodgkin's lymphomas for clinical usage was proposed (Table 1.4). This recognized three grades of lymphoma, low grade, intermediate grade and high grade, and was proposed, not as a classification, but as a common terminology for reporting lymphoma clinical trials.24 Serious criticisms were levelled at the working formulation, principally by Lukes and Lennert, who regarded it

as biologically imprecise with a division of distinctive entities between different clinical grades, and a lumping together of diverse lymphomas under terms such as diffuse mixed small and large cell and diffuse large cell lymphoma. They expressed the hope that the working formulation would not stifle research into the basic biology of malignant lymphoproliferative disease.24 Although proposed solely as a translational device, the working formulation was quickly adopted in North America as a classification, and during the 1980s and early 1990s became the standard classification. In Europe the working formulation was adopted by some centers, but the Kiel classification became predominant and was the most important in this continent, particularly after it was updated in 1988.25

REVISED KIEL CLASSIFICATION The Kiel classification was extensively updated in 1988 by Stansfeld and colleagues and now introduced clear delineation of B and T cell lymphoma entities.25 The classification was intended for nodal lymphomas and paid little attention to extra nodal disease. The updated Kiel classification (Table 1.5) was criticized for its level of complexity, particularly within the peripheral T cell lymphoma compartment where ten major subtypes were recognized. This was felt to lack clinical relevance and to be poorly reproducible by pathologists.26 The emergence of these two dominant classifications led to a major divergence of terminology between Europe and the United States, which led to difficulties in interpretation of the clinical and pathological literature. In order to resolve these difficulties, a group of 19 expert hematopathologists, who called themselves the International Lymphoma Study Group (ILSG), conducted a series of meetings in an attempt to identify distinct lymphoma entities within the field of lymphoproliferative

Table 1.5 Updated Kiel classification on non-Hodgkin's lymphoma

Low grade Lymphocytic-chronic lymphocytic and prolymphocytic leukemia; hairy cell leukemia Lymphoplasmacytic/cytoid Plasmacytic Centroblastic/centrocytic Centrocytic High grade Centroblastic Immunoblastic Large cell anaplastic Burkitt lymphoma Lymphoblastic Rare types

Lymphocytic-chronic lymphocytic and prolymphocytic leukemia Lymphoepithelioid Angioimmunoblastic Tzone Pleomorphic, small cell Pleomorphic, medium and large cell Immunoblastic Large cell anaplastic Lymphoblastic Rare types


disease, which could be reproducibly diagnosed and on which they could establish an acceptable terminology.27

REVISED EUROPEAN-AMERICAN LYMPHOMA CLASSIFICATION In 1994, Harris and co-workers published the Revised European-American Lymphoma (REAL) classification. This classification was a listing of lymphoid neoplasms which were distinctive biological entities and which could be reproducibly diagnosed by hematopathologists (Table 1.6). This listing delineates precursor and peripheral lymphoid neoplasms of both B and T cell lineage as well as including plasmacytoma/multiple myeloma and Hodgkin's disease. The classification is applicable to nodal and extranodal lymphoma alike, and is thus a significant advance on the Kiel classification.27'28 Although fiercely criticized by some when first published, the classification has been broadly accepted and welcomed by hematopathologists world-wide. Criticisms that were levelled at the REAL classification were that it had not been tested for its clinical and prognostic value, and there were no data as to how well it could be applied by hematopathologists.29 In order to study these questions, a group was established under the chairmanship of Professor J.O. Armitage from the University of Nebraska Medical Center at Omaha, which was termed the Lymphoma Classification Project.

LYMPHOMA CLASSIFICATION PROJECT In order to evaluate the recently proposed ILSG classification of non-Hodgkin's lymphoma, a group of five expert hematopathologists visited eight major oncology institutions. The objectives of this study were to determine how well the REAL classification could be applied by expert hematopathologists, and to compare its applicability with the working formulation and Kiel classification to study the clinical value of the classification and to gain some idea of the geographic variability in the incidence of non-Hodgkin's lymphoma. The results of this study showed that the REAL classification could be applied with a high degree of accuracy with an interobserver concordance rate of 85 per cent for the major lymphoma subtypes and an intraobserver concordance rate of 94 per cent when clinically insignificant discrepancies were discounted.30 The REAL classification was a good predictor of survival and failure-free survival. This study has validated the ILSG proposal, and shown the REAL classification to be superior to the working formulation and updated Kiel classification in terms of reproducibility and prognostic significance. The REAL classification and the data generated by the Lymphoma Classification Project have been of great

Table 1.6 Lymphoid neoplasms recognized by the International Lymphoma Study Group B cell neoplasms I Precursor B cell neoplasms: B precursor lymphoblastic leukemia/lymphoma II Peripheral B cell neoplasms 1. B cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma 2. Lymphoplasmacytoid lymphoma/immunocytoma 3. Mantle cell lymphoma 4. Follicle center lymphoma, follicular Provisional cytologic grades: I (small cell), II (mixed small and large cell), III (large cell) Provisional subtype: diffuse, predominantly small cell type 5. Marginal zone B cell lymphoma Extranodal (MALT type *monocytoid B cells) Provisional subtype: nodal (*monocytoid B cells) 6. Provisional entity: splenic marginal zone lymphoma (*villous lymphocytes) 7. Hairy cell leukemia 8. Plasmacytoma/plasma cell myeloma 9. Diffuse large B cell lymphoma Subtype: primary mediastinal (thymic) B cell lymphoma 10. Burkitt lymphoma 11. Provisional entity: high-grade B cell lymphoma, Burkitt-like T cell and putative natural killer (NK) cell neoplasms I. Precursor T cell neoplasm: T precursor lymphoblastic lymphoma/leukemia II. Peripheral T cell and NK cell neoplasms 1. T cell chronic lymphocytic leukemia/prolymphocytic leukemia 2. Large granular lymphocytic leukemia (LGL), T and NK cell types 3. Mycosis fungoides/Sezary syndrome 4. Peripheral T cell lymphoma, unspecified Provisional cytologic categories, medium-sized cell, mixed medium and large cell, large cell, lymphoepithelioid cell Provisional subtype: hepatosplenic y6 T cell lymphoma Provisional subtype: subcutaneous panniculiticTcell lymphoma 5. Angioimmunoblastic T cell lymphoma (AIL) 6. Angiocentric lymphoma 7. Intestinal T cell lymphoma (*enteropathy associated) 8. Adult T cell lymphoma/leukemia (ATLL) 9. Anaplastic large cell lymphoma (ALCL), CD 30+, T and null-cell types 10. Provisional entity: anaplastic large cell lymphoma, Hodgkin's like Hodgkin's disease I. Lymphocyte predominance II. Nodular sclerosis III. Mixed cellularity IV. Lymphocyte depletion V. Provisional entity: lymphocyte-rich classical Hodgkin's disease

WHO classification 7

value in formulating the forthcoming proposal from the WHO on the classification of hemopoietic neoplasms. WHO CLASSIFICATION The WHO classification, although not yet published, is being developed under the joint auspices of the Society for Hematopathology and the European Association for Haematopathology. A steering committee composed of

Drs C Berard, J Diebold, N Harris, E Jaffe and K Lennert has established ten committees, which are involved in the classification of hematolymphoid malignancy. Although a final version has not been published, the broad outlines of the classification are illustrated in Table 1.7, and the close similarity between the proposed WHO classification and the REAL classification are immediately apparent. It is to be hoped that, with the publication of the WHO classification, a period of stability in lymphoma

Table 1.7 World Health Organisation classification of neoplastic diseases of the hematopoietic and lymphoid tissues B cell neoplasias Precursor B cell neoplasms B cell lymphoblastic leukemia/lymphoma Peripheral B cell neoplasms B cell chronic lymphocytic leukemia/small lymphocytic lymphoma Variant: with monoclonal gammopathy/plasmacytoid differentiation; mu heavy chain disease B cell prolymphocytic leukemia Variant: hairy cell variant Lymphoplasmacytic lymphoma Variant: Waldenstrom's macroglobulinemia; gamma heavy chain disease Mantle cell lymphoma Variant: blastic Follicular lymphoma Grades: Grade 1 (centroblasts comprise 50 per cent of the follicle surface area) Variant: cutaneous follicular lymphoma Marginal zone B cell lymphoma of mucosa-associated lymphoid tissue Variant: alpha heavy chain disease Nodal marginal zone lymphoma ± monocytoid B cells Splenic marginal zone B cell lymphoma (± villous lymphocytes) Hairy cell leukemia Diffuse large B-cell lymphoma Variants: Centroblastic Immunoblastic Tcell or histiocyte rich Anaplastic large B cell Burkitt-like Lymphomatoid granulomatosistype Diffuse large B cell lymphoma, subtypes: Mediastinal (thymic) large B cell lymphoma Intravascular large B cell lymphoma Primary effusion lymphoma in HIV patients/pyotorax related Burkitt lymphoma Variant: with plasmacytoid differentiation (AIDSassociated) Plasmacytoma Variants: Solitary plasmacytoma of bone Extramedullary plasmacytoma

Plasma cell myeloma Variants: Indolent myeloma Smoldering myeloma Osteosclerotic myeloma (POEMS syndrome) Plasma cell leukemia Non-secretory myeloma Systemic light chain disease Primary amyloidosis T cell neoplasias Precursor Tcell leukemia/lymphoma Tcell lymphoblastic leukemia/lymphoma Peripheral T/NKcell neoplasms, predominantly leukemic/disseminated T cell prolymphocytic (T-PLL) T cell large granular lymphocyte leukemia NKcell leukemia Adult Tcell lymphoma/leukemia Peripheral T cell and NK cell neoplasms, predominantly nodal AIL Tcell lymphoma Peripheral T cell lymphoma (unspecified) T-zone Lymphoepithelioid (Lennert) lymphoma ALC lymphoma (T and null cell types) Peripheral T cell and NK cell neoplasms, predominantly extra nodal Mycosis fungoides Sezary syndrome Primary cutaneous CD 30-positive T cell lymphoproliferative disorders Primary cutaneous ALC lymphomas + borderline with lymphomatoid papulosis Subcutaneous panniculitic-like T cell lymphoma NK/Tcell lymphomas, nasal/nasal type Enteropathy-type intestinal T cell Hepatosplenic76Tcell lymphoma Hodgkin lymphoma (Hodgkin disease) Nodular lymphocyte-predominance Hodgkin lymphoma Classical Hodgkin lymphoma Hodgkin lymphoma, nodular sclerosis (Grades I and II) Hodgkin lymphoma, mixed cellularity Classical Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, lymphocyte depletion


terminology will pertain, so that prospective data on the clinical behavior of defined lymphoma entities may be accrued.

15. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for the classification of malignant lymphomata. BrJ Cancer 1975; 31 (suppl 2): 29-43. 16. Lennert K. Malignant lymphomas other than Hodgkin's disease. New York: Springer-Verlag, 1978.

REFERENCES

17. Lennert K. Immunology: morphology and function. Adv Exp Med Biol 1979; 114:1-9. 18. Lennert K, Collins RD, Lukes RJ. Concordance of the Kiel

1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med Chir Trans 1832; 17:68-114. 2. Wilkes Sir S. Cases of enlargement of the lymphatic glands and spleen (or, Hodgkin's disease), with remarks. Guys Hosp Rep 1865; 11: 56-67. 3. Greenfield WS. Specimens illustrative of the pathology of lymphadenoma and leucocythaemia. Trans Path Soc Land. 1878; 29: 272-304. 4. EwingJ. Neoplastic diseases. Philadelphia, London: WB Saunders, 1919. 5. Fox H. Remarks on microscopic preparations made from some of the original tissue described by Thomas Hodgkin, 1832. Ann Med Hist 1926; 8: 370-4. 6. Rappaport H. Tumors of the hematopoietic system, series 1, section III. Washington, DC: Armed Forces Institute of Pathology. 1966. 7. Lukes RJ, Collins RD. Immunologic characterization of human malignant lymphomas. Cancer 1974; 34 (suppl): 1488-503. 8. Lukes RJ, Collins RD. New approaches to the classification of the lymphomata. BrJ Cancer 1975; 31 (suppl 2): 1-28. 9. Lukes RJ, Collins RD. Lukes-Collins classification and its significance. Cancer Treat Rep 1977; 61: 971-9. 10. Lukes RJ, Lincoln TL, Parker JW, Alavaikko MJ. An

and Lukes-Collins classifications of non-Hodgkin's lymphomas. Histopathology 1983; 7: 549-59. 19. Dorfman RF. Classification of non-Hodgkin's lymphomas (letter). Lancet 1974; 2: 961-2. 20. Mathe G and Rappaport H. Histological and cytological typing of neoplastic diseases of hematopoietic and lymphoid tissues. Geneva: World Health Organisation, 1976. 21. Bennett MH, Farrer-Brown G, Henry K, Jell iff e AM. Classification of non-Hodgkin's lymphoma. Lancet 1974; ii: 405. 22. Henry K, Bennett MH, Farrer-Brown G. Morphological classification of non-Hodgkin's lymphomas. Rec Results Cancer Res 1978; 64: 38-56.

23. Nathwani BN, Kim H, Rappaport H, Solomon J, Fox M. Non-Hodgkin's lymphomas: a clinicopathologic study comparing two classifications. Cancer 1978; 41: 303-25. 24. Anonymous. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 1982; 49: 2112-35.

immunologic approach to classification of malignant

25. Stansfeld AG, Diebold J, Noe H, et al. Updated Kiel classification for lymphomas. Lancet 1988; 1: 292-3.

lymphomas: a cytokinetic model of lymphoid neoplasia. In: Clarkson B, et al., eds. Differentiation of normal and

26. Hastrup N, Hamilton-Dutoit S, Ralfkiaer E, Pallesen G. Peripheral T-cell lymphomas: an evaluation of

neoplastic hematopoietic cells. Cold Spring Harbor, NY:

reproducibility of the updated Kiel classification.

Cold Spring Harbor Laboratory, 1978; 935-52.

Histopathology 1991; 18: 99-105.

11. Lukes RJ, Taylor CR, Parker JW. Multi para meter studies in malignant lymphoma based on studies in 1186 cases. Prog Clin Biol Res 1983; 132E: 203-13. 12. Lukes RJ, Taylor CR, Parker JW, Lincoln TL, Pattengale PK, Tindle BH. A morphologic and immunologic surface marker study of 299 cases of non-Hodgkin lymphomas and related leukemias. Am} Pathol 1978; 90: 461-85. 13. Lukes RJ, Parker JW, Taylor CR, Tindle BH, Cramer AD, Lincoln TL. Immunologic approach to non-Hodgkin lymphomas and related leukemias. Analysis of the results of multiparameter studies of 425 cases. Semin Hematol 1978; 15: 322-51. 14. Gerard-Marchant R, Hamlin I, Lennert K, et al. Classification of non-Hodgkin's lymphoma. Lancet 1974; H: 406-8.

27. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92. 28. Chan JK, Banks PM, Cleary ML, et al. A proposal for classification of lymphoid neoplasms (by the International Lymphoma Study Group). Histopathology 1994; 25: 517-36. 29. Rosenberg SA. Classification of lymphoid neoplasms. Blood 1994; 84:1359-60. 30. Anonymous. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89: 3909-18.

2 Hodgkin's disease KA MACLENNAN, B VAUGHAN HUDSON AND G VAUGHAN HUDSON

9

Introduction Cell of origin of Hodgkin's disease

10

Mixed cellularity Hodgkin's disease 13 Clinical significance of morphological pattern in Hodgkin's

Lymphocyte-predominant Hodgkin's disease Nodular sclerosis

10 12

disease

14

References

14

Lymphocyte-depleted Hodgkin's disease

13

INTRODUCTION The first descriptions of the disease currently termed Hodgkin's disease are attributed to Thomas Hodgkin1 and the term Hodgkin's disease was generously applied by Sir Samuel Wilkes;2 however, there are several texts describing a similar disease process that antedate both these workers' manuscripts.3'4 These early descriptions of Hodgkin's disease were all concerned with the macroscopic appearances and distribution of affected lymph nodes, spleen and visceral organs as observed at post mortem examination. There thus exists some doubt as to the exact nature of the disease processes being described. Herbert Fox,5 after histological examination of pathological material stored at Guy's Hospital from three of Thomas Hodgkin's original cases, believed two were typical of Hodgkin's disease, and one to be an example of lymphosarcoma or leukaemia; other skilled observers have concurred with this view.6,7 During the latter half of the nineteenth century, many workers undertook histological examination of cases that were felt to be similar to Hodgkin's disease.8'11 There emerged from these descriptions an awareness that the normal structure of the lymph node was replaced by abnormal tissue, often described as fibrous tissue, and the disease was associated with unusual giant cells. In 1898, Sternberg gave a masterful description of these giant cells,12 which 4 years later was followed by the publication of Dorothy Reed's classic paper.13 Following the meticulous histological descriptions of Hodgkin's disease by these early microscopists, terminological confusion was soon to emerge and, by 1933, Walhauser was able to find 52 synonyms for this condition

(an unusually large number even for the field of lymphoreticular pathology).14 This ridiculous state of affairs was only resolved by the widespread adoption of the Jackson and Parker classification" (see below). In the early part of the twentieth century, some workers attempted to correlate the histological appearances of Hodgkin's disease with the clinical course. In 1919, Ewing recognized a rapidly fatal form of the disease characterized by depletion of lymphocytes and a sheetlike growth of pleomorphic mononuclear and multinuclear cells, which he termed Hodgkin's sarcoma.16 Rosenthal, in 1936, observed the inverse relationship between the number of lymphocytes and abnormal reticulum cells;17 he was also able to correlate survival and response to orthovoltage radiotherapy to the histological appearances. Following the work of Rosenthal, Jackson and Parker15'18"20 proposed their classification of Hodgkin's disease. Three histological subtypes were recognized: paragranuloma, granuloma and sarcoma, which showed a good correlation with clinical behavior and prognosis. Unfortunately, the classification proved to be of limited value as the majority of cases were classified as Hodgkin's granuloma15'21 and this subtype showed an extremely variable clinical course.22 These problems were overcome by the widespread adoption of the Lukes and Butler classification and its modification proposed at the Rye conference,23-26 which has remained essentially unchanged for over 20 years, and most pathologists believe they are familiar with the terminology and criteria employed. It is therefore surprising to find high levels of disagreement between pathologists in establishing the diagnosis of Hodgkin's disease and its classification, which may range

10 Hodgkin's disease

from 13 per cent27'28 to a staggering figure of 47 per cent, reported by Symmers.29 The reasons for the difficulties pathologists experience in the diagnosis of HD are not too difficult to understand. Hodgkin's disease is rare and most pathologists will see only a few cases a year. This, combined with the complexity of the histological picture, which may be closely mimicked by a variety of neoplastic and nonneoplastic lymphoproliferative conditions, will lead to errors in diagnosis.

CELL OF ORIGIN OF HODGKIN'S DISEASE There has been considerable controversy over the years about the cellular origin of the putative malignant cell in Hodgkin's disease (HD), the Hodgkin's and ReedSternberg cell (H-RS cell). Many candidates have been proposed that include histiocytes, interdigitating cells, follicular dendritic cells and lymphoid cells of both B and T cell lineage. One significant problem in establishing the lineage of the H-RS cell has been their relative paucity in tissue affected by HD, where they often make up less than 5 per cent of the total cell population. This has led investigators to study Hodgkin's cell lines and cases of HD containing numerous H-RS cells, which may show major differences to typical HD.3031 An early study of a case of H-RS cell-rich nodular sclerosis revealed a clonal immunoglobulin gene rearrangement.32 Although initially controversial, subsequent reports also found immunoglobulin (Ig) gene rearrangements in a percentage of cases. Other workers demonstrated T cell receptor rearrangements of both beta and gamma chains in some cases of HD.33 A novel approach of single cell microdissection of HRS cells was established, which allowed analysis of the Ig gene configuration by polymerase chain reaction (PCR). Initial reports showed clonal Ig gene rearrangement with somatic hypermutation within the H-RS cell population in the vast majority of the cases studied.34 Controversy soon followed with other workers providing dramatically different results despite using very similar methodology. In summary, one group were unable to detect any evidence of Ig gene rearrangement within H-RS cells,35 one group showed polyclonal Ig rearrangement36 and a third demonstrated a mixture of results, with some cases showing no Ig gene rearrangement,37 some polyclonal rearrangement,36 some clonal,38-10 and some mixed polyconal and clonal Ig gene rearrangement.41 These results are clearly incompatible. Evidence is now accumulating that the majority of cases of classical HD have clonal Ig gene rearrangement, with somatic hypermutation clearly identifying the H-RS cells as a neoplastic, germinalcenter-derived B cell. In addition, many cases display 'crippling mutations' such as stop codons within the rearranged Ig genes.42

Similarly controversial results have been found in lymphocyte-predominant nodular HD, with some workers demonstrating somatically hypermutated, clonally rearranged Ig genes, while others have found polyclonal patterns of Ig gene rearrangement within populations of microdissected lymphocytic and/or histiocytic (L & H) cells. Recently, three separate groups have demonstrated clonal Ig gene rearrangements within populations of microdissected L & H cells. These rearrangements are somatically hypermutated but lack the 'crippling mutations' seen in classical HD, and show evidence of continuing antigen selection in an analogous manner to follicle-center-derived non-Hodgkin's lymphomas.43'44

LYMPHOCYTE-PREDOMINANT HODGKIN'S DISEASE For many years, Hodgkin's disease with a predominance of lymphocytes has been recognized as having a more indolent natural history15,17,22,23,25,45-47 than the usual type of HD. Lukes and Butler described a form of HD that contained a spectrum of cytological appearances, which ranged from a predominance of mature lymphocytes to a histiocyte-rich cellular background which they termed lymphocytic and/or histiocytic (L & H) Hodgkin's disease;24 they recognized nodular and diffuse architectural patterns. These cytological and architectural patterns of L & H HD were amalgamated at the Rye conference26 and termed lymphocytic predominance. Lymphocyte-predominant (LP) Hodgkin's disease makes up a variable percentage of cases of HD in large series, depending on the stringency of the diagnostic criteria applied.48 In the British National Lymphoma Investigation (BNLI) series of 4249 cases, LP comprises 5.7 per cent and in the European Organisation for Research and Treatment of Cancer (EORTC)-GELA studies of localized HD (H 8), which include 722 centrally reviewed cases, LP makes up 4 per cent.49 It usually presents with localized, asymptomatic disease and often involves unusual sites, such as the suprahyoid neck, the periparotid lymph nodes and the inguinal region. There is a marked male predominance and patients are usually a decade older than the peak age incidence of the usual type of HD.50 For many years there was a lack of precision in the diagnosis of LP, with many cases of the usual type of HD that displayed a lymphocyte-rich cellular background being included in this category. In a seminal paper published in 1979, Poppema and co-workers51 recognized the cytological similarities between LP nodular HD and a reactive condition affecting germinal centers, termed progressive transformation.52'53 They postulated that LP nodular HD was a distinct form of HD, which arose in

Lymphocyte-predominant Hodgkin's disease 11

the B cell regions of the lymph node and was related to progressive transformation of germinal centers. In order to emphasize the differences between LP nodular and other histological subtypes of HD, they proposed the term nodular paragranuloma, which has been adopted by some workers.

Morphologic features Lymph nodes affected by LP nodular HD are enlarged and can reach significant sizes (up to 5 cm); their cut surface has a uniform fleshy appearance and occasionally residual remnants of lymph node may be observed, which are compressed at the periphery of an expansile tumor mass.54 Microscopically LP nodular HD is characterized by the presence of a macronodular growth pattern, which is expansile rather than infiltrative (Plate 1); nodules do not penetrate the lymph-node capsule or extend into perinodal tissue. Diffuse areas are sometimes seen. Exclusively diffuse LP HD is exceptionally rare in our experience, with the majority of cases being nonHodgkin's lymphomas of peripheral T cell or T cell-rich B cell type.55 The nodules of LP nodular HD often have a 'motheaten' appearance at low power (Plate 2), and are composed of small round or slightly irregular lymphoid cells with admixed large lymphoid cells, epithelioid histiocytes, dendritic reticulum cells and a Reed-Sternberg (RS) cell variant called the L & H or popcorn cell. The lymphocytes within the nodules show a close cytological similarity with mantle zone lymphocytes, which is confirmed by their phenotype. Epithelioid histiocytes may be scattered within the nodules or form loose aggregates; well-formed, sarcoid-like granulomata, if present, are usually seen at the periphery of the nodules and may form encircling rings (Plate 3). The histiocytes bear a close resemblance to those seen in mantle cell lymphoma, and possess an open nuclear chromatin with a single prominent nucleolus and well-defined eosinophilic cytoplasm. The nuclei of follicular dendritic cells are easily identified and multinucleated forms, resembling Warthin-Finkeldy giant cells are common (Plate 4). L & H cells have a characteristic morphology with a large, irregular and often lobulated nucleus with a prominent nucleolus which is often amphophillic and irregular (Plate 5). Classical RS cells are rare and are not essential for the diagnosis of LP nodular HD; in fact, if classical RS cells can be found with ease, the diagnosis of LP nodular HD should be changed to one of mixed cellularity as the clinical behavior of these cases is different from typical LP HD.56 The number of L & H cells is very variable and ranges from scanty to very numerous, making up more than 10 per cent of the cellular composition of the nodules; the latter is often seen in relapses of LP nodular. The number of L & H cells present does not

seem to influence the clinical behavior.50 L & H cells may be confined to the nodules or may spill out into the internodular region of the node. Immunocytochemistry The nodules of LP nodular HD are composed of polytypic small B cells expressing CD 20 and CD 79a57^ (Plate 6) and showing co-expression of IgM and IgD in a similar fashion to mantle zone B cells.61 Within the nodules is a meshwork of follicular dendritic cells (FDCs) revealed by staining for CD 21 and CD 35, and their processes often wrap around the L & H cells (Plate 7). The L & H cells uniformly express a B cell phenotype with strong expression of CD 20 and CD79a62'63 (Plate 8). There is evidence of immunoglobulin synthetic capacity as shown by the presence of J chain within the L & H cells,64 and some workers have shown the presence of kappa-light-chain restriction either by immunocytochemistry65 or by in situ hybridization for light-chain messenger RNA.66,67 The markers of classical H-RS cells, CD 30 and CD 15 are not usually detected on L & H cells68 (though there is some evidence for expression of a heavily sialylated form of CD 15, which is undetectable without prior neuraminidase digestion69). The presence of these markers should prompt consideration of a diagnosis of follicular colonization by classical HD (see below). There is frequent expression of epithelial membrane antigen by L & H cells70 and the presence of EpsteinBarr virus is not usually detectable.48,63,71 Within the nodules are numerous T cells, which express CD 3. Numerous CD 57-positive T cells are also seen and these may form rosettes around the L & H cells (Plate 9). The number of CD 57 cells has proved useful in the differential diagnosis of LP HD and lymphocyterich classical HD (LRCHD). Cases of LP have been shown to have >200 CD 57-positive cells per high-power field compared to an average of 45 CD 57-positive cells per high-power field in LRCHD.48 Non-Hodgkin's lymphoma arising in patients with LP nodular It is now clear from several large studies of patients with LP nodular HD that there is a markedly increased risk of non-Hodgkin's lymphoma (NHL), which ranges from an incidence of 3.8 per cent72 to nearly 10 per cent.73 The lymphomas associated with LP nodular HD may occur simultaneously74-77 or after a period of many years.72,75,78,79 They are usually of B cell lineage72,74,75 and there is some evidence that there may be a clonal relationship between the original LP and the subsequent B cell NHL;79,80 other workers have been unable to confirm this.78 The morphology of these secondary, high-grade B cell lymphomas is variable: some show features typical of diffuse


large B cell lymphoma exhibiting centroblastic or immunoblastic cytology, while others resemble sheets of L & H cells. Since the first recognition of T cell lineage NHL following LP nodular HD,72 subsequent reports have confirmed this association,81'82 and Weisenburger and co-workers have reported the concurrent presentation of T NHL and LP nodular HD.83 These may have a variety of histological patterns but the majority appear to fall within the peripheral T cell lymphoma, unspecified group of the Revised European-American Lymphoma (REAL) classification.84 A single case of composite T and B lineage lymphoma has been described in the setting of LP HD.85

NODULAR SCLEROSIS The presence of fibrosis and the proliferation of fibroblastic cells in HD has been recognized for over a century.10-12,17 The recognition by Smetana and Cohen21 of a sclerosing variant of Hodgkin's granuloma15 and its associated superior survival were among the first steps in the delineation of nodular sclerosis (NS). Lukes and co-workers23-25,86 described the histological features of NS, and stressed the importance of nodularity, lacunar cells and birefringent collagen band formation. Rappaport and colleagues emphasized the unique nature of NS by demonstrating the consistency of this histological pattern in sequential biopsies and from different anatomical locations.87,88

Morphological features Lymph node involvement by nodular sclerosis may be partial or complete. There is usually capsular and intranodal fibrosis, which may impart a firm rubbery texture. The cut surface may have a coarsely nodular appearance and areas of necrosis may be macroscopically apparent. Histologically, capsular thickening is present in the majority of cases (Plate 10) and there is a variable degree of intranodal sclerosis, which may range from occasional thin collagen bands to large areas of collagenous sclerosis that obliterate most of the nodal structure. Nodularity is a constant feature of NS, and may be present partially or throughout the lymph node. NS is associated with a particular H-RS cell variant termed the lacunar cell. The lacunar cell is most obvious in specimens fixed in formalin in whom paraffin processing dissolves the lipid-rich cytoplasm to leave a clear space; specimens fixed in mercuric-based fixatives do not show this helpful artefact. The nucleus of lacunar cells is typically twisted or lobulated with a prominent eosinophillic nucleolus (Plate 11). In recent years there has been considerable confusion over the precise criteria required to diagnose NS and this

has centred around the entity termed cellular phase NS. Lukes86 required the presence of intranodal collagen band formation in association with lacunar cells to establish a diagnosis of NS and recognized a cellular phase in which only a single band of collagen was found in association with the typical • cellular background of NS. Cases lacking collagen band formation were classified as mixed cellularity by Lukes. Other workers have classified cases as cellular-phase NS when lacunar cells are seen in the absence of collagen band formation.87,89 The advantage of adhering to the strict criteria proposed by Lukes and Butler24 is that they do enable pathologists to achieve very high levels of interobserver and intraobserver concordance (97 per cent)90 in the diagnosis of the NS subtype. The cellular nodules of NS show a wide range of cytological appearances ranging from a lymphocyte-rich cellular background with scanty lacunar cells to one of lymphocyte depletion and sheets of lacunar and H-RS cells. This latter pattern may be associated with areas of necrosis. In many cases there are also admixed histiocytes, eosinophils and plasma cells with the lymphocytes and lacunar cells. The cytological diversity of the cellular nodules of NS has prompted workers to develop grading systems for NS, which might correlate with prognosis (reviewed in MacLennan et a/.91). In a series of publications the BNLI proposed a grading system which recognized low-grade (Grade I) and high-grade (Grade II) subtypes of NS. 50,56,90-93 The histologic criteria for this grading system have been published in detail elsewhere90 and are only outlined here. Cases were classified as Grade II NS if more than 25 per cent of the cellular nodules showed lymphocytedepleted cytology. These lymphocyte-depleted nodules are often composed of sheets of mononuclear Hodgkin's and lacunar cells; an appearance that has been termed 'syncytial Hodgkin's disease' by some workers.94'95 Central necrosis and eosinophilic abcess formation within these lymphocyte-depleted nodules is sometimes observed (Plate 12). Also classified as Grade II NS were cases in which more than 25 per cent of the cellular nodules contained numerous pleomorphic H-RS cells in the absence of lymphocyte depletion. The rarest form of lymphocyte-depleted cytology was the bland-appearing fibrohistiocytic variety; if more than 80 per cent of the cellular nodules showed this feature, the case was classified as Grade II NS.93 The adverse prognostic significance of fibroblastic proliferation was also reported by Colby et a/.96 All other cases were graded as Grade I including borderline cases. Using this system significant differences in survival and disease-free survival are seen between the grades of NS (see below). Other workers have confirmed the clinical value of this grading system;97'101 some have not been able to demonstrate a difference in prognosis between the two grades of NS.102'103

Mixed cellularity Hodgkin's disease 13

Immunocytochemistry The phenotype of NS differs from LP nodular HD in that the nodules are composed predominantly of T cells104'105 (CD 3-positive, CD 45 Ro-positive) with a prevalence of CD 4-positive cells centrally and a rim of CD 8-positive lymphocytes at the periphery. The lacunar cells exhibit strong staining for CD 15 in over 80 per cent of cases and this staining is usually membrane and golgi associated; CD 30 is also expressed in the majority of cases106-110 (Plate 13). The expression of lymphoid lineage-restricted antigens on H-RS cells remains controversial with some groups claiming expression of CD 3 in a percentage of cases,111,112 whilst others find expression of B lineage antigens on a small percentage of H-RS cells,113 which may be seen in up to 60 per cent of cases of HD.114 There is variable expression of BCL 6 protein and CD 138.115,116 The significance of these phenotypic differences is unclear but in human immunodeficiency virus (HIV)-associated HD there is a marked predominance of CD 138-positive/BCL 6-negative H-RS cells.117 Some cases of anaplastic large cell lymphoma (ALCL) may display morphological features, which are reminiscent of NSHD particularly the Grade II subtype.118 So close may these similarities be that some workers have introduced the term 'ALCL Hodgkin's like';84 other workers feel that the vast majority of these cases are in fact related to classical HD and have used the term 'malignant lymphoma with features of Hodgkin's lymphoma and ALCL'.119 Immunocytochemistry can be helpful in distinguishing between HD and ALCL; whilst CD 30 is usually expressed by both, CD 15 staining is uncommon in ALCL and, when present, does not exhibit the membrane and Golgi staining characteristic of HD. Leukocyte common antigen (CD 45) is expressed in a percentage of ALCL118 but in our hands has proved of limited value. Recently antibodies to the p80 NPM-ALK fusion protein, generated by the 2;5 translocation,120 have become available,121,122 which stain just over half the cases of ALCL studied; no case of HD was labelled.122 Of interest is the detection of t(2;5) in a minor population of microdissected CD 30-positive cells from cases of classical HD123 and in the peripheral blood of normal individuals.124

LYMPHOCYTE-DEPLETED HODGKIN'S DISEASE Lymphocyte-depleted (LD) Hodgkin's disease is the rarest form of Hodgkin's disease and its frequency appears to be diminishing. It includes two distinctive morphological entities from the Lukes and Butler classification: diffuse fibrosis and reticular HD. It is now clear from various studies that many of the cases formally classified as LD were in fact examples of non-Hodgkin's

lymphomas125 often of anaplastic large cell type or of other HD subtypes, such as the Grade II form of NS.56 In a review of cases from the BNLI, many of the cases that were originally diagnosed as LD HD were reclassified as NHL and the incidence of true LD HD was below 2 per cent in this series. Patients with LD HD tended to be elderly and often presented with advanced symptomatic disease. Bone marrow disease occurred in over 60 per cent of cases.50 There was a low attainment of complete remission with combination chemotherapy and survival was poor.

Morphological features Lymphocyte-depleted Hodgkin's disease has a high frequency of extranodal involvement. In particular, the bone marrow is affected in many cases and may be the site of initial diagnostic biopsy (Plate 14). When lymph nodes are affected, the architecture is completely effaced. The diffuse fibrosis variant is characterized by a hypocellular lymph node often showing areas of geographic necrosis (Plate 15). In the background there is a pink fibrillary appearances of non birefringement fibrosis. Lymphocytes are relatively scanty and bizarre mononuclear and multinuclear Hodgkin's cells are seen. Classical Reed-Sternberg cells are often difficult to find. The reticular subtype of LD HD is characterized by a numerical predominance of H-RS cells. It has been our experience that the majority of cases initially diagnosed as reticular HD represents examples of non-Hodgkin's lymphomas.

MIXED CELLULARITY HODGKIN'S DISEASE In the Lukes and Butler classification, mixed cellularity Hodgkin's disease was used to classify cases of Hodgkin's disease that did not conform to the pathological criteria of LP, NS and LD HD. It thus contained a spectrum of cytological appearances ranging from lymphocyte-rich forms, which contained classical RS cells, to subtypes which showed foci of lymphocyte-depleted cytology not involving the whole lymph node. Many cases of mixed cellularity Hodgkin's disease have similarities to nodular sclerosis, such as focal nodularity and the presence of lacunar cells, but lack sufficient criteria to be diagnosed as NS. Other cases showed distinctive morphological patterns, which often involved alterations in the structure of the germinal center and the marginal zone B cell region.

Morphological features Classical mixed cellularity Hodgkin's disease is characterized by a diffuse architecture, which effaces the nodal


architecture completely. Typically the cytological background contains lymphocytes, macrophages, plasma cells and eosinophils, as well as mononuclear and classical Reed-Sternberg cells that are easy to find (Plate 16). There may be small foci of necrosis but this is much less common than in either NS or LD HD. Some cases may show the presence of lacunar cells or even areas of indistinct nodularity - features that suggest a close association with NS. In the absence of the three essential criteria for the diagnosis of NS (nodularity, intranodal collagen band formation and lacunar cells), these are best classified as mixed cellularity. Some workers prefer to classify these cases with NS features as HD unclassified between mixed cellularity and nodular sclerosis54 and some even put them into the cellular phase of NS. Several striking morphological patterns have been observed in mixed cellularity HD. One such case is inter follicular HD, highlighted by the Stanford Group, which is characterized by florid reactive follicular hyperplasia and an easily overlooked interfollicular infiltrate containing typical mononuclear Hodgkin's cells and RS cells126 (Plate 17). A variant of this form of HD is characterized by a marginal zone hyperplasia where the H-RS cells are seen to sit within a sea of marginal zone B cells. This has been termed HD occurring in monocytoid B cell clusters127 (Plate 18). In some cases of mixed cellularity HD the germinal centers are replaced by large expansile masses of mantle zone lymphocytes within which H-RS cells are readily found. The mantle cell nodules contain an expanded meshwork of follicular dendritic cells and, in many cases, the Hodgkin's cells express B cell antigens in addition to CD 15 and CD 30. Some workers have termed this follicular Hodgkin's disease.128 The term lymphocyte-rich classical Hodgkin lymphoma has been applied to morphological variants of HD characterized by an abundance of small lymphocytes with relatively scanty classical H-RS cells and very few eosinophils and plasma cells. In the REAL classification, LRCHD is a provisional entity84 and it has been formally adopted in the forthcoming World Health Organisation (WHO) classification.119 This histological subtype may be nodular or diffuse. The nodular subtype corresponds closely to the entity of follicular HD described by Isaacson and co-workers128 (Plate 19). The diffuse subtype is characterized by a predominance of small T lymphocytes and shows no evidence of involvement of germinal centers. In some cases of HD there are marked regressive changes within germinal centers that come to resemble the dendritic cell-only germinal centers that are seen in the hyaline vascular variant of Castleman's disease (Plate 20). These are surrounded by H-RS cells, which seem to localize preferentially at the junction of the marginal and mantle zones. The reasons for these different patterns of germinal-center reaction in mixed cellularity HD are

unknown but one might postulate they are related to the pattern of cytokine expression by the H-RS cells. Rare cases with the morphological features of the plasma cell variant of Castleman's disease in association with HD have been described.129

CLINICAL SIGNIFICANCE OF MORPHOLOGICAL PATTERN IN HODGKIN'S DISEASE Many believe that histopathology has little part to play in the prognostic assessment of patients with HD, and that the role of the pathologist is limited to accurate establishment of the diagnosis of HD and documentation of involvement of extranodal sites.130-132 In a series of publications over the past 10 years, the BNLI has documented the value of accurate histopathological classification in HD and shown that there are differences in the clinical presentation, response to therapy, freedom from relapse and overall survival between the different histological subtypes of HD. In addition it has demonstrated that there is clinical value in the subdivision of NS into two prognostic grades.50,56,90-93,133 It can be seen from the cause-specific survival curves from over 4000 patients that there are distinct differences in the rate of death from Hodgkin's disease in the different histological subtypes (Fig. 2.1).

Figure 2.1 Cause-specific actuarial survival curve for 4578 patients with Hodgkin's disease subdivided according to histological type, 1970-97. (Data from the British National Lymphoma Investigation.)

REFERENCES 1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med Chir Trans 1832; 17: 68-114. 2. Wilkes Sir S. Cases of enlargement of the lymphatic glands and spleen, (or, Hodgkin's disease), with remarks. Guys Hosp Rep 1865; 11: 56-67.

References 15 3. Malpighi. De viscerum structura. Bonn: Omnia Opera, 1666.

26. Lukes RJ, Craver LF, Hall TC, Rappaport H, Rubin P.

4. Craigie D. Elements of general and pathological anatomy. Edinburgh: Adam Black, 1828.

1966; 26:1311. 27. Chelloul N, Burke J, Motteram R, LeCapon J, Rappaport

5. Fox H. Remarks on microscopic preparations made from some of the original tissue described by Thomas Hodgkin, 1832. Ann Med History 1926; 8: 37(M. 6. Symmers WStC. The lymphoreticular system. In: Symmers WStC, ed. Systemic pathology. Edinburgh: Churchill Livingstone, 1978: 784-5. 7. Lennert K. Borderlands of pathological entities. In: Magrath IT, ed. The non-Hodgkin's lymphomas, 2nd edn. London: Arnold, 1997:133-67.

Report of the nomenclature committee. Cancer Res

H. HL-A antigens and Hodgkin's disease. Report on the histological analysis. In: Dausset J, Colombani J, eds. Histocompotability testing, Copenhagen: Munksgaard, 1972:769-71. 28. Miller TP, Byrne GE, Jones SE. Mistaken clinical and pathologic diagnoses of Hodgkin's disease. A Southwest Oncology Group study. Cancer Treat Rep 1982; 66: 645-51. 29. Symmers WStC. Survey of the eventual diagnosis in 600

8. Virchow R. Die Krankhaften Geschwuelste, Vol 2. Berlin: Hircwald, 1864.

cases referred for a second histologic opinion after an

9. Murchison C. Case of lymphadenoma of the lymphatic

Pathol 1968; 21: 650-3.

initial biopsy diagnosis of Hodgkin's disease. J Clin

system, spleen, liver, lungs, heart, diaphragm, dura mater etc. Trans Path Soc London 1870; 21: 372-89. 10. Langhans T. Das maligne lymphosarkom (pseudoleukaemia). Virchow Arch 1872; 54: 509-37.

30. Drexler HG and Minowada J. Hodgkin's disease derived cell lines: a review. Hum cell 1992; 5: 42-53. 31. Drexler HG. Recent results on the biology of Hodgkin and Reed-Stern berg cells. I. Biopsy material. Leuk

11. Greenfield WS. Specimens illustrative of the pathology

lymphoma 1992; 8: 283-313. 32. Linch DC, Jones HM, Berliner N, et al. Hodgkin-cell

of lymphadenoma and leucocythaemia. Trans Path Soc London 1878; 29: 272-304. 12. Sternberg C. Uber eine eigenartige unter dem Bilde der Pseudoleukamie verlaufende Tuberculose des lymphatischen Apparates.Z. Heilk. 1898; 18: 21-90. 13. Reed DM. On the pathological changes in Hodgkin's disease, with especial reference to its relation in tuberculosis. Johns Hopkins Hosp Rep 1902; 10:133-96. 14. Walhauser A. Hodgkin's disease. Arch Pathol 1933; 16: 522-62, 672-712. 15. Jackson H Jr, Parker F Jr. Hodgkin's disease and allied disorders. Oxford: Oxford University Press, 1947.

leukaemia of B-cell origin. Lancet 1985; 1: 78-80. 33. Griesser H, Feller AC, Mak TW, Lennert K. Clonal rearrangements of T-cell receptor and immunoglobulin genes and immunophenotypic antigen expression in different subclasses of Hodgkin's disease. IntJ Cancer 1987; 40:157-60. 34. Kuppers R, Hansmann ML, Diehl V, Rajewsky K. Molecular single-cell analysis of Hodgkin and Reed-Stern berg cells. Mol Med Today 1995; 1: 26-30. 35. Roth J, Daus H, Trumper L, et al. Detection of immunoglobulin heavy-chain gene rearrangement at

16. EwingJ. Neoplastic diseases. Philadelphia, London: WB Saunders, 1919.

the single-cell level in malignant lymphomas: no

17. Rosenthal SR. Significance of tissue lymphocytes in the

cells. IntJ Cancer 1994; 57: 799-804.

rearrangement is found in Hodgkin and Reed-Sternberg

prognosis of lymphogranulomatosis. Arch Pathol 1936; 21:628-46. 18. Jackson H Jr, Parker F Jr. Hodgkin's disease. I. General considerations. N EnglJ Med 1944; 230:1-8.

36. Ohshima K, Suzumiya J, Mukai Y, et al. Classical Hodgkin and Reed-Sternberg cells demonstrate a nonclonal immature B lymphoid lineage: evidence from a single cell assay and in situ hybridization. Hematol

19. Jackson H Jr, Parker F Jr. Hodgkin's disease. II.

Oncol 1996 14:123-36. 37. Trumper LH, Brady G, Bagg A, et al. Single-cell analysis

Pathology. N EnglJ Med 1944; 231: 35-44. 20. Jackson H Jr, Parker F Jr. Hodgkin's disease. III. Symptoms and course. N EnglJ Med 1994; 231: 636-46. 21. Smetana HF, Cohen BM. Mortality in relation to histologic type in Hodgkin's disease. Blood 1956; 11: 211^4. 22. Jelliffe AM, Thompson AD. The prognosis in Hodgkin's disease. BrJ Cancer 1955; 9: 21-36. 23. Lukes RJ. Relationship of histological features to clinical stages in Hodgkin's disease. AmJRoengenol 1963; 90: 944-55. 24. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin's disease. Cancer Res 1966; 26:1063-81. 25. Lukes RJ, Butler JJ, Hicks EB. Natural history of Hodgkin's disease as related to its pathologic picture. Cancer 1966; 34: 317-44.

of Hodgkin and Reed-Sternberg cells: molecular heterogeneity of gene expression and p53 mutations. Blood 1993; 81: 3097-115. 38. Hansmann ML, Kuppers R. Pathology and 'molecular histology' of Hodgkin's disease and the border to nonHodgkin's lymphomas. Baillieres Clin Haematol 1996; 9: 459-77. 39. Kuppers R, Rajewsky K. The origin of Hodgkin and Reed/Stern berg cells in Hodgkin's disease. Annu Rev /tfW7HA70/1998;16:471-93. 40. Vockerodt M, Soares M, Kanzler H, etal. Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin's disease. Blood 1998;92:2899-907.

16 Hodgkin's disease 41. Hummel M, Marafioti T, Ziemann K, Stein H. Ig rearrangements in isolated Reed-Stern berg eel Is: conclusions from four different studies. Ann Oncol 1996;7(suppl4):31-3. 42. Kanzler H, Kuppers R, Hansmann ML, Rajewski K. Hodgkin and Reed-Sternberg cells represent the outgrowth of a dominant tumour clone derived from (crippled) germinal centre B cells. J Exp Med 1996; 184: 1495-505. 43. Ohno T, Stribley JA, Wu G, Hinrichs SH, Weisenburger DD, Chan WC. Clonality in nodular lymphocyte predominant Hodgkin's disease. N EnglJ Med 1997; 337: 459-65. 44. Marafiota T, Hummel M, Anagnostopoulos I, el al. Origin of lymphocyte predominant nodular Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N EnglJ Med 1997; 337: 453-8. 45. Harrison CV. Benign Hodgkin's disease (Hodgkin's paragranuloma).) Path Bact 1952; 64: 513-18. 46. Lumb G, Newton KA. Prognosis in tumours of lymphoid tissue. Cancer 1957; 10: 976-93. 47. Lennert K, Mohri N. Histologische Klassifizierung und Vorkommen des M. Hodgkin. Internist 1974; 15: 57-65. 48. von Wasielewski R, Werner M, Fischer R, et al. Lymphocyte-predominant Hodgkin's disease: an immunohistochemical analysis of 208 reviewed Hodgkin's disease cases from the German Hodgkin Study Group. Am} Pathol 1997; 150: 793-803. 49. Henry-Amar M, MarnayJ. Personal communication, 1997. 50. MacLennan KA, Bennett MH, Bosq J, et al. The histology and immunohistology of Hodgkin's disease: the relationship to prognosis and clinical behavior. In: Sommers R, Henry-Amar M, Carde P, eds Treatment strategy in Hodgkin's disease. London, Paris: John Libbey, 1990:17-25. 51. Poppema S, Kaiserling E, Lennert K. Nodular paragranuloma and progressively transformed germinal centres: ultrastructural and immunohistologic findings. Virchows Arch B Cell Path 1979; 31: 211-25. 52. Lennert K, Muller-Hermelink HK. Lymphocyten und ihre Funkionsformen - Morphologic, Organisation und immunologische Bedeutung (lecture). Verhandl Anat Gesellschaft 1975; 69:19-62. 53. Muller-Hermelink HK, Lennert K. The cytologic, histologic and functional basis for a modern classification of lymphomas. In: Lennert K, in collaboration with Stein H, Mohri N, Kaiserling E, Muller-Hermelink HK, eds Malignant lymphomas other than Hodgkin's disease. New York: Springer, 1978: 38^1. 54. Neiman RS. Current problems in the histopathologic diagnosis and classification of Hodgkin's disease. Pathol Annu 1978; 13: 289-328. 55. Ramsey AD, Smith WJ, Isaacson PG. T-cell rich-B-cell lymphoma. AmJSurg Pathol 1988; 12: 433-43.

56. Bennett MH, MacLennan KA, Vaughan Hudson B, Vaughan Hudson G. The clinical and prognostic relevance of histopathological classification in Hodgkin's disease. ProgSurg Pathol 1989; 10:127-51. 57. Tiemens W, Visser L, Poppema S. Nodular lymphocyte predominance type of Hodgkin's disease is a germinal centre lymphoma. Lab Invest 1986; 54: 457-61. 58. Hansmann ML, Wacker HH, Radzun HJ. Paragranuloma is a variant of Hodgkin's disease with a predominance of B-cells. VirchowArch (Pathol Anat) 1986; 409: 171-81. 59. Coles FB, Cartun RW, Pastuszak WT. Hodgkin's disease, lymphocyte predominant type: immunoreactivity with B-cell antibodies. Mod Pathol 1988; 1: 274-8. 60. Pinkus GS. Said JW. Hodgkin's disease, lymphocytes predominance type, nodular - further evidence for a Bcell derivation. Am J Pathol 1988; 133: 211-17. 61. Poppema S. Lymphocyte-predominance Hodgkin's disease. Int Rev Exp Pathol 1991; 33: 53-79. 62. Kuzu I, Delsol G, Jones M, Gatter KC, Mason DY. Expression of the Ig-associated heterodimer (mb-1 and B 29) in Hodgkin's disease. Histopathology 1993; 22: 141-4. 63. Mason DY, Banks PM, Chan JKC, et al. Nodular lymphocyte predominance Hodgkin's disease: a distinct clinicopathological entity. AmJSurg Pathol 1994; 18: 526-30. 64. Stein H, Hansmann M-L, Lennert K, Brandtzaeg P, Gatter KC, Mason DY. Reed-Sternberg and Hodgkin's cells in lymphocyte predominance Hodgkin's disease of nodular subtype contain J cha\n.AmJ Clin Pathol 1986; 86: 292-7. 65. Schmidt C, Sargent C, Isaacson PG. L and H cells of nodular lymphocyte predominant Hodgkin's disease showimmunoglobulin light chain restriction. Am J Pathol 1991; 139:1281-9. 66. Hell K, PringleJH, Hansmann M-L, et al. Demonstration of light chain mRNA in Hodgkin's disease .J Pathol 1993; 17:137-43. 67. Stoler MH, Nichols GE, Symbula M, Weiss LM. Lymphocyte predominance Hodgkin's disease: Evidence for k light chain restricted monotypic B cell neoplasm. Am J Pathol 1995; 146: 812-18. 68. Nicholas DS, Harris S, Wright DH. Lymphocyte predominance Hodgkin's disease: an immunohistochemical study. Histopathology 1990; 16: 157-65. 69. Hsu SM, Ho YS, Li PJ, et al.t&H variants of Reed-Sternberg cells express sialyated Leu M1 antigen. AmJ Pathol 1986; 122:199-203. 70. Jack AS, Cunningham D, Soukop M, Liddle CN, Lee FD. Use of Leu M1 and antiepithelial membrane antigen monoclonal antibodies for diagnosing Hodgkin's diseasej Clin Pathol 1986; 39: 267-70. 71. Bosq J, Audouin J, Henry-Amar M, et al. Relationship between EBV infection, clinical, biological and histologic characteristics and response to therapy in

References 17

patients with Hodgkin's disease. In: Proceedings of the Third International Symposium on Hodgkin's Lymphoma. 1995: Abstracts. 72. Bennett MH, MacLennan KA, Vaughan Hudson B, Vaughan Hudson G. Non Hodgkins lymphoma arising in patients treated for Hodgkin's disease in BNLI: a 20 year experience. Ann Oncol 1991; 2 (suppl 2): 83-92. 73. Miettinen M, Franssila KO, Saxen E. Hodgkin's disease, lymphocytic predominance nodular increased risk for subsequent non-Hodgkin's lymphoma. Cancer 1983; 51: 2293-300. 74. Sundeen JT, Cossman J, Jaffe ES. Lymphocyte predominant Hodgkin's disease with coexistent 'large cell lymphoma': histological progression or composite malignancy? Am JSurgPathol 1988; 12: 599-606. 75. Hansmann ML, Stein H, Fellbaum C. etal. Nodular paragranuloma can transform into high-grade malignant lymphoma of B type. Hum Pathol 1989; 20: 1169-75. 76. Whittaker M, Foucar K, Keith T, McAneny B. Letter. Am J Surg Pathol 1989; 13: 715-16. 77. Grossman DM, Hanson CA, Schnitzer B. Simultaneous lymphocyte predominant Hodgkin's disease and large cell lymphoma. Am J Surg Pathol 1991; 15: 668-76. 78. Pan LX, Diss TC, Peng HJ, Norton AJ, Isaacson PG.

lymphocyte predominant Hodgkin's disease. Ann Diagn Pathol 1999; 3: 23-34. 86. Lukes RJ. Criteria for involvement of lymph node, bone marrow, spleen and liver in Hodgkin's disease. Cancer Res 1971; 31:1755-67. 87. Strum SB, Rappaport H. Interrelations of the histological types of Hodgkin's disease. Arch Pathol 1971; 91:127-34. 88. Strum SB, Rappaport H. Consistency of histological subtypes in Hodgkin's disease in simultaneous and sequential biopsy specimens. Natl Cancer Inst Monogr 1973;36:253-60. 89. Dorfman RF. The enigma of Hodgkin's disease: current concepts based on morphologic, clinical and immunologic observations. In: Hanaoka M, Kadin ME, Mikata A, Watanabe S, eds Lymphoid malignancies, immunocytology and cytogenetics. New York: Field and Wood, 1990:167-76. 90. MacLennan KA, Bennett MH, Vaughan Hudson B, Vaughan Hudson G. Diagnosis and grading of nodular sclerosing Hodgkin's disease: a study of 2190 patients. Int Rev Exp Pathol 1992; 33: 27-51. 91. MacLennan KA, Bennett MH, Tu A, etal. Prognostic significance of cytologic subdivision in nodular sclerosing Hodgkin's disease: an analysis of 1156

Nodular lymphocyte predominance Hodgkin's disease:

patients. In: Vavallia F, Bonadonna G, Rozencweig M,

a monoclonal or polyclonal B-cell disorder? Blood 1996; 87: 2428-34.

eds Malignant lymphomas and Hodgkin's disease:

79. Greiner TC, Gascoyne RD, Anderson ME, et al. Nodular lymphocyte-predominant Hodgkin's disease associated with large cell lymphoma: analysis of Iggene rearrangements by V-J polymerase chain reaction. Blood 1996; 88: 657-66. 80. Wickert RS, Weisenburger DD, Tierens A, Greiner TC, Chan WC. Clonal relationship between lymphocytic predominance Hodgkin's disease and concurrent or subsequent large cell lymphoma of B lineage. Blood 1995:86:2312-20. 81. Tefferi A, Wiltsie JC, Kurtin PJ. Secondary T cell

experimental and therapeutic advances. Dordrecht: Martinus Nijhoff Publishing, 1985:187-200. 92. Bennett MH, MacLennan KA, Easterling MJ, Vaughan Hudson B, Vaughan Hudson G, Jelliffe AM. Analysis of histological subtypes of Hodgkin's disease in relation to prognosis and survival. In: Quaglino D, Hayhoe FGJ, eds. The cytobiology of leukaemia and lymphomas, Serono Publications, Vol. 20, New York: Raven Press, 1985: 15-32. 93. MacLennan KA, Bennett MH, Tu A, Vaughan Hudson B, Vaughan Hudson G. The relationship of histopathology to survival and relapse. A study of 1659 patients. Cancer

82. Rysenga E, Linden MD, Carey JL, Ross CW, Schnitzer B,

1989;64: 1686-93. 94. Strickler JG, Michie SA, Warnke RA, Dorfman RF. The 'syncytial variant' of nodular sclerosing Hodgkin's disease. Am J Surg Pathol 1986; 10: 470-7.

Sawdyk M, Maeda K. Peripheral T-cell non-Hodgkin's

95. Ben-Yehuda-Salz D, Ben-Yehuda A, Polliack A, etal.

lymphoma in the setting of nodular lymphocyte predominance Hodgkin's disease. AmJHaematol 1992; 40: 232-3.

lymphoma following treatment of nodular lymphocyte

Syncytial variant of nodular sclerosing Hodgkin's

predominance Hodgkin's disease. Arch Pathol Lab Med 1995;119:88-91.

disease. A new clinicopathologic entity. Cancer 1990,

83. Delabie J, Greiner TC, Chan WC, Weisenburger DD. Concurrent lymphocyte predominance Hodgkin's disease and T-cell lymphoma. Am J Surg Pathol 1996; 20: 355-62. 84. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92.

65: 1167-72. 96. Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease: a clinicopathologic study of 659 cases. Cancer 1981; 49: 1848-58. 97. Gartner HV, Wherman M, Inniger R, Steinke B. Nodular sclerosing Hodgkin's disease: prognostic relevance of morphological parameters. In: First International Symposium on Hodgkin's Lymphoma, Cologne, 27A, 1987. 98. Jairam R, Vrints LW, Breed WPM, Wijlhuizen TJ, Wijnen

85. Hancock JC, Wells A, Hailing KC, et al. Composite B-cell

TJM. Histological subclassification of the nodular sclerotic

and T-cell lymphoma arising 24 years after nodular

subtype of Hodgkin's disease. NethJ Med 1988; 33:160-7.

18 Hodgkin's disease 99. Wijlhuizen TJ, Vrints LW, Jairam R, et al. Grades of nodular sclerosis (NSI-NSII) in Hodgkin's disease: are they independent prognostic values? Cancer 1989; 63: 1150-3. 100. Ferry JA, Linggood RM, Convery KM, Efird JT, Eliseo R, Harris ML Hodgkin's disease, nodular sclerosis type implications of histologic subdassification. Cancer 1993; 71:457-63. 101. Georgii A, Hasenclever D, Fischer R, etal. Histopathological grading of nodular sclerosing Hodgkin's reveals significant differences in survival and relapse rates under protocol-therapy. Proceedings of the Third International Symposium on Hodgkin's Lymphoma, Kbln, 1995, Abstract 83. 102. Masih AS, Weisenburger DD, Vose JM, Bast MA, Armitage JO. Histologic grade does not predict prognosis in optimally treated advanced stage nodular sclerosing Hodgkin's disease. Cancer 1992; 69: 228-32. 103. Hess JL, Bodis S, Pinkus G, Silver B, Mauch P. Histopathologic grading of nodular sclerosis Hodgkin's disease: lack of prognostic significance in 254 surgically staged patients. Cancer 1994; 74: 708-1714. 104. Borowitz MJ, Croker BP, Metzger RS. Immunohistochemical analysis of the distribution of lymphocyte subpopulations in Hodgkin's disease. Cancer Treat Rep 1982; 66: 667-74. 105. Abdulaziz S, Mason DY, Stein H, Gatter KC, Nash JRG. An immunohistological study of the cellular constituents of Hodgkin's disease using a monoclonal antibody panel. Histopathology 1984; 8:1-25. 106. Pinkus GS, Thomas P, Said JW. Leu M1 - a marker for Reed-Stern berg cells in Hodgkin's disease. AmJPathol 1985;119:244-52. 107. Hall PA, D'Ardenne AJ. Value of CD15 immunostaining in diagnosing Hodgkin's disease: a review of published literature.7 Clin Pathol 1987; 40:1298-304. 108. Hall PA, D'Ardenne AJ, Stansfield AJ. Paraffin section immunohistochemistry. II. Hodgkin's disease and large cell ana plastic (Ki1) lymphoma. Histopathology 1988; 13:161-9. 109. Chittal SM, Caveriviere R, Schwarting R, et al. Monoclonal antibodies in the diagnosis of Hodgkin's disease: the search for a rational panel. AmJSurg Pathol 1988; 12: 9-21. 110. Werner M, Georgii A, BernhardsJ, Hubner K, Schwarze E-W, Fischer R. Characterization of giant cells in Hodgkin's lymphomas by immunohistochemistry applied to randomly collected diagnostic biopsies from the German Hodgkin trial. Haematol Oncol 1990; 8: 241-50. 111. Cibull ML, Stein H, Gatter KC, Mason DY. The expression of the CD3 antigen in Hodgkin's disease. Histopathology 1989;15:597-605. 112. Casey TT, Olson SJ, Cousar JB, Collins RD. Immunophenotypes of Reed-Stern berg cells: a study of 19 cases of Hodgkin's disease in plastic-embedded sections. Blood 1989; 74: 2624-8.

113. Korkolopoulou P, Cordell J, Jones M,et al. The expression of the B-cell marker mb-1 (CD 79a) in Hodgkin's disease. Histopathology 1994; 24: 511-15. 114. Isaacson PG, Ashton-Key M. Phenotype of Hodgkin and Reed-Stern berg cells. Lancet 1996; 347: 481. 115. Carbone A, Gloghini A, Gaidano G, et al. Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease. Blood 1998; 92: 2220-8. 116. Carbone A, Gloghini A, Gattei V, et al. Reed-Sternberg cells of classical Hodgkin's disease react with the plasma cell-specific monoclonal antibody B-B4 and express human syndecan-1. Blood 1997; 89: 3787-94. 117. Carbone A, Gloghini A, Larocca LM,etal. Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. Blood 1999; 93: 2319-26. 118. Agnarrson BA, Kadin ME. Ki1 positive large cell lymphoma: a morphological study of 19 cases. AmJ Surg Pathol 1988; 12: 264-74. 119. Stein H. Hodgkin's disease. AmJ Surg Pathol 1997; 21: 119-20. 120. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in nonHodgkin's lymphoma. Science 1994; 262:1281-4. 121. Shiota M, Nakamura S, Ichinohasama R, et al. Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinctive clinicopathologic entity. Blood 1995; 86:1954-60. 122. Pulford K, Lamant L, Morris SW, et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosphormin (NPM) - ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 1997; 89:1394-404. 123. Trumper L, Daus H, Merz H, etal. NPM/ALK fusion mRNA expression in Hodgkin and Reed-Stern berg eel Is is rare but does occur: results from single-cell cDNA analysis. Ann Oncol 1997; 8 (suppl 2): 83-7. 124. Trumper L, Pfreundschuh M, Bonin FV, Daus H. Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. BrJ Haematol 1998; 103:1138^4. 125. Kant JA, Hubbard SM, Longo DL, Simon RM, DeVita VT, Jaffe ES. A critical appraisal of the pathologic and clinical heterogeneity of lymphocyte depleted Hodgkin's disease, y Clin Oncol 1986; 4: 284-94. 126. Doggett RS, Colby TV, Dorfman RF. Interfollicular Hodgkin's disease. AmJSurg Pathol 1983; 7:145-9. 127. Mohrmann RL, Nathwani BN, Brynes RK, Sheibani K. Hodgkin's disease occurring in monocytoid B-cell clusters. AmJ Clin Pathol 1991; 95: 802-8. 128. Ashton-Key M, Thorpe PA, Allen JP, Isaacson PG. Follicular Hodgkin's disease. Am J Surg Pathol 1995; 19: 1294-9. 129. Maheswaran PR, Ramsay AD, Norton AJ, Roche WR. Hodgkin's disease presenting with the histological

References 19

features of Castleman's disease. Histopathology 1991; 18: 249-53. 130. Torti FM, Dorfman RF, Rosenberg SA, Kaplan HS. The changing significance of histology in Hodgkin's disease. ProcAm Assoc Cancer Res 1979; 20: 401 (C-454). 131. Dorfman RF, Colby TV. The pathologists role in the management of patients with Hodgkin's disease. Cancer Treat Rep 1982; 66: 675-80.

132. Culline S, Henry-Amar H, Diebold J, et al. Relationship of histological subtypes to prognosis in early stage Hodgkin's disease: a review of 312 cases enrolled in a controlled clinical trial. EurJ Cancer 1989; 25: 551-6. 133. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, Bennet, MM, Jelliffe AM. A retrospective evaluation of radiotherapy as a curative agent in localised Hodgkin's disease. BrJ Cancer 1987; 56: 872.


3 Follicular lymphoma KAMACLENNAN

Introduction

21

Transformation

Morphology

21

Extranodal disease

Immunophenotype

22

References

INTRODUCTION The first description of the entity now termed follicular lymphoma was provided by Ghon and Roman in 1916,' but it was the publications of Brill et al.2 and Symmers3'4 that brought the entity of follicular lymphoma (FL) to the attention of clinicians and pathologists. Although initially there was confusion as to whether FL was a neoplastic condition, it gradually became clear that it was a distinctive form of low-grade non-Hodgkin's lymphoma. The favorable prognostic significance of a follicular pattern and a superior response rate to radiotherapy of FL were recognized.5 Studies undertaken by Rappaport and co-workers6 delineated histologic criteria for the recognition of FL; however, they felt that an origin from the germinal center was unproven and applied the term nodular lymphoma. Detailed morphologic and ultrastructural studies by Lennert and co-workers7-9 and Lukes and Collins10 clearly identified FL as a germinal center neoplasm. FL is characterized by the neoplastic proliferation of germinal center B cells (both centroblasts and centrocytes) arranged in rounded aggregates which recapitulate the non-neoplastic germinal center. Within the neoplastic follicle are reactive cellular elements, which inhabit the normal germinal center. These are follicular dendritic cells, macrophages and T cells. A description of the cytogenetic and molecular biologic events that occur in follicular lymphoma is provided in Chapters 9 and 12.

MORPHOLOGY Lymph nodes affected by FL are enlarged and usually

22 23 23

show complete effacement of their normal architecture by neoplastic follicles. These are relatively uniform in size when compared to reactive germinal centers and are closely packed with compression of the surrounding lymphoid architecture (Plate 21); this process involves the entire lymph node in the majority of cases.11 The neoplastic follicles show a uniformity in their cellular composition and lack the distinct 'zoning' seen in reactive germinal centers (Plate 22). The mantle zones of the follicles in FL are usually ill-defined and difficult to appreciate,12 a factor associated with an increased mortality rate by some workers.13 Follicular lymphoma may be completely follicular in architecture or may have diffuse areas, which may range from small foci to large expanses; the latter is often seen in association with centroblastic cytology. The prognostic significance of diffuse areas in FL remains unclear and some workers believe they are associated with a decreased median survival.14'15 This area was addressed as part of a larger investigation of lymphoma classification.16 It was found that, if there was unequivocal follicularity within a follicle center lymphoma, the extent of the diffuse area was unimportant prognostically.16 Follicular lymphomas may be associated with intranodal sclerosis either as collagen bands or as fine compartmentalizing fibrosis.17-19 Sclerosis associated with FL often occurs in retroperitoneal and inguinal lymph nodes, and is associated with a more favorable prognosis.17-19 In some cases of FL the neoplastic B cells may develop cytoplasmic vacuolation and resemble the signet ring cells of poorly differentiated adenocarcinoma. This change may affect a minor population of cells or be extensive (Plate 23). The cytoplasmic vacuoles in the signet ring variant of FL may be either clear or associated with pink globules; the former has been associated with

22 Follicular lymphoma

immunoglobulin G (IgG) production and the latter with IgM.20~23 Occasionally large quantities of extracellular eosinophilic material may be found within the follicles.24'25 Other rare variants of FL include cases showing marginal zone differentiation,26-30 rosette formation,31 a 'floral pattern' to the neoplastic follicles,32 epithelioid granuloma formation33'34 and pronounced plasma cell differentiation.35 With the exception of marginal zone differentiation, which is associated with a decreased survival,36 these variants do not affect prognosis. The neoplastic follicles of FL contain a variable composition of centroblasts and centrocytes, which may range from a predominance of centrocytes to rare cases in which the follicles contain sheets of centroblasts. This cytological variability has formed the basis for a series of grading systems for FL. These grading systems employ either a subjective assessment of the percentage of large cells present within the follicles37-40 or by counting the number of large non-cleaved cells per high-power field41 or both.42 Some have used a proliferative index as assessed by automated image analysis of Ki 67 staining in FL to predict prognosis; a high proliferative index also showed a close correlation with grading.43 Although differences in survival can be demonstrated between different grades of FL (Fig. 3.1), they are small and all the methods so far employed suffer from very poor interobserver concordance rates.44,45 Objective evidence of'cure' as evidenced by a plateau in the actuarial survival curve, is not seen for the majority of patients.

IMMUNOPHENOTYPE Phenotypically FL is seen to be composed of rounded aggregates of B cells with similarities to normal germinal center B cells. There is expression of pan-B cell antigens CD 19, 20 and 22, surface immunoglobulin and

Figure 3.1 Actuarial survival of patients subdivided using the Berard criteria into follicular lymphoma small, mixed and large cell types.

expression of CD 10. Antibodies to CD 10 are now available that work in routinely fixed and processed tissue46 (Plate 24). CD 5 and CD 43 are usually negative and there is no nuclear cyclin Dl expression. These are important discriminating features from mantle cell lymphomas.47-52 The neoplastic B cells in FL differ from normal germinal center B cells in the presence of BCL 2 protein within their cytoplasm in up to 85 per cent of cases53"55 (Plate 25). Cases of follicular lymphoma with predominantly large cell cytology express BCL 2 protein less frequently.55 The expression of BCL 2 protein is of practical value in the discrimination of FL from florid follicular hyperplasia as it is not expressed in the B cells of the latter condition. Cell adhesion molecules, such as VLA 4-VCAM and LFA1-ICAM, mediate the interactions between the neoplastic B cells and the follicular dendritic cells (FDCs), and appear to be significant in the retention of a follicular architecture.56-65 Follicular dendritic cells within reactive germinal centers show a degree of heterogeneity in their antigenic profile, in particular expression of CD 21 is restricted to FDCs in the apical light zone.66 As CD 21 is expressed in many examples of FL (Plate 26) this suggests there may be similarities between FL and the light zone of the germinal center. Numerous reactive T cells are also seen scattered within the follicles, which express pan-T cell antigens CD 3 and CD 2. Many are of the helper-subtype expressing CD 4 and show expression of CD 40 ligand.67 Some also express the germinal center T cell-associated marker CD 57.

TRANSFORMATION Transformation of FL into a diffuse, high-grade nonHodgkin's lymphoma is relatively common and is associated with a poor prognosis.68 The frequency of histologic transformation is variable and ranges from around 30 per cent69'70 to an actuarial prediction that 60 per cent of patients will transform.71 Transformation tends to occur early in the course of the disease, and is associated with adverse prognostic factors or failure to achieve complete remission; the rate of transformation shows a tendency to plateau at 6 years.69 Most transformed FLs show histologic features of diffuse large B cell lymphoma with centroblastic cytology.72 The genetic factors involved in transformation are at present unknown, somatic mutations in the translocated bcl 2 gene,73"75 cytogenetic abnormalities at 6q23-26 and 17p,76 and, mutations in p5377'78 or overexpression of p53 protein79 have been identified as possible factors. Rare case of FL may transform into high-grade nonHodgkin's lymphoma with variant histology, sometimes with 'Burkitt-like' features and an aggressive leukaemic course; these are often associated with t(8;14) with deregulation of c-myc, in addition to t(14;18).80-86 Rare

References 23

cases of transformation of FL to CD 30-large cell lymphoma with anaplastic features have been described.87

EXTRANODAL DISEASE

5. Gall EA and Mallory TB. Malignant lymphoma. A clinicopathologic survey of 618 cases. AmJ Pathol 1941; 18: 381-429. 6. Rappaport H, Winter WJ, Hicks. Follicular lymphoma: a re-evaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer

Follicular lymphoma is typically disseminated at presentation with the involvement of a wide range of organs whose function may or may not be compromised. One of the commonest sites of extranodal disease is the bone marrow, which shows histological evidence of disease in approximately three-quarters of cases.88 The earliest morphological features of bone-marrow infiltration by FL are paratrabecular aggregates of small B cells (Plate 27),89'91 which are admixed with follicular dendritic cells and T cells.54,92-94 More extensive marrow disease shows the presence of neoplastic follicles within the hemopoietic marrow.95 When extensive marrow involvement is present, the normal marrow elements are displaced by sheets of coalescing follicles and normal hemopoietic function may be compromised. Cytologically, small irregular B cells predominate. In the presence of heavy bone-marrow infiltration, FLs may develop a leukemic phase in which cytologically atypical lymphoid cells are found in the peripheral blood; the leukemic cell count may be very high96,97 (Plate 28). The spleen is commonly involved by FL. The lymphoma cells preferentially home in to the white pulp regions98"101 and form expansile white nodules measuring several millimetres in diameter, imparting a miliary appearance to the cut surface (Plate 29). Large tumor masses are not usually seen in the absence of high-grade transformation. Many other organs may be infiltrated by FL, including the liver,95 soft tissues102 and skin.103 In extranodal locations the follicular pattern may be difficult to discern and may require the immunohistochemical demonstration of a follicular dendritic cell meshwork.

1956; 9: 792-821. 7. Lennert K. Germinal centers and germinal center neoplasms. Nippon Ketsueki Gakkai Zasshi 1969; 32: 495-500. 8. Lennert K. Giant follicular lymphoma. Dtsch Med Wochenschr 1973; 98: 335-6. 9. Lennert K, Stein H, Kaiserling E. Cytological and functional criteria for the classification of malignant lymphomata. BrJ Cancer 1975; 31 (suppl 2): 29-43. 10. Lukes RJ, Collins RD. New approaches to the classification of the lymphomata. BrJ Cancer 1975; 31 (suppl 2): 1-28. 11. Nathwani BN, Winberg CD, Diamond LW, Bearman RM, Kim H. Morphologic criteria for the differentiation of follicular lymphoma from florid reactive follicular hyperplasia: a study of 80 cases. Cancer 1981; 48: 1794-806. 12. Crocker J, Jones EL, Curran RC. A quantitative study of the size of benign and malignant lymphoid follicles. 7 Clin Pathol 1983; 36:1055-61. 13. West KP, Potter LJ, Henderson SD, Lauder I. A retrospective study of follicular lymphomas. Histopathology 1989; 14: 629-36. 14. Ostrow SS, Diggs CH, Sutherland JC, Gustafson J, Wiernik PH. Nodular poorly differentiated lymphocytic lymphoma: changes in histology and survival. Cancer Treat Rep 1981; 65: 929-33. 15. Vose JM, Bierman PJ, Lynch JC, et al. Effect of follicularity on autologous transplantation for large-cell non-Hodgkin's lymphoma. J Clin Oncol 1998; 16: 844-9. 16. Anonymous. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89: 3909-18.

REFERENCES 1. Ghon A, Roman B. Ueber das Lymphosarkom. Frankfurt ZPathol 1916; 19:1-138. 2. Brill NE, Baehr G, Rosenthal N. Generalised giant lymph follicle hyperpalasia of the lymph follicles and spleen: a hitherto undescribed type. JAMA 1925; 84: 668-71. 3. Symmers D. Follicular lymphadenopathy with

17. Bennett MH. Sclerosis in non-Hodgkin's lymphomata. Br J Cancer 1975; 31 (suppl 2): 44-52. 18. Bennett MH, Millett YL Nodular sclerotic lymphosarcoma: a possible new clinico-pathological entity. Clin Radiol 1969; 20: 339^3. 19. Millett YL, Bennett MH, Jelliffe AM, Farrer-Brown G. Nodular sclerotic lymphosarcoma. A further review. BrJ Cancer 1969; 23: 683-92. 20. Kim H, Dorfman RF, Rappaport H. Signet ring cell

splenomegaly: a newly recognised disease of the

lymphoma. A rare morphologic and functional

lymphatic system. Arch. Pathol 1927; 3: 816-20.

expression of nodular (follicular) lymphoma. Am J Surg

4. Symmers D. Giant follicular lymphadenopathy with or without splenomegaly: its transformation into polymorphous cell sarcoma of the lymph follicles and its association with Hodgkin's disease, lymphatic leukaemia, and an apparently unique disease of the lymph nodes and spleen - a disease entity believed heretofore undescribed. Arch Pathol 1938; 26: 603-47.

PatholWJS; 2:119-32. 21. Harris M, Eyden B, Read G. Signet ring cell lymphoma: a rare variant of follicular lymphoma. J Clin Pathol 1981; 34:884-91. 22. Silberman S, Fresco R, Steinecker PH. Signet ring cell lymphoma. A report of a case and review of the literature. AmJ Clin Pathol 1984; 81: 358-63.

24 Follicular lymphoma

23. Spagnolo DV, Papadimitriou JM, Matz LR, Walters MN. Nodular lymphomas with intracellular immunoglobulin inclusions: report of three cases and a review. Pathology 1982; 14: 415-27. 24. Talerman A, Platenburg HP. Follicular lymphoma with deposits of amorphous hyaline material, y Pathol 1974; 112:27-31. 25. Chittal SM, Caveriviere P, Voigt JJ, et al. Follicular

38. Lukes RJ, Collins RD. Immunologic characterization of human malignant lymphomas. Cancer 1974; 34 (suppl): 1488-503. 39. Henry K, Bennett MH, Farrer-Brown G. Classification of the non-Hodgkin's lymphomas. In: Anthony P and Woolf N, eds. Recent advances in histopathology 10. Edinburgh: Churchill Livingstone. 1978: 275-302. 40. Anonymous. National Cancer Institute sponsored study

lymphoma with abundant PAS-positive extracellular

of classifications of non-Hodgkin's lymphomas:

material. Immunohistochemical and ultrastructural observations. AmJSurg Pathol 1987; 11: 618-24.

summary and description of a working formulation for

26. Chan JK, Ng CS, Hui PK. An unusual morphological variant of follicular lymphoma. Report of two cases. Histopathology 1988; 12: 649-58. 27. Hernandez AM, Nathwani BN, Nguyen D, et al. Nodal benign and malignant monocytoid B cells with and without follicular lymphomas: a comparative study of follicular colonization, light chain restriction, bcl-2, and t(14;18) in 39 cases. Hum Pathol 1995; 26: 625-32. 28. Nathwani BN, Hernandez AM, Deol I, Taylor CR. Marginal zone B-cell lymphomas: an appraisal. Hum Pathol 1997; 28: 42-6. 29. Ree HJ, Leone LA. Prognostic significance of parafollicular small lymphocytes in follicular lymphoma: clinicopathological studies of 82 cases of primary nodal origin. Cancer 1978; 41:1500-10. 30. Schmid U, Cogliatti SB, DissTC, Isaacson PG. Monocytoid/marginal zone B-cell differentiation in follicle centre cell lymphoma. Histopathology 1996; 29: 201-8. 31. Frizzera G, Gajl-Peczalska K, Sibley RK, Rosai J, Cherwitz D, Hurd DD. Rosette formation in malignant lymphoma. Am J Pathol 1985; 119: 351-6. 32. GoatesJJ, Kamel OW, LeBrun DP, Benharroch D, Dorfman RF. Floral variant of follicular lymphoma. Immunological and molecular studies support a neoplastic process. AmJSurg Pathol 1994; 18: 37-47. 33. Kojima M, Nakamura S, Motoori T, et al. Centroblastic and centroblastic-centrocytic lymphomas associated with prominent epithelioid granulomatous response without plasma cell differentiation: a clinicopathologic study of 12 cases. Hum Pathol 1996; 27: 660-7. 34. Naresh KN. Morphological spectrum of follicle center cell lymphomas associated with infiltration of epithelioid histiocytes. Hum Pathol 1997; 28:114-15. 35. Frizzera G, Anaya JS, Banks PM. Neoplastic plasma cells in follicular lymphomas. Clinical and pathologic findings in six cases. Virchows Arch A Pathol Anat Histopathol 1986; 409:149-62. 36. Nathwani BN, Anderson JR, Armitage JO, et al. Clinical significance of follicular lymphoma with monocytoid B-cells. Non-Hodgkin's lymphoma classification project. Hum Pathol 1999; 30: 263-8. 37. Rappaport H. Tumors of the hematopoietic system.

clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 1982; 49: 2112-35. 41. Mann RB, Berard CW. Criteria for the cytologic subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol 1983; 1:187-92. 42. Jaffe ES, Raffeld M, Medeiros LJ. Histopathologic subtypes of indolent lymphomas: caricatures of the mature B-cell system. Semin Oncol 1993; 20: 3-30. 43. Martin AR, Weisenburger DD, Chan WC, et al. Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood 1995; 85: 3671-8. 44. Metter GE, Nathwani BN, Burke JS, et al. Morphological subclassification of follicular lymphoma: variability of diagnoses among hematopathologists, a collaborative study between the Repository Center and Pathology Panel for Lymphoma Clinical Studies.7 Clin Oncol 1985; 3: 25-38. 45. Nathwani BN, Metter GE, Miller TP, et al. What should be the morphologic criteria for the subdivision of follicular lymphomas? Blood 1986; 68: 837-45. 46. Mclntosh GG, Lodge AJ, Watson P, et al. NCL-CD10-270: a new monoclonal antibody recognizing CD10 in paraffin-embedded tissue. Am J Pathol 1999; 154: 77-82. 47. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol 1992; 16, 637^10. 48. Contos MJ, Kornstein MJ, Innes DJ, Ben-Ezra J. The utility of CD20 and CD43 in subclassification of low-grade Bcell lymphoma on paraffin sections. Mod Pathol 1992; 5: 631-3. 49. Isaacson PG. Malignant lymphomas with a follicular growth pattern. Histopathology 1996; 28: 487-95. 50. Swerdlow SH, Zukerberg LR, Yang Wl, Harris NL, Williams ME. The morphologic spectrum of nonHodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements. Am J Surg Pathol 1996; 20: 627-40. 51. Treasure J, Lane A, Jones DB, Wright DH. CD43 expression in B cell lymphoma. J Clin Pathol 1992; 45: 1018-22. 52. Vasef MA, Medeiros LJ, Koo C, McCourty A, Byrnes RK. Cyclin D1 immunohistochemical staining is useful in distinguishing mantle cell lymphoma from other low-

Washington, DC: Armed Forces Institute of Pathology,

grade B-cell neoplasms in bone marrow. AmJ Clin

1966.

Pathol 1997; 108: 302-7.

References 25 53. Ashton-Key M, DissTC, Isaacson PG, Smith ME. A comparative study of the value of immunohistochemistry and the polymerase chain reaction in the diagnosis of follicular lymphoma. Histopathology 1995; 27: 501-8. 54. Ben-Ezra JM, King BE, Harris AC, Todd WM, Kornstein MJ. Staining for Bcl-2 protein helps to distinguish benign from malignant lymphoid aggregates in bone marrow biopsies. Mod Pathol 1994; 7: 560-4. 55. Gaulard P, d'Agay MF, Peuchmaur M, etal. Expression of the bcl-2 gene product in follicular lymphoma. AmJ Pathol 1992; 140:1089-95. 56. Lampert IA, Van Noorden S. Acetyl cholinesterase is expressed in the follicular dendritic cells of germinal centres: differences between normal and neoplastic follicles.yPof/70/1996; 180:169-74. 57. Liu YJ, Grouard G, de Bouteiller 0, Banchereau J. Follicular dendritic cells and germinal centers. Int Rev Cytol 1996; 166:139-79. 58. Vyth-Dreese FA, Dellemijn TA, van Oostveen JW, Feltkamp CA, Hekman A. Functional expression of adhesion receptors and costimulatory molecules by fresh and immortalized B-cell non-Hodgkin's lymphoma cells. Blood 1995; 85: 2802-12. 59. Ishii G, Harigaya K, Soeta S, Mikata A. VLA-4-dependent adhesion in follicular non-Hodgkin's lymphomas. Hematol Pathol 1995; 9:155-69. 60. Kuriyama Y, Nakano M, Kawanishi Y, Iwase 0, Kuge S, Toyama K. Significance of VLA-4 and LFA-1 expressions in neoplastic follicle formation and its deterioration in B-cell non-Hodgkin's lymphomas. Leuk Lymph 1994; 13: 123-9. 61. Ree HJ, Khan AA, Elsakr M, Liau S, Teplitz C. Intercellular adhesion molecule-1 (ICAM-1) staining of reactive and neoplastic follicles. ICAM-1 expression of neoplastic follicle differs from that of reactive germinal center and is independent of follicular dendritic cells. Cancer 1993; 71: 2817-22. 62. Gloghini A, Carbone A. The nonlymphoid microenvironment of reactive follicles and lymphomas of follicular origin as defined by immunohistology on paraffin-embedded tissues. Hum Pathol 1993; 24: 67-76. 63. Petrasch S, Kosco M, Schmitz J, Wacker HH, Brittinger G. Follicular dendritic cells in non-Hodgkin lymphoma express adhesion molecules complementary to ligands on neoplastic B-cells. BrJ Haematol 1992; 82: 695-700. 64. Freedman AS, Munro JM, Morimoto C, et al. Follicular non-Hodgkin's lymphoma cell adhesion to normal germinal centers and neoplastic follicles involves very late antigen-4 and vascular cell adhesion molecule-1. S/oo 55 years, 2.7). However, no dose response was evident. Turning to occupational exposure to chemicals, the findings are also quite varied. Early reports of an association of HD with herbicide exposure (primarily chlorophenols) have not been supported in a large casecontrol study in Kansas (USA).46 There are general findings of increased risk with employment in the rubber, plastics or synthetics industry and paper mill workers, but no specific exposures are evident.18 It is of interest that HD is one of the handful of malignancies that is not related to radiation exposure.47,48 This observation underscores the notion that the pathogenesis of HD is unique among the malignancies.

SUMMARY Much of the epidemiological and molecular biological evidence points to dysfunctional immunological control of latent EBV infection. The epidemiological evidence points to age at infection as an important modifier of risk. However, the current evidence does not fit together easily. What is needed is epidemiological research that concurrently integrates the molecular, serological and risk factor data. The possibility that a second virus is involved warrants consideration. Smithers49 has postulated a mechanism by which chronic antigenic stimulation could act in the pathogenesis of HD. He commented that'... we are bound to look at the evidence for the effect of prolonged pressures on the cell-mediated arm of the immune system and for feed-back failure of restraint in influencing the development of this disease.' It may be that, in HD, an alteration in gene expression occurs as a consequence of continuing antigenic stimulation from a chronically expressed

166 Hodgkin's disease EBV infection. However, in this case, the gene involved is not one controlling proliferation, but rather one controlling the expression of the normal, functionally active mediators released by antigen-stimulated cells. The alteration of gene expression may be quantitative change, resulting in a greatly amplified message. Alternatively, it may be that the gene product that normally shuts down the messages by feedback inhibition is underexpressed or dysfunctional. The result would be an immune system that is continually 'turned on', that is, an immune system that is perpetually mobilized in response to a chronic antigen and thus unable to respond to others. This hypothesis can be used to explain the biological paradox of HD: the malignant properties reflect the underlying genetic changes, the histological features reflect the response of normal immune cells to the perpetual stimulation, and the immune defects reflect the resulting imbalance in the immune response system.50

REFERENCES 1. Miller BA, Ries LAG, Hankey BF et al., eds. SEER cancer statistics review: 1973-1990. Washington DC: National Cancer Institute, NIH Publ. no. 93-2789,1993. 2. Evans AR, Hancock BW, Brown MJ, Richmond J. A small cluster of Hodgkin's disease. Br Med J 1977; 1: 1056-7. 3. Mueller N, Grufferman S. The epidemiology of Hodgkin's disease. In: Mauch P, Armitage JO, Diehl V, Hoppe RT, Weiss LM, eds Hodgkin's disease. Philadelphia: Lippencott Williams &Wilkins 1999; 61-78. 4. Clemmesen J. To the epidemiology of Hodgkin's lymphogranulomatosis.y Beige Radiol 1981; 3: 263-71. 5. Correa P, O'Connor GT. Epidemiologic patterns of Hodgkin's disease. Int J Cancer 1971; 8:192-201. 6. Gutensohn (Mueller) N, Cole P. Epidemiology of Hodgkin's disease in the young. Int J Cancer 1977; 19: 595-604. 7. Parkin DM, Muir CS, Whelan SL et al., eds. Cancer incidence in five continents, Vol. VI. IARC publication no. 120. Lyon: IARC, 1992. 8. Stiller CA. What causes Hodgkin's disease in children? Eur J Cancer 1998; 34: 523-8. 9. Glaser SL, Swatz WG. Time trends in Hodgkin's disease incidence: the role of diagnostic accuracy. Cancer 1990; 66: 2196-204. 10. Hu E, Hufford S, Lukes R, etal. Third-world Hodgkin's disease at Los Angeles County-University of Southern California Medical Center. J Clin Oncol 1988; 6:1285-92. 11. MacMahon B. Epidemiology of Hodgkin's disease. Cancer Res 1966; 26: 1189-2000. 12. Henderson BE, Dworsky R, Pike MC, et al. Risk factors for nodular sclerosis and other types of Hodgkin's disease. Cancer Res 1979; 39: 4507-11. 13. Cozen W, Katz J, Mack T. Risk patterns of Hodgkin's disease in Los Angeles vary by cell type. Cancer Epidemiol Prevent 1992; 1:261-8.

14. Glaser SL. Regional variation in Hodgkin's disease incidence by histologic subtype in the US. Cancer 1987; 60: 2841-7. 15. Alexander FE, Ricketts TJ, McKinney PA, et al. Community lifestyle characteristics and incidence of Hodgkin's disease in young people. IntJ Cancer 1991; 48: 10-14. 16. Glaser SL Reproductive factors in Hodgkin's disease in women: a review. Am J Epidemiol 1994; 139: 237^6. 17. Lambe M, Hsieh CC, Tsaih SW, Adami J, Glimelius B, Adami HO. Childbearing and the risk of Hodgkin's disease. Cancer Epidemiol Biomarkers Prev 1998; 7: 831-4. 18. Mueller N. Hodgkin's disease. In: Schottenfeld D, Fraumeni J Jr, eds Cancer epidemiology and prevention, 2nd edn. New York: Oxford University Press, 1996: 893919. 19. Gutensohn (Mueller) N. Social class and age at diagnosis of Hodgkin's disease: new epidemiologic evidence on the 'two-disease' hypothesis. Cancer Treatment Rep 1982; 66: 689-95. 20. Alexander FE, McKinney PA, Williams J, et al. Epidemiological evidence for the 'two-disease hypothesis' in Hodgkin's disease. IntJ Epidemiol 1991; 20: 354-61. 21. Abramson JH, Pridan H, Sacks Ml, etal. A case-control study of Hodgkin's disease in Israel.) Natl Cancer Inst 1978;61:307-14. 22. Evans AS. The spectrum of infections with Epstein-Barr virus: a hypothesis. J Infect Dis 1971; 124: 330-7. 23. Evans AS, Gutensohn (Mueller) N. A population-based case-control study of EBV and other viral antibodies among persons with Hodgkin's disease and their siblings. Int J Cancer 1984; 34:149-57. 24. Mueller N, Evans A, Harris NL, et al. Hodgkin's disease and Epstein-Barr virus: altered antibody pattern before diagnosis. N Engl J Med 1989; 320: 689-95. 25. Lehtinen T, Lumio J, Dillner J, et al. Increased risk of malignant lymphoma indicated by elevated Epstein-Barr virus antibodies - a prospective study. Cancer Causes Control 1993; 4:187-93. 26. Rocchi G, Tosato G, Papa G, et al. Antibodies to Epstein-Barr virus-associated nuclear antigen and to other viral and non-viral antigens in Hodgkin's disease. /Art7 Cancer 1975; 16: 323-8. 27. Weiss LM, Strickler JG, Warnke RA, et al. Epstein-Barr viral DNA in tissue of Hodgkin's disease. Am J Pathol 1987; 129:86-91. 28. Weiss LM, Movahed LA, Warnke RA, etal. Detection of Epstein-Barr viral genomes in Reed-Stern berg cells of Hodgkin's disease. N Engl J Med 1989; 320: 502-6. 29. Pallesen G, Hamilton-Dutoit SJ, Rowe M, etal. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 1991; 337: 320-2. 30. Knecht H, Brousset P, Bachmann E, etal. Latent membrane protein 1: a key oncogene in EBV-related carciogenesis?/4rto Hematol 1993; 90: 167-71. 31. Herbst H, Niedobitek G. Epstein-Barr virus and Hodgkin's disease. IntJ Clin Lab Res 1993; 23:13-16.

References 167

32. Glaser SL, Lin RJ, Steward SL, et al. Epstein-Barr virus-

42. Grufferman S, Cole P, Smith PG, et al. Hodgkin's disease

associated Hodgkin's disease: epidemiologic characteristics in international data. Int J Cancer 1997: 70: 375-86. 33. Frisan T, SjbbergJ, Dolcetti R, etal. Local suppression of

in siblings. N Engl J Med 1977; 296: 248-50. 43. Grufferman S, Barton JW III, Eby NL. Increased sex concordance of sibling pairs with Behcet's disease, Hodgkin's disease, multiple sclerosis and sarcoidosis. Am

Epstein-Barr virus (EBV)-specific cytotoxity in biopsies of EGV-positive Hodgkin's disease. Blood 1995; 86:1493-501. 34. Mueller NE. Epstein-Barr virus and Hodgkin's disease: an epidemiological paradox. Epstein-Barr Virus Rep 1997; 4: 1-2. 35. Jarrett RF. Epstein-Barr virus and Hodgkin's disease. Epstein-Barr Virus Rep 1998; 5: 77-85. 36. Mueller N. Overview of the epidemiology of malignancy in immune deficiency. JAIDS 1999; 21: S5-S10. 37. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDSassociated malignant disorders. Lancet 1998; 351:1833-9. 38. Roithmann S, Tourani J-M, Andrieu J-M. Hodgkin's disease in HIV-infected intravenous drug abusers. N Eng J MedWW; 323:275-6.

J Epidemiol 1987; 126: 365-9. 44. Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N EnglJ Med 1995; 332: 413-18. 45. Bernard SM, Cartwright RA, Darwin CM, et al. Hodgkin's disease: case control epidemiological study in Yorkshire. BrJ Cancer W87; 55:85-90. 46. Hoar SK, Blair A, Holmes EF, et al. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma.y/AM/4 1986; 256: 1141-7. 47. Hainan, KE. Failure to substantiate two cases of alleged occupational radiation carcinogenesis. Lancet 1988; 1: 639.

39. Hessol NA, Katz MH, Liu JY, et al. Increased incidence of

48. Boice JD Jr, Land CE, Preston DL. Radiation. In:

Hodgkin's disease in homosexual men with HIV infection. Ann Intern Med 1992; 117: 309-11. 40. Knowles DE, Chamulak GA, Subar M, et al. Lymphoid neoplasia associated with the acquired immunodefi-

prevention 2nd edn. New York: Oxford University Press 1996; 319-54. 49. Smithers D. On some general concepts in oncology with

ciency syndrome (AIDS): the New York University Medical Center experience with 105 patients (1981-1986). Ann Intern Med 1988; 108: 744-53. 41. Grufferman S, Delzell E. Epidemiology of Hodgkin's disease. Epidemiol Rev 1984; 6: 76-106.

Schottenfeld D, Fraumeni J, eds Cancer epidemiology and

special references to Hodgkin's disease. Int J Radial Oncol Biol Phys 1983; 9: 731-8. 50. Mueller NE. The epidemiology of Hodgkin's disease. In: Selby D, McElwain TJ, eds Hodgkin's disease Oxford: Blackwell Scientific Publications, 1987; 68-93.


14 Non-Hodgkin's lymphoma RACARTWRIGHT

Introduction Descriptive epidemiology Analytic epidemiology

169 170

The future References

174 174

172

INTRODUCTION The epidemiology of non-Hodgkin's lymphoma (NHL) presents serious difficulties. As a result there are still many gaps in our knowledge of the distribution and causes of these conditions. There are several reasons for this. The classification systems have been in flux for many years. As opinions about the disease have changed, so a series of classifications have been produced. This had led to problems for epidemiologists who collect routine and often historical information from cancer registries or from other special studies. All the various classifications, dating back over 30 years, have been used by epidemiologists at one time or another, many of which are regarded as out of date by contemporary histopathologists. Two aspects of these classifications should be noted: what is included or excluded as 'NHL', and the internal subtypes of the disease. Both have changed and these changes vary from country to country. Thus comparisons over time and/or internationally are fraught with difficulties of interpretation. Classification errors might account for 10-15 per cent of wrongly associated cases.1 This has led many epidemiologists simply to avoid the issue of the need to account for or incorporate subtypes of NHL in their studies. They have assumed NHL to be one cohesive pathological entity. This is nowadays at odds with the concepts of the histopathologists whose classification strategies have gradually shifted from those which purely reflected disease outcome to those more truly in line with the recognized pathogenic processes. In addition, most epidemiologists have tended to ignore the site of origin of the NHL. A further noteworthy event has been that the use of cell-surface markers has led to more undifferentiated tumors being classified as NHL.

A related difficulty lies in the pathological status of Hodgkin's disease (HD). Originally regarded as distinct entities, the pathological boundaries between HD and NHL have become increasingly blurred. This is particularly true in the older, non-nodular sclerosing cases where a decline in case numbers has been interpreted as a possible diagnostic artefact of a tendency to classify more such cases as NHL. Further, many risk factors for HD, particularly, but not exclusively, in older cases, are similar to those for NHL. The boundaries between chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are also blurred from an epidemiological viewpoint, although they are relatively clear diagnostically. The relatively rare lymphoblastic lymphoma is regarded as part of the acute lymphoblastic leukemia (ALL) spectrum and is not referred to in this chapter, along with CLL and MM. In summary, because of the chaos of classification and the limitation of many earlier epidemiological studies, much of the descriptive epidemiology of NHL is difficult to interpret, and could be full of spatial and temporal artefacts. Some of the earlier epidemiological attempts to find causal links may also be seriously flawed as a consequence of the pooling of all NHL cases together or the inappropriate use of systems of classification. This could mean that highly significant risk factors have been diluted or completely lost. Although most of these challenges are now being addressed by epidemiologists, the data from this new generation of studies are just becoming available. However, the reader must still interpret epidemiology data with caution. For example, Anderson et al. found substantial differences in the geographical distribution of NHL subtypes (by the Revised European-American Classification).2

170 Non-Hodgkin's lymphoma

DESCRIPTIVE EPIDEMIOLOGY

Rates by classification of NHL by all type and all sites In view of the difficulties noted in the introduction, only the recently available data are supplied. Table 14.1 gives incidence rate data by age and sex for recently acquired information from parts of the UK, collected as a result of a special study spanning 1984-1993.3 These rates are typical of many European populations in that they are greater in males at all ages and show a steadily increasing incidence in both sexes with the highest rate being in the elderly.

Internationally, however, there are greater differences and some selected populations are given in Table 14.2 to reflect this. These are taken from data computed by the International Agency for Research on Cancer4 and roughly represent cases occurring between the years 1982 and 1989. Higher childhood rates are seen in certain countries, such as in parts of sub-Saharan Africa, where it is largely due to the Burkitt-type lymphoma.5 Asian children living in the UK may have a higher NHL rate than in the white population.6 This is also true in some Arab children.7 Generally, Middle Eastern and Caucasian populations have the highest rates of NHL in all older age groups. There is some slight evidence to suggest rates in Europe are higher in the north and central parts than in the far south.4

Table 14.1 Age-specific incidence rate (x per 100 000 per year) for cases of NHL collected from geographically defined areas of the UK 1984-1993 inclusive based on 13 901 cases

0-4 10-14 20-24 30-34 40-44 50-54 60-64 70-74 80-84 90+

0.61 1.07 1.56 2.93 7.22 1449 23.34 41.85 48.02 47.92

0.46 0.35 0.82 2.21 5.03 9.54 16.97 28.07 31.26 20.00

Rates by all histological types by site until recently mere nas been very little systematic data reported by the site of origin of the NHL. A recent special collection from the UK3 has allowed this to be rectified. Table 14.3 gives the relative proportion of the various sites based on the first histopathology report in each case. The 'skin' site includes mycosis fungoides and Sezary's syndrome. Table 14.4 gives some age-specific incidence rates for these sites. The rarity of some sites is noteworthy as is the brief span of risk for others, e.g. the testes.

0.54 0.72 1.20 2.58 6.13 12.01 20.01 33.98 36.79 25.55

Table 14.2 Age-specific incidence rates in selected populations

South America Columbia

1.0

0.7

2.1

0.9

1.7

2.9

10.1

9.6

19.0

32.9

North America Connecticut whites Connecticut blacks

0.8 1.4

1.5 0.0

0.8 1.5

0.6 1.6

4.3 3.4

2.4 4.5

16.0 11.2

14.2 6.7

79.0 44.2

58.0 21.6

Asia India - Bombay

0.8

0.3

1.1

0.3

1.5

1.0

5.9

5.6

19.9

15.5

Israel Jews

1.6

0.9

1.9

0.3

3.3

3.6

15.5

18.3

5.6

Japan Miyagi

0.7

0.7

3.0

1.4

1.8

1.2

5.0

3.3

33.3

19.5

Europe Finland Belarus Soab- Basque

1.3 1.3 1.1

0.6 0.9 2.3

1.8 1.3 1.6

0.5 0.9 3.4

3.1 1.6 2.6

1.7 1.1 1.3

14.9 4.2 8.0

10.0 2.2 6.6

48.5 12.5 38.8

38.2 6.4 19.4

Australasia New South Wales

1.2

0.6

1.0

0.5

4.5

2.3

18.0

14.7

63.1

46.5

44.4

Descriptive epidemiology 171

Table 14.3 Site of origin of non-Hodgkin's lymphoma in cases aged 0-79 based on 12 033 cases collected 1984-1993

Lymph node, marrow, blood, tonsils Gastrointestinal tract Skin Bone, orbit, jaw Spleen Liver Central nervous system Testes Breast Other

80.00 8.35 6.12 1.37 1.15 0.98 0.11 0.07 0.05 1.80

Seascale near British Nuclear Fuels Ltd, Sellafield.17 The inclusion in such studies of NHL in both children and young adults (under age 25) is controversial, as they are pooled with ALL cases. It is unlikely that the NHL cases have all been of the lymphoblastic type. The major type of 'clustering' occurs within families. Secular trends

Variation in rates in the UK by all histological types and sites The use of panel-reviewed data has enabled local variation to be examined in the UK at various geographical levels from that of administrative county to the small electoral wards. This highlights various features, particularly a non-random distribution of cases between both counties and administrative districts, with an excess of cases in the south of England compared to the north.3 This has been confirmed in a mortality study.8 Further, the data confirm an excess of cases in predominantly rural areas, an observation made also in North America.9 At the electoral ward level, a non-random and unusual case distribution has been described in parts of the UK,10,11 suggesting local rural excesses. Local case clusters have also been described for the disease in Africa, owing to Burkitt's lymphoma and its links with the EpsteinBarr virus (EBV) and malaria.12 Post hoc clusters in neighborhoods have been described occasionally in various countries.13-16 However, the number of reports are limited compared to HD or leukemia, for example. It should also be noted that NHL in young people has been associated with the 'cluster' reports relating to nuclear power plants of various kinds in the UK, e.g.

One of the most remarkable features of NHL epidemiology is the increase in recorded rates of the condition over the years. This increase is true for most age groups over 30 years of age and for both sexes. No study has shown any increasing trend in childhood NHL.18 This is particularly so for Caucasian populations, and has been recorded from Europe, North America and Australasia. The increase is also seen in black populations in the USA but at a lower rate, and is not seen in African or southwest Asian peoples.19 The same trends have also been seen in UK populations.20 In a series from Yorkshire utilizing a reviewed histopathology panel dataset for 1977-1992, the increase is a remarkable 5 per cent per annum21 but this has been exceeded by a series from France.22 NHL sited in the central nervous system (CNS) has been shown to be on the increase in London.23 However, a Danish study has shown no increase in NHL of the gastrointestinal tract.24 There is no doubt that the trends exist. The controversy revolves around the reasons for it. Because of the problems outlined in the introduction, it has long been argued that the increases are artefactual and the result of increased diagnostic acumen, an increased biopsy rate and the improved ability to distinguish NHL from other tumors. This could, for example, account for some increase in CNS lymphomas due to the advent of better imaging techniques.23,25 To investigate one aspect of this, two series of nodal tumors were abstracted from the same geographical area some years apart and all were reviewed again by a panel. The results showed a uniform increase in incidence in all ages over 30 for NHL, whilst HD only showed an increase in the elderly. The latter

Table 14.4 Age-specific incidence (x per 100000 per year) of NHL non-Hodgkin's lymphomas of all histopathological types by site (sexes pooled where appropriate)

Lymph node, marrow, blood, tonsils Gastrointestinal tract Skin Bone, orbit, jaw Spleen Liver Central nervous system

Testes Breast

0.28 0 0.02 0 0 0.2 0 0 0

0.37 0.07 0.01 0 0 0.01 0.01 0.04 0

1.65 0.12 0.19 0.05 0 0.01 0.02 0 0.09

9.44 0.98 0.83 0.12 0.08 0.11 0.14 0.08 0.05

28.22 2.77 2.22 0.38 0.44 0.33 0.33 0.61 0.25


could be due to increased or more thorough investigations, whilst the former argues for a biological and not a spurious phenomenon.26 Nowadays the consensus is for the existence of a real 'biological' increase but of unknown causation (see later). Some attempts have been made to examine which, if any, subtypes are increasing. Some studies have suggested a general increase using various classification systems but one has implied that large cell disease is responsible.27 If the rates of increase continue, varying between 3 and 10 per cent per annum, NHL will be amongst the commonest cancers in Europe in the next few years.28

ANALYTIC EPIDEMIOLOGY Given the caveats noted in the introduction, piecing together the jigsaw of published studies can be difficult, in some cases, to the point of speculation. However, it is apparent when reviewing the literature that the attention of research workers has fallen into three broad categories: aspects of altered immunity (using its broadest interpretation), occupational studies, and a ragbag of 'lifestyle' studies. The most plausible area of research is that dealing with aspects of immune competence.

Studies of altered immunity INHERITED SYNDROMES AND SUSCEPTIBILITY VIA INDIVIDUAL INHERITED GENETIC SEQUENCES

Several studies have suggested that a slight excess of lymphoma cases occur in blood relatives. The significance of this is not yet known; however, there are a range of generally rare, but well-defined and usually simply inherited conditions that have an excess of NHL as part of a syndrome. Such conditions are typified by ataxia telangiectasia. This is an autosomal recessive condition due to a gene deficit on chromosome 1 lq.29 The syndrome gives a progressive ataxia, many infections and progeria. Immunologically, there are a complex array of deficits, including impaired synthesis of immunoglobulin A (IgA).30 A wide range of cancers occur in these individuals but these include NHL probably more frequently than any other.31 Although such a condition is very rare, theoretically the unaffected heterozygotes could occur quite commonly in the population and it is thus a question of great significance to learn of the health of such individuals. So far only studies of the parents of cases (who are necessarily heterozygotes) have been published, with a suggestion of excess cancers but with such small case numbers that the results are difficult to interpret.32 However, the same argument would be true of all the other autosomal recessive and sex-linked conditions of impaired immunity.

These would include Chediak-Higashi syndrome,33 Wiskott-Aldrich syndrome,34 Bloom's syndrome,35 common variable immunodeficiency, the various agammaglobulinaemias and the severe combined immunodeficiency disorder.36 If the Hardy-Weinberg law of population genetics holds for all these very rare homozygous or sex-linked conditions, the frequency of the heterozygotes in the general population would be quite common. It will be necessary to identify the molecular characteristics of the gene sites in order to identify the carriers and then to determine the status of such people as possibly susceptible to NHL. The potential underlying genetic defects could represent a major initiating cause of NHL, although it would be unlikely to be the only step required to manifest the disease in these heterozygotes. IMMUNODEFICIENCY DUE TO PAST MEDICAL HISTORY

There is an excess of various cancers in patients following organ transplantation, consistent with the intensity of the immunosuppressive regimen.37 The risk of NHL in such patients can be very high, between 20- and 60-fold, but varying from study to study. One other consistently common secondary malignancy is skin carcinoma.38 Some series suggest that extranodal NHL of the CNS is particularly common. Individuals receiving immunosuppressive therapy without transplantation also have a risk of NHL;39 for rheumatoid arthritis cases the risk is roughly ten-fold. There is, however, a problem with all these studies. This is highlighted by more recent reports, which recognize the existence of post-transplant lymphoproliferative disease,40 the diagnosis of which may have been confused in earlier studies, with the contemporary understanding of NHL. Even if this is the case, some underlying risk must exist for NHL in those immunosuppressed by drug therapy. A further complexity in interpreting this outcome for conditions such as rheumatoid arthritis is that the condition itself, not necessarily with the use of immunosuppressive therapy, may have an excess of NHL,41-43 although only a 2-4-fold excess has been observed. This may also apply to other chronic conditions associated with altered immunity such as systemic lupus.44 VIRAL IMMUNOSUPPRESSION

The role of EBV in African Burkitt's lymphoma and in nasopharyngeal carcinoma, in concert with other chronic parasitic infections, is well recognized.45,46 The role of EBV in other NHL types is less well understood, although a small number of cases do have active EBV involvement. However, in most instances, EBV does not appear to be a significant pathogenic factor in the majority of NHL cases. The role of human immunodeficiency

Analytic epidemiology 173

virus (HIV) as an immune depleting agent, is much clearer, however, both from studies of HIV in the general public and in hemophiliacs given HIV-positive Factor VIII preparations. As far as acquired immunodeficiency syndrome (AIDS) cases are concerned, roughly 3 per cent acquire some type of NHL. This equates to a 60-fold risk when cases are contrasted with the general unaffected population.47 Of the NHL in a series from the USA, nearly 60 per cent were described as 'immunoblastic', approximately 20 per cent as primary CNS tumors and approximately 20 per cent as 'Burkitt' in type. The risk in a series of purely HIV-infected hemophiliacs was half that of the AIDS study noted above. Almost all such cases were described as extranodal but for a very wide range of sites, including gastrointestinal tract, skin and CNS.48 The relationship between human T-cell lymphotropic virus type 1 (HTLV-1) and the development of acute T cell leukemia/lymphoma is now much clearer in the endemic areas of Japan and the Caribbean. In Jamaica the risk of NHL in those infected with HTLV-1 is roughly 10-fold.49 Most HTLV-1 infections are a result of vertical transmission and thus the condition lends itself to public health measures. Other HTLV-1 endemic areas have been identified in Africa50 and the USA51 and South America.52 The role of needle transmission and the status of HTLV-2 are still under investigation. The newly identified herpes-like agent associated with Kaposi's sarcoma may also have a role in NHL.53 Known or unknown viruses have also been postulated to account for the excess of NHL found in blood transfusion recipients.54 CHEMICALLY INDUCED IMMUNOSUPPRESSION

Many of the chemicals possibly linked to NHL are thought to have immunosuppressive qualities.55

for in the calculation. These could be the mundane explanation as to why NHL excesses occur quite commonly in this type of literature. The links with occupations have been extensively reviewed elsewhere56 and the salient results are listed below. AGRICULTURE

Various occupations related to agriculture have been associated with an excess risk of NHL.57 Overall, at least 20 studies have seen statistical excesses in farmers, horticulturists and contract applicators.56 In addition, a lowgrade NHL excess is seen in farm animal breeding workers.58 However, a large study of herbicide production workers showed no NHL excess,59 nor has any study of dioxin-exposed workers shown any NHL excess, although the general population of Seveso does show a statistical excess but only for males.60 Attention has been given to the particular exposures of farmers themselves and what substances, if any, might be responsible. One review suggested that 2;4D is significantly involved,61 while another study has incriminated atrazine.62 In a more recent workers-exposure study, no significant excess of NHL emerged for any subtype of phenoxyherbicides, chlorophenols or dioxins with only a minor possible effect of usage of the insecticide lindane.63'64 No firm biological evidence has so far been found to support causal links between NHL and any such substances. It has been clearly demonstrated that veterans of the Vietnam war show an excess of NHL.65 This remains unexplained but it has been suggested that the phenomenon may be a result of exposure to defoliants. However, close examination of the data show this excess is confined to naval veterans. Studies of possible links between Agent Orange and contaminants with NHL and sarcoma are ongoing.66

Occupational links PETROCHEMICAL INDUSTRY

The risks associated with NHL's links with immune alterations range from four-fold rising to roughly 60fold. The occupational risks, however, are very different, with risks being four-fold at most but usually far smaller. Despite this, the literature on this aspect of etiology is very large. This should not be taken as a sign that occupations are deemed to be particularly significant in the pathogenesis of these conditions. Occupational cohort and other studies 'turn up' statistically significant results, a proportion at random, and there are large numbers of such studies. Secondly, the calculation of'expectated case numbers' in these studies is made on a basis of known national rates. In the case of NHL, these may be too low, owing to the problems of basic ascertainment (see 'Introduction'), that is, the comparison between a wellinvestigated cohort and national rates are inappropriate. Also the increasing trends in incidence are not accounted

At least four studies have shown a statistical excess of NHL with the petrochemical industry.56 However, two cohort studies were negative.67,68 This indicates the risk may be weak or of uncertain significance. OTHER INDUSTRIES

A wide variety of other industries have been named sporadically as having an excess risk of NHL. These include, firefighters,69 flour industry workers,70 asbestos exposed workers,71,72 dry cleaners,73 nickel refinery workers,74 carpenters, painters, plasterers and others in the wood and building trades.75-77 All the risks are either very low or based on very small numbers and, with a few exceptions, have little support from biological studies.78 Most of these observations are unsupported by independent studies.


Lifestyle and other exposures

REFERENCES

Most studies have shown little statistically significant relationship between NHL and cigarette smoking. There are, however, studies showing, albeit weak, risks and some evidence of a dose response relationship and a relationship of risk to age.79-81 Attempts to analyse the relationship between smoking and different subtypes of NHL are fraught with difficulty, the association with follicular lymphomas possibly being the strongest.82 The evidence for a relationship with exposure to ionizing irradiation is equally sparse, amounting to very little risk consequential on the atomic bomb explosions83 or from diagnostic X-rays,84 but the results from alphairradiation via the use of diagnostic thorotrast demonstrate a definite risk, although this is difficult to quantify.85 Despite this, there are no unequivocal data available to suggest a simple relationship in risk between NHL and these two acknowledged human carcinogens. This maybe due to the protean nature of NHL, with possibly a strong risk with some subtypes of NHL only, or perhaps because lymphomagenesis is solely dependent on chronic immune interference. As to other exposures, there is in general no convincing aspect of dietary exposure linked to risk of NHL,86-87 including non-alcoholic beverages88 and alcohol.89 In some populations, data suggested a possible link to meat intake.90 It has been suggested that the use of hair colorants gives a risk of NHL91 but this has been challenged.92 Attempts have been made to associate residential proximity to industrial sites with the risk of NHL in adults or children, with varying success and little by way of convincing results.93-95

1. Palackdharry CS. The epidemiology of non-Hodgkin's lymphoma: why the increased incidence? Oncology 1994; 8: 67-75. 2. Anderson JR, Armitage JO, Weisenburger DD, for the NonHodgkin's Lymphoma Classification Project. Epidemiology of the non-Hodgkin's lymphomas: distribution of the major subtypes differ by geographical locations. Ann Oncol 1998; 9: 717-20. 3. Cartwright RA, McNally RJQ, Rowland DJ, etal. The descriptive epidemiology of leukaemia and related conditions in parts of the United Kingdom 1984-1993. London: Leukaemia Research Fund, 1997. 4. Parkin DM, Muir CS, Whelan SL, eds. Cancer incidence in five continents, Vol. VI. IARC Scientific Publications 120. Lyon: IARC, 1992. 5. Stiller CA, Parkin DM. International variations in the incidence of childhood lymphomas. Paediat Perinatal Epidemiol 1990; 4: 303-24. 6. Powell J, Parkes SE, Cameron AH, et al. Is the risk of cancer increased in Asians living in the UK? Arch Disease Childhood 1994; 71: 398-403. 7. Revesz T, Mpofu C, Oyejide C. Ethnic differences in the lymphoid malignancies of children in the United Arab Emirates. A clue to aetiology? Leukemia 1995; 9:189-93. 8. Swerdlow A, Silva Ide S. Atlas of cancer incidence in England and Wales 1968-85. Cancer Research Campaign. Oxford: Oxford University Press, 1993. 9. Pickle LW, Mason TJ, Howard N, et al. Atlas of US cancer mortality among whites: 1950-1980. DHHS Publ No. (NIH) 87-2900. Washington, DC: US Government Printing Office, 1987. 10. Eddington GM. The Burkitt lymphoma in the Northern Savannah of Nigeria. Prog Clin Biol Res 1981; 53: 133-49. 11. Barnes N, Cartwright RA, O'Brien C, et al. Variation in lymphoma incidence within Yorkshire health region. BrJ Cancer W87; 56:169-72. 12. Smith PG. Current assessment of 'case clustering' of lymphomas and leukaemias. Cancer 1978; 42:1026-34. 13. Schimpff SC, Schimpff CR, Brager DM, et al. Leukaemia and lymphoma patients interlinked by prior social contact. Lancet 1975; i: 124-9. 14. Dowsett EG. Leukaemia in Kingston, Surrey, 1958-64: an epidemiological study. BrJ Cancer 1966; 20:16-31. 15. Mainwaring D, Martin J. Leukaemia and reticuloses. Br Med J 1968;ii:702. 16. Kolandaivelu G. A cluster of non-Hodgkin's lymphoma. Indian Paediat 1988; 25: 583. 17. Draper GJ, Stiller CA, Cartwright RA, et al. Cancer in Cumbria and in the vicinity of the Sellafield nuclear installation, 1963-1990. BrMedJ 1993; 306: 89-94. 18. Blair V, Birch JM. Patterns and temporal trends in the incidence of malignant disease in children: I. Leukaemia and lymphoma. EurJ Cancer 1994; 30A: 1490-9. 19. Devesa SS, Fears T. Non-Hodgkin's lymphoma time

THE FUTURE A close reading of the preceding chapter will have suggested ways in which epidemiological studies of NHL can be improved and indeed some such studies are now underway, with better diagnostic and exposure markers. The problems as to how to subdivide the disease and why the condition is increasing so much and in such a widespread fashion, however, still remain. Common sense would suggest that the pathways of greatest influence upon lymphomagenesis are through the many areas of immune depletion. Unless major selective pressures exist, the gene pool of immune deficiency syndrome heterozygotes is unlikely to be increasing disproportionately to the total population. Further, whatever is causing an increase must be very common. It has been argued that this could be due to the immune modifying effects of sunlight,28 but other models based on antibiotic usage and traffic pollution also exist. Given the future potential burden of the disease on society, studies to address these and related issues are necessary.

References 175

20.

21.

22.

23. 24.

25. 26.

27.

28.

29.

30. 31.

32.

33.

34.

35.

36.

trends: United States and international data. Cancer Res 1992; 52 (suppl.): 5432s-40s. Cartwright RA, McKinney PA, Barnes N. Epidemiology of the lymphomas in the United Kingdom: recent developments. Bailliere's Clin Haematol 1987; 1: 59-76. McNally RJQ, Alexander FE, Staines A, et al. Effect of age, period and cohort on the incidence of non-Hodgkin's lymphoma in Yorkshire, UK, 1978-1991. IntJ Epidemiol 1997; 26: 32-46. Warren HW, Anderson JH, O'Gorman P, et al. A phase II study of regional 5-flourouracil infusion with intravenous folinic acid for colorectal liver metastases. BrJ Cancer 1994; 70: 677-80. Lutz JM, Coleman MP. Trends in primary cerebral lymphoma. BrJ Cancer 1994; 70: 716-8. d'Amore F, Brincker H, Gronbaek K, et al. Non-Hodgkin's lymphoma of the gastrointestinal tract: a populationbased analysis of incidence, geographic distribution, clinicopathologic presentation features and prognosis.J Clin Oncol 1994; 12:1673-84. Grant JW, Isaacson PG. Primary central nervous system lymphoma. Brain Pathol 1992; 2: 97-109. Barnes N, Cartwright RA, O'Brien C, et al. Rising incidence of lymphoid malignancy; true or false? BrJ Cancer 1988; 53: 393-8. Weisenburger DD. Epidemiology of non-Hodgkin's lymphoma: recent findings regarding an emerging epidemic. Ann Oncol 1994; 5: S19-S24. Cartwright RA, McNally R, Staines A. The increasing incidence of non-Hodgkin's lymphoma (NHL): the possible role of sunlight. Leuk Lymphoma 1994; 14: 387-94. Gatti R, Berkel I, Boder E, et al. Localisation of an ataxiatelangiectasia gene to chromosome 11q22-23. Nature 1989; 336: 577-80. Buckley RH. Immunodeficiency diseases. JAMA 1987; 258:2841-50. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia.y Nat Cancer Instl 986; 77: 89-92. Swift M, Reitnauer P, Morrell D, et al. Breast and other cancers in families with ataxia-telangiectasia. N EnglJ Med 1987; 316:1289-94. Merino F, Henle W, Duque-Ramirez P. Chronic active Epstein Barr virus infection in patients with Chediak-Higashi syndrome.y Clin Immunol 1986; 6: 299-305. Perry GS, Spector B, Schuman LM, et al. The Wiskott-Aldrich syndrome in USA and in Canada (1892-1979). J Pediat 1980; 97: 72-4. Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterised by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics 1954; 13:133-9. Strigini P, Carobbi S, Sansone R, et al. Molecular epidemiology of cancer in immune deficiency. Cancer Detect Prevent 1991; 15:115-27.

37. Kinlen LJ. Immunosuppressive therapy and cancer. Cancer Surveys 1982; 1: 565-83. 38. Kinlen LJ, Sheil AGR, Peto J, et al. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. BrMedJ 1979; 2: 1461-6. 39. Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. AmJ Med 1985; 78(suppl 1A): 44-9. 40. Morgan G, Superina RA. Lymphoproliferative disease after pediatric liver transplanation.y PediatSurg 1994; 29:1192-6. 41. Tennis P, Andrews E, Bombardier C, et al. Record linkage to conduct an epidemiologic study on the association of rheumatoid arthritis and lymphoma in the province of Saskatchewan, Canada.) Clin Epidemiol 1993; 46: 685-95. 42. Gridley G, McLaughlin JK, Ekbom A, et al. Incidence of cancer among patients with rheumatoid arthritis. J Nat Cancer Inst 1993; 85: 307-11. 43. Isomaki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis.) ChronicDis 1978; 31: 691-6. 44. Dupla ML, Khamashta M, Garcia VP, et al. Malignancy in systemic lupus erythematosus: a report of five cases in a series of 96 patients. Lupus 1993; 2: 377-80. 45. de The G. Virus-associated lymphomas, leukaemias and immunodeficiencies in Africa. IARC Scientific Publication 63. Lyon: IARC, 1984; 727-44. 46. de The G. Epstein-Barr virus behaviour in different populations and implications for control of Epstein-Barr virus-associated tumours. Cancer Res 1976; 36: 692-5. 47. Beral V, Peterman T, Berkelman R, et al. AIDS-associated non-Hodgkin's lymphoma. Lancet 1991; 337: 805-9. 48. Ragni MV, Belle SH, Jaffe RA, et al. Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas and other malignancies in patients with hemophilia. Blood 1993; 81:1889-97. 49. Mann A, Cleghorn FR, Falk RT, et al. Role of HTLV-I in development of non-Hodgkin's lymphoma in Jamaica and Trinidad and Tobago. Lancet 1993; 342:1447-50. 50. Muller N. The epidemiology of HTLV-I infection. Cancer Causes Control 1991; 2: 37-52. 51. MacMahon B. Epidemiological evidence on the nature of Hodgkin's disease. Cancer Res 1966; 26:1189-2000. 52. Gerard Y, Lepere JF, Pradinaud R, et al. Clustering and clinical diversity of adult T-cell leukemia/lymphoma associated with HTLV-I in a remote black population of French Guiana. IntJ Cancer 1995; 60: 773-6. 53. Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection. N EnglJ Med 1995; 332:1181-91. 54. Blomberg J, Moller T, Olsson H, et al. Cancer morbidity in blood recipients- results of a cohort study. EurJ Cancer 1993;29A:2101-5. 55. Hardell L, Axelson 0. Environmental and occupational aspects on the etiology of non-Hodgkin's lymphoma. Onto/fta 1998; 10:1-5.

176 Non-Hodgkin's lymphoma 56. McNally RJQ, Cartwright RA. Epidemiology of nonHodgkin's lymphoma. In: Burnett A, Armitage J, Newland A, Keating A, eds Cambridge Medical Review. London: 1994; 3:1-34. 57. Blair A, Linos A, Stewart PA, et al. Comments on occupational and environmental factors in the origin of non-Hodgkin's lymphoma. Cancer Res 1992; 52: 5501 s-2s. 58. Amadori D, Nanni 0, Falcini F, et al. Chronic lymphocytic leukaemias and non-Hodgkin's lymphomas by histological type in farming-animal breed ing workers: a population case-control study based on job titles. Occupat Environ Med 1995; 52: 374-9. 59. Saracci R, Kogevinas M, Bertazzi P-A, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027-32. 60. PA Pesatori, Consonni D, et al. Cancer incidence in a population accidentally exposed to 2,3,7,8tetrachlorodibenzo-para-dioxin. Epidemiology 1993; 4: 398-406. 61. Zahm SH, Blair A. Pesticides and non-Hodgkin's lymphoma. Cancer Res 1992; 52: 5485s-8s. 62. Zahm SH, Weisenburger DD, Cantor KP. Role of the herbicide atrazine in the development of non-Hodgkin's lymphoma. ScandJ Work Environ Health 1993; 19: 108-14. 63. Blair A, Cantor KP, Zahm SH. Non-Hodgkin's lymphoma and agricultural use of the insecticide lindane. AmJ Indust Med 1998; 33: 82-7. 64. Kogevinas M, Kauppinen T, Winkelmann R, et al. Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols and dioxins: two nested case-control studies. Epidemiology 1995; 6: 396-402. 65. Namboodiri KK, Harris RE. Hematopoietic and lymphoproliferative cancer among male veterans using the veterans administration medical system. Cancer 1991;68:1123-30. 66. Kramarova E, Kogevinas M, Anh CT, et al. Exposure to Agent Orange and occurrence of soft-tissue sarcomas or non-Hodgkin lymphomas: an ongoing study in Vietnam. Environ Health Perspect 1998; 106(suppl 2): 671-8. 67. Ott MG, Olson RA, Cook RR, et al. Cohort mortality study of chemical workers with potential exposure to the higher chlorinated dioxins. J Occupat Med 1987; 29: 422-9. 68. Christie D, Robinson K, Gordon I, et al. A prospective study in the Australian petroleum industry. II. Incidence of cancer. BrJ Indust Med 1991; 48: 511-14. 69. Sama SR, Martin TR, Davis LK, et al. Cancer incidence among Massachusetts firefighters, 1982-1986. AmJ Indust Med 1990; 18: 47-54. 70. Alavanja MCR, Blair A, Masters MN. Cancer mortality in the US flour industry, y Natl Cancer Inst 1990; 82: 840-8. 71. Lieben J, Harrisburg PA. Malignancies in asbestos workers. Arch Environ Health 1966; 13: 619-21.

72. Gerber MA. Asbestosis and neoplastic disorders of the hematopoietic system. AmJClin Pathol 1969; 53: 204-8. 73. Blair A, Stewart PA, Tolbert PE, et al. Cancer and other causes of death among a cohort of dry cleaners. BrJ Indust Med 1990; 47:162-8. 74. Egedahl RD, Carpenter M, Homik R. An update of an epidemiology study at a hydrometallurgical nickel refinery in Fort Saskatchewan, Alberta. Health Rep 1993; 5:291-302. 75. Edling C, Jarvholm B, Andersson L, et al. Mortality and cancer incidence among workers in an abrasive manufacturing industry. BrJ Indust Med 1987; 44: 57-9. 76. Scherr PA, Hutchison GB, Neiman RS. Non-Hodgkin's lymphoma and occupational exposure. Cancer Res 1992; 52: 5503s-9s. 77. Perrson B, Dahlander A-M, Fredriksson M, et al. Malignant lymphomas and occupational exposures. BrJ Indust Med 1989; 46: 516-20. 78. Garry VF, Danzl TJ, Tarone R, et al. Chromosome rearrangements in fumigant appliers: possible relationship to non-Hodgkin's lymphoma risk. Cancer Epidemiol Biomarkers Prevent 1992; 1: 287-91. 79. Brown LM, Everett GD, Gibson R, et al. Smoking and risk of non-Hodgkin's lymphoma and multiple myeloma. Cancer Causes Control 1992; 3: 49-55. 80. Linet MS, McLaughlin JK, Hsing AW, et al. Is cigarette smoking a risk factor for non-Hodgkin's lymphoma or multiple myeloma? Results from the Lutheran Brotherhood cohort study. Leak Res 1992; 16: 621-4. 81. Freedman DS, Tolbert PE, Coates R, Brann EA, Kjeldsberg CR. Relation of cigarette smoking to non-Hodgkin's lymphoma among middle-aged men. Am J Epidemiol 1998;148:833-41. 82. Herrinton LJ, Friedman GD. Cigarette smoking and risk of non-Hodgkin's lymphoma subtypes. Cancer Epidemiol Biomarkers Prev 1998; 7: 25-8. 83. Nishiyama H, Anderson RE, Ishimaru T, et al. The incidence of malignant lymphoma and multiple myeloma in Hiroshima and Nagasaki atomic bomb survivors. Cancer 1973; 32:1301-9. 84. Boice JD, Morin MM, Glass AG. Diagnostic X-ray procedures and risk of leukemia, lymphoma and multiple myeloma. JAMA 1991; 265:1290-4. 85. Visfeldt J, Andersson M. Pathoanatomical aspects of malignant haematological disorders among Danish patients exposed to thorium dioxide. Acta Pathol Microbiol Immunol Scand 1995; 103: 29-36. 86. Ward MH, Zahm SH, Wisenburger DD, et al. Dietary factors and non-Hodgkin's lymphoma in Nebraska (United States). Cancer Causes Control 1994; 5: 422-32. 87. Scott D. Nutritional factors and the development of nonHodgkin's lymphoma: a review of the evidence. Cancer Res 1992;52:5492s-5s. 88. Tavani A, Negri E, Franceschi S, et al. Coffee consumption and risk of non-Hodgkin's lymphoma. EurJ Cancer Prevent 1994; 3: 351 -6.

References 177

89. Brown LM, Gibson R, Burmeister LF, et at. Alcohol consumption and risk of leukemia, non-Hodgkin's lymphoma and multiple myeloma. Leuk Res 1992; 16: 979-84. 90. De Stefani E, Fierro L, Barrios E, Ronco A. Tobacco, alcohol, diet and risk of non-Hodgkin's lymphoma: a

study of permanent hair dye use and hematopoietic cancer. 7 Natl Cancer Inst 1994; 86:1466-70. 93. Linos A, Blair A, Gibson RW, et al. Leukemia and nonHodgkin's lymphoma and residential proximity to industrial plants. Arch Environ Health 1991; 46: 70-4. 94. Lyons RA, Monaghan SP, Heaven M, et al. Incidence of

case-control study in Uruguay. Leuk Res 1998; 22:

leukaemia and lymphoma in young people in the

445-52.

vicinity of the petrochemical plant at Baglan Bay, South

91. Zahm SH, Weisenburger DD, Babbitt PA, et al. Use of hair coloring products and the risk of lymphoma, multiple myeloma and chronic lymphocytic leukemia. Am J Public Health 1992; 82: 990-7. 92. Grodstein F, Hennekens CH, Colditz GA, et al. A prospective

Wales, 1974 to 1991. Occupat Environ Med 1995; 52: 225-8. 95. Sans S, Elliott P, Kleinschmidt I, et al. Cancer incidence and mortality near the Baglan Bay petrochemical works, South Wales. Occupat Environ Med 1995; 52: 217-24.


PART

Clinical Management

Hodgkin's disease: clinical features Imaging of lymphoma Localized Hodgkin's disease Localized non-Hodgkin's lymphoma Advanced Hodgkin's disease Aggressive non-Hodgkin's lymphoma Lymphoblastic lymphoma in adults Follicular lymphoma Other low-grade non-Hodgkin's lymphomas High-dose therapy AIDS-related lymphoma Cutaneous lymphomas Pediatric lymphomas Lymphoma in the elderly Infections Long-term problems The way forward

181 205 221 247 269 287 299 309 325 331 351 359 371 385 399 421 437

4


15 Hodgkin's disease: clinical features PWM JOHNSON, PJ SELBY AND BW HANCOCK

Introduction

181

Prognostic factors

Presenting features of Hodgkin's disease

181

Diagnosis and staging

184

Patterns of recurrence Hodgkin's disease in special situations

Paraneoplastic manifestations of Hodgkin's disease

188

Contrasts with non-Hodgkin's lymphoma

Clinical approach to the patient with Hodgkin's disease

188

References

INTRODUCTION Thomas Hodgkin first described the 'morbid appearances of the absorbant glands and spleen' in six patients with lymph node enlargement at Guy's Hospital in London in January 1832.1 Samuel Wilks in 1865 first used the term 'Hodgkin's disease' in describing a condition involving bulky lymphadenopathy and 'a deposit of a morbid kind in internal viscera, more especially in the spleen'.2 Sternberg3 and Reed4 later identified the characteristic giant cells now given their names. Such cells had also been mentioned by Olivier and Ranvier,5 Tuckwell,6 Langans,7 Greenfield8 and Gowers.9 Treatment with radiotherapy began with Pusey10 in 1902 and was developed by Gilbert in 1939," leading to the work of Peters in Toronto,12 and major contributions at Stanford University by Henry Kaplan.13,14 Single-agent chemotherapy began in the 1940s,15 and this was followed 20 years later by useful combination chemotherapy16 and then effective quadruple combination chemotherapy.17,18 It is perhaps surprising that with such a long history there still seems to be a great deal to learn about the clinical features of Hodgkin's disease. Understanding of these features, their prognostic significance and their biological basis continues to develop. The subject is still in evolution, and thinking around the clinical features is adapted to changing concepts of histopathology and pathogenesis. Treatment decisions continue to be based predominantly upon anatomical staging of the disease and simple indicators of its severity, but there is some dissatisfaction with the lack of predictive power in this approach, particularly its inability to pick out those for

191 194 195 196 198

whom conventional therapy is likely to fail. It is to be hoped that novel methods of prognostic division may emerge in the next few years to overcome this deficiency.

PRESENTING FEATURES OF HODGKIN'S DISEASE The clinical features of Hodgkin's disease have probably changed little despite changing interpretations. The epidemiology of the disease has been discussed in Chapter 13 but certain aspects are relevant to the patterns of presentation. The illness is more common in males, particularly among cases occurring in childhood. The well-known bimodal age incidence varies according to the geographical location, with more childhood and adolescent patients in less developed countries, and a generally higher peak age at presentation in the Western world.19 The clinical pattern of the disease at presentation also varies between units and hospitals and trials groups. Patients with localized disease are seen more often in radiotherapy centers, and advanced systemic disease may lead to a referral to a medical oncology unit. This largely explains the wide variations between reported series. Table 15.1 contains the clinical features of patients who presented to three different research groups in the UK during the last three decades: the Royal Marsden Hospital, the United Kingdom Central Lymphoma Group and the British National Lymphoma Investigation. These show considerable variation in the gender ratio, presence of systemic symptoms, clinical

182 Hodgkin's disease: clinical features

Table 15.1 Clinical features of Hodgkin's disease at presentation

Sex Male Female

77 152

33.6 66.4

148 79

65.2 34.8

182 122

59.9 40.1

172 117

59.5 40.5

117 112

51.1 48.9

79 148

34.8 65.2

84 220

27.6 72.4

87 202

30.1 69.9

27 89 64 49

11.8 38.9 27.9 21.4

13 78 77 54

5.9 35.1 34.7 24.3

10 71 121 93

3.3 23.4 42.6 30.7

8 58 135 88

2.8 20.1 46.7 30.4

10 12 70 137

4.4 5.2 30.6 59.8

11 20 50 135

5.1 9.3 23.2 62.5

5 2 47 250

1.6 0.7 15.5 82.2

2 6 54 227

0.7 2.1 18.7 78.6

193 36

84.3 15.7

198 20

90.8 9.2

273 31

89.8 10.2

250 39

86.5 13.5

139 90

60.7 39.3

172 47

78.5 21.5

246 58

80.9 19.1

220 69

76.1 23.9

117 112

51.1 48.9

81 145

35.8 64.2

103 198

34.2 65.8

95 186

33.8 66.2

171 58

74.7 25.3

193 33

85.4 14.6

281 20

93.4 6.6

252 29

89.7 10.3

197 32

86.0 14.0

230 23

89.8 10.2

220 9

96.1 3.9

173 20

89.6 10.4

199 30

86.9 13.1

191 36

84.1 15.9

B symptoms

No Yes Clinical stage

I II III IV Histology

LD LP MC NS Involvement of: Liver

No Yes Spleen

No Yes Mediastinum

No Yes Bulky mediastinum

No Yes Lung

No Yes Marrow

No Yes Inguinal nodes

No Yes

The authors are grateful to Dr Gillian Vaughan Hudson (BNLI) and Dr Michael Cullen (CLG) for provision of the data included in the table from Hancock et al.20 and Cullen et al.21 BNLI = British National Lymphoma Investigation, CLG = Central Lymphoma Group, LD = lymphocyte depleted, LP = lymphocyte predominant, MC = mixed cellularity, NS = nodular sclerosing.

stage, histologic subtypes, and involvement of various visceral and lymph node sites. This reflects selective referral patterns and differences in investigation policies. The National Survey of Patterns of Care for Hodgkin's Disease of the Commission on Cancer of the American College of Surgeons reported findings in 9482 patients from 611 geographically scattered hospitals (Fig. 15.1).

The authors estimated that this series included some 45 per cent of the US annual incidence during the study period, and it represents a useful unselected description of the clinical features of the disease.22 Painless enlargement of lymph nodes, usually in the neck, but occasionally in the axilla or inguinal region, is the most common presentation. Spontaneous waxing

Presenting features 183 Table 15.3 Stage distribution at presentation24

Image Not Available

IA IB AIM

11 0.8 12

20

HA IIB IIAE IIBE

29 10 5 2.8 47

} 4 I 26

All II IMA IIIB IIIAE IIIBE

All III Figure 15.1 Clinical examination findings at presentation. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., from Kennedy BJ, et a I. National survey of patterns of care for Hodgkin's disease. Cancer 7985; 56: 2547-56. © 7985 American Cancer Society.

and waning of nodes is well recognized. Systemic symptoms, such as, fever, night sweats, weight loss or itching, occur in about one-third of patients initially. In a few patients pain is experienced in the nodes, often in the chest, after drinking alcohol - a symptom usually associated with nodular sclerotic histology.23 Table 15.2 gives an overall impression of the pattern of Hodgkin's disease at presentation from across the literature. There are still few examples of detailed studies that add much to this general understanding. The outstanding early work at Stanford24 is summarized in Table 15.3. It is derived from Table 15.2 Sites of involvement with Hodgkin's disease at presentation

Right neck nodes Left neck nodes Mediastinum Axillary nodes Hilar nodes Para-aortic nodes Iliac nodes Inguinal and femoral nodes Mesenteric nodes Splenic hilar, celiac, portal nodes Spleen Liver Lung Bone Bone marrow

55-60 60-70 60-65 20-25 10-25 25-35

10-15 5-15 5-10 10-20 30

5-15 10-20 5-15 5-15

5 10 2 5 33 per cent), most authors find a higher risk of relapse after radiotherapy than for patients without such bulk.133-137 There are, however, some analyses that do not show this effect, probably as a result of differences in radiotherapy technique.138-139 The high relapse rate, which is seen in many centers after radiotherapy alone, is reduced by the addition of combination chemotherapy.140 However, presence of a very bulky (> 45 per cent thoracic diameter) mediastinal mass remains a significant predictor of treatment failure even after modern chemotherapy.130 FAMILIAL LONGEVITY

Bjorkholm et al 141 showed that parental longevity influenced the outcome of 98 patients with Hodgkin's disease. Although patients aged less than 50 at the time of diagnosis were not affected, patients more than 50 years old had a better outlook if their parents had been long lived. There was a significant excess of death from tuberculosis in the parents of patients who did badly with Hodgkin's disease. The authors postulated that this observation might be explained by a familial deficiency in T cell immunity. PERSONALITY

A single study has been reported, which investigated the relation between personality and outcome in malignant lymphoma. Sixty-three newly diagnosed patients were graded by the Personality Inventory questionnaire at the time of diagnosis and the L-score was found to be an independent predictor for survival in multivariate analysis, as was the Hospital Anxiety and Depression score.142

Multivariate analysis and models Many different prognostic models and indices have been proposed for Hodgkin's disease. Some of these are

described in Table 15.8. Four of these models were evaluated in a study of 344 patients with advanced Hogdkin's disease included in the Groupe d'Etudes des Lymphomes de 1'Adulte (GELA) study.145 Patients with at least three adverse factors according to the Memorial Sloan-Kettering Cancer Centre or the European Bone Marrow Transplant criteria had a higher risk of failing with conventional treatment; however, based on survival rate, no very high risk group could be identified. For such models, three features can be used to describe their utility. These are the statistical significance of the factors included, the fit of the data to the chosen model and the predictive power of the model. Most reports of prognostic models describe their statistical significance and goodness of fit. Until recently, no good method was available to evaluate predictive power in survival time models. The predictive power of a set of prognostic factors is their ability on average to make accurate predictions of what will happen to patients. If a model is fitted well by the data, it does not necessarily imply that, for an individual patient, the prediction will be precise. Without quantification of the predictive power, highly significant P values of covariates in an adequate fitting model may give a misleading impression of accuracy and utility.146 As an example of this problem, data have been analysed from over 1000 patients treated in the UK in the Royal Marsden Hospital series, the United Kingdom Central Lymphoma Group and the British National Lymphoma Investigation.20,21,147 The data were used to evaluate the meaning of prognostic factors for complete remission, recurrence and survival. The data on log rank results for the entire database are shown in (Table 15.9). After Cox proportional hazards analysis independent prognostic factors were age, clinical stage IV, mediastinal bulk and albumin. In this analysis, choice of chemotherapy was also significant, with poorer results for patients receiving only alkylating agent-based combinations compared to those who received alternating regimens including doxorubicin and etoposide. In this analysis, the ability of the prognostic factors to predict patient outcome was examined. The proportion of variance that was explained by the best prognostic factor analysis was surprisingly small for the prediction of complete remission (7 per cent of variance explained), survival to 5 years (9 per cent of variance explained) and estimated survival probability (10-14

Table 15.8 Prognostic models in Hodgkin's disease factors found predictive of outcome in multivariate analysis 132

Gobbi (1988) Wagstaff (1988)143 Proctor (1991 )144 Hasenclever(1996)129 Sarris (1996)108

586 301 92 validated in 455

1618 155 validated in 226

Age, stage, gender, histology, erythrocyte sedimentation rate, albumin Age, stage, gender, lymphocyte count Age, stage, hemoglobin, lymphocyte count Age, stage, gender, white blood cell count, hemoglobin, albumin Age, lactatedehydrogenase, (32 microglobulin

194 Hodgkin's disease: clinical features Table 15.9 Analysis of prognostic factors in a combined UK series of patients

Sex

Male

654

73.9

Female

395

73.3

0.1

0.814

367 682

79.2 70.7

4.8

0.28

I, II, III

759

77.8

IV

284

62.4

27.7

< 0.001

Involvement of: Liver No 914 Yes 126

75.3 60.6

15.9

< 0.001

Spleen No Yes

74.8 69.7

3.7

0.53

B symptoms

No Yes Clinical stage

Mediastinum No Yes

777 264

PATTERNS OF RECURRENCE 396 641

73.7 73.4

0.8

0.362

Bulky mediastinum No 897 Yes 140

74.4 67.9

1.5

0.222

Lung No Yes

77.3 64.3

2.8

0.094

Marrow No

400 55

393

76.2

29

61.2

3.1

0.078

Inguinal nodes No Yes

390 66

78.5 59.8

10.7

0.001

Age < 45 >45

790 259

78.4 59.0

59.2

< 0.001

463 319

82.0 62.3

33.5

< 0.001

585 229

78.1 62.9

15.?

< 0.001

Yes

Albumin

> 36 11 50 per cent, this was scored as a prediction.) These analyses are also disappointing. Without using the statistical model, prediction of complete remission is

Following radiotherapy for localized disease, the factors predicting risk of recurrence are well documented. When patients are carefully selected, surgically staged and treated with extended-field radiotherapy, the recurrence rate is less than 20 per cent. However, unselected clinical stage I and II patients may have relapse rates of over 50 per cent.148 Most such recurrences occur in lymph nodes lying outside the radiotherapy field. Recurrence after chemotherapy occurs in 20-40 per cent of cases and in the great majority this is at sites of previous disease. In the remainder it is generally in closely related sites.149 Most recurrences occur within 3 years of the end of treatment. However, late recurrences are well recognized up to 20 years.150 In one large series of 1360 patients from Stanford University, the actuarial risk of recurrence after 3 years was 12.9 per cent, and 52 patients suffered recurrences between 3 and 15 years.151 Most recurrences of Hodgkin's disease are diagnosed clinically or on chest X-ray. In the Stanford series it is notable that only 13 patients of 52 called attention to their relapse (three by palpating their own nodes; ten by reporting systemic symptoms). The remainder were diagnosed by physicians at follow-up. In the Christie Hospital, Manchester, UK, among 135 relapses, 113 patients reported lumps or systemic symptoms themselves. However, in 22 cases the recurrence was detected by physical examination or tests (most commonly chest X-ray).152 Most recurrences will be detected if patients are asked to return if they have symptoms. A few more will be found by examination and investigations. Frequent, detailed follow-up is unlikely to have a large impact on outcomes.

Hodgkin's disease in special situations 195

HODGKIN'S DISEASE IN SPECIAL SITUATIONS

Hodgkin's disease in pregnancy (see also Chapter 19)

Fertility in Hodgkin's disease

Being a condition predominantly affecting young adults, Hodgkin's disease is occasionally diagnosed during pregnancy, at a rate of between 1 in 1000 and 1 in 6000.165 In fact, some large-scale epidemiologic studies have suggested a protective effect with increasing parity, although it is possible that confounding factors may be responsible for the association.166 In such cases, decisions regarding investigation and therapy are clearly complicated.167,168 The balance between effective treatment of the mother and the potential effects upon the fetus will differ considerably according to the maturity of the gestation and the extent of the disease. While it is necessary to consider each individual case with great care, certain general statements may be made. The first of these is that the prognosis of Hodgkin's disease diagnosed during pregnancy does not appear to differ greatly from that diagnosed at other times, in retrospective series.165,169 The pattern of disease is similar and metastatic involvement of the placenta or fetus is extremely rare.170 The need to limit radiation exposure to the fetus throughout gestation restricts the staging investigations that may be used. Whilst chest X-rays may be performed in the third trimester, the use of CT results in too high an exposure and is not employed. Ultrasound examination or MRI may provide alternative methods, but often staging is incomplete and treatment must be given on a pragmatic basis with limited information. For early pregnancy (up to 20 weeks), limited radiotherapy to sites in the chest may be used, although a full mantle field is thought too likely to result in fetal damage, particularly neurological. Chemotherapy is very rarely used during the first trimester, owing to the very high incidence of malformation or abortion.171 For those mothers presenting during early pregnancy with advanced disease requiring treatment, termination of pregnancy may be the only option offering a reasonable prospect of a cure. In later pregnancy, the options are greater; in some cases, it may be possible to defer full staging and therapy until the fetus reaches adequate maturity and can be delivered. For mothers with localized disease, radiotherapy is an option and the risks of mantle irradiation appear to be acceptable.169 For those with advanced disease there is some information to suggest that chemotherapy may be given relatively safely,171 although growth retardation is commonly seen and the long-term sequelae have not been characterized. Theoretical considerations of germ cell damage make the use of alkylating agents inadvisable.

In males, oligozoospermia, poor motility and an increased proportion of abnormal forms are commonly found at presentation, particularly in patients with advanced disease,153,154 and histopathological changes may be seen in the testes of such patients. In females, although the effects are less well documented, disturbances of menstrual function may occur. Chemotherapy, particularly with alkylating agents, can directly damage spermatogenesis and this damage may be permanent.155,58 Early in the course of treatment with MOPP-like regimens, irreversible azoospermia is seen; this also applies to alternating and hybrid regimens (e.g. MOPP/ABVD, LOPP/EVAP, ChlVPP/EVA, ChlVPP/PABlOE, see Chapter 19). Where alkylating agents are avoided (e.g. in anthracycline-based regimens, such as ABVD) fertility is usually preserved.159 In females, chemotherapy progressively damages and irreversibly destroys ovarian follicles; this manifests as oligomenorrhea or amenorrhea and a reduced reproductive span. These changes occur more often in older women and are again particularly a feature of alkylating agent-based regimens.158,,60-163

Exposure of both male and female gonads to therapeutic radiotherapy results in severe damage to these organs; radiation effects are dose related but the threshold dose for damage may be as low as 0.5 Gy. A dose of 4 Gy will produce permanent infertility in a third of even young women and prolonged, possibly irreversible, sterility in men. The likely effects of treatment with chemotherapy or radiotherapy should be discussed with patients. For males, sperm banking should be offered whenever possible. For females, effective techniques for oocyte or ovarian tissue preservation are desirable; as yet, however, these available remain experimental and not generally available. Embryo storage is generally precluded by the need to stimulate the ovaries artificially for some weeks prior to harvesting of oocytes and subsequent fertilization, thus causing unacceptable delays in starting treatment. For patients remaining fertile after treatment, it is prudent to delay starting a family for at least a year; not least because it is during this time that the risk of relapse is highest but also because of the theoretical risk of mutagenesis. However, children successfully conceived after treatment do not appear to have an increased incidence of congenital or later-onset medical problems.164 Males remaining sterile after chemotherapy do not suffer androgen lack. In females, estrogen production is affected and, where premature menopause is confirmed, hormone replacement therapy should be given.

HIV-related Hodgkin's disease Epidemiologic studies have indicated an increased incidence of Hodgkin's disease among the HIV-positive


population. One such study yielded an odds ratio of 36.6 (95 per cent confidence limits 0-78.12).172 Several series of cases have been reported in the literature and, in all, the clinical characteristics among HIV-positive patients show a bias towards unfavorable features. These include a higher frequency of mixed cellularity histology, systemic symptoms, stage IV disease and extranodal involvement, particularly of the bone marrow.173,176 The finding of Epstein-Barr virus involvement is universal174,175177,178 and the prognosis is generally reported as poor, with median survival between 1 and 2 years.175,179 As for non-Hodgkin's lymphomas, the prognosis correlates to some extent with the severity of HIV-disease, being worse in those with a low CD 4+ count. In one series no patient with initial CD 4 count below 300/ml survived 2 years.173

CONTRASTS WITH NON-HODGKIN'S LYMPHOMA The clinical features and investigation of nonHodgkin's lymphomas (NHLs) are described fully in Chapters 18, 20-23. However, some general comments can be made to highlight important differences from Hodgkin's disease. NHLs are commoner than Hodgkin's disease in the UK in the ratio of 3.5 to I.180 Their incidence is increasing, whereas that of Hodgkin's disease seems stable. The NHLs are a heterogeneous group of malignancies whose behavior varies from indolent to rapidly lethal; high-grade tumors arise in all age groups although their incidence increases with age, while low-grade tumors are generally confined to later life. They are only marginally commoner in men than women and there is a marked geographical variation in incidence. Their presentation is variable; localized lymphadenopathy particularly in the neck is common, as in Hodgkin's disease, but in contrast unusual nodes may be involved, or there may be more generalized bulky and 'centrifugal' lymphadenopathy. Over one-quarter start outside the classic lymph node areas - most often the gut and Waldeyer's ring but almost any tissue can be affected (Table 15.10) - an extreme rarity in Hodgkin's disease. Knowing the stage of the patient's disease is not so important nowadays for determining treatment but it still has a bearing on prognosis. The Ann Arbor criteria are still useful, although sometimes not entirely appropriate because of the protean patterns of nodal and extranodal spread. For example, NHL starting in the Waldeyer's ring is nowadays generally described as being 'extranodal', which is at variance with the original Ann Arbor definitions. This may in part account for the different recorded incidence rates for 'extranodal' lymphoma. In addition, some series report all cases where

the primary presentation is believed to be extranodal, including disseminated disease. The extent of investigation will be determined largely by the clinical status of the patient and the histopathological subtype. In general, full hematological and biochemical investigation is necessary, and radiological investigations must include, at the very least, chest X-ray to detect mediastinal and hilar lymphadenophathy and some investigation to establish the presence or not of abdominal disease. In the past this was often lymphangiography; current 'state of the art' CT scanning has made this redundant, particularly since it is now evident that, unless the lymphoma is truly localized (an uncommon situation), chemotherapy is likely to be needed as part of the planned treatment. Clinical staging tends to underestimate the incidence of systemic disease. Bone marrow biopsy should be assessed, since marrow involvement will be found in over 30 per cent of cases and, in certain forms with a poor prognosis, particularly of the lymphoblastic type, cerebrospinal fluid should be cytologically examined. The clinicopathological heterogeneity of the NHLs makes it very difficult to define prognostic factors. Perhaps the best researched group is that of the diffuse large cell lymphomas. For example, major centers treating this subtype, which accounts for over a third of NHLs, have collaborated to develop an International Prognostic Index (IPI). Based on data from over 3000 patients, this index clearly distinguishes subgroups that differ in terms of tumor response, relapse and overall survival.186 The IPI is based on straightforward clinical and biological data (age, Ann Arbor stage, serum LDH level, performance status and number of extranodal sites of disease). In its age-adjusted simplified version, it enables clinicians to make appropriate choices of treatment, and can be used to select and stratify patients entering prospective clinical trials. Such factors may vary during the course of the disease and in a study of such variations (involving 1271 patients on GELA trials), it was concluded that, while IPI factors are relevant to short-term follow-up, only performance status was predictive of patients' ability to tolerate induction chemotherapy and only tumor stage was predictive of long-term survival.187 Unfortunately, with several other putative prognostic indices, the number of patients assessed is not large enough to give statistically relevant guidelines. Relatively simple predictors of adverse prognosis which merit further study include the following: • • • •

T cell immunophenotype;188 low serum albumin;189,190 raised ferritin;191 raised b2 microglobulin.192

Other more sophisticated but generally expensive and time-consuming investigations take into account the intrinsic biological characteristics of lymphoma cells.193

Contrasts with non-Hodgkin's lymphoma 197

Table 15.10 The incidence of extranodal lymphoma

All NHL Extranodal NHL

8767 1467(17%)

Gastrointestinal Stomach 346 (23.5%) Small intestine 110(7.5%) Large intestine 82 (5.5%) Head and neck Tonsil Nasopharynx Tongue Nose Salivary gland Thyroid Other Skin

142 (9.5%) 37 (2.5%) 20(1.0%) 33 (2.0%) 69 (4.5%) 36 (2.5%) 48 (3.5%) 110(7.5%)

1257 463(37%)a,b

580 236(41 %)a

832 299 (36%)a

2007 394(20%)

87(17.0%) 41 (8.0%) 11 (2.0%)

54 (23.0%) 13(5.5%) 16(6.5%)

46(15.5%)' 56(18.5%)f 16(5.5%)'

53(13.5%) 25 (6.5%) 16(4.0%)

d

25(10.5%) 11 (4.5%) 5 (2.0%) 3(1.0%) 3(1.0%) 4(1.5%) 2(1.0%)

28 (9.5%) 26 (8.5%)

2 (0.5%)

47 (12.0%) 15(4.0%) 5(1.5%) 20 (5.0%) 16(4.0%) 27 (7.0%) 13 (3.5%)

12 (4.0%)

33 (8.5%)

d d

17(3.5%) 17(3.5%) 25 (5.0%) 3 (0.5%)

e

4(1.5%)

56(11.0%)

4(1.5%)

Connective tissues 90 (6.0%)

12 (2.5%)

5 (2.0%)

6 (2.0%)

11 (3.0%)

Bone

69 (4.5%)

41 (8.0%)

6 (2.5%)

19(6.5%)

19(5.0%)

Lung

53 (3.5%)

24 (5.0%)

11 (4.5%)

7 (2.5%)

3(1.0%)

Breast

33 (2.0%)

6(1.0%)

5 (2.0%)

—

5(1.5%)

Testis

23(1.5%)

15(3.0%)

4(1.5%)

1 (0.5%)

14 (3.5%)

Orbit (and eye)

32 (2.0%)

4(1.0%)

7 (3.0%)

7 (2.5%)

31 (8.0%)

c

8

Central nervous system

23(1.5%)

33 (6.5%)

15(6.5%)

3(1.0%)

34 (9.0%)

Marrow

—

89(17.5%)

33 (14.0%)

—

—

Liver

6 (0.5%)

27 (5.0%)

—

—

1 (0.5%)

Female genital

16(1.0%)

6(1.0%)

1 (0.5%)

2(0.5)

2(0.5)

Others

89 (6.0%)

29 (5.5%)

9 (4.0%)

64(21.5%)

4(1.0%)

a b c d e f g

Including disseminated disease at presentation. Including cases with more than one presenting site. Including orbital connective tissue. Excluding Waldeyer's ring. Excluding mycosis fungoides. Excluding 47 cases of gastrointestinal presentation where the origin is uncertain or multiple. Brain only.

Although numbers of patients studied are small, the following predictive factors have been reported: • • •

•

genetic abnormalities - a number of these have been described (see Chapter 9); abnormalities in cell cycle regulation - in general high proliferative activity adversely affects survival;194-197 pattern of expression of adhesion molecules - variably reported to be predictive of outcome, but CD 44 (hyaluronate receptor) expression in particular seems to be an adverse marker;198-199 cytokine levels - poor outcome has been described

•

with elevated levels of IL-6, IL-10 and tumor necrosis factor oc (TNFa); 200-202 lymphoma cell chemosensitivity indicators - MDR and bcl-2 expression at diagnosis are unfavorable prognostic factors.203,204

The shortcomings of the Ann Arbor staging classification are particularly well demonstrated with the follicular lymphomas. In a study of 398 patients entered into British National Lymphoma Investigation trials between 1974 and 1980, the Ann Arbor system fared poorly as a prognostic indicator; most powerfully significant factors


for cause-specific survival were the number of lymph node regions involved, splenomegaly, constitutional symptoms and age. With the exception of splenomegaly, other studies have shown similar findings.205,208 The factors described above for aggressive NHLs186 may also be relevant to the follicular lymphomas,209 and likewise molecular and cytogenetic markers may be of prognostic value. However, it is still difficult to pick out a group of patients with such adverse features as to warrant more intensive (or experimental) treatment at presentation.

16.

17.

18.

19.

REFERENCES 1. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Med Chir Trans 1832; 17: 68-114. 2. Wilks Sir S. Cases of enlargement of the lymphatic glands and spleen (or Hodgkin's disease) with remarks. , Guy's Hospital Rep 1865; 11: 56-67. 3. Sternberg C. Uber eine eigenartige unter dem Bilde der Pseudoleukamie verlaufende Tuberculose des lymphatischen Apparates. Z Heilk 1898; 19: 21-90. 4. Reed DM. On the pathological changes in Hodgkin's disease, with especial reference to its relation to tuberculosis. Johns Hopkins Hasp Rep 1902; 10:133-96. 5. Olivier A, Ranvier L. Observation pour sevir a I'histoire de I'adenie Memoires lus a la societe de biologie, 1867: 99-112. 6. Tuckwell HM. Enlargement of lymph glands in the abdomen with formation of peculiar morbid growths in the spleen and peritoneum. Trans Path Soc. London, 1870; 21: 362-5. 7. Langans T. Das maligne lymphosarkom. VirchowsArch PathAnat 1872; 54: 509-37. 8. Greenfield S. Specimens illustrative of the pathology of lymphadenoma and leucocythaemia. Trans Path Soc. London,1878; 29:272-304. 9. GowersWR. Hodgkin's disease. In: Reynolds JRed./l system of medicine. London: Macmillan, 1878: 306-52. 10. Pusey WA. Cases of sarcoma and of Hodgkin's disease treated by exposure to x rays: a preliminary report. JAMA 1902; 38:166-9. 11. Gilbert R. Radiotherapy in Hodgkin's disease (malignant granulomatosis): anatomic and clinical foundations; governing principles; results. Am Roentgenol 1939; 41: 198-241. 12. Peters MV. A study of survivals in Hodgkin's disease treated radiologically. Am J Roentgenol 1950; 63: 299-311. 13. Kaplan HS. The radical radiotherapy of regionally localised disease. Radiology 1962; 78: 553-61. 14. Kaplan HS. Long term results of palliative and radical radiotherapy of Hodgkin's disease. Cancer Res 1966; 26: 1250-2. 15. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ,

20.

21.

22.

23.

24.

25. 26.

27.

28.

29.

30.

31.

Culman AZ, McLennon MT. Nitrogen mustard therapy.7 Am Med Ass 1946; 132:126-32. Lacher ML), DurantJR. Combined vinblastine and chlorambucil therapy of Hodgkin's disease. Ann Intern Med 1965; 62: 468-76. De Vita VT, Serpick A, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 1970; 73: 881-95. De Vita VT, Simon RM, et al. The curability of advanced Hodgkin's disease with chemotherapy. Ann Intern Med 1980; 92: 587-95. Correa P, O'Conor GT. Epidemiologic patterns of Hodgkin's disease. IntJ Cancer 1971; 8:192-201. Hancock BW, Vaughan HG, Vaughan HB, Bennett MH. LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial. 7 Clin Oncol 1992; 10:1252-8. Cullen MH, Stuart NS, Woodroffe C, Murphy A, Fletcher J, Blackledge GR. ChlVPP/PABlOE and radiotherapy in advanced Hodgkin's disease.J Clin Oncol 1994; 12: 779-87. Kennedy BJ, Loeb V, Peterson VM, et al. National survey of patterns of care for Hodgkin's disease. Cancer 1985; 56: 2547-56. Atkinson MK, McElwain TJ, Peckham MJ, Thomas PRM. Hypertrophic pulmonary osteoarthropathy in Hodgkin's disease; reversal with chemotherapy. Cancer 1976; 38: 1729-34. Selby P, McElwain T. Clinical features of Hodgkin's disease. Hodgkin's disease. Oxford: Blackwell Science, 1987; 94-125. Kaplan HS. Hodgkin's disease. 2nd edn. Cambridge, MA: Harvard University Press, 1980. Magrini SM, Cellai E, Papi MG, Pertid M, Lastrucci L, Ponticelli P. Therapeutic implications of the peculiar clinical characteristics of Hodgkin's disease in clinical stages l-ll with isolated neck presentation. Radiol Med. Torino, 1995; 90:108-12. Enrici RM, Osti MF, Anselmo AP, Banelli E, Cartoni C, Sbarbati S. Hodgkin's disease stage I and II with exclusive subdiaphragmatic presentation. The experience of the Departments of Radiation Oncology and Hematology, University 'La Sapienza' of Rome. Tumori 1996; 82: 48-52. Barrett A, Gregor A, McElwain TJ, Peckham MJ. Infradiaphragmatic presentation of Hodgkin's disease. Clin Radiol 1981; 32: 221-4. Krikorian JG, Portlock CS, Rosenberg SA, Kaplan HS. Hodgkin's disease, stages I and II, occurring below the diaphragm. Cancer 1979; 43:1866-71. Dimitrovsky E, Martin SE, et al. Lymph node aspiration in the management of Hodgkin's disease.) Clin Oncol 1986; 4: 306-10. Rosenberg SA, Kaplan HS. Evidence for an orderly progression in the spread of Hodgkin's disease. Cancer Res 1966; 26:1225-31.

References 199

32. Smithers DW. Spread of Hodgkin's disease. Lancet 1970; i: 1262-7.

52. Harper PG, Fischer C, MacLennan K, Souhami RL Presentation of Hodgkin's disease as an endobronchial

33. Smithers DW. Modes of spread. In: Smithers DW, ed. Hodgkin's disease. Edinburgh: Churchill Livingstone, 1973:107-17.

lesion. Cancer 1984; 53:147-50. 53. Perez-Soler R, McLaughlin P, Velasquez WS, et al.

34. Mauch PM, Kalish LA, Kadin M, Coleman CN, Osteen R, Hellman S. Patterns of presentation of Hodgkin disease: implications for etiology and pathogenesis. Cancer 1993; 71: 2062-71. 35. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin's disease staging. Cancer Res 1971; 31:1860-1. 36. Specht L, Nordentoft AM, Cold S, Clausen NT, Nissen Nl.

Clinical features and results of management of superior vena cava syndrome secondary to lymphoma. J Clin Oncol 1984; 2: 260-6. 54. Sextro M, Diehl V, Franklin J, Hansmann ML, Anagnostopoulos I. Lymphocyte predominant Hodgkin's disease - a workshop report. European Task Force on Lymphoma. Ann Oncol 1996; 4: 61-5. 55. Aisenberg AC, Kaplan MM, Rieder SG, Goldman JM.

Tumor burden as the most important prognostic factor in early stage. Cancer 1988; 61:1719-27.

Serum alkaline phosphatase at the onset of Hodgkin's disease. Cancer 1970; 26: 318-26. 56. Glees JP, Barr LC, McElwain TJ, Peckham MJ, Gazet J-C.

37. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos

The changing role of staging laparotomy in Hodgkin's

GP. Report of a committee convened to discuss the evaluation and staging of Hodgkins disease, J Clin Oncol 1989; 7:1630-6.

disease: a personal series of 310 patients. BrJ Surg 1982; 69:181-7. 57. Thyss A, Schieder M, Caldani C, Viot M, Bourry J. Re-

38. Glatstein E, Guernsey JM, Rosenberg SA, Kaplan HS. The

evaluation of alkaline phosphatase measurement

value of laparotomy and splenectomy in the staging of Hodgkin's disease. Cancer 1969; 24: 709-18. 39. Glatstein E, Trueblood HW, Enright LP, Rosenberg SA, Kaplan HS. Surgical staging of abdominal involvement

during Hodgkin's disease by electrophoretic isoenzyme separation. BrJ Cancer 1985; 52:183-7. 58. Fabian CJ, Mansfield CM, Dixon DO, et al. Incidence of liver involvement and correlation of biopsy results with

in unselected patients with Hodgkin's disease. Radiology 1970; 97: 425-32. 40. Dorfman RF. Relationship of histology to site in Hodgkin's disease. Cancer Res 1971; 31:1786-93. 41. LandbergT, Larsson L-E. Hodgkin's diseaseretrospective clinico-pathologic study in 149 patients. Acta Radiol 1969; 8: 390-414. 42. Yu A, Steinfeld AD. Hodgkin's disease presenting in epitrochlear nodes. Med Pediat Oncol 1984; 12: 244-6. 43. Cionini L, Bastiani P, Biti G, et al. Waldeyer's ring involvement in Hodgkin's disease. Radiother Oncol 1985; 3:299-302. 44. Kapadia SB, Roman LN, Kingma DW, Jaffe ES, Frizzera G. Hodgkin's disease of Waldeyer's ring. Clinical and histoimmunophenotypic findings and association with Epstein-Barr virus in 16 cases. Am J Surg Pathol 1995; 19:1431-9. 45. Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease: a clinicopathologic study of 659 cases. Cancer 1981; 49: 1848-58. 46. McDonald JS. Lung involvement in Hodgkin's disease. Thorax 1977; 32: 664-7. 47. Whitcomb ME, Schwartz Ml, Keller AR, et al. Hodgkin's disease of the lung. Am Rev Resp Dis 1972; 106: 79-85. 48. Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease at autopsy: 1972-1977. Cancer 1981; 47:1852-62. 49. Homan R, Lechner K, Neumann E, et al. Primary Hodgkin's disease of the lung. Blut 1983; 47: 231-5.

Ann Arbor clinical criteria and response to chemotherapy in advanced Hodgkin's disease: a SWOG study. In: Cavalli F, Bonadonna G, Rosencweig M, eds. Malignant lymphoma and Hodgkin's disease: experimental and therapeutic advances. The Hague: Martinus Nijhoff, 1985: 409-16. 59. Trewby PN, Portmann B, Brinkley DM, Williams R. Liver disease as the presenting manifestation of Hodgkin's disease. Q J Med 1979; 189:137-50. 60. Sacks E, Donaldson SS, Gordon J, et al. Epitheloid granulomas associated with Hodgkin's disease. Cancer 1979; 41: 562-7. 61. Aderka D, Kraus M, Avido I, etal. Hodgkin's disease and non-Hodgkin's lymphoma masquerading as idiopathic liver granulomas. Am J Gastroenterol 1984; 79: 642-4. 62. Trier H, Christensen M. Hodgkin's disease in sarcoidosis. Acta Med Scand 1985; 218:137-40. 63. Perera DR, Greene ML, Fenster LF. Cholestasis associated with extrabiliary Hodgkin's disease; report of three cases and review of four others. Gastroenterology 1974; 67: 680-5. 64. Peck B. Hypertrophic osteoarthropathy with Hodgkin's disease in the mediastinum.y/4M/4 1976; 238:1400-1. 65. Friedman M, Kim TH, Panahon AM. Spinal cord compression in malignant lymphoma. Treatment and results. Cancer 1976; 37:1485-91. 66. Higgins SA, Peschel RE. Hodgkin's disease with spinal cord compression. A case report and a review of the

50. Yousem SA, Weiss LM, Colby TV. Primary pulmonary

literature. Cancer 1995; 75: 94-8. 67. Sapozink MD, Kaplan HS. Intracranial Hodgkin's disease.

Hodgkin's disease. Cancer 1986; 57:1217-24. 51. Selby P, McElwain T. Hodgkin's disease. Oxford:

68. Vera R, Enriquez R, Papac R. Hodgkin's disease,

Blackwell Scientific Publications, 1987.

Cancer 1983; 52:1301-7. intracranial involvement. Amy Clin Oncol 1985; 8: 73-6.

200 Hodgkin's disease: clinical features 69. Dillman RO, Much J, Greco CM, et al. Leptomeningeal Hodgkin's disease. Ann Intern Med 1980; 92: 714-15. 70. Orlowski EP, Hansen RM, Anderson T, et al. Hodgkin's disease with leptomeningeal involvement. Cancer 1984; 53:1833-5. 71. Bartl R, Frisch B, Burkhardt R, Huhn D, Pappenberger R. Assessment of bone marrow histology in Hodgkin's disease: correlation with clinical factors. BrJ Haematol 1982;51:345-60. 72. Carde P, MacKintosh FR, Rosenberg SA. A dose and time response analysis of the treatment of Hodgkin's disease with MOPP chemotherapy.) Clin Oncol 1983; 1: 146-53. 73. Hayhoe FGJ, Burns GF, Cawley JC, Stewart JW. Cytochemical, ultrastructural and immunological studies of circulating Reed-Sternberg cells. BrJ Haematol 1978; 38: 485-90. 74. Linch DC, Berliner N, O'Flynn, et al. Hodgkin cell leukaemia of B cell origin. Lancet 1985; i: 78-80. 75. Filly R, Blank N, Castellino RA. Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin's disease and nonHodgkin's lymphoma. Radiology 1976; 120: 277-81. 76. Huber SC, Webb WR, Kuykendall JD, Meier WL Abnormal cardiac silhouette in a patient with Hodgkin's disease. JAMA 1978; 239: 2785-6. 77. ReiffersJ, Pars J B, HuguesA, Hoerni B. Hodgkin's disease localised in the thyroid gland. Nouv Presse Med 1976; 5:1590. 78. Al Kutoubi MA, Patep PR, Coulter C. Laryngeal involvement in Hodgkin's disease. BrJ Radiol 1985; 58: 184-6. 79. Champion A, Coup AJ, Hancock BW. Hodgkin's disease and chronic renal failure. Cancer 1976; 38:1867-8. 80. Hung LHY, Kartz DM. Hodgkin's disease of the endometrium. Arch Pathol Lab Med 1983; 109: 952-3. 81. Routledge RC, Haun IM, Morris Jones PH. Hodgkin's disease complicated by the nephrotic syndrome. Cancer 1976; 38:1735-40. 82. Shapiro CM, VanderLaan BF, Wellington J, Sloan DR. Nephrotic syndrome in two patients with cured Hodgkin's disease. Cancer 1985; 55:1799-804. 83. Hancock BW, Richmond J, Powell T, Emmanuel IG. Intrathoracic Hodgkin's disease presenting as hypertrophic osteoarthropathy. BrJ Radiol 1976; 49: 647-9. 84. Dimopoulos MA, Cabanillas F, Lee JJ, Swan F, Fuller L, Allen PK. Prognostic role of serum beta 2-microglobulin in Hodgkin's disease.) Clin Oncol 1993; 11:1108-11. 85. Jochelson MS, Herman TS, Stomper PC, Mauch PM, Kaplan WD. Planning mantle radiation therapy in patients with Hodgkin disease. Am J Roentgenol 1988; 151:1229-31. 86. Hagemeister FB, Purugganan R, Podoloff DA, Hess M, Rodriguez MA. The gallium scan predicts relapse in patients with Hodgkin's disease. Ann Oncol 1994; 2: 59-63.

87. Salloum E, Brandt DS, Caride VJ, Cornelius E, Zelterman D, Cooper DL. Gallium scans in the management of patients with Hodgkin's disease: a study of 101 cases. Blood 1996; 10(suppl 1): 229a. 88. Devizzi L, Gasparini M, Santoro A, et al. The role of gallium-67 scan in staging and restaging patients with Hodgkin's disease. Ann Oncol 1996; 7(suppl 3): 35. 89. Bangerter M, Griesshammer M, Binder T, Hafner M, Heimpel H, Reske SN. New diagnostic imaging procedures in Hodgkin's disease. Ann Oncol 1996; 4: 55-9. 90. Rosenberg SA. Hodgkin's disease of the bone marrow. Cancer Res 1971; 31:1733-6. 91. Macintyre EA, Vaughan Hudson B, Linch DC, Vaughan Hudson G, Jelliffe AM. The value of staging bone marrow trephine biopsy in Hodgkin's disease. EurJ Haematol 1987; 39: 66-70. 92. Munker R, Hasenclever D, Brosteanu 0, Hiller E, Diehl V. Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases, y Clin Oncol 1995; 13: 403-9. 93. Haybittle JL, Hayhoe FG, Easterling MJ, Jelliffe AM, Bennett MH. Review of British National Lymphoma Investigation studies of Hodgkin's disease and development of prognostic index. Lancet 1985; 1: 967-72. 94. Henry-Amar M, Friedman S, Hayat M, Somers R, Meerwaldt JH, Carde P. Erythrocyte sedimentation rate predicts early relapse and survival in early-stage Hodgkin disease. Ann Intern Med 1991; 114: 361-5. 95. Wrigley PFM, Hamilton Fairley G, Matthias JQ. Anaemia and bone marrow involvement in Hodgkin's disease. In: Smithers DW, ed. Hodgkin's disease. Edinburgh: Churchill Livingstone, 1973:154-63. 96. Eisner E, Ley AB, Meyer K. Coomb's positive haemolytic anaemia in Hodgkin's disease. Ann Intern Med 1967; 66: 258-73. 97. Levine AM, Thornton P, Forman SJ, et al. Positive Coomb's test in Hodgkin's disease: significance and implications. Blood 1980; 55: 607-10. 98. Waddell CC, Cino PL. Immune thrombocytopenia purpura occurring in Hodgkin's disease after splenectomy. Am J Hematol 1979; 7: 381-7. 99. Murphy WG, Perry DJ, Allan NC, Stockdill G. Hodgkin's disease presenting as idiopathic thrombocytopenic purpura. Postgrad Med j 1984; 60: 614-15. 100. Weitberg AB, Harmon DC. Autoimmune neutropenia, haemolytic anaemia and reticulocytopenia in Hodgkin's disease. Ann Intern Med 1984; 100: 702-4. 101. Garcia R, HernandezJM, Caballero MD, Gonzalez M, Galende J. Serum lactate dehydrogenase level as a prognostic factor in Hodgkin's disease. BrJ Cancer 1993; 68:1227-31. 102. Zaloga GP, Eil C, Medbury CA. Humoral hypercalcaemia in Hodgkin's disease. Arch Intern Med 1985; 145:155-6. 103. Gause A, Scholz R, Klein S, et al. Increased levels of circulating interleukin-6 in patients with Hodgkin's disease. Haematol Onco/1991; 9: 307-13.

References 201 104. Denizot Y, Fixe P, Liozon E, Brigaudeau C, Praloran V. Serum IL-6 concentrations in lymphomas. BrJ Haematol 1995; 90: 731-2. 105. Blay J-Y, Farcet J-P, Lavaud A, Radoux D, Chouaib S. Serum concentrations of cytokines in patients with Hodgkin's disease. EurJ Cancer Part A1994; 30A: 321-4. 106. Gorschluter M, Bohlen H, Hasenclever D, Diehl V, Tesch H. Serum cytokine levels correlate with clinical parameters in Hodgkin's disease. Ann Oncol 1995; 6: 477-82. 107. KurzrockR, Redman J, Cabanillas F, Jones D, RothbergJ, Talpaz M. Serum interleukin levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms. Cancer Res 1993; 53: 2118-22. 108. Sarris AH, Straus D, Preti A, et al. A prognostic model for advanced Hodgkin's disease at MD Anderson validated with an independent set of patients treated at Memorial Sloan-Kettering. Blood 1996; 88(suppl 1): 226a. 109. Sarris AH, Kliche KO, Pethambaram P, etal. Interleukin10 levels are often elevated in serum of adults with Hodgkin's disease and are associated with inferior failure-free survival. Ann Oncol 1999; 10: 433-40. 110. Hamon MD, Unal E, Macdonald I, Shamim F, Boesen E, Prentice HG. Plasma soluble interleukin 2 receptor levels in patients with malignant lymphoma are correlated with disease activity but not cellular immunosuppression. Leak Lymphoma 1993; 10:111-5. 111. Gause A, Jung W, Schmits R et al. Soluble CD8, CD25 and CD30 antigens as prognostic markers in patients with untreated Hodgkin's lymphoma. Ann Oncol 1992; 3(suppl 4): 49-52. 112. Gnant M, Mader RM, Djavanmard M, Jakesz R, Steger GG. Soluble interleukin-2 receptor is a powerful prognostic marker in Hodgkin's disease. Proceedings of the Annual Meeting of the American Society of Clinical Oncology 1995: 648a. 113. Enblad G, Sundstrom C, Gronowitz S, Glimelius B. Serum levels of interleukin-2 receptor (CD25) in patients with Hodgkin's disease, with special reference to age and prognosis. Ann Oncol 1995; 6: 65-70. 114. Nadali G, Vinante F, Ambrosetti A, et al. Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin's disease and correlate with clinical features and prognosis. J Clin Oncol 1994; 12: 793-7. 115. Gause A, Pohl C, Tschiersch A, et al. Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin's disease. Blood 1991; 77:1983-8. 116. Christiansen I, Enblad G, Kalkner KM, Gidlof C, Glimelius B, Totterman TH. Soluble ICAM-1 in Hodgkin's disease: a promising independent predictive marker for survival. Leuk Lymphoma 1995; 19: 243-51. 117. Gruss H-J, Dolken G, Brach MA, Mertelsmann R, Herrmann F. The significance of serum levels of soluble 6- kDa receptors for tumor necrosis factor in patients with Hodgkin's disease. Leukemia 1993; 7:1339-43.

118. DenzH, Prth B, Weiss G, et al. Serum soluble tumour necrosis factor receptor 55 is increased in patients with haematological neoplasiasand is associated with immune activation and weight loss. EurJ Cancer 1993; 29A: 2232-5. 119. Gruss H-J, Dolken G, Brach MA, Mertelsmann R, Herrmann F. Serum levels of circulating ICAM-1 are increased in Hodgkin's disease. Leukemia 1993; 7: 1245-9. 120. Nadali G, Vinante F, Rigo A, et al. Correlation between clinical features and circulating levels of soluble intercellular adhesion molecule-1 in Hodgkin's disease. Int J Clin Lab Res 1995; 25: 84-7. 121. Pizzolo G, Vinante F, Nadali G,et al. ICAM-1 tissue overexpression associated with increased serum levels of its soluble form in Hodgkin's disease. BrJ Haematol 1993;84:161-2. 122. Tubiana M, Henry-Amar M, Burgers MV, et al. Prognostic significance of erythrocyte sedimentation rate in clinical stage ll-lll of Hodgkin's disease. J Clin Oncol 1984; 2:194-200. 123. Carde P, Burgers JM, Henry AM, Hayat M, Sizoo W. Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors. J Clin Oncol 1988; 6: 239-52. 124. Mauch P, Larson D, Osteen R, et al. Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 1990; 8: 257-65. 125. Kaldor JM, Day NE, Clarke EA, Van LF, Henry AM. Leukemia following Hodgkin's disease. N EnglJ Med 1990; 322: 7-13. 126. Carde P, Hagenbeek A, Hayat M, et al. Clinical staging versus laparotomyand combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1993; 11: 2258-72. 127. Abrahamsen AF, Hannisdal E, Nome 0, et al. Clinical stage I and II Hodgkin's disease: long-term results of therapy. Ann Oncol 1996; 7:145-50. 128. Cox DR. Regression models and life tables. J R Stat Soc 1972; 34: 187. 129. Hasenclever D, Diehl V for the International Prognostic Factors Project on Advanced Hodgkin's Disease. A prognostic score for advanced Hodgkin's disease. N Engl J Med 1998; 339:1506-14. 130. Hasenclever D, Diehl V. A numerical index to predict tumour control in advanced Hodgkin's disease. Blood 1996; 88(suppl 1): 673a. 131. Dady PJ, McElwain TJ, Austin DE, et al. Five years experience with ChlVPP: effective low-toxicity combination chemotherapy for Hodgkin's disease. BrJ Cancer 1982; 45: 851-9. 132. Gobbi PG, Cavalli C, Federico M, Bertoloni D, Di PU, Rossi A. Hodgkin's disease prognosis: a directly predictive equation. Lancet 1988; 1: 675-9.

202 Hodgkin's disease: clinical features 133. Mauch P, Hellman S. Mediastinal Hodgkin's disease. Haematol Oncol 1984; 2: 69-71. 134. Mauch P, Tarbell N, Weinstein H, et al. Stage IA and MA supradiaphragmatic Hodgkin's disease: prognostic factors in surgically staged patients treated with mantle and para-aortic irradiation.J Clin Oncol 1988; 6: 1576-83. 135. TharTL, Million RR, Housner RJ, et al. Hodgkin's disease stage I and II, relationship of recurrence to size, radiation and dose and number of sites involved. Cancer 1979; 43:1101-5. 136. Lee CK, Bloomfield CD, Goldman Al, et al. Prognostic significance of mediastinal involvement in Hodgkin's disease treated with curative radiotherapy. Cancer 1980; 46: 2403-9. 137. Liew KH, Easton D, Horwich A, Barrett A, Peckham MJ. Bulky mediastinal Hodgkin's disease, management and prognosis. Haematol Oncol 1984; 2: 45-59. 138. Cosset JM, Henry-Amar M, Carde P, et al. The prognostic significance of large mediastinal masses in the treatment of Hodgkin's disease. The experience of the Institute Gustave-Roussy. Haematol Oncol 1984; 2: 33-43. 139. Zucali R, Zanini M, Banfi A. Significance of mediastinal involvement in early Hodgkin's disease. Haematol Oncol 1984; 2: 72-4. 140. Radford JA, Cowan RA, Ryder WDJ, et al. Four weeks of neo-adjuvant chemotherapy significantly reduces the progression rate in patients treated with limited field radiotherapy for clinical stage IA/IIA Hodgkin's disease. Results of a randomised pilot study. Ann Oncol 1996; 7(suppl 3): 10. 141. Bjorkholm M, Wedelin C, Holm G, Essy-Ehsing B. Familial longevity and prognosis in Hodgkin's disease. Cancer 1984; 54:108-92. 142. Walker LG, Ratcliffe MA, Dawson AA. Does personality affect survival in lymphoma patients? Psychol Oncol 1995; 4: 98. 143. Wagstaff J, Gregory WM, Swindell R, Crowther D, Lister PA. Prognostic factors for survival in stage NIB and IV Hodgkin's disease: a multivariate analysis comparing two specialist treatment centres. BrJ Cancer 1988; 58: 487-92. 144. Proctor SJ, Taylor P, Donnan P, Boys R, Lennard A, Prescott RJ. A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. EurJ Cancer 1991; 27: 624-9. 145. Ferme C, Bastion Y, Brice P, et al. for the Groupe d'Etudes des Lymphomes de'Adulte. Prognosis of patients with advanced Hodgkin's disease. Cancer 1997; 80:1124-33. 146. Korn EL, Simon R. Measures of explained variation for survival data. Stat Med 1990; 9: 487-503. 147. Selby P, Patel P, Milan S, et al. ChlVPP combination chemotherapy for Hodgkin's disease: long-term results. BrJ Cancer 1990; 62: 279-85.

148. Tubiana M, Henry-Amar M, Hayat M. Prognostic significance of the number of involved areas in the early stages of Hodgkin's disease. Cancer 1984a; 54: 885-94. 149. Young RC, Canellos GP, Chabner BA, Hubbard SM, De Vita VT Jr. Patterns of relapse in advanced Hodgkin's disease treated with combination chemotherapy. Cancer 1978;42:1001-7. 150. Oza AM, Ganesan TS, Leahy M, et al. Patterns of survival in patients with Hodgkin's disease: long follow up. Ann Oncol 1993; 4: 385-92. 151. Herman TS, Hoppe RT, Donaldson SS, et al. Late relapse among patients treated for Hodgkin's disease. Ann Intern Med 1985; 102: 292-7. 152. Radford JA, Eardley A, Woodman C, Crowther D. Follow up policy after treatment for Hodgkin's disease: too many clinic visits and routine tests? A review of hospital records. BrMedJ 1997; 314: 343-6. 153. Vigersky R, Chapman RM, BerenbergJ, et al. Testicular dysfunction in untreated Hodgkin's disease. Am J Med 1982; 73: 482-6. 154. Hendry WF, Stedronska J, Jones CR, Blackmore CA, Barrett A, Peckham MJ. Semen analysis in testicular cancer and Hodgkin's disease: pre-and post-treament findings and implications for cryopreservation. BrJ Urol 1983; 55: 769-73. 155. Chapman RM, Sutcliffe SB, Rees LH, et al. Cyclical combination chemotherapy and gonadal function. Lancet 1979; 1:285-9. 156. Waxman JHX, Terry YA, Wrigley PFM, et al. Gonadal function in Hodgkin's disease: long-term follow-up of chemotherapy. BrMedJ 1982; 285:1612-13. 157. Whitehead E, Shalet SM, Blackledge G, et al. The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male. Cancer 1982; 49: 418-22. 158. Clark ST, Radford JA, Crowther D, Swindell R, Shalet SM. Gonadal function following chemotherapy for Hodgkin's disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol 1995; 13:134-9. 159. Viviani S, Santoro A, Ragni G, et al. Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. EurJ Cancer Clin Oncol 1985; 21: 601-5. 160. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic-induced ovarian failure in women with Hodgkin's disease. JAMA 1979; 242:1877-81. 161. Horning SJ, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N EnglJ Med 1981; 304:1377-82. 162. Schilsky RL, Sherins RJ, Hubbard SM, Wesley MN, Young RC, DeVita VT. Long term follow-up of ovarian function in women treated with MOPP chemotherapy for Hodgkin's disease. 4m7 Med 1981; 71: 552-6. 163. Whitehead E, Shalet SM, Blackledge G, Todd I, Crowther D, Beardwell CG. The effect of combination chemotherapy on ovarian function in women treated for Hodgkin's disease. Cancer 1983; 52: 988-93.

References 203 164. Swerdlow AJ, Jacobs PA, Marks A, et al. Fertility, reproductive outcomes, and health of offspring, of patients treated for Hodgkin's disease: an investigation including chromosome examinations. BrJ Cancer 1996; 74: 291-6. 165. Lishner M, Zemlickis D, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Maternal and foetal outcome following Hodgkin's disease in pregnancy. BrJ Cancer 1992; 65:114-17. 166. Kravdal 0, Hansen S. Hodgkin's disease: the protective effect of childbearing. IntJ Cancer 1993; 55: 909-14. 167. Sutcliffe SB. Treatment of neoplastic disease during pregnancy: maternal and fetal effects. Clin Invest Med 1985; 8: 333-8. 168. Doll DC, Ringenberg QS, Yarbro JW. Management of cancer during pregnancy. Arch Intern Med 1988; 148: 2058-64. 169. Woo SY, Fuller LM, Cundiff JH, Bondy ML, Hagemeister FB, Mclaughlin P. Radiotherapy during pregnancy for clinical stages IA-IIA Hodgkin's disease. IntJ Radial Oncol Biol Phys 1992; 23: 407-12. 170. Rothman LA, Cohen CJ, Astarloa J. Placental and fetal involvement by maternal malignancy: a report of rectal carcinoma and review of the literature. AmJObstet Gynecol 1973; 116:1023-34. 171. Yahalom J. Treatment options for Hodgkin's disease during pregnancy. Leuk Lymphoma 1990; 2: 151-61. 172. Serraino D, Pezzotti P, Cozzi-Lepri A, Grigoletti E, Tirelli U, Rezza G. Incidence of Hodgkin's disease in a cohort of HIV seroconverters. Proc ASC01996.15: a847. 173. Levy R, Colonna P, Tourani JM, Gastaut JA, Brice P, Raphael M. Human immunodeficiency virus associated Hodgkin's disease: report of 45 cases from the French registry of HIV-associated tumors. Leuk Lymphoma 1995; 16:451-6. 174. Bellas C, Santon A, Manzanal A, et al. Pathological, immunological, and molecular features of Hodgkin's disease associated with HIV infection: comparison with ordinary Hodgkin's disease. AmJSurg Pathol 1996; 20: 1520-4. 175. Levine AM. HIV-associated Hodgkin's disease: biologic and clinical aspects. Hematol Oncol Clin North Am 1996; 10:1135-48. 176. Errante D, Zagonel V, Vaccher E, Serraino D, Bernardi D, Sorio R. Hodgkin's disease in patients with HIV infection and in the general population: comparison of clinicopathological features and survival.Ann Oncol 1994; 2: 37-40. 177. Gloghini A, Boiocchi M, De RV, etal. High incidence of monoclonal EBV episomes in Hodgkin's disease and anaplastic large-cell Ki-1-positive lymphomas in HIV-1positive patients. IntJ Cancer 1993; 54: 53-9. 178. Herndier BG, Sanchez HC, Chang KL, Chen YY, Weiss LM. High prevalence of Epstein-Barr virus in the Reed-Stern berg cells of HIV- associated Hodgkin's disease. Am J Pathol 1993; 142:1073-9.

179. Tirelli U, Errante D, Dolcetti R, Gloghini A, Serraino D, Vaccher E. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995; 13:1758-67. 180. Leukaemia Research Fund Centre for Clinical Epidemiology. An Atlas of Leukaemia and Lymphoma. London: Leukaemia Research Fund, 1990: 81-9. 181. Freeman C, Berg JW, Cutler SJ. Occurrence and Prognosis of Extranodal Lymphomas. Cancer 1972; 29: 252-60. 182. d'Amore F, Christensen BE, Brincker H, et al. Clinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas. EurJ Cancer 1991; 27:1201-8. 183. Otter R, Gerrits WBJ, Sandt MMVD, et al. Primary extranodal and nodal non-Hodgkin's lymphoma. A survey of a population-based registry. EurJ Cancer Clin Oncol 1989; 25:1203-10. 184. Modan B, Shani M, Goldman B, et al. Nodal and extranodal malignant lymphoma in Israel: an epidemiological study. BrJ Haematol 1969; 16: 53-9. 185. Dobson LS, Hancock H, Bright N, Robinson MH, Hancock BW. Localised non-Hodgkin's lymphoma: the Sheffield Lymphoma Group experience (1970-1995). Int JOncol1998;13:1313-18. 186. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive nonHodgkin's lymphoma. N EnglJ Med 1993; 329: 987-94. 187. Mounier N, Morel P, Haioun C, et al. fortheGroupe d'Etudes des Lymphomes de'Adulte: a multivariate analysis of the survival of patients with aggressive lymphoma. Cancer 1998; 82:1952-62. 188. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms. A proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92. 189. Cowan RA, Jones M, Harris M, et al. Prognostic factors in high and intermediate grade non-Hodgkin's lymphoma. BrJ Cancer 1989; 59: 276-82. 190. Coiffier B, Gisselbrecht C, Vose JM, et al. Prognostic factors in aggressive malignant lymphomas. Description and validation of a prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol 1991; 9: 211-19. 191. Hancock BW, May K, Bruce L, et al. Haematological and immunological markers in malignant lymphoma. TumourDiagWSQ; 1:140-4. 192. Johnson PWM, Whelan J, Longhurst S, et al. b-2 Microglobulin: a prognostic factor in diffuse aggressive non-Hodgkin's lymhomas. BrJ Cancer 1993; 67: 792-7. 193. Salles G. Towards new prognostic factors in diffuse large cell non-Hodgkin's lymphoma. Ann Oncol 1996; 7: 993-6. 194. Cowan RA, Harris M, Jones M, et al. DNA content in high and intermediate grade non-Hodgkin's lymphoma. Prognostic significance and clinicopathological correlations. BrJ Cancer 1989; 60: 904-10.

204 Hodgkin's disease: clinical features 195. Akerman M, Brandt L, Johnson A, et al. Mitotic activity in non-Hodgkin's lymphoma. Relation to the Kiel classification and to prognosis. BrJ Cancer 1987; 55: 219-23. 196. Joensuu H, Ristamaki R, Sbderstrom KO, et al. Effect of treatment on the prognostic value of S-phase fraction in non-Hodgkin's lymphoma. J Clin Oncol 1994; 12: 2167-75. 197. Miller TP, Grogan TM, DahlbergS, et al. Prognostic significance of the Ki-67 associated proliferative antigen in aggressive non-Hodgkin's lymphomas: a prospective Southwest Oncology Group trial. Blood 1994; 83: 1460-6. 198. Jalkanen S, Joensuu H, Soderstrom KO, et al. Lymphocyte homing and clinical behaviour of nonHodgkin's lymphoma.y Clin Invest 1991; 87:1835-40. 199. Salles G, Zain M, Jiang WM, et al. Alternatively spliced CD44 transcripts in diffuse large-cell lymphomas: characterization and comparison with normal activated B-cells and epithelial malignancies. Blood 1993; 82: 3539-47. 200. Seymour JF, Talpaz M, Cabanillas F, et al. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma.J Clin Oncol 1995; 13: 575-82. 201. BlayJ-Y, Burdin N, Rousset F, et al. Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. Blood 1993;82:2169-74. 202. Salles G, Bienvenu J, Bastion Y, et al. Elevated circulating alpha-TNF and soluble TNF-receptor levels

203. 204.

205.

206.

207.

208. 209.

are associated with adverse prognostic factors and poor outcome in lymphoma patients. BrJ Haematol 1996; 93: 352-9. Yuen AR, Sikic Bl. Multidrug resistance in lymphomas. J Clin Oncol 1994; 12: 2453-9. Hill ME, Maclennan KA, Cunningham DC, et al. Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma-a British National Lymphoma Investigation study. Blood 1996; 88: 1046-51. Boiocchi M, De RV, Bloomfield CD, Goldman A, Dick F, et al. Multivariate analysis of prognosis factors in the nonHodgkin's malignant lymphomas. Cancer 1974; 33: 870-9. Gospodarowicz MK, Bush RS, Brown TC, et al. Prognostic factors in nodular lymphomas: a multivariate analysis based on the Princess Margaret Hospital experience. Int J Radial Oncol Biol Phys 1984; 10: 489-97. Romaguera JE, McLaughlin P, North L, et al. Multivariate analysis of prognostic factors in stage IV follicular lowgrade lymphoma: a risk model.J Clin Oncol 1991; 9: 762. Coiffier B, Bastion Y, Berger F, et al. Prognostic factors in follicular lymphomas. Semin Oncol 1993; 20(suppl 5): 89. Lopez-Guillermo A, Montserrat E, Bosch F, et al. Applicability of the international index for aggressive lymphomas to patients with low-grade lymphoma.y Clin Oncol 1994; 12:1343-8.

16 Imaging of lymphoma K SANDRASEGARAN, PJ ROBINSON AND A SPRIGG

Introduction Imaging characteristics of nodes Chest Abdomen and pelvis Skeletal system Head and neck Central nervous system

205 205 206 207 210 211 213

INTRODUCTION Hodgkin's disease (HD) is primarily a nodal disease, with extranodal involvement being rare at presentation. Extension of nodal involvement is typically by a contiguous pattern, for example, supraclavicular to anterior mediastinal nodes. The Ann Arbor classification, which is described elsewhere, is used for staging disease extent and for grading prognosis. Non-Hodgkin's lymphoma (NHL) presents with extranodal disease in 20-40 per cent of cases. Nodal involvement is typically more bulky than in HD, with more widespread and non-contiguous disease being common at presentation. The Ann Arbor classification is less useful in NHL, with disease bulk, histology and biochemical markers being important prognostic factors. Differences between HD and NHL in pathology, clinical presentation and in the natural history of the disease are sufficiently great to require different imaging strategies during staging and follow-up. In this chapter, we will first discuss the imaging of nodal and extranodal disease in various sites. Specific requirements for the imaging of pediatric andacquired immunodeficiency syndrome (AIDS)-related lymphomas are described, and strategies are suggested for the selection and timing of follow-up imaging. IMAGING CHARACTERISTICS OF NODES The recognition of disease in nodes depends on their enlargement; involvement of normal-sized nodes cannot

214 214 216 216 217 218

Breast Lymphoma in patients with AIDS Lymphoma in children Imaging in the follow-up of lymphoma New imaging techniques in lymphoma References

be detected by computed tomography (CT), ultrasonography (US) or magnetic resonance imaging (MRI) at present. Discrimination between minor nodal enlargement by lymphoma, and reactive or inflammatory enlargement is also impossible by current imaging methods. Nodes are readily distinguished from surrounding fat on CT and appear as masses of uniform attenuation similar to that of muscle. Groups of nodes appear lobulated, and necrosis or calcification is rare unless there has been previous treatment. Nodes typically show little enhancement after contrast medium injection, although moderate enhancement may be seen in nodular sclerosing HD. They rarely cause invasion of surrounding tissue, but often displace or compress adjacent structures. There is considerable normal variation in the size of nodes. Table 16.1 indicates the size criteria for enlargement of nodes in various anatomic sites.1,2 Subcarinal nodes measuring 10 mm are usually normal Table 16.1 Maximum normal sizes of lymph nodes on computed tomography

Mediastinal and hilar Axillary Paracardiac Para-aortic Retrocrural Portocaval Mesenteric Iliac and inguinal

10 10 8 10 6 8 8 10

206 Imaging of lymphoma

unless there is also involvement of tracheobronchial nodes. In the abdomen the maximum size of normal nodes increases with distance from the diaphragm and decreases with age. Normal nodes cannot usually be differentiated from surrounding fat on US. Enlarged reactive and lymphomatous nodes are echopoor without distal enhancement. Malignant nodes tend to be more rounded but it is not usually possible to distinguish them from benign enlargement. On Tl-weighted magnetic resonance (MR) images, lymph nodes have low signal and contrast well against the high signal of surrounding fat. On Tl-weighted images, nodes have a homogeneously high signal. A mixed high and intermediate signal on T2-weighted images is occasionally seen in untreated nodular sclerosing HD, but is typical after treatment. Gallium localizes in viable tumor cells to a degree, which varies with histologic grading and with disease activity. Gallium uptake is highest in HD and high-grade NHL. Since gallium is taken up by normal liver and bone marrow, and is partly excreted via the bowel, interpretation of planar images of the abdomen is more difficult than in the chest. With optimum technique, gallium-67 scanning has been claimed to have greater than 90 per cent sensitivity, specificity and accuracy in detecting active disease in the thorax.3

CHEST Intrathoracic involvement at the time of initial presentation is found in 65-85 per cent of patients with HD and 25-40 per cent of patients with NHL.4,5 In HD, mediastinal lymphadenopathy is common and typically affects paratracheal and anterior mediastinal nodes (Fig. 16.1). Posterior mediastinal nodes are rarely involved. In the absence of mediastinal disease, hilar adenopathy is uncommon and involvement of the lung

Figure 16.1 CT scan at the level of the aortic arch showing enlarged axillary, anterior mediastinal and azygous nodes in Hodgkin's disease.

parenchyma rare in HD, unless there has been previous radiotherapy to the mediastinum. The pattern is less predictable in NHL and isolated pulmonary disease may occur. The thymus is considered to be a lymphatic organ and so there is little need to determine whether an anterior mediastinal mass is of thymic or nodal origin. Thymic enlargement is seen on CT in 30-50 per cent of patients with HD.6 The thymus remains enlarged in about a third of cases after treatment. Lung manifestations include direct extension from involved nodes, pulmonary nodules with or without cavitation, collapse from bronchial infiltration by tumor or obstruction by nodes and, rarely, interstitial infiltration. CT is the staging method of choice. When the above changes are seen in the untreated patient, pulmonary involvement can be diagnosed with confidence.7 In the treated patient, however, biopsy may be needed to differentiate pulmonary relapse from infection, radiation pneumonitis or drug-induced lung disease. Pleural effusions are seen in 7-10 per cent of untreated adult patients. They are not of prognostic importance, unless associated with a pleural mass, since they rarely contain malignant cells and usually resolve on treatment of adenopathy. Invasion of the chest wall may occur in NHL with involvement of internal mammary nodes and the thoracic spine may be involved by extension from posterior mediastinal nodes. Cardiophrenic nodes (Fig. 16.2) may produce diaphragmatic invasion (Fig. 16.3). Histologic evidence of pericardial invasion is rarely obtained but about 5 per cent of patients have pericardial effusions on CT at the time of presentation.7 Myocardial involvement is rare and has a poor prognosis.

Figure 16.2 CT scan at the level of the right hemidiaphragm showing enlarged nodes in the right cardiophrenic angle and adjacent to the apex of the heart. Histology: NHL

Abdomen and pelvis 207

value in initial diagnosis or staging. The role of positron emission tomography (PET) in staging lymphoma appears promising but still needs further investigation (see later).

ABDOMEN AND PELVIS

Figure 16.3 CT through the superior part of the liver showing a large non-enhancing mass of lymphoma arising in the left hemidiaphragm infiltrating the left lobe of the liver and other adjacent viscera. Histology: NHL

Staging of thoracic lymphoma In addition to initial chest X-ray, thoracic CT should be routinely performed in all lymphoma patients. Scans should be examined with lung windows as well as soft tissue windows. The routine use of intravenous contrast enhancement is not necessary in adults but may be useful in cases where there is difficulty in interpretation, e.g. in patients with aberrant mediastinal vessels or in the absence of intrathoracic fat. If the results of CT are doubtful or inconclusive, MRI may be helpful to improve the definition of chest wall or mediastinal disease (Fig. 16.4). Where cardiac involvement is suspected, echocardiography can be added to detect small pericardial effusions. Gallium-67 single photon emission computed tomography (SPECT) should detect the presence of active disease in patients with residual masses after treatment of mediastinal HD,8 but has little

Figure 16.4 ~[2-weighted MRI scan through mid-thorax showing a multinodular mass of fairly high signal intensity surrounding the great vessels (areas of signal void) and invading the right anterior chest wall. A large right pleural effusion is present. Histology: NHL

Lymphoma should be considered in the diagnosis of any unusual mass within the abdomen. Lymphoma can involve nodes in the retroperitoneum, mesentery, porta hepatis, splenic hilum, around the pancreas or the major vascular bundles. CT is the first-line imaging technique (Fig. 16.5). Where there are no superficial nodes available for excision biopsy, CT- or US-guided fine-needle aspiration is usually adequate to arrive at a diagnosis of NHL. In HD, a core specimen is normally required. The relatively rare condition of primary splenic lymphoma typically presents with single or multiple masses in the spleen.9 Much more frequently the spleen is involved concurrently with nodal lesions elsewhere; in such cases, splenic disease is typically diffuse with only a small minority of cases showing nodules larger than 1 cm in size. The problem of detecting secondary splenic involvement in lymphoma is still largely unsolved. Staging laparotomy has shown that, at the time of the presentation, the spleen is infiltrated in about 30-40 per cent of patients with Hodgkin's disease and in 10-40 per cent of those with NHL.10~12 In 10 per cent of patients presenting with thoracic HD, splenic involvement is the sole site of infradiaphragmatic disease13 so detection of splenic disease changes both staging and treatment. In patients with disease above and below the diaphragm, the additional detection of splenic disease does not often change staging but may indicate a different treatment plan. The size of the spleen is not much help, since diffuse infiltration may be present in spleens of normal size, while mild to moderate reactive splenomegaly occurs in

Figure 16.5 CT at the level of L1/2 showing multiple enlarged para-aortic and mesenteric nodes surrounding the inferior vena cava, aorta and left renal vein.


about 30 per cent of patients with HD and up to 70 per cent of those with NHL; however, marked splenomegaly in NHL almost always indicates infiltration. Diffuse infiltration of the spleen cannot be reliably detected by ultrasound, by CT, or by unenhanced or gadoliniumenhanced MRI. Discrete nodules, when large enough to be visible, are hypoechoic on ultrasound and show low attenuation with reduced contrast enhancement compared to normal splenic tissue on CT (Fig. 16.6). On MRI, the lesions are hypointense or isointense on Tlweighted MRI images, hyperintense on 77-weighted images and show reduced enhancement after gadolinium compared to normal spleen (Fig. 16.7). The presence of enlarged nodes at the splenic hilum may be taken as an indicator of parenchymal involvement of the spleen. Sensitivity of ultrasound and CT in detecting splenic disease is about 35 per cent.14 CT following intravenous or intra-arterial iodized oil has been reported to improve the detection of diffuse hepatosplenic lymphoma15 but the side effects of the contrast agent have prohibited its widespread adoption. Superparamagnetic iron oxide particles are ingested by

Figure 16.6 Unenhanced CTscan through the upper abdomen showing multiple low-attenuation lesions in both liver and spleen. Note also the enlarged retrocrural lymph nodes. History: Hodgkin's disease.

Figure 16.7 Abdominal MRI in NHL (a) Transverse T2weighted scan through upper abdomen showing multiple lesions of increased signal intensity in liver and spleen, (b) Coronal STIR images showing one of the larger liver lesions with high signal and also multiple bone deposits showing areas of high signal affecting most of the vertebral bodies, (c) Transverse T2-weighted scan through the renal areas showing multiple splenic lesions of increased signal, together with numerous enlarged para-aortic nodes. (Courtesy of DrAlan Chalmers.)

Abdomen and pelvis 209

normal reticuloendothelial cells and produce a marked reduction in signal intensity on both Tl- and Unweighted MRI. Initial trials suggest that diffuse lymphomatous involvement of the liver or spleen might be detected even in organs of normal size.16 Further experience with this technique is needed. Primary hepatic lymphoma is a very rare tumor of middle-aged whites that is occasionally associated with cyclosporin treatment. It presents as a solitary mass involving Kupffer cells, sometimes with lymph nodes at the porta hepatis. Secondary hepatic lymphoma is associated with lymph node disease and at presentation is seen in 5-10 per cent of NHL patients and 10-20 per cent of HD patients.11,12,15 The liver is never involved in the absence of splenic disease (except possibly in some patients with AIDS), whereas the spleen is often involved without the liver being affected. As with splenic disease, involvement is diffuse in 90 per cent of cases17 and not reliably detectable on US, CT or MRI. Nodular disease in the liver looks similar to that in spleen (Fig. 16.6 and 16.7). Hepatomegaly in NHL is likely to signify liver involvement but is non-specific in HD. Disease of the bile ducts and gall bladder is rare but has been described in AIDS-related lymphoma. Parenchymal involvement of the pancreas occurs in 0.5-2 per cent of NHL patients12,18 and develops in association with disease in adjacent nodes. The incidence is higher in patients with high-grade histology, particularly Burkitt's lymphoma. Appearances on US, CT and MRI may be indistinguishable from those of pancreatic carcinoma except that dilatation of the pancreatic and biliary ducts is relatively uncommon. It may be difficult to differentiate peripancreatic lymphadenopathy from pancreatic disease. Percutaneous needle biopsy has been reported to be diagnostic in 95 per cent of cases.18 Renal lymphoma is usually an incidental finding on CT. It is often a late manifestation, being seen at initial staging in only 3-6 per cent of cases. Bilateral disease is rare initially but commonly develops in the late stages.19,20 Intravenous urography is frequently normal, whereas US usually shows single or multiple hypoechoic foci without distal acoustic enhancement.20 Occasionally echogenic nodules or multiple cystic lesions are seen. The typical appearance on CT is that of multiple intrarenal nodules with attenuation similar to or less than that of normal renal cortex. The nodules show less enhancement than normal renal tissue after intravenous contrast injection. Most cases are associated with lesions in the retroperitoneal nodes, liver or spleen. When renal lymphoma is suspected, contrast-enhanced CT is required for staging. When there is evidence of lymphoma at other sites, typical CT appearances may be taken to indicate renal involvement (therefore Stage IV disease) but, in the minority of cases presenting with primary renal lymphoma, a guided biopsy is required. Ultrasound may be used for following up those lesions that are clearly visible by this technique.

Adrenal involvement occurs in 1-4 per cent of patients with lymphoma21,22 and in the majority of cases is associated with retroperitoneal lymphadenopathy. The usual appearance is that of homogenous enlargement of one or both glands, which typically resolves with treatment. A solitary adrenal mass without retroperitoneal lymphadenopathy in a lymphoma patient does not necessarily signify adrenal infiltration since incidental non-functioning adenomas are relatively common, particularly in older patients. Bladder involvement is usually asymptomatic and is most often picked up on staging CT. The appearances are those of a large multinodular intramural mass or widespread thickening of the bladder wall. Most cases of prostatic lymphoma are intermediate or high-grade NHL. There is usually extensive involvement of the whole gland and adjacent tissue. NHL of prostate is typically associated with disease in bone, Waldeyer's ring, liver, mesenteric and inguinal nodes. The prognosis is very poor.22 Primary testicular lymphoma accounts for one-third of testicular tumors presenting in patients aged over 50 years. It is always due to intermediate- or high-grade NHL; bilateral disease is present in 10-25 per cent of cases.23 Primary imaging is by ultrasound, which usually shows well-defined homogeneous masses with reduced echogenicity in an enlarged testis. The appearances are characteristic given the age of patient. Staging is crucial since the 2-year survival of Stage I-II patients is 45 per cent compared with 1 per cent for Stage III-IV.24 Testicular lymphoma is typically associated with involvement of the central nervous system (CNS), Waldeyer's ring and the lungs. Staging may include sonography of both the testes, abdominal CT, chest X-ray, lumbar puncture and clinical examination with endoscopic biopsy of the nasopharynx.23 Ovarian lymphoma, which is typically solid homogeneous masses of NHL with low vascularity on ultrasound, usually presents late and has a poor prognosis, whereas lymphoma of the uterus more commonly has an earlier presentation with a 73 per cent 5-year survival for Stage I-II disease.22 Staging should include pelvic ultrasound and abdominopelvic CT. In gastrointestinal (GI) lymphomas, the clinical stage affects the prognosis more than histology or location.23,25 Regional lymph node involvement implies significantly worse prognosis. HD rarely involves the GI tract, whereas in NHL the GI tract is the commonest extranodal site of disease with involvement in 5-15 per cent of patients at the time of presentation.25 The stomach is affected in about half of these cases [including those arising in mucosa-associated lymphoid tissue (MALT) which have similar imaging appearances], the small bowel is affected in a third, and large bowel involvement accounts for the remainder. NHL is the cause of 2-5 per cent of gastric tumors.26 Radiologic appearances include enlarged gastric rugae, ulceration, aneurysmal dilatation


Figure 16.8 CT through the upper abdomen showing extensive gastric wall thickening. Histology: NHL.

and multiple polyps. It may be impossible to differentiate from adenocarcinoma on CT, but lymphoma is suggested if there is gross thickening of the entire stomach wall, clear separation between stomach wall and adjacent organs, lymphadenopathy above and below the renal hilum, or extension across the pylorus into the duodenum (Fig. 16.8). Because the lesion infiltrates the submucous gastric wall, endoscopic biopsies may miss the pathology in up to 20 per cent of cases.26 Lymphoma is probably the commonest primary tumor of small bowel, accounting for about 20 per cent of cases. Typically it shows a constrictive, nodular or ulcerative appearance on barium studies, and associated mesenteric nodes may be shown by CT. Multiple lesions occur in about 10 per cent of cases.25 The rare primary lymphoma of large bowel usually affects either cecum or rectum. Secondary spread is associated with multiple lesions affecting any part of the colon. The incidence is highest in AIDS patients and in those with poorly differentiated NHL.

Staging of abdominal lymphoma CT is usually the initial mode of investigation. Where only lymph node disease is expected, oral contrast is used and there is no necessity for intravenous contrast. Contrast-enhanced images are useful if extranodal involvement is suspected. Lymphangiography (LAG) and gallium-67 scanning probably make no additional contribution to the staging of abdominal NHL. In early HD, LAG has historically been thought to be superior to CT in staging para-aortic nodes27 but other authors have recently found no advantage.28 MRI can detect retroperitoneal and pelvic nodal disease as sensitively as CT. Mesenteric nodes are not well seen due to the mobility of the bowel. GI lymphoma is usually diagnosed on endoscopy or barium studies, but CT is also required for staging. In patients presenting with lymphoma elsewhere, barium

studies are not routinely required to look for GI involvement, except in those with NHL of Waldeyer's ring, who have a 6-15 per cent probability of asymptomatic GI disease.29 The use of laparotomy has declined considerably in the last decade. It is inappropriate in patients with NHL and Stage III/IV HD. HD patients with Stage I or II and features suggesting a poor prognosis, e.g. bulky tumors or B symptoms, now receive chemotherapy without laparotomy. Those with very good prognosis, i.e. single site, small tumor load and no symptoms, will probably be cured by radiotherapy alone without laparotomy, and even if they relapse will be salvaged by chemotherapy. Consequently, staging laparotomy is reserved for an ever-decreasing group of HD patients with intermediate prognosis. In the absence of axillary or inguinal nodes that can easily be biopsied surgically, CT- and US-guided core biopsies performed with spring-loaded firing devices have an important role in the diagnosis and staging of lymphoma. The role of fine-needle aspiration biopsy (FNAB) in this situation is controversial. The development of ancillary diagnostic techniques, such as immunologic markers and cytogenetics, has increased the specificity and accuracy of FNAB in diagnosis of high-grade NHL. Accuracies of up to 90 per cent have been quoted.30,31 However, the exclusion value of a negative FNAB remains low in patients with HD and intermediate-grade lymphoma.32 FNAB, however, has a useful role in the assessment of residual masses following treatment (see later).

SKELETAL SYSTEM It is important to differentiate between bone marrow and osseous involvement. At presentation, bone marrow involvement is rare in HD but is found in 20-40 per cent of NHL patients;11,12,33 this indicates Stage IV disease and is associated with worse prognosis than involvement of liver, lung or osseous bone. Bone marrow aspirates are relatively late indicators of marrow involvement. In a large study of NHL patients, marrow biopsy increased the staging in 32 per cent of cases, mostly from Stage II to Stage IV.33 The performance of bilateral bone marrow biopsies increases the pick-up rate of positive cases by 10 per cent to 40 per cent compared with single site biopsies.34 Bone marrow involvement in low-grade NHL is typically diffuse but in intermediate- to high-grade NHL and in HD marrow disease is likely to be focal. Bone scintigraphy and CT are not accurate in assessing marrow disease. On MRI, tumor deposits have a low signal on Tl -weighted images and a high signal on T2weighted sequences. Tumor deposits down to 3 mm in size can be detected as having a high signal on short-tau inversion recovery (STIR) sequences.

Head and neck 211

Osseous involvement occurs in 1-2 per cent at presentation and 5-15 per cent during the course of the disease35 in adult lymphoma patients. The incidence is much higher in children. Primary bone lymphoma (also termed reticulum cell sarcoma or histiocytic lymphoma) is another rare form of NHL. By definition there is no lymphadenopathy and a single bone, typically femur or pelvis, is involved, so the lesion is automatically classified as Stage I. Secondary bone lymphoma is seen in NHL and HD, and tends to involve the axial skeleton, especially the spine. Spread may be hematogenous (Stage IV) or from adjacent lymphadenopathy. In either case the prognosis is relatively favorable; the survival with hematogenous bone involvement is 50 per cent at 10 years. Abnormal biochemistry is a poor predictor of bone involvement. Plain radiographs may show a permeative or moth-eaten appearance. Periosteal reaction is more common in HD. Pelvic bone lesions often have soft tissue extension. Sclerotic lesions are more frequent in HD and following treatment. Primary bone lesions usually show reduced signal intensity on Tl -weighted MRI but their appearance on T2-weighted imaging is variably isointense or hypointense.36'37.

Staging of lymphoma of osseous bone and marrow Skeletal radiographs need only be performed in those with bone or joint pain, and in areas of bone disease suspected by CT, chest X-ray or bone scintigraphy. Bone scintigraphy has a sensitivity and accuracy of 95 per cent in detecting bone involvement35 but it is not routinely indicated, since most cases of bone lymphoma are revealed on initial chest X-ray and CT. It is used for patients who have localized skeletal symptoms and those with known bone involvement for staging and followup. CT or MRI is valuable in assessing soft-tissue extension of lymphoma. Currently, iliac crest biopsy to detect marrow disease is routine, although PET using 2-[18F]fluoro-2-deoxy-Dglucose (FDG) may provide a less invasive alternative because it samples the whole skeleton and is probably at least as accurate.38,39 A case can also be made for the use of MRI (Tl-weighted and STIR sequences) of the pelvis, spine and proximal femora in patients with negative marrow biopsies who would otherwise be candidates for radiotherapy, e.g. Stage I high-grade NHL. In such patients a positive MR study may be followed by appropriately sited biopsy.

per cent of all HD cases, including those without throat symptoms or radiological evidence of disease, have positive nasopharyngeal biopsies and some authors advocate nasopharyngeal biopsy as part of routine staging of HD.40 About a third of patients with clinical Stage I or II disease will have infradiaphragmatic disease, so abdominal CT is mandatory. Abdominal disease is particularly likely in those with bulky supraclavicular lymphadenopathy or bilateral neck disease, and in those with mixed cellularity on histology. With NHL, the head and neck is a primary site for involvement in about 10 per cent of patients and about half of these will also have systemic involvement.41,42 NHL is limited to nodes in a third of head and neck cases, with deep lymphatic chains being the most common sites. Extranodal tissue such as Waldeyer's ring and paranasal sinuses account for the majority of head and neck NHL. The nasopharyngeal adenoids together with oropharyngeal, faucal and lingual tonsils make up the Waldeyer's ring of extranodal lymphatic tissue. It is the commonest site of NHL in the head and neck region (Fig. 16.10). In 6-15 per cent of cases, there is coexistent disease of the GI tract (most often stomach) and barium studies are indicated even in the absence of symptoms.43 On CT, head and neck lymphoma typically is homogeneous, has similar attenuation to muscle and shows little enhancement. On MRI it is of low signal on Tl-weighted images and intermediate signal on T2-weighted images. There is moderate enhancement with gadolinium.

HEAD AND NECK HD of the head and neck is typically limited to lymph nodes; extranodal disease is manifest clinically in less than 1 per cent of cases (Fig. 16.9). However, about 20

Figure 16.9

CT scan through the level of the hyoid showing a

lymph node mass compressing the right submandibular gland. Histology: Hodgkin's disease.


Figure 16.10 C7 scan through the level of the angle of the mandible showing an ill-defined soft tissue mass extending into the oropharynxfrom the right tonsillar fossa. Histology: NHL

Tonsillar lymphoma is frequently associated with widespread nodal disease and prognosis is consequently poor. Recurrence after treatment usually occurs within a year and tends to involve bone marrow, the GI tract or the CNS. After squamous cell carcinoma, NHL is the second

Figure 16.11 Transverse Tl-weighted (a) and T2-weighted (b) MRI scans through the orbits showing an extensive tumor mass with moderately high signal intensity on both T7 and T2 scans enveloping the anterior and lateral aspects of the left globe together with the lacrimal gland. Histology: NHL. (Courtesy of Dr Ashley Guthrie.)

most common tumor of the paranasal sinuses. Extension into the infratemporal fossa and cheek may occur without visible bone destruction. Clinically and radiologically lymphoma can mimic squamous carcinoma, although bone destruction is usually not as extensive as in carcinoma, and lymphadenopathy tends to be bilateral, without calcification or necrosis. Lymphoma is also suggested if nodes are large and in atypical sites, such as retropharyngeal, submental, submandibular or posterior triangle chains. Occasionally it may be difficult to differentiate tumor mass from retained secretions on CT and, in these cases, T2- weigh ted MRI or Tl- weigh ted sequence with gadolinium should allow discrimination. Primary orbital NHL is the commonest orbital malignancy in adults and is bilateral in up to 40 per cent of cases.42 Most cases are associated with systemic disease, which may present up to 5 years later.41 NHL may resemble reactive lymphoid hyperplasia, but homogeneity and bone destruction are indicative of the former, while scleral thickening and infiltration of retro-orbital fat are suggestive of the latter.44 Either CT or MRI can be used to demonstrate disease in the retrobulbar space, around the globe, optic nerves and muscles, and within the lacrimal glands (Fig. 16.11 and 16.12). The examination protocol should include the neck to evaluate cervical nodal disease and, if CT is used, images with bone windows should be included. Intraocular involvement is rare and is almost always associated with CNS involvement. NHL of salivary gland is rare and, although it is usually part of widespread disease, the prognosis is good.43 The parotid gland is the most frequently affected. The tumor can usually be distinguished from adjacent parotid tissue and fat on CT or MRI; the imaging features are similar to those of lymphoma elsewhere in the head and neck region. Single lymphomatous masses can-

Central nervous system 213

studies of the upper GI tract and small bowel. In patients with paranasal sinus lymphoma, ideally both CT and MRI with axial and coronal sections as well as intravenous contrast enhancement are necessary to delineate extension of the tumor. CT shows bone destruction better, while MRI is superior in delineating soft tissue and intracranial extension. These patients also have a high risk of associated meningeal disease so cerebrospinal fluid (CSF) sampling may be helpful.

CENTRAL NERVOUS SYSTEM

Figure 16.12 CT through orbits showing obliteration of the contents of the left orbit by infiltrating tumor. Histology: NHL Note the spread of the tumor into the infratemporal fossa on the left and previous surgery to right globe. (Courtesy of Dr Ashley Guthrie.)

not be distinguished from the more common pleomorphic adenoma. Multiple NHL masses may look similar to Warthin's tumor or metastasis, but bilaterality and the presence of periparotid lymphadenopathy are suggestive of lymphoma. Thyroid NHL occurs more commonly in females, is associated with chronic thyroiditis and is bilateral in half the cases. Ultrasound is sensitive but not specific for diagnosing NHL. A variety of patterns have been reported, including discrete hyperechoic nodules, multiple lesions of complex echogenicity, diffusely hypoechoic goitre or even thyroid enlargement with normal echopattern.45 On CT, the typical appearance is a low attenuation nodular mass with extracapsular spread and adjacent nodal involvement. Unlike anaplastic carcinoma, necrosis and calcification are rare. In the absence of nodal involvement, the prognosis is good (80 per cent - 5-year survival) but it is much worse with nodal disease (30 per cent - 5-year survival).46

Lymphomas account for about 2 per cent of primary brain tumors. Brain involvement occurs in 10-15 per cent of NHL47 at some time but, of those presenting initially with CNS involvement, the vast majority (over 90 per cent) are primary lymphoma.41 Brain involvement in HD is so rare that a space-occupying lesion in the brain of a patient with known HD should suggest a second diagnosis. Primary brain lymphoma has been previously termed reticulum cell sarcoma, microglioma and round cell sarcoma. Most cases present as solitary masses, which, unlike gliomas, tend to affect central sites, particularly the periventricular areas, basal ganglia, corpus callosum and thalamus. With disease progression, 30 per cent of patients will develop multifocal involvement and about 10 per cent will develop diffuse parenchymal infiltration. On CT, about two-thirds of the lesions are hyperdense and less than 10 per cent are hypodense.48 Surrounding edema and central necrosis are much less commonly seen than with gliomas. Homogeneous enhancement with contrast is typical, although patchy or peripheral enhancement may occur. Non-enhancement and the presence of edema are associated with a poorer prognosis. On Tl -weighted MR images, parenchymal lesion are isointense or hypointense compared with gray matter and show enhancement with gadolinium. The lesions are hyperintense or isointense to gray matter on T2weighted images, which also show the presence of edema. Leptomeningeal spread is seen in both NHL and HD (Fig. 16.13).

Staging of head and neck NHL Staging of CNS lymphoma Where extranodal disease is suspected, CT is required for anatomic definition and radiotherapy planning. All patients with head and neck NHL should have abdominal CT because of the high prevalence of coexisting infradiaphragmatic disease. If CT is equivocal, e.g. with dental artefacts and in the difficult supraclavicular region, MRI may be helpful; we would recommend coronal STIR and transverse T2 -weighted sequences. In Stage I and Stage II disease, bone marrow biopsy should be carried out since these procedures result in upstaging in about 15 per cent of cases. Patients with Waldeyer's ring involvement, as already mentioned, should have barium

CT and MR are equally effective in detecting primary brain lymphoma.48 Meningeal deposits are best seen on gadolinium-enhanced Tl-weighted MRI, which is considerably more sensitive than contrast-enhanced CT. Coronal sections are recommended. Lymphoma of the spinal cord and meninges is rare, and both CT and MRI are recommended in staging. Tumor in the spinal cord, meninges, paraspinal soft tissue and vessels is well shown by MRI (Fig. 16.14). CT is superior in showing the extent of cortical bone destruction. In the absence of neurological symptoms, CNS


2 those who are immunocompromised, especially with AIDS, in whom the risk of CNS involvement is increased by a factor of 500; 3 those with diffuse NHL, and with involvement of testes or bone marrow, who have a 25 per cent risk of developing CNS involvement.49

BREAST

Figure 16.13 Transverse T2-weighted MRI scan through mid-brain and posterior fossa, showing multiple areas of high signal intensity on the surface of the cerebellar hemispheres. Histology: NHL (Courtesy of Dr Keith Blanshard.)

Primary lymphoma accounts for 0.1-0.5 per cent of breast tumors with a disproportionate (6 per cent) of cases occurring in males and on the right side.50 The mammographic appearance is usually that of a welldefined mass (Fig. 16.15) with minimal irregularity of contour and no microcalcification. Fibrous reaction distorting the breast architecture and nipple retraction are rare. Diffuse or localized skin thickening may occur due to lymphatic obstruction. Occasionally there is diffuse increase in breast density. Ipsilateral axillary lymphadenopathy is seen in 35-40 per cent of cases and is associated with poor prognosis. The mammographic appearances overlap with those of carcinoma but the presence of bilateral lymphadenopathy is suggestive of lymphoma. Staging procedures for breast lymphoma should include chest radiograph and thoracoabdominal CT. The roles of ultrasound and MRI are not yet clear.

LYMPHOMA IN PATIENTS WITH AIDS screening is not required in routine staging of lymphoma, except in the following patients, who should have lumbar puncture and, if possible, MRI of brain and spinal cord: 1 those with very high grade histology, i.e. lymphoblastic lymphoma and small cell non-cleaved (Burkitt's and non-Burkitt's) lymphoma;

Figure 16.14 Transverse T2-weighted MRI scan through the mid-thoracic spine showing intradural, but extra medullary infiltration by tumor spreading from the paraspinal muscles on the left and also extending into the left subpleural space. Histology: NHL. (Courtesy of DrAlan Chalmers.)

AIDS-related lymphomas have several features that are distinct from lymphoma in other patients. Peripheral lymphadenopathy is relatively uncommon and the diagnosis of lymphoma often depends on guided biopsy of liver or para-aortic nodes.

Figure 16.15 CT through the mid-thorax showing a large homogenous tumor in the left breast. Histology: NHL.

Lymphoma in patients with AIDS 215

Hodgkin's disease in AIDS patients HD is increasingly recognized as a complication of human immunodeficiency virus (HIV) infection although at present it is not one of the major diagnostic criteria for defining a diagnosis of AIDS in HIV-positive patients. The distinctive features of HD in AIDS patients include the following:51-53 1 most patients present at Stage III or Stage IV; 2 there is a high incidence of bone marrow involvement even in the absence of splenic disease; 3 mesenteric nodes are involved in 20 per cent of cases; 4 nodal disease is often non-contiguous, e.g. pelvic and mediastinal lymphadenopathy occur without paraaortic disease.

Non-Hodgkin's lymphoma in AIDS patients Like HD, NHL in AIDS patients shows many unique features:54-56 1 the signs and symptoms are non-specific, e.g. CNS lymphoma often presents with altered personality, which is also a feature of other CNS complications of AIDS; 2 peripheral lymphadenopathy is absent in half of cases; 3 high-grade B cell type histology occurs in over 50 per cent of cases compared with less than 5 per cent in the general population; 4 involvement of multiple extranodal sites occurs in 75-95 per cent of cases; 5 primary brain lymphoma accounts for about 25 per cent of AIDS-related lymphoma (ARL), whereas only 2 per cent of non-AIDS NHL presents in this way. 6 median survival is very poor, being less than 6 months compared to 40 per cent 5-year survival of Stage III and IV NHL in the general population.

Imaging features of ARL Mediastinal and hilar node lesions are less bulky and less commonly found than in non-AIDS patients. Mediastinal nodes measuring 5-10 mm in diameter must be regarded with suspicion and larger intrathoracic lymph nodes are more likely to be caused by fungal or mycobacterial infection than lymphoma. Fineneedle aspiration biopsy with the appropriate immunochemistry is usually adequate for diagnosis in NHL, whereas in HD, because of the importance of structural elements in the histology, a cutting needle sample or open biopsy is better. CNS lymphoma in AIDS tends to be multifocal with lesions smaller than 2 cm in size. Subarachnoid invasion is seen in a quarter of the cases48 with epidural involvement in 6 per cent. With larger lesions, central necrosis is

common, so a rim enhancement pattern is seen on CT or gadolinium-enhanced MRI. Neither technique can differentiate this appearance from infective complications, such as toxoplasmosis and biopsy may be required for firm diagnosis. However, recent radionuclide SPECT studies using either thallium-201 or technetium-99mlabeled methoxyisobutyl nitrile (MIBI) have made this distinction by showing focal uptake in areas of tumor, whereas infective lesions showed little or no concentration of the tracer.57,58 MRI is more sensitive than CT in detecting parenchymal and leptomeningeal disease, and is the imaging method of choice. AIDS-related NHL occasionally presents with multiple discrete intramedullary spinal masses. About a quarter of AIDS-related lymphomas include bowel lesions,55 typically the mouth, rectum and terminal ileum. The barium findings are similar to those of lymphoma in non-AIDS patients. CT is necessary to demonstrate the full extent of bowel wall thickening and to detect mesenteric disease. It may be difficult to differentiate rectal lymphoma from inflammatory perirectal disease seen in homosexual men. Occasionally lymphoma may present as diffuse peritoneal nodularity without visible lymph node enlargement, mimicking carcinomatosis. Abdominal and pelvic lymphadenopathy in AIDS may be due to several causes. AIDS-related complex (a syndrome seen in HIV-positive patients without overt neoplasia) may cause generalized enlargement of nodes up to 1.5 cm. Nodes larger than this are abnormal, the likely causes being lymphoma, Kaposi's sarcoma, or Mycobacterium avium intracellulare (MAI) infection. Kaposi's sarcoma generally spares mesenteric nodes and causes less bulky lymph node enlargement. MAI typically produces bulky nodes with central low density due to necrosis. Ultrasound or CT-guided biopsy is recommended in order to distinguish these conditions from NHL. Focal lesions in the liver are more common (25-50 per cent) than in lymphomas in other patients (5-10 per cent).51,53 Appearances on CT and ultrasound are similar to those of lymphoma nodules in non-AIDS patients. Ultrasound and CT are both fairly insensitive in detecting diffuse liver and spleen involvement, and needle biopsy is usually required.51 The incidence of renal involvement is about 7-11 per cent.52 The typical appearance is that of multiple focal lesions, which are of low attenuation on CT and are hypoechoic on ultrasound. Diffuse enlargement of both kidneys in AIDS is more likely to be due to AIDS-related glomerular disease, which is a focal and segmental glomerulosclerosis manifest by renal failure and proteinuria.

Staging of ARL Lymphoma affects the chest much less frequently than infections, which may mimic it. Definitive diagnosis


requires bronchoscopic biopsy or lavage in cases of diffuse disease and percutaneous biopsy with localized disease. CT may be useful in assessing mediastinal lymphadenopathy prior to a transcarinal needle biopsy. Since abdominal node disease tends to be bulky, there is a case for using ultrasound, which is comparable with CT in detecting liver lesions, as the initial screening investigation. If ultrasound is negative, or where involvement of bowel or other extranodal organs (e.g. psoas muscle) is suspected, CT is required. Lumbar puncture is required in all ARL cases. With positive CSF assay or clinical signs of CNS involvement, MRI should be carried out because its sensitivity is greater than that of CT in detecting brain and meningeal lymphoma. Bone marrow aspiration is required routinely owing to the high incidence of marrow lesions.

ographs are required prior to anesthesia, since large anterior mediastinal masses may compress the trachea in a sedated child lying supine. A nasogastric tube may be used to give sedation and oral contrast. At the end of the scan, residual contrast is aspirated from the stomach. We routinely use a clip-on transcutaneous oxygen saturation monitor (pulse oximeter) on sedated children. Mediastinal sonography is useful for follow-up of lymph node masses in the mediastinum or abdomen and planning biopsy. Bone marrow biopsies, preferably following MRI of the pelvis and femurs, are routine. CNS staging is usually performed by assaying CSF. Cranial MRI or CT, with contrast, are reserved for those with appropriate symptoms.

IMAGING IN THE FOLLOW-UP OF LYMPHOMA LYMPHOMA IN CHILDREN The principles of diagnosis and staging of lymphoma in the pediatric population are the same as those for adults. Hodgkin's disease accounts for 40 per cent of childhood lymphomas and has a peak incidence in teenagers. Childhood NHLs tend to be of high-grade histology. T cell histology is found in 30 per cent of pediatric NHL and presents with thoracic disease. Mediastinal lymphadenopathy may be large enough to cause dysphagia or superior vena caval obstruction. On the other hand, B cell NHL presents with extranodal disease in the abdomen or head and neck region. Burkitt's lymphoma is an unusual form of high-grade B cell NHL that occurs in an epidemic form in tropical Africa and New Guinea. Involvement of the maxilla or mandible is found in 60 per cent of these patients and the abdomen is affected in a similar proportion. American or European Burkitt's lymphoma is sporadic and is less strongly associated with the Epstein-Barr virus. In pediatric B cell NHL gastrointestinal disease tends to occur in the ileocecal region and intussusception may be the mode of presentation. Disease of the pancreas, kidneys, mesentery, ovaries and thyroid glands are common. Ascites and occasionally pleural effusion are present. Lymphadenopathy in the thorax or abdomen is unusual and, when present, is confined to the iliac and inguinal regions. There is an increased frequency of involvement of the CNS (20 per cent) and bone marrow (20 per cent). Staging pediatric lymphoma

In all cases CT of the chest and abdomen is performed as a baseline study. Intravenous contrast is routinely used. Good bowel opacification is also vital. Those under 2 years of age usually need sedation. This is best done in the presence of an anesthetist during a dedicated pediatric scanning session. Frontal and lateral chest radi-

Assessment of response to treatment In the phase of active treatment, imaging is used as a guide to therapeutic response. This is particularly true with cyclical chemotherapy, which should be discontinued or changed if the patient fails to show objective evidence of response. If there is visible intrathoracic disease, chest X-ray should be repeated at each clinic visit, which typically is monthly. CT may be repeated after each two cycles of chemotherapy, which usually means a gap of 6-8 weeks between scans. In our institution, chest, abdominal and pelvic scans, without intravenous contrast enhancement, are performed in all follow-up patients referred for CT, although there may be a case for a study limited to the regions showing disease on initial staging in NHL patients treated with chemotherapy.59 Also, a less detailed and frequent follow-up has been advocated for patients with HD (see Chapter 15).

Assessment of a residual mass Imaging is also used to confirm remission. The definition of complete remission requires that all previously abnormal investigations, including imaging studies, are repeated and found to be normal. In practice, residual mediastinal masses are common in HD or T cell NHL. Continuing regression of a mass with treatment implies persistence of active disease. Once the mass has reached a stable minimum size, further investigation may be necessary if there is clinical doubt about its activity (Fig. 16.16). Serial CT scans are the usual method of assessing the status of a residual mass and are performed every 2-3 months. Up to 15 per cent of residual masses may show a change in attenuation but an increase in size is highly suspicious of relapse. Masses that remain static after 1 year's follow-up can be considered inactive residue. Using gallium-67 imaging with SPECT, sensitivity and

New imaging techniques in lymphoma 217

Figure 16.16 Resolution of lymph node disease with treatment. Unenhanced CTscans through upper abdomen before (a) and after (b) treatment for abdominal Hodgkin's disease.

specificity of over 80 per cent has been quoted in assessing the activity of residual mediastinal masses.60 In HD, 67 Ga is fairly sensitive in detecting active disease residues after treatment but a negative result is less reliable in defining remission.61 Some histological subtypes of NHL and many necrotic tumors do not take up gallium and the accuracy of this method is lower for abdominal disease. On MRJ carried out 6-12 weeks after treatment, a reduction in the signal on a T2-weighted sequence usually means replacement of tumor by mature fibrosis. However, persistence of high signal is not specific to tumor and can be caused by inflammatory edema, cyst formation or partial volume averaging with fat. A change in signal from low to high on serial T2-weighted MRI is highly suggestive of relapse. There may be a role for MRI in predicting the size of a residual mass by measurement of T2-weighted signal intensities on the pre- and posttreatment scans.62 Fine-needle aspiration biopsy can be performed if there is clinical or radiological doubt of the activity of the residual mass. The accuracy of FNAB in the followup situation is good, and complications are rare even when biopsies of deep mediastinal structures are performed. If FNAB is negative, when there is strong clinical suspicion of relapse, a cutting needle or surgical biopsy is indicated. Detection of late relapse

The third function of follow-up is to detect relapse, which occurs in 10-40 per cent of patients with HD and in up to 60 per cent of NHL patients. Over 85 per cent of HD patients who relapse do so within 3 years of treatment.63 The timing of radiological reassessment depends on the clinical context. If a residual mass of uncertain significance exists, it should be assessed as above. If

remission has been complete, then 6-monthly CT scans during the first 3 years are sufficient. There are no clear rules for the length of long-term follow-up. In most institutions follow-up spans at least 10 years. A shorter follow-up may be reasonable for high-grade NHL, which can be considered to be cured if the patient survives for 5 years. Most late relapses are diagnosed clinically or with simple tests such as blood counts and chest X-rays, so after 3 years of treatment expensive imaging techniques, such as CT scans, should only be performed if there is clinical suspicion of relapse.

NEW IMAGING TECHNIQUES IN LYMPHOMA

Positron emission tomography Several studies have shown that PET with FDG is useful in staging64-66 and predicting response to therapy67 in lymphoma. PET has been shown to be at least as sensitive as CT in detecting disease in lymph nodes and extranodal sites.65-66-68 PET may also be useful in predicting the behavior of a residual mass after treatment.65,69 Further studies have suggested that it may be possible to differentiate cerebral lymphoma from infective lesions in HIV-positive patients.70 FDG uptake is related to histological grading, so PET may be negative in low-grade NHL71 and MALT lymphomas,'68 whilst false-positive results have been found in cases of rebound thymic hyperplasia,72 infection, fractures and other metabolically active benign lesions. PET using 11C-labeled methionine has also been found to be sensitive for detecting lymphoma lesions but less clearly related to histological grading and prognosis than FDG.73


Somatostatin receptor scintigraphy

12. Chabner BA, Johnson RE, Young RC, et al. Sequential nonsurgical and surgical staging of non-Hodgkin's

The accuracy of somatostatin receptor scintigraphy with 11 'In-labeled octreotide (DTPA-pentetriotide) in staging and restaging of lymphoma has been tested in several trials.74-76 In general, the sensitivity is better for head and neck or thoracic tumors than for disease in the abdomen.74-75 This would in part explain the greater sensitivity of this technique in detecting the tumor site in Hodgkin's disease compared to non-Hodgkin's lymphoma.76 The place of this method in staging of lymphoma remains to be confirmed. Immunoscintigraphy with radiolabeled antibodies is undergoing early trials and results of controlled studies are awaited.

lymphoma. Ann Intern Med 1976; 85:149-54. 13. Reznek H, Richards MA. The radiology of lymphoma. Clin Haematol 1987; 1:77-107. 14. Castellino RA, Hoppe RT, Blank N, et al. Computed tomography, lymphography and staging laparotomy: correlation in initial staging of Hodgkin's disease. Am J Roentgenol 1984; 143: 37-41. 15. Thomas JL, Bernadino ME, Vermess M, et al. EOE-13 in the detection of hepatosplenic lymphoma. Radiology 1982; 145: 629-34. 16. Weisslander R, Elizondo G, Stark DD, et al. The diagnosis of splenic lymphoma by MR imaging: value of superparamagnetic iron oxide. AmJ Roentgenol 1989; 152: 175-80. 17. Zornoza J, Dood GD. Lymphoma of the gastrointestinal

REFERENCES

tract. Semin Roentgenol 1980; 15: 272-87. 18. Webb TH, Lillemoe KD, Pitt HA, Jones RJ, Cameron JL. Pancreatic lymphoma. Is surgery mandatory for

1. Glazer GM, Gross BH, Quint LE, Francis IR, Bookstein FL, Oringer MB. Normal mediastinal lymph nodes: number and size according to American Thoracic Society mapping. Am J Roentgenol 1985; 144: 261-5. 2. Dorfman RE, Alpern MB, Gross BH, Sandier MA. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology 1991; 180: 319-22. 3. Mclaughlin AF, Magee MA, Greenough R, et al. Current role of gallium scanning in the management of lymphoma. EurJ Nud Med 1990; 16: 755-71. 4. Filly R, Blank N, Castellino RA. Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin's disease and non-Hodgkin's lymphoma. Radiology 1976; 120: 277-81. 5. Castellino RA, Blank N, Hoppe RT, Cho C. Hodgkin's disease: contribution of chest CT in the initial staging evaluation. Radiology 1986; 160: 603-5. 6. Heron CW, Husband JE, Williams MR Hodgkin's disease: CT of the thymus. Radiology 1988; 167: 647-51. 7. Blank N, Castellino RA. The intrathoracic manifestations of the malignant lymphomas and leukaemias. Semin Roentgenol 1980; 15: 227-46. 8. Kostakoglu L, Yeh SD, Portlock C, et al. Validation of gallium-67 citrate SPECT in biopsy confirmed residual Hodgkin's disease in the mediastinum. J Nud Med 1992; 33:345-50. 9. Dachman AH, BuckJL, Krishnan J, Aguilera NS, Buetow PC. Primary non-Hodgkin's splenic lymphoma. Clin Radiol 1998; 53:137-42. 10. Kadin ME, Glatstein EJ, Dorfman RE. Clinicopathologic studies in 117 untreated patients subject to laparotomy for the staging of Hodgkin's disease. Cancer 1977; 27: 1277-94. 11. Castellino RA, Goffinet DR, Blank N, Parker BR, Kaplan HS. The role of radiography in the staging of nonHodgkin's lymphoma with laparotomy correlation. Radiology 1974; 110: 329-38.

diagnosis and treatment? Ann Surg 1989; 209: 25-30. 19. Heiken JP, Gold RP, Schnur MJ, King DL, Bashist B, Glazer HS. Computed tomography of renal lymphoma with ultrasound correlation. J ComputAssist Tomog 1983; 7:245-50. 20. Horii SC, Bosniak MA, Megibow AJ, Raghavendra BN, Subramanium BR, Rothberg M. Correlation of CT and ultrasound in the evaluation of renal lymphoma. Urol Radiol 1983; 5: 69-76. 21. Moulton JS, Moulton JS. CT of adrenal glands. Semin Roentgenol 1988; 23: 288-303. 22. Charnsangavej C. Lymphoma of the genitourinary tract. Radiol Clinics North Am 1990; 28: 865-77. 23. Bragg DG, Colby TH, Ward JH. New concepts in the non-Hodgkin's lymphomas: radiologic implications. Radiology 1986; 159: 289-304. 24. Duncan PR, Gowing NFC, McElwain TJ, Peckham MJ. Extranodal non-Hodgkin's lymphoma presenting in the testicle: a clinical and pathological study of 24 cases. Cancer 1980; 45:1578-84. 25. Lewin KL, Ranchod M, Dorfman RF. Lymphomas of the gastrointestinal tract: a study of 117 cases presenting with gastrointestinal disease. Cancer 1978; 42: 693-707. 26. Dragosick SB, Bauer P, Radaszkiewicz TUS. Primary gastrointestinal non-Hodgkin's lymphomas: a retrospective clinico-pathologic study of 150 cases. Cancer 1984; 152: 291-6. 27. Castellino RA, Hoppe RT, Blank N, et al. Computed tomography, lymphography and staging laparotomy: correlation in initial staging of Hodgkin's disease. AmJ Roentgenol 1984; 143: 37-41. 28. Stomper PC, Cholewinski SP, ParkJ, Bakshi S, Barcos MP. Abdominal staging of thoracic Hodgkin's disease: CTlymphangiography-Ga-67 scanning correlation. Radiology 1993; 187: 381-6. 29. Saul SC, Kapaida SB. Primary lymphoma of Waldeyer's ring. Clinicopathologic study of 68 cases. Cancer 1985; 56:157-66.

References 219 30. Carter TR, Feldman PS, Innes DJ, Frierson HF, Frigy AF. The role of fine needle aspiration cytology in the diagnosis of lymphoma. Acta Cytol 1988; 32: 848-53. 31. Pontifex AH, Klimo P. Application of aspiration biopsy cytology to lymphomas. Cancer 1984; 53: 553-6. 32. Cafferty LL, Katz RL, Ordonez NG, Carrasco CH, Cabanillas FR. Fine needle aspiration diagnosis of intraabdominal and retroperitoneal lymphomas by a morphologic and immunocytochemical approach. Cancer 1990; 65: 72-7. 33. Pond GD, Castellino RA, Horning S, Hoppe RT. NonHodgkin's lymphoma: influence of lymphography, CT and bone marrow biopsy on staging and management. Radiology 1989; 170:159-64. 34. Coller BS, Chabner BA, Gralnick HR. Frequency and patterns of bone marrow infiltration in non-Hodgkin's lymphomas: observations on the value of bilateral biopsies. Am] Haematol 1977; 3:105-19. 35. Anderson KC, Kaplan WD, Leonard RCF, Skarin AT, Canellos GP. Role of 99mtechnetium-methylene diphosphonate bone imaging in the management of lymphoma. Cancer Treat Rep 1985; 69:1347-51. 36. Hermann G, Klein MJ, Abdelwahab IF, Kenan S. MRI appearance of primary non-Hodgkin's lymphoma of bone. Skeletal Radiol 1997; 26: 629-32. 37. White LM, Schweitzer ME, Khalili K, Howarth DJ, Wunder JS, Bell RS. MR imaging of primary lymphoma of bone: variability of T2-weighted signal intensity. AmJ Roentgenoll998; 170:1243-7. 38. Carr R, Barrington SF, Madan B, etal. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood 1998; 91: 3340-6. 39. Moog F, Bangerter M, Kotzerke J, Guhlmann A, Frickhofen N, ReskeSN. 18-F-fluorodeoxyglucose-positron emission tomography as a new approach to detect lymphomatous bone marrow. J Clin Oncol 1998; 16: 603-9. 40. Biorklund A, Cavallin-Smith E, Landberg T, Lindberg LG, Akerman M. Biopsy of the nasopharynx as a staging procedure in Hodgkin's disease. Acta Radiol 1976; 15: 387-93. 41. Bragg DG. Radiology of the Lymphomas. Curr Probl Diagnos Radiol 1987; 16:183-206. 42. Harnsberger RH, Bragg DG, Osborn AG, et al. NonHodgkin's lymphoma of the head and neck: CT evaluation of nodal and extranodal sites. Am J Neuroradiol 1987; 8: 673-9. 43. Cobleigh MA, Kennedy JL Non-Hodgkin's lymphoma of the upper aerodigestive tract and salivary glands. Otoloaryngol Clinics North Am 1986; 19: 685-710. 44. Westacott S, Garner A, Moseley IF, Wright JE. Orbital lymphoma versus reactive lymphoid hyperplasia: an analysis of the use of computed tomography in differential diagnosis. BrJ Ophthalmol 1991; 75: 722-5. 45. Chisin R, Weber AL. Imaging of lymphoma manifestations in the extracranial head and neck region. Leuk Lymphoma 1994; 12:177-89. 46. DePena CA, Van Tassel P, Lee Y-Y. Lymphoma of the head and neck. Radiol Clin North Am 1990; 28: 723-43.

47. Herman TS, Hammond N, Jones SE, Butler JJ, Byrne GE, McKelvey EM. Involvement of the CNS by non-Hodgkin's lymphoma. The south-western oncology group experience. Cancer 1979; 43: 390-7. 48. Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg 1988; 68: 835-53. 49. Young RC, Howser DM, Anderson T, et al. Central nervous complications of non-Hodgkin's lymphoma: potential role for prophylactic therapy. AmJ Med 1979; 66: 435-43. 50. Schouten JT, Weese JL, Carbonne PP. Lymphoma of the breast. Ann Surg 1981; 194: 749-53. 51. Townsend RR, Laing FC, Jeffrey RB, Bottles K. Abdominal lymphoma in AIDS: evaluation with US. Radiology 1989; 171:719-24. 52. Nyberg DA, Jeffrey RB, Federle MP, Bottles K, Abrams Dl. AIDS-related lymphomas: evaluation by abdominal CT. Radiology 1986; 159: 59-63. 53. Jeffrey RB, Nyberg DA, Bottles K, et al. Abdominal CT in acquired immunodeficiency syndrome. Am J Roentgenol 1986; 146: 7-13. 54. Nyberg DA, Federle MP. AIDS-related Kaposi sarcoma and lymphomas. Semin Roentgenol 1987; 22: 54-65. 55. Ziegler JL, Beckstead JA, Volberding PA, et al. NonHodgkin's lymphoma in 90 homosexual men. N EnglJ Med 1984; 311:565-70. 56. Lowenthal DA, Strauss DJ, Campbell SW, Gold JWM, Clarkson BD, Koziner B. AIDS-related lymphoid neoplasia. Cancer 1988; 61:2325-37. 57. Lorberboym M, Wallach F, Estok L, et al. Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 1998; 39:1366-9. 58. Naddaf SY, Akisik MF, Aziz M, et al. Comparison between 201 TI-chloride and "Tc(m)-sestamibi SPET brain imaging for differentiating intracranial lymphoma from nonmalignant lesions in AIDS patients. Nucl Med Commun 1998; 19: 47-53. 59. Thomas JL, Barnes PA, Bernadino ME, Hagemeister FB. Limited CT studies in monitoring treatment of lymphoma. AmJ Roentgenol 1982; 138: 537-9. 60. Front D, Israel 0, Epelbaum R, et al. Ga-67 SPECT before and after treatment of lymphoma. Radiology 1990; 175: 515-19. 61. BogartJA, Chung CT, Mariados NF, et al. The value of gallium imaging after therapy for Hodgkin's disease. Cancer 1998; 82: 754-9. 62. Nyman R, Rehn SM, Glimelius BLG, et .al. Residual mediastinal masses in Hodgkin's disease; prediction of size with MR imaging. Radiology 1989; 170: 435-40. 63. Herman TS, Hoppe RT, Donaldson SS. Late relapse among patients treated for Hodgkin's disease. Ann Intern Med 1985;102:292-7. 64. Newman JS, Francis IR, Kaminski MS, Wahl RL. Imaging of lymphoma with PET with 2-[F-18]-fiuoro-2-deoxy-Dglucose: correlation with CT. Radiology 1994; 190: 111-16.


65. Stumpe KD, Urbinelli M, Steinert HC, Glanzmann C, Buck

71. Goldberg MA, Thrall JH, Alpert NM, Mueller PR, Fischman

A, von Schulthess GK. Whole-body positron emission

AJ, Lee MJ. Fluorodeoxyglucose PET of abdominal and

tomography using fluorodeoxyglucose for staging of lymphoma: effectiveness and comparison with computed tomography. EurJ Nucl Med 1998; 25: 721-8. 66. Rodriguez M. Computed tomography, magnetic resonance imaging and positron emission tomography in non-Hodgkin's lymphoma. Acta Radiol 1998; 417 (suppl): 1-36. 67. Okada J, Arimizu N, Imaseki K, et al. FDG-PET for predicting the prognosis of malignant lymphoma. Ann Nucl Med 1994; 8:187-91. 68. Rodriguez M, Glimelius B, Hagberg H, et al. [18F]FDG PET in gastric non-Hodgkin's lymphoma. Acta Oncol 1997; 36: 577-84. 69. De Wit M, Hossfeld DK, Clausen M, Herbst K, Beyer W, Bumann D. Whole-body positron emission tomography (PET) for diagnosis of residual mass in patients with lymphoma. Ann Oncol 1997; 8 (suppl): 57-60. 70. Villringer K, Schwaiger M, Pfister HW, et al. Differential

pelvic neoplasms: potential role in oncologic imaging. Radiographics 1993; 13:1047-62. 72. Weinblatt ME, Kochen J, Babchyck B, Belakhlef A, Zanzi I. False-positive FDG-PET imaging of the thymus of a child with Hodgkin's disease.) Nucl Med 1997; 38: 888-90. 73. Nuutinen J, Leskinen S, Lindholm P, et al. Use of carbon11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas. EurJ Nucl Med 1998; 25: 729-35. 74. Cerulus G, Leonard JP. A comparison of 111ln-octreotide and 67 Ga scintigraphy in malignant lymphoma. Nucl MedCommun 1997; 18: 616-22. 75. Ivencevic V, Emrich D, Hiddemann W, et al. Somatostatin receptor scintigraphy in the staging of lymphomas. Leuk Lymphoma 1997; 26:107-14. 76. Van den Anker-Lugtenburg PJ, Krenning EP, Lamberts SW, Lowenberg B. The relevance of somatostatin receptor

diagnosis of CNS lesions in AIDS patients by FDG-PET. 7

expression in malignant lymphomas. Metabolism 1996;

Comput Assist Tomogr 1995; 19: 532-6.

45 (suppl 1): 96-7.

17 Localized Hodgkin's disease SB SUTCLIFFE,AR TIMOTHY AND MH ROBINSON

Introduction

221

Management of Stage MIA Hodgkin's disease

222

Side effects of radiation therapy Conclusion

Localized disease and the determination of prognostic factors Radiation therapy for localized Hodgkin's disease Systemic therapy for localized Hodgkin's disease

226 234

INTRODUCTION The prognosis for patients with Hodgkin's disease has improved dramatically over the past 30 years. This is well illustrated by examination of incidence and mortality rates for Hodgkin's disease from a population database of approximately 10 million individuals within the Province of Ontario, Canada (Fig. 17.1). Incidence has remained fairly constant with a rate of approximately 2.85 per 100000 persons. It is noteworthy that, unlike non-Hodgkin's lymphoma, the incidence rate is not rising and there has been no identification of predetermining conditions, e.g. congenital, iatrogenic

Figure 17.1

Incidence and mortality rates for Hodgkin's

disease, male and female, Province of Ontario, Canada 1969-1992 (age adjusted to the world standard population). Data kindly provided by the Ontario Cancer Registry.

References

236 237 239 240

or acquired immunodeficiency states, Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, chronic immunoproliferative conditions (Sjogren's disease, Hashimoto's disease). Furthermore, the demographics of Hodgkin's disease and the bimodal incidence relative to age remain constant. Mortality, however, has declined substantially from a rate of approximately 1.46 (1965) to 0.47 per 100000 persons in 1992. In this context, mortality should be considered as a 'cause-specific' survival end point inasmuch as the information is derived from death certificate data - deaths from causes other than Hodgkin's disease will not necessarily be included in the analysis of Hodgkin's disease mortality. Important components of interpretation would include the continuous decline in mortality throughout the 30-year period, a mortalityrincidence ratio of approximately 50 per cent prior to the advent of four-drug combination chemotherapy (Fig. 17.1)1 and a current mortaliry:incidence ratio of approximately 17 per cent. Throughout the past 30 years, the prevailing philosophy of management has focused upon the highest overall and cause-specific survival rates, and the highest progression-free or relapse-free rates with individual or combined modality therapy. More recently, this philosophy has been tempered as it is increasingly recognized that: • the most important end point is overall survival, i.e. all causes of death must be considered, given the increasing recognition of treatment-related causes of death offsetting incremental cause-specific survival gains;

222 Localized Hodgkin's disease

• the most effective treatment strategy is that which achieves the highest overall survival with the least amount of therapy and the greatest functional integrity. Several developments have taken place in management of Hodgkin's disease over the last three decades: • the determination of prognostic factors, i.e. the identification of determinants of treatment and outcome, including stage of disease (clinical or pathological); • the role of radiation therapy, i.e. the selection of patients for whom radiation therapy alone results in the highest level of disease control and the definition of late radiation-related morbidity and mortality; • the role of chemotherapy, either alone or in combination with radiation therapy, and the identification of the most effective regimens with the least associated morbidity and mortality. For each of these developments, the extent to which they have contributed to overall survival, i.e. procedure, treatment and disease-related causes of death, is an important consideration with respect to further improvements in patient management. The relationship of treatment efficacy to treatment-related morbidity and mortality, particularly in early-stage Hodgkin's disease, will in large measure determine current and future therapeutic practice.

LOCALIZED DISEASE AND THE DETERMINATION OF PROGNOSTIC FACTORS The definition of early, or localized, Hodgkin's disease has developed along two lines: the description of disease extent, and the definition of prognostic factors.

Description of disease extent

Table 17.1

Ann Arbor classification for staging of Hodgkin's

disease. Reproduced from Sutcliffe SB. Hodgkin's disease: chemotherapy method. In: Raquel RE, ed. Conn's current therapy. Philadelphia: W.B. Saunders Co., 1995

I II III

IV

Fever Night sweats Weight loss

Single lymph node region Two or more lymph node regions on the same side of the diaphragm Lymph nodes on both sides of diaphragm (the spleen is considered a lymph node in this classification) Disseminated involvement of one or more extralymphatic organs or tissue, with or without associated lymph node involvement

>38.4°C; repeat episodes; no documented infectious cause Repeated episodes, sufficient to moisten night attire or bed linens >10+% body weight in 6 months prior to diagnosis, in absence of other identifiable cause

a All stages can be A (asymptomatic) or B (symptomatic). Stage III can be subdivided into III, (involvement of upper abdomen, i.e. spleen, splenic hilar, celiac or porta hepatis nodes) or III2 (involvement of lower abdomen, i.e. para-aortic, mesenteric, pelvic or inguinofemoral nodes). Stage IV, disseminated involvement, is distinguished from E disease (applicable to Stages l-lll), in which extension into an extranodal site occurs contiguous with adjacent nodal disease. The distinction of E disease from Stage IV disease is therapeutically valid only if the extranodal extension can be encompassed with the nodal disease and relevant lymphatic pathways in an appropriate irradiation field to the full therapeutic radiation dose. b If any or all symptoms are present, disease is classified as B; if all symptoms are absent, disease is classified as A. Other relevant symptoms/history include lassitude, anorexia, generalized pruritus, alcohol-induced pain and immunodeficiency state (congenital or acquired, e.g. HIV infection or predisposition; therapeutic immunosuppression).

This is the determination of the anatomic distribution of disease according to the Ann Arbor classification2 (Table 17.1) and subsequent refinements.3 The principal purpose of staging is to establish the most appropriate selection for localized therapy (radiotherapy), systemic therapy (chemotherapy), or both, and to categorize patient groups reproducibly to allow comparison of outcomes between different treatments and treating institutions. The approach to staging has evolved through the following.

resonance imaging and radioscintigraphy (gallium scans, bone scans). Bone marrow aspiration and biopsy evaluation have traditionally been a component of clinical staging, although current practice would probably limit its application to those with advanced clinical stage, adverse prognostic factors or abnormal hematology. Furthermore, a positive study would constitute a pathological stage.

CLINICAL STAGING

SURGICAL (OR PATHOLOGICAL STAGING)

This is the description of disease extent by history, including the evaluation of systemic symptoms, physical examination, hematological and biochemical parameters, imaging studies including plain radiographs, computerized tomography, lymphography, magnetic

Staging laparotomy with splenectomy, liver biopsy(ies) and lymph node mapping was introduced by the Stanford group in the late 1960s as a means of more accurately denning those with localized disease as defined by the Ann Arbor classification, and thereby

Determination of prognostic factors 223

more appropriately defining the extent and configuration of irradiation fields.4 Twenty-five years of experience with surgico-pathological staging has established the following benefits. 1 Staging laparotomy and splenectomy remains the most accurate means of evaluating the abdomen in Hodgkin's disease. In those with supradiaphragmatic clinical Stage I and II disease, it is the only certain way to establish the approximately 25-30 per cent of otherwise unselected patients, or the 15-20 per cent of patients selected by other clinical prognostic factors, who have occult abdominal disease.4-8 Likewise, splenectomy remains the only reliable means of assessing splenic disease below the threshold of clinical detection.9 2 The probability of occult intra-abdominal disease and the patterns of intra-abdominal involvement have been defined as a result of surgical staging. The spleen, the splenic hilar and the celiac axis nodes are me most likely sites of involvement in those with clinical Stage I and II supradiaphragmatic disease. Mesenteric and porta hepatic nodes are very rarely involved, and liver involvement rarely, if ever, occurs without splenic disease and correlates with the extent of splenic involvement. Para-aortic node involvement is commonly associated with splenic involvement. 3 Aspects of the pathobiology of disease have been defined, e.g. the variation in histology from presentation site to lesser areas of involvement defined at laparotomy and the lympho-depleting character of the ongoing natural history of disease. In addition, the origins of the disease in T celldependent areas of lymphoid tissue (the paracortex of lymph nodes and the periarteriolar sheath within the spleen) were defined by examination of grossly uninvolved tissues sampled at laparotomy. 4 The sensitivity and specificity of imaging and percutaneous biopsy procedures have been defined, and their limitation with respect to disease distribution and mass size characterized. 5 Clinical characteristics at presentation and related prognostic factors can be correlated with the probability of abdominal disease, its distribution and the likelihood of single versus multiple sites of involvement.6,7 6 Oophoropexy can be performed for those who would receive lower abdominal or pelvic irradiation. 7 Abdominal radiation fields may be minimized to avoid unnecessary exposure to organs that would otherwise be included in fields determined according to clinical staging practices, e.g. the exposure of the left lower lobe of the lung, upper half of left kidney, and portions of stomach and bowel within fields designed to irradiate the spleen, splenic hilar nodes and lymphatic pathways along the splenic artery.

8 Hematological tolerance to chemotherapy or to total nodal irradiation may be enhanced, although this remains a controversial issue.10,11 9 Laparotomy findings have prognostic relevance beyond documentation of involvement, e.g. pathological Stage III A, versus IIIA2,12 number of sites of involvement in pathological Stage IIIA, and splenic involvement and the probability of liver disease.13 There are also several important adverse issues relating to surgical staging. These are listed below. 1 The procedure has a recognized sampling error, particularly in the upper abdomen in the mid-line between T12 (celiac axis node level and a common site of involvement) and L 2/3 [the root of the mesentery and the superior (L 1/2) and inferior mesenteric (L 2/3) nodal levels]. 2 The spleen must be removed to be properly assessed, thereby conferring the hazards of the postsplenectomy state. 3 The procedure has a small mortality rate (less than 1 per cent), but a significant morbidity rate, including bowel obstruction, deep vein thrombosis, urinary tract infections and wound dehiscence.14 4 Postsplenectomy myocardial infarction possibly related to thrombocythaemia and altered coagulability states. 5 Controversy relating to an increased risk of acute leukemia in patients treated for Hodgkin's disease following splenectomy.15,16 While there appears to be no increased risk of acute leukemia following splenectomy for traumatic rupture and other benign and malignant causes,17 other factors are also of relevance in the Hodgkin's disease population, e.g. immune dysfunction postsplenectomy and possible increased dosages of chemotherapeutic agents in splenectomized versus non-splenectomized patients. 6 Costs and delay in therapy associated with a major surgical procedure and any associated complications. 7 With selection using multiple favorable prognostic factors at presentation, the probability of having abdominal disease defined by laparotomy is less than 20 per cent.7 Accordingly, some 80 per cent of patients are exposed to a major non-therapeutic procedure that is unlikely to influence management or outcome. Given that staging laparotomy and splenectomy is a well-characterized procedure with highly reproducible findings between similarly selected patients within and between institutions, the question as to the impact of surgical versus clinical staging upon overall survival is important. Has any of the improvement in survival for patients with Hodgkin's disease over the past 25 years been due to surgical staging and the increased accuracy of definition of disease extent it offers?


Firstly, would it be expected that improvements in staging technology would influence survival? This has been addressed by Bradford-Hill ('the fallacy of attribution'18 and Bush ('stage migration')19 - the apparent improvement in overall survival by improving the staging methodology. As shown in Fig. 17.2, various subgroups of patients, all equal in number, are characterized by a survival probability that becomes progressively less according to a stage designation shown above the boxes. The overall survival of the group is 50 per cent. A more refined description of stage is employed as shown beneath the boxes. The reclassification into new stages affects survival by stage, even though the overall survival (50 per cent) is unchanged. Expressed more simply, the outcome depends upon the available therapy and not upon the description applied to the disease, unless the staging procedure, in and of itself, modifies the natural history of the disease. Secondly, is there any historical precedent for the view that surgically staged patients fare better than clinically staged patients during the same era of treatment? While this evidence is circumstantial given the retrospective nature of the data, a comparison of survival in a large cohort from Stanford University (predominantly surgically staged) and from Princess Margaret Hospital, Toronto (clinically staged) between 1968 and 1977 revealed no difference in outcome between the two groups.20 Finally, the most compelling evidence derives from the analysis of prospective randomized trials in early-stage Hodgkin's disease conducted by the European Organisation for Research and Treatment of Cancer (EORTC). In the H-2 study, a comparison of two differing radiation techniques according to whether laparotomy and splenectomy was performed revealed no difference in survival rates in the total cohort or the subset receiving no additional maintenance chemotherapy.21 The H-6 study, involved a randomization of'favorable' patients as judged by presentation prognostic factors, between surgical staging and clinical staging (H6-F group). Surgically staged patients were treated with mantle radiation or combined modality therapy, with clinically

staged patients receiving subtotal nodal irradiation encompassing the spleen. No difference in cause-specific survival was noted between the two trial arms, but overall survival by 10 years of follow-up was actually worse in the laparotomy arm due to an excess of both early and late deaths, including a small number of postlaparotomy myocardial infarctions.22 It is also pertinent to ask which groups of patients derive a benefit from laparotomy and splenectomy. By conventional wisdom, it would seem to be those who have a negative procedure (pathological Stage I-II) in whom radiation is deemed appropriate therapy, or those with a positive result (pathological Stage III-IV) in whom chemotherapy is the most appropriate treatment. A theoretical analysis is presented in Fig. 17.3 based upon anticipated results of performing laparotomy and splenectomy in clinical Stage I and II patients, and applying optimal therapeutic outcomes as defined in the literature. The analysis indicates that the proportion of patients with unselected clinical Stage I and II disease who can remain disease-free following radiation therapy alone is approximately 60 per cent. This figure is in accordance with the 61 per cent relapse-free rate reported in a series of 252 patients with clinical Stage I and II Hodgkin's disease treated with radiation therapy alone between 1968 and 1977.23 Thus, the proportion of patients who remain permanently relapse-free following radiation is the same whether laparotomy is employed or not; the radiocurable population exists more as a function of radiation fields employed than as a consequence of surgical staging. The real population deriving benefit from laparotomy are those who are found to have occult intra-abdominal disease and receive chemotherapy. Paradoxically, laparotomy is selecting for benefit from chemotherapy, not from radiation therapy.

Definition of prognostic factors While improvements in therapy have been such as to minimize the impact of prognostic factors defined prior

Figure 17.2 Diagram illustrating how the results in each stage can be improved by 'improving' the staging methods. Reproduced with permission from Bush RS. Malignancies of the ovary, uterus and cervix: the management of malignant disease series; 2. Peckham MJ, Carter RL, gen. eds. London: Edward Arnold, T 979:34.

Determination of prognostic factors 225

Figure 17.3

Theoretical

analysis of treatment outcome for 100 patients with clinical stage I and II Hodgkin's disease based on anticipated surgical staging results. PS = pathological stage, XRT = radiotherapy, CT = chemotherapy.

to therapy as a means of estimating survival, these factors have become increasingly incorporated into decision making with regard to optimal therapy. As many of these factors are inter-related, multivariate analyses are required to establish independent determinants of outcome. Even so, the variation in patient assessment, therapy, prognostic factors examined and the differing methods of assigning values, and the differing types of statistical analyses used render exact comparison and uniform conclusions difficult. Three general questions may be asked of prognostic factors: 1 What are the independent determinants of prognosisf For what endpoints or outcome do they predict? With what disease or treatment-related process do they correlate? Recent reviews have addressed the first two questions.24-25 In the absence of definitive information on the biology of treated and untreated disease, answers to the third question are purely speculative. The principal prognostic factors for localized Hodgkin's disease are shown in Table 17.2. Systemic symptoms are recognized in the Ann Arbor classification (Table 17.1). A recent re-evaluation of systemic symptoms indicates that severe pruritus, a symptom not incorporated in the Ann Arbor classification, also confers an adverse prognosis.26,27 Systemic symptoms confer an adverse prognosis in relation to primary disease control and cause-specific survival28 and are correlated strongly with extent of disease defined by stage or total tumor burden.28,29 The prognostic significance of anatomical stage as described by the Ann Arbor classification has been confirmed repeatedly over the last three decades. However,

clinical experience has indicated that subgroups of patients with widely differing prognoses exist within individual Ann Arbor stages. Specific examples would include: the favorable prognosis of isolated unilateral high cervical nodes or unilateral inguinal or femoral nodes within Stage I disease; the adverse prognosis of bulky mediastinal disease (see section on 'Mediastinal adenopathy' later); the adverse impact of IIIAj versus III A2 disease;12,13 the extent of splenic involvement;30 inguinal adenopathy in advanced stage disease;31 and bone marrow involvement in Stage IV disease.32 Agreement exists that both anatomic stage and volume of disease (total tumor burden), whether considered separately or in conjunction, constitute highly significant independent prognostic determinants.33 The principal

Table 17.2 Prognostic factors in Stage I and II Hodgkin's disease.

Factor

Variables

Stage Symptoms

I v II Ann Arbor classification Fever (>38.5°C), weight loss (>10%), night sweats, severe pruritus LPand NSvsMCand LD NS types I and II > 3 sites vs < 3 Bulk and number of sites None or small vs large > 50 years vs < 50 years Male vs female >50 mm/h vsl/3 of the transthoracic diameter on a posterio-anterior radiograph or > 10 cm by direct measurement of the maximal mediastinal contour. The importance of the definition of bulky (massive) mediastinal disease derives from the high intrathoracic failure rate with conventionally planned radiation fields.71,75,92-98 Such failures are usually within field, marginal and within the thoracic cavity, including lung, pleural, chest wall, pericardial, pleural or pericardial effusions or any combination of the above. The pattern of failure of massive mediastinal disease treated by conventional radiation technique almost certainly has less to do with tumor bulk than with the lymphatic anatomy of intrathoracic structures, and the limitations posed upon the concept of prophylactic or extended fields by the limiting radiation tolerance of the lungs.98,99 The lymphatic network of the lungs comprises superficial lymphatics draining from the visceral pleural surface and the alveoli to a deep lymphatic plexus following the bronchioles and bronchi to the hilar nodes. Nodes are located at second- and first-order


bronchi, and communicate within pulmonary hilar and mediastinal nodes. Non-encapsulated lymph follicles do not occur distal to the bronchioles but small aggregates of lymphocytes occur in loose connective tissue throughout the lung. The parietal pleura drains through intercostal lymphatics anteriorly to internal mammary nodes and posteriorly to intercostovertebral nodes. The lower portion of the parietal pleura interconnects with diaphragmatic lymphatics. Lymphatics of the pericardium drain inferiorly to the diaphragmatic network, superiorly to the brachiocephalic nodes and the anterior and posterior mediastinal nodes. Extensive mediastinal disease may exist as discrete clusters of enlarged nodes or as conglomerate masses that may result in: • extension to the internal mammary nodes and anterior chest wall with intercostal spread, parietal pleural masses, paravertebral mass formation or pleural effusion; • extension along bronchi resulting in extensive interstitial spread with or without endobronchial disease; • direct lung infiltration; • pneumonic infiltration from bronchovascular spread with consolidation and, less commonly, cavitation; • extension through the pericardium and myocardium with costophrenic adenopathy, pericardial effusion and/or diaphragmatic involvement. The patterns of intrathoracic spread have previously been described from historic clinical series and autopsy reports, but may now be much more clearly appreciated with the routine use of computerized tomography (CT) and magnetic resonance imaging (MRI). With the use of conventionally applied radiation fields, full-thickness lung shields are used to minimize lung dose. Even with such shielding, the lung scatter dose approximates 20 per cent of the tumor dose with allowance for lung density. Lung blocks are also planned according to the radiological mediastinal contour, as defined at simulation, with a margin of approximately 1 cm around soft-tissue contours and with acknowledged shielding of intercostal lymphatics, a large part of the pericardium and most of the diaphragm. Even if'shrinking field' techniques are employed for bulky mediastinal disease to allow redesign of lung blocks as the radiological mediastinal contour recedes, it does not follow that all original disease recedes with the radiologic contour, thereby introducing the risk of dose heterogeneity throughout the tumor volume. Most importantly, disease can change in size but necessarily in anatomic position, e.g. hilar nodes, E-lesions, lung extensions. The problem of massive mediastinal disease is that of including all known disease and lymphatic channels involved by contiguous or retrograde spread within a radiation field that can be treated to a tumoricidal dose given the limiting tolerance of the lung and, to a lesser

extent, the entire pericardium. Support for this hypothesis is evident from the change in overall and intrathoracic recurrence patterns using either whole thoracic radiation with lung dose attenuation100 or combined modality therapy.101 In current practice, combined modality therapy is the standard approach for patients with bulky mediastinal disease. Staging laparotomy adds nothing to the management plan. Chemotherapy is the initial therapy and, given a high probability of response, permits a more optimal radiation volume to be defined. Split-course therapy, choice of chemotherapy regimen, number of cycles of therapy, chemotherapy end-point (partial or complete response), radiation as therapeutic or adjuvant modality, and radiation dose and field arrangement are all variables of the combined modality approach. Notwithstanding these variations, the probability of relapse with radiation of 40-70 per cent, depending on mass size, may be improved to 15-25 per cent with combined modality therapy. Despite this improvement in progression-free rate, the choice of initial therapy has no bearing on overall survival.71,72,75,92,102 An additional consideration for patients with large mediastinal disease is the interpretation of the mediastinal contour following therapy. A persisting abnormal mediastinal contour is quite common.103-105 Important interpretational features include the stability of the radiological appearance, comparison of pre- and post-treatment gallium studies, and CT and MRI characteristics. Alternate pathologies, e.g. thymic cysts, should also be considered.106 While the majority of situations of stable, gallium-negative residual abnormality do not constitute active disease based on longer term follow-up observation, no clear unambiguous management guidelines exist. Given that the further therapeutic options could range from observation to radiation to high-dose therapy with marrow/stem cell transplantation, guided thoracoscopic mediastinal biopsy(ies) may be appropriate. It is also probable that functional or biological evaluation through modalities such as positron-emission tomography may help further in the interpretation of residual mediastinal abnormalities post-therapy.

Technical aspects of radiation therapy The preceding sections on supradiaphragmatic disease and infradiaphragmatic presentation have established that the control of localized Hodgkin's disease is dependent on two factors: a tumoricidal radiation dose, and the inclusion of the known extent of disease and adjacent clinically non-involved areas and their lymphatic connections within the irradiated volume. As noted previously, 'in-field' failure is extremely uncommon when tumoricidal doses of radiation are achieved uniformly throughout the radiation field. The vast majority of radiation 'failures' occur distant to the radiation field and

Radiation therapy 233

reflect the clinical expression of occult disease that is not incorporated into the treatment plan. The important technical aspects of radiation relate mainly to the following: • the achievement of a uniform tumoricidal radiation dose throughout a large treatment volume; • the complicated, irregularly shaped fields resulting from the spatial relationship between the treatment volume and adjacent normal tissues; • the limiting tolerance of critical normal structures within, or close to, the treatment volume; • the variation in external surface contour and internal tissue densities within the irradiated volume, and their impact upon dose homogeneity; • the variable depth of involved tissues within the treatment volume from superficial nodal sites to mid-thoracic or abdominal regions; • the need to achieve a reproducible, accurate and consistent treatment over the duration of a fractionated daily treatment program.107,408 Most commonly 'mantle' and 'inverted Y' fields are treated with a parallel-pair technique using megavoltage photon beams in the range of 4-18 MV. Optimal beam energy is largely determined by maximum patient separation, or thickness, within the treatment field. Depth dose characteristics increase as a function of increasing photon energy - 60Co beams may result in an uneven dose distribution with unacceptably high maximum to mid-plane dose unless used at an extended skin-surface distance. High-energy photon beams (> 10 MV) will have minimal dose variation at a depth beyond the maximum dose (Dmax) but may have a dose 'build-up' zone, which could result in 'underdose' to superficial nodal regions. This 'sparing' of superficial tissues is favorable in terms of skin reaction, but unfavorable if superficial nodes are also 'spared'. In this circumstance, bolus (tissue equivalent material) may be used to bring the maximum dose closer to the skin surface, but with resultant loss of skin sparing and enhanced acute skin reaction. The treatment geometry is dependent on the required field size, the desired penumbra width and the treatment unit characteristics. Given the treatment source-patient distance and the necessity for interposed beammodifying devices (blocks, attenuators, compensators, etc.), rigorous attention to the daily reproduction of treatment geometry is essential. Ideally, isocentric megavoltage units will be used to treat anterior and posterior fields on a daily basis with the patient in a supine or prone position to avoid variation that might otherwise result from supine and prone setups with fixed units. To confirm the suitability of the planned treatment volume in relation to disease distribution and to achieve a technically reproducible setup on a daily basis, patients should undergo simulation prior to therapy. All subsequent procedures are referenced to the simulation process, which includes the validation of treatment vol-

ume, the position of beam-modifying devices, and contour characterization and placement of reference points or tattoos for reproducible positioning. Any simulation errors will be reproduced throughout the treatment, thus emphasizing the need for accurate simulation and verification of daily reproducibility of technique through the use of portal images or treatment check films.109,110 The Patterns of Care Study110 clearly established the unacceptably high in-field and marginal failure rates associated with inadequately planned or unreproducible treatment techniques. Patient immobilization devices, shielding blocks for critical normal tissues, compensators to adjust for surface contour irregularity and attenuators to deliver modified dosage to regions of limited tolerance are required to establish reproducible, uniformly distributed irradiation to the desired treatment volume. Special consideration is required when matching supra and infradiaphragmatic fields to avoid areas of 'overdosage' to critical normal tissue, e.g. spinal cord, or 'underdosage' within areas that may harbor overt or occult disease. The construction of such junctions is dependent on technique and may involve the use of customized shielding, junction wedges or 'moving' field borders. Dose uniformity throughout the radiation field and daily fraction size have an important bearing not only on local tumor control but also on normal tissue morbidity. Of particular importance are: the use of beams of appropriate photon energy to avoid significant maximum dose versus tumor dose/mid-plane dose differences; equally weighted beams from anterior and posterior to avoid inappropriately high anterior or posterior dose within the treatment volume; planning techniques that achieve dose homogeneity across the treatment volume; and fractionation techniques that treat both anterior and posterior portals each treatment day to achieve an individual fraction dose of 175-185 cGy. The importance of irradiation technique cannot be overemphasized. Radiation results in very high levels of local disease control when appropriately planned and executed. Radiation also contributes to late morbidities, which have a mortality rate in excess of the mortality rate of the disease for those presenting with Stage I and II disease.79 The morbidity of radiation, and hence the mortality, has an important relationship with radiation dose - both 'intended' dose and actually delivered dose. It is salutary to note that radiation field size does not influence survival given the availability of effective chemotherapy111 but does influence survival as a function of late, radiation-related mortality.

Radiation therapy for salvage of locally recurrent disease Local in-field recurrence following appropriate radiation therapy is uncommon. Retreatment with radiation with


curative intent is rarely feasible in the original field given the limiting tolerance of normal tissues within the proposed retreatment volume. Chemotherapy is the standard and practical treatment of choice. Localized radiation for recurrence distant to the irradiation field is also rarely attractive from a theoretical consideration, i.e. the concept of accuracy of knowledge of disease extent given recurrence in sites of previously occult involvement despite wide field irradiation, or from a practical consideration, e.g. normal tissue tolerances, extranodal disease, low probability of salvage with radiation, and availability of effective chemotherapy with high potential for cure. Isolated local recurrence may occur, however, in a small proportion of patients treated initially with chemotherapy alone for unfavorable local disease or advanced disease. Experience with radiation therapy for salvage in this setting is limited by its relative rarity, differences in patient identification and selection, literature availability and reporting bias. It is clear, however, that a small number of patients with locally recurrent disease postchemotherapy may achieve long-term disease-free survival after salvage radiation.112-115 Factors that are most likely to have a bearing on the success of salvage radiotherapy are those that relate to the success of radiation as sole therapy, e.g. absence of symptoms, localized Stage I and II with a limited number of nodal sites, age, histology, erythrocyte sedimentation rate (ESR) and non-bulky mediastinum. A disease-free interval between local recurrence and prior chemotherapy of greater than 12 months has also been noted to be associated with a higher probability of salvage by radiation therapy.115 The importance of defining this small and highly selected cohort of patients derives from the desirability of avoiding intensive chemotherapy salvage with autologous marrow or stem-cell transplantation with its associated morbidity and mortality, if lesser therapy with radiation can achieve long-term disease control.

SYSTEMIC THERAPY FOR LOCALIZED HODGKIN'S DISEASE

Combined modality therapy versus radiation therapy The beneficial impact of adjuvant chemotherapy following radiation has long been established in the context of disease-free survival, particularly in populations selected according to unfavorable presentation characteristics. Thus, the evolution of practice from the late 1970s and early 1980s acknowledged the higher recurrence rates following radiation for symptomatic patients with more advanced or bulky localized disease, and established an improved relapse-free rate with subsequent adjuvant chemotherapy. The logical progression was the primary

use of chemotherapy with adjuvant radiation, thereby rendering 'unfavorable' presentations 'favourable' for conventionally applied radiation, or for fields more restricted in size or dose. The two principal questions relating to combined modality therapy versus radiation therapy as optimal initial treatment for early stage Hodgkin's disease - is there a significant improvement in disease-free survival and also in overall survival? - have been addressed in a number of randomized clinical trials. In the EORTC HI trial, otherwise unselected clinical Stage I and IIA+B patients were randomized to mantle irradiation with adjuvant maintenance vinblastine for 2 years for those with mixed cellularity and lymphocyte-depletion histology.62 At 12 years of follow-up, disease free rates of 38 per cent and 58 per cent characterized the radiation-only versus radiation plus chemotherapy arms, respectively, but overall survival rates were 58 per cent and 65 per cent. Nissen and Nordentoft73 compared subtotal nodal irradiation versus mantle plus MOPP chemotherapy in patients with PS I/IIA+B disease. At 6 years of follow-up, disease-free survival rates were 68 per cent and 95 per cent, respectively, but overall survival was no different (92 per cent and 88 per cent). Mantle radiation was compared with mantle and MVPP chemotherapy in PS I/II A+B patients by Anderson et al.67 Disease-free rates at 5 years were 69 per cent and 93 per cent, respectively, with overall survival rates of 94 per cent and 91 per cent. A chemotherapy regimen modified to avoid the gonadal and late second cancer risks of MOPP - vinblastine, bleomycin and methotrexate (VBM) - was combined with involved field radiation and compared with subtotal nodal irradiation in patients with PS I/II A+B and IIIA Hodgkin's disease by Horning et al.116 A significant difference in disease-free survival was noted with the combined modality therapy (97 per cent versus 72 per cent) but overall survival was equivalent (100 per cent and 97 per cent). A single arm confirmatory study of effectiveness of VBM plus involved field radiation has been reported but with reservations regarding treatment morbidity.117 In the EORTC H5 trial, patients with clinical Stage I and II unfavorable disease were randomized between subtotal nodal irradiation versus 'sandwich' MOPP.118 At 9 years of follow-up, disease-free survival differences were 66 per cent and 83 per cent, respectively, with a non-significant difference in overall survival (73 per cent and 88 per cent). The EORTC #7 trial has examined subtotal nodal irradiation compared with EBVP (epirubicin, bleomycin, vinblastine and prednisone) with involved field radiation in 254 patients with favorable clinical Stage I/II Hodgkin's disease. At 3 years of follow-up, failure-free survival rates of 81 per cent and 79 per cent, and overall survival rates of 99 per cent and 100 per cent, respectively, have been recorded.64 The German Hodgkin's Study Group has conducted a randomized study in patients with CS/PS I, II and IIIA disease with risk factors (mediastinal mass, extranodal

Systemic therapy 235

lesions, splenomegaly) comparing low-dose (20 Gy) versus high-dose (40 Gy) radiation in various field dispositions with all patients receiving eight-drug combination therapy. To date, this study, last updated through presentation at the Third International Symposium on Hodgkin's Lymphomas in Cologne 1995, has yielded no differences in overall survival or freedom from treatment failure for any group.119,120 However, interim analysis of their more recent study suggests that two cycles of ABVD plus radiotherapy is better than radiotherapy alone in extending the duration of freedom from treatment failure in early stage (I, II) Hodgkin's disease.121 In an attempt to establish whether the failure of all randomized studies to demonstrate a difference in overall survival related to sample size and statistical power, Specht reported a meta-analysis of all randomized trials, published or unpublished, of radiation therapy and combined modality therapy.33 She concluded that combined modality therapy was associated with a proportional reduction of approximately 15 per cent in the hazard of death, but that this reduction was not statistically significant. There was no additional indication that combined modality therapy differed in impact according to age, stage or presence of symptoms. In a more recent meta-analysis of 1688 patients in 13 trials of radiotherapy plus chemotherapy alone, Specht et al concluded that the addition of chemotherapy to radiotherapy has a large effect on disease control but only a small effect on overall survival.58

Chemotherapy versus radiation therapy Two randomized studies have addressed the issue of chemotherapy versus radiation therapy. The Italian study compared a random allocation to mantle followed by para-aortic radiation with six cycles of MOPP therapy in a total of 89 adult patients with PS I/IIA Hodgkin's disease. Initial disease control was achieved in all radiation patients (n = 45) and 40 of 44 receiving chemotherapy. At an 8-year median follow-up, overall survival was significantly higher in the radiation (93 per cent) compared with the chemotherapy group (56 per cent). Freedom from progression rates (76 per cent and 64 per cent) and relapse-free survival rates (70 per cent and 71 per cent) were not significantly different. Eight patients (of 44 treated with MOPP) died of Hodgkin's disease and three additional MOPP-treated patients died of a second cancer.74 The National Cancer Institute (NCI) study compared radiation alone (predominantly subtotal nodal) with MOPP chemotherapy in patients with Stage I/II A+B and IILAj disease.75 Over the time course of the study initiated in 1978, the majority of patients were surgically staged, those with bulky mediastinal masses were excluded in 1981 and those with Stage IIIA1 disease in 1983. Of the 51 patients receiving radiation, the pro-

jected 10-year disease-free survival and overall survival rates were 60 per cent and 76 per cent compared with 86 per cent and 92 per cent for the 54 patients randomized to MOPP. With exclusion of patients with large mediastinal masses and Stage IIIA1 disease, features recognized to be unfavorable for radiation therapy alone, disease-free and overall survival rates for radiation and chemotherapy were 67 per cent and 82 per cent, and 85 per cent and 90 per cent, respectively, with no significant difference between the two arms. These two studies, apparently with differing conclusions, raise questions relating to the relatively poor performance of the MOPP regimen in the Italian study and the unexpectedly high cause-specific and overall mortality with chemotherapy, and the relatively poor performance of the radiation therapy arm in the NCI study. They would also indicate that the superiority of radiation or chemotherapy, based upon random allocation in appropriately selected cohort Stage I and II Hodgkin's disease patients, remains to be determined and that overall survival remains the single most important end point, given both disease and treatment-related mortality. Non-randomized studies of chemotherapy alone for management of early-stage Hodgkin's disease have been reported, with somewhat variable results. Expected high remission rates with relapse rates up to 30 per cent have been reported by Ziegler et a1., Olweny et al, Lauria et al. and Bubman et al.122-125 Colonna and Andrieu126 reported a low complete remission rate in a small series of clinically staged patients with adverse prognostic factors in Algeria. Al-ldrisse and Ibrahim83 reported a more favorable experience from Saudi Arabia in patients with adverse prognostic factors characteristic of non-Western patient populations. These studies highlight the differing distribution of prognostic factors in patient populations with earlystage disease in Western and non-Western countries, and the practical and pragmatic considerations that influence treatment choice given limited access to radiation therapy appropriate to the technical complexity and quality assurance required for optimal radiation for Hodgkin's disease.81,83

Chemotherapy versus combined modality therapy Chemotherapy alone (cyclophosphamide and vinblastine on day 1, and procarbazine and prednisone on days 1-14 on a 28-day cycle for six cycles - CVPP) was compared with the same regimen with radiation therapy (30 Gy) delivered to involved node areas between cycles three and four of chemotherapy by Pavlovsky et al.127 in patients with CS I/II Hodgkin's disease. A significant difference in disease-free survival was evident with the CVPP + radiotherapy arm (71 per cent versus 62 per cent) but no overall survival difference was apparent


(89 per cent and 82 per cent). Subset analysis by favorable versus unfavorable attributes (age >45 years, >2 involved nodal areas, or bulky disease) revealed no difference in disease-free or overall survival by treatment arm for the favorable group (77 per cent versus 70 per cent, and 92 per cent versus 91 per cent, respectively). Radiotherapy plus CVPP was a more effective therapy for the unfavorable group (disease-free survival 75 per cent versus 34 per cent, and overall survival 84 per cent and 66 per cent, respectively). The broader applicability of this study has been tempered by the limited usage of the CVPP regimen, particularly in the low dose-intensive manner employed, and more specifically for those with unfavorable prognostic factors at presentation.

In any combined modality program, where both treatments are known to have effects on cardiorespiratory function and an independent risk for second malignancy, the degree to which modification in one or both therapies modifies the late effect risk is largely unknown. Given the lack of an established overall survival benefit with combined modality therapy, the independent contribution of both radiation and chemotherapy and the unknown, but probably enhanced, interaction between the two modalities for late malignancy risk, the increasing use of combined modality therapy in early stage Hodgkin's disease requires careful examination.

MANAGEMENT OF STAGE IIIA HODGKIN'S DISEASE

Choice of chemotherapy regimen Systemic therapy for advanced Hodgkin's disease is addressed in Chapter 19. While the principle of employing regimens of established efficacy in advanced Hodgkin's disease has most commonly been applied for those with unfavorable early-stage disease, the following modifications have been introduced. 1 The cumulative amount of chemotherapy has been reduced, particularly with the MOPP regimen or its variants, to reduce gonadal impacts.128 2 The ABVD regimen (Adriamycin, bleomycin, vinblastine, imidazole carboxamide) has become a preferred regimen to MOPP, given equivalent or superior efficacy and significantly less gonadal morbidity and second tumor risk. 3 The radiation volumes and doses have been modified to minimize acute single modality effects, diminish enhanced morbidity of combined modality therapy and minimize late complications. 4 New regimens have been developed to minimize gonadal and late second malignancy risks of combined modality therapy, e.g. the ABVD regimen, the VBM regimen,116 the VAPEC-B regimen;129 the EBVP regimen (epirubicin, bleomycin, vinblastine and prednisone) has been demonstrated to be equivalent to subtotal nodal irradiation when combined with involved field radiation in favorable CS I/II patients, but it has been established to be less effective than MOPP/ABV with involved field radiation in those with unfavorable CS I/II disease.64 In the design of combined modality regimens, two inter-related considerations are paramount. (1) Is the regimen of equal efficacy to existing regimens? In this consideration, both disease control and overall survival end points are mandatory. (2) Given equal efficacy, does the combination result in lesser acute or late complications, particularly those that compromise function or result in treatment-related death?

The management of Stage IIIA Hodgkin's disease has evolved over the past 25 years through a more detailed understanding of intra-abdominal disease distribution achieved through staging laparotomy, derivation of prognostic factors adverse for control with radiation alone and through the increasing use of chemotherapy with curative intent. As defined in the Ann Arbor classification, Stage III disease includes disease on both sides of the diaphragm confined to nodes and/or spleen, with or without extranodal extension (E. lesions) but without extranodal dissemination (Stage IV disease). Definition of clinical Stage III disease may be achieved through a positive lymphogram (pelvic or retroperitoneal lymphadenopathy imaged via the bipedal route to approximately the second lumber vertebral level), palpable splenomegaly (acknowledged to be unreliable unless the spleen size is greater than 500 g or approximately three times normal size), imaging evidence of intra-abdominal or pelvic adenopathy, e.g. CT, ultrasound, MRI or gallium imaging (recognizing the sensitivity and specificity limitations of these examinations for nodes that are not grossly enlarged or non-gallium avid), or evidence of splenic deposits through CT or MRI evaluation. Notwithstanding the method of disease definition, radiation therapy alone is an inappropriate treatment for clinical Stage IIIA or IIIB disease based on disease progression rates exceeding 50 per cent.130,131 Although higher control rates with radiation alone have been cited in clinical Stage IIIA disease,132 chemotherapy is currently considered standard management of clinical Stage IIIA/B disease. The initial heterogeneity of experience with radiation therapy alone for clinical Stage IIIA was put into perspective with the routine practice of staging laparotomy, and splenectomy in patients with supradiaphragmatic clinical Stage I and II disease. Both the reliability of a positive lymphogram to describe retroperitoneal and pelvic disease, and the unreliability of clinical investigation of the upper abdomen to define nodal or splenic

Side effects of radiation therapy 237

disease were established. The important distinction of upper abdominal disease in spleen or nodal sites (pathological Stage IIIAJ from lower abdominal disease (nodal involvement below the level of the superior mesenteric artery - IIIA2) was defined by Desser et al.12 The high relapse rate with radiation alone for those with PS IIIA2 compared with PS IILA1 disease was subsequently demonstrated.13,131,133 Further refinements included the description of extent and bulk of splenic disease, its correlation with liver involvement, and the lesser probability of disease control with radiation alone for those with more extensive splenic disease,30 with splenic and nodal disease30,134 or with a greater number of involved intraabdominal sites of disease.13 This cumulative experience has indicated that the role of radiation therapy in Stage IIIA disease should, at best, be reserved solely for those with PS IIIA1 disease with minimal splenic, splenic hilar or celiac axis adenopathy. For this surgically defined subgroup, relapse-free rate with radiation alone (subtotal nodal irradiation) may exceed 70 per cent.135 In parallel with this experience, two other considerations have arisen: • the examination of prognostic factors other than anatomical stage, their correlation with the probability and extent of occult intra-abdominal disease, and the derivation of successful management protocols with radiation alone or chemotherapy/combined modality therapy based on clinical staging methods without a requirement for staging laparotomy and splenectomy; • recognition that chemotherapy/combined modality therapy can achieve high overall survival and relapsefree rates in those with PS IIIA disease with adverse prognostic factors (extensive splenic involvement, IIIA2 disease, splenic and nodal disease and >5 sites of involvement).30,135-137 In summary, it is well established that the majority of patients with clinical Stage IIIA disease have an unacceptably high progression rate when treated with radiation alone, and should be managed with a chemotherapy or combined modality approach. Radiation therapy alone is only an appropriate consideration for those with minimal upper abdominal disease (IIIAj) defined by laparotomy and splenectomy.

SIDE EFFECTS OF RADIATION THERAPY

Acute

and fractionation schemes. Their impact is a consequence of reduced functional integrity in tissues with a high renewal capacity, e.g. hematological, gut, mucous membrane, skin, hair, etc. As dose-fractionation schemes are generally within tolerance for critical normal tissues, acute effects are commonly transient with a return to normal, or satisfactory, function. SUPRADIAPHRAGMATIC IRRADIATION

Fatigue Cumulative fatigue is common during therapy and patients may take several weeks to recover. Dry mouth, altered taste perception, parotid swelling and dental hygiene

Radiation field borders at the base of the skull encompass sublinguinal, submental and a portion of the parotid glands, and, depending on the superior extent of the field, some of the minor salivary glands in the mucosa of the floor of the mouth. During therapy, saliva consistency becomes thicker and more viscous, and a reduction in salivary flow with a more viscous character may persist as a more chronic side effect. Taste sensation is commonly altered, and contributes to anorexia and weight loss. Oral hygiene, and more particularly, assiduous dental care is necessary given the accelerated caries associated with the dry mouth. Dental consultation and advice on maintenance of oral care is an essential part of therapy. Nausea, emesis and weight loss

Many factors contribute to nausea and emesis, including physical effects of radiation, psychological components, including anxiety and anticipatory nausea, dry mouth and altered taste perception, fatigue and the necessity for daily therapy over 4 weeks. The use of agents such as dimenhydrinate, phenothiazine antiemetics, steroids or 3HT3 antagonists will usually allow maintenance of ambulatory therapy with minimal impairment of nutritional intake. Skin reaction

With megavoltage radiation therapy and appropriate attention to technique, skin reaction should be minimal. Techniques employing bolus (tissue equivalent material) applied to the skin to compensate for surface contour or separation variances will result in full dose on the skin surface, with consequent hyperpigmentation, and dry or moist desquamation in flexural areas. Avoidance of skin abrasion, e.g. wet shaving, the use of scents or deodorants, and sun exposure, minimizes any radiation-related acute skin effects. Dysphagia and mucositis

The acute side effects of radiation therapy occur during and up to 6-8 weeks following completion of treatment. They occur reproducibly in all patients and reflect dose-volume considerations, technical aspects of therapy

A sense of 'a lump in the throat' progressing to a severe sore throat is common during mantle therapy. Attention to food preparation, additives and meal frequency, and the use of topical or systemic analgesics can help to


reduce the effect of these symptoms. The introduction of a posterior cervical cord shield and an anterior larynx shield during therapy will ameliorate this symptom, and full recovery can be expected 1-2 weeks post-therapy. Excessive laryngeal mucous production is common resulting in persistent 'clearing of the throat' and occasional retching. Any acute voice change through laryngitis or laryngeal edema is fully reversible. Alopecia and facial hair loss

Epilation occurs within the irradiated volume. This usually results in occipital hair loss and loss of beard hair within the field. Regrowth of hair occurs following therapy. Dry shaving is preferable during therapy to avoid skin abrasion. Hematological suppression

Mantle irradiation alone rarely causes hematological suppression of concern. It is extremely unusual to require any blood component support or management of neutropenia. Hematologic suppression is not uncommon, however, in combined modality therapy, and with subtotal nodal or wide-field abdominal irradiation. Regular blood count supervision and either hematologic support, or treatment delay, should be exercised as necessary. INFRADIAPHRAGMATIC IRRADIATION

Upper abdominal or inverted Y ± spleen/splenic pedicle fields result in fatigue and hematological consequences as described in mantle fields. Gastrointestinal effects

Nausea, emesis and weight loss characterize wide-field irradiation, and are managed with dietary modifications, antiemetics, sedatives and hydration as necessary. Increased bowel motility is common with bowel cramps, flatulence, borborygmi and diarrhea. Milk products may exacerbate these symptoms owing to the acute effects of bowel mucosal injury on lactose tolerance. Agents to reduce bowel motility and good dietary management are usually effective in allowing completion of therapy without interruption.

Chronic side effects of radiation therapy Chronic or delayed side effects of therapy reflect permanent loss of functional integrity in tissues due to epithelial or stromal vascular injury and, as such, are irreversible. Chemotherapy, when combined with radiation therapy, may have an exacerbating role. Pulmonary

Symptomatic acute pneumonitis is rarely encountered unless large volumes of lung are included in the irradiation field, or concurrent chemotherapy with adriamycin and/or bleomycin is administered. Manifest clinically as dyspnea with a dry, unproductive cough,

fever and as patchy infiltrates within the radiation volume on X-ray, the situation may be improved with high-dose steroids. In a prospective study of pulmonary effects of therapy, Horning et al.138 defined three cohorts of patients - mediastinal radiotherapy, mediastinal radiotherapy plus bleomycin, and bleomycin alone. A decrease in forced vital capacity and diffusing capacity was noted in the majority of patients over the first 15 months after therapy with recovery by 36 months posttreatment. At 3 years or more post-therapy, approximately one-third of patients receiving radiation had forced vital capacity (FVC) values of 10 cm), the use of chemotherapy and RT, and stage (extrathoracic versus localized).

SUMMARY The term localized non-Hodgkin's lymphoma encompasses an exceptionally heterogeneous group of diseases that may affect any organ or body part. It is unclear why some sites or organs are affected more than others. However, the role of antigenic stimulation, autoimmunity and immune dysregulation as an important component of the etiology and pathogenesis of non-Hodgkin's lymphoma is becoming increasingly recognized through

observations relating to congenital and acquired immunodeficiency states, Hashimoto's and Sjogren's syndrome, Crohn's disease, intestinal immunoproliferative disease and the role of Helicobacter pylori in MALT lymphoma. Knowledge arising from a more complete understanding of the biology and the genetic basis of lymphoma will undoubtedly lead to improved recognition of distinct clinical entities and refinements in patient management. The experience available to guide management of patients with localized nodal and primary extranodal lymphomas is limited. Large retrospective studies are available for nodal and commonly encountered lymphomas (GI tract, Waldeyer's ring, bone, orbital and thyroid lymphoma), while only infrequent case reports are available in uncommon presenting sites (adrenal, liver, spleen, etc.). Treatment results and the curability of some tumors may be obscured by the heterogeneity of presentations. Future studies of different treatment strategies recognizing distinct histopathologic entities may help to clarify the outcome. In summary, although their clinical behavior may differ, the principles of therapy of localized nodal and primary extranodal non-Hodgkin's lymphoma are similar. The choice of local versus systemic therapy is established by considering histologic type and tumor characteristics, including disease extent and bulk. In general, low-grade lymphomas are treated with RT alone, and intermediateand high-grade lymphomas are treated with chemotherapy followed by RT. The choice of brief chemotherapy followed by RT, a full curative course of chemotherapy followed by adjuvant RT, or chemotherapy alone is based chiefly on tumor bulk, the presence of adverse prognostic factors, such as B symptoms and high LDH, and the anatomic extent of disease. Special consideration has to be given to organs where curative doses of RT compromise function. CNS prophylaxis with intrathecal methotrexate or cytarabine may be necessary in patients with testis lymphoma and tumor involving parameningeal sites. These principles are most important in cases of primary extranodal lymphomas involving rare sites, where the available literature may not reflect the optimal approach. An attempt has been made to summarize the principles of management of lymphoma that allow an appropriate treatment strategy for lymphoma presenting in any organ or site. However, further refinements in the management of these diseases are required to maximize cure rates, and to reduce immediate and long-term morbidity of the disease and its treatment. Gains in our understanding of the genetic and molecular basis of non-Hodgkin's lymphoma have to be translated into medical practice to benefit patients with malignant lymphoma. Such improvements can only be achieved through prospective clinical trials, which, owing to the infrequent occurrence of each disease, will require international collaboration.

References 263

REFERENCES 1. Castellino R. Diagnostic imaging evaluation of Hodgkin's disease and non-Hodgkin's lymphoma. Cancer 1991; 67: 1177-80. 2. Kaplan W, Jochelson M, Herman T, el al. Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Oncol 1990; 8:1966-70. 3. Front D, Bar-Shalom R, Israel 0. The continuing clinical role of gallium 67 scintigraphy in the age of receptor imaging. Semin Nud Med 1997; 27: 68-74. 4. Janicek M, Kaplan W, Neuberg D, Canellos GP, Shulman LN, Shipp MA. Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive nonHodgkin's lymphoma treated with high-dose CHOP chemotherapy. J Clin Oncol 1997; 15:1631-7. 5. Fleming ID, Cooper JS, Henson DE, et al. AJCC Cancer Staging Manual. Non-Hodgkin's lymphoma, 5th ed. Philadelphia: Lippincott-Raven, 1997. 6. d'Amore F, Brincker M, Gronbaek K, et al. Non-Hodgkin's lymphoma of the gastrointestinal tract: a population-

15. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive nonHodgkin's lymphoma. N EnglJ Med 1993; 329: 987-94. 16. Lopez-Guillermo A, Montserrat E, Bosch F, Terol M, Campo E, Rozman C. Applicability of the International Index for aggressive lymphomas to patients with lowgrade lymphoma. J Clin Oncol 1994; 12:1343-8. 17. Aviles A. The International Index is not useful in the classification of low-grade lymphoma [letter]. J Clin Oncol 1994; 12: 2766-8. 18. Ansell SM, Habermann TM, Kurtin PJ, etal. Predictive capacity of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma. J Clin Oncol 1997;15:2296-301. 19. Jelic S, Frim 0, Gligorijevic G,

al. A controversial issue:

could a watch-and-wait policy for patients with nonHodgkin's lymphoma clinical stage I or IE with no lymphoma left following diagnostic surgery be justified? Results of a single centre study. Hematol Oncol 1997; 15: 53-61. 20. Romaguera J, Velasquez W, Silverrnintz K, et al. Surgical debulking is associated with improved survival in Stage

based analysis of incidence, geographic distribution,

l-ll diffuse large cell lymphoma. Cancer 1990; 66:

clinicopathologic presentation features, and prognosis.

267-72.

Danish Lymphoma Study Group. J Clin Oncol 1994; 12: 1673-84. 7. Rohatiner A, d'Amore F, Coiffier B, et al. Report on a

21. Seifert E, Schulte S, Stolte M. Long-term results of treatment of malignant non-Hodgkin's lymphoma of the stomach. Z Gastroenterol 1992; 30: 505-8.

workshop convened to discuss the pathological and

22. Thirlby R. Gastrointestinal lymphoma: a surgical

staging classifications of gastrointestinal tract

perspective. Oncology 1993; 7: 29-32. 23. McLaughlin P, Fuller L, Redman J, etal. Stage l-ll lowgrade lymphomas: a prospective trial of combination chemotherapy and radiotherapy. Ann Oncol 1991; 2:

lymphoma. Ann Oncol 1994; 5: 397-400. 8. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89: 3909-18. 9. Tsutsui K, Shibamoto Y, Yamabe H, et al. A

137-40. 24. Lawrence T, Urba W, Steinberg S, et al. Retrospective analysis of stage I and II indolent lymphomas at the

radiotherapeutic experience for localized extranodal

National Cancer Institute. Int J Radiat Oncol Biol Phys

non-Hodgkin's lymphoma: prognostic factors and re-

1988;14:417-24.

evaluation of treatment modality. Radiother Oncol 1991; 21:83-90. 10. d'Amore F, Christensen B, Brincker H, et al. Clinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas. Danish LYFO Study Group. EurJ Cancer 1991; 27:1201-8. 11. Mackintosh I, Cowan R, Jones M, Harris M, Deakin D, Crowther D. Prognostic factors in stage I and II high and intermediate grade non-Hodgkin's lymphoma. EurJ Cancer Clin Oncol 1988; 24:1617-22. 12. Seymour I, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol 1995; 13: 575-82. 13. Sutcliffe S, Gospodarowicz M, RS Bush et al. Role of radiation therapy in localized non-Hodgkin's lymphoma. Radiother Oncol 1985; 4: 211 -23. 14. Velasquez W, Fuller L, Jagannath S, et al. Stages I and II

25. Mac Manus M, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996; 14:1282-90. 26. Taylor R, Allan S, Mclntyre M, et al. Low grade stage I and II non-Hodgkin's lymphoma: results of treatment and relapse pattern following therapy. Clin Radiol 1988; 39: 287-90. 27. Soubeyran P, Eghbali H, Bonichon F, Coindre T, Richaud P, Hoerni B. Localized follicular lymphomas: prognosis and survival of stages I and II in a retrospective series of 103 patients. Radiother Oncol 1988; 13: 91-8. 28. Paryani S, Hoppe R, Cox R, Colby T, Rosenberg S, Kaplan H. Analysis of non-Hodgkin's lymphomas with nodular and favorable histologies, stages I and II. Cancer 1983; 52: 2300-7. 29. Gospodarowicz M, Sutcliffe S, Wells W, Tsang R, Group

diffuse large cell lymphomas: prognostic factors and

TPMHL. Results of involved field radiotherapy in clinical

long-term results with CHOP-bleo and radiotherapy. Blood 1991; 77: 942-7.

of the ASTRO, San Diego, California, 1992.

stage I and II low grade lymphoma. 34th Annual Meeting

264 Localized non-Hodgkin's lymphoma 30. Vaughan-Hudson B, Vaughan-Hudson T, MacLennan K. Clinical stage I non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. BrJ Cancer 1994; 69:1088-93. 31. Jeffery G, Mead G, Whitehouse J, Ryall R. Involved field radiotherapy or chemotherapy in the management of stage I nodal intermediate grade non-Hodgkin's lymphoma. BrJ Cancer 1991; 64: 933-7. 32. Horwich A, Catton C, Quigley M, Easton D, Brada M. The management of early-stage aggressive non-Hodgkin's lymphoma. Hematol Oncol 1988; 6: 291-8. 33. Gospodarowicz M, Sutcliffe S, Brown T, Chua T, Bush R. Patterns of disease in localized extranodal lymphomas.y Clin Oncol 1987; 5: 875-80. 34. Kaminski M, Coleman C, Colby T. Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Ann Intern Med 1986; 104: 747-56. 35. Hallahan D, Farah R, Yokes E, el al. The patterns of failure in patients with pathological stage I and II diffuse histiocytic lymphoma treated with radiation therapy alone. IntJ Radial Oncol Biol Phys 1989; 17: 767-71. 36. Hagberg H, Pettersson U, Glimelius B, Sundstrom C. Prognostic factors in non-Hodgkin lymphoma stage I treated with radiotherapy. Acta Oncol 1989; 28: 45-50. 37. Fisher R, Gaynor E, Dahlberg S. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N EnglJ Med 1993; 328:1002-6. 38. Bajetta E, Valagussa P, Bonadonna G, etal. Combined modality treatment for stage l-ll non-Hodgkin's lymphomas: CVP versus BACOP chemotherapy. IntJ Radiat Oncol Biol Phys 1988; 15: 3-12. 39. Tondini C, Zanini M, Lombard! F, etal. Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I and II histologically aggressive non-Hodgkin's lymphomas.y Clin Oncol 1993; 11: 720-25. 40. Yahalom I, Varsos G, Fuks Z, Myers L, Clarkson B, Straus D. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma. Results of a prospective randomized study. Cancer 1993; 71: 2342-50. 41. Young R, Longo D, Glatstein E, Ihde D, Jaffe E, DeVita VJr. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 1988; 25(suppl 2): 11-16. 42. GlickJ, Kim K, Earle I, O'Connell M. An ECOG randomized phase III trial of CHOP vs. CHOP + radiotherapy for intermediate grade early stage non-Hodgkin's lymphoma. ProcAm Soc Clin Oncol 1995; 14(391): 1221. 43. Miller TP, Dahlberg S, Cassady R, etal. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade nonHodgkin's lymphoma. N EnglJ Med 1998; 339: 21-6.

44. Gospodarowicz M, Sutcliffe S. The extranodal lymphomas. Semin Radiat Oncol 1995; 5:1-21. 45. Aisenberg AC. Extranodal lymphoma: presentation, natural history, and special treatment considerations. Philadelphia: Lea and Febiger, 1991: 235-310. 46. Salhany K, Pietra G. Extranodal lymphoid disorders. Am J Clin Pathol 1992; 99: 472-85. 47. Economopoulos T, Asprou N, Stathakis N, etal. Primary extranodal non-Hodgkin's lymphoma in adults: dinicopathological and survival characteristics. Leuk Lymphoma 1996; 21:131-6. 48. d'Amore F, Christensen BE, Brincker H, etal. dinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas. Danish LYFO Study Group. EurJ Cancer 1991; 27:1201-8. 49. Freeman C, Berg JW, Culter SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972; 29: 252-60. 50. Devesa SS, Fears T. Non-Hodgkin's lymphoma time trends: United States and International data. Cancer Res 1992; 52: 5432-40. 51. Dobson LS, Hancock H, Bright N, Robinson MH, Hancock BW. Localised non-Hodgkin's lymphoma: the Sheffield Lymphoma Group experience (1970-1995). IntJ Oncol 1998; 13:1313-18. 52. Gospodarowicz MK, Sutcliffe SB, Brown TC, Chua T, Bush RS. Patterns of disease in localized extranodal lymphomas.y Clin Oncol 1987; 5: 875-80. 53. Reddy S, Pellettiere E, Saxena V, Hendrickson F. Extranodal non-Hodgkin's lymphoma. Cancer 1980; 46: 1925-31. 54. Robinson BW, Benjamin CS. Extranodal non-Hodgkins lymphoma in rare sites. Austral Radiol 1987; 31: 418-20. 55. Rudders RA, Ross ME, DeLellis RA. Primary extranodal lymphoma - response to treatment and factors influencing prognosis. Cancer 1978; 42: 405-16. 56. Sutcliffe SB, Gospodarowicz MK. Localized extranodal lymphomas. In: Keating A, Armitage J, Burnett A, Newland A, eds. Hematological oncology. Cambridge: Cambridge University Press, 1992:189-222. 57. Tsutsui K, Shibamoto Y, Yamabe H, et al. A radiotherapeutic experience for localized extranodal non-Hodgkin's lymphoma: prognostic factors and reevaluation of treatment modality. Radiother Oncol 1991; 21:83-90. 58. Dawson I, CornesJ, Morson B. Primary malignant lymphoid tumours of the intestinal tract: report of 37 cases with a study of factors influencing prognosis. BrJ Surg 1961; 49: 80-9. 59. Herrmann R, Panahon AM, Barcos MP, etal. Gastrointestinal involvement in non-Hodgkin's lymphoma. Cancer 1980; 46: 215-22. 60. Lewin K, Ranchod M, Dorfman R. Lymphomas of the gastrointestinal tract: a study of 117 cases presenting with gastrointestinal disease. Cancer 1978; 42: 693-707.

References 265 61. Morgan G, Vornanen M, Puitinen J, etal. Changing trends in the incidence of non-Hodgkin's lymphoma in Europe Biomed Study Group. Ann Oncol 1997; 8(suppl 2): 49-54. 62. Aisenberg AC. Coherent view of non-Hodgkin's lymphoma. J Clin Oncol 1995; 13: 2656-75. 63. Laing RW, Hoskin P, Hudson BV, et al. The significance of MALT histology in thyroid lymphoma: a review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol 1994; 6: 300-4. 64. Isaacson PG. Gastric lymphoma and Helicobacter pylori. N EnglJ Med 1994; 330:1310-11. 65. Isaacson P. The MALT lymphoma concept updated. Ann Onco/1995;6:319-20. 66. Thieblemont C, Bastion Y, Berger F, et al. Mucosaassociated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 1997; 15:1624-30. 67. Jaffe ES, Krenacs L, Raffeld M. Classification of T-cell and NK-cell neoplasms based on the REAL classification. Ann Owco/1997;8(suppl2):17-24. 68. Drillenburg P, van der Voort R, Koopman G, et al. Preferential expression of the mucosal homing receptor integrin a4b7 in gastrointestinal non-Hodgkin's lymphomas. Am J Clin Pathol 1997; 150: 919-27. 69. Krol AD, Hermans], Dawson L, etal. Treatment, patterns of failure, and survival of patients with stage I nodal and extranodal non-Hodgkin's lymphomas, according to data in the population-based registry of the Comprehensive Cancer Centre West. Cancer 1998; 83:1612-19. 70. Otter R, Bieger R, Kluin PM, Hermans], Willemze R. Primary gastrointestinal non-Hodgkin's lymphoma in a population-based registry. BrJ Cancer 1989; 60: 745-50. 71. Ducreux M, Boutron M-C, Piard F, Carli P-M, Faivre J. A 15-year series of gastrointestinal non-Hodgkin's lymphomas: a population-based study. BrJ Cancer 1998; 77: 511-14. 72. Gospodarowicz M, Sutcliffe S, Clark R, etal. Outcome analysis of localized gastrointestinal lymphoma treated with surgery and postoperative radiation. Int J Radiat Oncol Biol Phys 1990; 19:1351-55. 73. Shepherd F, Evans W, Kutas C, et al. Chemotherapy following surgery for stages IE and ME non-Hodgkin's lymphoma of the gastrointestinal tract. J Clin Oncol 1988; 6: 253-60. 74. Koch P, Grothaus-Pinke B, Hiddemann W, etal. Primary lymphoma of the stomach: three-year results of a prospective multicenter study. The German Multicenter Study Group on GI-NHL. Ann Oncol 1997; 8 (suppl 1): 85-8. 75. Maor M, Velasquez W, Fuller L, Silvermintz K. Stomach conservation in stages IE and ME gastric non-Hodgkin's lymphoma. J Clin Oncol 1990; 8: 266-71. 76. Taal B, Burgers T. Primary non-Hodgkin's lymphoma of the stomach: endoscopic diagnosis and the role of surgery. ScandJ Gastroenterol 1991; 188(suppl): 33-37.

77. Taal B, Burgers T, Heerde Pv, Hart A, Somers R. The clinical spectrum and treatment of primary nonHodgkin's lymphoma of the stomach. Ann Oncol 1993; 4: 839^6. 78. Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998; 16: 1916-21. 79. Roggero E, Zucca E, Pinotti C, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1995; 122: 767-9. 80. Weston A, Campbell D, McGregor D, Cherian R. Endoscopic and histologic resolution of gastric pseudolymphoma (reactive lymphoid hyperplasia) following treatment with bismuth and oral antibiotics [Review]. Digest Dis Sci 1994; 39: 2567-74. 81. Montalban C, Manzanal A, Boixeda D, et al. Helicobacter pylori eradication for the treatment of low-grade gastric MALT lymphoma: follow-up together with sequential molecular studies. Ann Oncol 1997; 8(suppl 2): 37-9. 82. Gospodarowicz M, Bush R, Brown T, Chua T. Curability of gastrointestinal lymphoma with combined surgery and radiation. Int J Radiat Oncol Biol Phys 1983; 9: 3-9. 83. Domizio P, Owen R, Shepherd N, Talbot I, Norton A. Primary lymphoma of the small intestine: a clinicopathological study of 119 cases. Am J Surg Pathol 1993;17:429-42. 84. Morton J, Leyland M, Vaughan Hudson G, et al. Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases. BrJ Cancer 1993; 67: 776-82. 85. Haber D, Mayer R. Primary gastrointestinal lymphoma. Semin Oncol 1988; 15:154-69. 86. Al-Bahrani Z, Al-Mohindry H, Bakir F, Al-Saleem T. Clinical and pathologic subtypes of primary intestinal lymphoma: experience with 132 patients over a 14-year period. Cancer 1983; 52:1666-72. 87. McGurk M, Goepel J, Hancock BW. Extranodal lymphoma of the head and neck: a review of 49 consecutive cases. Clin Radiol 1985; 36: 455-8. 88. Conley S, Staszak C, Clamon C, Maves M. Non-Hodgkin's lymphoma of the head and neck: the University of Iowa experience. Laryngoscope 1987; 97: 291-300. 89. Wulfrank D, Speelman T, Pauwels C, Roels H, Schryver AD. Extranodal non-Hodgkin's lymphoma of the head and neck. Radiother Oncol 1987; 8:199-207. 90. Ossenkoppele G, Mol J, Snow G. Radiotherapy versus radiotherapy plus chemotherapy in Stages I and II NonHodgkin's lymphoma of the upper digestive and respiratory tract. Cancer 1987; 60:1505-9. 91. Fuller L, Hagemeister P, Sullivan M, Velasquez W. Hodgkin's disease and non-Hodgkin's lymphomas in adults and children. New York: Raven Press, 1988. 92. Aviles A, Delgado S, Ruiz H, Torre ADI, Guzman R, Talavera A. Treatment of non-Hodgkin's lymphoma of Waldeyer's ring: radiotherapy versus chemotherapy

266 Localized non-Hodgkin's lymphoma versus combined therapy. EurJ Cancer B Oral Oncol 1996; 32:19-23. 93. Jaffe ES, Krenacs L, Raffeld M. Classification of T-cell and NK-cell neoplasms based on the REAL classification. Ann Oncol 1997; 8(suppl 2): 17-24. 94. Laing R, Todd D, Chan T, et al. Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 1995; 13: 666-70. 95. Aviles A, Rodriguez L, Guzman R, Talavera A, Garda E, Diaz-Maqueo J. Angiocentric T-cell lymphoma of the nose, paranasal sinuses and hard palate. Hematol Oncol 1992; 10:141-7. 96. Weiss L, Arber D, Strickler J. Nasal T-Cell lymphoma [Review]. Ann Oncol 1994; 5: S39-42. 97. Cheung MMC, Chan KC, Lau WH, et al. Primary nonHodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 1998; 16: 70-7. 98. Li Y-X, Coucke PA, Li G-Y, etal. Primary non-Hodgkin's lymphoma of the nasal cavity. Prognostic significance of paranasal extension and the role of radiotherapy and chemotherapy. Cancer 1998; 83: 449-56. 99. Laing RW, Hoskins P, Vaughan Hudson B, et al. The significance of MALT histology in thyroid lymphoma: a review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol 1994; 6: 300-4. 100. Blair TJ, Evans RG, Buskirk SL, Banks PM, Earle JD. Radiotherapeutic management of primary thyroid lymphoma. Int J Radial Oncol Biol Phys 1985; 11: 365-70. 101. Tsang R, Gospodarowicz M, Sutcliffe S, Sturgeon J, Panzarella T, Patterson B. Non-Hodgkin's lymphoma of the thyroid gland: prognostic factors and treatment outcome. Int J Radial Oncol Biol Phys 1993; 27: 599-604. 102. Hardman-Lea S, Kerr-Muir M, Wotherspoon A, Green W, Morell A, Isaacson P. Mucosal-associated lymphoid tissue lymphoma of the conjunctiva. Arch Ophthalmol 1994; 112:1207-12. 103. Dunbar S, Linggood R, Doppke K, Duby A, Wang C. Conjunctiva! lymphoma: results and treatment with a single anterior electron field. A lens sparing approach. IntJ Radial Oncol Biol Phys 1990; 19: 249-57. 104. Jereb B, Lee H, Jakobiec F, Kutcher I. Radiation therapy of conjunctiva! and orbital lymphoid tumors. Int J Radial Oncol Biol Phys 1984; 10:1013-19. 105. Bessell E, HenkT, Wright J, Whitelocke R. Orbital and conjunctival lymphoma treatment and prognosis. Radiolher Oncol 1988; 13: 237-44. 106. Fitzpatrick P, Macko S. Lymphoreticular tumors of the orbit. Int J Radial Oncol Biol Phys 1984; 10: 333-40. 107. Doll D, Weiss R. Malignant lymphoma of the testis. AmJ Med 1986; 81: 515-24. 108. Connors J, Klimo F, Voss N, Falrey R, Jackson S. Testicular lymphoma: improved outcome with early brief chemotherapy.) Clin Oncol 1988; 6: 776-81.

109. Crellin A, Vaughan Hudson B, Bennett M, Harland S, Vaughan Hudson G. Non-Hodgkin's lymphoma of the testis. Radiolher Oncol 1993; 27: 99-106. 110. Touroutoglou N, Dimopoulos M, Younes A, el al. Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy.) Clin Oncol 1995; 13:1361-7. 111. MartensonJJ, Buskirk S, llstrup D, et al. Patterns of failure in primary testicular non-Hodgkin's lymphoma. J Clin Oncol 1988; 6: 297-302. 112. Melekos M, Matsouka P, Fokaefs E, Pantazakos A, Repanti M. Primary non-Hodgkin's lymphoma of the urinary bladder. Eur Urol 1992; 21: 85-8. 113. Heaney I, Dellellis R, Rudders R. Non-Hodgkin's lymphoma arising in the lower urinary tract. Urology 1985; 25: 479-84. 114. Ohsawa M, Aozasa K, Horiuchi K. Malignant lymphoma of bladder. Report of three cases and review of the literature [Review]. Cancer 1993; 72:1969-74. 115. Dimopoulos MA, Daliani D, Pugh W, Gershenson D, Cabanillas F, Sarris AH. Primary ovarian non-Hodgkin's lymphoma: outcome after treatment with combination chemotherapy. Gynecol Oncol 1997; 64: 446-50. 116. Osborne B, Robboy S. Lymphomas or leukemia presenting as ovarian tumours: an analysis of 42 cases. Cancer 1983; 52:1933-43. 117. Harris N, Scully R. Malignant lymphoma and granulocytic sarcoma of the uterus and vagina. A clinicopathologic analysis of 27 cases. Cancer 1984; 53: 2530-45. 118. Stroh E, Besa P, Cox J, Fuller L, Cabanillas F. Treatment of patients with lymphomas of the uterus or cervix with combination chemotherapy and radiation therapy. Cancer 1995; 75: 2392-9. 119. Prevot S, Hugol D, Audouin J, et al. Primary nonHodgkin's malignant lymphoma of the vagina. Report of 3 cases with review of the literature [Review]. Palhol Res Practice 1992; 188: 78-85. 120. Giardini R, Piccolo C, Rilke F. Primary non-Hodgkin's lymphomas of the female breast. Cancer 1992; 69: 725-35. 121. Liu F, Clark R. Primary lymphoma of the breast. Clin Radiol 1986; 37: 567-70. 122. DeBlasio D, McCormick B, Straus D, et al. Definitive irradiation for localized non-Hodgkin's lymphoma of breast. IntJ Radial Oncol Biol Phys 1989; 17: 843-6. 123. Fairbanks R, Bonner J, Inwards C, el al. Treatment of stage IE primary lymphoma of bone. Int J Radial Oncol Biol Phys 1994; 28: 363-72. 124. Rathmell A, Gospodarowicz M, Sutcliffe S, Clark R. Localised lymphoma of bone: prognostic factors and treatment recommendations. The Princess Margaret Hospital Lymphoma Group. BrJ Cancer 1992; 66: 603-6. 125. Cordier J, Chailleux E, Lauque D, et al. Primary pulmonary lymphomas. A clinical study of 70 cases in nonimmunocompromised patients. Chest 1993; 103: 201-8.

References 267 126. Kennedy], Nathwani B, BurkeJ. Pulmonary lymphomas and their pulmonary lymphoid lesions: a clinics pathologic and immunologic study of 64 patients. Cancer 1985; 56: 539-52. 127. DeAngelis L. Current management of primary central nervous system lymphoma. Oncology 1995; 9: 63-71. 128. Dorreen MS, Ironside JW, BradshawJD, Jakubowski J, Timperley WR, Hancock BW. Primary intra-cerebral lymphoma: a clinico-pathological analysis of 14 patients presenting over a 10 year period in Sheffield. Quart J Med 1988; 67: 387-404. 129. Cappellani G, Giuffre F, Tropea R, et al. Primary spinal epidural lymphomas. Report of ten cases. J Neurosurg Sd 1986; 30:147-51. 130. Lachance D, Brizel D, Gockerman J, et al. Cydophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy. Neurology 1994; 44:1721-7. 131. Schiff D, Suman VJ, Yang P, Rocca WA, O'Neill BP. Risk factors for primary central nervous system lymphoma. A case-control study. Co/?cer1998; 82: 975-82. 132. DeAngelis L, Yahalom J, Heinemann M, Cirrincione C, Thaler H, Krol G. Primary CMS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology 1990; 40: 80-6. 133. Laperriere NJ, Cerezo L, Milosevic MF, Wong CS, Patterson B, Panzarella T. Primary lymphoma of brain: results of management of a modern cohort with radiation therapy. Radiother Oncol 1997; 43: 247-52. 134. Hough RE, Smith CML, Nakielny RA, etal. Primary intracerebral lymphoma: a clinico-pathological study of 28 patients Int J Oncol 1999; 14: 647-52. 135. Nelson D, Martz K, Bonner H, etal. Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radial Oncol Biol Phys 1992; 23: 9-17. 136. Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin's lymphoma. Cancer 1994; 74:1383-97. 137. Krogh-Jensen M, d'Amore F, Jensen M, etal. Incidence, clinicopathological features and outcome of primary central nervous system lymphomas. Population-based data from a Danish lymphoma registry. Danish Lymphoma Study Group, LYFO. Ann Oncol 1994; 5: 349-54. 138. Berry M, Simpson W. Radiation therapy in the management of primary malignant lymphoma of the brain. IntJ Radial Oncol Biol Phys 1981; 7: 55-9. 139. DeAngelis L, Yahalom L, Thaler H, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992; 10: 635-43. 140. Socie G, Piprot-Chauffat C, Schlienger M, et al. Primary

lymphoma of the central nervous system. Cancer 1990; 65: 322-6. 141. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol 1998; 16: 859-69. 142. Neuwelt E, Goldman D, Dahlborg S, et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 1991; 9:1580-90. 143. Sandor V, Stark-Vanes V, Pearson D, etal. Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 1998; 16: 3000-6. 144. Schultz C, Scott C, Wasseman T. Pre-irradiation chemotherapy (CTX) with Cytoxan, Adriamycin, vincristine, and Decadron (CHOD) for primary central nervous system lymphomas (PCNSL): Initial Report of Radiation Therapy Oncology Group (RTGG) protocol 88-06. ProcAm Soc Clin Oncol 1994; 13:174. 145. Bessell EM, Graus F, Punt JAG, etal. Primary nonHodgkin's lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. 7 Clin Oncol 1996; 14: 945-54. 146. BlayJ-Y, ConroyT, Chevreau C, etal. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. 7 Clin Oncol 1998; 16:864-71. 147. DeAngelis L. Primary central nervous system lymphoma [Review]. Rec Results Cancer Res 1994; 135:155-69. 148. Pollack I, Lunsford L, Flickinger I, Dameshek H. Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 1989; 63: 939-47. 149. Qualman S, Mendelsohn G, Mann RB, Green WR. Intraocular lymphoma: natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer 1983; 52: 878-86. 150. Corriveau C, Fasterbrook M, Payne D. Intraocular lymphoma and the masquerade syndrome. CanJ Opthalmol 1986; 21:144-49. 151. Michelson J, Michelson P, Borden G, Chisari F. Ocular reticulum cell sarcoma. Arch Ophthalmol 1981; 99: 1409-12. 152. Trudeau M, Shepherd F, Blackstein M, Gospodarowicz M, Fitzpatrick P, Moffat KP. Intraocular lymphoma: report of three cases and review of the literature. Am J Clin Oncol 1988; 11: 126-30. 153. Strauchen J, Dalton J, Friedman A. Chemotherapy in the management of intraocular lymphoma. Cancer 1989; 63:1918-21. 154. Rathmell AJ, Gospodarowicz MK, Sutcliffe SB, etal. Localized extradural lymphoma: survival, relapse pattern and functional outcome. The Princess Margaret Hospital Lymphoma Group. Radiother Oncol 1992; 24: 14-20. 155. Eeles R, O'Brien P, Horwich A, Brada M. Non-Hodgkin's lymphoma presenting with extradural spinal cord compression: functional outcome and survival. BrJ Cancer 1991; 63:126-9.

268 Localized non-Hodgkin's lymphoma 156. Mackintosh F, Colby T, Podolsky W, et al. Central nervous system involvement in non-Hodgkin's lymphoma: an analysis of 105 cases. Cancer 1982; 49: 586-95. 157. Rijlaarsdam J, Willemze R. Primary cutaneous B-Cell lymphomas [Review]. Leuk Lymphoma 1994; 14: 213-18. 158. Willemze R, Beljaards R, Rijlaarsdam U. Classification of primary cutaneous large cell lymphomas [Review]. Dermatol Clinics 1994; 12: 361-73. 159. Willemze R, Beljaards R, Rijlaarsdam U. Classification of primary cutaneous T-cell lymphomas [Review]. Histopathology 1994; 24: 405-15. 160. Jaffe ES, Burg G. Report of the symposium on Cutaneous Lymphomas: Sixth International Conference on Malignant Lymphoma. Ann Oncol 1997; 8(suppl 1): 83-4. 161. Slater D. MALT and SALT: the clue to cutaneous B-cell lymphoproliferative disease. BrJ Dermatol 1994; 131: 557-61. 162. Garbe C, Stein H, Dienemann D, Orfanos C. Borrelia bwrgdo//e/7-associated cutaneous B cell lymphoma: clinical and immunohistologic characterization of four cases. J Am Acad Dermatol 1991; 24: 584-90. 163. Harris N, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92. 164. Chow VT. Cancer and viruses. Ann Acad Med Singapore 1993; 22:163-9. 165. Kurtin P, DiCaudo D, Habermann T, Chen M, Su W. Primary cutaneous large cell lymphomas. Morphologic,

immunophenotypic, and clinical features of 20 cases. Am J Surg Pathol 1994; 18:1183-91. 166. Beljaards R, Meijer C, Putte SVD, 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: 53-60. 167. Lindholm J, Barren D, Williams M. Ki-1 positive cutaneous large cell lymphoma of T-cell origin. Report of an indolent subtype. J Am Acad Dermatol 1989; 20: 342. 168. Beljaards R, Kaudewitz P, Berti E, etal. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer 1993; 71: 2097-104. 169. DeCoteauJF, ButmarcJR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin. Blood 1996;87:3437-41. 170. Rodriguez L, Pugh WC, Romaguera JE, Luthra R, Hagemeister FB, McLauglin P. Primary mediastinal large cell lymphoma is characterised by an inverted pattern of large tumoral mass and low beta 2 microglobulin levels in serum and frequently elevated levels of serum lactate dehydrogenase. Ann Oncol 1994; 5: 847-9. 171. Lamarre L, Jacobson JO, Aisenberg AC, etal. Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases. Am J Surg Pathol 1989; 13: 730-9.

19 Advanced Hodgkin's disease BW HANCOCK ANDPJSELBY

Introduction Stage IMA Hodgkin's disease Advanced Hodgkin's disease Use of maintenance chemotherapy Use of MOPP-like regimens Use of MOPP alternatives Use of alternating regimens Use of hybrid regimens

269 270 270 270 271 272 274 274

INTRODUCTION The dismal prognosis previously associated with the diagnosis of advanced Hodgkin's disease was irrevocably altered by the dramatic results first reported by De Vita and co-workers using the now famous cyclical four-drug MOPP combination (see Table 19.2).' With longer follow-up of this population, the possibility of cure was realized in over half of those treated.2 Nevertheless, a proportion of patients appear destined to fail treatment. Either complete remission is not achieved with first-line induction therapy or patients subsequently relapse after apparent successful eradication of disease. Many such patients ultimately die as a direct consequence of progressive Hodgkin's disease. As a result, work continues at major treatment centers (Table 19.1) to enhance the results of existing treatment programs, but also to develop new drug and radiotherapy combinations and to find new ways of delivering such therapy. This work has been conducted along two lines: through controlled randomized clinical trials; and through the retrospective analysis of patients who have completed treatment. This chapter is concerned chiefly with the findings of the former studies, although both have offered valuable guides to the design of subsequent studies, and reference will be made to retrospective analysis where appropriate. Comparing different trials is fraught with difficulty: patient numbers are often too small; the results from single-institution selective studies are generally better than those from co-operative groups;

Combined modality therapy Conclusions Salvage therapy Novel therapies New drugs Pregnancy References

275 276 277 278 279 279 279

different indices of response and survival are chosen in describing results; and lengths of follow-up (important Table 19.1 Lymphoma groups studying the treatment of advanced Hodgkin's disease Barts BNLI CALGB Christie CLG ECOG EORTC GATLA GELA GHSG Marsden MDA MSKCC NCI NCI NLG NLSG NTI SECSG Stanford SWOG WCOG WCSG Yale

St Bartholomew's Hospital, UK British National Lymphoma Investigation, UK Cancer and Leukemia Group B, USA Christie Hospital, UK Central Lymphoma Group, UK Eastern Co-operative Oncology Group, USA European Organisation for Research and Treatment of Cancer Grupo Argentine de Tratamiento de Leucemia Aguda, Argentina Group d'Etude Lymphome Adulte, France German Hodgkin's Study Group, Germany Royal Marsden Hospital, UK MD Anderson Cancer Center, USA Memorial Sloan Kettering Cancer Center, USA National Cancer Institute, Canada National Cancer Institute, USA Norwegian Lymphoma Group Nebraska Lymphoma Study Group National Tumor Institute, Italy South Eastern Cancer Study Group, USA Stanford University Medical Center, USA South West Oncology Group, USA West Coast Oncology Group, USA Western Cancer Study Group, USA Yale Cancer Center, USA

270 Advanced Hodgkin's disease

in a disease with a long natural history) are varied. Additionally, overall survival may or may not include death from other causes. Thus, only broad comparisons are possible.

STAGE MIA HODGKIN'S DISEASE The management of stage IIIA Hodgkin's disease has posed special problems, principally as a result of its watershed position between limited and advanced stages. In two respects it fulfills criteria of both stages: the Hodgkin's disease still being confined to lymph nodes, yet having spread to both sides of the diaphragm. Moreover, at one time the outlook for patients with Stage III Hodgkin's disease was as unfavorable as those with more advanced illness. Subsequently, the introduction of total nodal irradiation (TNI) provided the first means by which such patients could be cured of their disease.3'7 Nevertheless, initial enthusiasm was tempered by results that indicated that, in general, both survival and freedom of relapse were still less favorable than in early-stage disease.8,9 Attempts have been made to subdivide Stage III Hodgkin's disease according to the anatomical extent of disease. Disease limited to the spleen and/or upper abdominal nodes was designated substage III1; involvement of low abdominal nodes was designated substage III2 regardless of whether or not this was in addition to upper abdominal disease. In a partly randomized, partly retrospective analysis, Desser and his colleagues studied the outcome of patients in these subgroups and demonstrated better survival for patients at substage III, than III2, the respective 5-year figures being 93 per cent and 57 per cent.8 The concept of prognostically significant substages of IIIA was further followed-up in two subsequent studies: one a prospective clinical trial, the other a retrospective review of a large number of patients treated at several centers in the United States.10,11 Both confirmed the value of sub-staging. However, the Stanford group were unable to confirm this but identified a group of patients in whom prognostic distinctions could be made on the extent of splenic infiltration with .Hodgkin's disease found at laparotomy.12 Similar conclusions were reached by United Kingdom Lymphoma Investigation.13 On the other hand, Neeley et al. applied the Stanford criteria of splenic involvement to the distribution of substages, in patients treated in Chicago.12 Using these criteria, threequarters of substage II^A patients were found to have extensive splenic disease and over half of substage III2A patients had minimal involvement of the spleen, suggesting that the patient subgroups were biologically identical, although defined differently. Most of these early studies were complicated by the heterogeneity of investigation (particularly the role of pathological as

opposed to clinical staging) and treatment (varying from TNI to chemotherapy alone to combined modality therapy). With the advent of computed tomography (CT) scanning, the virtual demise of lymphangiography and diagnostic laparotomy and splenectomy, together with the apparent rarity of Stage III a'nd the feeling that radiotherapy alone is inadequate treatment to secure longterm remissions in the majority of instances, it is now generally felt that this stage should be treated primarily with chemotherapy as with other patients with 'advanced' Hodgkin's disease.

ADVANCED HODGKIN'S DISEASE Despite the conspicuous success of the MOPP regimen, two factors have led many groups of workers to devise other drug combinations (Table 19.2): • the considerable short-term morbidity of MOPP (particularly nausea, vomiting and phlebitis); • the realization that up to half the patients will ultimately fail this therapy. Many studies aimed at surmounting these problems have been reported; broadly they can be grouped into the following lines of approach: • the use of maintenance chemotherapy beyond complete remission; • the use of MOPP-like regimens in which the principal toxic drug mustine is substituted by an alternative alkylating agent; • the use of chemotherapy combinations comprising drugs of quite distinct pharmacological properties from those used in MOPP; • the addition of radiotherapy in a combined modality treatment plan; • the use of alternating 'non-cross-resistant' combination regimens; • the use of hybrid 'non-cross-resistant' combination regimens.

USE OF MAINTENANCE CHEMOTHERAPY In the early years of MOPP chemotherapy, the value of maintenance after induction and consolidation chemotherapy was assessed in randomised studies by the NCI, where patients were randomly allocated to receive either no further treatment, two cycles of MOPP every 3 months for 15 months, or BCNU (carmustine) given as a single drug every 3 months for 15 months. The study was stopped when it became apparent that no survival advantage was demonstrated to any of the groups.14 In the BNLI study15,16 where patients were randomized to maintenance with CVB every 3 months for 12 months, or to no further

Use of MOPP-like regimens 271

Table 19.2 Some chemotherapy acronyms in Hodgkin's disease

ABOD ABVD B-CAVe BAVS (ABOS) BCNU-VPP BCVPP BCVPP-Bleo BEACOPP BMOPP BOPP CABS

CAD CCNU-VP ChlVPP

CVB COPP CVPP CVPP

60 44 113 35 33 19 56 77 15 21 59 65 42 28 15 91 26 27

EVA

110,111

EVAP

61 40 109 4 1 18 36 84 147 62 125

LOPP MIME MOP-BAP MOPP MOPP-Bleo MVPP MVVPP NOVP PABIOE PACE/BOM

VAPEC-B

34,43 148

VBM

126

PAVe

Adriamycin (doxorubicin), bleomycin, Oncovin (vincristine), dacarbazine Adriamycin (doxorubicin), bleomycin, Velbe (vinblastine), dacarbazine Bleomycin, CCNU (lomustine), Adriamycin (doxorubicin), vinblastine Bleomycin, Adriamycin (doxorubicin), vincristine, streptozocin BCNU (carmustine), vinblastine, procarbazine, prednisolone BCNU (carmustine), cyclophosphamide, vinblastine, procarbazine, prednisolone BCVPP-bleomycin Bleomycin, etoposide, Adriamycin (doxorubicin)-COPP Bleomycin-MOPP BCNU (carmustine), Oncovin (vincristine), procarbazine, prednisolone CCNU (lomustine), Adriamycin (doxorubicin), bleomycin, streptozocin CCNU (lomustine), Alkeran (melphalan), desacetyl vinblastine amide sulfate (vindesine) CCNU (lomustine), vinblastine, prednisolone Chlorambucil, vinblastine, procarbazine, prednisolone CCNU (lomustine), vinblastine, bleomycin Cyclophosphamide, Oncovin (vincristine), procarbazine, prednisolone Cyclophosphamide, vinblastine, procarbazine, prednisolone CCNU (lomustine), vinblastine, procarbazine, prednisolone Etoposide, vinblastine, Adriamycin (doxorubicin) Etoposide, vinblastine, Adriamycin (doxorubicin), prednisolone Leukeran (chlorambucil), vinblastine, procarbazine, prednisolone Methyl GAG, ifosfamide, methotrexate, etoposide MOP-bleomycin, Adriamycin (doxorubicin), prednisolone Mechlorethamine (mustine), Oncovin (vincristine), procarbazine, prednisolone MOPP- bleomycin Mustine (mechlorethamine), vinblastine (Velbe), procarbazine, prednisolone Mechlorethamine (mustine), vincristine, vinblastine, procarbazine, prednisolone Novantrone (mitoxantrone), Oncovin (vincristine), Velbe (vinblastine), prednisolone Prednisolone, Adriamycin (doxorubicin), bleomycin, Oncovin (vincristine) Prednisolone, Adriamycin (doxorubicin), cyclophosphamide, etoposide, bleomycin, Oncovin (vincristine), methotrexate Procarbazine, Alkeran (melphalan), vinblastine Vincristine, Adriamycin (doxorubicin), prednisolone, etoposide, cyclophosphamide, bleomycin Vinblastine, bleomycin, methotrexate

treatment, again no survival advantage was seen. Certainly the overwhelming body of evidence does not support the theoretical advantage of maintenance chemotherapy beyond remission induction.17'22 As a result, the use of maintenance chemotherapy has been dropped by almost all treatment centers around the world. It is generally agreed that a minimum of six cycles of conventional chemotherapy are sufficient; attempts to shorten this are being evaluated23 but as yet benefits are unproven.

USE OF MOPP-LIKE REGIMENS The role of prednisolone in the MOPP combination had never been conclusively resolved. The original MOPP regimen used prednisolone only in the first and fourth cycles of treatment;1 however, many other centers have modified the regimen to include the steroid in every cycle of treatment. In the large retrospective Stanford

review24 there was no disadvantage demonstrated to those patients who had never received prednisolone during induction. The complete response rates were nearly identical. On the other hand, the BNLI in a prospective partially randomized study demonstrated a striking difference in complete response rates in those patients treated with steroids. Additionally, these patients had a survival advantage.15'16'25 The main way in which MOPP has been varied is by substitution of the putatively most toxic agent (mustine) by another alkylating agent. In various regimens (see Table 19.2), cyclophosphamide,26 CCNU (lomustine),27 chlorambucil,28-30 BCNU (carmustine)21'31-34 and melphalan (Alkeran)35 have been substituted. Often vincristine and vinblastine have been interchanged36 and the most commonly added cytotoxic has been bleomycin.15'18 Of the randomized studies, the CALGB substituted BCNU (carmustine) for mustine with identical complete remission (CR) and overall survival.21'35 This study also randomized to two three-drug regimens (in which either

272 Advanced Hodgkin's disease

procarbazine or the alkylating agent was removed); the three-drug schedules were significantly inferior on all response and survival parameters. The ECOG substituted vinblastine for vincristine and instead of mustine used both BCNU and cyclophosphamide.19'37 They found improved freedom from relapse for BCVPP but overall survivals were similar; BCVPP was, however, less toxic. The SWOG added bleomycin to MOPP and their initial favorable results, both in terms of the remission rate and overall survival, led them to conclude that the addition of low-dose bleomycin to MOPP (MOPP-Bleo) should be the basis for their future studies.4,18 Addition of doxorubicin (adriamycin) to this regimen (MOPP/BAP) improved the CR rate but no significant differences were seen in survival although MOPP/BAP proved superior in prognostically more favourable patients.4,38The BNLI also added bleomycin to MOPP; although the CR rates were better for BMOPP, overall survival data are similar after long-term follow-up.15,16 The BNLI followed this study by substituting mustine in MOPP with chlorambucil (Leukeran).39 This ensued from the finding of McElwain and his colleagues that substituting chlorambucil for

mustine in the MVPP regimen (i.e. ChlVPP) gave equally good results, yet was far less toxic for the patients.28 The BNLI randomized study confirmed these data, which still hold good with long-term follow-up.39-41 The WCSG, in a small study, found that substituting CCNU for mustine and procarbazine, improved remission and survival, but the results were not significantly different.42 Stanford substituted Alkeran for mustine in their PAVe/radiotherapy regimen and found this effective and well tolerated.34,43 From such studies we can conclude that substitution of mustine by other agents gives results as good as those for MOPP with less short-term toxicity. The addition of drugs such as bleomycin and/or doxorubicin may give marginal improvements. Prednisolone seems to be an essential component of the regimen.

USE OF MOPP ALTERNATIVES (Table 19.3) Doxorubicin-containing regimens (such as ABVD) were originally developed as second-line regimens for

Table 19.3 Advanced Hodgkin's disease: comparison between MOPP and other regimens

64

58 78

MOPP-Bleo became standard for subsequent studies

77 (P = 0.05)

61 (5 years) 66

60 68

MOP-BAP superior in prognostically more favorable patients

MOPP BOPP

63 67

1 Approx. 55 j(5 years)

Upprox. 50

No significant differences

91 IV

MOPP MOP

69 36

—

60 (5 years) 30 (P< 0.01)

Prednisolone essential

1976-1979 (15)

166 MB, III IV

MOPP B-MOPP

51 65

60 (10 years)

39

Similar survival data

70

42

1979-1983 (15,39-41)

299 III, IV

MOPP LOPP

63 57

60 (10 years)

52 54

LOPP less toxic

55

ECOG

1972-1976 (19,37)

293 III, IV

MOPP BCVPP

73 77

50 (5 years) 65 (P = 0.02)

61 65

Overall survival similar. BCVPP less toxic

NTI

1973-1974 (45, 46)

76IIB-IVB

MOPP ABVD

63 71

50 (10 years)

39 54

ABVD probably superior

63

1974-1982 (46, 47)

232 MB, III

3 MOPP/RT/ 3 MOPP 3 ABVD/RT/ 3 ABVD

81

76 (10 years)

64

Long term toxicity less with ABVD

92 p 0.7

PSCT patients had more rapid engraftment and shorter hospital stays

109

Yes

HD and NHL

28

34% RFS

53% RFS

110

No

HD and NHL

142

44% Rel/Prog

45% Rel/Prog

23

No

NHL

158

23% 3-year FFS

40% 3-year FFS

0.014

111

No

HD

242

28% 4-year FFS

25% 4-year FFS

0.9

112

No (casecontrolled analysis)

HD and NHL

166

36% PFS

39% PFS

0.8

113

No

HD and NHL

41

11/19CCR 18/22CCR (12-40 months) (2-17 months)

24

No

HD NHL

47 53

50% 3-year EFS 41% 3-year EFS

HD and NHL

58

No differences in survival

114

Yes

33% 3-year EFS 36% 3-year EFS

PSCT patients had more rapid engraftment Difference only significant in good prognosis patients

PSCT patients had more rapid engraftment and less toxicity

PSCT patients had more rapid engraftment, shorter hospital stays, less blood product use and lower costs)

0.63 0.99 PSCT patients had more rapid engraftment, shorter hospital stays, less blood product use

ABMT = autologous bone marrow transplantation, PSCT = peripheral blood stem cell transplantation, HD = Hodgkin's disease, NHL = nonHodgkin's lymphoma, RFS = relapse-free survival, Rel/Prog = relapse or progression, FFS = failure-free survival, PFS = progression-free survival, CCR = continuous complete remission, EFS = event-free survival.

342 High-dose therapy

leukemia.117 Disadvantages of allogeneic transplantation include the increased mortality associated with graft versus host disease and the lack of a suitably matched sibling donor in most circumstances. Several institutions have reported comparative results of autologous and allogeneic bone marrow transplantation for lymphoma. Jones et al. noted that the actuarial relapse probability was 46 per cent following autologous bone marrow transplantation in a cohort of Hodgkin's and nonHodgkin's lymphoma patients, as compared with 18 per cent following allogeneic transplantation (P - 0.02).118 However, event-free survival was 47 per cent following allogeneic transplantation and 41 per cent following autologous transplantation (P - 0.8), owing to the higher transplant-related mortality associated with allogeneic transplantation (42 per cent vs 13 per cent; P = 0.01). A similar trial from Wayne State compared autologous and allogeneic bone marrow transplantation in 66 patients with relapsed or refractory non-Hodgkin's lymphoma of all histologic grades.119 Relapse probability was significantly higher in patients who received autologous bone marrow; however, death due to infectious complications and graft versus host disease were more frequent in allogeneic marrow recipients and progression-free survival rates were not statistically different (Fig. 24.8). A matched-pair analysis of 202 patients from the European Bone Marrow Transplant Group noted that progressionfree survival was 49 per cent following allogeneic transplantation and 46 per cent following autologous transplantation for non-Hodgkin's lymphoma.120 Progression-free survival in patients with lymphoblastic lymphoma was 48 per cent following allogeneic transplantation compared with 24 per cent following autologous transplantation (P = 0.035). Procedure-related mortality in patients with intermediate- and high-grade lymphoma was 28 per cent compared with 14 per cent following autologous transplantation (P = 0.008). There was a significantly lower relapse rate in patients with

Figure 24.8

chronic graft versus host disease compared with patients who had no chronic graft versus host disease. These results suggest that a graft versus lymphoma effect exists, although they can also be used to support ' the theory that relapse rates are lower following allogeneic transplantation due to lack of tumor contamination. A trial incorporating significant numbers of syngeneic transplants would be required to answer this question. There is increasing enthusiasm for employing allogeneic transplantation for low-grade lymphoma. Investigators from the MD Anderson Cancer Center reported a 2-year disease-free survival of 59 per cent in 15 patients undergoing allogeneic transplantation for low-grade lymphoma.121 An International Bone Marrow Transplant Registry survey reported that 3-year diseasefree survival was 43 per cent in 81 patients undergoing allogeneic bone marrow transplantation for low-grade non-Hodgkin's lymphoma.122 Comparative trials of autologous and allogeneic transplantation in Hodgkin's disease also suggest the presence of a graft versus lymphoma effect. Investigators from Seattle reported a relapse rate of 45 per cent following matched allogeneic transplantation for Hodgkin's disease compared with 76 per cent for patients undergoing autologous bone marrow transplantation.123 Event-free survival rates were not statistically different, however. An analysis of 100 HLA-identical sibling allogeneic transplants for Hodgkin's disease reported to the International Bone Marrow Transplant Registry noted a 14 per cent 3year disease-free survival rate.124 Treatment-related mortality was 61 per cent. A European Bone Marrow Transplant Registry study matched 45 HLA-identical allogeneic Hodgkin's disease transplant recipients to 45 autologous bone marrow transplant recipients.125 Overall survival at 4 years was 25 per cent following allogeneic transplantation and 37 per cent following autologous bone marrow transplantation. The actuarial 4-year rate

Probability of (a) disease progression, and (b) progression-free survival in 66 patients with relapsed and refractory non-

Hodgkin's lymphoma randomized to autologous or allogeneic bone marrow transplantation.™

Purging 343

of procedure-related mortality was 48 per cent following allogeneic transplantation and 27 per cent following autologous transplantation (P = 0.04). The procedure-related mortality of allogeneic transplantation makes it difficult to recommend this approach routinely. However, allogeneic transplantation may be considered for younger patients and those with bone marrow involvement, high-grade histology and poor prognostic features. The results of allogeneic transplantation for low-grade lymphoma make this approach a reasonable consideration for younger patients, although long-term follow-up studies are needed. The high mortality associated with allogeneic transplantation for Hodgkin's disease suggest that this approach should only be considered for carefully selected patients.

PURGING The greatest concern associated with autologous transplantation for lymphoma involves the risk of infusing malignant cells with the graft. This risk is eliminated with allogeneic transplantation, but procedure-related mortality and lack of donor availability limits use of this approach. Another approach involves the removal of malignant cells (purging) from the autograft, which can be accomplished in a variety of ways.126 While the removal of malignant cells from the autograft makes theoretical sense, there is relatively little information on the clonogenicity of contaminating cells. Even if these cells are clonogenic, there is little information on the effects of cryopreservation, the number of reinfused cells that might be necessary to cause relapse and the effects of high-dose therapy on the microenvironment. Relapse occurs after allogeneic transplantation and so not all relapses can be attributed to infusion of malignant cells. Most relapses after autologous transplantation occur at sites of prior disease, suggesting that relapse most commonly results from deficiencies in the preparative regimen rather than reinfusion of malignant cells. Furthermore, retrospective analyses,19,20,22 as well as a matched-pair analysis from the European Bone Marrow Transplant Registry,127 have failed to identify significant benefits from purging autologous transplants for lymphoma. There is a significant amount of evidence that does suggest a benefit from purging, however. Studies in which autologous bone marrow cells have been marked with the neomycin-resistance gene have demonstrated that contaminated grafts may contribute to relapse in some cases of acute and chronic myelogenous leukemia.128,129 Similar studies in patients with non-Hodgkin's lymphoma and a variety of solid tumors are ongoing. Early disseminated relapse in some patients undergoing autologous bone marrow transplantation for non-Hodgkin's lymphoma

also suggests that some relapses may be secondary to contaminated marrow.130,131 Additional indirect evidence of the importance of contaminating cells is demonstrated by studies from Sharp et al. who investigated the outcome of autologous transplantation in relation to the presence of contaminating tumor cells.132 Five-year relapse-free survival was 64 per cent in non-Hodgkin's lymphoma patients who received peripheral stem cell transplants with collections that did not contain detectable tumor cells compared with 57 per cent for autologous bone marrow transplant patients whose marrow contained no detectable tumor cells and 17 per cent for autologous bone marrow transplant patients whose harvests contained tumor cells. Gribben et al. performed purged autologous bone marrow transplants in 114 patients with non-Hodgkin's lymphoma in whom lymphoma cells were detectable prior to transplantation by means of the polymerase chain reaction for bcl-2 translocations.133 Following purging, with monoclonal antibodies and complement, 57 patients had detectable lymphoma cells in the marrow and 57 patients had no detectable cells. Diseasefree survival was significantly higher in patients with no detectable lymphoma cells after purging (Fig. 24.9). Also, in a retrospectively analysed French study of 120 autografted patients, improved outcome was noted for marrow purging in vitro with mafosfamide.134 These results suggest that purging may be useful, although the presence of tumor cells in the marrow product and the ability to purge successfully may simply be markers for disease sensitivity or a measure of disease aggressiveness. These controversies may only be settled in the context of a prospective trial.

Figu re 24.9 Disease-free survival following purged autologous bone marrow transplantation in 114 patients with B cell nonHodgkin's lymphoma. 'Negative' denotes patients without detectable lymphoma cells in the bone marrow following purging, and 'Positive' denotes patients who had residual detectable lymphoma cells.™


CURRENT STATUS There now seems to be a world-wide consensus of opinion as to the role of high-dose chemotherapy and transplantation.135,137 For chemotherapy-sensitive relapsed Hodgkin's disease and aggressive non-Hodgkin's lymphoma this is now the gold standard for patients judged appropriate for such therapy; there may also be a role in patients with partially responsive but progressively improving disease. For patients in first remission, those with aggressive non-Hodgkin's lymphoma with poor-risk disease should be encouraged to enter ongoing trials; if not, the option of high-dose treatment should be discussed. For refractory Hodgkin's disease but not aggressive non-Hodgkin's lymphoma, this is also a reasonable treatment option. For low-grade non-Hodgkin's lymphoma, the procedure should be studied in clinical trials. This is also the case for mantle cell lymphoma, although high-dose chemotherapy is commonly offered following conventional cytoreductive chemotherapy. The value of allogeneic stem cell transplant is still unproven, but this may be considered in relapsed aggressive non-Hodgkin's lymphoma and in Hodgkin's disease, where there is a HLA-identical sibling donor, for relapse following autologous stem cell transplant.

FUTURE DIRECTIONS The increasing use and safety of autologous transplantation for lymphoma has led to the recognition that relapse is now the major complication of transplantation rather than procedure-related mortality. Future efforts will focus on improving the results of transplantation. This goal can be accomplished in four ways. 1 Decrease transplant-related mortality. Mortality following autologous transplantation for lymphoma has fallen to levels below 5 per cent at most institutions and further reductions are unlikely to substantially improve overall survival. Nevertheless, continued efforts at decreasing morbidity and mortality will allow the use of transplantation to be increased, and will allow use in poor-prognosis patients who might not otherwise be transplant candidates. 2 Improvements in preparative regimens. Doses of available chemotherapy agents are unlikely to be escalated much further without incurring doselimiting non-hematopoietic toxicity. Studies investigating the use of radioactive antibodies as a means of more selective radiation delivery are under way. Unless new drugs are developed or agents are developed to protect non-hematopoietic organs, it is unlikely that substantial improvements in preparative regimens will be forthcoming.

3 Purging. The role of purging is unclear. If infused marrow cells do contribute to relapse, then development and incorporation of successful purging techniques or the use of positive selection techniques may lead to improved transplant results. 4 Post-transplant therapy. Relapse is the major cause of transplant failure. Ongoing trials are investigating the use of post-transplant consolidation radiation, as well as immunotherapy with interferon, conjugated antibodies and interleukin-2. The graft versus lymphoma effect following allogeneic transplantation suggests that this form of transplantation will gain increasing use if mortality can be decreased. It should also be possible to achieve this effect using immune modulation and non-myeloablative allogeneic transplantation.

REFERENCES 1. ArmitageJO, VoseJM, Bierman PJ. Salvage therapy for patients with non-Hodgkin's lymphoma. J Natl Cancer Inst Monogr l990; 10: 39-43. 2. Rodriguez MA, Cabanillas FC, Velasquez W, et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP.y Clin Oncol 1995; 13:1734-41. 3. Buzaid AC, Lippman SM, Miller TP. Salvage therapy of advanced Hodgkin's disease. Am J Med 1987; 83: 523-32. 4. Canellos GP. Is there an effective salvage therapy for advanced Hodgkin's disease? Ann Oncol 1991; 2(suppl 1):1-7. 5. Longo DL, Duffey PL, Young RC, et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol 1992; 10: 210-18. 6. Frei E, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980; 69: 585-94. 7. Clifford P, Clift RA, Duff JK, et al. Nitrogen-mustard therapy combined with autologous marrow infusion. Lancet'1961;1:687-90. 8. Kurnick NB. Autologous and isologous bone marrow storage and infusion in the treatment of myelosuppression. Transfusion 1962; 2:178-87. 9. McFarland W, Granville NB, Dameshek W: Autologous bone marrow infusion as an adjunct in therapy of malignant disease. Blood 1959; 14: 503-21. 10. Appelbaum FR, HerzigGP, Ziegler JL, et al. Successful engraftment of cryopreserved autologous bone marrow in patient with malignant lymphoma. Blood 1978; 52: 85-95. 11. Applebaum FR, Deisseroth AB, Graw RG, et al. Prolonged complete remission following high dose chemotherapy of Burkitt's lymphoma in relapse. Cancer 1978; 41:1059-63.

References 345 12. Bennett CL, Armitage JL, Armitage GO, et al. Costs of care and outcomes for high-dose therapy and autologous transplantation for lympoid malignancies: results from the University of Nebraska 1987 through 1991.7 Clin Oncol 1995; 13: 969-73. 13. Miller CB, Piantadosi S, Vogelsang GB, et al. Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant. J Clin Oncol 1996; 14:1327-32. 14. Darrington DL, Vose JM, Anderson JR, et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994; 12: 2527-34. 15. Bhatia S, Ramsay N, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood 1996; 87: 3633-9. 16. Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987; 316:1493-8. 17. Colombat P, Gorin N-C, Lemonnier M-P, et al. The role of autologous bone marrow transplantation in 46 adult patients with non-Hodgkin's lymphomas.J Clin Oncol 1990; 8: 630-7. 18. Phillips GL, Fay JW, Herzig RH, et al. The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 1990; 75: 831-8. 19. Petersen FB, Appelbaum FR, Hill R, et al. Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle. J Clin Oncol 1990; 8: 638-47. 20. Weisdorf DJ, Haake R, Miller WJ, et al. Autologous bone marrow transplantation for progressive non-Hodgkin's lymphoma: clinical impact of immunophenotype and in vitro purging. Bone Marrow Transplant 1991; 8:135-42. 21. Lazarus HM, Crilley P, Ciobanu N, et al. High-dose carmustine, etoposide, and cisplatin and autologous bone marrow transplantation for relapsed and refractory lymphoma. J Clin Oncol 1992; 10:1682-9. 22. Gulati S, Yahalom J, Acaba L, et al. Treatment of patients with relapsed and resistant non-Hodgkin's lymphoma using total body irradiation, etoposide, and cyclophosphamide and autologous bone marrow transplantation. J Clin Oncol 1992; 10: 936-41. 23. Vose JM, Anderson JR, Kessinger A, et al. High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma.y Clin Oncol 1993; 11:1846-51. 24. Rapoport AP, Rowe JM, Kouides PA, et al. One hundred autotransplantsfor relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome..J Clin Oncol 1993; 11: 2351-61.

25. WheelerC, Strawderman M, Ayash L, et al. Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide. J Clin Oncol 1993; 11:1085-91. 26. Weaver CH, Petersen FB, Appelbaum FR, et al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.y Clin Oncol 1994; 12: 2559-66. 27. Horning SJ, Negrin RS, Chao NJ, et al. Fractionated totalbody irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and nonHodgkin's lymphoma.y Clin Oncol 1994; 12: 2552-8. 28. van Besien K, Tabocoff J, Rodriguez M, et al. High-dose chemotherapy with BEAC regimen and autolous bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remission, but a high rate of regimen-related toxicity. Bone Marrow Transplant 1995; 15: 549-55. 29. Mills W, Chopra R, McMillan A, et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma.y Clin Oncol 1995; 13: 588-95. 30. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive nonHodgkin's lymphoma. N EnglJ Med 1993; 329: 987-94. 31. Moskowitz CH, Portlock CS, Simonaitis NA, et al. The international prognostic index (IPI) predicts response and event free survival in an intent to treat autologous stem cell transplantation (ASCT) program for refractory and relapsed intermediate grade non-Hodgkin's lymphoma (IGL). ProcAm Soc Clin Oncol 1996; 15: 415. 32. Vose JM, Bierman PJ, Lynch JC, et al. Effect of follicularity on autologous transplantation for large-cell nonHodgkin's lymphoma.y Clin Oncol 1998; 16: 844-9. 33. Popat U, Prezepiork D, Champlin R, et al. High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome. J Clin Oncol 1998; 16: 63-9. 34. Clift RA, Buckner CD, Thomas ED, et al. The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 1987; 2: 243-58. 35. Freedman AS, RitzJ, Neuberg D. Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma. Blood 1991; 77: 2524-9. 36. Fouillard L, Gorin NC, Laporte JPH, et al. Feasibility of autologous bone marrow transplantation for early consolidation of follicular non-Hodgkin's lymphoma. EurJ Haematol 1991; 46: 279-84. 37. Colombat PH, Donadio D, Fouillard L, et al. Value of autologous bone marrow transplantation in follicular lymphoma: a France autogreffe retrospective study of 42 patients. Bone Marrow Transplant 1994; 13:157-62.


38. Schouten HC, Colombat PH, Verdonck LF, et al. Autologous bone marrow transplantation for low-grade non-Hodgkin's lymphoma: the European Bone Marrow Transplant Group experience. Ann Oncol 1994; 5(suppl 2): S147-9. 39. Rohatiner AZS, Johnson PWM, Price CGA, et al. Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for

50. Crump M, Smith AM, Brandwein J, et al. High-dose etoposide and melphalan, and autologous bone marrow transplantation for patients with advanced Hodgkin's disease: importance of disease status at transplant.) Clin Oncol 1993; 1: 704-11. 51. Gianni AM, Siena S, Bregni M, et al. High-dose sequential chemo-radiotherapy with peripheral blood progenitor cell support for relapsed or refractory

recurrent follicular lymphoma. 7 Clin Oncol 1994; 12:

Hodgkin's disease - a 6-year update. Ann Oncol 1993; 4:

1177-84.

889-91.

40. Cervantes F, Shu XO, McGlave PB, et al. Autologous bone marrow transplantation for non-transformed low-grade non-Hodgkin's lymphoma. Bone Marrow Transplant 1995; 16: 387-92. 41. Bastion Y, Price P, Haioun C, et al. Intensive therapy with peripheral blood progenitor cell transplantation in

52. Yahalom J, Gulati SC, Toia M, et al. Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease.? Clin Oncol 1993; 6:1062. 53. Reece DE, Connors JM, Spinelli JJ, et al. Intensive

60 patients with poor-prognosis follicular lymphoma.

therapy with cyclophosphamide, carmustine, etoposide

Blood 1995; 86: 3257-62.

± cisplatin, and autologous bone marrow

42. Haas R, Moos M, Karcher A, et al. Sequential high-dose therapy with peripheral-blood progenitor-cell support

transplantation for Hodgkin's disease in first relapse

in low-grade non-Hodgkin's lymphoma.7 Clin Oncol 1994; 12:1685-92. 43. Bierman P, Vose J, Anderson J, et al. High-dose therapy

1193-9. 54. Chopra R, McMillan AK, Linch DC, et al. The place of

with autologous hematopoietic rescue for follicular non-Hodgkin's lymphoma. ProcAm Soc Clin Oncol 1996; 15:1272. 44. Bartlett NL, Rizeq M, Dorfman RF, et al. Follicular large-

after combination chemotherapy. Blood 1994; 83:

high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A singlecenter eight-year study of 155 patients. Blood 1993; 81: 1137-45. 55. Bierman PJ, Bagin RG, Jagannath S, et al. High dose

cell lymphoma: intermediate or low grade? ? Clin Oncol

chemotherapy followed by autologous hematopoietic

1994; 12:1349-57.

rescue in Hodgkin's disease: long term follow-up in 128

45. Schouten HC, Bierman PJ, Vaughan WP, et al. Autologous bone marrow transplantation in follicular non-Hodgkin's lymphoma before and after histologic transformation. Blood 1989; 74: 2579-84. 46. Foran JM, Apostolidis J, Papamichael D, et al. High-dose

patients. Ann Oncol 1993; 4: 767-73. 56. Nademanee A, O'Donnell MR, Snyder DS, et al. Highdose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients

therapy with autologous haematopoietic support in

with relapsed and refractory Hodgkin's disease: results

patients with transformed follicular lymphoma: a study

in 85 patients with analysis of prognostic factors. Blood

of 27 patients from a single centre. Ann Oncol 1998; 9: 865-9. 46a. Apostolidis J, Gupta RK, Grenzelias D, et al. High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 2000; 18: 527-36. 47. Carella AM, Congiu AM, Gaozza E, et al. High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian study group report.? Clin Ortco/1988;6:1411-16. 48. Phillips GL, Wolff SN, Herzig RH, et al. Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 1989; 73: 2086-92. 49. Reece DE, Barnett MJ, Connors JM, et al. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease.? Clin oncol 1991;9:1871-9.

1995; 85:1381-90. 57. Burns LJ, Daniels KA, McGlave PB, et al. Autologous stem cell transplantation for refractory and relapsed Hodgkin's disease: factors predictive of prolonged survival. Bone Marrow Transplant 1995; 16:13-18. 58. Jagannath S, Armitage JO, Dicke KA, et al. Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol 1989; 7:179-85. 59. Armitage JO, Bierman PJ, Vose JM, et al. Autologous bone marrow transplantation for patients with relapsed Hodgkin's disease. Am J Med 1991; 91: 605-11. 60. Bierman PJ, Anderson JR, Freeman MB, et al. High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following first relapse after chemotherapy. Ann Oncol 1996; 7:151-6. 61. Spinolo JA, Jagannath S, Velasquez W, et al. Cisplatin-CBVwith autologous bone marrow transplantation for relapsed Hodgkin's disease. Leuk Lymphoma 1993; 9: 71-7.

References 347 62. Moormeier JA, Williams SF, Kaminer LS, et al. Autologous bone marrow transplantation followed by involved field radiotherapy in patients with relapsed or refractory Hodgkin's disease. Leuk Lymphoma 1991; 5: 243-8. 63. Surbone A, Armitage JO, Gale RP. Autotransplantations in lymphoma: better therapy or healthier patients? Ann Intern Med 1991; 114:1059-60. 64. Bosly A, Coiffier B, Gisselbrecht, et al. Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen. J Clin Oncol 1992; 10:1615-23. 65. Philip T, Hartmann 0, Pinkerton R, et al. Curability of relapsed childhood B-cell non-Hodgkin's lymphoma after intensive first line therapy: a report from the Societe Francaise d'Oncologie Pediatrique. Blood 1993; 81:2003-6. 66. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N EnglJ Med 1995; 333: 1540-5. 67. Yuen AR, Blume KG, Rosenberg SA, et al. Comparison between autologous bone marrow transplantation (ABMT) and conventional salvage therapy for recurrent or refractory Hodgkin's disease. Blood 1994; 10(suppl 1): 234a. 68. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993; 341:1051-4. 68a. Lazarus HM, Rowlings PA, Zhang M-J, et al. Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the autologous blood and marrow transplant registry. J Clin Oncol 1999; 17: 534-45. 69. Bonfante V, Santoro A, Devizzi L, et al. Outcome of patients with Hodgkin's disease relapsing after alternating MOPP/ABVD. ProcAm Soc Clin Oncol 1993; 12: 364. 70. Reece DE, Barnett MJ, Shepherd JD, et al. High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV ± P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy. Blood 1995; 86: 451-56. 71. Gulati SC, Shank B, Black P, et al. Autologous bone marrow transplantation for patients with poorprognosis lymphoma. J Clin Oncol 1988; 6:1303-13. 72. Milpied N, Ifrah N, Kuentz M, et al. Bone marrow transplantation for adult poor prognosis lymphoblastic lymphoma in first complete remission. BrJ Haematol 1989; 73: 82-7. 73. Santini G, Congiu AM, Coser P, et al. Autologous bone marrow transplantation for adult advanced stage lymphomblastic in first CR. A study of the NHLCSG. Leukemia 1991; 5(suppl 1): 42-5.

74. Baro J, Richard C, Calavia J, et al. Autologous bone marrow transplantation as consolidation therapy for non-Hodgkin's lymphoma patients with poor prognostic features. Bone Marrow Transplant 1991; 8: 283-9. 75. Verdonck LF, Dekker AW, de Gast GC, et al. Autologous bone marrow transplantation for adult poor-risk lymphoblastic lymphoma in first remission.J Clin Oncol 1992; 10: 644-6. 76. Nademanee A, Schmidt GM, O'Donnell MR, et al. Highdose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: a pilot study. Blood 1992; 80:1130-4. 77. Freedman AS, Takvorian T, Neuberg D, et al. Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell nonHodgkin's lymphoma in first remission: a pilot study.J Clin Oncol 1993; 11: 931-6. 78. Jackson GH, Lennard AL, Taylor PRA, et al. Autologous bone marrow transplantation in poor-risk high-grade non-Hodgkin's lymphoma in first complete remission. BrJcancer1994;70:501-5. 79. Sweetenham JW, Proctor SJ, Blaise D, et al. High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with highgrade non-Hodgkin's lymphoma: the EBMT experience. Ann Oncol 1994; 5(suppl 2): S155-9. 80. Jost LM, Jacky E, Dommann-Scherrer C, et al. Short-term weekly chemotherapy followed by high-dose therapy with autologous bone marrow transplantation for lymphoblastic and Burkitt's lymphomas in adult patients. Ann Oncol 1995; 6: 445-51. 81. Fanin R, Silvestri F, Geromin A, et al. Primary systemic CD30 (KM)-positive anaplastic large cell lymphoma of the adult: sequential intensive treatment with the FMACHOP regimen (± radiotherapy) and autologous bone marrow transplantation. Blood 1996; 87:1243-8. 82. Pettengell R, Radford JA, Morgenstern GR, et al. Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkin's lymphoma. J Clin Oncol 1996; 14: 586-92. 83. Haioun C, Lepage E, Gisselbrecht C, et al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: a study of 464 patients. J Clin Oncol 1994; 12:2543-51. 84. Haioun C, Lepage E, Gisselbrecht C, et al. for the Group d'Etude des Lymphomes de I'Adulte. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive nonHodgkin's lymphoma: updated results of the prospective study LNH87-2J Clin Oncol 1997; 15: 1131-7.

348 High-dose therapy 85. Reyes F, Lepage E, Morel P, et al. Failure of inductive high-dose chemotherapy (HDC) in poor-risk patients (PTS) with aggressive lymphoma. Updated results of the randomized LNH93-3 study. Blood 1997; 90: 594a. 86. Kaiser U, Uebelacker I, Havemann K. High dose chemotherapy with autologous stem cell transplantation in high grade NHL: first analysis of a randomized multicenter study. Bone Marrow Transplant 1998;21:S177. 87. Santini G, Salvagno L, Leoni P, et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma. Results of a prospective randomized trial by the Non-Hodgkin's Lymphoma Cooperative Study group.) Clin Oncol 1998; 16:2796-802. 88. Klimo P, Connors JM. Updated clinical experience with MACOP-B. Semin Hematol 1987; 24(suppl 1): 26-34. 89. Gianni AM, Bregni M, Siena S, et al. 5-year update of the Milan Cancer Institute randomized trial of high-dose sequential (HDS) vs MACOP-B therapy for diffuse largecell lymphomas. ProcAm Soc Clin Oncol 1994; 13: 373. 90. Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N EnglJ Med 1997; 336:1290-7. 91. Schenkein DP, Miller KB, Sweet M, et al. A phase II trial of filgrastim (G-CSF) supported high dose sequential chemotherapy and peripheral blood stem cell (PBSC) transplantation as initial therapy for high-risk nonHodgkin's lymphoma (NHL). A multicenter pilot study. fi/ood1995;86:964a. 92. Haq R, Sawka CA, Franssen E, et al. Significance of a partial or slow response to front-line chemotherapy in the management of intermediate-grade or high-grade non-Hodgkin's lymphoma: a literature review. J Clin OA7«>/1994;12:1074-84. 93. Verdonck LF, van Putten WLJ, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N EnglJ Med 1995; 332:1045-51. 94. Martelli M, Vignetti M, Zinzani PL, et al. High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomized Italian multicenter study.7 Clin Oncol 1996; 14: 534-42. 95. Philip T, Hartmann 0, Biron P, et al. High-dose therapy and autologous bone marrow transplantation in partial remission after first-line induction therapy for diffuse non-Hodgkin's lymphoma. J Clin Oncol 1988; 6:1118-24. 96. Haioun C, Lepage E, Gisselbrecht C, et al. High-dose therapy followed by stem cell transplantation in partial response after first-line induction therapy for aggressive non-Hodgkin's lymphoma. Ann Oncol 1998; 9 (suppl 1): S5-8.

97. Carella AM, Carlier P, Congiu A, et al. Autologous bone marrow transplantation as adjuvant treatment for highrisk Hodgkin's disease in first complete remission after MOPP/ABVD protocol. Bone Marrow Transplant 1991; 8: 99-103. 98. Moreau P, Milpied N, Mechinaud-Lacroix F, et al. Early intensive therapy with autotransplantation for high-risk Hodgkin's disease. Leak Lymphoma 1993; 12: 51-8. 99. Stockerl-Goldstein KE, Horning SJ, Chao NJ, et al. Evaluation of two preparative regimens for autologous bone marrow transplantation for non-Hodgkin's lymphoma: the Stanford experience. ProcAm Soc Clin Oncol 1996;15:336. 100. Mounier N, Gisselbrecht C. Conditioning regimens before transplantation in patients with aggressive nonHodgkin's lymphoma. Ann Oncol 1998; 9(suppl 1): S15-21. 101. Fielding AK, Philip T, Carella A, et al. Autologous bone marrow transplantation for lymphomas - a 15 year European Bone Marrow Transplant Registry (EBMT) experience of 3325 patients. Blood 1994; 84(suppl 1): 536a. 102. Mills W, StrangJ, Goldstone AH, et al. Dose intensification of etoposide in the BEAM ABMT protocol for malignant lymphoma. Leuk Lymphoma 1995; 17: 263-70. 103. Wheeler C, Antin JH, Churchill WH, et al. Cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose finding study. 7 Clin Oncol 1990; 8: 648-56. 104. Weaver CH, Appelbaum FR, Petersen FB, et al. High-dose cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation in patients with lymphoid malignancies who have received doselimiting radiation therapy.) Clin Oncol 1993; 11:1329. 105. Stiff PJ, Dahlberg S, Forman SJ, et al. Autologous-bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens - a Southwest Oncology Group trial. J Clin Oncol 1998; 16: 48-55. 106. Press OW, EaryJF, Appelbaum FR, et al. Radiolabeledantibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 1993; 329: 1219-24. 107. Bierman PJ, Vose JM, Leichner PK, et al. Yttrium 90labeled antiferritin followed by high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis Hodgkin's disease. J Clin Oncol 1993; 11: 698-703. 108. Shpall E, Jones RB. Release of tumor cells from bone marrow. Blood 1994; 83: 623-5. 109. Weisdorf D, Daniels K, Miller W, et al. Bone marrow vs. peripheral blood stem cells for autologous lymphoma transplantation: a prospective randomized trial. Blood 1993;82(suppl1):444a.

References 349 110. Brice P, Marolleau JP, Pautier P, et al. High dose chemotherapy and autologous stem cell transplantation for advanced lymphomas: comparison of bone marrow versus peripheral blood stem cell (PBSC) in 147 patients. Br J Haematol 1994;87:27. 111. Bierman P, VoseJ, Anderson J, et al. Comparison of autologous bone marrow transplantation (ABMT) with peripheral stem cell transplantation (PSCT) for patients (PTS) with Hodgkin's disease (HD). Blood 1993; 10(suppl 1): 445a. 112. Liberti G, Pearce R, Taghipour G, et al. Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a casecontrolled analysis of the EBMT registry data. Ann Oncol 1994;5(suppl2):S151-3. 113. AgerS, Scott MA, Mahendra P, et al. Peripheral blood stem cell transplantation after high-dose therapy in patients with malignant lymphoma: a retrospective comparison with autologous bone marrow transplantation. Bone Marrow Transplant 1995; 16: 79-83. 114. Schmitz N, Linch DC, Dreger P, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 1996; 347: 353-7. 115. Janssen W, Smilee R, Elfenbein G. A prospective radomized trial comparing blood- and marrow-derived stem cells for hematopoietic replacement following high-dose chemotherapy.) Hemother 1995; 4:139-40. 116. Smith TJ, Hillner BE, Schmitz N, et al. Economic analysis of a randomized clinical trial to compare filgrastimmobilized peripheral-blood progenitor-cell transplantation and autologous bone marrow transplantation in patients with Hodgkin's and nonHodgkin's lymphoma. J Clin Oncol 1997; 15: 5-10. 117. Butturini A, Bortin MM, Gale RP. Graft-versus-leukemia following bone marrow transplantation. Bone Marrow Transplant 1987; 2: 233-42. 118. Jones RJ, Ambinder RF, Piantadosi S, et al. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 1991; 77: 649-53. 119. Ratanatharathorn V, Uberti J, Karanes C, et al. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 1994; 84: 1050-5. 120. Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic bone marrow transplantation for nonHodgkin's lymphoma: a case-controlled analysis of the European bone marrow transplant group registry data. J Clin Oncol 1992; 10:1690-5. 121. van Besien KW, Mehra RC, Giralt SA, et al. Allogeneic bone marrow transplantation for poor-prognosis lymphoma: response, toxicity, and survival depend on disease histology. Am J Med 1996; 100: 299-307.

122. van Besien K, Rowlings PA, Sobocinski KA, et al. Allogeneic bone marrow transplantation for low grade lymphoma. Blood 1995; 86 (suppl 1): 209a. 123. Anderson JE, Litzow MR, Appelbaum FR, et al. Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience. J Clin Oncol 1993; 11: 2342. 124. Gajewski JL, Phillips GL, Sobocinski KA, et al. Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease. J Clin Oncol 1996; 14: 572-8. 125. Milpied N, Fielding AK, Pearce RM, et al. Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin's disease. J Clin Oncol 1996; 14:1291-6. 126. Rizzoli V, Carlo-Stella C. Stem cell purging: an intriguing dilemma. Exp Hematol 1995; 23: 296-302. 127. Williams CD, Pearce R, Taghipour G, et al. Purging of bone marrow in autologous bone marrow transplantation for non-Hodgkin's lymphoma: a case-matched comparison with unpurged cases by the EBMT lymphoma registry. Blood 1993; 82 (suppl 1): 444a. 128. Brenner MK, Rill DR, Moen RC. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 1993; 341: 85-6. 129. Deisseroth AB, Zu Z, Claxton D, et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 1994;83:3068-76. 130. Vaughan WP, Weisenburger DD, Sanger, et al. Early leukemic recurrence of non-Hodgkin's lymphoma after high-dose anti-neoplastic therapy with autologous marrow rescue. Bone Marrow Transplant 1987; 1: 373-8. 131. Rossetti F, Deeg HJ, Hackman RC. Early pulmonary recurrence of non-Hodgkin's lymphoma after autologous marrow transplantation: evidence for reinfusion of lymphoma cells. Bone Marrow Transplant 1995;15:429-32. 132. Sharp JG, Kessinger A, Mann S, et al. Outcome of high-dose therapy and autologous transplantation in non-Hodgkin's lymphoma based on the presence of tumor in the marrow or infused hematopoietic harvest. J Clin Oncol 1996; 14: 214-19. 133. Gribben JG, Freedman AS, Neuberg D, et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. NEnglJMed 1991; 325:1525-33. 134. Fouillard L, Laporte JP, Labopin M, et al. Autologous stem-cell transplantation for non-Hodgkin's lymphomas: the role of graft purging and radiotherapy posttransplantation - results of a retrospective analysis on 120 patients autografted in a single institution. J Clin Oncol 1998; 16: 2803-16.


135. Goldman JM, Schmitz N, Niethammer D, Gratwohl A, for

136. Vose JM. High-dose chemotherapy and hematopoietic

the Accreditation Sub-Committee of the European

stem cell transplantation for relapsed or refractory

Group for Blood and Marrow Transplantation. Allogeneicand autologous transplantation for

diffuse large-cell non-Hodgkin's lymphoma. Ann Oncol 1998; 9(suppl 1): S1-3.

haematological disease, solid tumours and immune disorders: current practice in Europe in 1998. Bone Marrow Transplant 1998; 21:1-7.

137. Perry AR, Goldstone AH. High-dose therapy for diffuse large-cell lymphoma in first remission. Ann Oncol 1998; 9(suppl 1): S9-14.

25 AIDS-related lymphoma AM LEVINE

Epidemiology Etiology and pathogenesis Pathologic aspects Clinicopathologic correlations Clinkal features Prognostic factors for survival

351 351 352 353 353 353

EPIDEMIOLOGY Lymphoma became an acquired immunodeficiency syndrome (AIDS)-defining condition in 1985 and its incidence has continued to increase, coincident with the progressive prolongation of survival in patients with human immunodeficiency virus (HIV) infection. While lymphoma currently comprises approximately 3 per cent of all initial AIDS-defining conditions, it accounts for as many as 12-16 per cent of all AIDS-related deaths, as reported from one large teaching hospital in the UK.1 In one particular study of antiretroviral therapy (primarily zidovudine) in patients with AIDS, conducted at the National Cancer Institute, USA, the incidence of lymphoma was approximately 19 per cent at 36 months of follow-up.2 Although the use of zidovudine has been questioned as potentially etiologic in the pathogenesis of these lymphomas, recent population-based studies have not confirmed this hypothesis.3 While the relative risk of lymphoma in the setting of HIV is approximately 100-fold greater than expected in the general population, the relative risk increases substantially among patients who have already been diagnosed with full-blown AIDS. Thus, the risk of immunoblastic lymphoma is approximately 627-fold over expected, Burkitt's lymphoma is increased approximately 220-fold, and the relative risk of diffuse large cell lymphoma is increased 145-fold in patients with AIDS, when compared with the population in general.4 While highly active antiretroviral therapy (HAART) has been associated with a significant decline in the incidence of various opportunistic infections and Kaposi's

Treatment options in newly diagnosed AIDS lymphoma Therapy for patients who have failed or relapsed after initial chemotherapy Primary CMS lymphoma References

353 356 356 356

sarcoma,5'6 such a decrease has only recently been described in terms of AIDS-related lymphoma, which now appears to have decreased by approximately 50 per cent, when the years 1997-1999 are compared to earlier time frames.7 It is in this latter period that widespread use of HAART therapy has been documented. Lymphoma occurs with approximately equal frequency in all population groups at risk for HIV infection, including injection drug users, homosexual or bisexual men, transfusion recipients, and patients with hemophilia.8 Thus, in a group of 1295 HIV-infected men with hemophilia, 5.5 per cent eventually developed lymphoma, with a mean latency period between initial HIV infection and lymphoma diagnosis of 59 months.9 AIDSrelated lymphoma is seen more frequently in men than in women, which is also the case in de novo lymphoma, unrelated to underlying HIV infection. While Kaposi's sarcoma may be diagnosed in persons with relatively high CD 4 cells, patients with AIDSrelated lymphoma tend to present with more advanced HIV disease. Thus, the median CD 4 cell count for patients with systemic AIDS lymphoma has ranged from 100 to 200/dl, while CD 4 cells less than 50/dl have been found in the majority of patients with AIDS-related primary central nervous system (CNS) lymphoma.2,10

ETIOLOGY AND PATHOGENESIS The AIDS-related lymphomas arise as a consequence of long-term stimulation and proliferation of B lymphocytes, due to several factors, including HIV itself,11 as well

352 AIDS-related lymphoma

as to Epstein-Barr virus (EBV).12 Aside from its direct ability to stimulate B cells, HIV may also be operative indirectly, by inducing the expression of a number of cytokines, which in turn serve to increase B cell activation and proliferation. Thus, interleukin-6 (IL-6) and IL-10, each induced by HIV, have been associated with both autocrine and paracrine growth of lymphoma cells in vitro,13,14 while elevated serum levels of IL-6 have been shown to correlate with increased likelihood of developing lymphoma over time.2 In the setting of chronic B cell proliferation, ongoing for a decade or more, the chance of an acquired genetic error may be increased, leading to aberrent expression of certain oncogenes and/or tumor suppressor genes, often by means of the chromosomal translocations that have been described in AIDS-related lymphoma - t(8;14); t(8;22); t(8;2).15 For example, with juxtaposition of the c-myc oncogene on chromosome 8 next to the transcriptionally active immunoglobulin heavy- or light-chain genes on chromosome 14 and 22 or 2, c-myc activation may occur, leading to a selective growth advantage, and the eventual development of a monoclonal B cell lymphoma, arising from a polyclonal B cell response.16,17This specific pathogenic mechanism may be operative in the small non-cleaved variants of AIDS lymphoma, in which other molecular biologic abnormalities have also been described, including abnormal expression of the p53 tumor suppressor gene18 and the ras oncogene, among others. The molecular pathogenesis of AIDS-related immunoblastic lymphoma appears to be distinct from that of small non-cleaved lymphoma.19 Thus, the immunoblastic lymphomas are more likely to be driven by EBV, with absence of c-myc dysregulation. Clonal integration of EBV has been demonstrated within tumor cells, with expression of various latent EBV proteins in essentially all cases of AIDS-related primary CNS lymphoma20 and in as many as two-thirds of systemic lymphomas.21 Defective EBV immunity maybe important.22 The specific molecular aberrations described in patients with AIDS-related diffuse large cell lymphoma appear distinct as well, with abnormal bcl-6 expression described in approximately 40 per cent of such cases.23 Of interest is the fact that bcl-6 expression has also been found in HIV-negative cases of diffuse large cell lymphoma.

PATHOLOGIC ASPECTS Well over 95 per cent of all AIDS lymphomas thus far reported have been of B lymphoid origin. The B cell nature of this malignancy has been demonstrated by immunophenotypic study, revealing evidence of B cell lineage, with frequent expression of CD 19, CD 20 and CD 22 antigens, usually with monoclonal surface immunoglobulin, and a lack of T cell antigens.24

The full spectrum of B cell neoplasia has been reported in HIV-infected patients, including B cell acute lymphoblastic leukemia, B cell chronic lymphocytic leukemia, plasmacytoma, multiple myeloma, and low-, intermediate- and high-grade lymphomas.25 Despite this wide spectrum of reported disease, the vast majority of AIDS lymphomas have been of high-grade type, including either the immunoblastic or small non-cleaved types, the latter of which may further be subclassified into Burkitt's or non-Burkitt's subtype. These tumors comprise as many as 70-90 per cent of all cases,26 representing a significant departure from the usual setting in de novo lymphoma, in which these high-grade types comprise approximately 10 per cent of all cases. Aside from the high-grade lymphomas, intermediate-grade, diffuse large cell lymphoma is also commonly diagnosed in the setting of HIV infection. The specific proportions of small non-cleaved, immunoblastic and diffuse large cell lymphomas diagnosed in various series have differed, perhaps because of the known complexity and lack of reproducibility of lymphoma classification in general.27 However, 113 cases of AIDS-related lymphoma were recently reviewed by a pathology study group in France, with consensus review required for all cases. Small non-cleaved lymphoma comprised 36 per cent of the group, while large cell immunoblastic accounted for 29 per cent and diffuse large cell lymphoma was diagnosed in 31 per cent. The remainder were not classifiable.28 The vast majority of AIDS lymphomas have been monoclonal B cell tumors, as demonstrated by immunoglobulin gene rearrangement after Southern blot analysis.19,26 Of interest, however, is that multiple monoclonal B cell expansions (oligoclonal lymphomas) have also been described, with the presence of one or more faint rearrangement bands in addition to the predominant clone.29 Recently, genotypically polyclonal B cell lymphomas have been reported, which lack evidence of EBV infection.30 While encountered only rarely in other series, these polyclonal lymphomas comprised 40 per cent of the systemic lymphomas reported by the group in San Francisco, and were defined by lack of IH rearrangement, while light-chain expression or gene rearrangement were not evaluated. Although clear 'clones' of B cells were described within these polyclonal tumors, the authors chose to term these tumors 'polyclonal' rather than oligoclonal. It is possible, then, that these polyclonal, EBV-negative lymphomas are similar to the oligoclonal tumors described by others. Further clarification is awaited. Of interest, is the fact that patients with 'polyclonal' lymphomas were found to survive significantly longer than those with 'monoclonal' disease. Although not considered as part of the AIDS epidemic, T cell lymphomas have also been described in HIV-infected patients. The incidence of T cell lymphoma has not increased since the onset of AIDS and these cases are currently considered to represent chance

Treatment options in newly diagnosed AIDS lymphoma 353

occurrence.26 However, rather unusual T cell lymphomas have been described, including cases of Ki-1 -positive, large cell anaplastic lymphoma. The clinical and pathologic characteristics of this disease appear similar to those seen in de novo Ki-1-positive lymphoma and the significance of these cases remains undefined.31,32 Interestingly, CD 30-positive anaplastic lymphoma, presenting as disease localized to body cavities, has been associated with the presence of a newly described human herpes virus, also detected within Kaposi's sarcoma tissues in HIV-infected individuals.33

C LIN I CO PATHOLOGIC CORRELATIONS The vast majority of primary CNS lymphomas are of the immunoblastic or large cell type. Furthermore, these tumors are uniformly associated with EBV.20 In a series of 113 patients with AIDS lymphoma, in which consensus pathology review was accomplished on all cases, the large cell or immunoblastic lymphomas were also more likely to involve the gastrointestinal tract and oral cavity, when compared to patients with small non-cleaved lymphoma. In the latter individuals, lymphoma was more likely to involve the bone marrow, lymph nodes and/or muscles.28 The majority of large-scale, prospective, multiinstitutional studies have found no differences in response or survival among patients with the various pathologic types of systemic AIDS lymphoma.26,34,36 It should be noted, however, that patients with primary CNS lymphoma do particularly poorly, with median survival in the range of only 2-3 months.37 These patients are usually diagnosed with immunoblastic lymphoma. Whether the poor survival is related to the specific site of disease within the CNS or to the pathologic type of disease per se remains to be clarified. Nonetheless, patients with systemic immunoblastic lymphomas seem to fare the same as those with the other pathologic types.2636

CLINICAL FEATURES Systemic 'B' symptoms are expected in approximately 80 per cent of patients with systemic AIDS lymphoma and in 90 per cent of those with disease primary to the CNS.26 It is mandatory to exclude the presence of an occult opportunistic infection before ascribing these symptoms to the lymphoma itself. An advanced stage of disease is expected in the majority of patients with extranodal involvement reported in 60-90 per cent of all large series.26,34,36 The likelihood of disseminated involvement is so great that, for all practical purposes, such patients must be assumed to have extensive disease and treated with systemic chemotherapy, even if dissemination is not confirmed on

routine staging evaluation. Common sites of extranodal involvement include the CNS in approximately 30 per cent at diagnosis, the gastrointestinal tract in 25 per cent and bone marrow in approximately 25 per cent. Essentially, any other site in the body may also be involved, including the heart, rectum, soft tissues, oral cavity and others.

PROGNOSTIC FACTORS FOR SURVIVAL In various prospective and retrospective studies, four factors have been shown to predict survival in patients with AIDS related lymphoma. These include history of AIDS prior to the lymphoma, CD 4 cells /1989;142:531-6. 14. Masood R, Zhang Y, Bond MW, et al. lnterleukin-10 in an autocrine growth factor for acquired immunodeficiency syndrome-related B cell lymphoma. Blood 1995; 85: 3423-30. 15. Bernheim A, Berger R. Cytogenetic studies of Burkitt lymphoma: leukemia in patients with acquired immunodeficiency syndrome. Cancer Genet 1988; 32: 67-74. 16. Subar M, Neri A, Inghirami G, et al. Frequent c-myc oncogene activation and infrequent presence of EpsteinBarr virus genome in AIDS-associated lymphomas. Blood 1988; 72: 667-71. 17. Bhatia K, Spangler G, Gaidano G, et al. Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas. Blood 1994; 84: 883-8. 18. Nakamura H, Said JW, Miller CW, Koeffler HP. Mutation and protein expression of p53 in acquired immunodeficiency syndrome related lymphomas. Blood 1993; 82: 731-5. 19. Ballerini P, Gaidano G, GongZ, et al. Molecular pathogenesis of HIV associated lymphomas. AIDS Res Hum Retroviruses 1992; 8: 731-5. 20. MacMahon EME, GlassJD, Hayward SD, et al. Epstein Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 1991; 338: 969-74.

21. Shibata D, Weiss LM, Hernandez AM, et al. Epstein Barr virus associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. Blood 1993; 91: 2102-9. 22. Kersten MJ, Van Gorp J, Pals ST, Boon F, van Oers MH. Expression of Epstein-Barr virus latent genes and adhesion molecules in AIDS-related non-Hodgkin's lymphomas: correlation with histology and CD4-cell number. Leuk Lymphoma 1998; 30: 515-24. 23. Gaidano G, Lo Coco F, Ye BH, et al. Rearrangements of the bcl-6 gene in acquired immunodeficiency syndromeassociated non-Hodgkin's lymphoma: association with diffuse large cell subtype. Blood 1994; 84: 397-402. 24. Hamilton-Dutoit SJ, Pallesen G, Granzmann MB, et al. AIDS-related lymphoma: histopathology, immunophenotype and association with Epstein Barr virus as demonstrated by in situ nucleic acid hybridization. Am] Pathol 1991; 138:149-63. 25. loachim HL, Dorsett B, Cronin W, et al. Acquired immunodeficiency syndrome associated lymphomas: clinical, pathological, immunologic and viral characteristics of 111 cases. Human Pathol 1991; 22: 659-73. 26. Levine AM. Acquired immunodeficiency syndromerelated lymphoma (Review). Blood 1992; 80: 8-20. 27. NCI Non-Hodgkin's Lymphoma Classification Project Writing Committee. Classification of non-Hodgkin's lymphomas: reproducibility of major classification systems. Cancer 1985; 55: 91-5. 28. Raphael M, Gentilhomme 0, Tulliez M, et al. Histopathologic features of high-grade non-Hodgkin's lymphomas in acquired immunodefiency syndrome. The French Study Group of Pathology for Human Immunodeficiency Virus-associated tumors. Arch Pathol Lab Med 1991; 115:15-20. 29. Pelicci PG, Knowles DM II, Arlin ZA, et al. Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndromerelated lymphoproliferative disorders: implications for lymphomagenesis..J Exp Med 1986; 164: 2049-76. 30. Shiramizu B, Herndier B, Meeker T, et al. Molecular and immunophenotypic characterization of AIDS-associated EBV negative polyclonal lymphoma. J Clin Oncol 1992; 10: 383-9. 31. Chadburn A, Cesarman E, Jagirdar J, et al. CD30 (Ki-1) positive anaplastic large cell lymphomas in individuals infected with the HIV. Cancer 1993; 72: 3078-90. 32. Tirelli U, Vaccher E, Zagonel V, et al. CD30 (Ki-1) positive anaplastic large cell lymphomas in 13 patients with and 27 patients without HIV infection: the first comparative clinicopathologic study from a single institution that also includes 80 patients with other HIV related systemic lymphomas. J Clin Oncol 1995; 13: 373-80. 33. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcomaassociated herpesvirus-like DNA sequences in AIDSrelated body cavity-based lymphomas. N EnglJ Med 1995; 332:1186-91.

358 AIDS-related lymphoma 34. Ziegler JL, Beckstead JA, Volberding PA, et al. NonHodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N EnglJ Med 1984; 311: 565-70. 35. Kaplan LD, Abrams Dl, Feigal E, et al. AIDS-associated non-Hodgkin's lymphoma in San Francisco. JAMA 1989; 261:719-24. 36. Levine AM, Wernz JC, Kaplan L, et al. Low dose chemotherapy with central nervous system prophylaxis and azidothymidine maintenance in AIDS-related lymphoma: a prospective multi-institutional trial. JAMA 1991; 266: 84-8. 37. Baumgartner JE, Rachlin JR, Beckstead JH, et al. Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 1990; 73: 206-11. 38. Vaccher E, Tirelli U, Spina M, et al. Age and serum lactate dehydrogenase level are independent prognostic factors in HIV related non-Hodgkin's lymphomas: a single institution study of 96 patients. J Clin Oncol 1996; 14:2217-23. 39. Gill PS, Levine AM, Krailo M, et al. AIDS-related malignant lymphoma: results of prospective treatment trials. J Clin Oncol 1987; 5:1322-8. 40. Dugan M, Subar M, Odajnyk C, et al. Intensive multiagent chemotherapy for AIDS related diffuse large cell lymphoma. Blood 1986; 68:124a. 41. Kaplan LD, Kahn JO, Crowe S, et al. Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus associated non-Hodgkin's lymphoma: results of a randomized trial.J Clin Oncol 1991; 9: 929. 42. Walsh C, Wernz J, Levine AM, et al. Phase I study of m-BACOD and granulocyte-macrophage colony stimulating factor (GM-CSF) in HIV associated nonHodgkin's lymphoma. J AIDS 1993; 6: 265-71. 43. Kaplan L, Straus D, Testa M, Levine AM. Randomized trial of standard dose mBACOD with GM-CSF versus reduced dose mBACOD for systemic HIV-associated lymphoma: ACTG #142. ProcAm Soc Clin Oncol 1995; 14: 288. 44. Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. N EnglJ Med 1997; 336: 1641-8. 45. Tirelli U, Errante D, Okssenhendler E, et al. Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poor prognosis AIDS-related non-Hodgkin's lymphoma. Ann Oncol 1992; 3: 843-7. 46. Levine AM, Tulpule A, Espina B, et al. Low dose m-BACOD with zalcitabine (ddC) in patients with AIDS lymphoma: correlations between serum IL-6, systemic 'B' symptoms, viral burden and response to therapy. Blood 1994; 84: 519a. 47. Tosi P, Gherlinzoni F, Visani G, et al. AZT plus

48.

49.

50.

51.

52.

53.

54. 55.

56.

57.

58.

59.

60.

methotrexate in HIV-related non-Hodgkin's lymphomas. Leak Lymphoma 1998; 30:175-9. Ratner L, Redden D, Hamzeh F, et al. Chemotherapy for HIV associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy (HAART) is not associated with excessive toxicity. Third National AIDS Malignancy Conference. Bethesda: MD J AIDS 1999; 21: A32,1000 (abstract 92). Sparano JA, Lee S, Henry DH, et al. Infusional cyclophosphamide, doxorubicin and etoposide in HIV associated non-Hodgkin's lymphoma: a review of the Einstein, Aviano, and ECOG experience in 182 patients. Abstracts of the 4th International AIDS Malignancy Conference; May 16-18, 2000. Bethesda, MDJAcquir Immune Defic Syndr Hum Retrovirol 2000; 23: A11 (abstract S15). Sparano JA, Wiernik PH, Hu X, et al. Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated nonHodgkin's lymphoma. J Clin Oncol 1996; 14: 3026-35. Little RF, Pearson D, Gutierrez M, et al. Dose adjusted chemotherapy with suspension of antiretroviral therapy for HIV associated non-Hodgkin's lymphoma. Abstracts of the 4th International AIDS Malignancy Conference; May 16-18,2000. Bethesda; MDJ Acquir Immune Defic Syndr Hum Retrovirol 2000; 23: A11 (abstract S16). Levine AM, Weiss GR, Tulpule A, et al. Multicenter Phase II study of mitoguazone (MGBG) in relapsed or refractory AIDS-lymphoma. ProcAm Soc Clin Oncol 1985; 14: 288. Scadden DT, Doweiko J, Schenkein D, et al. A phase I/I I trial of combined immunoconjugate and chemotherapy for AIDS-related lymphoma. Blood 1993; 82: 386a. Fine HA, Mayer RJ. Primary central nervous system lymphoma [Review]. Ann Intern Med 1993; 119:1093-104. Gill PS, Graham RA, Boswell W, et .al. A comparison of imaging, clinical and pathologic aspects of space occupying lesions within the brain in patients with acquired immunodeficiency syndrome. AmJPhysiol Imaging 1986; 1:134-41. Cinque P, Brytting M, Vago L, et al. Epstein Barr virus DNA in cerebrospinal fluid from patients with AIDSrelated primary lymphoma of the central nervous system. Lancet 1993; 342: 398-401. Formenti SC, Gill PS, Lean E, et al. Primary central nervous system lymphoma in AIDS: results of radiation therapy. Cancer 1989; 63:1101-7. Goldstein JD, Dickson DW, Moser FG, et al. Primary central nervous system lymphoma in acquired immunodeficiency syndrome: a clinical and pathologic study with results of treatment with radiation. Cancer 1991; 67: 2756-65. DeAngelis LM, Yahalom J, Heinemann MH, et al. Primary CMS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology 1990; 40: 80-6. DeAngelis LM, Yahalom J, Rosenblum M, et al. Primary CNS lymphoma: managing patients with spontaneous and AIDS-related disease. Oncology 1987; 1: 52.

26 Cutaneous lymphomas RTHOPPEANDYH KIM

Introduction

359

Other cutaneous lymphomas

Mycosis fungoides and the Sezary syndrome

359

References

INTRODUCTION The cutaneous lymphomas are not very common, but include an interesting group of diseases that have a different natural history, management and prognosis than the majority of other nodal, extranodal or systemic lymphomas. They are difficult to classify according to existing classification systems, and it is most helpful to categorize them according to T cell or B cell lineage and then further subclassify them according to critical clinical or histopathological criteria. The T cell lymphomas include mycosis fungoides/Sezary syndrome, peripheral T cell lymphomas, lymphoblastic lymphoma, angiocentric lymphoma, human T cell lymphomotrophic virus type 1 (HTLV-1) lymphoma, the majority of CD 30 (Ki-1) positive (anaplastic large cell) cutaneous lymphomas and pleomorphic small/large cell lymphomas. There is also a lymphoma-like cutaneous T cell lymphoproliferative disease called lymphomatoid papulosis. The Revised European-American Lymphoma (REAL) classification1 allows identification of distinct cutaneous disease entities. In this classification, mycosis fungoides, Sezary syndrome and CD 30-positive lymphoproliferative disease of the skin (primary cutaneous anaplastic large-cell lymphoma) are confirmed as the major specific cutaneous peripheral T cell malignancies. The B cell lymphomas include both follicular and diffuse lymphomas derived from follicular center cells and are often classified according to the criteria of the Working Formulation. Primary B cell lymphomas (defined as malignant B cell proliferations presenting with cutaneous involvement alone and no evidence of extracutaneous manifestations over a period of at least 6 months from presentation) may also be subtyped according to a European Organisation for Research and

367 368

Treatment of Cancer classification.2 The major subtypes are follVe center cell lymphoma of the head and trunk, and immunocytoma (subtypes with indolent behavior) and B cell lymphoma of the leg (with intermediate behavior). It will be interesting to see how these entities fare when studied prospectively. Virtually any type of lymphoma may have cutaneous manifestations. Quite often, the skin involvement is only incidental and will not influence management programs. Examples include angiocentric T cell lymphoma, HTLV1-related lymphoma, lymphoblastic lymphoma, and systemic (Stage IV) B cell or peripheral T cell lymphomas. This chapter will deal only with lymphomas that are manifest primarily in the skin. These include mycosis fungoides/Sezary syndrome, primary cutaneous (Stage IE or HE) B cell lymphoma and Ki-1-positive cutaneous lymphomas. These account for about 65, 25 and 10 per cent of primary cutaneous lymphomas, respectively.

MYCOSIS FUNGOIDES AND THE SEZARY SYNDROME Etiology and epidemiology

Mycosis fungoides (ME) is the most common cutaneous lymphoma. However, it accounts for only 0.5 per cent of the new cases of non-Hodgkin's lymphoma diagnosed in the USA each year.3 The peak age at presentation is 55-60 years and there is a 2:1 male preponderance. The incidence in African-Americans is about twice that of whites. It is uncommon in Asians. The etiology of ME is unknown. Environmental and occupational exposures have been implicated in its etiology but a large case-controlled study fails to support this

360 Cutaneous lymphomas

hypothesis.4 A viral etiology was proposed based on the isolation of HTLV-1 from a patient with cutaneous lymphoma resembling MR However, this proved not to be MF but rather HTLV-1-related adult T cell lymphoma. Some studies have demonstrated a higher risk for MF in the presence of certain histocompatibility antigens and others have identified specific chromosomal abnormalities in patients with MF. However, the significance of these observations is unknown.

Pathology Skin biopsies in cases of MF demonstrate characteristic abnormal cells infiltrating the epidermis (epidermotropism) as single cells or in clusters (Pautrier microabscesses). The neoplastic cells are mononuclear and contain hyperconvoluted nuclei with a cerebriform appearance.5 Typically, the biopsy will show an upper dermal infiltrate, which also includes histiocytes, eosinophils and plasma cells. Based upon the severity of the epidermal and dermal involvement, categories 'diagnostic of, 'consistent with' and 'suggestive of MF are defined.6 Immunohistochemical staining evaluating the expression of specific T cell antigens on the surface of the infiltrating lymphocytes has become an important tool in the diagnosis of MF. When the routine histology is equivocal, the immunophenotypic results may help in confirming or refuting the diagnosis, which may be important for clinical management. These studies indicate that the majority of cases of MF exhibit a helper/inducer T cell phenotype (CD 4+).7 The pan-T cell antigens CD 2, CD 3 and CD 5 are usually expressed. In many instances, the neoplastic cells lose other mature T cell antigens, such as Leu-8 or CD 7. This finding may help in the differential diagnosis of MF from benign dermatoses.7 CD 25 (TAC)and Ki-67 are variably expressed. CD 30 (Ki-1) expression is associated with a poor prognosis. Rare cases of MF have been demonstrated to be CD 8+ (cytotoxic/suppressor T cell phenotype). Evaluation of skin biopsies to detect T cell receptor (TCR) gene rearrangements, or 'genotyping', may also be helpful in the differential diagnosis of early MF. TCR gene rearrangements can be detected by Southern blot analysis or methods utilizing polymerase chain reaction amplification.8 Genotyping is not a common or essential diagnostic procedure, but is usually reserved for situations where both the routine histology and immunophenotyping results are only equivocal despite a clinical presentation strongly suggestive of MF. In general, multiple lesions in a single patient biopsied at the same time or different lesions biopsied sequentially in the same patient will demonstrate consistent rearrangements. The pathology of extracutaneous disease poses special problems. Enlarged lymph nodes may only demonstrate dermatopathic lymphadenitis, with sinus histiocytosis,

an abundance of pigment-laden macrophages and a variable number of atypical lymphocytes with cerebriform nuclei. The degree of lymph node abnormality is quantified in a 'lymph node classification system'. Lymph nodes are classified as LNO to LN4, corresponding to involvement ranging from 'no atypical lymphocytes' (LNO) to 'partial or complete replacement of nodal architecture by atypical lymphocytes or frankly neoplastic cells' (LN4). Classical lymph node involvement correlates with LN4. This descriptive system for grading lymph node involvement has prognostic relevance.9 Clonal TCR p-gene rearrangements have been identified in lymph nodes of patients with MF. Rearrangements are generally absent in histologically uninvolved lymph nodes (LNO-2), present in half of lymph nodes with dermatopathic changes (LN3), and in most of lymph nodes effaced with lymphoma (LN4).10 The presence of gene rearrangements is associated with a worse prognosis and probably explains the observation in earlier studies that palpable adenopathy, even when showing only dermatopathic change on biopsy, is associated with a worse outcome.11 Studies of the peripheral blood mononuclear cells of MF patients using Southern blot analysis reveal that clonal TCR b-gene rearrangements are uncommon in patients with patch, plaque or tumorous disease (Tl, T2, T3), but prevalent in erythrodermic MF (T4), and present in most cases of Sezary syndrome.12 Approximately one-third of patients with histologically proved lymph node involvement show clonal rearrangement in the peripheral blood and this is associated with a worse prognosis.

Clinical presentation and natural history Mycosis fungoides often has a long natural history. The diagnosis may be preceded by a prediagnostic (premycotic) phase lasting 5-10 years or longer, marked by scaly or pruritic patches similar to those seen in patients with benign skin conditions, such as psoriasis, parapsoriasis, eczematous dermatitis, photodermatitis or drug reactions. These lesions may respond to treatment with topical corticosteroids. Biopsies during this phase are non-specific. In its earliest diagnostic phase, well-defined patches or plaques of variable size and shape are generally present. The disease is often confined to the bathing trunk distribution, although any body surfaces may be affected. Occasionally, there may be prominent poikiloderma (skin atrophy, dyspigmentation and telangiectasia), alopecia or follicular mucinosis. Pruritus is generally a prominent symptom. As the disease progresses, patches may evolve into infiltrated plaques with a more generalized distribution. With generalized disease, the palms and soles are frequently involved. Infiltration of the hair follicles may result in alopecia. Patients with a history of plaque

Mycosis fungoides and the Sezary syndrome 361

disease may develop ulcerated or exophytic tumors. Occasional patients present de novo with tumors, socalled tumor cTemblee. Extensive involvement of the face may result in the appearance of'leonine fades'. Another phase of skin involvement is generalized erythroderma (I'homme rouge or the 'red man syndrome'). The erythema may be accompanied by either very atrophic or lichenified skin, and plaques or tumors may also be present. These patients are almost always intensely symptomatic secondary to pruritus and scaling. If peripheral blood involvement is present (atypical 'Sezary' cells >5 per cent of circulating lymphocytes), these patients are considered to have the Sezary syndrome (SS).13 Lymphadenopathy and splenomegaly are often present, as well. About 15-20 per cent of patients will develop manifestations of extracutaneous disease.6 This is often manifest initially by regional lymphadenopathy in regions draining extensive skin involvement. Visceral involvement may develop subsequently, with the lungs, spleen, liver, upper aerodigestive and gastrointestinal tracts most frequently affected. Autopsy studies have shown that involvement of any organ may occur in the final stages of disease. The likelihood of developing extracutaneous disease is correlated with the extent of skin involvement, ranging from less than 10 per cent for patch/plaque disease to greater than 30 per cent for patients with cutaneous tumors or erythroderma. In large cohorts of patients with long-term follow-up, the median survival of patients who are diagnosed with MF is nearly 10 years. Among patients who present with limited patch or plaque disease, the majority (80 per cent) will die from unrelated causes, such as cardiopulmonary disease or other cancers. Patients who are treated at the time that disease is in the limited plaque phase of skin involvement enjoy a long-term survival equivalently to an age-, gender- and race-matched population.14 The risk for these patients to develop progressive disease is less than 10 per cent. However, for patients who present with tumorous involvement or the Sezary syndrome, or who develop extracutaneous spread, the prognosis is poor. The majority of these patients (76-95 per cent) will die from MF or complications related to the disease, such as infection and sepsis, and their median survival is less than 3 years.6 An analysis of

Table 26.1 TNMB classification for mycosis fungoides

T1 T2 T3 T4

Limited patch/plaque (< 10% of skin surface) Generalized patch/plaque (> 10% of skin surface) Tumors Generalized erythroderma

NO N1 N2 N3

Lymph nodes clinically uninvolved Lymph nodes enlarged, histologically uninvolved Lymph nodes clinically uninvolved, histologically involved Lymph nodes enlarged and histologically involved

MO M1

No visceral disease Visceral disease present

BO B1

No circulating atypical cells (< 5% of lymphocytes) Circulating atypical cells (> 5% of lymphocytes)

patients with erythrodermic MF or SS managed at Stanford demonstrates that patient age, stage of disease and peripheral blood involvement are independent prognostic factors, and patient survival varies widely, from only 1.5 to more than 10 years, depending upon these variables.15

Staging The TNMB staging classification system for MF is summarized in Table 26.1.16 Approximately 20-25 per cent of patients will present with limited plaque (Tl), 35-40 per cent with generalized plaque (T2), 20-25 per cent with tumorous (T3) and 15-20 per cent with erythroderma (T4). The extent of skin involvement is a very important prognostic factor. Actuarial survivals for patients with MF, based on the extent of skin involvement, are shown in Fig. 26.1. The 10-year survivals are 87, 57, 25 and 29 per cent for patients with Tl, T2, T3 and T4 disease, respectively. The current status of patients is displayed in Table 26.2. • Stage groupings can be defined by the TNMB criteria (Table 26.3). Clinical groupings based on this staging system define patients with a good, intermediate or poor prognosis. Patients with limited or generalized plaque disease and no evidence of extracutaneous spread (Stage I-IIA) have a median survival of nearly 18 years; patients

Table 26.2 Current status of 555 patients with mycosis fungoides (MF) managed at Stanford University

Alive, NED Alive, with disease Dead, NED Dead from MF NED = no evidence of disease.

67 (55) 35 (29) 17(14) 2(2)

45(22) 58 (28) 67 (33) 35(17)

12(9) 19(15) 26 (20) 71 (55)

7(7) 9(9) 33 (33) 52 (51)

362 Cutaneous lymphomas Figure 26.1

Actuarial

survival of 556 patients treated at Stanford University categorized by the extent of skin involvement Patients with cutaneous tumors (T3) or erythroderma (T4) have a similar prognosis. 1 = T1(n = 122);

2 = T2(n = 205); 3 = T3(n = 128); 4 = T4(n = 101).

Table 26.3 Stage classification of mycosis fungoides

IA IB MA IIB MIA NIB IVA IVB

T1 T2 T1-2 T3 T4 T4 T1-4 T1-4

NO MO N1 N0-1 NO N1 N2-3 NO-3

MO MO MO MO MO MO MO M1

with cutaneous tumors or erythroderma (Stage IIB-III) have a median survival of about 3.5 years; and patients with extracutaneous disease (Stage IV) have a median survival of only 1.5 years. Figure 26.2 displays the survival of patients according to these stage groupings.

Routine staging studies include a careful examination of the skin (especially the scalp, palms, soles and perineum), a complete blood count, analysis of peripheral blood for Sezary cells, screening chemistries and chest Xray. Lymph node biopsies are obtained if lymphadenopathy is present. Patients with lymph node biopsies showing only reactive or dermatopathic changes with just a small number of atypical cells (LN1 or LN2) have a 5-year survival of 80 per cent, those with large clusters of paracortical atypical cells (LN3) have a 5-year survival of 30 per cent, and those with effaced nodes (LN4) have a 5-year survival of only 15 per cent.9 Biopsy documentation of suspected visceral disease is indicated since other disease processes may mimic the clinical appearance of ME Imaging studies such as computed tomography (CT) scans should only be completed

Figure 26.2

Actuarial

survival of 556 patients treated at Standford University categorized by overall clinical stage. 1 = Stage IA/IB/IIA

(n = 326);

2 = StagellB/lll(n = 175); 3 = Stage IV (n = 55).


if there is suspicion of extracutaneous disease. Routine imaging studies are otherwise unproductive.

Topical and regional therapy The successful management of MF requires effective skin treatment. Non-specific topical therapy, such as emollients, antipruritics, anti-inflammatories and hydrocortisone, may provide some relief of symptoms, especially in patients with minimal disease. Definitive management includes topical therapies, such as photochemotherapy, nitrogen mustard and irradiation. With these therapies, patients may experience an initial apparent exacerbation of disease, related to the inflammatory reaction that may develop in areas of minimal disease. With continuation of therapy, however, a response will become evident. Supportive treatments, such as emolliation, topical steroids and oral antipruritics, are often used in conjunction with definitive therapy. PHOTOTHERAPY

Phototherapy involves the use of ultraviolet (UV) radiation in the UVA or UVB wavelength region. Long-wave UVA has an advantage over UVB owing to the greater depth of penetration of its photons into the dermal infiltrates of MF. For limited disease, UVB alone or home UV phototherapy (UVA + UVB) may be an effective modality. More commonly, the UV is used with psoralen, a photosensitizing agent, as psoralen plus UVA (or PUVA). Topical photochemotherapy (PUVA) consists of oral 8-methoxypsoralen (0.4-0.6 mg/kg) followed 1.5-2 hours later by exposure to UVA light. The psoralen intercalates between pyrimidine base pairs within DNA and on exposure to ultraviolet light in the 360 nm range forms monofunctional and bifunctional adducts that inhibit DNA replication. The UVA penetrates the epidermis and upper dermis. Patients receive a timed exposure to UVA light in a phototherapy unit (PUVA box). The initial dose and dose increment is a function of skin type and type of skin involvement by MF. Patients with erythroderma tolerate only very low starting doses and dose increments. Only the eyes are shielded routinely. All other body surfaces may be treated; however, certain areas, such as the perineum, axillae and other skin fold areas, may not receive adequate exposure. In the initial clearing phase, patients are treated 2-3 times per week with at least 48 hours between treatments in order to monitor for delayed erythema. After skin clearance, a maintenance program with decreasing treatment frequency is initiated. The average time to clearance is 2-6 months and the likelihood of clearance is related to the extent of skin involvement. Patients with minimal patch disease achieve complete response rates as high as 90 per cent. For patients with more infiltrated plaques, the complete response rate is 60-80 per cent.17 If maintenance therapy is discontinued, the majority of patients

will relapse. However, another response may follow resumption of treatment. Acute complications of PUVA treatment include erythema, other phototoxic reactions, pruritus, skin dryness and nausea. Potential long-term complications include increased risk of cataracts (requiring the use of UVAopaque goggles during therapy). Photoprotection must be continued for 24 hours following psoralen ingestion. Some patients who undergo long-term continuous treatment with PUVA are at risk for developing secondary cutaneous squamoproliferative lesions, including basal cell and squamous carcinomas. Among patients treated for MF, this risk is greatest for patients who have undergone long-term treatment with multiple topical therapies.18 Indications for PUVA treatment include the primary therapy of patients with limited or generalized plaque phase of skin involvement or as a secondary therapy following the failure of other topical modalities. PUVA may also be effective in patients with erythroderma, provided that very low daily exposures are utilized to avoid phototoxicity reactions.19 In patients with the Sezary syndrome, PUVA may be supplemented by systemic therapies, such as interferon-a, or chlorambucil and prednisone. TOPICAL CHEMOTHERAPY

A common therapy for MF is topical nitrogen mustard (mustine; mechlorethamine; HN2). This maybe applied as an aqueous solution prepared by the patient or in an ointment base, such as aquaphor, prepared by the pharmacist. Its mechanism of action of is uncertain. It is not likely to act as a direct alkylating agent and it is more likely that one of the degradation products is the active agent. Nitrogen mustard is applied daily. For the aqueous preparation, it is applied to the skin with a cloth or brush at a concentration of 10-20 mg per 100 ml of water. Nitrogen mustard ointment is prepared at a concentration of 10-20 mg per 100 g of aquaphor. The skin may be treated in its entirety, although the face, scalp, intertriginous and genital areas are not usually included in the initial treatment unless there is evidence of active disease. The aqueous and aquaphor preparations appear to have similar clinical efficacy.20 The choice is often dependent on convenience or patient preference. For patients with disease limited to a single skin region, treatment may be restricted to that region. Complete response (CR) rates range from 30 to 70 per cent, with the likelihood of response dependent on initial extent of skin involvement: about 50 per cent for limited plaque and 25 per cent for generalized plaque disease.14'20'21 The median time to skin clearance is about 8 months. Maintenance treatment is generally continued for 1-2 years after skin clearance. When treatment is discontinued, more than half of patients will relapse, almost


always in the skin, but most will respond to a resumption of therapy. The proportion of patients treated with topical nitrogen mustard who have a durable complete response is about 20 per cent but it may be as high as 45 per cent in patients with limited plaque disease.14 The primary complication of topical nitrogen mustard therapy is an acute or delayed hypersensitivity reaction, which develops in about 30 per cent of people treated with the aqueous preparation and in less than 5 per cent of patients treated with the ointment preparation.20 Desensitization may be accomplished with a variety of topical or systemic desensitization programs. There is no systemic absorption of topically applied nitrogen mustard, thus systemic complications, such as hematologic depression or sterility, are not potential toxicities. Occasional patients treated with topical nitrogen mustard develop secondary squamoproliferative lesions of the skin.21 This has been a problem primarily for patients treated with multiple sequential topical therapies.18 Topical nitrogen mustard is indicated as initial primary therapy for patients with limited patch or plaque disease or those with less-infiltrated generalized plaque disease. Another chemotherapeutic agent that has been used topically is carmustine (BCNU).22 Carmustine powder is dissolved in water to achieve a concentration of 10-20 mg per cent. It is applied to individual lesions daily until a response is achieved. Maintenance therapy is not employed. The efficacy of carmustine is similar to topical nitrogen mustard; however, because of the systemic absorption of carmustine, the potential hematologic complications are greater and the maximum duration of treatment is limited. In addition, patients treated with carmustine tend to develop telangiectasias in areas where the drug is applied. However, the frequency of hypersensitivity reactions to carmustine is reportedly quite low. Topical phosphocholines have also been used in a small group of patients with MR Phosphocholines inhibit tumor cell growth directly by inhibition of protein kinase C and induction of cellular differentiation.23 They may also have immunoregulatory effects by stimulation of cytokines, activation of monocytes and enhancement of peptide binding to class II major histocompatibility complex (MHC). In a recent study of 12 patients with MF, topical application of hexadecylphosphocholine resulted in responses in 50 per cent of patients and a 17 per cent CR rate.23 RADIATION THERAPY

Mycosis fungoides is an extremely radiosensitive neoplasm and modest doses are capable of achieving longterm local control. Spot (local) treatment with orthovoltage X-rays (150-250 kV) or low-energy electrons (6-9 MeV) may be used in the management of individual plaques or tumors. Fractionated doses of

15-25 Gy generally suffice for local control. Spot therapy may be used in conjunction with PUVA or topical nitrogen mustard. For treating large surfaces of skin, techniques of total skin electron beam therapy (EBT) have been developed. Patients are treated in the standing position, 3-4 m distant from a linear accelerator. Treatment at this distance provides for an ability to treat large surfaces. A rotating platform or multiple patient positions during treatment allows treatment of the entire circumference.24 The 80 per cent depth dose with 6-9 MeV electrons is 3.7-7 mm, a depth ideally suited for treating MF, yet sparing deeper tissues. At Stanford, the weekly dose is 3-4 Gy in four fractions. Most patients will tolerate 4 Gy per week, but lower doses may be used for patients with erythroderma, atrophic skin or a previous history of EBT. The total dose is generally 36 Gy administered over a 10-week period, with a 1 week break after the first 18-20 Gy in order to provide for some relief from the generalized skin erythema that often accompanies EBT. In the standard course of treatment, only the eyes are shielded. Additional individualized shielding is utilized as clinical circumstances indicate. Certain portions of the body surface (top of the scalp, the perineum and the soles of the feet) are 'shadowed' and receive relatively lower electron doses. Supplemental treatment to these areas must be provided. The most common acute complication of total skin EBT is erythema and desquamation. This is generally only a minor problem if a 1-week split is incorporated midway through treatment. Intermediate-term complications include alopecia, which is incomplete and usually only temporary if the scalp dose can be limited to 24 Gy. Most patients experience temporary fingernail and toenail loss 2-4 months following completion of treatment. Most report an inability to sweat properly for the first 6-12 months following therapy and thereafter note chronically dry skin that requires regular emolliation. In long-term follow-up, occasional patients display scattered telangiectasias, rarely evident on casual examination. Long-term effects are very dependent on details of treatment technique. Although secondary malignancies, such as squamous cell and basal cell cancers of the skin, are probably increased after the use of total skin EBT, the patients in whom these have become problematic are those who have received repeated treatment with multiple therapies including irradiation, topical nitrogen mustard and PUVA.18 Radiation may also provide a very important palliative benefit for patients with localized extracutaneous disease. Megavoltage photons (4 MeV or greater) may be used to treat symptomatic adenopathy or visceral sites of disease, with techniques similar to those used for other lymphomas. The dose should be titrated to the response, but typically may be limited to 24-36 Gy. In large series, the complete response rates for patients


with patch or plaque disease average 80 per cent.6,25 The complete response rate for patients who present with tumorous involvement is 60-70 per cent. As many as 55 per cent of patients with limited plaque disease and 25 per cent of patients with generalized plaque disease who achieve a complete response will enjoy long-term freedom from relapse after the completion of therapy. When patients experience a relapse, it is generally in the skin. Total skin EBT is indicated as primary therapy for patients with generalized plaque (T2) or tumor-stage (T3) diseases. In tumorous disease, thicker lesions require supplemental small-field radiation therapy. Despite the high likelihood of relapse, a significant palliative benefit is achieved by the use of total skin EBT. Furthermore, relapse of disease after treatment is often limited in extent and may be managed readily by the use of small-field orthovoltage or electron irradiation, topical nitrogen mustard, etc. The risk of relapse may be reduced by the routine use of adjuvant therapies, such as topical nitrogen mustard or PUVA, but the utility of this approach has not been proved.26 Second complete courses of total skin treatment may be given to selected patients with the expectation of excellent palliative responses.27 Systemic treatment CHEMOTHERAPY

Systemic chemotherapy, so effective in the management of other lymphomas, has contributed little to the management of patients with MR6,28 The most commonly utilized single agents are methotrexate and chlorambucil. Most effective combinations include cyclophosphamide, vincristine and prednisone, with or without Adriamycin.2930 Complete response rates are about 25 per cent (range 11-57 per cent) with response durations of 3-20 months.6,28 Few patients achieve durable complete responses and cure of advanced disease is uncommon. Systemic management is often employed for patients with the Sezary syndrome.6,13,29 A common treatment combines chlorambucil and prednisone.31 The chlorambucil dose is initially 2 mg/day, titrated according to response and toxicity (leukopenia and thrombocytopenia). Prednisone is started at 20 mg/day, decreasing as palliation is achieved. If a systemic response is achieved but cutaneous symptoms present, topical therapy such as low-potency corticosteroids, low-dose PUVA or low concentration nitrogen mustard may be added.6 Some newer drugs show promise in early clinical trials. Fludarabine, a purine antimetabolite, has demonstrated clinical activity against MF (overall response rate 19 per cent, CR rate 3 per cent).32 Another drug that may be useful is 2'-deoxycoformycin (pentostatin), which inhibits adenosine deaminase, an enzyme with a high level of activity in T cells and required for DNA synthesis. This drug has demonstrated activity in MF and a variety of other non-Hodgkin's lymphomas. The

response rate in MF may be as high as 50 per cent.33 A small trial has reported a 33 per cent response rate to 2chlorodeoxyadenosine (2-CDA; cladribine).34 Because of the inefficacy of systemic chemotherapy and its significant potential complications, chemotherapy treatment generally is limited to patients with refractory, progressive disease and for palliative therapy of extracutaneous disease. It is often used in conjunction with other forms of topical therapy, such as palliative radiation therapy. BIOLOGICAL AGENTS

The interferons, which have antiproliferative, cytotoxic and immunoregulatory functions, have shown some utility in the management of MF. Interferon-a (IFN-a) is the interferon with the most profound antitumor activity.35,36 Response rates are reported to be about 50 per cent, with a duration of about 6 months. The likelihood of response correlates with stage of disease, intensity of prior therapy and dose of interferon. The greatest likelihood of response is in patients with limited disease, little prior therapy and interferon doses as high as 50 x 106 u/day for 5 days, every 3 weeks. Other schedules call for administration of the drug thrice weekly on alternate days at a dose of 3-5 million units with an escalating dose until response is achieved or toxicity intervenes. It is indicated primarily for palliative management of refractory or advanced disease, and is often used in combination with other topical or systemic therapies. Patients experience mild to moderate systemic reactions, including fatigue, anorexia, decreased performance status and leukopenia. Another biological therapy that has been utilized in MF is anti-T cell monoclonal antibodies. Trials have been reported with a pan-T cell murine monoclonal antibody (anti-Leu 1), an 131T-radiolabeled version (T101), and a pan-T cell anti-CD 5 antibody linked to ricin. Treatment is often limited by the development of human antimouse antibodies (HAMA). In order to avoid the development of HAMA, a chimeric (mouse-human) antihelper T cell (anti-CD 4) antibody has been used to provide a more specific treatment against the MF subset of T cells.37 The responses to antibody therapy are generally brief. However, given even minimal responses, this modality deserves further evaluation. Toxicities may include lowgrade fever, malaise, pruritus, urticaria and occasional dyspnea. Radiolabeled antibodies also may cause myelosuppression. Another approach in the treatment of MF is the use of recombinant fusion toxins - growth factor-cytotoxin fusion proteins designed specifically to kill defined cell populations. One example of this approach is the interleukin-2 (IL-2)-diphtheria toxin fusion protein. This fusion protein is cytotoxic only for cells expressing high-affinity IL-2 receptors. Once bound to such cells, the fusion protein is internalized by endocytosis, followed by


inhibition of protein synthesis and eventual cell death. A phase I clinical trial using the IL-2-diphtheria toxin fusion protein has demonstrated significant clinical response with minimal toxicity in a group of patients with refractory disease.38 The retinoids are natural or synthetic analogs of vitamin A, which promotes differentiation and inhibits proliferation of epithelial tissues. Treatment with retinoids, such as isotretinoin, achieves reported response rates of 45 per cent (20 per cent complete) in patients with MR39 Newer retinoids with potentially higher potency without increased toxicity are in clinical trials. Retinoids are indicated primarily for palliative therapy for refractory or advanced disease, usually as an adjuvant to other topical or systemic therapy. Potential toxicities include photosensitivity and dryness of the skin, and the mucous membranes, myalgias, arthralgias and fatigue. The teratogenic effects of retinoids must be considered in women of childbearing age. Because of their potential hepatotoxic and hyperlipidemic effects, liver function and lipid panel (triglycerides/cholesterol) must be monitored during treatment. PHOTOPHERESIS

Extracorporeal photopheresis (ECPP) is a form of extracorporeal PUVA.40 Psoralens are administered orally, followed by UV irradiation of the lymphocyte-enriched peripheral blood through an extracorporeal circuit. The blood is then reinfused into the patient. The treatment is administered on two consecutive days monthly, with the frequency titrated to response. Treatment may be tapered prior to discontinuation, but maintenance therapy is often required. In one report on this treatment, the majority of patients (73 per cent) responded to therapy.40 The likelihood of response was greatest among patients with erythroderma who had only a small number of Sezary cells, who had an overall response rate of 83 per cent.41 The mechanism of action of ECPP remains unclear. It is hypothesized that there may be a dual effect: a direct cytotoxic or antiproliferative effect on the neoplastic cells and an 'immune-enhancing' effect on the competent lymphocytes against the neoplastic cells. Compared with other systemic therapies, ECPP has minimal toxicity. Some patients may experience nausea, mostly due to the ingested psoralen, and some experience a transient low-grade fever or slight malaise after treatment. As with conventional PUVA, photoprotection must be employed for up to 24 hours after administration of psoralens.

Combined modality therapy Combined modality therapy includes combined topical therapies, and combined topical and systemic treatment. Because of the reliably high complete response rate to

total skin EBT and the high risk for relapse after completion of that treatment, topical adjuvant therapy is often utilized after completion of EBT. Adjuvant therapies have included topical nitrogen mustard and PUVA. Either of these adjuvants may prolong the duration of the disease-free interval but it is not clear that the longterm likelihood of relapse is altered.26 Topical and systemic therapies have also been combined. Anecdotal reports of successful treatment with combined EBT and systemic chemotherapy led to the initiation of a randomized trial at the National Cancer Institute.42 Patients with all stages of disease were randomized to conservative therapy (sequential treatment with topical nitrogen mustard PUVA, total skin EBT, oral methotrexate and systemic combination chemotherapy) or combined therapy (total skin EBT combined with cyclophosphamide, doxorubicin, etoposide and vincristine chemotherapy) at the outset. The overall response rate was significantly higher in the combined therapy group (90 vs 65 per cent; P = 0.003). However, actuarial disease-free and overall survival were similar for either management approach. The median survival after combined therapy was 91 months, compared to > 76 months (median not yet reached) after conservative therapy. Clearly, more effective systemic management programs are needed in order to improve the efficacy of combined modality therapy. Another innovative approach is the combination of PUVA with IFN-a.43 Reports indicate an overall response rate of nearly 90 per cent and a complete response rate greater than 60 per cent. Currently, a national trial is being designed to test the value of adjuvant interferon administered after successful topical therapy, nitrogen mustard (PUVA or EBT). IFN-oc has also been combined with etretinate, ECPP and pentostatin. These series are small, but in each there appears to be an enhanced efficacy with the addition of IFN-a.

Guidelines for treatment Patients with limited plaque disease (Tl) can be treated effectively with either topical nitrogen mustard or PUVA. When nitrogen mustard is employed, treatment is initiated to the entire skin, since other areas of disease activity may become evident secondary to the inflammatory reaction provoked by the nitrogen mustard. After a period of several weeks, treatment may then be limited to the affected region, if the initial disease was limited to one body region. Treatment is continued daily until complete skin clearance and for as long as a year thereafter. There is no evidence that more prolonged maintenance therapy is beneficial. If response is particularly slow, the concentration of the nitrogen mustard may be increased to 30-50 mg per cent, especially to small areas, or the frequency of application may be increased to twice a day.

Other cutaneous lymphomas 367

PUVA may also be employed for limited plaque disease. Treatment is initiated thrice weekly until skin clearance is achieved, after which the frequency of treatment is gradually decreased to as infrequently as once every 2 weeks. Maintenance therapy should be discontinued within 1 year in order to minimize the risks of cutaneous carcinogenesis. Our usual choice is to initiate treatment with topical nitrogen mustard, since it is easier for the patient, requires only occasional visits to the clinic for surveillance, results in excellent long-term outcome14 and it is less expensive than PUVA. Unilesional MF may be treated with local irradiation followed by observation. Patients with generalized plaque disease may be treated with either nitrogen mustard, PUVA or total skin EBT. Irradiation should be considered for patients with very thickened plaques, owing to the greater depth of penetration of EBT. It should also be considered for patients with a recent history of rapid progression of disease. Patients treated with either nitrogen mustard or PUVA should be followed closely, with EBT initiated if there is disease progression. Generally, following completion of EBT, adjuvant treatment with topical nitrogen mustard is appropriate and may be continued for a year or longer. Patients with limited or generalized plaque disease who fail to respond to one therapy, or who begin to progress after an initial response, may be treated with an alternative topical therapy. There is no evidence that the development of resistance to one modality affects subsequent response to an alternative modality.14 The majority of patients with tumorous involvement have generalized disease and the greatest likelihood of a response is with EBT. Individual tumor lesions may be given boost doses of radiation. In view of the high risk for relapse after irradiation, even among those patients who achieve a complete response, adjuvant therapy (e.g. nitrogen mustard) should be used. Adjuvant topical nitrogen mustard (in an aquaphor base) provides the dual role of treatment for residual disease and emolliation of the skin, often chronically dry after completion of EBT. Patients with a discrete number of tumors sometimes may be treated with localized irradiation to individual tumors combined with topical nitrogen mustard or PUVA. Rare patients may present with isolated tumors, e.g. pagetoid reticulosis or WoringerKolopp disease, a hyperkeratotic, verrucous form of MF that presents with limited involvement of a single site, often an extremity. These patients are candidates for treatment with localized irradiation alone. Patients with erythroderma are the most challenging to manage. They usually have very atrophic skin and are exquisitely sensitive to cutaneous therapies. If there is no peripheral blood involvement, treatment may be initiated with photopheresis. Low-dose PUVA (care must be taken to avoid phototoxic reactions) also may be effective treatment for this stage of disease. In the presence of

peripheral blood involvement (Sezary syndrome), systemic management with chlorambucil and prednisone or photopheresis may be beneficial. If a systemic response is achieved but cutaneous symptoms persist, topical therapy, such as low-potency corticosteroids, low-dose PUVA or low concentrations of nitrogen mustard, may be added. Combined modality programs employing IFN-oc are also often useful in these patients. Patients with extracutaneous disease, especially that involving lymph nodes, may be treated with megavoltage photon irradiation to local symptomatic sites for palliation. Systemic chemotherapy or biological therapies are appropriate to consider in these patients, as well. Owing to the inadequacy of standard therapy, all patients with extracutaneous disease or the Sezary syndrome should be considered candidates for investigational therapies. It may, for example, be possible to select out patients with Sezary syndrome on the basis of a prognostic risk index;44 in this prospective study of 62 patients, survival in the low-risk group was 58 per cent at 5 years compared with 5 per cent in the high-risk group.

OTHER CUTANEOUS LYMPHOMAS Other cutaneous lymphomas have a male preponderance and the median age of onset is about 60 years. Microscopically, the infiltrate in the non-MF cutaneous lymphomas is usually limited to the dermis, sparing the epidermis and dermal-epidermal junction (Grenz zone) until rather late in the course of disease, when secondary ulceration may occur. Immunoperoxidase studies indicate that 50-75 per cent are of B cell origin. Prognosis is related to age, histology and stage.45,46 The most common histologic subtypes of B cell lymphoma are diffuse large cell and immunoblastic, which account for one-half to two-thirds of cases.47 The lowgrade cutaneous lymphomas, such as small lymphocytic, must be distinguished from benign lymphocytic infiltrates, such as lymphocytoma cutis. This is best done by genotyping (gene rearrangement studies), which reveals a polyclonal nature of lymphocytoma cutis, in contrast to the monoclonality of the cutaneous lymphomas. Primary cutaneous B cell lymphomas Cutaneous B cell lymphomas often present as nodules. The predominant site is the head and neck area. Regional lymph nodes are uncommonly affected. The staging evaluation should include studies generally employed for other patients with non-Hodgkin's lymphoma, including physical examination, complete blood counts, screening chemistries, a chest X-ray, CT scan of the chest, abdomen and pelvis, and a bone marrow biopsy. Following an incisional biopsy, patients with localized involvement of the skin (Stage IE), may be treated with


local irradiation. The primary lesion with 1-2 cm margins is included in the field. A dose of 36-40 Gy for low-grade and 40-44 Gy for intermediate- or highgrade lymphomas will generally suffice. Depending on the depth of the lesion, 6-12 MeV electrons may be required. If an excisional biopsy was performed, the role for local irradiation is not as well established, but quite often used. At least half of these patients will be cured.45,47 Systemic treatment may be reserved for those patients who have a relapse of disease after localized radiation treatment. The most common site of failure is in distant skin sites. The 10-year survival of patients who present with Stage IE disease is 60-70 per cent.45,47,48 Patients with Stage HE disease (regional lymph nodes involved) are best treated with combined modality therapy, including a primary doxorubicin-containing chemotherapy and involved field irradiation. For patients with Stage III or IV disease, the cutaneous involvement is considered incidental unless it is particularly bulky and poses a problem for local control with chemotherapy, in which case adjuvant irradiation may be added.

extracutaneous sites (either concurrently or subsequently) is the most important prognostic factor for these patients.49 Patients with extracutaneous disease should be treated systemically. For patients with disease limited to the skin, the prognosis may vary somewhat if the disease is primary or secondary (prior T cell lymphoproliferative disease, such as MF or lymphomatoid papulosis), but this issue has not been clearly resolved.54'55 If localized, the primary lesion(s) of CD 30-positive lymphoma may be treated either by excision, with or without postexcision radiation, or primary radiation therapy. There is no evidence that systemic management is indicated for patients with a localized disease process. Even where there are multiple skin lesions, an expectant policy may be warranted before initiating any chemotherapy, since the skin nodules may show spontaneous regression.

REFERENCES 1. Harris NL, Jaffe ES, Stein H, et a I. A revised European-American classification of lymphoid

CD BO/Ki-1-positive cutaneous lymphoproliferative diseases A group of cutaneous lymphoproliferative diseases expresses the CD 30 (Ki-1 or BerH-2) antigen. This includes frank lymphomas and borderline lesions, such as lymphomatoid papulosis. The CD 30 antigen is expressed by highly activated B and T cells, and is characteristic of Reed-Sternberg cells in Hodgkin's disease. CD 30-positive lymphomas include anaplastic largecell and non-anaplastic non-Hodgkin's lymphomas.49 Nearly all (80 per cent) of the anaplastic large-cell lymphomas are of the T cell type. The non-anaplastic variety may be of the T or B cell type, and often are classified as diffuse large cell in the Working Formulation. Lymphomatoid papulosis is a disease marked by waxing and waning nodular skin lesions. Treatment is generally symptomatic, since the lesions regress spontaneously. Studies of TCR gene rearrangements indicate that it is a monoclonal T cell proliferation.50 Lymphomatoid papulosis may arise independently, or it may precede or follow a diagnosis of mycosis fungoides or Hodgkin's disease. The relationship between these diseases is not clearly understood.51 However, the REAL classification acknowledges that primary cutaneous anaplastic largecell lymphoma appears to represent a histologic and clinical continuum with lymphamatoid papulosis.52 CD 30-positive anaplastic large-cell lymphoma of the skin is not associated with the same poor prognosis as systemic anaplastic large-cell lymphoma.53 Patients who present with this lymphoma should undergo staging similar to that of other patients with newly diagnosed non-Hodgkin's lymphoma. The. discovery of disease in

neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92. 2. Kerl H, Cerroni L Primary B-cell lymphomas of the skin. Ann Oncol 1997; 8(suppl 2): S29-S32. 3. Weinstock MA, Norm JW. Mycosis fungoides in the United States. Increasing incidence and descriptive epidemiology. JAMA 1988; 260: 42-6. 4. Whittemore AS, Holly EA, Lee IM, et al. Mycosis fungoides in relation to environmental exposures and immune response: a case-control study. J Invest Dermatol 1989; 93: 626-9. 5. Lutzner M, Edelson R, Schein P, et al. Cutaneous T-cell lymphomas: the Sezary syndrome, mycosis fungoides, and related disorders. Ann Intern Med 1975; 83: 534-52. 6. Hoppe RT, Wood GS, Abel EA. Mycosis fungoides and the Sezary syndrome: pathology, staging, and treatment. Curr Problems Cancer 1990; 14: 295-361. 7. Wood GS, Weiss LM, Warnke RA, et al. The immunopathology of cutaneous lymphomas: immunophenotypic and immunogenotypic characteristics. Semin Dermatol 1986; 5: 334. 8. Weinberg J, Rook A, Lessin S. Molecular diagnosis of lymphocytic infiltrates of the skin. Arch Dermatol 1993; 129: 1490-500. 9. Sausville EA, EddyJL, Makuch RW, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the Sezary syndrome: definition of three distinctive prognostic groups. Ann Intern Med 1988; 109: 372-82. 10. Lynch J, Linoilla I, Sausville E, et al. Prognostic implications of evaluation for lymph node involvement by T-cell antigen receptor gene rearrangement in mycosis fungoides. Blood 1992; 79: 3293-9.

References 369 11. Hoppe R, Fuks Z, Bagshaw M. Radiation therapy in the management of cutaneous T-cell lymphomas. Cancer Treatment Rep 1979; 63: 625. 12. Bakels V, Van Oostveen J, Gordijn R, Walboomers J, Meijer C, Willemze R. Diagnostic value of T-cell receptor beta gene rearrangement analysis on peripheral blood lymphocytes of patients with erythroderma.y Invest Dermatol 1991; 97: 782-6. 13. Wieselthier JS, Koh HK. Sezary syndrome: diagnosis, prognosis, and critical review of treatment options. J Am Acad Dermatol 1990; 22: 381. 14. 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: 1309-13. 15. Kim YH, Bishop K, Varghese A, Hoppe RT. Prognostic factors in erythrodermic mycosis fungoides and Sezary syndrome. Arch Dermatol 1995; 131:1003-8. 16. Bunn PA, Lamberg SI. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treatment Rep 1979; 63: 725. 17. Rosenbaum MM, Roenigk HJ, Caro WA, et al. Photochemotherapy in cutaneous T cell lymphoma and parapsoriasis en plaques. Long-term follow-up in fortythree patients. J Am Acad Dermatol 1985; 13: 604-12. 18. Abel EA, Sendagorta E, Hoppe RT. Cutaneous malignancies and metastaticsquamouscell carcinoma following topical therapies for mycosis fungoides. JAm Acad Dermatol 1986; 14:1029-38. 19. Abel E, Sendagrta E, Hoppe R, Hu C-H. PUVA treatment of erythrodermic and plaque-type mycosis fungoides: ten-year follow-up study. Arch Dermatol 1987; 123: 897. 20. Hoppe RT, Abel EA, Deneau DG, et al. Mycosis fungoides: management with topical nitrogen mustard, J din Oncol 1987; 5:1796-803. 21. Vonderheid EC, Tan ET, Kantor AF, et al. Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. J Am Acad Dermatol 1989; 20: 416. 22. Zackheim HS, Epstein EH, Crain WR. Topical carmustine (BCNU) for cutaneous T cell lymphoma: a 15-year experience in 143 patients. J Am Acad Dermatol 1990; 22: 802. 23. Dummer R, Krasovec M, Roger J, Snidermann H, Burg G. Topical administration of hexadecylphosphocholine in patients with cutaneous lymphomas: results of a phase I/I I study. JAm Acad Dermatol mi; 29: 963-70. 24. Hoppe RT, Cox RS, Fuks Z, et al. Electron-beam therapy for mycosis fungoides: the Stanford University experience. Cancer Treatment Rep 1979; 63: 691-700. 25. Jones GW, Tadros A, Hodson Dl, et al. Prognosis with newly diagnosed mycosis fungoides after total skin electron radiation of 30 or 35 GY. Int J Radial Oncol Biol Phys 1994; 28: 839-45. 26. Price NM, Hoppe RT, Constantine VS, et al. The treatment of mycosis fungoides: adjuvant topical mechlorethamine after electron beam therapy. Cancer 1977; 40: 2851-3.

27. Becker M, Hoppe RT, Knox Sj. Multiple courses of highdose total skin electron beam therapy in the management of mycosis fungoides. Int J Radial Oncol Biol Phys 1995; 32:1445-9. 28. Broder S, Bunn PA. Cutaneous T-cell lymphomas. Semin Onco/1980;7:310. 29. Molin L, Thomsen K, Volden G, et al. Combination chemotherapy in the tumour stage of mycosis fungoides with cyclophosphamide, vincristine, VP-16, adriamycin and prednisolone (COP, CHOP, CAVOP): a report from the Scandinavian Mycosis Fungoides Study Group. Ada Derm Venereol (Slockholm) 1980; 60: 542. 30. Tirelli U, Carbone A, Veronesi A, et al. Combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) in TNM-dassified stage IV mycosis fungoides. Cancer Treatment Rep 1982; 66:167. 31. Winkelmann RK, Diaz-Perez JL, BuechnerSA. The treatment of Sezary syndrome. JAm Acad Dermatol 1984; 10:1000. 32. Von Hoff DD, Dahlberg S, Hartstock RJ, et al. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group study. Postgrad MedJ 1990; 66: 773-5. 33. Mercieca J, Matutes E, Dearden C, et al. The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype. 7 C/m Oncol 1994; 12: 2588-93. 34. Kuzel T, Samuelson E, Roenick H, et al. Phase II trial of 2chlorodeoxyadenosine (2-CDA) for the treatment of mycosis fungoides or the Sezary syndrome. ProcAm Soc Cl'in Oncol 1992; 11:1089. 35. Kohn EC, Steis RG, Sausville EA, et al. Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sezary syndrome. Dermatol Clin 1990; 8:169-71. 36. Olsen EA, Rosen ST, Vollmer RT, et al. Interferon alfa-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol 1989; 20: 395. 37. Knox SJ, Levy R, Hodgkinson S, et al. Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides. J Am Acad Dermatol 1991; 216-20. 38. Hesketh P, Caguioa P, Koh H, et al. Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous Tcell lymphoma. J Clin Oncol 1993; 11:1682-90. 39. Molin L, Thomsen K, Volden G, et al. Oral retinoids in mycosis fungoides and Sezary syndrome: a comparison of isotretinoin and etretinate. A study from the Scandinavian Mycosis Fungoides Group. Ada Derm Venereol (Stockh) 1987; 67:179-82. 40. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N EnglJ Med 1987; 316: 297. 41. Heald P, Rook A, Perez M, et al. Treatment of erythodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol 1992; 27: 427-33.

370 Cutaneous lymphomas 42. Kaye FJ, Bunn PA, Steinberg SM, et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N EnglJ Med 1989; 321: 1784. 43. Kuzel T, Gilyon K, Springer E, et al. Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma../ Natl Cancer I nst 1990; 82: 203-7. 44. Bernengo MG, Quaglino P, Novell! M, et al. Prognostic factors in Sezary syndrome: a multivariate analysis of clinical, haematological and immunological features. Ann Oncol 1998; 9: 857-63. 45. Burke JS, Hoppe RT, Cibull ML, et al. Cutaneous malignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Canter 1981; 47: 300-10. 46. Webb A, McCarthy K, Cunningham D, et al. Multicentre retrospective review of primary cutaneous lymphoma excluding mycosis fungoides. Ann Oncol 1996; 7(suppl 3): 131. 47. Esche BA, Fitzpatrick PJ. Cutaneous malignant lymphoma. IntJ Radiation Oncol Biol 1986; 12: 2111-5. 48. Joly P, Charlotte F, Leibowitch M, et al. Cutaneous lymphomas other than mycosis fungoides: follow-up study of 52 patients. J Clin Oncol 1991; 9:1994-2001. 49. Paulli M, Berti E, Rosso R, et al. CD30/KM-positive lymphoproliferative disorders of the skin dinicopathologic correlation and statistical analysis of 86

50.

51.

52.

53.

54.

55.

cases: a multicentric study from the European Organization for Research and Treatment of Cutaneous Lymphoma Project Group. 7 Clin Oncol 1995; 13: 1343-54. Weiss LM, Wood GS, Trela M. Clonal T-cell populations in lymphomatoid papulosis: evidence for a lymphoproliferative etiology in a clinically benign disease. N Engl J Med 1986; 315: 475-9. DavisTH, Morton CC, Miller CR, et al. Hodgkin's disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone. N EnglJ Med 1992; 326:1115-22. Jaffe ES, Krenacs L, Raffeld M. Classification of T-cell and NK-cell neoplasms based on the REAL classification. Ann Oncol 1997; 8(suppl 2): S17-S24. DeBruin PC, Beljaards RC, VanHeerde P, et al. Differences in clinical behaviors and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 1993; 23:127-35. Kaudewitz P, Stein H, Dallenbach F. Primary and secondary cutaneous Ki-1+(CD30+) anaplastic large cell lymphomas. Am J Pathol 1989; 135: 359-67. Beljaards R, Kaukdewitz P, Berti E, et al. Primary cutaneous large cell lymphomas: definition of a new type of cutaneous lymphoma with a favorable prognosis: a European multicenter study on 47 patients. Cancer 1993; 71: 2097-104.

27 Pediatric lymphomas JS MALPAS''

Introduction

371

Hodgkin's disease

376

Epidemiology

Long-term effects of therapy Future developments

379

Biology

371 372

Non-Hodgkin's lymphoma

372

References

381

INTRODUCTION Lymphomas account for 11.5 per cent of cancers in children aged 0-14 years.1 The incidence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) is approximately equal. There has been an increase in some childhood cancer recorded by the surveillance, epidemiology, end results (SEER) programme, but this has been slight in the lymphomas1 and the effect on mortality is countered by a dramatic recent improvement in survival, particularly in the case of childhood NHL.2 The frequency with which lymphomas occur, and their curability, merit special consideration, but other features of special interest in children are the almost universal occurrence of high-grade lymphomas, the high frequency of extranodal presentation of NHL, and the importance of considering the effects of treatment on all aspects of development and organ function. The occurrence of long-term toxicity in children and adolescents is of the greatest importance and is now influencing new treatment programs.

EPIDEMIOLOGY The incidence of lymphoma varies with geographical site. In NHL, Burkitt's lymphoma, for example, is very common in the sub-Saharal region of Africa, while the sporadic version is relatively rare in Western countries.

* With a contribution from Professor C.R. Pinkerton, Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.

380

In HD, the highest rates for children are seen in Costa Rica and among Hispanics in Los Angeles, and the lowest in Japan.3 The incidence of NHL rises in children with the greatest frequency in the 9-11 year age group. HD is rare in children under the age of 5, but increases steadily, falling again in early adulthood to give a bimodal peak. In NHL and HD the incidence in boys is two to three times that in girls. As adolescence approaches this ratio becomes less so that incidence is approximately equal by the time adulthood is reached. The incidence of the various subtypes of HD is variable, with nodular sclerosing histology most frequent in the USA, UK and Australia, while mixed cellularity is more common in Turkey, the Middle East and other areas of poor socioeconomic conditions. Middle Eastern countries also show the highest incidence of lymphocytedepleted pathology.4 It has recently been suggested that HD is a heterogenous entity, composed of two different diseases - nodular sclerosing disease and mixed cellularity disease. The former is dramatically increased in adolescence5 and is commoner in more affluent societies.6 The definitive cause of lymphoma is at present unknown. A number of factors which predispose to NHL or HD have been identified.7

Non-Hodgkin's lymphoma Human T cell lymphoma virus type 1 (HTLV-1) causes adult T cell lymphoma/leukemia but is not associated with childhood disease. Infection, particularly with the acquired immunodeficiency syndrome (AIDS) viruses, is now giving rise to an increased incidence of NHL, presumably as a result of the acquired immunodeficiency

372 Pediatric lymphomas

state. This is unlikely to account for the occurrence of NHL in children and, indeed, for the long-term steady increase seen in its occurrence in adults. The Epstein-Barr virus (EBV) is thought to be a necessary cause of Burkitt's lymphoma in Africa and many lymphomas that are due to immunodeficiency. However, EBV is not associated with other forms of childhood NHL as far as can be determined. Rare genetic syndromes associated with immunodeficiency, such as Wiskott-Aldrich syndrome, ataxia telangectasia and the X-linked lymphoproliferative syndrome are most frequently complicated by NHL.

c-myc from chromosome 8 to the immunoglobulin (Ig) heavy-chain region on chromosome 141(8;14), bringing the c-myc gene into apposition with the Ig heavy-chain gene promoter.11 In T cell malignancies, rearrangements of the T cell receptor genes are seen but these are variable. Features of the cytogenetics of childhood lymphoma are given in more detail when the individual entities are considered later. There are no constant changes in HD, although a number of chromosomes, including 1, 2, 7, 11, 14, 15 and 21, have shown changes which may be non-random.

Hodgkin's disease NON-HODGKIN'S LYMPHOMA The early peak of HD incidence and the clustering of HD cases both suggest a virus of low infectivity.7 EBV remains a prime candidate and studies of HD material from children support this.8,9 It is now thought that about three-quarters of childhood HD, and a relatively higher proportion of the mixed cellularity subtype may be a rare response to EBV infection, together with an as yet unidentified cofactor related to affluence.6

BIOLOGY Immunophenotyping The realization that all lymphomas were related to lymphoid cells of the T and B lineage has been of great importance in the understanding of the biology of these neoplasms, and has helped with their classification. Identification of the lymphoid cell surface antibodies, and their grouping into 'cluster of differentiation' (CD) types, have helped to divide lymphomas into B cell and T cell proliferations, and the very immature pre-B cell lineage. These groups have their counterpart in the lymphoblastic leukemias. There is correlation with the clinical presentation and the natural history, and in consequence the phenotype is of great importance to the clinician. A more detailed presentation of the patterns seen in childhood NHL is given later. In HD, CD determinants have not been of clinical relevance, although at this stage it has been shown that Reed-Sternberg cells consistently express high levels of CD 3010 and this has enabled study of their origin.

Classification A daunting feature of NHL is the number of classifications of histology that have been produced, and this also applies to the childhood disease. Recently the Kiel system was largely used in Europe and the Working Formulation (WF) in the USA. In an attempt to facilitate international studies of lymphoma, the revised European-American (REAL) classification has been devised.12 (see also Chapter 1.) Virtually all childhood NHL is in the category known as 'aggressive'. It is probably most helpful to summarize the histology, immunophenotype and cytogenetic features of the lymphoid malignancies seen in children. B CELL NEOPLASMS

Precursor B lymphoblastic lymphoma This entity has previously been described as lymphoblastic (under the Rappaport classification), lymphoblastic B cell type (Kiel classification), lymphoblastic (WF classification) and is called 'precursor B lymphoblastic lymphoma' in the REAL classification. The morphology of the cells is that of lymphoblasts, which are larger than the small lymphocytes and have frequent mitoses. Immunophenotypically they show terminal deoxynucleotidyl transferase (tdt), CD 19, CD 79a and CD 10 (the latter occurring in over 50 per cent of cases). Genetic features are Ig heavy-chain gene rearrangements. The majority of precursor B lymphoblastic disease presents as leukemia but about 20 per cent will be lymphomatous in children.

Cytogenetics

Diffuse large B cell lymphoma

Non-random cytogenetic abnormalities have been described in childhood NHL but not, so far, in HD. The outstanding cytogenetic abnormality is that seen in Burkitt's lymphoma, where an 8; 14 translocation is a common feature. Most cases show a translocation of

This has been known under the Rappaport classification as diffuse histiocytic lymphoma, under Kiel as centroblastic or B immunoblastic, and as diffuse large B cell (REAL). The cells are large with nuclei at least twice the size of a small lymphocyte. Some cells are large and cleaved, and

Non-Hodgkin's lymphoma 373

may be multilobulated. Rarely, they show appearances identical with those of anaplastic large-cell lymphoma. The immunophenotype shows positive surface immunoglobulin in more than 50 per cent of cases, CD 19, CD 20, CD 22 and CD 79a are positive, bcl-2 gene rearrangements occur in about a third. Burkitt's lymphoma

In the Rappaport classification this was known as undifferentiated lymphoma (Burkitt type); Kiel classified it as Burkitt's lymphoma; WF defined it as 'small non-cleaved cell Burkitt type'; it is also known as high-grade B cell lymphoma (Burkitt type) or Burkitt's lymphoma (REAL). The morphology is highly characteristic, with large monomorphic cells with cytoplasmic lipid vacuoles. The immunophenotype is characteristic, with immunoglobulin on the surface (SIg M), CD 19, CD 20, CD 22, CD 79a and CD 10 being positive, and CD 5 negative. Genetic changes of a non-random type are translocations t(8;14), or t(2;8) or t(8;22). T CELL NEOPLASMS Precursor T lymphoblastic lymphoma

In the Rappaport classification, this was known as 'poorly differentiated lymphocytic diffuse', Kiel classified it as'T lymphoblastic', and WF as 'lymphoblastic convoluted or non-convoluted'. It is known as 'precursor T-lymphoblastic in the REAL classification. Its morphology is identical to that of the precursor B lymphoblastic cells described above. The immunophenotype of the majority is CD 7+ or CD 3+. About 50 per cent of tumors are tdt+, CD la+. B cell-associated antigens are all negative. The cells can express gd, y8 or no T cell receptor molecules. Among the genetic features, rearrangements of T cell receptor gene and IgH gene have been noted, but are variable. About 40 per cent of childhood lymphomas belong in this category. Anaplastic large-cell (CD 30) lymphoma

This was known as 'diffuse histiocytic' under Rappaport classification, as 'large cell anaplastic' under Kiel, and was not listed under WF. Various other names have been applied, including 'malignant histiocytosis' and 'histiocytic medullary reticulosis'. The tumor has recently been recognized in children by the use of the Ki-1 (CD 30) antibody. The morphology is of large blastic cells with pleomorphic horseshoe-shaped or multiple nuclei, mimicking the Reed-Sternberg cell, and has been defined as anaplastic large-cell lymphoma (ALCL). The immunophenotype shows CD 30, CD 45 and CD 25 positivity in about 50 per cent of cases, and epithelial membrane antigen (EMA) positivity in about 50 per cent of systemic tumors. The majority show a translocation t(2;5) or the ALK-NPM transcript.13 This tumor is being increasingly frequently recog-

nized in children. A number were previously misdiagnosed as HD and the incidence is now thought to be possibly as high as 15 per cent. Clinical features of NHL in children Extranodal presentation is a feature of childhood NHL.14 There is a high frequency of abdominal presentation, with just under half (45 per cent) of children presenting in this way, while mediastinal presentations (30 per cent) are the next most common. Head and neck presentations (Fig. 27.1) comprise the remaining 25 per cent, together with a variety of relatively uncommon primary presentations, such as bone, kidney and skin. In a review of the use of radiology in childhood NHL, the radiological features of a series of 80 children15 confirmed the abdomen as the most frequent primary site, and computed tomography (CT) scanning showed the highest frequency of involvement in the gastrointestinal tract and mesenteric retroperitoneal lymph nodes. Renal, liver and splenic involvement also occurred (Table 27.1). Presentation is usually with a rapidly increasing abdominal mass. Occasionally pain may mimic various abdominal conditions, including acute appendicitis, or there may be features of acute intestinal obstruction. A laparotomy may be undertaken but, if a tumor is disclosed, minimal surgical intervention with a biopsy should be encouraged, and on no account should major resection be undertaken. With the increasing availability of CT or ultrasound-guided needle biopsy, the use of laparotomy is declining. In the mediastinum, the tumors are also rapidly growing, and may present with superior mediastinal obstruction, giving rise to marked respiratory distress or dysphagia. These tumors may be complicated by pleural or pericardial effusions. They present a diagnostic dilemma, because the children may be so ill that an anesthetic for a biopsy cannot be given. Pleural fluid aspiration or a fine-needle biopsy under local anesthetic are probably safest. Patients with this form of the disease usually have involvement of the bone marrow, testis and (very rarely) the central nervous system at presentation, so that examination of these areas is mandatory. In the head and neck, the region of Waldeyer's ring and the superficial lymph nodes in the neck are the third most common site (Fig. 27.1). Features of nasal obstruction, such as snoring or a persistent nasal discharge, or difficulty in breathing or swallowing, are often seen at presentation. Other rare sites of presentation are the orbit, the thyroid gland, kidney, bones, epidural spaces and skin. Diagnosis and staging The diagnosis must always be made on histological or cytological examination of tissue, of either nodes,

374 Pediatric lymphomas Table 27.1 Distribution of disease by primary site in 80 children presenting with non-Hodgkin's lymphoma (after reference 15)

Abdomen Gastrointestinal Mesenteric retroperitoneal lymph nodes Renal Liver and spleen

21 (26) 15 3 2 1

Extranodal head and neck Tonsil Nasopharynx Mandible Maxilla Palate Parotid Orbit

18(23) 7 5 2 1 1 1 1

Mediastinum

16(20)

Peripheral lymph nodes Cervical Axillary Pelvic Submandibular Cervical, axillary and inguinal

15(19) 9 2 2 1 1

Other Testes Penis Ovary Skin Bone

10(13) 2 1 1 4 2

Total

80 (100)

effusions or bone marrow smears, and all should be subject to histology, immunochemistry, phenotyping and cytogenetic assessment, which underlines the necessity for early referral to a center specializing in pediatric oncology. Diagnosis and staging must be expedited - a prolonged staging procedure is not acceptable. A suggested list of practical investigations is given in Table 27.2. Since treatment will depend on the stage of the disease, it is important to use these investigations to determine the anatomical spread of the disease as soon as possible. It is generally accepted that the Ann Arbor staging scheme is not appropriate for childhood nonHodgkin's lymphoma. A number of other schemes have been advanced, but the classification introduced by Murphy16 at St Jude's Children's Research Hospital has been widely adopted. This staging system is shown in Table 27.3. In addition to staging and assessment, the child's general condition must be assessed, with particular reference to dehydration, infection, poor nutrition, anemia and thrombocytopenia. The correction of dehydration and the reduction of uric acid level with allopurinol or uric oxidase are of particular importance, as a preliminary to the introduction of chemotherapy. Cytotoxics may induce a tumor lysis syndrome, causing a major metabolic disturbance with, amongst other features, 'phosphate shower', uric acid nephropathy and cardiac dysfunction. Many protocols now use a relatively low dose of antitumor agents at the beginning of induction which may reduce tumor lysis, but more importantly, avoids the additional early complications of myelosuppression and mucosilis in the event of severe lysis syndrome.

Figure 27.1 This shows the almost complete occlusion of the airway of a boy with non-Hodgkin's lymphoma, with massive infiltration of Waldeyer's ring.

Non-Hodgkin's lymphoma 375 Table 27.2 Non-Hodgkin's lymphoma diagnostic and staging procedures 1. Surgical biopsy with review by lymphoma pathologist 2. Cytology of pleural, pericardia! or cerebrospinal fluids 3. History detailing sweating, fever, weight loss 4. Physical examination of all lymph node sites, Waldeyer's ring, liver, spleen and testes 5. Full blood count, bone marrow examination, cerebrospinal fluid examination if not done already 6. Evaluation of liver function, kidney function, estimation of serum uric acid, serum electrolytes and lactic dehydrogenase 7. Computed tomography scanning or ultrasound of abdomen; chest X-ray; postnasal films if indicated

Treatment The dramatic improvement seen in the outlook for childhood NHL over the past two decades has been the result of a succession of steps in improving management. The first was the realization that NHL was a disseminated disease at presentation and that local measures, such as surgery or radiotherapy, had only a very limited role to play. Recognition of the value of combinations of active drugs given in a manner similar to that used in acute leukemia was the next major step, and results were very much improved by closer attention to supportive care and by the proper management of infections, Table 27.3 Stjude staging for childhood non-Hodgkin's lymphoma Stage I A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum or abdomen. Stage II A single tumor (extranodal) with regional node involvement. Two or more nodal areas on the same side of the diaphragm. Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm. A primary gastrointestinal tract tumor usually in the ileocecal area with or without involvement of associated mesenteric nodes only. Stage III Two single tumors (extranodal) on opposite sites of the diaphragm. Two or more nodal areas above and below the diaphragm. All the primary intrathoracic tumors (mediastinal, pelvic, thymic). All extensive primary intra-abdominal disease. Stage IV Any of the above with initial central nervous system and/or bone marrow involvement.

biochemical and hematological problems, and appreciation of the tumor lysis syndrome. It was recognized that all children had high-grade lymphomas, but that some were of the lymphoblastic type, mostly T cell, requiring not only intensive initial therapy, but long-term continuation or maintenance therapy. They could thus be distinguished from other high-grade B cell lymphomas, where short intensive courses were more appropriate and highly successful. The development of protocols has produced a greater than 80 per cent cure rate in children treated in a number of countries.13,17,18 The question of how much treatment is necessary to ensure a cure but nevertheless avoid serious long-term toxicity is now of prime importance. Where possible, the total dose of chemotherapy is being reduced and, in particular, the quantity of alkylating agents and anthracyclines. In this way, second malignancy may be avoided and fertility may be preserved. The avoidance of anthracyclines, which produce cardiac dysfunction, is also being explored. The necessity for including children with NHL in national protocols to enable these questions to be addressed cannot be overemphasized. SURGERY

The role of surgery is limited and extensive resection of lymphoma, particularly in the abdomen, is to be deprecated. There is no good evidence that in high-grade lymphoma 'debulking' improves prognosis and, indeed, by delaying the start of chemotherapy, it may increase initial mortality. When surgery is unavoidable, such as with intussusception, obstruction or perforation, supportive care with blood products, antibiotics and careful fluid replacement is essential. RADIOTHERAPY

Lymphoma is very sensitive to radiotherapy but its indication in childhood NHL is increasingly limited. Even in localized disease it has no place and a number of randomised studies have confirmed this.19 Where there is overt lymphomatous involvement of the central nervous system, craniospinal irradiation together with chemotherapy is the treatment of choice. Otherwise it should not be used in disseminated NHL but it can occasionally be helpful in the relief of symptoms, such as localized bone pain or the rapid onset of spinal cord compression. CHEMOTHERAPY

Cure rates have improved dramatically to around 80 per cent and chemotherapy has become the mainstay of treatment, adapted to the different subtypes of NHL, particularly Burkitt's and the lymphoblastic lymphomas.20 Since all tumors are high grade, therapy is indicated as soon as the diagnosis and staging is complete. Histology is helpful in deciding the appropriate program, with


patients with T cell lymphoma responding to a 'leukemia-type' protocol with induction, consolidation and maintenance, while B cell lymphomas can be successfully managed with intensive short-term therapy. This was confirmed in a classical study21 in which the ISA L2 protocol was compared with COMP. Other protocols developed in the USA, Europe and Great Britain are given in Table 27.4. Many programmes contain a cytoreductive phase, with lower doses of active agents given initially, followed by a more intensive induction. A consolidation phase follows during which central nervous system chemotherapy prophylaxis is introduced. Patients with lymphoblastic disease then progress to a maintenance or continuation phase. As can be seen from the pivotal studies from the 1980's shown in Table 27.4, response rate and event-free survival was high. These protocols, however, are constantly being revised, so that entry into current study protocols is advisable. Escalating the doses of drugs, such as cyclophosphamide, methotrexate and cytarabine, with minimum delay and shorter duration schedules is improving survivals further for advanced disease.22,25 However, for children presenting with localized disease, more moderate approaches may be appropriate26 and the current collaborative venture between the French Societe Francaise d'Oncologie Pediatrique (SFOP), the United Kingdom Childrens Cancer Study Group (UKCCSG) and the United States Childrens Cancer Group (USCCG) should resolve this and other unanswered questions.27

extranodal sites, for example, head and neck and gastrointestinal tract, and involvement of other organs, particularly the bone marrow and central nervous system, is common. In young adults these lymphomas were shown to be potentially curable with standard NHL regimens28 but the prognosis remained poor, particularly in those patients with bad prognosis disease. Intensive regimens have achieved excellent results, with over two-thirds of patients surviving.29,31 Recently, it has become evident, based on the experience with childhood Burkitt's lymphoma, that excellent results can be achieved with short but very intensive chemotherapy; the disease is frequently cured despite involvement of the bone marrow or central nervous system. One approach has been to consolidate remission with autologous bone marrow transplant;32 however, short-duration high-dose chemotherapy has been highly successful in both children and adults.22,32,35 A major lead has come from the National Cancer Institute (NCI), which has been involved in studies for many years. They have developed various protocols for adults, the most successful of which has been cyclophosphamide, vincristine, doxorubicin, methotrexate (CODOX-M),36 where the dose of cyclophosphamide and methotrexate has been escalated. For poor-prognosis disease, a non-cross-resistant protocol incorporating ifosfamide, etoposide and cytarabine (IVAC) was added. For the small number who relapse, high-dose therapy with autologous or allogeneic stem cell transplant may be of value.37

Burkitt's lymphoma Burkitt's lymphoma (and Burkitt-like lymphoma) merit special mention as they are models for successful chemotherapy. These are rare, fast-growing and aggressive B cell neoplasms, which most commonly occur in children and young adults. While the African form of the disease is commonly localized to the jaw and is cured by relatively simple chemotherapy, the Western form commonly presents with bulky, widespread disease and has a worse prognosis. These tumors commonly arise at

HODGKIN'S DISEASE Clinical presentation In developed countries, children with HD are relatively well at presentation, only some 20-30 per cent having fever, sweats or a 10 per cent loss of weight.38,39 Massive disease such as that seen in Fig. 27.2 is uncommon in Western countries, but seen frequently in the Middle

Table 27.4 Studies in childhood non-Hodgkin's lymphoma that form the basis of current practice

Lymphoblastic III

24

III III IV

38

German BFM StJ Judes French 1MB 84

III and IV III and IV mostly

LSA2-L2

76 at 2 years

21

57 at 2 years

21 24

Non-lymphoblastic COMP

75 15 29 216

75

at21 months 53j 81 at 2 years 78 at median 41 months

18 17

LSA2-L2 = 10 drug leukemia-type regimen, COMP = cyclophosphamide, oncovin, methotrexate, prednisone, BFM = Berlin, Frankfurt, Munster, 1MB = lymphoma maligne Burkitt.

Hodgkin's disease 377

Table 27.5 Hodgkin's disease: diagnostic and staging procedures 1. Surgical biopsy reviewed by lymphoma pathologist 2. Clinical history noting fever, sweating and weight loss of > 10 per cent, ie. 'B' symptoms 3. Physical examination noting Waldeyer's ring, and liver and spleen enlargement 4. Complete blood count and erythrocyte sedimentation rate 5. Postnasal space X-rays 6. Chest X-ray 7. Computed tomography scan of chest and abdomen 8. Abdominal ultrasound as baseline for follow-up 9. Bone marrow trephine if indicated by extensive disease or B symptoms 10. Additional procedures being assessed: gallium-67 scanning and magnetic resonance imaging

Radiology

Figure 27.2

Massive cervical lymphadenopathy in a young

boy from the Middle East.

East. Lymphadenopathy is commonly seen in the cervical and supraclavicular region.39 Other presentations include mediastinal obstruction with breathlessness, dysphagia and early morning facial edema. Subdiaphragmatic presentations are on the whole uncommon.

Diagnosis and staging Diagnosis must be based on the histology of a lymph node biopsy, or (where this is not possible or there is adequate experience) guided needle biopsy may be appropriate. A suggested programme for staging is given in Table 27.5. General assessment should include an estimate of the hemoglobin, white blood cell count and platelets, and an erythrocyte sedimentation rate. Except in children with extensive disease or 'B' symptoms, bone marrow trephine biopsy is unlikely to show involvement, and aspirations are nearly always unhelpful.39 Biochemistry and, in particular, liver function tests, should be available, but interpretation of the alkaline phosphatase in the young child needs to be done with caution. Normal values for alkaline phosphatase in children are available.40

Ultrasound and CT scanning have now replaced lymphangiography as appropriate radiology for HD. A chest X-ray and views of the postnasal space should be routinely performed. Care may be necessary to differentiate an enlarged thymus from a mediastinal mass. Staging laparotomy Surgical procedures to examine and biopsy the abdominal contents, and proceed to either partial or complete splenectomy are no longer used. The reasons for this are the undoubted morbidity from recurrent intestinal obstruction and the vulnerability of the splenectomized child to life-threatening or fatal infection. More recently, an increase in the second malignancy rate has been noted in splenectomized children.41,42 The frequency with which combined modality therapy, with chemotherapy and in-field radiotherapy, is now being used has also rendered this procedure unnecessary. When treatment procedures are dependent on accurate staging, laparotomy was the only way to ensure that radiotherapy, when used alone, includes all areas of disease. The spleen had to be removed in its entirety, because partial splenectomy results in a false-negative rate. Staging The Ann Arbor staging system, or its more recent modification, the Cots wold classification, is in use (Table 27.6). The propensity to relapse caused by large mediastinal masses where the tumor is greater than a third of


Table 27.6 Staging of Hodgkin's disease: Ann Arbor and Cotswold modification Stage I Involvement of a single lymph node (I) or a single extralymphatic organ (IE) Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (ME) Stage III Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organs or sites (HIE) or by involvement of the spleen (IMS) or both (IIISE) Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissue with or without associated lymph node enlargement Each stage is divided into A and B categories: A No systemic symptoms B Unexplained weight loss of > 10% of body weight within last 6 months or unexplained fever (about 38°C) and/or night sweats X Mediastinal masses greater than one-third thoracic diameter or > 10 cm in diameter

the chest diameter and by other masses > 10 cm is recognized in the Cotswold classification.43

Treatment The two modalities available for treatment of HD are radiotherapy and chemotherapy. With the introduction of linear accelerators and the definition of a curative dose, extended field radiotherapy in pathologically staged patients was highly effective as a primary treatment in adults, and it subsequently was used in children. Serious effects on growth and development were soon evident (Fig. 27.3). The use of mantle irradiation in the

Figure 27.3

The late results of mantle irradiation given 5

years previously, with clavicular shortening and failure of development of the upper thorax.

young child prevented proper development of the upper half of the trunk, and there was marked loss of neck tissue. Involved field irradiation alone44'45 produced disappointing relapse-free survivals (Table 27.7). Multidrug combinations of chemotherapy, such as MOPP, having been shown to be effective in adult HD, were demonstrated to be equally so in children. Because of the nausea and vomiting induced by these therapies, they were not well tolerated in the child, however, and alternative therapies were introduced, such as chlorambucil, vincristine, procarbazine, prednisolone (ChlVPP) and ABVD (Table 27.8). Giving MOPP alone produced relapse-free survival of between 80 and 90 per cent.38 The use of alkylating agents in large doses has produced a definite increase in second malignancies and this, together with the almost universal sterility caused in boys and the serious effects on fertility in girls, has made this approach less acceptable. Combined modality therapy reported from Stanford, London and France has produced excellent disease-free survival (Table 27.7). Randomized trials comparing the use of pathological staging, plus extended or in-field radiotherapy and

Table 27.7 Treatment of Hodgkin's disease in children

Radiotherapy only Radiotherapy IF Radiotherapy EF

51 54

PS IA IIA PS l-ll

72 28

95 96

Jereb et al. (44) Sullivan et al. (45)

Radiotherapy + chemotherapy MOPP x 6 ChlVPP x 3-6 4 ABVD or 4-6 MOPP/ABVD

75 84 157

PS I-IV CS I-IV CS I-IV

89 82 88

90 94 95

Russell et al. (46) Robinson et al. (39) Dionet et al. (47)

Chemotherapy only MOPP or ChlVPP

53

CS I-IV

92

94

Ekert et al. (48)

PS = pathological stage, CS = clinical stage, RFS = relapse-free survival, EF = extended field, IF = involved field.

Long-term effects of therapy 379

Table 27.8 MOPP-alternative chemotherapeutic regimens

ChlVPP49 Chlorambucil 6 mg/m2 per day po Procarbazine 100 mg/m2 per day po Prednisolone 40 mg/day po Vinblastine 6 mg/m2 iv 14-day cycles with a 14-day rest period.

1-14 1-14 1-14a 1 and 8

50

ABVD

Adriamycin 25 mg/m2 iv Bleomycin 10 mg/m 2 iv Vinblastine 6 mg/m2 iv Dacarbazine 1 50 mg/m2 iv 14-day cycles with 14-day rest periods.

1 and 14 1 and 14 1 and 14

1-5

a

Reduced appropriately in children, iv = intravenous, po = oral.

chemotherapy, with clinical staging and combined modality therapy will never now be done. However, a useful comparison of the two approaches to treatment has been reported.51 In 171 children treated at Stanford and at St Bartholomew's and Great Ormond Street Hospitals in London, the Stanford children were pathologically staged, while the London children were clinically staged. The two groups were remarkably similar. At 10 years the survival of both groups was 91 per cent. There was a trend for the relapse-free interval to be lower in the London children (83 per cent compared to 90 per cent at Stanford), but this was not significant. Other groups have also reported similar results, with long-term survival rates consistently around 80 per cent.52-55 Many children who are survivors of earlier studies and were subjected to laparotomy and splenectomy are now on long-term follow-up, and the problem of preventing fatal infections from encapsulated organisms is frequently encountered. The current recommendation is for the use of a polyvalent vaccine such as Pneumovax (which should be renewed every 5 years) and the administration of Haemophilus B immunization at the same time, together with long-term oral prophylactic penicillin. Results in HD are now so good with combined modality therapy that the question of how far can either of these modalities be reduced can be asked. How far can anthracyclines, such as doxorubicin, be eliminated or should alkylating agents no longer be given? The problems of what to do about resistant and relapsing disease, and the role of intensive chemotherapy supported by either autologous bone marrow transplantation or peripheral blood stem cells remain to be investigated.

LONG-TERM EFFECTS OF THERAPY Because of the earlier success in producing a high rate of durable remissions in HD, there is more information

about the incidence of long-term side effects than is available for childhood NHL. Nevertheless, a number of excellent studies in leukemia and lymphoma are applicable, and have been included.

Cardiotoxicity The cardiotoxicity of anthracyclines is well known in adults and has been demonstrated in children treated with these drugs in combinations for acute leukemia.56,57 It has been shown that girls are more susceptible than boys58 and that, the older the child at the time of therapy, the less toxicity ensues. Removal of anthracyclines from both NHL and HD treatment protocols could possibly prejudice the response and survival of children. Treatment programs have therefore been devised in which an attempt is made to reduce the amount of anthracycline and alkylating agent by alternating standard regimens containing these with other regimens that do not. In this way the total cumulative dose of each agent can be reduced. A review of the long-term outcome of an ABVD/MOPP combination in childhood HD59 reported no deleterious effect on cardiac function in children given a total cumulative dose of 150 mg/m2 in 29 patients studied 22-132 months after completion of therapy. However, in those children treated on trials at St Jude from 1968-90, as well as excess mortality from second cancers and infections, there was a significantly increased mortality from cardiac disease. All patients were male and had had extended field radiotherapy and no anthracycline-containing chemotherapy.60 In a study of 103 young survivors of NHL treated on National Cancer Institute protocols, a predominate late effect was cardiotoxicity related to doxorubicin therapy in doses exceeding 200 mg/m2.61

Pulmonary function Bleomycin has produced lung fibrosis with consequent deterioration in pulmonary function, and is a constituent of the ABVD program. In 40 children who were long-term survivors of HD and had received ABVD as part of their treatment, 27 had normal pulmonary function, ten had mild and three moderate impairment of gas transfer, obstructive or restrictive patterns, 6-121 months after completion of therapy.59 This study emphasizes the need for studies of both heart and lung function during the course of therapy, and assessment at the end of treatment programmes, with long-term subsequent follow-up.

Endocrine function Dysfunction occurs primarily in the thyroid and gonads after radiation to fields including the sites of these


organs, or after chemotherapy, particularly with alkylating agents. Biochemical evidence of thyroid dysfunction is seen after mantle radiotherapy, although overt hypothyroidism is uncommon. Elevated levels of thyroid stimulating hormone (TSH) and low levels of thyroid have been seen.62 Biochemical evidence shows that hypothyroidism can recover spontaneously.63 Long-term followup of children with raised TSH has indicated a liability to thyroid carcinoma as a second malignancy in those children who had thyroid irradiation.64 There is a mandatory requirement for regular examination of the thyroid, both clinically and by ultrasound, in these children. Gonadal dysfunction

Until recently it has not been possible to say with certainty whether survivors of NHL will have progeny with a propensity to develop cancer. Considerable reassurance comes from a study of 382 offspring of parents surviving acute leukemia or NHL.75 A total of 2776 person-years of follow-up were accrued by these children, with a mean and median follow-up of 7.3 and 5.8 years, respectively. No malignant neoplasms occurred in the whole population, and the authors conclude that there is no added risk of developing malignancy in this cohort. Psychosocial aspects There has been concern that a higher incidence of psychological disturbance is seen in the long-term survivors of childhood lymphomas.75 Marital difficulties and problems at work seem to be more frequent, although educational achievement is normal or even enhanced.76 Major concerns are the discrimination of employers and difficulty in obtaining insurance.

Gonadal dysfunction has been described in adult females65 and males,66 and the effect of MOPP chemotherapy on adolescent Ugandan boys67 was one of the earliest accounts of the problem of infertility in these children. Studies of testicular function in the long term68'69 have shown a high proportion of infertility in boys treated with alkylating agents. In these boys, estimations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) have shown gradual elevation over time. A disturbing feature of these postpubertal patients was a fall in testosterone levels in some, despite a high level of LH. This would suggest that premature Leydig cell dysfunction is a real possibility. In reviewing the Stanford experience,70 similar findings of infertility in boys were seen. In girls, however, the findings were more hopeful, for 87 per cent had normal menstrual function at a median follow-up of 9 years.

It is very probable that more sophisticated means of discriminating between the various subvarieties of lymphoma will define new entities. This has already happened with the recent recognition of childhood anaplastic large-cell lymphoma, with a Ki-1 (CD 30) phenotype which is certainly more frequent in children than was originally thought.

Second malignancy

Prospects for therapy

Acute myeloid leukemia and a variety of solid tumors occur following treatment for HD. A follow-up of 979 children under the age of 16 at diagnosis71 showed that leukemia and lymphoma occurred with increasing frequency up to 5 years after treatment, and then plateaued. The incidence of solid tumors (usually occurring within an irradiated site) was progressive and still rising after 30 years of follow-up. The risk of second leukemia was greater in those children who had undergone splenectomy. It has been suggested that survivors of pediatric HD require lifelong evaluation and cancer screening.72 In 883 children with NHL treated between 1974 and 1985,10 deaths (2 per cent) out of the 476 children who died in the series were due to second primary tumors.73 Six had acute myeloid leukemia, two had osteosarcoma and two had astrocytomas as second tumors. The majority occurred in the first 10 years of follow-up. While the deaths from second tumors appear to decline over time, deaths from late effects of therapy appear to increase.74

Population based data on childhood NHL and HD show very good results at 5 years2 of 73 and 93 per cent, respectively. The priorities for new studies do, however, differ. In NHL there is still some way to go to achieve better survival rates either by intensifying conventional therapy, by the use of high-dose therapy supported by bone marrow transplantation or peripheral blood stem cells, or by the possible use of some form of targeted therapy using, for example, interleukin-2 or other cytokines. In HD the priority is the development of treatment programs with minimal effects on fertility, heart and lung function. In both NHL and HD, programs to reduce the incidence of late second primary tumors need to be developed. In NHL the prospects for improvement in firstgeneration protocols (e.g. CHOP) by the multidrug second- and third-generation programs did not appear too good, given the results of a randomized study in adults comparing CHOP with more intensive regimens.77

FUTURE DEVELOPMENTS New entities

References 381

However, with more recently introduced intensive regimens with dose escalation of agents, such as cyclophosphamide, methotrexate and cytarabine, even Burkitt's lymphoma presenting with central nervous system involvement is curable in the majority of cases.20 While high-dose therapy with or without total body irradiation is technically feasible, it only rescues about 15 per cent of children treated.78 Attention needs to be focused on the high incidence of drug resistance in relapsed lymphoma. In HD the aim has been to reduce long-term side effects by avoiding alkylating agents or anthracyclines with cardiotoxic properties. Thus, regimens such as ABVD have been preferred or used in combination with MOPP.58 Epirubicin and etoposide were used in the vincristine, etoposide, epirubicin, prednisolone (VEEP) combination79 but a disturbing early relapse rate led to the abandonment of this regimen. A study of the features of relapsed and resistant childhood HD80 showed that most relapses occurred within 2 years, and that the overall survival of these relapsed children was only 45 per cent at 10 years. Those who relapsed in the first year, or at multiple sites, had the worst prognosis. In children who have disease that remains chemosensitive, highdose therapy with support is probably currently the best option as conventional relapse protocols are disappointing. The prospects for survival of children with lymphoma have improved beyond all expectation in the last three decades. With the introduction of new chemotherapeutic agents and the exploitation of the latest discoveries in molecular biology, it is to be hoped that future progress is still possible.

ACKNOWLEDGEMENTS I am very grateful to Mrs Io Barton for her expert typing of this manuscript.

REFERENCES 1. Miller RW. Childhood cancer. Cancer 1994; 75: 395-405. 2. Stiller CA. Population-based survival rates for childhood cancer in Britain. BrMedJ 1994; 309:1612-6. 3. Parkin DM, Stiller CA, Draper GJ, et al. The international incidence of childhood cancer. Int J Cancer 1988; 42: 511-20. 4. Padmalatha C, Ganick DJ, Hafez GR, et al. Hodgkin's disease and non-Hodgkin's lymphoma in children and young adults - a clinical pathological study of 127 cases. Med Pediat Oncol 1982; 10:175-84. 5. Medeiros LJ, Greiner TC. Hodgkin's disease. Cancer 1995; 75: 357-69. 6. Stiller CA. What causes Hodgkin's disease in children? Review. EurJ Cancer 1998; 34: 523-8.

7. Hartge P, Devesa S, Fraumeni J. Hodgkin's and nonHodgkin's lymphoma. In: Cancer Surveys 19/20: Trends in Cancer Incidence and Mortality. London: Imperial Cancer Research Fund, 1994; 423-53. 8. Coates PJ, Mak WP, Slavin G, et al. Detection of simple copies of Epstein-Barr virus in paraffin wax sections by non-radioactive in situ hybridisation. J Clin Pathol 1991; 44:487-91. 9. Khan G, Gupta RK, Coates PJ, et al. Epstein-Barr virus infection and bcl-2 proto-oncogene expression. Am J Pathol 1993; 143:1270-4. 10. Stein H, Gerdes J, Schwab U, et al. Identification of Hodgkin and Sternberg-Reed cells as a unique cell type derived from a newly-detected small cell population. Int J Cancer 1982; 30: 445-59. 11. Gupta RK, WhelanJS, Lister TA, et al. Direct sequence analysis of the t(14;18) chromosomal translocation in Hodgkin' disease. Blood 1992; 79: 2084-8. 12. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms-a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92. 13. Brugieres L, Caillaud JM, PatteC, et al. Malignant histiocytosis: therapeutic results in 27 children treated with a single polychemotherapy regimen. Med Pediat Oncol 1989; 17:193-6. 14. Murphy SB, Fairclough DL, Hutchison RE, et al. NonHodgkin's lymphomas of childhood: an analysis of the histology, staging and response to treatment of 338 cases at a single institution. J Clin Oncol 1989; 7: 186-93. 15. NgYY, HealyJC, Vincent \M,et al. The radiology of nonHodgkin's lymphoma in childhood - a review of 80 cases. Clin Radiol 1994; 49: 594-600. 16. Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin's lymphoma: dissimilarities from lymphomas in adults. Semin Oncol 1980; 7: 332-9. 17. Patte C, Philip T, Rodary C, et al. High survival rate in advanced B-cell lymphomas and leukaemias without CMS involvement with a short intensive polychemotherapy. Results from a French Pediatric Oncology Society randomised trial of 216 children. J Clin Oncol 1991; 9: 123-32. 18. Murphy SB, Bowman WP, Abromowitch M, et al. Results of treatment of advanced-stage Burkitt's lymphoma and B cell (Sig+) acute lymphoblastic leukaemia with highdose fractionated cyclophosphamide and co-ordinated high-dose methotrexate and cytarabine. J Clin Oncol 1986; 4:1732-9. 19. Link MP, Donaldson SS, Berard CW, et al. Results of treatment of childhood localised non-Hodgkin lymphoma with combination chemotherapy with and without radiotherapy. N EnglJ Med 1990; 322: 1769-74. 20. Patte C. Non-Hodgkin's lymphoma. Paediatric update. EurJ Cancer 1998; 34: 359-63.

382 Pediatric lymphomas 21. Anderson JR, Wilson JJ, Jenkin RT, et al. The results of a randomised therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2). N Eng J Med 1983; 308: 559-65. 22. Patte C, Philip T, Rodary C, et al. High survival rate in advanced stage B-cell lymphomas and leukaemias without CMS involvement with a short intensive polychemotherapy. Results of a randomized trial from the French Pediatric Oncology Society (SFOP) on 216 children. J Clin Oncol 1991; 9:123-32. 23. Magrath IT, Adde M, Shad A, et al. Adults and children with small non cleaved cell lymphoma have a similar excellent out-come when treated with the same chemotherapy regimen. J Clin Oncol 1996; 14: 925-34. 24. Reiter A, Schrappe M, Parwaresch R, et al. Non-Hodgkin's lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage. A report of the Berlin-Frankfurt-Munster Group.7 Clin Oncol 1995; 13: 359-72. 25. Atra A, Gerrard M, Hobson R, Imeson JD, Ashley S, Pinkerton CR, on behalf of the UKCCSG. Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin's lymphoma (B-NHL) - results of the UKCCSG 9003 protocol. BrJ Cancer 1998; 77: 2281-5. 26. Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB. Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N EnglJ Med 1997; 337: 1259-66. 27. Pinkerton CR. Commentary. EurJ Cancer 1998; 34: 362-3. 28. Anderson JR, Wilson JF, Jenkin TDR, et al. Childhood nonHodgkin's lymphoma. The results of a randomised therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-LJ. N EnglJ Med 1983; 308: 559-65. 29. Bernstein Jl, Coleman NC, Strickler JG, et al. Combined modality therapy for adults with small non-cleaved cell lymphoma (Burkitt's and non-Burkitt's types). J Clin Oncol 1986; 4: 847-58. 30. LopezTM, Hagemeister FB, McLaughlin P, et al. Small non-cleaved cell lymphoma in adults: superior results for stages l-lll disease.) Clin Oncol 1990; 8: 615-22. 31. Longo DL, Duffey PL, Jaffe ES, et al. Diffuse small noncleaved cell, Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy. J Clin Oncol 1994; 12: 2153-59. 32. McMaster ML, Greer JP, Greco A, et al. Effective treatment of small-non cleaved-cell lymphoma with high-intensity, brief-duration chemotherapy. J Clin Oncol 1991; 9: 941-6. 33. Schwenn MR, Blattner SR, Lynch E, Weinstein JJ: HiCCOM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt's lymphoma and Bcell acute lymphoblastic leukaemia. J Clin Oncol 1991; 9: 133-8.

34. Philip T, Meckenstock R, Deconnick E, et al. Treatment of poor prognostic Burkitt's lymphoma in adults with the Societe Francaise d'Oncologie Pediatrique LMB protocol - a study of the Federation Nationale des Centres de Lutte Centre le Cancer (FNLCC). EurJ Cancer 1992; 28A: 1954-9. 35. Gasparini M, Rottoli L, Massimino M, et al. Curability of advanced Burkitt's lymphoma in children by intensive short-term chemotherapy. EurJ Cancer 1993; 29A: 692-8. 36. Magrath IT, Janus C, Edwards BK, et al. An effective therapy for both undifferentiated (including Burkitt's) lymphomas and lymphoblastic lymphomas in children and young adults. Blood 1984; 63: 1102-11. 37. Philip T, Pinkerton R, Hartmann 0, et al. The role of massive therapy with autologous bone marrow transplantation in Burkitt's lymphoma. Clin Hematol 1986; 15: 205-18. 38. Donaldson SS. Hodgkin's disease in children. Semin Oncol 1990; 17: 736-48. 39. Robinson R, Kingston JE, Noguera Costa R, et al. Chemotherapy and irradiation in Hodgkin's disease. Arch Dis Childhood 1984; 59:1162-9. 40. Nelson WE. Table in: Behrman RE, Vaughan VC, Nelson WE, eds Textbook of Pediatrics. Philadelphia: WB Saunders, 1987:1582. 41. Rosenberg SA. Exploratory laparotomy and splenectomy for Hodgkin's disease - a commentary [editorial]. J Clin Oncol 1988; 6: 574-5. 42. Meadows AT, Obringer AC, Monero 0, et al. Second malignant neoplasms following childhood Hodgkin's disease: treatment and splenectomy risk factors. Med Pediat Oncol 1989; 17: 477-84. 43. Lister TA, Crowther D. Staging for Hodgkin's disease. Semin Oncol 1990; 17: 696-703. 44. Jereb B, Tan C, Bretsky S, et al. Involved field (IF) irradiation with or without chemotherapy in the management of children with Hodgkin's disease. Med Pediat Oncol 1984; 12: 325-32. 45. Sullivan MP, Fuller LM, Chen T, et al. Intergroup Hodgkin's disease study in children of Stage I and II - a preliminary report. Cancer Treatment Rep 1982; 66: 937-47. 46. Russell KJ, Donaldson SS, Cox RS, et al. Childhood Hodgkin's disease: patterns of relapse. J Clin Oncol 1984; 2: 80-7. 47. DionetC, Oberlin 0, HalrandJL, et al. Initial chemotherapy and low-dose irradiation in limited fields in childhood Hodgkin's disease - results of a joint cooperative study by the French Society of Paediatric Oncology (SFOP) and Hopital St Louis, Paris. Int J Radial Oncol Biol Phys 1988; 15: 341 -6. 48. Ekert H, Waters KD, Smith PJ, et al. Treatment with MOPP and ChlVPP chemotherapy only for all stages of childhood Hodgkin's disease. J Clin Oncol 1988; 6: 1845-50.

References 383 49. Dady PJ, McElwain TJ, Austin DE, et al. Five year experience with ChlVPP. Effective low toxicity combination chemotherapy for treatment of Hodgkin's disease. BrJ Cancer 1982; 45: 851-9. 50. Bonnadonna G, Zucali R, Monfardini S, et al. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine and imidazole carboxamide versus MOPP. Cancer 1975; 36: 252-9. 51. Donaldson SS, Whitaker SJ, Plowman PN, et al. Stage l-ll pediatric Hodgkin's disease: long term follow-up demonstrates equivalent survival following different management schemes..J Clin Oncol 1990; 8:1128-37. 52. Jenkin DR, Chan H, Freedman M, et al. Hodgkin's disease in children: treatment results with MOPP and low-dose, extended-field irradiation. Cancer Treatment Rep 1982; 66: 949-59. 53. Oberlin 0, Leverger G, Pacquement H, et al. Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology. J Clin Oncol 1992; 10:1602-8. 54. Schellong G, Bramswig JH, Hornig-Franz I. Treatment of children with Hodgkin's disease: results of the German Pediatric Oncology Group. Ann Oncol 1992; (suppl 4): 73-6. 55. Maity A, Goldwein JW, Lange B, et al. Comparison of highdose and low-dose radiation with and without chemotherapy for children with Hodgkin's disease: an analysis of the experience at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania. J Clin Oncol 1992; 10: 929-36. 56. Lipschultz SE, Colon SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy of acute lymphoblastic leukaemia in childhood. N Engl J Med 1991; 324: 808-15. 57. Steinherz LJ, Steinherz PG, Tan CT, et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapyJ/W/l 1991; 266:1672-7. 58. Silber JH, Jakacki Rl, Larsen RL, et al. Forecasting cardiac function after anthracyclines in childhood - role of dose, age and gender. In: Bricker JT, Green DM, D'Angio GJ, eds Cardiac toxicity after treatment for childhood cancer. New York: Wiley-Liss Inc., 1992: 95-102. 59. Hunger SP, Link MP, Donaldson SS. ABVD/MOPP and lowdose involved-field radiotherapy in pediatric Hodgkin's disease - the Stanford experience. J Clin Oncol 1994; 12: 2160-6. 60. Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment for Hodgkin's disease.; Clin Oncol 1998; 16: 3592-600. 61. Haddy TB, Adde MA, McCalla J, et al. Late effects in longterm survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 1998; 16: 2070-9. 62. Shalet SM, Rosenstock JD, Beardwell CG, et al. Thyroid dysfunction following external irradiation to the neck for Hodgkin's disease in childhood. Clin Radiol 1977; 8: 511-5.

63. Donaldson SS, Kaplan HS. Complications of treatment of Hodgkin's disease in children. Cancer Treatment Rep 1982; 66: 977-89. 64. Shafford EA. Personal communication. 65. Chapman RM, Sutcliffe SB, Malpas JS. Cytotoxic induced ovarian failure in women with Hodgkin's disease. JAMA 1979; 242:1877-1. 66. Waxman JH, Terry YA, Wrigley PFM, et al. Gonadal function in Hodgkin's disease: long term follow up of chemotherapy. BrMedJ 1982; 285:1612-3. 67. Sherins RJ, Olweny CLM, Ziegler JL Gynaecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin's disease. N Engl y Med 1978;299:12-16. 68. Shafford EA, Kingston JE, Malpas JS, et al. Testicular function following the treatment of Hodgkin's disease in childhood. BrJ Cancer 1993; 68:1199-204. 69. Aubier F, Flamont F, Brauner R, et al. Male gonadal function after chemotherapy for solid tumours in childhood.; Clin Oncol 1984; 7: 304-9. 70. Ortin TTS, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin's disease in childhood - the Stanford experience. Int J Radial Oncol Biol Phys 1990; 19: 873-80. 71. Robertson CM, Stiller CA, Kingston JE. Causes of death in children diagnosed with non-Hodgkin lymphoma between 1974 and 1985. Arch Dis Childhood 1992; 67: 1378-83. 72. Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS. Second cancers following pediatric Hodgkin's disease. J Clin Oncol 1998; 16: 536-44. 73. Robertson CM, Hawkins MM, Kingston JE. Late deaths and survival after childhood cancer - implications for care. Br MedJ 1994; 309:162-6. 74. Hawkins MM, Draper GJ, Winter DL. Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin's lymphoma. BrMedJ 1995; 71: 1335-9. 75. Wasserman AL, Thompson El, Wiliams JA, et al. The psychological status of survivors of childhood/adolescent Hodgkin's disease. AmJ Dis Childhood 1987; 141: 626-31. 76. Allen A, Malpas JS, Kingston JE. The educational achievements of survivors of childhood cancer. Pediat Hematol Oncol 1990; 7: 339-45. 77. Fisher Rl, Gaynor ER, Dahlberg S, et al. A Phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate or high-grade non-Hodgkin's lymphoma. Results of SWOG 8576 (Intergroup 0067) the National High Priority Lymphoma study. Ann Oncol 1994; 5: 591-5. 78. Philip T, Hartmann 0, Pinkerton CR, et al. Curability of relapsed childhood B-cell non-Hodgkin's lymphoma after intensive first line therapy. A report from the Societe Francaise d'Oncologie Pediatrique. Blood 1993; 81: 2003-6.

384 Pediatric lymphomas 79. O'Brien MER, Pinkerton CR, Kingston JE, et al. 'VEEP' in

80. James ND, Kingston JE, Plowman PN, et al. Outcome of

children with Hodgkin's disease - a regimen to decrease

children with resistant and relapsed Hodgkin's disease,

late sequelae. BrJ Cancer 1992; 65: 756-60.

BrJ Cancer 1992; 66:1155-8.

28 Lymphoma in the elderly PWM JOHNSON

Introduction - the scale of the problem Is lymphoma in the elderly a different disease? Is advanced age perse a prognostic factor? Age-specific considerations in lymphoma treatment

385 386 386 388

INTRODUCTION - THE SCALE OF THE PROBLEM The increasing longevity of the population and the escalating incidence of neoplasia with age (1000-fold between the ages of 40 and 801) have combined to produce a rising number of elderly patients with all types of malignancy. Lymphoma, particularly of non-Hodgkin's types (NHL) is no exception to this.2 In populationbased registries the median age at presentation of NHL is 65, with up to 40 per cent over the age of 70.3'4 In addition, the age-adjusted annual incidence of NHL has more than doubled in the last 40 years, and data from the North American surveillance, epidemiology and endresults (SEER) program shows a nearly 60 per cent increase between 1973 and 1989, much of this in the elderly.5 The largest rise has been seen among Caucasian males aged 75 or older, where a 300-400 per cent increase occurred in the same interval6 (Fig. 28.1). Hodgkin's disease has not shown the same degree of rise and the age-adjusted incidence remains stable. The bimodal age distribution with one peak in the third decade and a rising incidence from the fifth decade onwards persists, although a proportion of cases in the older population have now been recognized as low-grade NHL. The relative proportion of elderly patients in different series varies considerably according to patterns of referral. A population-based survey from Stockholm in the 1970s had 43 per cent of patients over the age of 507 and a national study in the USA had 20 per cent of cases presenting at over 60 years.8 However, the International Database in Hodgkin's Disease (IDHD), which collated data on over 14 000 patients from 20

Treatment strategies Conclusions References

390 393 393

groups world-wide, had only 8 per cent over the age of 60 and a report from a single center (Stanford) had only 4 per cent in this age group.9 Despite their numerical importance, lymphomas in the elderly have been relatively little studied. In reported trials of treatment, the usual median age of patients with NHL is around 50 and for Hodgkin's disease 35. Most protocols exclude patients older than 65 or 70. In a registration study of seven centers in the South-West Oncology Group, among 76 elderly patients with aggressive lymphomas, only 21 (28 per cent) entered trials, principally due to exclusion from protocol criteria (39 cases) or elective choice of different therapy (16 cases).10 As a consequence, it is difficult to know whether the strategies for treatment established in younger populations may be

Figure 28.1 Overall incidence of non-Hodgkin's lymphoma in Yorkshire showing a rising trend over time. Data from Yorkshire Cancer Registry.

386 Lymphoma in the elderly

extrapolated to the elderly. The difficulties of selection bias are well documented in lymphoma trials and may just as well apply to age as any other criterion. These problems have led to the organization of some trials specifically designed to optimize lymphoma cure rates in the elderly. Previous reluctance to employ intensive chemotherapy in older patients is being overcome by the realization that life expectancy at the age of 85 is 7 years in women and 51/2 years in men,11 so that treatment having a significant impact upon 5-year survival is of considerable importance. Similarly, the finding that intensive treatment may result in improved quality of life if the response rate is increased, has demonstrated that an impact on duration of life is not necessarily at the expense of its quality.

IS LYMPHOMA IN THE ELDERLY A DIFFERENT DISEASE? Non-HodgkirTs lymphoma The biology and behavior of NHL in the elderly does not appear to differ significantly from that occurring in younger patients, although some points have been made in the literature (without great consistency), particularly concerning histologic types and the sites of disease. The distribution of histologic subtypes is generally similar in older patients, with diffuse large cell being the commonest and comprising about 40 per cent of most series.4,12,13 Two registry studies have suggested a disproportionate increase in diffuse histology with age,4,14 although this may be attributable to referral bias against low-grade lymphomas, fewer diagnostic biopsies being performed in elderly patients with lymphadenopathy but no other symptoms. There is, however, evidence to suggest less follicular lymphoma, and more immunocytoma and mantle cell lymphoma in the elderly.4,15 The data relating the extent of disease to age are conflicting, suggesting that there is probably no true correlation. One registry study suggested more localized disease among the elderly,4 although this may be a function of less intensive staging investigations. Conversely, in 157 patients, the Nebraska Lymphoma Study Group showed no difference in stage distribution with age,16 a finding confirmed in a single-center study of 192 patients with uniform staging investigations.17 Most critically, the International NHL Prognostic Factors Project, including over 3000 patients treated at different centers in Europe and North America, showed no difference in the distribution of risk categories for patients above or below the age of 60.18 The frequency of extranodal involvement is a further point of contention but again there is probably no substantial difference. The Danish registry study4 and several retrospective analyses from single centers19 suggested a higher rate of extranodal

involvement in the elderly, although this was not apparent in the larger series from the Nebraska Lymphoma Study Group,16 where the rates were identical at all ages. Hodgkin's disease The unusual age distribution of Hodgkin's disease suggests strongly that different pathogenetic processes may be responsible for the younger and older peaks of incidence. Evidence in support of this comes from an epidemiological study of cases in the UK, which showed different geographic associations in patients below the age of 35 and above 50, with trends of risk according to the socioeconomic status of the areas moving in opposite directions.20 The contentious question of the role of the Epstein-Barr virus has impinged upon this issue, with the finding that the viral genome may be more frequently detected in patients below the age of 15 and over the age of 50 than in the young adult group.21 This finding is consistent with the differing pattern of histologic types in the elderly, where mixed cellularity disease is as common as nodular sclerosis.722 The detection of both viral genome and protein has been shown most commonly in mixed cellularity disease.23,24 As well as having an increased proportion of mixed cellularity disease, the elderly more often have B symptoms, advanced stage, poor performance status, raised sedimentation rate and low serum albumin.25,'26 All these features suggest a different biological pattern and may contribute to their poorer prognosis, as outlined later.

IS ADVANCED AGE PER SE A PROGNOSTIC FACTOR? A previous review27 found that the data relating age to the outcome of therapy in NHL were inconclusive. This situation has been largely remedied since that time with the publication of several retrospective series.

Intermediate- and high-grade nonHod gkin's lymphoma The diffuse aggressive lymphomas have been the subject of several studies concerning prognostic factors (Table 28.1). These in general confirm that the elderly tolerate conventional combination chemotherapy less well, are less likely to reach complete remission, have less durable remissions and overall have shorter survival times. The International NHL Prognostic Factors Project has been particularly influential in this analysis, although some doubts remain concerning the variety of treatment regimens employed and their possible impact upon the outcomes. The least secure information concerns the complete

Is advanced age per se a prognostic factor? 387

Table 28.1 Studies relating the outcome of treatment for diffuse aggressive lymphoma to age

16 28 90 91 17 92 93 94 18

CAP/BOP (157) m-/M-BACOD (121) CHOP, etc. (105) LNH-84 (737) CHOP/m-BACOD(192) MACOP-B (126) CHOP-B (250) CHOP-M(118) Various (3273)

63 58 50 55 56 54 56

29 (65) 28 (60) 36 (65) 9(65) 38 (65) 32 (60) 50 (56) 36(60) 41 (60)

Yes

No

No

No

No No

No Yes

No No No Yes Yes

Yes Yes -

Yes (M)

No Yes (M) Yes (M) Yes (M) Yes (M)

Yes Yes Yes (marginal)

(M) = multivariate analyses of overall survival, CR = complete response.

response rates and the durability of remission. Data from one single-center study shows identical responses in the different age groups,28 another shows a non-significant reduction16 and the International Project shows a relatively minor difference in complete response (CR) rates (68 per cent up to age 60 and 62 per cent above). Similarly, durability of remission appears much less in the elderly population in the International Project, although this result was not anticipated from the studies previously published.16,17,28 It is quite likely that the singlecenter series employed more uniform dose intensities than the International Collaborative project and this may account for the differences. An earlier analysis from the Southwest Oncology Group showed that a difference in response rates in the elderly was abolished, if only patients initially receiving full doses of chemotherapy were considered. There was no difference in the duration of remissions.29 Few of the series subsequently published take systematic account of dose reductions, which are often applied ad hoc for the elderly and which the data from SWOG suggest may be responsible for an inferior outcome. Clearly the reasons for initial dose reduction may relate to the condition of the patient in many cases, but the data support the administration of full doses if this is feasible. The impact of age on overall survival seems securely established by the multivariate analyses cited, despite some negative results in other series. The studies which have shown a significant relationship between age and survival include some using standardized chemotherapy and have taken account of the causes of death. In the overwhelming majority of cases, death is due to either lymphoma or toxicity, and comparison of mortality rates to age-matched cohorts of the general population shows a significant reduction in longevity. It has been suggested, however, that, in elderly patients with aggressive lymphomas treated with doxorubicin-based chemotherapy (CHOP), the risk of treatment-related death maybe associated with poor performance status rather than with increasing chronological age.30

Low-grade non-Hodgkin's lymphoma In low-grade lymphomas, the influence of patient age on survival is more difficult to judge, appearing to show significance in proportion to the number of patients with advanced disease over 60 included in the study. In series with only one-quarter to one-third over 60, age has not emerged as significant,31,32 whereas with half or more over 60 it does.33,35 A retrospective analysis of 212 patients with follicular lymphomas treated at St Bartholomew's Hospital over a 20-year period demonstrated age as a significant predictor of survival in multivariate analysis, not only at the time of presentation but also following recurrence.36 The International Prognostic Factor index has been applied to low-grade lymphomas and discriminates groups of differing prognosis as well as in aggressive lymphoma, suggesting that the same factors (including age) predict the outcome of treatment.37

Hodgkin's disease Many studies have established age as an adverse prognostic factor in Hodgkin's disease, with a continuous decline in overall and cause-specific survival rates from the age of 40 onwards.7,25,38 This appears to hold for both limited39,40 and extensive disease.26,38,41 The largest reported series from the USA examined the outcomes in 6314 patients with disease of all stages and found a significant decline in 5- and 10-year survival with advancing age, a decline which persisted when only deaths related to lymphoma or its treatment were included (Fig. 28.2).8 The most comprehensive data on the prognostic significance of age come from the IDHD, as shown in Table 28.2. In stepwise proportional hazards models, the relative risk of death from all causes was 5.09 in patients over 60, for deaths due to Hodgkin's disease it was 3.21 and for deaths from unrelated causes (but including ischemic heart disease and second malignancy) it was 14.28. (All


It is important to note that the bad prognostic influence of age in Hodgkin's disease has been tested in multivariate analyses, given the differences in histologic subtype and extent of disease in the elderly, which might anyway be expected to worsen the prognosis. The treatment of Hodgkin's disease at all stages is thus less successful in the elderly: complete response rates are lower, and cause-specific survival is shorter. If remission is achieved, however, the effect of age on its duration is relatively small by comparison with the influence on overall survival, and negligible in early stage disease. The differences in more advanced disease may well be attributable to reduced dosing. It is notable that the results of 'salvage' chemotherapy for recurrence after apparently successful primary treatment are particularly poor in the elderly42,43 and even the incidence of second malignancies is higher.44,46 Clearly, some of these findings may be attributable to suboptimal treatment in frail older patients and their poor tolerance of therapy, but it is difficult to avoid the conclusion that the underlying biology of the disease differs in this age group.

AGE-SPECIFIC CONSIDERATIONS IN LYMPHOMA TREATMENT There is a variety of factors, apart from the different patterns of disease, which may influence the success of treatment for malignant lymphoma in the elderly. Figure 28.2 Ten-year cause-specific survival of patients with Hodgkin's disease, divided by age at diagnosis, o—o = < 75 years (n = 343), •—• = 75-24 years (n = 1572), D—D = 25-34 years (n = 1180), — = 35-49 years (n = 992), — = 50-64 years (h = 1020), m—m = 65 years (n = 911). Reproduced with permission from Kennedy et al. National survey of patterns of care for Hodgkin's disease. Cancer 7985; 56:2547-56.

these figures are statistically significant with P < 0.001). For all clinical stages of disease, age greater than 50 was associated with a significantly lower complete response rate in stepwise logistic regression.

Pharmacology Most early clinical studies of pharmacology, particularly pharmacokinetics, were carried out in a young population of patients. Some observations have been made concerning the different handling of drugs with age but there remain significant gaps in the state of knowledge. Several factors alter pharmacokinetics in the elderly. Although little difference has been demonstrated in absorption, first-pass metabolism or protein binding,47 the rise in body fat and fall in lean mass and body water with age can reduce the volume of distribution,

Table 28.2 Results of stepwise proportional hazards models on relapse-free and overall survival among 14315 patients registered on the International Hodgkin's Disease Database. All the risk ratios are significant with P < 0.001 except *, where P < 0.01

IA IIA IB/MB IMA 1MB IV

2542 4038 1617 1301 1267 819

1.35(40) NS NS 1.47* (50) 1.74* (60) 1.78(50)

9.41 6.07 3.83 4.18 4.00 2.86

4.26 2.93 2.46 2.48 2.99 2.10

23.44 16.34 18.97 8.91 8.75 14.15

Age-specific considerations in lymphoma treatment 389

particularly of water-soluble drugs. More significant is the alteration in excretory capacity of the kidneys and liver with age. The glomerular filtration rate falls by 10 per cent per 10 years after the fourth decade,48 which may have an appreciable effect on renally excreted drugs, such as cyclophosphamide, melphalan and methotrexate. Liver function shows a similar decline, with a reduction in size and hepatic blood flow: from 1400 ml/minute at 30 to 800 ml/minute at 75.49 The interindividual variation of hepatic metabolism at all ages makes it difficult to predict specific alterations in drug handling, but the available studies suggest that oxidative pathways are more likely to decline with age than conjugation.50 ANTITUMOR ANTIBIOTICS

The excretion of doxorubicin and daunorubicin is predominantly biliary. This leads to a reduction in their clearance with age,51 contributing to a lowered threshold for the well-described dose-dependent incidence of cardiotoxicity. Whereas this becomes a significant risk at a cumulative dose of 450 mg/m2 in the younger population, beyond the age of 70 the figure is nearer to 300 mg/m2. Because of this, mitoxantrone is becoming more widely used as an alternative agent on the basis of its considerably lower potential for cardiotoxicity at equitherapeutic doses. Bleomycin-induced pulmonary toxicity is also reported more frequently in the elderly.52 Whether this is due to a decrease in the 50 per cent of excretion, which occurs through the kidneys or slower conversion to inactive metabolites in the lungs, is not known. ALKYLATING AGENTS

Cyclophosphamide metabolism may be influenced unpredictably by increasing age. The volume of distribution (approximating that of body water) is reduced, but so is hepatic oxidative metabolism to 4-hydroxycyclophosphamide and phosphoramide mustard. A reduction in renal clearance may also result in a prolonged half-life, both for the parent drug and its metabolites.53 Overall, the effect of age is likely to relate closely to the renal function and, provided this is maintained, no specific adjustment is required. Chlorambucil at the doses commonly employed does not appear to be handled differently in the elderly. ANTI METABOLITES

Methotrexate is predominantly cleared by the kidneys and, even in the absence of frank renal impairment, the initial half-life increases with age, resulting in increased toxicity.54 A reduction in the dose and, where appropriate, an increase in duration of folinic acid rescue are indicated in the elderly. There are no systematic data regarding the metabolism of fludarabine in older patients, but no undue toxicity has been reported from extensive trials in patients with chronic lymphatic leukemia and low-grade lymphoma.55

PLANT ALKALOIDS

The vinca alkaloids appear to be less rapidly cleared by hepatic metabolism in older patients, with considerably increased neurotoxicity as a consequence.38 In general it is recommended that the dose is electively reduced in patients over the age of 70. The handling of etoposide varies widely between individuals and, although it is not systematically influenced by age,56 unpredictable myelosuppression is more commonly reported.

Hematologic tolerance The most obvious reason for attenuation of treatment intensity in the elderly is the possibility of a decline in hemopoietic reserve. In practice, there is little evidence that this is the case, in the healthy resting state at least. A study comparing the numbers of bone marrow progenitors in healthy subjects over the age of 70 and in a control group aged 20-25 showed no difference in either erythroid or myeloid cell mass.57 Longitudinal studies similarly have shown no decline in hematocrit or cell numbers with age. The response to marrow stimulation is, however, blunted in the elderly at least partly owing to impaired production of colony stimulating factors by the stroma, as has been demonstrated in vitro using interleukin-1 as a trigger.58 Exogenous administration of granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3) or erythropoietin has been shown to produce identical initial responses in patients above or below the age of 65,59 but more prolonged administration reveals a divergence between the age groups, with the older patients apparently unable to sustain the same rate of increase. After 5 days of G-CSF, patients aged 20-30 showed a mean 80-fold increase in the numbers of circulating granulocyte-macrophage colony forming units (CFU-GM), whilst those aged 70-80 showed only a mean 40-fold rise.60 These factors may clearly have an adverse effect on recovery times following myelosuppressive treatment. A recent study from South America has suggested that, within the older population, further subdivision by age may be appropriate: among patients treated with CHOP and granulocyte-macrophage colony stimulating factor (GM-CSF), those over 70 were significantly more prone to myelosuppression, neutropenic fever and dose delays than those between 60 and 70.61 In older patients with malignancy, the proliferative response of the bone marrow may be blunted even before treatment. Studies in small cell lung cancer patients younger than 60 have shown an increase in myeloid cell mass compared to healthy controls, a response absent in those older than 60. Erythroid mass was decreased in both age groups compared to healthy controls, but significantly more so in the older group.62


Despite these observations, in patients without other significant illnesses, the incidence and severity of myelosuppression do not appear to be much greater in the elderly. A large South-West Oncology Group trial in diffuse large cell lymphoma failed to demonstrate a significant difference in the frequency of severe leukopenia or thrombocytopenia, even for 23 patients over 65 who received full-dose CHOP as initial therapy.29 This observation is supported by data from a study in 62 patients over the age of 65 also treated for aggressive lymphoma, among whom no increase in marrow toxicity was seen with increasing age.63 In Hodgkin's disease, the Cancer and Leukemia Group B showed a significantly higher incidence of severe hematological toxicity in patients over the age of 60, with 33 per cent affected compared to 14 per cent in the younger group.38 This, however, remains the only large series of lymphoma patients given uniform treatment in which hematologic toxicity and age have been reliably correlated. In general, doses have been electively reduced in the elderly,64 making direct comparisons impossible.

Non-hematologic tolerance and co-morbidity Age-related factors, which may limit the capacity to tolerate chemotherapy or radiotherapy, can apply to almost any bodily system. In general, these assume relevance in proportion to the intensity of treatment, with lesser degrees of toxicity compensated by the normal responses. Adaptation to stress is, however, blunted in almost every respect with advancing age, although there have been few systematic studies in relation to cancer treatment. The capacity for tissue repair is a particular consideration in lymphoma therapy, especially in relation to gastrointestinal, neurologic and pulmonary damage. Toxicity in all these tissues is more marked as a rule in the elderly, with a corresponding increase in mortality from causes other than lymphoma.16,65 The progressive declines in both cell-mediated and humoral immune effectors with age are well documented.66 These may result in both increased toxicity of treatment and a higher rate of recurrence, if host immunity is partly responsible for restraint or elimination of the malignant cell population. The co-existence of other illnesses is a further aspect of medical care in an elderly population that may significantly affect the capacity to deliver curative treatment. One series of elderly patients with Hodgkin's disease included one-third with significant co-morbidity.64 Numerically most important among these is cardiovascular disease. The changes in the healthy cardiovascular system which progress with age include a loss of elasticity both in arterial walls and the myocardium. If hypertension and coronary ischemia are superimposed on

these, the ability to increase cardiac output in response to stress is markedly impaired.67 At least one study has shown a history of cardiac disease to have a significantly adverse prognostic influence on the outcome of treatment for lymphoma, as a consequence of increased early deaths.68

TREATMENT STRATEGIES Diffuse large cell NHL The treatment of aggressive lymphomas in the elderly has been studied increasingly in the last 5 years, to some extent recapitulating the development of successive generations of combination chemotherapy in the younger population. Several regimens have been developed specifically for use in this age group. This followed the anticipated finding of increased treatment-related mortality in older patients treated with full-dose CHOP or similar, often approaching 30 per cent.65,69 As has already been described, elective reduction in dose intensity reduces toxicity at the expense of outcome. The challenge, therefore, is to design a regimen that can be administered with less toxicity than CHOP, but for which the response rate and durability of remission are similar. LOCALIZED DISEASE

The relatively uncommon presentation of Stage I or IIA disease is probably best treated by an abbreviated course of chemotherapy and involved field radiotherapy, with a high expectation of cure.70 An analysis of 75 patients over the age of 70 treated in Omaha, Nebraska, showed the use of combination CAP-BOP chemotherapy with radiotherapy to give a 5-year failure-free survival of 47 per cent, compared to 35 per cent for CAP-BOP alone and 10 per cent for radiotherapy alone (P = 0.016).68 Although this was a retrospective analysis, multivariate statistics suggested a genuine benefit for combined treatment. In a randomized study of all ages by the SouthWest Oncology Group, the use of three cycles of CHOP followed by involved field radiotherapy resulted in a similar response rate and freedom from progression to eight cycles of CHOP, but survival in the latter arm was inferior due to a higher mortality from the complications of therapy, particularly cardiac disease.71 If anything, the results of local radiotherapy alone are less favorable in the older age group and this approach should be reserved for those in whom only symptomatic palliative treatment is possible. ADVANCED DISEASE

As already mentioned, the trade-off between sufficient intensity of treatment and excessive toxicity is more acute

Treatment strategies 391

Table 28.3 Results of treatment with regimens specifically designed for older patients with diffuse aggressive lymphomas (adapted from reference 95)

65 96 72 72 69 16 17 97 98 99 100 101 102 77 77 103 104 105 106 78 107

CHOP

20

75

45

13

25

-

30

CNOP

30 76 72 141 112 60 29 31 21 21 52 55 40 32 63 26 40 60 67 41

70 71 70 71 66 72 76

60 31 49 -

12 13 26 37 15 >18 12 16 22 20 48 9 6 25 >24 >24

26 42 48 36 58 21 30 45 48 40 45 38 -

13 17 -

0 11 6 1 7 0 0 19 0 0 6 2 5 6 8 15 0 2 0 2

CNOP CHOP COPA CAP/BOP m-BACOD VNCOP-B CEMP

E+ P IfmVP

VMP MVP Ld-ACOP-B VABE P/DOCE BECALM

PEN P-VABEC P-VEBEC MiCEP

All > 70

76 75 72 73 75 75 74 67 71 73

61 65 76 58 48 75 46 55 65 63 62 42 59 75 66 68

55 50 63

70 48 12 37 30 52 45 41 50 45 35 -

CR = complete response.

in the elderly. In many cases the threshold for cure is not attainable by conventional approaches, such as CHOP, and considerable effort has been spent in devising means by which the therapeutic index may be improved. The three principal strategies have been different drugs, different schedules and haemopoietic growth factors. To date, few randomized trials have been completed but there is a wealth of phase II data (Table 28.3). The greatest interest in different drugs has related to newer anthracycline derivatives or substitutes. Mitoxantrone in particular has been put forward as a less cardiotoxic agent with apparently comparable cytotoxicity to doxorubicin. Certainly the treatment-related mortality in trials of CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisolone) and VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, bleomycin) was much lower than expected. Three randomised studies have been performed. The first report suggested that CNOP using 10 mg/m2 mitoxantrone had an inferior complete remission rate and overall survival rate compared to CHOP using 50 mg/m2 of doxorubicin.72 The median survival in the CNOP arm was 12 months compared to 26 months after CHOP and, disappointingly, there appeared to be no significant difference in hematologic toxicity or the incidence of neutropenic fever. Also, in a European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Comparative Group study, CHOP

proved significantly superior to VMP (etoposide, mitoxantrone and prednimustine) in patients aged 70 years or over; overall survival was 65% with CHOP and only 30% with VMP.73 The British National Lymphoma Investigation found an opposite result when substituting mitoxantrone 7 mg/m2 for doxorubicin 35 mg/m2 in a weekly alternating schedule in a randomized study of 463 patients older than 60. The treatment failure rate was significantly lower in the mitoxantrone arm, with a significantly higher actuarial 4-year survival of 55 per cent versus 35 per cent.74 The final analysis of data from this study will be important in determining the place of alternative anthracyclines in the elderly. Another recent randomized study by the Group d'Etude des Lymphomes de 1'Adulte (GELA) has demonstrated that, even when an epipodophyllotoxin is used, an anthracycline still adds to the probability of cure in this age group.75 Patients were randomized to receive cyclophosphamide/teniposide/ prednisolone with or without pirarubicin. With a median follow-up of 4 years 7 months, there was a small but significant improvement in the pirarubicin arm (26 per cent projected 5-year survival compared to 19 per cent) despite a higher proportion of patients in this arm having an elevated lactate dehydrogenase level at presentation. The investigation of different treatment schedules has mirrored the studies performed in younger patients.


While the large Intergroup study comparing CHOP with third-generation regimens in patients up to 81 failed to demonstrate a difference in any subgroup,76 there are particular reasons to prefer weekly regimens in the elderly. Among these are the opportunities for more frequent medical supervision during treatment and the capacity to reduce doses electively before extreme myelotoxicity develops. The approach of the Vancouver group in modifying weekly regimens by removal of methotrexate, substitution of epirubicin for doxorubicin and shortening to 8 weeks' therapy appears to have produced good results with a 45 per cent 3-year overall survival.77 Similar findings have come from an Italian study of P-VEBEC (prednisolone, vinblastine, etoposide, bleomycin, epirubicin, cyclophosphamide) with a reported 55 per cent overall survival at a median of 24 months.78 Another group has tested consolidation with idarubicin, cisplatin and prednisolone following PVABEC and reported promising results in an initial study with actuarial 4-year survival of 92 per cent, although the median follow-up was less than this.79 Clearly selection bias may have contributed greatly to these results and randomized testing will be an important field in the next few years. The use of hemopoietic growth factors to shorten neutropenia and possibly reduce mucositis is an obvious extension to treatment of aggressive lymphoma in the older patient. A cost-benefit analysis comparing two consecutive cohorts of patients receiving CHVmP/VB (cyclophosphamide, doxorubicin, teniposide, prednisolone, vincristine, bleomycin) with and without GCSF gave comparable response rates but markedly fewer treatment delays, severe myelosuppression, mucositis and days in hospital for those receiving G-CSF.80 The costs of supportive therapy with antibiotics and blood products were significantly lower in the G-CSF arm, although the cost of the growth factor itself overturned this advantage with a mean 57 per cent increase in the total cost per patient. Randomized studies are now required to examine whether the added cost will be justified by an increased cure rate or whether non-hematologic toxicity will become limiting. One such study in Italy has used VNCOP-B with half the patients randomized to receive G-CSF.81 The response rates, recurrencefree survival and overall survival were identical in the two arms, although, as expected, the incidence of severe neutropenia and clinically relevant infection were significantly reduced by G-CSF. There is at least sufficient data to suggest hypotheses worth testing in older patients with aggressive lymphomas, although the apparent lack of progress beyond CHOP in the younger age group is discouraging. Careful randomized trials are under way and in planning to examine the newer regimens, the role of growth factors and other approaches, such as the addition of monoclonal antibodies,82 and the results will be awaited with interest.

Low-grade NHL The relatively straightforward therapies employed against low-grade lymphomas generally require little adjustment in the elderly. Expectant management is often an attractive option for those without compressive symptoms, rapid progression or bone marrow compromise. Involved field radiotherapy may be useful both for long-term control of early disease and palliation of more advanced cases. Age is not necessarily a contraindication to splenectomy, either for hypersplenism or if this is the only site of disease. There is no good evidence that treatment intensity is a critical factor in determining survival following chemotherapy, so that single agents such as chlorambucil or fludarabine may be chosen for their limited toxicity without compromising outcome. Given their minimal contribution to response rates and potential for toxicity, corticosteroids are best avoided unless specifically indicated for autoimmune cytopenias or reversal of marrow suppression prior to starting cytotoxic therapy. The concomitant use of interferon in follicular lymphoma may improve response rates when given with chemotherapy and may prolong remission when used for maintenance.83 The elderly tolerate interferon reasonably well at the doses commonly used in low-grade lymphoma, although there is a higher incidence of toxicity requiring interruption of administration, usually fatigue or myelosuppression. Myocarditis may also be more common. Taken overall, the treatment of low-grade lymphoma in the elderly may be carried out in a way broadly similar to treatment in the younger population, although the results remain inferior. It is not clear why this should be, since the majority of deaths are due to lymphoma and mortality due to the toxicity of treatment does not appear to be more frequent.36 Newer approaches using treatment intensification are clearly not applicable, although the upper age limit is gradually rising as hemopoietic progenitor support becomes more efficient. New agents such as purine analogs are profitably tested in the older population with recurrent disease and, given the shorter survival times with conventional approaches, this may be a group in which improvements in survival will be most readily demonstrated.

Hodgkin's disease From the previous discussion of prognostic factors, it is clear that Hodgkin's disease in the older patient may require a different approach to that in the younger patient. The particular circumstance where age may determine the initial treatment is that of localized disease, since the figures suggest a higher rate of recurrence in patients over 40 treated with radiotherapy alone, except in those rare cases with lymphocyte-predominant

References 393

disease confined above the thyroid notch.40 The EORTC H5U trial showed that the treatment of choice for patients with early-stage Hodgkin's disease over the age of 40 includes chemotherapy. Patients in this age group were randomized between subtotal or total nodal irradiation and six cycles of MOPP with mantle radiotherapy given between the third and fourth cycles. Those treated with the combined modalities showed a significantly better recurrence-free survival, although the overall survival figures are difficult to interpret owing to an excess of apparently unrelated deaths in the radiotherapy arm.84 The documented poor response to 'salvage' treatment in older patients with recurrent disease following initial radiotherapy is a further incentive to the use of a combination approach from the outset,43 although the intensity of chemotherapy required and the extent of radiotherapy have yet to be determined. Both are almost certainly less than the amounts used in H5U, and the current EORTC study employs involved-field irradiation with anthracycline-containing chemotherapy.85 It may be that the VBM regimen developed at Stanford will prove equally effective with less toxicity.86 A further step would be to exclude radiotherapy from treatment altogether, for which there is some support in the data from the National Cancer Institute study comparing MOPP with radiotherapy.87 This might have the advantage of avoiding the high incidence of ischemic heart disease which complicates mediastinal irradiation in the older patient. Advanced Hodgkin's disease offers less scope for different treatment of the elderly. The emerging data concerning the superiority of anthracycline-containing regimens confirms the persistently worse prognosis for older patients despite the improvements overall. No regimens specifically designed for use in the elderly have been tested and, indeed, the relatively small numbers in this group would make randomized trials of sufficient power difficult to complete. Provided the patient can tolerate it, combination chemotherapy at full doses remains the treatment of choice.88 Patients receiving suboptimal doses of chemotherapy have a markedly worse prognosis, both through failure to reach complete remission89 and higher rates of recurrence.64 Hemopoietic growth factors may be helpful in maintaining treatment intensity, although no trial addressing this point has been completed.

lymphoma there is considerable potential for application of new agents to chronic recurring disease with a poor survival pattern, where improvements may be demonstrable in relatively small trials. In diffuse aggressive lymphoma, the approaches of weekly alternating chemotherapy and growth factor support may be rescued from the equivocal position they have occupied since the randomized studies in younger patients.

REFERENCES 1. Kennedy B. Needed: clinical trials for older patients. J Clin oncol 1991;9:718-20. 2. Weisenburger D. Epidemiology of non-Hodgkin's lymphoma: recent findings regarding an emerging epidemic. Ann Oncol 1994; 5: S19-S24. 3. Otter R, Gerrits WBJ, van der Sandt MM, et a\. Primary extranodal and nodal non-Hodgkin's lymphoma. EurJ Cancer Clin Oncol 1989; 25:1203-10. 4. d'Amore F, Brincker H, Christensen B, et al. Non-Hodgkin's lymphoma in the elderly. Ann Oncol 1992; 3: 379-86. 5. Miller BA, Ries LAG, Hankey BF, et al. Cancer statistics review: 1973-1989, National Cancer Institute. Bethesda, MD: National Institute of Health, NIH Pub. No. 92-2789, Vol. 17,1992:1-16. 6. Devesa S, Fears T. Non-Hodgkin's lymphoma time trends: United States and international data. Cancer Res 1992; 52: 5432s-40s. 7. Wedelin C, Bjorkholm M, Biberfeld P, et al. Prognostic factors in Hodgkin's disease with special reference to age. Cancer 1984; 53:1202-8. 8. Kennedy B, Loeb V, Peterson V, et al. National survey of patterns of care for Hodgkin's disease. Cancer 1985; 56: 2547-56. 9. Austin-Seymour M, Hoppe R, Cox R, et al. Hodgkin's disease in patients over sixty years old. Ann Intern Med 1984; 100:13-18. 10. Neilan BA, LeBlanc M, Dahlberg SJ, et al. A SWOG registration study of elderly patients with unfavourable histology non-Hodgkin's lymphoma. ProcAm SocClin oncol 1996;15:A1313. 11. Cohen H. Geriatric principles of treatment applied to medical oncology: an overview. Semin Oncol 1995; 22: 1-2.

CONCLUSIONS The investigation and treatment of lymphoma in older patients is steadily becoming a distinct field of enquiry. The special difficulties of cytotoxic and radiotherapy administration in this age group pose additional problems. In Hodgkin's disease at least, a different underlying biology may be at work, with distinct therapeutic implications for early-stage disease in particular. In low-grade

12. Tirelli U, Zagonel V, Serraino D, et al. Non-Hodgkin's lymphoma in 137 patients aged 70 years or older: a retrospective European Organisation for Research and Treatment of Cancer Lymphoma Group study.J Clin oncol 1988;6:1708-13. 13. Carbone A, Volpe R, Gloghini A, et al. Non-Hodgkin's lymphoma in the elderly. 1. Pathologic features at presentation. Cancer 1990; 66:1991-4. 14. Barnes N, Cartwright R, O'Brien C, et al. Variation in lymphoma incidence within Yorkshire Health Region. BrJcancer1987;55:81-4.

394 Lymphoma in the elderly 15. The non-Hodgkin's Lymphoma Classification Project. Effect of age on the characteristics and clinical behaviour of non-Hodgkin's lymphoma. Ann Oncol 1997; 8: 973-8. 16. Vose J, ArmitageJ, Weisenburger D, et al. The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma. J Clin Oncol 1988; 6:1838-44. 17. Grogan L, Corbally N, Dervan P, et al. Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin's lymphoma treated with standard-dose Adriamycin-based regimens. Ann Oncol 1994;5:s47-s51. 18. The International NHL Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-94. 19. Mead G, MacBeth F, Williams C, et al. Poor prognosis non-Hodgkin's lymphoma in the elderly: clinical presentation and management. Quart J Med 1984; 211: 381-90. 20. Alexander F, McKinney P, Williams J, et al. Epidemiological evidence for the 'two-disease hypothesis' in Hodgkin's disease. Int J Epidemiol 1991; 20: 354-61. 21. JarrettRF, Gallagher A, Jones DB,etal.Detection of EBV genomes in Hodgkin's disease: association with age. 7

30. Gomez H, Hidalgo M, Casanova L, et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis.) Clin Oncol 1998; 16: 2065-9. 31. Gallagher CJ, Gregory WM, Jones AE,etal.Follicular lymphoma: prognostic factors for response and survival.J Clin Oncol 1986; 4:1470-80. 32. Bastion Y, Berger F, Bryon PA, et al. Follicular lymphomas: assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 1991; 2(suppl 2): 123-9. 33. Gospodarowicz MK, Bush RS, Brown TC, et al. Prognostic factors in nodular lymphomas: a multivariate analysis based on the Princess Margaret Hospital Experience. Int J Radiat Oncol Biol Phys 1984; 10: 489-97. 34. Leonard RCF, Hayward RL, Prescott RJ, et al. The identification of discrete prognostic groups in low grade non-Hodgkin's lymphoma. Ann Onco/1991; 2: 655-62. 35. Soubeyran P, Eghbali H, Bonichon F, et al. Low-grade follicular lymphomas: analysis of prognosis in a series of 281 patients. EurJ Cancer 1991; 27:1606-13. 36. Johnson PWM, Rohatiner AZS, Whelan JS, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20 year study from a single center.J Clin Oncol 1995; 13:140-7.

Clin Pathol 1991; 44: 844-8. 22. Moore DF, Hagemeister FB, Rodruigez MA, et al. Clinical characteristics and outcome of Hodgkin's disease (HD) in 125 patients (PT) 60 years of age and older. Blood 1994;10:163A.

37. Lopez-Guillermo A, Montserrat E, Bosch F, et al.

23. Staal SP, Ambinder R, Beschorner WE, et al. A survey of

therapeutic response and survival in advanced

Epstein-Barr virus DMA in lymphoid tissue: frequent detection in Hodgkin's disease. AmJ Clin Pathol 1989; 91:1-5.

Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. 7 Clin Oncol 1994; 12:1343-8. 38. Peterson B, Pajak T, Cooper M, et al. Effect of age on Hodgkin's disease. Cancer Treatment Rep 1982; 66: 889-98. 39. Tubiana M, Henry-Amar M, Hayat M, et al. The EORTC

24. Pallesen G, Hamilton-Dutoit SJ, Rowe M, et al. Expression

treatment of early stages of Hodgkin's disease: the role

of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 1991; 337: 320-2. 25. Haybittle J, Hayhoe F, Easterling M, et al. Review of British National Lymphoma Investigations Studies of

of radiotherapy. IntJ Radiat Oncol Biol Phys 1984; 10:

Hodgkin's disease and development of prognostic index. Lancet 1985; 27: 967-72. 26. Oza A, Ganesan T, Dorreen M, et al. Patterns of survival

197-210. 40. Sutcliffe S, Gospodarowicz M, Bergsagel D, et al. Prognostic groups for management of localized Hodgkin's disease. J Clin Oncol 1985; 3: 393-401. 41. Somers R, Carde M, Henry-Amar M, et al. A randomized study in Stage 1MB and IV Hodgkin's disease comparing

in patients with advanced Hodgkin's disease (HD)

eight courses of MOPP versus an alternation of MOPP

treated in a single centre over 20 years. BrJ Cancer

with ABVD: a European Organisation for Research and

1992;65:429-37.

Treatment of Cancer Lymphoma Cooperative Group and

27. Sweetenham J, Williams CJ. Malignant lymphoma in the elderly. In: Hamblin TA, ed. Haematological problems in the elderly. Balliere's Clinics in Haematology, Vol. 1. London: BailliereTindall, 1987; 493-511. 28. Shipp M, Harrington D, Klatt M,et al. Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 1986; 104: 757-65. 29. Dixon D, Neilan B, Jones S, et al. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986; 4: 295-305.

groupe Pierre-et-Marie-Curie controlled clinical trial.7 Clin Oncol 1994; 12: 279-87. 42. Bennett J, Andersen J, Begg C, et al. Age and Hodgkin's disease: the impact of competing risks and possibly salvage therapy on long term survival: an ECOG study. LeukRes 1993; 17: 825-32. 43. Specht L, Horwkh A, Ashley S. Salvage of relapse of patients with Hodgkin's disease in clinical stages I and II who were staged with laparotomy and initially treated with radiotherapy alone. A report from the international database on Hodgkin's disease. Int J Radiat Oncol Biol Physics 1994; 30: 805-11.

References 395 44. Biti G, Cellai E, Magrini SM, et al. 2nd solid tumors and leukemia after treatment for Hodgkins-disease - an analysis of 1121 patients from a single institution. IntJ Radial Oncol Biol Phys 1994; 29: 25-31. 45. Dietrich PY, Henry-Amar M, Cosset JM, et al. 2nd primary cancers in patients continuously disease-free from hodgkins-disease-a protective role for the spleen. Blood 1994; 84:1209-15. 46. Van Leeuwen FE, Klokman WJ, Hagenbeek A, et al. Second cancer risk following Hodgkins-disease - a 20year follow-up-study.J Clin Oncol 1994; 12: 312-25. 47. Castleden C, George C. The effect of ageing on hepatic clearance of propranolol. BrJ Clin Pharmacol 1979; 7: 49-54. 48. Wilkinson G. Drug distribution and renal excretion in the elderly. Chronic DisJ 1983; 36: 91-102. 49. Woodhouse K. Drugs and the ageing gut, liver and pancreas. Clinics Gastmenterol 1985; 14: 863-81. 50. Mooney H, Roberts R, Cooksley W, et al. Alterations in the liver with ageing. Clinics Gastroenterol 1985; 14: 757-71. 51. Robert J, Hoerni B. Age dependence of the early phase pharmacokinetics of doxorubicin. Cancer Res 1983; 43: 4467-69. 52. Blum R, Carter S, Agre K. A clinical review of bleomycin -a newantineoplasticagent. Cancer 1973; 31: 903-14. 53. Juma FD, Rogers HJ & Trounce JR. Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites. EurJ Clin Pharmacol 1981; 19: 443-51. 54. Hansen HH, Selawry OS, Holland JF, et al. The variability of individual tolerance to methotrexate in cancer patients. BrJ Cancer 1971; 25: 298-305. 55. Hoeck-Pott C, Hiddemann W. Purine analogs in the treatment of low-grade lymphomas and chronic lymphocytic leukemias. Ann Oncol 1995; 6: 421-33. 56. Smyth R, Pfeffer M, Scalzo A, et al. Bioavailability and pharmacokinetics of etoposide (VP-16). Semin Oncol 1985; 12: 48-51. 57. Lipschitz D, Udupa K, Milton K, et al. Effect of age on hematopoiesis in man. Blood 1984; 63: 502-9. 58. Lee MA, Segal GM, Bagby GC. The hematopoietic microenvironment in the elderly: defects in IL-1induced CSF expression in vitro. Exp Hematol 1989; 17: 952-6. 59. Shank WJ, Balducci L. Recombinant hemopoietic growth factors: comparative response in younger and older subjects.J Am GeriatricSoc 1992; 40:151-4. 60. Chatta GS, Price TH, Allen RC, et al. Effects of in vivo recombinant methionyl human granulocyte colonystimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers. Blood 1994; 84: 2923-9. 61. Gomez H, Mas L, Casanova L, et al. Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colonystimulating factor: identification of two age subgroups

62. 63. 64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

with differing hematologic toxicity. J Clin Oncol 1998; 16: 2352-8. Lipschitz DA. Age-related declines in hemopoietic reserve capacity. Semin Oncol 1995; 22(suppl 1): 3-5. Montgomery P, Beck T, Smith C, et al. Chemotherapy in the elderly. ProcAm Soc Clin Oncol 1982; 1: 56. Levis A, Depaoli L, Urgesi A, et al. Probability of cure in elderly Hodgkin's disease patients. Haematologica 1994; 79: 46-54. Armitage J, Potter J. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am GeriaticSoc 1984; 32: 269-73. Roberts-Thompson 1C, Whittingham S, Youngchaiyua U, et al. Aging, immune response and mortality. Lancet 1974; 877: 368-70. Bender AD. The effects of increasing age on the distribution of peripheral blood flow in man. J Am Geriatric Soc 1965; 13:192-8. Vose J, Ruby E, Bierman P, et al. Elderly patients with localized diffuse large-cell non-hodgkins-lymphoma (nhl) - improved results with initial chemotherapy. Blood 1994;84: A 383. O'Connell M, EarleJ, Harrington D, et al. Initial chemotherapy doses for elderly patients with malignant lymphoma. J Clin Oncol 1986; 4:1418-22. Oguchi M, Izuno I, Takei K, et al. Treatment for nonHodgkin's lymphoma (stage I, II) of the elderly: usefulness of local and regional irradiation and reduced dose chemotherapy. IntJ Radiat Oncol Biol Phys 1997; 37: 87-92. Miller TP, DahlbergS, CassadyJR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade nonHodgkin's lymphoma. N EnglJ Med 1998; 339: 21-6. Sonneveld P, de Ridder M, van der Lelie H, et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkins lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995; 13: 2530-9. Tirelli U, Errante M, Van Glabbeke M, et al. CHOP is the standard regimen in patients > 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16: 27-34. Cunningham D, Mainwaring PN, Gregory W, et al. A BNLI randomised study of PAdriaCEBO vs PMitCEBO in patients with high-grade lymphoma over 60 years of age. ProcAm Soc Clin Oncol 1998; 17:12a. Bastion Y, Blay J-Y, Divine M, et al. Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival -A Groupe d'Etude des Lymphomes de I'Adulte study on 453 patients older than 69 years. J Clin Oncol 1997; 15: 2945-53.

396 Lymphoma in the elderly 76. Fisher Rl, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphomas. N EnglJ Med 1993; 328:1002-6. 77. O'Reilly S, Klimo P, Connors J. Low-dose ACOP-B and VABE: weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma. 7 Clin Oncol 1991;9:741-7. 78. Bertini M, Freilone R, Vitolo U, et al. P-VEBEC: a new 8weekly schedule with or without rG-CSF for elderly patients with aggressive non-Hodgkin's lymphoma (NHL). Ann Oncol 1994; 5: 895-900. 79. Caracciolo F, Capochiani E, Papineschi F, et al. Consolidation therapy with idarubicin, cisplatin and prednisolone after P-VABEC regimen in the treatment of intermediate and high grade non-Hodgkin's lymphoma of the elderly. Leak Lymphoma 1997; 24: 355-61. 80. Zagonel V, Babare R, Merola M, et al. Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin's lymphoma treated with combination chemotherapy. Ann Oncol 1994; 5: S127-S132. 81. Zinzani PL, Pavone E, Storti S, et al. Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-hodgkins-lymphoma. Blood 1997; 89: 3974-9. 82. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (antiCD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92:1927-32. 83. Solal-Celigny P, Lepage E, Brousse N, et al. Recombinant Interferon Alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N EnglJ Med 1993; 329:1608-14. 84. Carde P, Burgers J, Henry-Amar M, et al. Clinical Stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors.) Clin Oncol 1988; 6: 239-52. 85. Cosset J, Thomas J, Noordijk E. The current EORTC strategy for stage l-ll Hodgkin's disease. In: Somers R, Henry-Amar M, Meerwaldt JK, Carde P, eds Treatment strategy in Hodgkin's disease. Paris: Colloques INSERM, 1990; 196: 63-5. 86. Horning S, Hoppe R, Hancock SL, et al. Vinblastine, bleomycin and methotrexate: an effective adjuvant in favourable Hodgkin's disease.J Clin Oncol 1988; 6: 1822-31. 87. Longo D, Glatstein E, Duffey P, et al. Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial.J Clin Oncol 1991; 9: 906-17. 88. Diazpavon JR, Cabanillas F, Majlis A, et al. Outcome of Hodgkin's disease in elderly patients. Hematol Oncol 1995; 13:19-27.

89. Erdkamp F, Breed W, Bosch L, et al. Hodgkin's disease in the elderly - a registry-based analysis. Cancer 1992; 70: 830-4. 90. Slymen D, MillerT, Lippman S, et al. Immunobiologic factors predictive of clinical outcome in diffuse largecell lymphoma. J Clin Oncol 1990; 8: 986-93. 91. Coiffier B, Gisselbrecht C, Vose J, et al. Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy.J Clin Oncol 1991; 9: 211-9. 92. Hoskins P, Ng V, Spinelli J, et al. Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 1991; 9: 220-6. 93. Velasquez W, Jagannath S, Tucker S, et al. Risk classification as the basis for clinical staging of diffuse large-cell lymphoma derived from 10-year survival data. Blood 1989; 74: 551-7. 94. Dhaliwal HS, Rohatiner AZS, Gregory W, et al. Combination chemotherapy for intermediate and high Grade non-Hodgkin's Lymphoma. Brj Cancer 1993; 68: 767-74. 95. Coiffier B. What treatment for elderly patients with aggressive lymphoma. Ann Oncol 1994; 873-5. 96. Sonneveld P, Michiels J. Full-dose chemotherapy in elderly patients with non-Hodgkin's lymphoma. A feasibility study using a mitoxantrone-containing regimen. Brj Cancer 1990; 65:105-8. 97. Zinzani P, Bendandi M, Gherlinzoni F, et al. VNCOP-B regimen in the treatment of high-grade non-Hodgkin's lymphoma in the elderly. Haematologica 1993; 78: 378-82. 98. Ansell SM, Falkson G. A phase-ll trial of a chemotherapy combination in elderly patients with aggressive lymphoma. Ann Oncol 1993; 4:172. 99. Tirelli U, Carbone A, Zagonel V, et al. Non-Hodgkin's lymphoma in the elderly: prospective studies with specifically devised chemotherapy regimens in 66 patients. EurJ Cancer Clin Oncol 1987; 23: 535-40. 100. Tigaud J, Demolombe S, Bastion Y, et al. Ifosfamide continuous infusion plus etoposide in the treatment of elderly patients with aggressive lymphoma. A phase II study. Hematol Oncol 1991; 9: 225-33. 101. Tirelli U, Zagonel V, Errante D, et al. A prospective study of a new combination chemotherapy regimen in patients older than 70 years with unfavourable non-Hodgkin's lymphomaj Clin Oncol 1992; 10: 228-36. 102. Salvagno L, Contu A, Bianco A, et al. A combination of mitoxantrone, etoposide and prednisone in elderly patients with non-Hodgkin's lymphoma. Ann Oncol 1992; 3: 833-7. 103. O'Reilly s, Connors J, Howdle S, et al. In search of an optimal regimen for elderly patients with advancedstage diffuse large-cell lymphoma: results of Phase II study of P/DOCE chemotherapy.; Clin Oncol 1993; 11: 2250-7.

References 397 104. McMaster M, Johnson D, Greer}, et al. A brief-duration combination chemotherapy for elderly patients with poor-prognosis non-Hodgkin's lymphoma. Cancer 1991; 67:1487-92. 105. Goss P, Burkes R, Rudinskas L, et al. Prednisone, oral etoposide, and novantrone for treatment for nonHodgkin's lymphoma: a preliminary report. Semin Hematol 1994; 31: s23-s29.

106. Martelli M, Guglielmi C, Coluzzi S, et al. P-VABEC: a prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin's lymphoma. J Clin Oncol 1993; 11: 2362-9. 107. Bellesi G, Rigacci L, Alterini R, et al. A new protocol (MiCEP) for the treatment of intermediate or high-grade non-Hodgkin's lymphoma in the elderly. Leuk Lymphoma 1996; 20: 475-80.


29 Infections BCROSSEANDPJSELBY

Introduction Factors underlying infections Common pathogens

399 399 401

INTRODUCTION Infections are a major problem in lymphoma patients and their treatment is a major part of lymphoma management. These patients are prone to infection because of the underlying disease and its treatment with chemotherapy, radiotherapy and biological therapy. The range and seriousness of infections experienced by lymphoma patients has been significantly increased by recent trends towards more intensive chemotherapy for high-risk and relapsed patients, which results in elective severe myelosuppression. The ability to manage such infections promptly and effectively is a hallmark of highquality care for lymphoma patients. We discuss the management of these infections here; the management of chronic viral or intracellular infections, which predispose to lymphoma, is discussed elsewhere (see Chapter ID-

FACTORS UNDERLYING INFECTIONS The barriers to infection in any patient include those physical barriers in the skin, respiratory and gastrointestinal tract that normally exclude infectious organisms, together with the cellular and humoral immune responses involving lymphocytes, neutrophils, macrophages, immunoglobulins and complement. A defect in any of these can predispose to infection in lymphoma patients. Table 29.1 shows the factors that predispose to infection in lymphoma patients.1 The disease-related immune deficiencies in lymphoma patients are still only partially understood.

Antimicrobial therapy References

404 412

Classical teaching has been that patients with Hodgkin's disease have a longstanding, disease-related cellular immune deficiency, which may persist after effective treatment. Non-Hodgkin's lymphoma patients have defects in humoral immunity, which usually recover after effective treatment. In each case, the immune deficiency is said to be more severe in patients whose disease is more advanced and extensive. In reality, the situation is more complex. The degree of immune deficiencies varies between different types of lymphomas and the situation is always complicated by the effects of surgery, such as splenectomy, radiotherapy, chemotherapy and, more recently, biological therapy. Although neutrophils usually work normally in lymphoma patients,2 modern treatments commonly reduce neutrophil numbers. This myelosuppressive decrease in the ability to counteract infection is the dominant failure in patients undergoing very intensive chemotherapy regimens even with hemopoietic support with peripheral stem cell or bone marrow transplants. Work on the impaired cellular immune responses in Hodgkin's disease has been carried out in the last four decades.3-7 Patients with active disease have evidence of impaired T cell function, and this may persist in some patients for over 10 years following radiotherapy8 or chemotherapy.9 Splenectomy will also add an element of humoral immune deficiency, particularly to encapsulated organisms such as pneumococcus, Haemophilus influenzae type b and Neisseria meningitidis.10,11 This leads to a firm recommendation for pneumococcal, Haemophilus influenzae type b and meningococcal vaccination, and prophylactic penicillin in these patients.12 The mechanisms underlying initial and persistent T lymphocyte dysfunction in Hodgkin's disease patients appear to be complex with an extensive literature

400 Infections

Table 29.1 Factors which predispose to infection in lymphoma patients Malignancy Immune system dysfunction Granulocytopenia Decreased immunoglobulin Defective cellular function Abnormal cytokine activity Organ system dysfunction Obstruction Neurologic dysfunction Invasion Skin ulceration Hypercortisolism Renal failure Malnutrition Co-existing disease HIV infection, congenital immunodeficiency Underlying chronic illness (diabetes mellitus, chronic bronchitis) Specific treatment Radiation therapy Mucositis, fibrosis Granulocytopenia Lymphopenia Chemotherapy Granulocytopenia Mucositis Cell-mediated immune defects Skin ulceration, phlebitis Corticosteroids Cell-mediated immune defects Surgery Postoperative infections Splenectomy Supportive care Invasive devices Parenteral nutrition Transfusion Medication for symptom control

describing partly characterized serum factors and affected cellular populations.13,15 Cytokine production in response to lymphocyte stimulation and failure of response to cytokines may also play a part.15-17 Even in the absence of therapy many patients with nonHodgkin's lymphoma have B lymphocyte-related immune defects. Classical examples are myeloma and chronic lymphocytic leukemia but similar defects are found in diffuse large cell B lymphomas, although they are less persistent after effective therapy.5,6 Patients with reduced B cell function and low immunoglobulin concentrations are particularly predisposed to infection in which antibody, by opsonization, is important. Pneumococcus, Haemophilus and Neisseria are therefore significant infections in chronic lymphocytic leukemia (CLL) and myeloma patients1,18,19 and infections are most commonly

in the lung and less often elsewhere.20 A total of 30-40 per cent of CLL patients have hypogammaglobulinemia with a consequent increase in infection risk.21,22 The expansion of differentiated malignant B cells displaces and probably suppresses normal differentiated B cell function, including the production of immunoglobulin.1,23 These abnormalities are features of well-differentiated lymphocytic lymphomas and occasionally of follicular lymphomas and diffuse large B cell lymphomas. The deficiencies in cell-mediated immunity found in lymphomas, particularly Hodgkin's disease, classically predispose to intracellular pathogens, such as herpes viruses including simplex, zoster and cytomegalovirus, intracellular bacteria such as Listeria and Mycobacteria, and the higher fungi and protozoans.19,24,25 Mechanisms of cell-mediated immune deficiency in lymphoma patients may be in part explained by failure of cytokine release or cytokine response, and the presence of immune suppressive cytokines, such as transforming growth factor b.26 The granulocytopenic lymphoma patient during conventional or intensive chemotherapy is especially vulnerable to infection. Every patient who has a neutrophil count of less than 0.1 x 109/1 for more than 3 weeks will develop an infection27 and the risk depends on the duration of neutropenia particularly. Although granulocytopenia may be defined as a neutrophil count of less than 1 x 10V1, the risk of infection and subsequent fatality does not increase substantially until the neutrophil count is below 0.5 x lo9/1.1,25,27,28 The probability of febrile neutropenia relates very closely to the duration of neutropenia < 0.5 x 109/1. This is illustrated in Fig. 29.1 (from Blackwell and Crawford.29) Fever in severely neutropenic patients are often of unknown origin and no microbiological diagnosis is possible. However, in most large trials, about 60 per cent of these fevers respond to antibacterial treatment suggesting an underlying bacterial cause.30,31 If a lymphoma patient is febrile but not granulocytopenic, it is possible to document an infectious cause for the fever in about 20 per cent of patients; in granulocytopenic lymphoma patients, the figure rises to 50 per cent and above.31,32 In the granulocytopenic

Figure 29.1

The probability of febrile neutropenia related to

the duration of neutropenia. Reprinted from reference 29.

Common pathogens 401

lymphoma patients, over 60 per cent of infections arise from endogenous flora.32,33 Altered endogenous colonizing bacteria are noted during hospitalization and treatment for lymphoma and other cancers.34 These new colonizing organisms are major sources of infection, and are responsible for some of the more severe and antibiotic-resistant bacterial infections in immunecompromised patients. For instance, patients who carry Pseudomonas have a 76 per cent infection rate with that organism when immunocompromised, compared to 13 per cent of non-carriers. Colonization with Klebsiella, Proteus and Pseudomonas is a feature of granulocytopenia.34'35 The significance of colonization and hospital acquired bacteraemia was well illustrated in a study in the 1980s, which showed a 40 per cent mortality from hospital nosocomial infections compared to 30 per cent in those acquired in the community, often from urinary tract infections.36 Physical factors play an important part in the acquisition of infections. Any instrumentation of the pulmonary or gastrointestinal tracts may cause infections.37 However, in oncology, current practice is dominated by infections acquired as a result of indwelling venous catheters and this risk increases with their duration in place.38 Press et al. estimated 1.4 infections per 1000 days of catheter insertion for Hickman lines,39 while others comment that the risk of infection may be higher than this.40 Although recent practice has concentrated on endogenous infections, and altered colonization or indwelling lines, environmental factors are still important and may permit exogenous infection. The association of Legionella, Pseudomonas and Aeromonas with wet places in hospitals, such as air-conditioning systems, sinks and plant pots is well known. Aspergillus is a significant part of the outside air and is increased by building works particularly. Pulmonary involvement resulting from airborne transmission is the rule for Aspergillus-rtlaied infections in hospitals,41 although some of these maybe reactivation of latent infections after intensive therapy.42,43 In lymphoma patients, the principal surgical predisposition to infection arises from splenectomy. This leads to failure to clear encapsulated pathogens early in the infection.44 The British National Lymphoma Investigation studied infection in splenectomized Hodgkin's disease patients, and found that, 5 years after a staging splenectomy, serious infections occurred in 3 per cent and most of these were fatal;45 others have estimated the risk of life-threatening sepsis to be about 5 per cent following splenectomy.11,46 Extended-field radiotherapy may produce long-lived lymphopenia and reduce T lymphocyte function.47 Chemotherapy predisposes to infection in most cases by inducing neutropenia and mucositis. Mucositis after chemotherapy usually occurs towards the end of the first week, lasts for a little over 1 week and heals without scarring. Myelosuppression varies in its timing between

different drugs. Drugs that are cell-cycle specific affect rapidly proliferating hemopoietic precursors and therefore have an early onset (within a week) and a short duration of neutropenia (a week or less). Drugs that are less cell-cycle specific produce neutropenia with a nadir at 10-14 days and neutropenia lasting 1-2 weeks. These include many commonly used cytotoxics, such as doxorubicin and cyclophosphamide. Late onset and prolonged myelosuppression lasting several weeks can occur with stem cell toxic chemotherapy, such as nitrosoureas and melphalan and carboplatin. Chemotherapy-induced immune suppression without myelosuppression can have important clinical effects. Corticosteroids have wide-ranging immunosuppressive effects.1 Feld et ol. noted that procarbazine increased the rate of herpes zoster infections in lung cancer patients;48 Hughes et ol. found that Pneumocystis carinii was greatly increased in leukemia patients treated with cytosine arabinoside.49 Of current importance in the management of lymphoma patients is the lymphocytotoxic effect of halogenated purine analogs, particularly fludarabine and 2-chlorodeoxyadenosine, recently introduced as effective treatments for low-grade lymphomas. These drugs have significant utility.50,52 Infections of the kind usually associated with defects in cell-mediated immunity have been a feature of halogenated purine analog trials.52,55 In Redman's study among 72 patients treated with lowgrade lymphoma,52 eight developed herpes zoster, two Pneumocystis carinii pneumonia and one disseminated cytomegalovirus infection.

COMMON PATHOGENS Pathogens associated with immune deficiency are summarized in Table 29.2 (from McGeer and Feld, 1994).

Bacteria Common respiratory tract bacteria including Streptococcus pneumoniae and Haemophilus influenzae are frequent sources of infection. Gram-negative bacteria remain a frequent cause of infection, with Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae prominent. Infections with Staphylococcus aureus, Staphylococcus epidermidis, Corynebacterium and, less commonly, Clostridium, also occur. Recently severe infections with Viridans streptococci, such as Streptococcus mitis and sanguis have occurred.56 Infection with multiply resistant strains of enterococci are a problem in some institutions.57 Multiple bacteria may be found in some severely immune-compromised patients.34,58 For bacterial infections in immune compromised patients the principal trend in the last two decades has been an increase in Gram-positive bacteremia and a relative decrease in infections with Gram-negative rods.

402 Infections Table 29.2 Pathogens associated with immune deficiency. Reprinted from reference 1 Granulocytopenia Bacteria Staphylococci Viridans group streptococci Corynebacterium jekeium Enterococci Escherichia coli Klebsiella-Enterobacter-Serratiaspeaes Pseudomonas aeruginosa Fungi Candida species Aspergillus species Zygomycetes Hypogammaglobulinemia Bacteria Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Staphylococcus aureus Pseudomonas aeruginosa Cell-mediated immune dysfunction Viruses Varicella-zoster Herpes simplex Cytomegalovirus Adenovirus Bacteria Salmonella species Listeria monocytogenes Legionella species Nocardia species Mycobacteria Fungi Candida species Aspergillus species Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Parasites Pneumocystis carinii Toxoplasma gondii Cryptosporidium species Strongyloides stercoralis

Serial studies by the Antimicrobial Group of the European Organisation for Research and Treatment of Cancer (EORTC) have been evaluated by Klastersky et aly and they showed an increase in Gram-positive bacteremia from 31 to 41 per cent of patients in their studies.34,59 This presumably results from the use of effective antibiotics against Gram-negative organisms and the frequent use of indwelling lines. Staphylococcus aureus is less often a cause of serious infection, whereas Staphylococcus epidermidis is more frequent, reflecting the use of central lines. Current problems include antibiotic-resistant coagulase-negative Staphylococci, such as Staphylococcus epidermidis and an apparent recent increase in Staphylococcus aureus infections.60 The importance of Legionella infection has been recognized and its frequency probably reflects infection sources in heat-exchange units and warm water reservoirs.

Viruses Herpes viruses (particularly herpes simplex, varicellazoster and cytomegalovirus virus) represent an important source of infection and occasional fatality in immunecompromised patients and are particularly important to diagnose because of the potential for effective therapy since the introduction of acyclovir and related antiviral drugs.61 Reactivation of endogenous virus plays an important part in these infections. In addition to herpes viruses, a very wide range of other viral infections occur in severely immune-suppressed patients, particularly after bone marrow and peripheral blood stem cell transplantation, including adenovirus, influenza virus, parainfluenza virus and respiratory syncytial virus.34,62,64

Fungi In severely immune-compromised patients, particularly those with prolonged granulocytopenia, fungal infections can be a major source of morbidity and mortality. This is particularly a problem in heavily treated acute leukemia patients, but may also occur in solid tumor and lymphoma patients.41 Pre-mortem diagnosis is difficult. Risk factors include corticosteroids and indwelling central venous catheters as well as neutropenia. The common pathogens are Candida and Aspergillus species.41,65,66 Neutropenic patients are vulnerable to rare infections with Mucoraceae, Fusarium, Pseudallescheria, Malassezia and Trichosporon infections.34 In addition to the general predisposition to fungal infections seen in most immune-suppressed patients, lymphoma patients appear to have a particular predisposition to invasive infections with Cryptococcus neoformans, Histoplasma capsulatum, Coccidiomycosis and Blastomycosis.19,34,67-69 Broad-spectrum antibiotic usage predisposes to invasive fungal infection probably by reducing gut anaerobic organism content. Fungal infections in neutropenic patients typically occur later than bacterial infections, with a median onset of about 10 days from the onset of granulocytopenia.43 Protozoa Although recently the frequency of Pneumocystis carinii infection in heavily treated lymphoma patients has decreased, this needs to be monitored carefully as prophylactic therapy for neutropenic episodes with cotrimoxazole is replaced in some units with quinolone prophylaxis.

Reactivation of latent infections Some infections, often after an initial acute phase, result in a persistent latent infection. Changes in immune

Common pathogens 403

competence, which result from lymphoma or immunosuppressive therapy, or intensive therapy with peripheral blood or stem cell transplantation, can alter the control of this latent infection and result in an acute reactivation illness. The classical examples are herpes virus infections. Herpes simplex virus (HSV) is a common latent infection and, after intensive chemotherapy or bone marrow transplantation, 50-80 per cent of patients who are seropositive to HSV will develop an acute reactivation.1'70'72 Almost any cancer patient having cyclical conventional doses of chemotherapy may develop an acute reactivation, which is most commonly orolabial but can occasionally be esophageal or systemic. This can happen to head and neck cancer patients having radiation therapy. Cytomegalovirus may be reactivated causing a severe pneumonitis after intensive therapy and bone marrow transplantation.73,74 This may be commoner in cancer patients who have not undergone intensive therapy than has previously been recognized.75 Varicella-zoster virus reactivation is a feature of lymphoma patients, particularly those with Hodgkin's disease, and those who have undergone intensive therapy with peripheral blood or bone marrow transplantation.72,76,78 Less frequently Epstein-Barr virus reactivation may occur and result in a lymphoproliferative syndrome,79 and this may be associated with subsequent large B lymphomas, as discussed elsewhere in this book (see Chapter 5). Human herpes virus-6 reactivation has been described in association with interstitial pneumonitis and bone marrow suppression,80,81 although so far this has only been identified in association with intensive therapy and allogeneic bone marrow transplantation, which is used only infrequently in lymphoma patients. Viruses with major hepatic pathogenicity may be influenced significantly by the use of chemotherapy. A life-threatening syndrome of activation of chronic active hepatitis due to hepatitis B by withdrawal of chemotherapy, steroids or interferon has been described,82,83 and this may also occur with hepatitis C infection.84 Lymphomas complicating organ transplantation are now seen regularly in transplant units and so the infective complications of these complex situations require careful attention. Reactivation of JC virus in the central nervous system causes progressive multifocal leukoencephalopathy. This is described in Hodgkin's disease,85 although now is seen more often in acquired immunodeficiency syndrome (AIDS).1 Adenoviral pneumonia can occur due to reactivation of a latent adenovirus infection62,86 but this is a feature of intensive therapy with transplantation usually. Other organisms that may rarely give rise to reactivation infections include Histoplasma capsulatum, Coccidioides immitis and Blastomyces dermatitidis. Reactivation of tuberculosis is more frequent in patients with lymphoma than the general population.19

Atypical mycobacterial infection of the lung occur more frequently in cancer patients than in the general population.1,87,88 Toxoplasmosis may be reactivated in severely immune-deficient patients.89,90 Pneumocystis carinii pneumonia occurring in immune-deficient patients may result from reactivation or new acquisition.1 Patients who are chronic carriers of the helminth Strongyloides stercoralis may develop hyperinfection when they become immune-suppressed.91 Other rare examples of reactive infections are with Histoplasma capsulatum, Coccidioides immitis and Blastomyces dermatitidis.1

Mycobacterial infections in lymphoma patients Tuberculosis was recognized as having an increased frequency in Hodgkin's disease in the last century, often leading to diagnostic difficulty.92,93 The advent of AIDS has, however, recently increased the incidence and clinical problem of mycobacterial infection in the immunecompromised patient. Atypical mycobacterial infection with Mycobacterium avium (M. avium) is now the single most important cause of systemic bacterial infection in patients with AIDS.92,94 Multiple drug-resistant mycobacteria are characterized in AIDS patients and represent a threat to other immune-suppressed patients. Mycobacterium avium in AIDS patients typically causes a disseminated disease with bacteremia, diarrhea, lymphadenopathy and hepatosplenomegaly. It is not particularly a cause of pulmonary disease. The first patient with M. avium infection complicating acute myelocytic leukemia has been described95 and also complicating chronic myelogenous leukemia.96 A heart transplant patient with Mycobacterium scrofulaceum has been described, and mycobacterial infections are reported in about 1 per cent of renal and liver transplant recipients.97,100 Steroid therapy for sarcoidosis has been associated with an atypical mycobacterial infection.101 It would be expected that atypical mycobacterial infections would be seen in patients with lymphoma. One rare case of central nervous system (CNS) involvement by M. avium has been described in a patient with Hodgkin's disease.102 Treatment of atypical mycobacterium in immunesuppressed patients is a specialist area for physicians with experience in the management of AIDS. New macrolides or azalides, such as clarithromycin and azithromycin, have significant clinical efficacy in atypical mycobacterial infections including M. avium. Roxithromycin has significant activity in experimental systems. Physicians managing lymphoma patients, particularly those receiving intensive therapies, clearly will have to remain alert to the possibility of tuberculosis and atypical mycobacterial infection in a wide range of clinical situations in future.

404 Infections

ANTIMICROBIAL THERAPY The range of microbes that cause infection in immunecompromised cancer patients is very wide. A full review of the treatment of all of them is beyond the scope of this book. However, there are areas of therapeutics that have been developed especially for the management of immune-compromised patients with cancer, particularly lymphoma. These are listed below and reviewed in the following text. 1 empirical use of antibiotics in febrile neutropenic lymphoma patients; 2 prevention of bacterial infections in neutropenic patients; 3 prevention and treatment of herpes virus infections; 4 prevention and treatment of fungal infections; 5 prevention and treatment of Pneumocystis carinii infections; 6 use of hemopoietic growth factors for the prevention and treatment of infections in neutropenic lymphoma patients.

Empirical use of antibiotics in febrile neutropenic lymphoma patients

The principles that underlie the use of antibiotics for the treatment of patients with neutropenia are similar whether that patient has neutropenia from cyclical combination chemotherapy from intensive treatment with peripheral blood stem cell support, or from marrow failure due to lymphoma infiltration or myelodysplasia. The clinical approach to the neutropenic lymphoma patient has evolved over the last three decades to a policy of early elective empirical therapy, where a bacterial infection is suspected. Most commonly, the initial clinical sign pointing towards infection risk will be fever, but it is critically important to recognize that even overwhelming sepsis in severely neutropenic patients may be associated with no fever and no physical signs of a localized infection. The non-specifically 'ill' neutropenic patient should therefore be regarded as having a high risk of infection. The approach to febrile or afebrile

patients who are suspected on clinical grounds of harbouring infection includes a careful history and physical examination, microbiological studies, including blood cultures and cultures of urine and sputum, and an X-ray of the chest. Stool cultures will be appropriate in some patients and serological screening for evidence of viral infection, for example, in others. Cross-sectional imaging studies with computerized tomography or magnetic resonance imaging are rarely indicated. They will have a place in assessing a small number of patients with localizing symptoms and signs of uncertain origin, such as drowsiness, focal CNS signs, persisting jaundice, or derangement of liver function tests and features suggestive of septic collections in the pelvis or under the diaphragm. The recognition that the early (empirical) use of broad-spectrum antibiotics was appropriate emerged during the 1960s and 1970s.103-107 In the absence of early empirical therapy, the mortality of bacterial sepsis is so high and so rapid in severely neutropenic patients that a policy of early introduction of antibiotics has become the cornerstone of management. Although this policy is established, there remains an active field of enquiry into the best antibiotic regimen to be employed. The changing pattern of microbial culture in these patients has been reviewed earlier. The increasing recognition of a higher proportion of Gram-positive cocci as a cause of sepsis in this group and a lower proportion of patients with Gram-negative rods has altered the recommendations for empirical antibiotic therapy. The introduction of new antibiotics has led to reexamination of existing policies. It is recognized that, under different circumstances, different regimens may be appropriate, and the appropriate policy for any hospital or unit must be worked out after careful discussions between specialists in oncology, internal medicine, infectious diseases, microbiology and specialist members of the professions allied to medicine who work in these multidisciplinary teams. The antibiotic policy used in our own hospital is summarized in Table 29.3. It should be emphasized that this is an example of the sort of policy that can be used rather than a prescription for other units. Some options for empirical antibiotic therapy are discussed below.

Table 29.3 An antibiotic policy Initial management Careful history and examination in an attempt to determine any primary site of infection. Note that rectal and vaginal examinations should not be performed in neutropenic patients. The perineum should, however, be inspected if indicated. Criteria for infection: • Single temperature > 38.5°C • Oral temperature > 38.5°C for 2 hours or more • Unexplained clinical deterioration (even without fever) Neutropenia • Total white cell count less than 1 x 10YI

Antimicrobial therapy 405

Initial investigations Blood cultures (including quantitative blood cultures from lines and from the peripheral blood). Repeat daily if remain febrile. • • • •

Urine Swab infected sites Chest X-ray Others as guided by clinical picture

Antibiotics Note special precautions for patients receiving cisplatin or high-dose carboplatin Therapy - low risk of line infection First line3 Gentamicin iv + Piperacillin iv 4 g qid • Response in fever, continue until neutropenic recovers • No response after 48-72 hours, change to second line Second line

Imipenem iv 500 mg qid • Response in fever, continue until neutropenic recovers • No response after 48-72 hours, change to third line

Third line

Add Amphotericin B iv 0.5 mg/kg initially increasing to 1 mg/kg/day following a 1 mg test dose. In serious infections, therapeutic doses should be reached within 24 hours

3

Penicillin allergy • Replace Piperacillin with Ceftazidime • 5-10% chance of cross-reactivity

a

Poor Renal Function • Use Ceftazidime in place of Gentamicin + Piperacillin

3

Cisplatin chemotherapy or high-dose carboplatin • Ceftazidime should be used in place of Gentamicin and Piperacillin as first-line antibiotics in this group of patients since renal handling of Gentamicin may be substantially impaired • Gentamicin may be used in this group of patients on failure of Ceftazidime but special attention to Gentamicin levels will be required with monitoring after the second, or at latest third dose of therapy

Therapy - high risk of line infection High risk of line infection • Inflamed exit site/tunnel • Pyrexia/rigors post-flushing • Previous history of line infection • Other soft-tissue infection First line

Vancomycin iv 1 g bd (dose altering according to levels) + Ceftazidime iv 1 gtid • Response in fever, continue until neutropenic recovers • No response after 48-72 hours, change to second line

Second line

Imipenem iv 500 mg qid • Response in fever, continue until neutropenic recovers • No response after 48-72 hours, change to third line

Third line

Add Amphotericin B iv

Duration of treatment Negative cultures - at least 5 days treatment (at least 72 hours apyrexial) irrespective of WCC Positive cultures - at least 7 days treatment (at least 72 hours apyrexial) irrespective of WCC Systemic fungal infections may require at least 6 weeks treatment Indications for change to second- or third-line antibiotics • Failure of fever to remit within 48 hours • After 72 hours or after initial control of fever, rise in temperature of > 1°C on two consecutive readings • Clinical deterioration, e.g. hypotension, drug intolerance Third-line antibiotics If the temperature remains elevated, or there is clinical deterioration on second-line antibiotics, a third-line regimen is needed. The choice of third-line regimen depends greatly on the patient's condition and the findings on clinical examination. Patients should be discussed with the unit microbiologist. In anerobes are suspected (e.g. perianal infection), Metronidazole iv 500 mg tid may be added (unless receiving Imipenem, which already covers anerobes). iv = intravenously, WCC = white cell count.

406 Infections SINGLE-AGENT ANTIBIOTIC THERAPY

OTHER REGIMENS

Early attempts at single-agent antibiotic therapy involved aminoglycosides or broad-spectrum penicillins, such as carbenicillin.106'108'109 These drugs proved relatively ineffective and toxic, and were abandoned in favor of combination antibiotic treatments. However, recently, potent, broad-spectrum, single agents, such as ceftazidime or imipenem, have become available. They appear to be adequate in many circumstances and have a place in current practice.106,110,111). The broad-spectrum of imipenem and of ceftazidime argues in favor of their use as single-agent treatments but resistant organisms can still emerge. The known pattern of resistance among organisms in a single institution must be considered and the options for modifying therapy have to be carefully set.

Cephalosporins/glycopeptide combinations

COMBINATION ANTIMICROBIAL THERAPY

The rationale for a combination of drugs for treating neutropenic fever and bacterial infection in neutropenic patients is: 1 2 3 4 5

to provide a broad-spectrum of cover; to provide a balance of pharmacokinetic characteristics; to provide penetration of tissues; to reduce the emergence of antimicrobial resistance; to provide potential drug synergy.

The introduction of the combination of gentamicin and carbenicillin by Klastersky and colleagues in the 1970s was a milestone in thisfield.112,113The combination was superior to the then available antipseudomonal blactam antibiotics or single aminoglycosides. The Plactam antibiotics have evolved over recent years with more potent and broader spectrum second- and thirdgeneration drugs. Piperacillin is considerably more potent than carbenicillin and has replaced it in routine clinical practice. Ceftazidime has significantly enhanced activity against Gram-negative bacteria and is widely used as a first choice cephalosporin in this situation. Tobramycin and amikacin have marginal differences from gentamicin but there is little evidence that any of the newer aminoglycosides will supplant gentamicin at present in all patients.114 Single daily dosage of an aminoglycoside has been used quite widely115 but has not yet supplanted multiple daily dosing, and the evidence for greater efficacy of single daily dosing is still incomplete.116 Replacement of the aminoglycosides by a second P-lactam antibiotic has been evaluated in a number of studies. These were initially disappointing.30 More potent penicillins and cephalosporins have been used in combination but again have not found wide acceptance.106 The addition of a third drug to the p-lactam/aminoglycoside policy is not established, although clinical judgement is necessary to allow for the use of an appropriate third drug where there is a high index of suspicion of a resistant infection.

Ceftazidime plus vancomycin has been widely used because of the increasing incidence of Gram-positive infections and its lack of nephrotoxicity An alternative approach is to add vancomycin when a Gram-positive organism has been confirmed by microbiological cultures.107,117,118 Teicoplanin is probably as effective as vancomycin and is well tolerated.119 Quinolone antibiotics

Quinolone antibiotics, such as ciprofloxacin and ofloxacin, have a broad spectrum of activity and the advantage of being orally active for continuation therapy. An initial trial was disappointing for ciprofloxacin120 and it is not widely used as a single agent currently. However, high-dose therapy with quinolones and the use of quinolones in combination remains under evaluation. The recently reported result of the EORTC Antimicrobial Therapy Group121 compared piperacillintazobactam plus amikacin with ceftazidime plus amikacin. There were marginal advantages to the piperacillin-tazobactam arm with shorter time to loss of fever and a higher success rate. The difference, however, did not result in any difference in mortality between the two groups. DURATION AND MODIFICATION OF THERAPY

Changes in therapy have to be guided by the patient's clinical status and microbiological findings. Most practitioners continue with an antibiotic regimen until the patient has recovered from neutropenia with > 1 x 109 neutrophils/1. If the patient fails to improve clinically with reduction in fever, the option for additional or alternative antibiotic regimens exists and examples are given in Table 29.3. Persisting fever despite potent antibacterial therapy should suggest the use of an antifungal or an antiviral agent, particularly when neutropenia is likely to be prolonged.122,'123

Prevention of bacterial infections in neutropenic patients Since the risk of bacterial infection in neutropenic lymphoma patients is high and can be predicted quite accurately, a range of preventive strategies have been tried. A cornerstone of any such strategy remains attention to hand hygiene, and asepsis procedures on the part of medical staff and health care workers. The use of physical protective environments with laminar air flow has declined because of the cost of providing these facilities for large numbers of patients. However, early studies did show a reduction in the risk of pathogenic infection in such environments.124 Suppression of alimentary tract organisms by the


administration of oral non-absorbable antibiotics, often together with an antifungal agent, has been widely used. This is only possible in patients who have elective intensive procedures. The combination of physical protection and non-absorbable antibiotics was shown to improve remission and survival in non-Hodgkin's lymphoma patients treated in the 1970s.109 However, such facilities may be less necessary in an era of improved antibiotic therapy. Cotrimoxazole (trimethoprim-sulphamethoxazole) was originally evaluated to prevent Pneumocystis carinii infections in myelosuppressed patients.125 These patients also had a significant reduction in bacterial infection; subsequent studies show that they have fewer days of fever, a delay in the onset of new fever and a decreased number of infective episodes compared with untreated controls (Walsh et al).124 The use of cotrimoxazole has been evaluated in acute leukemia, mixed patients including lymphoma, and lung cancer. The results are somewhat conflicting.124 There is an impression that cotrimoxazole prophylaxis will result in a reduction in the incidence of infection but no evidence of improved survival for patients. Concerns about routine cotrimoxazole prophylaxis include myelosuppression by trimethoprim, which is a potent antifolate, the emergence of resistant organisms and toxicity. Bow and Ronald found lower responses to therapeutic antibacterials in patients who had received cotrimoxazole prophylaxis and the use of cotrimoxazole appeared to predict for subsequent antibacterial failure independently.126 Our present policy is to use prophylactic cotrimoxazole in patients at risk of Pneumocystis carinii pneumonia but not to use it routinely for the prophylaxis of bacterial infection. Quinolone antibiotics have potential as prophylactic agents because of their favorable toxicity profiles, a broad spectrum of antibacterial activity and good oral absorption. Trials have not yielded consistent results but, in the setting of acute leukemia at least, one trial suggested ciprofloxacin to be superior to cotrimoxazole.127 This was not confirmed by Donnelly et al.128 Comparison of norfloxacin and ciprofloxacin shows some superiority for ciprofloxacin but no difference in overall survival between the two groups.129 Quinolone antibiotics overall seem to reduce the number of infections in patients when used as prophylactic agents,124 and may be more effective in this respect than cotrimoxazole or oral nonabsorbable antibiotics. However, reports of resistant organisms are emerging and it is not clear at this stage that a routine policy of prophylaxis using quinolone antibiotics is appropriate. It may be more appropriate to reserve these potent antibiotics for therapy in febrile neutropenic patients and minimize the risk of emergence of resistant organisms. Follow-up of the impact of quinolone prophylaxis has been described in one center.130 They studied the development of quinolone-resistant organisms after the introduction of norfloxacin prophylaxis in 1987. The

first resistant bacteremia was noted 3 years later and eventually 37 per cent of E. coli isolated from septic patients were resistant to quinolones. Whether this argues against quinolone prophylaxis or against the wide use of quinolones in the community, both of which might have explained the increasing resistance, is unclear. However, the significance of quinolone resistance and its frequency is well illustrated by these studies. Rubie et al. studied the role of vancomycin flushing of subcutaneous ports to indwelling venous catheters.131 They reduced infections due to coagulase-negative staphylococci from 24 to 4 per cent.131 There were no infections with vancomycin-resistant organisms. Vassilomanolakis et al. studied vancomycin prophylaxis during the insertion of central venous catheters and reduced infection rates from 55 to 6 per cent,132 although these data are inconclusive because the study was abbreviated and some difficulties of data interpretation therefore remain. Nevertheless, the use of vancomycin prophylaxis should be considered a suitable subject for further study.

Prevention and treatment of herpes virus infections The approach to the management of each of the herpes simplex viruses in immune-compromised lymphoma patients is different. However, the drugs available are relatively few. ACYCLOVIR

Acyclovir is a synthetic nucleoside analog. It is selectively phosphorylated by viral thymidine kinase and the acyclovir triphosphate is a selective inhibitor of viral DNA polymerase. This yields an excellent therapeutic ratio against herpes simplex virus and varicella-zoster virus, but limited efficacy against other herpes viruses. Acyclovir was introduced into clinical practice and shown to have efficacy against herpes simplex and varicella-zoster virus in the UK in the late 1970s, and has been the mainstay of the treatment of virus infections in the immune-compromised patient since that time. GANCICLOVIR

Ganciclovir is also a nucleoside analog with a similar mechanism of action to acyclovir. However, it is activated by cellular thymidine kinases and, therefore, has a lower degree of selective toxicity against virus-infected cells and is moderately myelosuppressive. OTHER ANTIVIRAL AGENTS

Foscarnet has significant activity against cytomegalovirus, but also renal and bone marrow toxicity.133 A newer nucleotide analog, hydroxy-phosphonyl-methoxypropyl

408 Infections

cytosine, has potent activity against cytomegalovirus but is also nephrotoxic.134 Antiviral chemotherapy for herpes virus infections in immune-compromised patients has been reviewed by Reusser et al.lK The indications may be summarized briefly as shown below. Herpes simplex virus

Prevention Acyclovir is an effective and well-tolerated agent for the prevention of herpes simplex virus reactivation in patients who are at high risk. This may be used in patients undergoing intensive elective chemotherapy with hemopoietic support, such as lymphoma patients undergoing peripheral blood stem cell transplant supported intensive chemotherapy.70,72,78,136,139 Prophylactic use of acyclovir is justified in patients who are serum positive for previous HSV infection but probably not those who are seronegative because of the lower incidence of infection. Dosage recommendations are given in Table 29.4. Treatment of HSV infection Acyclovir is a highly effective treatment for immune-compromised patients with mucocutaneous or visceral disease. It is sufficiently bioavailable orally to be effective by this route in patients who are otherwise fit with good gastrointestinal function. Dosage recommendations are given in Table 29.4. Herpes simplex virus pneumonia and encephalitis should be treated at a higher dose and intravenously, but the outcome is not always favorable due to established tissue damage.140 Resistance to acyclovir can occur principally through a deficiency in the viral thymidine kinase enzyme. Although uncommon, this is a significant clinical problem, and current evidence135 favors the use of foscarnet in patients with clinically and microbiologically resistant herpes simplex virus infection. Varicella-zoster virus (VZV)

Prevention Lymphoma patients susceptible to varicella-zoster should be isolated from VZV patients

because of a high attack rate of VZV. Non-immune patients may benefit from zoster immune globulin if initiated within 96 hours of exposure.141 Intravenous and oral acyclovir therapy for VZV is given at higher doses than for simplex virus infections because of the lower sensitivity of VZV in vitro and in vivo. Acyclovir is effective in suppressing VZV reactivation in prophylactic studies following intensive therapy for hematological malignancies.72,142 Once long-term oral prophylaxis with acyclovir has been discontinued, VZV reactivation can occur and so treatment needs to be prolonged. Concerns about acyclovir resistance in this setting have been voiced.135 Treatment The goal of therapy for varicella or herpes zoster in immunocompromised patients is the prevention or treatment of visceral dissemination, which is associated with a substantial mortality.141 Acyclovir is an effective treatment for established VZV infection in immunocompromised patients, will prevent progression and dissemination, and has supplanted treatment with vidarabine.143 Pharmacokinetic considerations (poor oral bioavailability) suggests that acyclovir should be administered intravenously in established VZV infections in immunocompromised individuals and the oral route used only with caution. Penciclovir, a newer nucleotide analog, has in vitro efficacy against HSV and VZV, and a prolonged halflife.144 Famciclovir, the oral form of penciclovir, is more bioavailable following oral administration than acyclovir and shows considerable promise as an oral antiviral agent.135 Cytomegalovirus (CMV) infection

Prevention The risk of serious cytomegalovirs infection is principally identified in patients with acute leukemia and is seen in lymphoma patients after bone marrow transplantation. The incidence of CMV infection after allogeneic bone marrow transplantation is 40-50 per cent.145 This is particularly the case in seropositive,

Table 29.4 Dosage recommendations for prophylaxis and treatment of HSV and VZV infections. Reprinted from reference 735

HSV prophylaxis HSV-seropositive patients HSV therapy Mucocutaneous or esophageal disease Encephalitis, pneumonia VZV therapy Varicella, herpes zoster

5 mg/kg (every 12 hours) intravenously 200 mg 5 times daily orally 5 mg/kg (every 8 hours) intravenously 200-400 mg 5 times daily orally 10 mg/kg (every 8 hours) intravenously 10 mg/kg (every 8 hours) intravenously 800 mg 5 times daily orally in selected patients

HSV = herpes simplex virus, VZV = varicella-zoster virus.


previously infected, bone marrow recipients.146 The incidence of life-threatening CMV pneumonia in bone marrow transplant patients is between 10 and 20 per cent depending on the center.135 CMV exogenous infection can be reduced by the use of seronegative blood products for seronegative bone marrow transplant recipients and the use of leucocyte-depleted blood products.147"148 Unfortunately, despite initial encouraging observations, passive administration of CMV immunoglobulin will not prevent CMV pneumonia. High-dose (500 mg/m2 8-hourly) intravenous acyclovir will reduce CMV infection when followed by high-dose prolonged oral acyclovir for 6 months compared to controls on low-dose treatment. However, the CMV pneumonia rate was not different in the two groups.149 Prophylactic ganciclovir appeared to reduce CMV infection, but again does not prolong survival and gives only incomplete protection against CMV pneumonia. Early treatment with ganciclovir may be a preferable policy.135 Treatment Ganciclovir has a role in the treatment of established CMV pneumonia.150,153 It is usually given at a dose of 5 mg/kg 12 hourly, for 14-21 days. The addition of CMV specific immune globulin has yielded favorable results in uncontrolled trails and the combination of immune globulins plus ganciclovir has become the conventional treatment for CMV pneumonia.135 For other manifestations of CMV infection including gastrointestinal and cerebral infections, ganciclovir should be tried, in some cases in combination with foscarnet.154

Prevention and treatment of fungal infections Fungal infection is a major cause of morbidity in immune-suppressed lymphoma patients, particularly

those who have undergone intensive therapy. A total of 15-30 per cent of patients with leukemia and lymphoma have fungal infection at the time of autopsy.155,156 Fifteen per cent of patients who had undergone bone marrow transplantation for various indications had invasive fungal infection.157 The responsible organisms are listed above (Table 29.2). The drugs available for treating fungal infections are still relatively few and are listed in Table 29.5. AMPHOTERICIN B This is still the most useful single agent for treating active systemic fungal infection because of its broad spectrum, including Aspergillus as well as Candida and rarer fungi. Amphotericin B is the drug of choice for empirical antifungal therapy in neutropenic patients and for the treatment of all other fungal infections, with the exception of oromucosal and oesophageal candidiasis. Its problem lies in its significant toxicity when given intravenously and its lack of oral bioavailability. Following a test does (1 mg) therapeutic doses (1 mg/kg) should be attained within 24 hours for severe infections, although some authors recommend not exceeding 50 mg in the first 24 hours.155 A gradual increase in dosage may be justified in less urgent situations, due to side effects. Lipid vehicles to carry amphotericin significantly reduce or abolish its nephrotoxicity. They should be considered in patients with concomitant renal impairment, or nephrotoxic therapy or those intolerant of conventional amphotericin B.158,159 However, some concerns have been expressed about their efficacy at the same dosages as conventional amphotericin B and higher dosages may be required.160 Early enthusiasm for a bedside emulsion of intralipid 20 per cent and conventional amphotericin B161 has been tempered by the demonstration of instability and the formation of precipitations.162

Table 29.5 Commercially available systemic antifungal agents. Reprinted from reference 155

Amphotericin B-desoxycholate

Empirical therapy in neutropenic cancer patients Invasive candidiasis, aspergillosis, zygomycoses, cryptococcosis, acute disseminated histoplasmosis

Flucytosine (in combination with amphotericin B)

Invasive aspergillosis, acute and chronic (hepatosplenic) disseminated candidiasis with susceptible strains, cryptococcosis

Fluconazole

Prophylaxis of mucosal and invasive candidiasis Mucosal candidiasis Selected cases of invasive candidiasis

Itraconazole

Prophylaxis of fungal infections (investigational) Petriellidiosis, selected cases of invasive aspergillosis

Ketoconazole

Oral thrush, esophageal candidiasis

Rifampicin (only in combination with amphotericin)

Invasive aspergillosis not responding to amphotericin B and contraindications to flucytosine

410 Infections FLUCONAZOLE AND OTHER DRUGS

Fluconazole, the most fully evaluated and least toxic of the azole antifungal antibiotics, is well absorbed orally and can be given parenterally. It is clinically active against Candida species (except naturally resistant krusei and glabrate) and well tolerated. Fluconazole is widely used for mucosal candidiasis and is useful for the treatment of invasive candidiasis.163,164 Itraconazole has a broader spectrum of activity to include some Aspergillus species and it may be used particularly under circumstances where amphotericin is potentially too toxic.165,166 Azole antifungals act by depleting fungal cell membranes of ergosterol, a critical target for amphotericin B. Theoretically azole antifungals and amphotericin B may be antagonistic155,167,168 but this may not be true for all fungal infections.169 FLUCYTOSINE

Flucytosine may be used in addition to amphotericin in the treatment of acute and chronic disseminated candidiasis and invasive aspergillosis.155 ANTIFUNGAL PROPHYLAXIS

There is no routine approach available for prophylaxis of systemic fungal infection. Mucosal infection may be readily avoided by topical non-absorbable agents, such as nystatin, amphotericin B or miconazole. Fluconazole given orally dramatically reduces the development of mucosal thrush155,170,171 and in some studies reduced disseminated invasive fungal infections. However, resistant fungal infections may be seen in patients treated with prophylactic fluconazole.172 None of the available studies showed that prophylactic fluconazole resulted in a reduced mortality in the patients treated.170-172 It is unlikely that prophylactic fluconazole will reduce invasive Aspergillus infections. Prophylactic amphotericin B intravenously has been used in some studies with encouraging claims.173 Although no routine prophylactic regimen can be recommended to avoid systemic fungal infection, if local factors appear to point towards a particularly high risk of invasive candidiasis, then fluconazole should be considered; a similar logic would apply to a center with a very high incidence of invasive aspergillosis and the use of amphotericin B. PLACE OF ANTIFUNGAL THERAPY IN NEUTROPENIC FEVER

In patients with persistent fever after broad-spectrum antibiotic therapy, it is recommended practice to start empirical antifungal therapy with amphotericin B.123 This should only be considered if neutropenia is likely to be prolonged and severe, or if there are concomitant risk factors for fungal infection.174'176 The timing of the introduction of antifungal therapy remains a matter for

clinical judgement and must be influenced by local experience. Our practice is given in Table 29.3.

Prevention and treatment of Pneumocystis carinii infections Lymphoma patients are at risk of infection with Pneumocystis carinii, although the reported incidence is low, with an estimated attack rate between 0.1 and 1 per cent per year.177 Certain chemotherapy regimens may confer greater risk178 and the incidence varies between institutions.179 Pneumocystis pneumonia probably represents reactivation of latent infection, although evidence that the organism is reacquired at the time of clinical disease is accumulating.180 This has implications for prevention; exposure of high-risk patients to infected persons should be avoided, particularly in institutions where the incidence is high. PREVENTION

Standard prophylaxis of Pneumocystis carinii is with oral trimemoprim-sulphamethoxazole (co-trimoxazole) 960 mg bd daily or 2-3 times per week.179 Primary prophylaxis should be considered for patients in institutions where the incidence is high, for those on long-term steroids, and receiving certain chemotherapy regimens.178 Lymphoma patients have a low incidence of adverse reactions to cotrimoxazole in contrast to HIV patients.177,179 Alternative oral prophylactic agents, which could be considered in high-riskpatients unable to tolerate co-trimoxazole include pyrimethamine-sulfadioxine, pyrimethamine-dapsone, dapsone and atovaquone.179 Secondary prophylaxis should be considered for all patients following an acute infection, who continue to be immunosuppressed. TREATMENT

Co-trimoxazole is the treatment of choice for Pneumocystis carinii pneumonia (PCP). It is effective, well tolerated, inexpensive and readily available in both oral and intravenous forms. The intravenous route should be used in all but the mildest cases, and the recommended dose is 15 mg/kg per day trimethoprim plus 75 mg/kg per day sulphamethoxazole, continued for 21 days. Oral therapy, for mild cases and for continuing therapy, is 20 mg/kg per day trimethoprim plus 100 mg/kg per day sulphamethoxazole.179,181 Studies in the AIDS populations have shown that clindamycin-primaquine (600 mg qds iv plus 15 mg/day orally) and dapsone-trimethoprim (100 mg/day plus 20 mg/kg per day oral or iv) are effective alternative first-line agents.181 In patients failing to respond to first-line treatment, intravenous pentamidine (4 mg/kg per day iv) or atovaquone (750 mg tds orally for patients suitable for oral therapy) may be used. Trimetrexate probably has a role in patients who require parenteral treatment, who cannot tolerate or fail to respond to co-trimoxazole and pentamidine.


The outcome of severe infection with respiratory failure can be improved by the co-administration of corticosteriods. Appropriate regimens are prednisolone 40 mg bd for 5 days, then slowly reducing until day 21, or methylprednisolone 1 g daily for 3 days.180 Corticosteroids probably abrogate the flare in inflammation associated with dying organisms, a process thought to explain the deterioration seen in some patients after anti-Pneumocystis treatment has started.180 They should be prescribed at the commencement of specific anti-Pneumocystis treatment, even if the diagnosis is presumptive at this stage. The data supporting co-administration of steroids is very clear for patients with AIDS-related PCP. In a randomized controlled trial of patients receiving cotrimoxazole, among those receiving concurrent steroids, 9 out of 12 survived while only 2 out of 11 survived in the control group.182 This was confirmed in another trial.183 It is very likely to apply in patients with cancerand chemotherapy-related PCP.184

Use of hemopoietic growth factors for the prevention and treatment of infections in neutropenic lymphoma patients One of the most significant advances of the 1980s has

been the availability of hemopoietic growth factors (colony stimulating factors) for the clinical management and prevention of neutropenia in patients treated with chemotherapy, including those who also receive hemopoietic support in the form of a bone marrow transplant or peripheral blood stem cell transplant.

HEMOPOIETIC GROWTH FACTORS

Recombinant human hemopoietic growth factors of some clinical potential are listed in Table 29.6. Two hemopoietic growth factors are in routine clinical use. Recombinant human G-CSF and GM-CSF have both been demonstrated to reduce the length and severity of neutropenia, and the occurrence of infections in patients after chemotherapy. Both bacterially derived and yeast-derived forms are available. Their use has been reviewed by Lee and Crawford.185 Hemopoietic growth factors will stimulate myelopoiesis and speed up recovery from chemotherapy-induced neutropenia. Since the duration of neutropenia is a powerful determinant of the probability of infection (Figure 29.1), it would be predicted that shortening neutropenia would reduce infection and this is observed in clinical trials.

Table 29.6 Hemopoietic growth factors (HGFs). Reprinted from reference 185

GM-CSF

Neutrophils and neutrophil precursors, macrophages, megakaryocytes, erythroid cells

T lymphocytes, endothelial cells, fibroblasts

5q

G-CSF

Neutrophils and neutrophil precursors, endothelial cells, fibroblasts

Endothelial cells, monocytes, fibroblasts

17q

M-CSF(CSM)

Monocytes

Endothelial cells, monocytes, fibroblasts

5q

IL-3

Neutrophils, endothelial cells, multipotent progenitor cells

T lymphocytes

5q

IL-4

B and T lymphocytes

T lymphocytes

5q

IL-5

B lymphocytes, CFU-eosinophils

T lymphocytes

5q

IL-6

B and T lymphocytes, CFU-GEMM, CFU-GM, BFU-E, macrophages platelets, neural cells hepatocytes

Fibroblasts, leukocytes, epithelial cells

7p

IL-7

B lymphocytes

Leukocytes

8q

IL-8

T lymphocytes, neutrophils

Leukocytes

4

IL-9

BFU-E, CFU-GEMM

Lymphocytes

5q

IL-11

B, T lymphocytes, CFU-GEMM, platelets, macrophages

Macrophages

7

Erythropoietin

CFU-E, BFU-E

Kidney, liver

7q

Stem cell factor (c-kit ligand)

Primitive progenitor cells, mast cells

7

7

GM = granulocyte-macrophage, CSF = colony stimulating factor, G = granulocyte, M = macrophage, IL = interleukin, CFU = colony-forming unit, GEMM = granulocyte erythrocyte monocyte macrophage, BFU = burst forming units, E = erythroid.

412 Infections G-CSF

G-CSF stimulates the development of mature neutrophils from myeloid progenitors. It was initially described by Burgess and Metcalf in 1980,186 named GCSF by Nicola et al. in 1983187 and the gene cloned in 1986.188-189 It exists in a single copy of chromosome 17 q21-22 and codes for a 207 amino acid precursor from which 30 amino acids are removed to yield a 177 amino acid polypeptide of approximate molecular weight 25 kDa. It is made by neutrophils, mononuclear cells, endothelial cells and fibroblasts, and interacts with highaffinity cytokine receptors on the surface of neutrophils. Receptor expression is increased in infected patients. It is likely that G-CSF mediates neutrophil leucocytosis in infection. The encouraging observations of G-CSF in animal models led to its use in humans in volunteers and cancer patients190 in whom it caused an increase in neutrophil count as long as it was continued. Accelerated recovery from myelosuppression was seen in these early studies. The recombinant G-CSF was well tolerated with infrequent episodes of bone pain in the marrow-rich bones. Phase III randomized trials of G-CSF have shown: 1 G-CSF will shorten neutropenia by enhancing recovery; 2 the nadir neutrophil count is usually higher in GCSF-treated patients; 3 febrile episodes are reduced in G-CSF-treated patients with a reduction in antibiotic treatment and days of hospitalization in some studies; 4 there may be an improvement in response, duration and survival in the G-CSF-treated patients;185 5 G-CSF will shorten the period of neutropenia following autologous bone marrow transplantation. GM-CSF

Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes proliferation and differentiation of hemopoietic precursors into differentiated myeloid cells. It is derived from fibroblasts, endothelial cells, monocytes and activated T cells. It was originally purified by Gasson et al.191 The gene is found on the long arm of chromosome 5, close to several other hemopoietic growth factors.185 Its biology is similar to G-CSF with a high-affinity receptor, but its effects are less lineage specific, affecting granulocytes, macrophages, megakaryocytes and eosinophils. Animal experimentation and early phase I/II clinical trials support a role for GM-CSF in increasing neutrophil and macrophage production, and reducing postchemotherapy myelosuppression. It has mild toxicity including fever, some rash and flushing. Initial studies show that it shortens the period of neutropenia following chemotherapy in a range of cancers. Phase III clinical trials show reduction in neutropenia and days of hospitalization, although no benefits in thrombocytopenia.

CLINICAL USE OF HEMOPOIETIC GROWTH FACTORS IN LYMPHOMA

The clinical effects of hematopoietic growth factors in lymphoma patients are not in doubt. They are capable of inducing neutrophilia, shortening neutropenia and reducing infection. However, alternative approaches to managing infection exist and hemopoietic growth factors are complex, inconvenient and expensive. Care has to be taken in deriving appropriate indications.192'193 The following are our recommendations given the current state of knowledge. 1 The stimulation of bone marrow prior to the harvesting of peripheral blood stem cells for hemopoietic support in intensive therapy. This is discussed elsewhere in this volume but there is no doubt that hemopoietic growth factors have an established place in lymphoma care. In one study, cytokine-induced peripheral blood stem cells harvested by leucophoresis were used and compared to autologous bone marrow for hemopoietic support following intensive chemotherapy for lymphoma patients.194 They resulted in reduction in the duration of neutropenia, but no difference in the absolute incidence of infection or in overall survival. 2 In the management of neutropenic and septic patients who are severely ill, responding poorly or slowly to antibiotics and in whom a prolonged period of neutropenia is anticipated. 3 In the reduction of the duration of neutropenia electively in patients receiving combination chemotherapy who are, usually as a result of previous experience or therapy, known to be at risk of prolonged neutropenia but for whom maintenance of the dose of chemotherapy is judged to be clinically valuable. 4 In carefully designed randomized prospective studies, to evaluate whether higher response rates, remission, duration or survival can be achieved by growth factor support compared to chemotherapy alone. Hematopoietic growth factors are not routinely used following peripheral blood stem cell transplantation, where their effects are small, and they are not routinely used for all patients having cyclical combination chemotherapy for lymphoma.

REFERENCES 1. McGeer A, Feld R. Epidemiology of infection immunocompromised oncological patients. In: Glauser MP, Calandra T, eds Balliere's clinical infectious diseases, Vol. 1:3. London: Balliere Tindall, 1994: 415-38. 2. Hancock BW, Bruce L, Richmond J. Neutrophil function in lymphoreticular malignancy BrJ Cancer 1976; 33: 396-500.

References 413

3. Aisenberg AC. Studies on delayed hypersensitivity in Hodgkin's disease. 7 Clin Invest 1962; 41:1964-70. 4. Young RC, Corder MP, Haynes HA, et al. Delayed hypersensitivity in Hodgkin's disease AmJ Med 1972; 52: 63-72. 5. Hancock BW, Bruce L, Sugden P, et al. Immune status in untreated patients with lymphoreticular malignancy -a multifactorial study. Clin Oncol 1977; 3: 57-63. 6. Hancock BW, Bruce L, Ward AM, et al. The immediate effects of splenectomy, radiotherapy and cytotoxic chemotherapy on the immune status of patients with malignant lymphoma Clin Oncol 1977; 3:137-44. 7. Romagnani S, Ferrini PLR, Ricci M. The immune

20. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukaemia. Intravenous immunoglobulins for the prevention of infection in chronic lymphocytic leukaemia N EnglJ Med 1988; 319: 902-7. 21. Chapel HM, Bunch C. Mechanisms of infection in chronic lymphocytic leukaemia Semin Haematol 1987; 24:291-6. 22. Rozman C, Montserrat E, Vinolas N. Serum immunoglobulins in B chronic lymphocytic leukaemia. Natural history and prognostic significance Cancer 1988; 61: 279-83. 23. Jacobson Dr, Zolla-Pazner S. Immunosuppression and

derangement in Hodgkin's disease Semin Haematol

infection in multiple myeloma Semin Oncol 1986; 13:

1985;22:41-55.

282-90.

8. Fuks Z, Strober S, Bobrove AM, et al. Long term effects of radiation on T& B lymphocytes in peripheral blood of patients with Hodgkin's disease; Clin Invest 1976; 58: 803-14. 9. Fisher Rl, De Vita VT, Bostik F, et al. Persistent immunologic abnormalities in long term survivors of advanced Hodgkin's disease. Ann Intern Med 1980; 92: 595-9. 10. Hancock BW, Bruce L, Ward AM, et al. Changes in immune status in patients undergoing splenectomy for the staging of Hodgkin's disease Br Med J 1976; 313-5. 11. Weitzmann SA, Aisenberg AC, SiberGR, et al. Impaired humoral immunity in treated Hodgkin's disease N Engl J Med 1977; 297: 245-8. 12. Department of Health. Immunisation against infectious disease HMSO 1992; 100-3. 13. Fisher Rl, Van Haelan C, Bostik F. Increased sensitivity to normal adherent suppressor cells in untreated advanced Hodgkin's disease. Blood 1981; 57: 830-5. 14. Van Haelan CPJ, Fisher Rl. Increased sensitivity of lymphocytes from patients with Hodgkin's disease to concanavalin A induced suppressor cells) Immunol 1981;127:1216-20. 15. Manifold IH, Whitman MD, Bruce L, et al. Monocyte/lymphocyte interaction in Hodgkin's disease fir7 Cancer 1982; 46: 483. 16. Hawylowicz CM, Rees RC, Hancock BW, et al. Depressed killer cell activity in patients with malignant lymphoma and failure of NK cells to respond to interferon treatment EurJ Cancer 1982; 18:1081-8. 17. Gupta S, Fernandes G. Spontaneous and antibody dependent cellular cytotoxicity by lymphocyte

24. Hahn H, Kaufmann SHE. The role of cell mediated immunity in bacterial infections Rev Infect Dis 1981; 3: 1221-50. 25. Schimpff SC. Infections in the compromised host - an overview. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases. New York: Churchill Livingstone, 1990: 2258-65. 26. Sulitzeanu D. Immunosuppressive factors in human cancer Adv Cancer Res 1993; 60: 247-67. 27. Bodey GP, Buckley M, Sathe Y, et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukaemia. Ann Intern Med 1966; 64: 328-40. 28. Louria DB. Controversies in the management of infectious complications of neoplastic disease: introduction and epidemiology. Am J Med 1984; 76: 414-20. 29. Blackwell S, Crawford J. Filgrastim (r-metHuG-CSF) in the chemotherapy setting. In: Morstyn G, ed. Clinical practice. New York: Marcel Dekker, 1994: 103-16. 30. EORTC International Antimicrobial Therapy Cooperative Group. Three antibiotic regimens in the treatment of infection in patients with cancery Infect Dis 1978; 137: 14-29. 31. EORTC International Antimicrobial Therapy Cooperative Group. Gram positive bacteraemia in granulocytopenic cancer patients EurJ Cancer 1990; 29: 569-74. 32. Pizzo PA, Robichaud KJ, Wesley R, et al. Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes Medicine 1982; 61: 153-65.

subpopulations in peripheral blood and spleen from

33. Kramer BS, Pizzo PA, Robichaud KJ, et al. The role of

adult untreated with Hodgkin's disease Clin Exp

microbiologic surveillance and clinical evaluation in the management of cancer patients with fever and granulocytopenia Am J Med 1982; 72: 561-8. 34. De Pauw BE, Hoogkamp-Kolstanje MAA. Epidemiology

Immunol1981; 45: 205-14. 18. Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma Ann Intern Med 1982; 96: 47-50. 19. Feld R, Sutcliffe SB. Immune deficiency and infectious complications of Hodgkin's disease. In: Selby P,

of infections in patients with haematological malignancies and in bone marrow transplants. In:

McElwain TJ, eds Hodgkin's disease. Oxford: Blackwell

Glauser MP, Calandra T, eds Balliere's clinical infectious diseases, Vol. 1. London: BalliereTindall, 1994:

Scientific, 1987:301-38.

391-414.

414 Infections 35. Fainstein V, Rodriguez V, Turck M, et al. Patterns of oropharyngeal and fecal flora in patients with acute leukaemia J Infect Dis 1981; 144: 82-6. 36. Bryan CS, Reynolds KL, Brenner ER. Analysis of 1186 episodes of Gram negative bacteremia in non-university hospitals; the effects of antimicrobial therapy Rev Infect Dis 1983; 5: 629-38. 37. Bodey GP. Infection in cancer patients: a continuing association. Am J Med 1986; 81(suppl 1A): 11-26. 38. Lowder JN, Lazarus HM, Herzig RH. Bacteremias and fungemias in oncologic patients with central venous catheters. Changing spectrum of infection Arch Intern Med 1982; 142:1456-9. 39. Press OW, Petersen SR, Larson EB, et al. Hickman catheter infections in patients with malignancies Medicine 1984; 63:189-200. 40. Winston DJ, Dudnick DV, Chapin M, et al. Coagulasenegative staphylococcal bacteremia in patients receiving immunosuppressive therapy Arch Intern Med 1983; 143: 32-6. 41. Bodey GP, Bueltman B, Duguid W, et al. Fungal infections in cancer patients: an international autopsy survey EurJ Clin Microbiol Infect Dis 1992; 11: 99-109. 42. Robertson MJ, Larson RA. Recurrent fungal pneumonias in patients with acute non-lymphoblastic leukaemia undergoing multiple causes of intensive chemotherapy. Ann Intern Med 1988; 84: 233-9. 43. Saral R. Candida and Aspergillus infections in immunocompromised patients: an overview. Rev Infect Dis 1991; 13: 487-92. 44. Bohnsack JF, Brown EJ. The role of the spleen in resistance to infection Annu Rev Med 1986; 37: 49-59. 45. Jelliffe AM, Vaughan Hudson G. Staging laparotomy in Hodgkin's disease. In: Selby P, McElwain TJ, eds Hodgkin's disease. Oxford: Blackwell Scientific, 1987: 160-80. 46. Schwartz PE, Sterioff S, Mucha P, et al. Post splenectomy sepsis and mortality in adults JAMA 1982; 284: 2279-83. 47. Job G, Pfreundschuh M, Bauer M, et al. The influence of radiation therapy on T lymphocyte subpopulations defined by monoclonal antibodies Int J Radial Oncol BiolPhys 1984; 10: 2077-81. 48. Feld R, Evans WK, DeBoer G. Herpes zoster in patients with carcinoma of the lung J Med 1982; 73: 795-801. 49. Hughes WT, Feldman S, Aur RJA, et al. Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis. Cancer 1975; 36: 2004-9. 50. Keating MJ, Kantarjian H, Talpaz M, et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukaemia Blood 1989; 74:19-25. 51. Beutler E. Cladribine (2-chlorodeoxyadenosine) Lancet 1992; 340: 952-6

52. Redman JR,CabanillasF, VelasquezWs,etal.Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low grade lymphoma J Clin Oncol 1992; 10: 790-4. 53. Schilling PJ, Vadhan-Raj S. Concurrent cytomegalovirus and pneumocystis pneumonia after fludarabine therapy for chronic lymphocytic leukaemia N Englj Med 1990; 323: 833-4. 54. Anaissie E, Kontoyiannis DP, Kantarjian H, et al. Listeriosis in patients with chronic lymphocytic leukaemia who were treated with fludarabine and prednisone. Ann Intern Med 1992; 117: 466-9. 55. Spielberger RT, Stock W, Larson RA. Listeriosis after 2chlorodeoxyadenosine treatment N Englj Med 1993; 328:313-4. 56. Elting LS, Bodey GP, Keefe BH. Septicemia and shock syndrome due to viridans streptococci: a case control study of predisposing factors. Clin Infect Dis 1992; 14: 1201-7. 57. Wells VD, Wong ES, Murray BE, et al. Infections due to beta-lactamase producing, high level gentamicin resistant Enterococcusfaecalis. Ann Intern Med 1992; 116:285-92. 58. Cooper GS, Havlir DS, Shlaes DM, et al. Polymicrobial bacteremia in the late 1980s: predictors of outcome and review of the literature. Medicine 1990; 69: 114-23. 59. Klastersky J, Zinner SH, Calandra T, et al. Empiric antimicrobial therapy for febrile granulocytopenic cancer patients: lessons from four EORTC trials EurJ Cancer Clin Oncol 1988; 24: S35-S45. 60. Dugdale DC, Ramsey PG. Staphylococcus aureus bacteremia in patients with Hickman catheters Am J Med 1990; 89:137-9. 61. Selby P, Powles RL, Jameson B, et al. Parenteral acyclovir therapy for herpes virus infections in man Lancet W7B; ii: 1267-70. 62. Shields AF, Hackman RC, Fife KH, et al. Adenovirus infections in patients undergoing bone marrow transplantation N Englj Med 1985; 312: 529-33. 63. Englund JA, Sullivan CJ, Jordan C, et al. Respiratory syncytial virus infection in immunocompromised adults Ann Intern Med 1988; 109: 203-8. 64. Hertz Ml, Englund JA, Snover D, et al. Respiratory syncytial virus induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature Medicine 1990; 68:269-81. 65. Horn R, Wong B, Kiehn TE, et al. Fungemia in a cancer hospital: changing frequency, earlier onset and results of therapy Rev Infect Dis 1985; 7: 646-55. 66. Whimbey E, Kiehn TE, Brannon P, et al. Bacteremia and fungemia in patients with neoplastic disease. Am J Med 1987;82:723-30. 67. Kauffman CA, Israel KS, Smith JW. Histoplasmosis in immunosuppressed patients Am J Med 1978; 64: 923-32.

References 415 68. Onal E, Lopata M, Lorenco RV. Disseminated pulmonary blastomycosis in an immunosuppressed patient Am Rev Respir Dis 1976; 113: 83-6. 69. Korfel A, Menssen HD, Schwartz S, Thiel E. Cryptococcosis in Hodgkin's disease: description of two cases and review of the literature. Ann Hematol 1998; 76: 283-6. 70. Saral R, Ambinder FR, Burns WH, el ai Acyclovir prophylaxis against herpes simplex virus infection in patients with leukaemia Ann Intern Med 1983; 99: 773-6. 71. Nahmias AJ, Keyserling H, Lee FK. Herpes simplex viruses 1 and 2. In: Evans As, ed. Viral infections of humans: epidemiology and control, 3rd edn New York: Plenum Medical Book Co., 1989: 393-418. 72. Selby P, Powles RL, Easton D, et al. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation BrJ Cancer 1989;59:434-8. 73. Goodrich JM, Mori M, Gleaves C, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation N Engl J Med 1991; 325:1601-7. 74. Gold E, Nankervis GA. Cytomegalovirus In: Evans AS, ed. Viral infections of humans: epidemiology and control, 3rd edn. New York: Plenum Medical Book Co., 1989:169-90. 75. Mera JR, Whimbey E, Luna M, et al. Incidence of cytomegalovirus (CMV) pneumonia in adult nontransplant cancer patients: review of 9549 autopsies from 1964-1990.33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, 1992:116 (abstract). 76. Locksley RM, Flournoy N, Sullivan KM, et al. Infection with varicella-zoster virus after marrow transplantation J Infect Dis 1985; 152:1172-81. 77. Rusthoven JJ, Ahlgren P, Elhakim T, et al. Varicella-zoster infection in adult cancer patients: a population study Arch Intern Med 1988; 148:1561-6. 78. Perren TJ, Powles RL, Easton D, et al. Prevention of herpes zoster in patients by long term oral acyclovir after allogeneic bone marrow transplantation AmJ Med 1988; 85(suppl2A): 99-101. 79. Ho M, Jaffe R, Miller G, et al. The frequency of Epstein Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children Transplantation 1988; 45: 719-27. 80. Carrigan DR, Drobyski WR, Russler SK, et al. Interstitial pneumonitis associated with human herpes virus 6 infection after marrow transplantation. Lancet 1991; 338: 147-9. 81. Drobyski WR, Dunne WM, Burd EM, et al. Human herpes virus 6 (HHV 6) infection in allogeneic bone marrow transplant recipients: evidence of a marrow suppressive role for HHV 6 in vivo. J Infect Dis 1993; 167: 735-9. 82. Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy Ann Intern Med 1982; 96: 447-9.

83. Thung SN, Gerber MA, Klion F, et al. Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier Arch Intern Med 1985; 145:1313-14. 84. Fan FS, Tzeng CH, Hsiao Kl, et al. Withdrawal of immunosuppressive therapy in allogeneic bone marrow transplantation reactivates chronic viral hepatitis C Bone Marrow Transplant 1991; 8: 417-20. 85. Walker DL. Progressive multifocal leukoencephalopathy. In: Koetsier JC, ed. Handbook of clinical neurology, Vol. 3 Amsterdam: Elsevier Science, 1985: 503-24. 86. ZahradnikJM, Spencer JM, Porter DD. Adenovirus infection in the immunocompromised patient Am J Med 1980; 68: 725-32. 87. Akiyama H, Kontoyiannis DP, Kantarjian H, et al. Systemic infection due to atypical mycobacteria in patients with chronic myelogenous leukaemia who were treated with fludarabine and prednisone. Rev InfectDis1991;13:815-8. 88. Feld R, Bodey GP, Groschel D. Mycobacteriosis in patients with malignant disease Arch Intern Med 1976; 136:67-70. 89. Hakes TB, Armstrong D. Toxoplasmosis: problems in diagnosis and treatment Cancer 1983; 52:1535-40. 90. McCabe RE, Remington JS. Toxoplasma gondii. In: Mandell GL, Douglas RG, Bennett JE, eds Principles and practice of infectious Diseases. New York: Churchill Livingstone, 1990:2090. 91. Igra-Siegman Y, Kapila R, Sen P, et al. Syndrome of hyperinfection with Strongyloides stercoralis Rev Infect Dis 1981; 3: 397-407. 92. Young LS. Mycobacterial infections in immunocompromised patients. CurrOpin Infect Dis 1996; 9: 240-5. 93. Young LS. Mycobacterial diseases and the compromised host Clin Infect Dis 1993; 16(suppl 2): S436-S441. 94. KorvickJA, Benson CA, eds. Mycobacterium avium complex infection. New York: Marcel Dekker, 1996. 95. Claass A, Claviez A, Westphal E, et al. First case of disseminated Mycobacterium avium infection following chemotherapy for childhood acute myeloid leukaemia Infection l995;23:301-2. 96. Hermida G, Richard C, Baro J, et al. Allogenic BMT in a patient with CMLand prior disseminated infection by Mycobacterium avium complex Bone Marrow Transplant 1995; 16:183-5. 97. LeMense GP, VanBakel AB, Crumbly AJ III, et al. Mycobacterium scrofulaceum infection presenting as lung nodules in a heart transplant recipient. Chest 1994; 106: 1918-20. 98. Kibbler CC. Infections in liver transplantation: risk factors and strategies for prevention J Hasp Infect 1995; 30:209-17. 99. Tantawichien T, Suwangool P, Suvanapha R. Tuberculosis in renal transplant recipients. Transplantation 1994; 26: 2187-8. 100. Chen CH, Hsieh H, Lai MK. Pulmonary tuberculosis or MOTT infection in kidney transplant recipients Transplant Proc 1994; 26: 2136-7.

416 Infections

101. FaulkCT, LesherJLJr. Phaeohyphomycosis and Mycobacterium fortuitum abscesses in a patient receiving corticosteroids for sarcoidosis..Mm,4cfld Dermatol 1995; 33: 309-11. 102. Gyure KA, Prayson RA, Estes ML, et al. Symptomatic Mycobacerium avium complex infection of the central nervous system: a case report and review of the literature Arch Pathol Lab Med 1995; 119: 836-9. 103. Armstrong D, Young LS, Lieberman P, et al. Infectious complications of neoplastic disease. Med Clinics North Am 1971; 50: 356-67. 104. Young LS. Combination or single drug therapy for Gramnegative sepsis. In: Remington JS, Swartz MM, eds Current clinical trials in infectious diseases, Vol. 3. New York: McGraw-Hill, 1982:177. 105. Young LS. Empiral antimicrobial therapy in the neutropenic host N EnglJ Med 1986; 315: 580-1. 106. Young LS. Empirical antibiotic therapy in granulocytopenic cancer patients. In: Glauser MP, Calandra T, eds Balliere's clinical infectious diseases, Vol. 1:3. London: BalliereTindall, 1994: 545-62. 107. Bodey GP. Empirical antibiotic therapy for fever in

117. EORTC International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada Clinical Trials Group. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients.) Infect Dis 1991; 163:951-8. 118. Rubin M, Hathorn JW, Marshall D,et al. Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia Ann Intern Med 1988; 108: 30-5. 119. Nucci M, Biasoli I, Braggio S, et al. Ceftazidime plus amikacin plus teicoplanin or vancomycin in the empirical antibiotic therapy in febrile neutropenic cancer patients. Oncol Rep 1998; 5:1205-9. 120. Meunier F, Zinner SH, Gaya H, et al. Prospective randomised evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumours. The European Organisation for Research and Treatment of Cancer International Antimicrobial Therapy Cooperative Group. Antimicrob Agents Chemother 1991; 35: 873-8. 121. Cometta A, Zinner S, de Bock R, et al. Piperacillin-

neutropenic patients Clin Infect Dis 1993; 17:

tazobactam plus amikacin versus ceftazidime plus

S378-S384.

amikacin as a empiric therapy for fever in granulocytopenic patients with cancer. The

108. Bodey GP, Rodriguez V, Valdivieso M, et al. Amikacin for treatment of infections in patients with malignant diseases. 7 Infect Dis 1976; 134: S421-S427. 109. Bodey GP, Ketchel SJ, Rodriguez V. A randomised study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients. AmJ Med 1979; 67: 608-12. 110. Rolston KV, Berkey P, Bodey GP, et al. A comparison of imipenem to ceftazidime with or without amikacin as

International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer. Antimicrob Agents Chemother 1995; 39: 445-52. 122. Hughes WT, Armstrong D, Bodey GP, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever J Infect Dis 1990; 161: 381-96.

antibiotic therapy in cancer patients with fever and

123. Hughes WT, Flynn PM, Williams BG. Nosocomial infection in patients with neoplastic diseases. In: Mayhall CG, ed. Hospital epidemiology and infection control. Baltimore: Williams and Wilkins, 1990; 300-15.

neutropenia N EnglJ Med 1986; 315: 552-8.

124. Walsh TJ, Karp J, Hathorn JW, et al. Prevention of

empiric therapy in febrile neutropenic patients Arch Intern Med 1992; 152: 283-91. 111. Pizzo PA, Hathorn JW, HiemenzJ, et al. A randomized trial comparing ceftazidime alone with combination

112. Klastersky J, Cappel R, Daneau D. Clinical significance of in vitro synergism between antibiotics in Gram-negative infections Antimicrob Agents Chemother 1972; 2: 470-5. 113. Klastersky J, Cappel R, Daneau D. Therapy with carbenicillin and gentamicin for patients with cancer and severe infections caused by Gram-negative rods Cancer1973;31:331-7. 114. Young LS. Nosocomial infections in the immunocompromised aduhMm J Med 1981; 70: 398-402. 115. Gilbert DN. Once daily aminoglycoside therapy Antimicrob Agents Chemother 1991; 35: 399-405. 116. EORTC. Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and cetazadine for infection in patients with cancer and granulocytopenia Ann Intern Med 1993; 119: 584-93.

bacterial infections in neutropenia patients. In: Glauser MP, Calandra T, eds Balliere's clinical infectious diseases, Vol. 1:3. London: BalliereTindall, 1994: 469-98. 125. Hughes WT, Kuhn S, Chaudhary SC, et al. Successful chemoprophylaxis in Pneumocystis carinii pneumonitis. N EnglJ Med 1977; 279:1419-29. 126. Bow EJ, Ronald AR. Antibacterial chemoprophylaxis in neutropenic patients - where do we go from here? J Infect Dis 1993; 17: 333-7. 127. Dekker AW, Rozenberg-Arska M, Verhoef J. Infection prophylaxis in acute leukaemia: a comparison of ciprofloxacin with trimethoprim-sulfamethoxazole and colistin Ann Intern Med 1987; 106:

7-12.

128. Donnelly JP, Maschmeyer G, Daenen S. Selective oral antimicrobial prophylaxis for the prevention of infection in acute leukaemia -ciprofloxacin versus cotrimoxazole plus colistin. EurJ Cancer 1992; 28A: 873-8.

References 417 129. GIMEMA Infection Program. Prevention of bacterial infection in neutropenia patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin Ann Intern Med 1991;115:7. 130. Carratala J, Fernandez-Sevilla A, Tubau F, et al. Emergence of quinolone resistant Escheria coli bacteremia in neutropenic patients with cancer who have received prophylactic norfloxacin. Clin Infect Dis 1995;20:557-60. 131. Rubie H, Juricic M, ClaeyssensS, et al. Morbidity using subcutaneous ports and efficacy of vancomycin flushing in cancer Arch Dis Child 1995; 72: 325-29. 132. Vassilomanolakis M, Plataniotis G, Koumakis G, et al. Central venous catheter related infections after bone marrow transplantation in patients with malignancies: a prospective study with short course vancomycin prophylaxis Bone Marrow Transplant 1995; 15: 77-80. 133. Reusser P, Gambertoglio JG, Lilleby K, et al. Phase l-ll trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogeneic marrow transplant recipients; Infect Dis 1992; 166: 473-9. 134. Drew WL, Lalezari JP, Glutzer E, et al. The safety, pharmacokinetics and anti-CMV activity of weekly HPMPC in HIV positive patients excreting CMV. In: Michelson S, Plotkin S, eds Abstracts of the 4th International Cytomegalovirus Conference. Paris: Institut Pasteur, 1993. 135. Reusser P. Prophylaxis and treatment of herpes virus infections in immunocompromised cancer patients. In: Glauser MP, Calandra T, eds In Balliere's clinical infectious diseases, Vol. 1:3. London: BalliereTindall, 1994: 523-44. 136. Saral R, Burns WH, Laskin OL, et al. Acyclovir prophylaxis of herpes simplex virus infections: a randomized, double blind, controlled, trial in bone marrow transplant recipients N EnglJ Med 1981; 305: 63-7. 137. Gluckman E, LotsbergJ, Devergie A, et al. Prophylaxis of herpes infections after bone marrow transplantation by oral acyclovir. Lancet 1983; 11: 706-8. 138. Hann IM, Prentice HG, Blacklock HA, et al. Acyclovir prophylaxis against herpes virus infections in severely immunocompromised patients: randomised double blind trial BrMedJ 1983; 287: 384-8. 139. Shepp DH, Dandliker PS, Flournoy N, et al. Sequential intravenous and twice daily oral acyclovir for extended prophylaxis of herpes simplex virus infection in marrow transplant patients Transplantation 1987; 43: 654-8. 140. Zaia JA. Viral infections association with bone marrow transplantation Hematol Oncol Clinics North Am 1990; 4: 603-23. 141. Straus SE, OstroveJM, Inchauspe G, et al. Varicellazoster virus infections. Biology, natural history, treatment and prevention Ann Intern Med 1988; 108: 221-37.

142. Ljungman P, Wilczek H, Gahrton G, et al. Long term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro Bone Marrow Transplant 1986; 1:185-92. 143. Shepp DH, Dandliker PS, Myers JD. Treatment of varicella-zoster virus infection in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine N EnglJ Med 1986;314:208-12. 144. Earnshaw DL, Bacon TH, Darlison SJ, et al. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2 and varicella-zoster virus. Antimicrob Agents Chemother 1992; 36: 2747-57. 145. Wingard JR, Piantadosi S, Burns WH, et al. Cytomegalovirus infections in bone marrow transplant recipients given intensive cytoreductive therapy Rev Infect Dis 1990; 12(suppl 7): S793-S804. 146. Meyers JD, Ljungman P, Fisher LD. Cytomegalovirus excretion as a predictor of cytomegalovirus disease after marrow transplantation: importance of cytomegalovirus viremia J Infect Dis 1990; 162: 373-80. 147. Bowden RA, Sayers M, Flournoy N, et al. Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomagalovirus infection after marrow transplantation N Engl J Med 1986; 314:1006-10. 148. de Witte T, Schattenberg A, van Dijk BA, et al. Prevention of primary cytomegalovirus infection after allogeneic bone marrow transplant by using leukocyte poor random blood products from cytomegalovirus unscreened blood bank donors Transplantation 1990; 50: 964-8. 149. Prentice HG, Gluckman E, Powles RL, et al. Impact of long term acyclovir on cytomegalovirus infection and surgical after allogeneic bone marrow transplantation Lancet!994; 343: 749-53. 150. Selby P, Powles RL, Jameson B, et al. Treatment of cytomegalovirus pneumonitis after bone marrow transplantation with 9-[2-Hydroxy-1-(hydroxymethyl) Ethoxymethyl] guanine [letter]. Lancet 1986; i: 1377-8. 151. Emanuel D. Treatment of cytomegalovirus disease Semin Hematol 1990; 27(suppl 1): 22-7. 152. Ljungman P, Engelhard D, Link H, et al. Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovirand intravenous immune globulin: experience of European Bone Marrow Transplant Group Clin Infect Dis 1992; 14: 831-5. 153. Emanuel D, Cunningham I, Jules-Elysee K,et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovirand high dose intravenous immune globulin. Ann Intern Med 1988; 109: 777-82.

418 Infections

154. Van Droogenbroeck J, De Ceuninck M, Snoeck HW,

170. Goodman JL, Winston DJ, Greenfield RA, et al. A

Schroyens W, Berneman Z. Successful treatment of cytomegalovirus encephalitis in a patient with

controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow

Hodgkin's disease in remission. Ann Hematol 1998; 76: 179-81. 155. Schaffner A. Prophylaxis and treatment of fungal

transplantation N EnglJ Med 1992; 326: 845-51. 171. Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients

infections in cancer patients. In: Glauser MP,

with acute leukaemia: results of a randomised placebo-

Calandra T, eds Balliere's clinical infectious diseases,

controlled, double blind, multicenter trial. Ann Intern

Vol. 1:3. London: BalliereTindall, 1994: 499-522. 156. Donhuijsen K, Samandari S. Deep mycoses in leukaemias and malignant lymphomas Deutsche Med Wochensch 1985; 110: 903-7. 157. Meyers JD. Fungal infections in bone marrow transplant patients Semin Oncol 1990; 17:10-13. 158. Lopez Berestein G. Liposomal amphotericin B in the treatment of fungal infections Ann Intern Med 1986; 105:130-1.

Med 1993; 118: 495-503. 172. Wingard JR, Merz WG, Rinaldi MG, et al. Increase in Candida Krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole N EnglJ Med 1991; 325: 1274-7. 173. Rousey SR, Russler S, Gottlieb M, et al. Low dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation AmJ Med 1991; 91: 484-92.

159. Anaissie E, Paetznick V, Proffitt R, et al. Comparison of the in vitro antifungal activity of free and liposomeencapsulated amphotericin B. EurJ Clin Microbiol Infect 0/51991; 10: 665-8.

174. EORTC International Antimicrobial Therapy Cooperative Group. Empirical antifungal therapy in febrile granulocytopenic patients Am J Med 1989; 86: 668-72.

160. Janknegt R, van Etten EWM, de Marie S. Lipid

175. Sugar AM. Empiric treatment of fungal infections in the

formulations of amphotericin B. In: Andriole VT, Finch

neutropenic host. Review of the literature and

RG, eds Current opinion in infectious diseases, Vol. 9.

guidelines for use. Arch Intern Med 1990; 150:

London: Rapid Science Publishers, 1996; 403-6. 161. Chavanet PY, Garry I, Charlier N, et al. Trial of glucose versus fat emulsion in preparation of amphotericin for use in HIV infected patients with candidiasis Br MedJ 1992;305:921-825. 162. Trissel LA. Amphotericin B does not mix with fat emulsion Am J Health Systems Pharmacol 1995; 52: 1463-4. 163. Anaissie E, Bodey GP, Kantarjian H, et al. Fluconazole therapy for chronic disseminated candidiasis in patients with leukaemia and prior amphotericin B therapy. Am J Med 1991; 91:142-50. 164. Kauffman CA, Bradley SF, Ross SC, et al. Hepatosplenic

2258-64. 176. Walsh TJ, LeeJ, Lecciones J, et al. Empiric therapy with amphotericin B in febrile granulocytopenic patients Rev Infect Dis 1991; 13: 496-503. 177. KovacsJA, HiemenzJW, Macher AM. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immuodeficiency syndrome and patients with other immuodeficienciesAw? Intern Med 1984; 100: 663-71. 178. Browne MJ, Hubbard SM, Longo DL, et al. Excess prevalence of Pneumocystis carinii pneumonia in patients treated for lymphoma with combination chemotherapy Ann Intern Med 1986; 104: 338-44.

treatment of invasive aspergillosis: review of 2,121

179. Masur H. Prevention and treatment of pneumocystis pneumonia. N EnglJ Med 1992; 327: 26,1853-60. 180. Miller RF, Mitchell DM. Pneumocystis carinii pneumonia Thorax 1992;47:305-14.

published cases. Rev Infect Dis 1990; 12:1147-201.

181. Mitchell DM. AIDS and the lung. In: Lever AML, Sissons

candidiasis: successful treatment with fluconazole. AmJ Med 1991; 91:137-41. 165. Denning DW, Stevens DA. Antifungal and surgical

166. Hosteller JS, Denning DW, Steven DA. US experience

P, eds Medicine, Vol. 24: 9. Oxford: The Medicine Group,

with itraconazole in Aspergillus, Cryptococcus and Histoplasma infections in the immunocompromised

182. Gagnon S, Boota AM, Fischl MA, et al. Corticosteroids as

host Chemotherapy 1992; 38(suppl 1): 12-22. 167. Schaffner A, Frick PG. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis J Infect Dis 1985; 151: 902-10. 168. Schmitt HJ, Bernard EM, Edwards FF, et al. Combination therapy in a model of pulmonary aspergillosis Mycoses 1991;34:281-5. 169. Sugar AM, Hitchcock CA, Troke PF. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother 1995; 39: 598-601.

1996: 126-30. adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N EnglJ Med 1990; 323:1444-50. 183. Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N EnglJ Med 1990; 323: 1451-7 184. Pareja JG, Garland R, Koziel H. Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest 1998; 113:1215-24.

References 419 185. Lee ME, Crawford J. Colony stimulating factors for the prevention and treatment of infections in cancer patients In: Glauser MP, Calandra T, eds Balliere's clinical infectious diseases, Vol. 1:3. London: Balliere Tindall, 1994: 563-600. 186. Burgess AW, Metcalf D. Characterization of a serum factor stimulating the differentiation of myelomonocytic leukaemic cells IntJ Cancer 1980; 39: 647-54. 187. Nicola NA, Metcalf D, Matsumoto M, et al. Purification of a factor inducing differentiation in murine myelomonocytic leukaemia cells: identification as granulocyte colony stimulating factor (G-CSF)y Biol Chem 1983; 258: 9017-23. 188. Nagata S, Tsuchiya M, Asanon S, et al. Molecular cloning and expression of cDNA for human granulocyte colony stimulating factor Nature 1986; 319:415-18. 189. Souza LM, BooneTC, GabriloveJ, et al. Recombinant human granulocyte colony stimulating factor: effects on normal and leukaemic myeloid cells Science 1986; 232:61-5.

190. Bronchud MH, ScarffeJH, Thatcher N, et al. Phase l/ll study of recombinant human granulocyte colony stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer BrJ Cancer 1987; 56: 809-13. 191. Gasson JC, Kaufman SE, Weishart RN, et al. High affinity binding of granulocyte macrophage colony stimulating factor to normal and leukaemic human myeloid cells Proc NatAcadSci USA 1986; 83: 669-73. 192. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines) Clin Oncol 1994; 12: 2471-508. 193. Croockewit AJ, Bronchud MH, Aapro MS, et al. A European perspective on haematopoietic growth factors in haemato-oncology: report of an Expert Meeting of the EORTC EurJ Cancer 1997; 33:1732^6. 194. Schmitz N, Linch DC, Dreger P, et al. Randomised trial of filgrastim mobilised peripheral blood progenitor cell transplantation versus autologous bone marrow transplantation in lymphoma patients Lancet 1996; 347: 353-7.


30 Long-term problems M HENRY-AMAR

Introduction Non-malignant complications Secondary malignancies Quality of life in long-term survivors

421 421 426 429

INTRODUCTION With the careful application of appropriate staging techniques and treatment methods, the expected proportion of all patients presenting with Hodgkin's disease who should be cured of their disease is as high as 75 per cent as of 1992.1 This result is already achieved in early stage disease because modern treatment methods (high-dose extended-field or total lymphoid radiation therapy and/or cyclical multidrug chemotherapy) are widely applied. Long-surviving Hodgkin's disease patients, however, face new problems. As greater numbers of successfully treated patients are followed for longer periods of time, medical problems associated with residua of the disease and its therapy have become more apparent.2 Among these problems, secondary malignancies are the most serious because they are often fatal and, in a large proportion of cases, they arise as a consequence of treatment. Hodgkin's disease therapy may also result in severe infections, and thyroid, cardiovascular, pulmonary, digestive or gonadal dysfunction. Skeletalcomplications, mostly reported in children treated with extended-field irradiation delivering 30 Gy or more, have been dramatically lowered with the use of low-dose radiation in combination with chemotherapy or chemotherapy alone in pediatric patients. These complications will therefore not be discussed, although one might expect more complications in the skeleton years after the patients have been irradiated.3 Patients previously treated for a non-Hodgkin's lymphoma face a rather different situation than those with Hodgkin's disease. While major Hodgkin's disease treatment improvements occurred during the 1970s, the

Causes of death Conclusion Summary References

430 431 432 432

search for the best treatment strategy for non-Hodgkin's lymphoma is still being sought. Although the nonHodgkin's lymphoma incidence rate in the general population is higher than that of Hodgkin's disease, series available that include large numbers of patients treated according to protocols with sufficient follow-up to allow reliable estimations of long-term complications are very few. Most published studies focused on second cancer risk neglecting that of late non-malignant complications. This review will focus on the variety of medical problems considering successively non-malignant complications, secondary malignancies, long-term patient quality of life and causes of death. Because the vast majority of patients who achieve remission will remain symptomfree and do enjoy a normal life,4 an attempt will be made to provide estimated risk for individual based on available data.

NON-MALIGNANT COMPLICATIONS

Immunologic dysfunction The lymphoid organs are the most common sites involved with Hodgkin's disease and, to lesser extent, with non-Hodgkin's lymphoma, so it is not surprising that immune regulation disorders are observed. Functional status of the immune system is probably important in the maintenance of remission and protection against infection or secondary malignancies. Untreated Hodgkin's disease patients generally present with an immunodeficiency state, which was first reported by Reed in 1902.5

422 Long-term problems

Patients exhibit lymphocytopenia, which is mainly ascribed to a reduction of OKT4+ T cells and to lack of Tjo, cells. Their lymphocytes are poorly activated by mitogens and antigens. Patients are poor responders in the allogeneic mixed lymphocyte reaction. In contrast, B lymphocyte functions are well preserved in these patients, except in those with systemic symptoms. Therapeutic irradiation induces lymphocytopenia, which depends on target volume and dose delivered, and a profound depression of immune functions. While the immediate absolute B lymphocytopenia following irradiation seems to normalize within the first 1-2 years after therapy, in patients with non-Hodgkin's lymphoma in particular, prolonged T cell functional impairment is often observed in long survivors of Hodgkin's disease. Aggressive combination cytotoxic drug therapy, such as the MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) and its variants given for Hodgkin's disease, also induce an acute reduction of T and B lymphocytes with prolonged T cell functional impairment after cessation of chemotherapy. Spleen removal may result in persistent blood cell abnormalities, such as neutrophilia, lymphocytosis, eosinophilia and thrombocytosis. Splenectomy also induces delayed reduction of serum immunoglobulin M (IgM), and potentiates the progressive fall in serum IgM secondary to irradiation and cytotoxic drug therapy. All together, the asplenic state (either because of splenectomy or splenic irradiation), reduced IgM levels and impaired B cell responses contribute to the persistent lifelong risk of overwhelming postsplenectomy infections (OPSI).

Infectious complications Bacteria, fungi and parasites, as well as viruses, are microorganisms with a predilection for individuals with Hodgkin's disease.6 Pneumonia (37-57 per cent), bacteremia (25-33 per cent), skin infection (5-19 per cent) and meningitis (3-13 per cent) are the most common serious infections.2 Organisms frequently isolated include Streptococcus pneumoniae (21-32 per cent), Staphylococcus aureus (5-19 per cent) and Staphylococcus epidermidis (4-19 per cent). Gramnegative organisms are less common. A non-negligible number of isolates, however, are polymicrobial (15-21 per cent). Infections are often favored by immunologic dysfunction (Herpes zoster being the most characteristic consequence in Hodgkin's disease patients). The most feared splenectomy-related infection is OPSI, which can lead to death within hours of the first clinical manifestation. Patients to be submitted to splenectomy should be systematically given pneumococcal vaccine prior to surgery. Splenectomized patients and those whose spleen was irradiated should certainly be proposed for antibiotic (penicillin) prophylaxis as well as regular vaccination.

Thyroid dysfunction Thyroid dysfunction is among the most common Hodgkin's disease therapy-related complications, and was early recognized and treated. Because the thyroid is directly exposed to radiation, dysfunction often concerns hypothyroidism with consequent elevation of thyroid stimulating hormone (TSH), while no consistent effect of chemotherapy alone has been demonstrated. In the European Organization for Research and Treatment of Cancer (EORTC) trials, 3 years after treatment completion, patients expressed a 100 per cent increase in TSH level compared with the baseline, whatever the treatment administered, say mantle irradiation alone or combined modality with MOPP or MOPP/ABV (doxorubicin, bleomycin, vinblastine) hybrid chemotherapy.7 Hypothyroidism develops gradually. Thyroid function was evaluated in a series of 1787 Hodgkin's disease patients treated during the 1961-1989 period at Stanford University Medical Center.8 Of those patients, 97 per cent were irradiated as part of their treatment and 32 per cent of patients had clinical or biological evidence of thyroid disease. The 20-year cumulative incidence rate of thyroid disease was 50 per cent; the median time to occurrence was 4.6 years (range 0.2-25.6). Thyroid disease concerned hypothyroidism (20-year cumulative rate, 41 per cent), Graves' disease (20-year cumulative rate, 3.1 per cent), thyroiditis (20-year cumulative rate, 1.3 per cent), thyroidectomy (including 6 out of 26 for thyroid cancer; 20-year cumulative rate, 6.6 per cent) and clinically benign nodule (20-year cumulative rate, 3.3 per cent). Hypothyroidism, Graves' diseases and thyroiditis occurred earlier (median 4.0, 4.8 and 5.0 years from treatment initiation, respectively) than thyroidectomy and clinically benign nodule (median 14.0 and 12.6 years, respectively). In this series, hypothyroidism was dependent on radiation dose, age and sex. The 20-year cumulative incidence was less than 5 per cent in unirradiated patients; it was 30 per cent if radiation dose to thyroid was 7.5-30 Gy, and 45 per cent in patients whose thyroid was irradiated at a dose exceeding 30 Gy. The proportion of patients in whom hypothyroidism developed increased with age, from 17 per cent in those who were less than 5 years of age when treated to 39 per cent in those who were 15-20 years of age when treated; it gradually declined with advancing age to 17 per cent in patients who were over 70 years of age when treated. Risk factors analysis indicated that, in patients aged 17 years or older when irradiated, female sex [relative risk (RR) = 1.60, P < 0.001], chemotherapy (RR = 1.42, P < 0.001) and radiation dose (RR/lGy = 1.02, P = 0.035) significantly correlated with increased risk of hypothyroidism. Hypothyroidism might not only be related to radiation to the thyroid but also to radiodiagnostic iodine surcharge, since lymphangiography and, more recently, abdominal computed tomography are systematically

Non-malignant complications 423

performed during the initial work-up and repeated thereafter.9,10 The literature, however, is conflicting and the question remains to be clarified in larger series than already reported.11

Cardiovascular dysfunction Treatment-related cardiac complications do involve the three cardiac tunica. In Hodgkin's disease patients, they have been described as irradiation and chemotherapy related. Cardiac complications, such as myocardial infarction and coronary artery disease, arrhythmias, myocarditis, pericarditis, pericardial effusion and tamponade, have been well documented after radiation therapy to the mediastinum.12-13 They are related to the total radiation dose delivered, the fraction size and the volume irradiated. An excess of risk has been reported for a total dose over 40 Gy, a dose per fraction > 3 Gy, the use of a single anterior and anteriorily weighted radiation port and irradiation involving the whole pericardium. Pericarditis, both acute and chronic, whether or not associated with pericardial effusion, is the most common symptomatic complication. It has been reported to develop in 11 -50 per cent of patients. With the use of dose restriction to the whole heart, addition of a subcarinal block after 25 or 35 Gy in the absence of lower mediastinal involvement or large mediastinal adenopathies, and high-energy linear accelerator and dose per fraction < 2 Gy, more satisfactory results are obtained with cumulative rates often less than 5 per cent. Uncomplicated chronic pericardial effusions are frequently persistently asymptomatic and consequently are often not recognized. Chronic constrictive pericarditis, with or without effusion, is a more serious consequence of radiation therapy because it requires more invasive and aggressive therapy than effusion alone; it is also associated with a higher incidence of morbidity. The use of modern irradiation techniques, however, should make it exceptional. The availability of noninvasive diagnostic procedures, such as echocardiography and radionuclide cineangiography, has facilitated the recognition of myocardial damage. Complete cardiovascular work-up, however, is available in only a limited number of series.14,17 They generally conclude that myocardial damage is present in 25-50 per cent of long survivors whose mediastinum was irradiated, although a small proportion of patients spontaneously complain of symptoms. Left ventricular ejection fraction, which is used as a measure of systolic function, is usually normal when measured at rest with an abnormal response at exercise in a substantial number of patients. Transient left ventricular ejection fraction decrease was observed even 3 years after treatment completion in both patients treated with mantle irradiation or combined modalities.7,18 As Hodgkin's disease survivors age and become

exposed to the risk factors of coronary artery disease, the excess morbidity and mortality from coronary artery disease observed in large series has led to the conclusion that irradiation might cause, aggravate or accelerate atherosclerosis.19,23 Perhaps the most informative group to look at is the long-term survivors of pediatric Hodgkin's disease. In those children treated on trials at St Jude from 1968-1990, as well as excess mortality from second cancers and infection, there was a significantly increased mortality from cardiac disease (standard incidence ratio 22; 95 per cent confidence interval, 8-48); all patients were male and had had extended-field radiotherapy and no anthracycline-containing chemotherapy.24 In the EORTC series, the 10-year and 15-year cumulative incidence rates of myocardial infarction were 2.4 and 4.6 per cent respectively.25 The role of mediastinal irradiation on myocardial infarction risk was demonstrated in the Institute Gustave Roussy series, where the 10-year cumulative incidence rate was 3.9 per cent in patients who were given irradiation to the heart while no myocardial infarction was observed in patients who had no mediastinal irradiation.21 However, in a multicenter study on the late effect of treatment for early stage Hodgkin's disease in 611 patients, mediastinal radiotherapy was not found to be a significant risk factor for death from myocardial infarction; the radiation doses were lower than in most centers and follow-up shorter.26 Doxorubicin chemotherapy has been reported to induce cadiotoxicity in Hodgkin's disease.2'12 In most protocols, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), MOPP/ABVD or MOPP/ABV hybrid regimens, the cumulative dose of doxorubicin following six cycles of 100 per cent standard dose is 300 mg/m2 or less, with a rare incidence of clinical cardiomyopathy. In a study of 103 young survivors of high-grade nonHodgkin's lymphomas treated on National Cancer Institute protocols, a predominate late effect was cardiotoxicity related to doxorubicin therapy in doses exceeding 200 mg/m2.27 Whether doxorubicin potentiates irradiation-related cardiotoxicity remains unclear. In the Stanford series, no significant increase in death from acute myocardial infarction was observed after combined therapy with MOPP compared with radiotherapy alone.28,29 However, since average total mediastinal doses were lower, subcarinal blocking was more frequent and less cardiac volume may have been irradiated in patients who received combined therapy, the potentiating role of chemotherapy might have been underestimated.

Pulmonary dysfunction Radiation pneumonitis and pulmonary fibrosis represent the most common complications following mantle irradiation for Hodgkin's disease. Almost 20 per cent of patients develop X-ray changes that are characteristic of acute radiation pneumonitis within 1-3 months after


irradiation, although it may be delayed as long as 6 months.30 These changes are generally asymptomatic. When present, common symptoms include dyspnea on mild exertion, non-productive cough and low-grade fever, which, in most patients, do not require therapy or additional diagnostic evaluation. The incidence of radiation pneumonitis mainly depends on the total dose delivered to the mediastinum, the irradiated volume and the technique.31'32 It also depends on the fraction size for a given dose, with the larger the fraction size, the higher the probability of lung damage.33 The use of lung blocks and the administration of chemotherapy before irradiation in patients with large mediastinal masses limit the dose and reduce incidence to less than 5 per cent. Pulmonary fibrosis begins to appear 6 months after treatment and usually stabilizes after 12-18 months. The volume irradiated appears to be the most important factor for pulmonary fibrosis, although the risk can vary according to the type of combined modality therapy. After MOPP plus irradiation, the incidence of pulmonary changes was 15-22 per cent compared with 49 per cent after ABVD plus irradiation in a nonrandomized study.34 The incidence of radiation-induced lung damage, as determined by computed tomography changes (increase in lung density within the irradiated volume) was prospectively evaluated in patients treated with combined modality treatment with radiation therapy (35 Gy in 20 fractions) together with either MOPP (12 patients), ABVD (16 patients) or MOPP/ ABVD (12 patients).35 The actuarial risk of developing pneumonitis was 71 per cent in patients treated with ABVD and irradiation, 49 per cent in patients treated with MOPP and irradiation, and 52 per cent in patients treated with MOPP/ABVD and irradiation. Minor restrictive ventilatory defects (decreased vital capacity and total lung compliance) are seen after mediastinal irradiation.36 They are increased with combined modality treatment, in particular after ABVD and irradiation.25 37 ABVD-related pulmonary toxicity may be a consequence of bleomycin-induced pulmonary fibrosis and of doxorubicin-induced 'radiation recall' pneumonitis.38 In contrast, the risk of pulmonary dysfunction is low after chemotherapy alone but may have been underestimated, since series of patients initially treated with chemotherapy alone and carefully followed thereafter for late complications are limited.

Digestive complications Most late digestive complications of Hodgkin's disease therapy concern infections, ulcers, gastritis and small bowel obstructions or perforations. They are mainly related to staging laparotomy and/or abdominal irradiation. Among laparotomy-related complications, splenectomy-related OPSI is probably the most serious (see earlier). In a series of 133 patients followed 2.5-28 years

after laparotomy, 6.8 per cent developed OPSI of which one patient died.39 The role of pneumoccocal vaccine was clearly demonstrated: none of the 25 patients who received pneumoccocal vaccine before splenectomy developed OPSI, while 5 out of 44 patients (11 per cent) who were vaccinated after splenectomy and 4 out of 64 patients (6 per cent) who were not vaccinated developed OPSI. The influence of radiation dose was studied in a series of 855 patients (478 with Hodgkin's disease and 377 with seminoma) who were treated with infradiaphragmatic irradiation but with no whole abdominal irradiation. The incidence of major bowel complications (requiring hospitalization for management or surgery) significantly correlated with radiation dose delivered to the para-aortic region; for doses < 35 Gy, the 3-year cumulative rate was 1 per cent compared with 3 per cent for doses > 35 Gy (P = 0.03).40 The role of infradiaphragmatic irradiation technique as well as that of staging laparotomy was assessed in the EORTC trials. In these protocols, irradiation usually delivered 39-41 Gy to the para-aortic region; the proportion of late complications did not vary with radiation dose.41 Late digestive complications did not relate to staging laparotomy in patients whose abdomen was not irradiated. In contrast, both staging laparotomy and fractions > 2 Gy increased the risk, which was maximal in laparotomized patients treated with fractions of 3.3 Gy (5-year cumulative rate, 28 per cent).25 With modern irradiation techniques and withdrawal of staging laparotomy from most treatment strategies, these complications should no longer be observed.

Gonadal dysfunction With the increasing use of chemotherapy in the treatment of Hodgkin's disease, lasting effects on gonadal function have been reported. The magnitude of the effect can vary with the drug class or combination used in treatment, the total dose administered, and'the age and pubertal status of the patient at the time of therapy.42 In adult men, germinal depletion is accompanied by a marked reduction in testicular volume, oligospermia or azoospermia, and infertility. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels reflect the state of the seminiferous epithelium. Germinal depletion results in a significantly increased FSH level, while LH and testosterone levels tend to remain within normal range. Adult women become amenorrheic and may complain of menopausal symptoms of estrogen deficiency. Low circulating estrogen levels result in marked elevation of serum FSH and LH. Before the onset of puberty in boys, the testicular germinal epithelium appears to be more resistant to moderate doses of alkylating agents than is the adult testis. Chemotherapy administered to male patients during puberty has profound effects on both germ cell production and endocrine

Non-malignant complications 425

function. Gynecomastia, elevated serum FSH and LH levels, and low normal serum testosterone levels are frequently observed after MOPP therapy. In girls, there is a lack of information available concerning the effect of cytotoxic drugs on the prepubertal and pubertal ovary. It seems, however, that the immature ovary is relatively insensitive to cytotoxic chemotherapy. In contrast to a growing literature describing adverse effects of chemotherapy, there is a paucity of data concerning the effects of radiation on gonadal function in humans. The testis is highly sensitive to radiation because of rapid cell division of the germinal epithelium; azoospermia occurs when the testes are irradiated with as little as 1 Gy. Techniques to shield the testes from the radiation beam are available, which considerably limit the dose to the gonads. At a 5-6 Gy total dose, most women remain persistently amenorrheic with variations with age. Women younger than 20 years have approximately a 70 per cent chance of retaining regular cyclic menses, whereas by age 30 or older, only 20 per cent of treated women retain normal ovarian function. Appropriate gonadal shielding is very difficult for the ovary but oophoropexy can reduce ovarian exposure in approximately 50 per cent of women receiving pelvic irradiation. After 6-10 cycles of COPP (cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy given as sole treatment, 100 per cent (n = 92) of males were azoospermic 1-17 years after treatment completion, 97 per cent had testicular atrophy and germinal aplasia was shown in 100 per cent of the 19 patients submitted to testicular biopsy.43 Serum FSH level was increased threefold, while serum LH level increase was moderate. Similar findings were reported in a series of 50 male patients treated with either MVPP (mechlorethamine, vinblastine, procarbazine and prednisone) or ChlVPP/EVA (chlorambucil, vinblastine, procarbazine, prednisone, doxorubicin, vincristine and etoposide) chemotherapy for 5-8 cycles, with no difference between the two chemotherapy regimens.44 In female patients (n = 39), chemotherapy resulted in 76 per cent amenorrhea; of these, 60 per cent had persistent amenorrhea. As in men, there were no significant differences in the incidence of amenorrhea, or mean of serum FSH and LH levels between MVPP- and ChlVPP/EVAtreated women. These results were confirmed in the EORTC Hodgkin's disease trials in which patients were successively treated with irradiation alone or a combination of irradiation and MOPP, MOPP/ABV hybrid or ABVD, and in the Istituto Nazionale Tumori (Milan) series.7,45 Other chemotherapy regimens have been used in order to reduce the risk of long-term sequelae. VEEP (vincristine, epirubicin, etoposide and prednisone) chemotherapy alone (3-10 courses) was associated with 6 per cent (2 out of 33) abnormal sperm count; in females, none of the 22 patients tested had posttreatment gonadal toxicity.46 In a series of 75 boys treated with OPPA (vincristine, procarbazine, prednisone and

doxorubicin; two courses) and COPP (0-6 courses) chemotherapy, all had normal pubertal development, but 24 per cent and 88 per cent expressed elevated basal and stimulated LH, respectively, indicating chemotherapy-induced Leydig cell damage; in addition, there was 41 per cent and 53 per cent incidence of elevated basal and stimulated serum FSH levels, respectively, indicating severe spermatogenesis impairment.47 In this series, testicular dysfunction was observed in boys treated before as well as during puberty. However, increased basal serum FSH and LH levels were dose dependent: the higher the number of COPP courses, the higher the incidence rate. These results were confirmed in the Stanford series, where 83 per cent (10 out of 12) of boys who were treated with six cycles of MOPP with or without pelvic irradiation were azoospermic with no evidence of recovery after as long as 11 years of follow-up.48 The Stanford series also included gonadal evaluation of 86 girls. Seventy-five (87 per cent) had normal menstrual function but none of the girls who underwent pelvic irradiation without prior oophoropexy has maintained ovarian function. Therefore, the chance of maintaining gonadal function following combined modality treatment appears to be much greater among girls than boys. Series focusing on the effect on fertility of treatments given for non-Hodgkin's lymphoma are very few. After intensive chemotherapy administered in adult patients with intermediate- or high-grade non-Hodgkin's lymphoma, gonadal function was not altered in six out of seven women, and in seven out of 15 men given MACOP-B (cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomycin and prednisone) or VACOP-B (with etoposide replacing methotrexate) chemotherapy alone.49 In contrast, abnormal gonadal function was observed in two out of six patients in whom induction chemotherapy was followed by highdose chemotherapy (cyclophosphamide, BCNU and etoposide) and autologous bone marrow transplantation; a similar observation was made in three out of four patients in whom induction chemotherapy was followed by cyclophosphamide and total lymphoid irradiation given before autologous bone marrow transplantation. Since the same cytotoxic drugs inducing altered gonadal function are used in the treatment of non-Hodgkin's lymphoma and that of Hodgkin's disease, it is likely that similar gonadal dysfunction will be observed as followup increases. After treatment completion, most patients of reproductive age who desire children ask the following questions: Will my child have an increased risk of developing lymphoma? How long should I wait before becoming pregnant? Will the treatment I have had cause congenital defects in my child? The available data do not bring absolute answers since large studies with long-term follow-up have been infrequent. The outcome of pregnancies in patients (or their partners) who were successfully treated for Hodgkin's disease was addressed in a series of


104 adult females and 117 adult males.50 After treatment, 43 females and 51 males actively attempted conception; 35 (81 per cent) females and 25 (49 per cent) partners of male patients had 84 pregnancies, which resulted in 68 living children for a median of 11 years (minimum > 4.5 years). Among the 84 pregnancies, there were one premature birth at 29 weeks, three spontaneous abortions, 11 elective abortions and two stillbirths. There was no apparent increase in complications of pregnancies, spontaneous abortions or congenital abnormalities. The partners of male patients who were treated with combined modality treatment, however, had a lower frequency of pregnancy than did the female patients who attempted conception. There is no convincing evidence that the risk of Hodgkin's disease in offspring is genetically increased, although a large number of families have been reported to have multiple occurrences of Hodgkin's disease.51 Similarly, there is no evidence of significant increase in congenital defects in the offspring of these patients. Therefore, information from studies of progeny in Hodgkin's disease should not discourage patients in remission after treatment of their disease from childbearing.

SECONDARY MALIGNANCIES Several years after therapy, Hodgkin's disease patients have an increased risk of developing acute leukemia, mostly acute non-lymphoblastic leukemia (ANLL), nonHodgkin's lymphoma and second solid tumors.24,26,52,57 Since large series with sufficient follow-up have become available, more accurate risk assessments can be made. They concern patients who were treated during childhood as well as those who were adults when the disease developed. Much less information is available for patients with a previous history of non-Hodgkin's lymphoma, particularly in adult patients, because major therapeutic improvements are recent and because the average follow-up of patients cured from their disease is still short. However, series have recently been published indicating that second solid tumors are of major concern in these patients. Effects of ionizing irradiation The carcinogenic effects of ionizing irradiation have been assessed in several cohorts of people under various conditions of exposure: occupational cohorts, residential radon exposure, atomic bomb survivors, and patients exposed to diagnostic and therapeutic procedures. Ionizing irradiation can cause all types of tumor, with the exception of chronic lymphocytic leukemia.58 Among organs where tumors can develop, the thyroid, female breast and bone marrow are probably the most radiosensitive. Ionizing irradiation effects have been quantified

for low-radiation-dose ranges and extrapolation to highradiation-dose ranges cannot be easily achieved.59 In low-dose ranges, the cancer risk increases with dose. Therapeutic irradiation doses used in Hodgkin's disease fall in a very small range, making it difficult to assess a dose-response relationship between irradiation doses and risk of second tumor. More variations occurred in the past in the number of fractions used for a given dose. Therefore, in the analysis of risk factors for developing a second tumor, similar to that performed in the analysis of the incidence of non-malignant complications, the use of the linear quadratic model might better reflect the impact of irradiation on the risk than does the dose itself.33,41 Effects of chemotherapy The drugs used for cancer therapy have been extensively studied by the International Agency for Research on Cancer (IARC).60,61 Among those carcinogenic to humans (Group 1 of the IARC classification), the largest group is made up of the alkylating agents, including MOPP and other combined chemotherapy incorporating alkylating agents. Among agents probably carcinogenic to humans (IARC Group 2A) are doxorubicin, nitrogen mustard and procarbazine. Among agents possibly carcinogenic to humans (IARC Group 2B) are bleomycin and dacarbazine. All these drugs have been widely used in the treatment of lymphomas, alone or in combination with irradiation. The interpretation of the studies on the risk of second tumor following chemotherapy is difficult because, in patients who are long survivors, multiple agents have often been administered, patients might have relapsed and been treated with salvage chemotherapy, careful clinical follow-up may result in a more diligent case finding, and other confounding factors (sex, age, ethnic origin, smoking) have to be taken into the analysis.62 The most frequent secondary cancer associated with chemotherapy is ANLL. It typically occurs between 2 and 10 years after therapy, with the peak time interval around 5 years, although cases can be observed later.51,56,62,63 Secondary ANLL often presents initially as myelodysplastic syndrome with refractory pancytopenia and high rate of abnormalities of erythrocyte morphology. It is generally of myelogenous type, associated with clonal chromosome aberrations involving chromosomes 5,7,11,17,18 and 21. It is usually, but not always, refractory to treatment with a 76-100 per cent death rate within several months following diagnosis.52,64,65 Secondary ANLL and myelodysplastic syndrome after Hodgkin's disease Hodgkin's disease patients have a cumulative risk of developing secondary ANLL, which has been reported to be as high as 10 per cent at 10 years.66 The risk, however,

Secondary malignancies 427

greatly depends on the type of therapy received. It is much higher in patients treated with chemotherapy or with combined modality therapy than in patients treated with radiation therapy alone. The risk depends on the type of chemotherapy given (the higher risk being associated with MOPP and MOPP-like regimens) and on the amount of chemotherapy administered, and might be associated with the extent of radiation therapy.52'67 After irradiation alone, the 15-year probability of developing an ANLL was 0.2 per cent; it was nil in patients treated with localized (involved- or mantle field) irradiation compared with 3.4 per cent in patients treated with extended field (subtotal or total lymphoid) irradiation.64 In this series, patients treated with chemotherapy alone had a 15-year probability of secondary ANLL of 11.1 per cent, while those treated with combined modality therapy had a 15-year probability of 4.3 per cent. Among the latter, the risk was not increased in patients treated with chemotherapy and extended-field irradiation compared with those treated with chemotherapy and localized irradiation (4.4 vs 4.2 per cent, respectively). These results confirm previous findings concerning the small impact of irradiation when associated with chemotherapy,55-68,73 while opposite results have been reported.74,75 In all studies, however, the cumulative risk of secondary ANLL tends to plateau 10-15 years after treatment completion. An attempt to quantify the risk of developing a secondary ANLL or a myelodysplastic syndrome in relation to the type and/or the amount of chemotherapy delivered has been made in several studies. The risk increased with the number of cycles, the dose or the alkylating score.63,68,72,75,78 The risk of chemotherapy-related secondary ANLL was shown to correlate significantly with various drugs, such as mechlorethamine (alone or associated with procarbazine and/or vincristine), cyclophosphamide and procarbazine, vincristine and procarbazine, lomustine, chlorambucil, and vinblastine.63,68,70,72,77,79,80 Other risk factors reported to correlate with an increased risk of secondary ANLL are age at which Hodgkin's disease developed, clinical stage and splenic treatment (splenectomy and splenic irradiation). The effect of age remains controversial. In many studies, an increase in cumulative probability as well as in relative risk have been found in patients aged above 40 or 50,52,75,81,-83Whileothers the risk was not increased84 or decreased with older age.68,71,85 Advanced clinical stage was found associated with an increased risk, even after confounding factors have been considered in the analysis, which might suggest that the risk of developing a secondary ANLL is related to greater functional defect of the immune system of these patients compared with that of patients with early stage disease.68,69,81,85 Van Leeuwen et al. first pointed out that splenectomy is a risk factor for secondary ANLL.86 This finding was later confirmed in some studies,63,68,78,79,83 while in others no significant increased risk was associated with previous splenectomy.64,69,71,75,81,84,85

When increased, the risk is always limited in magnitude and cannot be compared with that associated with the use of alkylating agents. In a recent study, splenectomy was associated with an increased risk of leukemia (RR =13.3), non-Hodgkin's lymphoma (RR = 16.6) or Hodgkin's disease (RR = 18.2) in patients treated for benign hematological disorders.87 These findings together with the infection risk and other splenectomy-related morbidity have been considered by many investigators to exclude splenectomy from staging and treatment strategy in Hodgkin's disease. Secondary non-Hodgkin's lymphoma after Hodgkin's disease Non-Hodgkin's lymphoma was first described as possibly related to treatment in 1979.88 Significantly increased risk was confirmed in all further studies.69-71,75,81,82,84,89,90 Non-Hodgkin's lymphoma generally develops 5-15 years post-treatment; its cumulative incidence rate ranges from less than 1 per cent to 4-5 per cent at that time but might increase with longer follow-up.82 An increase in risk was associated with various factors, such as older age, male gender, lymphocytic-predominant Hodgkin's disease histological subtype and combined modality therapy.69,71,75,81,82,85,91 In a recent study involving 10 472 patients treated at 14 cancer centers in the USA and Canada, only mechlorethamine was associated with an increased risk (RR = 2.4; 95 per cent confidence interval, 1.2-4.8) of secondary non-Hodgkin's lymphoma.63 Immunodeficiency induced by the therapy or immunologic defects of the Hodgkin's disease itself as well as viruses, such as Epstein-Barr virus (EBV) or more recently human immunodeficiency virus (HIV), might be co-factors for the subsequent development of nonHodgkin's lymphoma, but their respective role remains unclear.92 Secondary solid tumors after Hodgkin's disease While the excess of secondary ANLL and non-Hodgkin's lymphoma is generally significant over the 1-14 year period after the start of initial therapy, that of secondary solid tumors becomes apparent after the fifth year, increasing with time. In large series, the 15-year cumulative incidence rate of secondary solid tumors varies from 10 to 15 per Cent.64,69,71,75,81,82,84 In all series with sufficient follow-up, solid tumors represent 2-3 times as many ANLL and nonHodgkin's lymphoma, indicating that secondary solid tumors have become the most serious complication in long survivors of Hodgkin's disease. In general population comparisons, however, relative risks are generally between 1.5 and 2.5, while that of ANLL or non-Hodgkin's lymphoma often exceed 10. This apparent discrepancy comes from the difference between the natural incidence of


ANLL and non-Hodgkin's lymphoma, which is low (less than 10 cases per 100 000 inhabitants per year), and that of solid tumors, which is much greater.93 Not all localizations have been found in excess; these generally concern lung (RR = 1.9-7.7), female breast (RR = 1.4-4.1), stomach (RR = 1.2-10), thyroid (RR = 2.4-68), bone (RR = 4.5-106) and melanoma (RR = 1.6-16), although other specific sites (such as the salivary glands, head and neck, small intestine and colon in males, pleura, cervix and ovary in females) have been associated with an increased risk.8.54,55,69,82,89,94 The reiatjve rjsk increase is almost inversely proportional to the natural incidence rate of a given site; it generally concerns few numbers, leading to absolute risks that are always less than one case per 100 person-years at risk. The search for risk factors for developing a second solid tumor often ends by demonstrating that, besides host factors (such as gender, age94a or cigarette smoking), radiation therapy is the main risk factor. This finding is not surprising since almost all sites associated with a significantly increased risk concern sites that might have been included in the radiation fields. Of the 23 second solid tumors that occurred in the EORTC series, 16 developed within an irradiated area; 13 of these 16 tumors occurred in patients initially treated with extended-field irradiation.90 In this series, the cumulative risk of second solid tumors was significantly higher in patients initially treated with extended-field irradiation compared with those treated with mantle irradiation when either all solid tumors (P = 0.01) or solid tumors that developed within an irradiated area (P = 0.009) were considered. A similar observation was made at the Institut Gustave Roussy concerning secondary gastric carcinomas. Six out of nine patients referred to this institution for gastric carcinoma presented with linitis plastica; all patients were previously treated with extended-field irradiation (including the stomach within the irradiation volume) and large fraction size (>2.5Gy).95 Chemotherapy given in combination with radiation therapy as part of initial treatment was shown to add to the risk of irradiation alone in one study.64 In a casecontrol study, chemotherapy was associated with a risk of lung cancer that was twice that of irradiation alone or combined modality treatment.96 These findings must be considered together with the results of a recent study in which chemotherapy as a whole or individual drugs were associated with second cancer risk.63 Irradiation to the thorax was associated with an increased risk (RR = 2.7) of solid tumors of the respiratory system and intrathoracic organs developing 10 years or more after exposure, while chemotherapy was associated with an increased risk (RR = 2.2) of these tumors developing early (within the 0-4-year period after exposure). Tumors of the bones, joints, articular cartilage and soft tissues preferentially developed after chemotherapy (RR = 6.0) whatever the period considered; drugs associated with an increase in risk were procarbazine (RR = 3.7), vincristine (RR = 2.8),

doxorubicin (RR = 4.2) and bleomycin (RR = 3.0). Irradiation to the abdomen (RR = 2.4) was associated with tumors of the female genital system developing late (over 10 years after exposure), while chemotherapy (RR = 3.5) was associated with these tumors developing 5 years or more after exposure; vincristine was associated with an increased risk (RR = 4.7), while hormones were associated with a decreased risk (RR = 0.2). Finally, an increased risk (RR = 8.3) of thyroid cancer was observed after chemotherapy for the 0-4-year period after exposure, principally after exposure to lomustine (RR = 7.3). These results, however, must be confirmed from an independent series of patients with sufficient follow-up and treated to modern standards. If confirmed, they should encourage oncologists to use chemotherapy in the treatment of Hodgkin's disease more carefully. Treatment of the spleen as a risk factor for second solid tumor was reported for the first time in 1994.75 The assumption was made that splenic irradiation should induce similar spleen function loss as does splenectomy. In a series of 1003 adult patients continuously disease-free, 56 second tumors developed (37 solid tumors, 11 ANLLs and 8 non-Hodgkin's lymphomas), 17 in patients whose spleen was not treated, 22 in splenectomized patients and 17 in patients whose spleen was irradiated. Splenectomy (RR = 2.95; P = 0.023) and splenic irradiation (RR = 5.35; P - 0.002) were found to be independent risk factors for solid tumors. No correlation between splenectomy and an increased risk of second cancer was found in two previous studies performed on large series of male American servicemen splenectomized for external trauma during World War II97 and Danish people splenectomized for traumatic splenic rupture or other non-carcinologic reasons.87 These findings provide an argument for secondary cancer risk being more likely to be related to the underlying patient conditions than to the splenectomy itself. Spleen treatment (spleen removal or splenic irradiation), however, might have a limited but significant impact in particular patient subgroups, possibly those with pronounced persistent immunodeficiency. In these subgroups, treatment strategies should therefore be carefully adapted to the initial clinical presentation and the patient's ab initio prognosis.

Secondary malignancies in childhood Hodgkin's disease Most of the knowledge on second cancer risk in patients treated for childhood Hodgkin's disease comes from the Late Effect Study Group. Updated results from 1380 patients treated from 1955 to 1986, with a median followup of 11.4 years, have been recently reported.53,98 In this series, 88 second cancers developed (56 solid tumors, 26 leukemias (including 24 ANLL and 6 non-Hodgkin's lymphomas) leading to 15-year cumulative incidence rates of 3.9,2.8 and 1.1 per cent, respectively. The median time to

Quality of life in long-term survivors 429

second cancer was shorter for leukemias (4.4 years) than for solid tumors (13.8 years). The leukemia risk was dependent on advanced stage, treatment type (higher after chemotherapy alone than after irradiation and chemotherapy), chemotherapy (higher after MOPP than after ABVD) and alkylating score; in contrast, the risk of leukemia was not significantly increased in patients who had undergone splenectomy. The only factor associated with an increased risk of secondary non-Hodgkin's lymphoma was the alkylating score (RR = 1.7). In this series, most solid tumors developed within radiation fields. These were most commonly localized to female breast (17 cases; RR = 75.3; cumulative incidence at 40 years of age, 35 per cent) and thyroid (10 cases; RR = 32.7). Overall, the 20-year cumulative incidence rate of secondary solid tumors was 12.6 per cent in female (8.8 per cent after secondary breast cancers have been excluded) and 3.9 per cent in male patients. Secondary solid tumors were also more frequent in children aged 10-16 years at Hodgkin's disease diagnosis than in younger children. Risk factors for breast cancer were age > 10 (RR = 1.9), and total radiation dose between 20 and 39 Gy (RR = 5.9) or > 40 Gy (RR = 23.7). This study confirms that the risk for breast cancer is higher in patients irradiated as children or adolescents than in patients irradiated over age 40 years.56,94,99,101 Children and adolescents are also at higher risk than adults for developing secondary bone sarcoma, connective tissue sarcoma or thyroid cancer.102 Since the treatment of Hodgkin's disease is similar in children and adults, it can be concluded that, for these localizations, children are more sensitive to ionizing radiation effects than are adults. A statistically significant association between secondary ANLLs and previous administration of alkylating agents has been reported, with higher doses inducing higher risks; the risk of ANLL and that of non-Hodgkin's lymphoma also correlated with splenectomy.53,73,98 Host factors such as age and gender might also influence the risk for secondary cancer. In a series of 191 children of whom 109 were initially treated with irradiation alone, 15 patients subsequently developed a second tumor 6-20 years after the diagnosis of Hodgkin's disease for a 15-year cumulative incidence rate of 12 per cent. The rates were 24 per cent in females (10 cases) and 5 per cent in males (5 cases) with a relative risk for female compared with male patients of 4.5 (P = 0.013).10° The 15 patients who developed a second tumor were all irradiated and 4 out of 10 second tumors in females developed in the breast, emphasizing the role played by irradiation in the genesis of second cancers.

Secondary malignancies after nonHodgkin's lymphoma Less information is available for non-Hodgkin's lymphoma but, indeed, in a recent report of young

long-term survivors, second malignancies were uncommon.27 In other series, both leukemias and solid tumors have been seen but, in contrast to that observed in Hodgkin's disease patients, second solid tumors represent 75-95 per cent of all secondary malignancies.103-105 This difference is partly explained by age at diagnosis of primary non-Hodgkin's lymphoma.93,105 In a series of 6171 patients treated during 1965-1980, increased risks (compared with a reference population) concerned secondary leukemias (RR = 3.99, almost all ANLL with RR = 4.83), secondary Hodgkin's disease (RR = 12.02, with 21 out of 22 cases histologically confirmed) and secondary solid tumors (RR = 1.28).105 Among the latter, the risk was significantly increased for lung (RR = 1.36), kidney (RR = 2.07), bladder (RR = 1.77), melanoma (RR = 2.38), brain and central nervous system (RR = 2.33). Overall, the risk was higher in men (RR = 1.51) than in women (RR = 1.18); it was independent of time since non-Hodgkin's lymphoma diagnosis. In this series, the 20-year cumulative incidence rate was 21.1 per cent (expected rate 15.4 per cent) and 19.3 per cent (expected rate 15.0 per cent) for secondary solid tumors taking at a whole. The risk of secondary malignancy, however, did not correlate to any particular therapeutic scheme, confirming that observed in two further studies.103,104 The relationship between the total dose of cyclophosphamide, the total irradiation dose to kidney and bladder, and the risk of kidney or bladder cancer was addressed in a case-control study.106 In this study, there was a significant increased risk (matched RR = 4.5) of bladder cancer in patients treated with cyclophosphamide (alone or in combination with other cytostatic drugs), with or without associated irradiation. The increase in risk also depended on the total dose of cyclophosphamide given (P < 0.005). Neither the cyclophosphamide dose nor irradiation were associated with an increased risk of secondary kidney carcinoma. In the last two decades, most if not all studies have focused on the potential risk for occurrence of a second tumor in relation to initial lymphoma treatment or to a specific agent. Recently, other factors (such as alterations in the retinoblastoma locus, germline mutations in p53, and congenital or acquired immunodeficiency states) have emerged as predisposing factors for the risk of developing a second tumor.102 Although not yet related to solid tumors secondary to Hodgkin's disease or nonHodgkin's lymphoma, the impact of host factors should certainly be considered in the future beyond that of the treatment itself.

QUALITY OF LIFE IN LONG-TERM SURVIVORS Treatment-related acute and chronic medical as well as psychosocial complications can interfere with the quality of life of Hodgkin's disease survivors.107-109 The range and


magnitude of psychosocial problems (physical impairments, social and familial morbidity, sexuality, discrimination in employment and in obtaining insurance) observed in Hodgkin's disease survivors have only recently been explored,110,111 which is not yet the case in patients cured of non-Hodgkin's lymphoma. Psychological and social disturbances are usually reported during and after treatment.110-113 The actual problem of quality of life in long-term survivors has been addressed in only a few studies, most of which are not comparative. In 1995, a study was conducted to compare the type and frequency of psychosocial difficulties among 93 French adult Hodgkin's disease survivors (4-17 years since treatment) with that of 186 healthy controls using a population-based case-control design.4 Hodgkin's disease survivors expressed more limitation in physical activities than controls because of residual physical (P < 0.001) and role-functioning (P < 0.001) impairments, persistence of dyspnea (P < 0.001) and chronique fatigue (P = 0.025) as measured by the EORTC QLQ-C30 core questionnaire.114 These results were in agreement with those previously reported in hospital series.110,111,115 Hodgkin's disease survivors also more often expressed difficulties (P = 0.015) in concentration or with memory than controls as previously reported.116,117 Global health status was equally scored as good by patients and controls, while data in the literature are conflicting.110,115,117 In the study by Joly et al.4 just as in the majority of cancer quality-oflife studies, no major late psychological or psychiatric distress were observed in both survivors and controls,115,118,119 while psychologically vulnerable cancer patient groups who remain distressed over time have been described.120 Familial disturbances are of great concern among long survivors from cancer. Data on interpersonal relationships and sexual activities are conflicting. In the study by Joly et a/.,4 patients experienced fewer separations or divorces, but similar sexual activity compared with controls. Changes in relationships with friends were also less frequent in cases than in controls, who reported to have lost more friends. Whereas married status at the time of diagnosis can influence survival, altered marriage practices were very limited among survivors from childhood and adolescent cancers as were changes in relationships with close friends as a result of the illness.108,110,121122 Other studies demonstrated that long-term Hodgkin's disease survivors might experience more frequent separations and divorces than the general population.110,113 General dissatisfaction with sex life or more changes in interest in sex and attractiveness have been reported.,108.111 Although cases had fewer children than controls, which was often related to chemotherapy-induced sterility, French patients and controls had similar familial status; familial relationships appeared to be satisfactory and did not influence the level of quality of life, in contrast to that observed in studies focusing on adolescent long-term survivors.1

Of the French newly diagnosed cancer patients who were working at the time of disease, 64 per cent reported a return at work after treatment;124 however, changes in employment or working position were mentioned by 38 per cent of patients, which is in agreement with the study by Joly et al.4 In the latter study, Hodgkin's disease survivors more frequently reported less professional ambition, as if they preferred to have more modest goals to allow more time for enjoying life, and they chose not to run after success as described by Siegel and Christ.108 In contrast, compared with their situation before the disease developed, patients enrolled in the Stanford series reported having increased their professional ambition.111 These conflicting results must be viewed cautiously because, in the Stanford series, no control group was available, the study was performed in 1985 in patients treated 1-21 years beforehand and involved people with different educational backgrounds. Most Hodgkin's disease survivors associate work-related problems with their illness.108,115 Work-related problems are reported in long-term cancer survivors concerning promotional and income prospects, closely related with problems in borrowing from banks or difficulties with insurance companies.110,115,117 Even in patients cured from their disease, problems regarding insurance and bank loans remain a major difficulty for long-term survivors in their daily life as well as in their professional life, in particular in those who wish to establish their own business.110,111,125 Although society remains slow to integrate the improved prognosis of Hodgkin's disease patients into its perception of these patients and into its employment and insurance policies, Hodgkin's disease survivors seem to have learned to cope with the problems related to their disease and its treatment.

CAUSES OF DEATH The risk of dying from specific causes after Hodgkin's disease has been reported in limited studies. After nonHodgkin's lymphoma, the risk of dying from causes other than disease progression has not been explored, that of death from secondary malignancy excepted. In 1986, Rubin et al. reported no significant difference between overall survival and survival corrected for second cancer mortality in a series of 320 clinical Stage I—IV patients,126 while the EORTC reported a 5 per cent difference in the 15-year survival rates between crude and corrected survival in a series of 1501 clinical Stage I-II patients.90,127 Similar findings were reported by the Stanford University group, the International Database on Hodgkin's Disease (IDHD) and the British National Lymphoma Investigation (BNLI).28,29,107,128 In these three series, in patients cured of Hodgkin's disease, intercurrent deaths represented the first cause, followed by secondary cancer-related and treatment-related deaths.

Conclusion 431

Intercurrent deaths were mainly from cardiovascular and infective complications. The risk of dying from cardiac failure was investigated in four Hodgkin's disease series. In a cohort of 957 patients diagnosed with Hodgkin's disease during 1942-1975, 25 coronary heart disease deaths were observed, giving a death rate relative to the general population rate of 0.91, not significantly different from 1.19 In contrast, the RRs of death were 1.97 (P < 0.001) in the Dutch series,129 3.2 (P < 0.01) in the Stanford series,29 2.8 (P < 0.001) in the IDHD series (unpublished results) and 8.63 (P < 0.001) in the EORTC series.127 Factors affecting death from cardiac failure were heart irradiation as part of the mantle field irradiation in almost all series, and male gender. In the Stanford series, mediastinal radiation dose above 30 Gy was associated with an increased risk (RR = 3.5) and patients treated with radiation therapy alone had a higher risk than those treated with combined modality therapy; the cumulative probability of dying from cardiac failure was 15.5 per cent in mates, while it was 3.5 per cent in females.22 In this series, the risk of dying from acute myocardial infarction or from other cardiac disease was much greater when patients were treated before the age of 20 (RR = 44.1 and 21.5, respectively); that of acute myocardial infarction decreased thereafter (from 7.3 in patients aged 20-29 to 1.8 in patients aged 50 or above) but remained significantly increased at all ages, whereas the risk of dying from other cardiac disease remained increased only in patients younger than 40 (RR = 8.8 and 4.8 in patients aged 20-29 and 30-39, respectively). The risk of both myocardial infarction-related and other cardiac diseaserelated death also significantly increased with time from initial Hodgkin's disease treatment. In the Stanford series, infective deaths concerned opportunistic infection, pneumonia and chronic disease, and asplenic sepsis.28 They were as frequent as cardiac deaths and were not influenced by the administration of previous MOPP chemotherapy. They might, however, have been a consequence of mediastinal and lung irradiation, splenectomy, or both. In patients treated with a combination of irradiation and MOPP, total nodal irradiation was shown to increase the risk of dying from other causes significantly (4 ANLL and 5 infections in 74 patients) compared with mantle and para-aortic irradiation (1 infection in 121 patients).130 Infective deaths represented 35 per cent of all intercurrent deaths that occurred in 774 patients aged 15-29, who remained disease-free in the BNLI series.128 In the IDHD series, infective deaths represented 34 per cent of all intercurrent deaths, corresponding to a RR of 9.0 (P < 0.001) (unpublished results). Overall, the risk of dying from other causes than Hodgkin's disease progression was analysed relative to that of the general population (matched for sex, age and country) in the IDHD series on all stages, and in the EORTC series on early stages. In the IDHD series, the

risk was 2.01 in males and 2.30 in females; it was 2.07 in patients with early stage disease and 2.13 in patients with advanced stage disease.107 The risk increased with time from initial treatment, from 1.79 in the 0-4-year period to 3.08 in the 15-19-year period; in contrast, the risk decreased with age at Hodgkin's disease diagnosis, from 4.13 in patients aged 15-19 to 1.42 in patients aged 60 or above. In this series, the 20-year cumulative probability of dying from intercurrent disease was above that of dying from Hodgkin's disease progression. In the EORTC series, patients cured from Hodgkin's disease had a risk of dying from causes unrelated to the disease itself multiplied by 3.11 (P < 0.001) compared to that of the general population.127 The risk was higher in females than in males (RR = 3.28 and 3.06, respectively); it was higher in patients aged 15-39 at diagnosis than in patients aged 40 and above (RR = 3.46 and 2.85, respectively). The risk increased with time from initial treatment, from 1.91 in the 0-2-year period to 3.85 in the 15-17-year period with a peak (RR = 5.79) during the 9-11-year period. Similar findings were observed in males and in females, and also in patients aged 15-39 and in older patients. Finally, in the Stanford series, the loss in the 20-year survival rate was 7 per cent due to death from a malignancy other than Hodgkin's disease; it was also 7 per cent due to death from acute myocardial infarction.28,29 In the EORTC series, second cancer and cardiac failure (sudden deaths of unspecified cause excluded) were responsible for a difference in the 20-year survival rate of 7.3 and 5.7 per cent, respectively.127 The BNLI reported a 5.5 per cent difference (deaths from all causes included) at 20 years between observed and expected survival rates in patients aged 15-29.128 In the IDHD series, deaths unrelated to Hodgkin's disease and its treatment were responsible for a decrease in the 15-year survival rate of 7 per cent.107

CONCLUSION Long-term non-malignant as well as malignant complications are seen because the treatment of Hodgkin's disease and, more recently, that of non-Hodgkin's lymphoma is successful. Non-malignant complications are likely to be related to treatment, although some problems might be associated with the disease itself. Modern irradiation techniques, new combination chemotherapies and new strategies should concur to decrease incidence rates. Even though malignant complications are mostly treatment-induced, the exact role of radiation therapy (dose and volume) and chemotherapy as risk factors for solid tumors remains to be assessed. Oncologists who nowadays tend to propose chemotherapy as the unique treatment in all stages of Hodgkin's disease should carefully balance the risk of radiationand chemotherapy-related malignant (leukemias and


solid tumors), and non-malignant complications.131 Treatment duration should also be considered because, the longer the treatment, the higher the probability of psychological distress. Most patients who achieve remission will remain disease-free as well as free of serious complications. Nonetheless, long-term survivors should be carefully followed at regular intervals to help prevent, or diagnose at an early stage, any complication that can occur a long period after the patient has been cured.132 Attempts should also be made by the medical community to convince society, life insurance companies and banks that they can help long-term survivors to enjoy a normal life.

5. Bjbrkholm M, Holm G, Mellstedt H. Immunocompetence in patients with Hodgkin's disease. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990:12-150. 6. Amstrong D, Minamoto GY. Infectious complications of Hodgkin's disease. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990:151-67. 7. Kluin-Nelemans JC, Henry-Amar M, Carde P, et al. Assessment of thyroid, pulmonary, cardiac and gonadal toxicity in stages l-ll Hodgkin's disease. Abstracts of the Third International Symposium on Hodgkin Lymphoma September 18-23,1995, Kbln, Germany, 1995: 90 (abstract 72). 8. Hancock SL, Cox RS, McDougall IR. Thyroid diseases

SUMMARY

after treatment of Hodgkin's disease. N EnglJ Med 1991; 325: 599-605.

Hodgkin's disease is considered a curable disease. The use of appropriate staging techniques and treatment methods has resulted in long-term cause-specific survival rates as high as 90 per cent in the early stages, and 75 per cent or greater in the advanced stages. In nonHodgkin's lymphomas, new therapeutic approaches are expected to result in a cure rate of 75 per cent or more. Long-surviving lymphoma patients, however, face new problems that have become apparent as larger numbers of successfully treated patients are followed for longer periods of time. These problems mostly concern chronic medical as well as psychosocial complications, which can interfere with quality of life. Lymphoma therapy may result in severe infections, or thyroid, cardiovascular, pulmonary, digestive or gonadal dysfunction. It may also result in secondary malignancy, which is considered the most serious complication. Because the vast majority of patients who are long-term survivors will remain symptom-free and do enjoy a normal life, long-term followup should concentrate on prevention and early detection of treatment-related complications, and of secondary malignancy.

9. Peerboom PF, Hassink EAM, Melkert R, et al. Thyroid function 10-18 years after mantle field irradiation for Hodgkin's disease. EurJ Cancer 1992; 28A: 1716-8. 10. Desablens B, Alliot C, Dierick A, et al. Hypothyroidism after Hodgkin's disease. Pathogenic hypothesis from a study of 51 patients treated by 3 courses of the ABVDMP regimen and 40 Gy radiotherapy. Abstracts of the Third International Symposium on Hodgkin Lymphoma, September 18-23,1995, Koln, Germany, 1995:117 (abstract 99). 11. Redman JR, Bajorunas DR. Therapy-related thyroid and parathyroid dysfunction in patients with Hodgkin's disease. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990:222-43. 12. Gerling B, Gottdiener J, Borer JS. Cardiovascular complications of the treatment of Hodgkin's disease. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990:267-95. 13. Mauch P. Controversies in the management of early stage Hodgkin's disease. Blood 1994; 83: 318-29. 14. Morgan GW, Freeman AP, McLean RG, et al. Late cardiac, thyroid, and pulmonary sequelae of mantle

REFERENCES

radiotherapy for Hodgkin's disease. Int J Radial Oncol Biol Phys 1985; 11:1925-31. 15. Pohjola-Sintonen S, Tbtterman KJ, Salmo M, et al. Late

1. Urba WJ, Longo DL Hodgkin's disease. N EnglJ Med

cardiac effects of mediastinal radiotherapy in patients

1986; 326: 678-87. 2. Bookman MA, Longo DL. Concomitant illness in patients

with Hodgkin's disease. Cancer 1987; 60: 31-7. 16. Gustavsson A, Eskilsson J, Landberg T, et al. Late cardiac

treated for Hodgkin's disease. Cancer Treat Rev 1986; 13:77-111. 3. Smith J, Griffiths H. The skeletalsystem. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences

effects after mantle radiotherapy in patients with Hodgkin's disease. Ann Oncol 1990; 1: 355-63. 17. Savage DE, Constine LS, Schwartz RG, et al. Radiation effects on left ventricular function and myocardial

of survival. Philadelphia: Lea & Febiger, 1990:

perfusion in long term survivors of Hodgkin's disease.

182-202.

Int J Radiat Oncol Biol Phys 1990; 19: 721 -7.

4. Joly F, Henry-Amar M, Arveux P, et al. Late psychosocial sequelae in Hodgkin's disease survivors: a French

18. PiergaJY, Maunoury C, Valette H, et al. Thallium-201 myocardial tomoscintigraphy before mantle field

population based case-control study.J Clin Oncol 1996;

radiotherapy for Hodgkin's disease. Ann Oncol 1996;

14: 2444-53.

7(suppl 3): 76.

References 433 19. Boivin JF, Hutchison GB. Coronary heart disease mortality after irradiation for Hodgkin's disease. Cancer 1982; 49: 2470-5. 20. Corn BW, Trock BJ, Goodman RL Irradiation-related ischemic heart disease. 7 Clin Oncol 1990; 8: 741-50. 21. Cosset JM, Henry-Amar M, Pellae-Cosset B, et al. Pericarditis and myocardial infarctions after Hodgkin's disease therapy at the Institut Gustave Roussy. Int J Radial Oncol Bio Phys 1991; 21: 447-9. 22. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 1993; 270:1949-55. 23. Joensuu H. Myocardial infarction after irradiation in Hodgkin's disease: a review. Recent Results Cancer Res 1993:130:157-73. 24. Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful treatment for Hodgkin's disease. J Clin Oncol 1998; 16: 3592-600. 25. Cosset JM, Henry-Amar M, Meerwaldt JH. Long-term toxicity of early stages Hodgkin's disease therapy: the EORTC experience. Ann Oncol 1991; 2(suppl 2): 77-82. 26. BrierleyJD, Rathmell AJ, Gospodarowicz MK, et al. Late effects of treatment for early-stage Hodgkin's disease. BrJ Cancer 1998; 77:1300-10. 27. Haddy TB, Adde MA, McCalla J, et al. Late effects in longterm survivors of high-grade non-Hodgkin's lymphomas.y Clin Oncol 1998; 16: 2070-9. 28. Hancock SL, Hoppe RT, Horning SJ, et al. Intercurrent death after Hodgkin's disease therapy in radiotherapy and adjuvant MOPP trials. Ann Intern Med 1998; 109: 183-9. 29. Hancock SJ, Cox RS, Rosenberg SA. Death after treatment of Hodgkin's disease. Ann Intern Med 1991; 114:810. 30. Tarbell NJ, Mauch P, Hellman S. Pulmonary complications of Hodgkin's disease treatment: radiation pneumonitis, fibrosis, and the effect of cytotoxic drugs. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990:296-305. 31. Hellman S, Mauch P, Goodman RL,etal. The place of radiation therapy in the treatment of Hodgkin's disease. Cancer 1978; 42: 971-8. 32. Kaplan HS, Stewart JR, Bissinger PA. Complications of intensive megavoltage radiotherapy for Hodgkin's disease. Natl Cancer Inst Monogr 1973; 36: 439-44. 33. Dubray B, Henry-Amar M, Meerwaldt JH, et al. Radiation-induced lung damage after thoracic irradiation for Hodgkin's disease: the role of fractionation. Rodiother Oncol 1995; 36: 211-7. 34. Zucali R, Pagnoni AM, Zanini M, et al. Radiological and spirometric evaluation of mediastinal and pulmonary late effects after radiotherapy and chemotherapy for Hodgkin's disease, j Eur Radiother (Paris) 1981; 2: 169-76. 35. Mah K, Keane TJ, Van Dyk J, et al. Quantitative effects of combined chemotherapy and fractionated radiotherapy

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

on the incidence of radiation-induced lung damage: a prospective clinical study. Int J Radial Oncol Biol Phys 1994; 28: 563-74. Gustavsson A, Eskilsson J, Landberg T, et al. Long-term effects on pulmonary function of mantle radiotherapy in patients with Hodgkin's disease. Ann Oncol 1992; 3: 455-61. Santoro A, Bonadonna G, Valagussa P, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. 7 Clin Oncol 1987; 5: 27-37. Young RC, Bookman MA, Longo DL. Late complications of Hodgkin's disease management. Natl Cancer Inst Monogr 1990; 10: 55-60. Jockovich M, Mendenhall NP, Sombeck MD, et al. Longterm complications of laparotomy in Hodgkin's disease. Ann Surg 1994; 219: 615-24. Coia LR, Hanks GE. Complications from large field intermediate dose infradiaphragmatic radiation: an analysis of the patterns of care outcome studies for Hodgkin's diseases and seminoma. Int J Radial Oncol Biol Phys 1988; 15: 29-35. Cosset JM, Henry-Amar M, Burgers JMV, et al. Late injuries of the gastrointestinal tract in the H2 and H5 EORTC Hodgkin's disease trials: emphasis on the role of exploratory laparotomy and fractionation. Radiother Onco/1988;13:61-8. Sherins RJ. Gonadal dysfunction. In: De Vita VT, Hellman S, Rosenberg SA, eds Cancer: Principles and Practice of Oncology, 4th edn. Philadelphia: Lippincott, 1993:2395-406. Charak BS, Gupta R, Mandrekar P, et al. Testicular dysfunction after cyclophosphamide-vincristineprocarbazine-prednisolone chemotherapy for advanced Hodgkin's disease. Cancer 1990; 65:1903-6. Clark ST, Radford JA, Crowther D, et al. Gonadal function following chemotherapy for Hodgkin's disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol 1995; G: 134-9. Bonfante V, Vivian! S, Devizzi L, et al. Fertility evaluation in patients with Hodgkin's disease. Abstracts of the Third International Symposium on Hodgkin Lymphoma, September 18-23,1995, Kbln, Germany, 1995: 88 (abstract 70). Hill M, Milan S, Cunningham D, et al. Evaluation of the VEEP regimen in adult Hodgkin's disease with assessment of gonadal and cardiac toxicity. J Clin Oncol 1995; 13: 387-95. BramswigJH, Heimes U, Heiermann E, et al. The effects of different cumulative doses of chemotherapy on testicular function. Cancer 1990; 65:1298-1302. Ortin TTS, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin's disease in childhood: the Stanford experience. IntJ Radial Oncol Biol Phys 1990; 19: 873-80.

434 Long-term problems 49. Muller U, Stahel RA. Gonadal function after MACOP-B or VACOP-B with or without dose intensification and ABMT in young patients with aggressive non-Hodgkin's lymphoma. Ann Oncol 1993; 4: 399-402. 50. Aisner J, Wiernik PH, Pearl P. Pregnancy outcome in patients treated for Hodgkin's disease.J C/w Oncol 1993; 11:507-12. 51. Redman JR, Bajorunas DR, Lacher MJ. Hodgkin's disease: pregnancy and progeny. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival Philadelphia: Lea & Febiger, 1990: 244-66. 52. Henry-Amar M, Dietrich PY. Acute leukemia after the treatment of Hodgkin's disease. Hematol Oncol Clinics North Am 1993; 7: 369-87. 53. Robison LL, Mertens A. Second tumors after treatment of childhood malignancies. Hematol Oncol Clinics North Am 1993; 7: 401 -5. 54. Tucker MA. Solid second cancers following Hodgkin's disease. Hematol Oncol Clinics North Am 1993; 7: 389-400. 55. Mauch P, Kalish LA, Marcus KC, et al. Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood 1996; 9: 3625-32. 56. Sankila R, Garwicz S, Olsen JH, et al. Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in five Nordic countries. J Clin Oncol 1996; 14:1442-6. 57. Horwich A, Swerdlow AJ, Barber JA, Vaughan Hudson G, Gupta RK, Linch D, Cunningham D, Lister TA. Analysis of second malignancy after Hodgkin's disease. BrJ Cancer 1998;78(suppl2). 58. National Research Council. Committee on the Biological Effects of Ionizing Radiations. The effects on populations of exposure to low levels of ionizing radiation. Washington, DC: National Academy Press, 1980. 59. National Research Council. Committee on the Biologic Effects of Ionizing Radiations. Health effects of exposure to low levels of ionizing radiation. Washington, DC: National Academy of Sciences, 1990. 60. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall evaluations of carcinogenicity. An updating of IARC Monographs, Vol. 1 -42 (suppl 7). Lyon: International Agency for Research on Cancer, 1987. 61. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some pharmaceutical drugs, Vol. 50. Lyon: International Agency for Research on Cancer, 1991. 62. Boffetta P, Kaldor JM. Secondary malignancies following cancer chemotherapy. Ada Oncol 1994; 33: 591-8. 63. Boivin JF, Hutchison GB, Zauber AG, et al. Incidence of second cancers in patients treated for Hodgkin's disease.) Natl Cancer Inst 1995; 87: 732-41.

64. Biti G, Cellai E, Magrini S, et al. Second solid tumors and leukemia after treatment for Hodgkin's disease: an analysis of 1121 patients from a single institution. IntJ Radiat Oncol Biol Phys 1994; 29: 25-31. 65. Harrison CN, Hudson GV, Devereux S, Linch DC. Outcome of secondary myeloid malignancy in Hodgkin's disease: the BNLI experience. EurJ Haematol 1998;61:109-12. 66. Blayney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin's disease. N EnglJ Med 1987; 316: 710-4. 67. Valagussa P, Bonadonna G. Hodgkin's disease and second malignancies. Ann Oncol 1993; 4: 94-5 (editorial). 68. Kaldor JM, Day NE, Clarke EA, et al. Leukemia following Hodgkin's disease. N EnglJ Med 1990; 322: 7-13. 69. Henry-Amar M. Second cancer after the treatment for Hodgkin's disease: a report from the International Database on Hodgkin's Disease. Ann Oncol 1992; 3(suppl4):S117-28. 70. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al. Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BrMedJ 1992;304:1137-43. 71. Abrahamsen JF, Andersan A, Hannisdal E, et al. Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time and age. J Clin Oncol 1993; 11: 255-61. 72. van Leeuwen FE, Chorus AMJ, van den Belt-Dusebout AW, et al. Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. J Clin Oncol 1994; 12:1063-73. 73. Beaty 0, Hudson MM, Greenwald C, et al. Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease.) Clin Oncol 1995; 13: 603-9. 74. Andrieu JM, Ifrah N, Payen C, et al. Increased risk of secondary acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy for Hodgkin's disease. J Clin Oncol 1990; 8:1148-54. 75. Dietrich PY, Henry-Amar M, Cosset JM, et al. Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 1994; 84:1209-15. 76. Tucker MA, Meadows AT, Boice JD, et al. Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst 1987; 78: 459-64. 77. Henry-Amar M, Pellae-Cosset B, Bayle-Weisgerber C, et al. Risk of secondary acute leukemia and pre-leukemia after Hodgkin's disease: the Institut Gustave Roussy experience. Recent Results Cancer Res 1989; 117: 270-83.

References 435

78. Meadows AT, Obringer AC, Marrero 0, et al. Second malignant neoplasms following childhood Hodgkin's disease: treatment and splenectomy as risk factors. Med Pediat Oncol 1989; 17: 477-84. 79. van der Velden JW, van Putten WL, Guinee VF, et al. Subsequent development of acute non-lymphocytic leukemia in patients treated for Hodgkin's disease. Int J Cancer 1988; 42: 252-5.

93. Parkin DM, Muir CS, Whelan SL, et al. eds Cancer incidence in five continents, Vol. VI. World Health Organization, IARC Scientific Publications no. 120. Lyon: International Agency for Research on Cancer, 1992. 94. Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 1993; 85:25-31. 94a. Swerdlow AJ, Barber JA, Vaughan Hudson G, et al. Risk

80. Devereux S, Selassie TG, Vaughan Hudson G, et al.

of second malignancy after Hodgkin's disease in a

Leukaemia complicating treatment for Hodgkin's

collaborative British cohort: the relation to age at

disease: the experience of the British National Lymphoma Investigation. BrMedJ 1990; 301:1077-80. 81. Rodriguez MA, Fuller LM, Zimmerman SO, et al. Hodgkin's disease: study of treatment intensities and incidence of second malignancies. Ann Oncol 1993; 4:125-31. 82. van Leeuwen FE, Klokman WJ, Hagenbeek A, et al. Second cancer risk following Hodgkin's disease: a 20year follow-up study. 7 Clin Oncol 1994; 12: 312-25. 83. Brusamolino E, Orlandi E, Astori C, et al. Myelodysplasia and leukemia in Hodgkin's disease are related to age, splenectomy, and combined radio-chemotherapy with MOPP and nitrosoureas. Abstracts of the Third International Symposium on Hodgkin Lymphoma, September 18-23, Koln, Germany, 1995: 222 (abstract 189). 84. Tucker MA, Coleman NC, Cox RS, et al. Risk of secondary malignancies following Hodgkin's disease after 15 years. N EnglJ Med 1988; 318: 76-81. 85. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al. Risk of second primary cancer after Hodgkin's disease in patients in the British National Lymphoma Investigation: relationships to host factors, histology and stage of Hodgkin's disease, and splenectomy. BrJ Cancer 1993; 68:1006-11. 86. van Leeuwen FE, Somers R, Hart AAM. Splenectomy in Hodgkin's disease and second leukaemias. Lancet 1987; ii: 210-11 (letter). 87. Mellemkjoer L, Olsen JH, Linet MS, et al. Cancer risk following splenectomy. Cancer 1995; 75: 577-83. 88. Krikorian JG, Burke JS, Rosenberg SA, et al. Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease. N EnglJ Med 1979; 300: 452-8. 89. Kaldor JM, Day NE, Band P, et al. Second malignancies following testicular cancer, ovarian cancer, and Hodgkin's disease: an international collaborative study among cancer registries. IntJ Cancer 1987; 39: 571-5. 90. Henry-Amar M. Quantitative risk of second cancer in patients in first complete remission from early stages of Hodgkin's disease. Natl Cancer Inst Monogr 1988; 6: 65-72. 91. Bennett MH, MacLennan KA, Vaughan Hudson G, et al. Non-Hodgkin's lymphoma arising in patients treated for Hodgkin's disease in the BNLI: a 20-year experience. Ann Oncol 1991; 2(suppl 2): 83-92. 92. Zarrabi MH, Rosner F. Second neoplasms in Hodgkin's

treatment. J Clin Oncol 2000; 18: 498-509. 95. Dietrich PY, Bellefqih S, Henry-Amar M, et al. Linitis plastica after Hodgkin's disease. Lancet 1993; 342: 57-8 (letter). 96. Kaldor JM, Day NE, BellJ, et al. Lung cancer following Hodgkin's disease: a case-control study. Int J Cancer 1992;52:677-81. 97. Robinette CD, Fraumeni JF Jr. Splenectomy and subsequent mortality in veterans of the 1939-1945 war. Lancet 1977; 2:127-9. 98. Bhatia S, Robison LL, Oberlin 0, et al. Breast cancer and other second neoplasms after childhood Hodgkin's disease. N EnglJ Med 1996; 334: 745-51. 99. Land CE. A nested case-control approach to interactions between radiation dose and other factors as causes of cancer. RERF. Commentary and Review Series CR1-90. Hiroshima: Radiation Effects Research Foundation, 1990. 100. Tarbell NJ, Gelber RD, Weinstein HJ, Mauch P. Sex differences in risk of second malignant tumours after Hodgkin's disease in childhood. Lancet 1993; 341: 1428-32. 101. Wolf J, SchellongG, Diehl V. Breast cancer following treatment of Hodgkin's disease - more reasons for less radiotherapy? EurJ Cancer 1997; 33: 2293-4. 102. Tucker MA. Secondary cancers. In: De Vita VT, Hellman S, Rosenberg SA, eds Cancer: principles and practice of oncology, 4th edn. Philadelphia: Lippincott, 1993: 2407-16. 103. Lavey RS, Eby NL, Prosnitz LR. Impact on second malignancy risk of the combined used of radiation and chemotherapy for lymphomas. Cancer 1990; 66: 80-8. 104. Lishner M, Slingerland J, Barr),etal.Second malignant neoplasms in patients with non Hodgkin's lymphoma. Hematol Oncol 1991; 9:169-79. 105. Travis LB, Curtis RE, Glimelius B, et al. Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 1993; 85:1932-7. 106. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst 1995; 87: 524-30. 107. Henry-Amar M, Somers R. Survival outcome after Hodgkin disease: a report of the International Data

disease: current controversies. Hematol Oncol Clinics

Base on Hodgkin's Disease. Semin Oncol 1990; 17:

North Am1989;3:303-18.

758-68.


108. Siegel K, Christ GH. Hodgkin's disease survivorship: psychosocial consequences. In: Lacher MJ, Redman JR, eds Hodgkin's disease: the consequences of survival. Philadelphia: Lea & Febiger, 1990: 383-99. 109. Yellen SB, Cella DF, Bonomi A. Quality of life in people with Hodgkin's disease. Oncology 1993; 7: 41-52. 110. Cella DF, Tross S. Psychological adjustment to survival from Hodgkin's disease. J Consult Clin Psychol 1986; 54:

120. Ell K, Nishimoto R, Morvay T, et al. A longitudinal analysis of psychological adaptation among survivors of cancer. Cancer 1989; 63: 406-13. 121. Byrne J, Fears TR, Steinhorn SC, et al. Marriage and divorce after childhood and adolescent cancer. JAMA 1989; 17: 2693-9. 122. Goodwin JS, Hunt WC, Key CR, et al. The effect of marital status on stage, treatment and survival of

616-22. 111. Fobair P, Hoppe R, Bloom J, et al. Psychosocial problems among survivors of Hodgkin's disease. 7 Clin Oncol 1986; 4: 805-14.

cancer patients. JAMA 1987; 258: 3125-30. 123. Zeltzer LK. Cancer in adolescents and young adults psychosocial aspects: long term survivors. Cancer 1993; 71:3463-8.

112. Kornblith AB, Anderson J, Cella DF, et al. Hodgkin's

124. Schraub S, Briand M, Bosset JF, et al. Professional rehabilitation of cancer patients after treatment. Bull

disease survivors at increased risk for problems in psychosocial adaptation. Cancer 1992; 70: 2214-24. 113. Wasserman AL, Thompson El, WilimasJA, et al. The psychological status of survivors of childhood/adolescent Hodgkin's disease. AmJ Dis Children 1987; 141: 626-31. 114. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer /nsM 993; 85: 365-76. 115. van Tulder MW, Aaronson NK, Bruning PF. The quality of life of long term survivors of Hodgkin's disease. Ann Oncol 1994; 5:153-8. 116. Devlen J, Maguire P, Phillips P, et al. Psychological problems associated with diagnosis and treatment of lymphomas: Prospective study. BrMedJ 1987; 295: 955-7. 117. Hoerni B, Zittoun R, Rojouan J, et al. Retentissement psychosocial du traitement de la maladie de Hodgkin: appreciation par questionnaire aupres de 150 malades.

Cancer (Paris) 1982; 69: 393-8. 125. McKenna RJ, Black B, Hughes R, et al. Workgroup #2: insurance and employability. Cancer 1993; 71: 2414-8. 126. Rubin P, Zagars G, Chuang C, et al. Hodgkin's disease: is there a price for successful treatment? A 25-year experience. Int J Radial Oncol Biol Phys 1986; 12: 153-66. 127. Henry-Amar M, Somers R. Long term survival in early stages Hodgkin disease: the EORTC experience. In: Somers R, Henry-Amar M, Meerwaldt JH, Carde P, eds Colloque Treatment strategy in Hodgkin's disease INSERM, Vol. 196. London: John Libbey Eurotext, 1990: 151-66. 128. Vaughan Hudson B, Vaughan Hudson G, Linch DC, et al. Late mortality in young patients cured of Hodgkin's disease. Ann Oncology 1994; 5(suppl 2): S65-6. 129. van Rijswijk REN, Verbeek J, Haanen C, et al. Major complications and causes of death in patients treated for Hodgkin's disease.J Clin Oncol 1987; 5:1624-33. 130. Mauch P, Canellos GP, Rosenthal DS, et al. Reduction of fatal complications from combined modality therapy in Hodgkin's disease.; Clin Oncol 1985; 3: 501-5.

Bull Cancer (Paris) 1986; 73: 620-6. 118. Derogatis LR, Morrow GR, Petting J, et al. The prevalence

131. Longo DL. Chemotherapy alone in the treatment of

of psychiatric disorders among cancer patients. JAMA 1983; 249: 751-7. 119. Teta MJ, Del Po MC, Kasl SV, et al. Psychosocial consequences of childhood and adolescent cancer

patients with early stage Hodgkin's disease. Ann Oncol 1996; 7(suppl 4): S85-9. 132. Green DM, Hyland A, Barcos MP, et al. Second malignant neoplasms after treatment for Hodgkin's disease in

survival. 7 Chrome Dis 1986; 39: 751-9.

childhood or adolescence. J Clin Oncol 2000; 18:1492-9.

31 The way forward BW HANCOCK, PJ SELBY, JO ARMITAGE AND KA MACLENNAN

This book has been written in the early aftermath of a wave of reclassification of malignant lymphoma, which has introduced into recognition and usage the Revised European-American Lymphoma classification and the World Health Organisation classification derived from it. This has taken the field forward and brought together histopathological subdivisions with the recognition of entities useful to clinical lymphoma specialists. Closer links between lymphoma morphology, clinical features and molecular pathology have emerged with a few quite specific associations, such as the chromosome 2'-5'translocation and anaplastic lymphoma, to add to those previously identified. Within each division and subdivision of the new classification, there is still considerable heterogeneity not only in morphology, clinical features and tempo but also, most importantly for the patient, in outcome. It is still not possible to predict for an individual in any category the likely outcome. Broad predictors are helpful to patients and healthcare professionals. For example, patients with localized asymptomatic Hodgkin's disease can be given a great deal of very real reassurance about their outcome, following one of several treatment routes. The difficulty for them may be to choose the best treatment route to achieve cure without lasting toxicity; patients with mantle cell lymphoma have to know that their chances of cure are relatively small whatever approach to treatment is taken. Although considerable progress has been made in the development of prognostic indices, their limitations have been highlighted in the chapters of this textbook when it comes to individual patient prediction. They still have not achieved sufficient accuracy to allow tailor-made choices to be made for many patients, apart from the appropriate choice for their histopathological category refined by the existing prognostic indices. Future work will allow further refinement of the identification of appropriate prognostic groupings, more accurate descriptions of likely outcomes and better choices of treatment for each individual patient. Most work to date has concentrated on histopathology and

clinical manifestations. The residual variance in outcome seems to depend on the biological features of the tumor and its chemosensitivity. There are already encouraging indications that biological predictors will be helpful, using cytokines, cytokine receptors and molecular characteristics of the tumors themselves. Prediction of chemosensitivity, in advance of exposure to drugs, is still a vexed question and assays based on drug exposure in vitro remain disappointing. Perhaps the accurate detection and quantification of drug targets and co-factors will be more useful in future. Individual drug selection remains a relatively distant ambition for the management of lymphoma patients. The treatments for lymphoma have improved steadily over the years, due to both the more intelligent use of previous treatments and the development of previously unrecognized therapies. In terms of conventional management certain treatment guidelines can be given. For localized Hodgkin's disease (HD) and nonHodgkin's lymphoma (NHL), radical radiotherapy may be curative. However, there is now good evidence, at least for localized NHL, that chemotherapy (for example, three courses of CHOP) prior to involved-field radiotherapy improves overall survival. For localized HD, 'minimal' chemotherapy prior to involved-field radiotherapy reduces the risk of relapse and of long-term sequelae, but the effect on overall survival is likely to be minimal (given the already acknowledged excellent survival in this group). Thirty years of experience with cyclical combination chemotherapy in advanced HD with MOPP descendants and alternatives (particularly ABVD) has improved the ultimate prognosis only marginally. Further significant improvements are unlikely to come from manipulation of such conventional therapies and long-term toxicities must be better addressed. For intermediate/high-grade NHL, CHOP remains 'standard' therapy - but not with any degree of complacency, since cure rates remain below 50 per cent. For both HD and aggressive NHL, future success may depend on altering the doses or schedules rather than the chemotherapeutic agents

438 The way forward

themselves. High-dose chemotherapy with autologous or allogeneic stem cell support is slowly finding its place; intensive or escalated, growth factor-supported regimens (often involving combined modality, chemotherapy/ radiotherapy, approaches) are also showing promise. Low-grade NHL remains a frustrating and worrying lymphoma to treat; experimental (including immunemodulatory) approaches seem particularly relevant to this indolent disease. For all types of lymphoma, it would be nice if we could select patients for different approaches on the basis of predicted prognosis but, as we have seen, this is presently not possible for the majority of patients. For example, we still do not know the best strategy for the utilization of dose escalation as treatment in each subtype of lymphoma. In some types of lymphoma, the best strategy will be utilization of high-dose therapy and transplantation as a rescue for patients who have failed initial therapy, while in others it may be that this will be best used as an adjuvant to primary therapy. In still other types of lymphoma, high-dose therapy and transplantation may not be effective. The optimal type of cellular rescue product in transplantion is unknown. The relative merits of allogeneic cells, autologous cells, cord blood cells, cells from related or unrelated donors, and the value of in vitro marrow treatment are all uncertain. Once again,

the same answer is unlikely to be correct for each disease and clinical situation. The place of immunological therapy for lymphoma, after a long gestation, is beginning to be established with the recognition of modest but consistent activity for anti-B cell monoclonal antibodies - so far principally anti-CD 20. Other approaches hold promise, such as adjuvant immune therapy in patients undergoing highdose therapy and transplantation. Whether this should be done with infusion of immunologically active cells, the use of various drugs, such as interferon or other cytokines, or other as yet undiscovered approaches remains unknown. Modifications in the transplant process in an attempt to alter the incidence of graft versus host disease and to increase the likelihood of a graft versus lymphoma effect are promising. Finally, transplantation may be the best setting for the application of gene therapy in the treatment of patients with lymphoma. Collaboration between scientists and clinicians remains essential and patients should be given the opportunity to be involved in well-designed clinical trials whenever possible. They should be treated by multi-disciplinary teams working in well-resourced centers. We have seen exciting advances in diagnosis, classification and treatment of lymphomas with great benefits to patients in recent decades. We are confident there are more benefits to come.

Index Page numbers in bold type refer to main discussions, those in italics indicate figures and tables.

abdominal disease Burkitt's lymphoma, 49, 86 pediatric non-Hodgkin's lymphoma, 373 and pelvic disease AIDS-related lymphoma, 215 imaging, 207-10,211,215 ABMTsee bone marrow transplantation, autologous ABVD (Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine), 236, 378, 379, 381 plus radiation, long-term side-effects, 423,424 acquired immune deficiency syndrome (AIDS)-related lymphomas,

351-8 clinical features, 353 clinicopathologic correlations, 353 epidemiology, 351 etiology and pathogenesis, 351-2 Epstein-Barr virus (EBV), 87,120,165 p53 mutations, 143, 352 and HIV in Hodgkin's disease, 195-6, 215 imaging, 214-16 pathological aspects, 352-3 prognostic factors, 353 treatment options, 353-6 following initial chemotherapy failure or relapse, 356 see also human immunodeficiency virus (HIV) acute lymphoblastic leukemia (ALL), B and T lineage, 56-7 and lymphoblastic lymphoma, 299-300 acute non-lymphoblastic leukemia (ANLL), secondary, 426-8 acyclovir, 407 adrenal involvement, imaging, 209 adult T cell leukemia/lymphoma (ATLL), 58-9, 288 HTLV-1 infection, 115-16,121 age factors Hodgkin's disease, 161-3,164,181,191 familial longevity, 193 and incidence, 385-6 as prognostic factor, 387-8 non-Hodgkin's lymphoma, 770, 777 agriculture, 173 AIDS see acquired immune deficiency syndrome AIL see angioimmunoblastic T cell lymphoma ALCL see anaplastic large cell lymphoma ALK see anaplastic lymphoma kinase alkylating agents see chlorambucil; cyclophosphamide ALL see acute lymphoblastic leukemia (ALL), B and T lineage allogeneic bone marrow transplantation see bone marrow transplantation, allogeneic alopecia, 238 amphotericin B, 409 anaplastic large cell lymphoma (ALCL) chromosome translocation, 141-2 pediatric, 373

of T cell lineage (KM), 60-1 AIDS-related, 353 chromosome translocation, 96,141-2 cutaneous, 80-1, 261-2, 368 anaplastic lymphoma kinase (ALK), 61, 96 angiocentric T and/or NK cell lymphoma, 82 angiofollicular lymphoid hyperplasia of the hyalin-vascular type see Castleman's disease angioimmunoblastic T cell lymphoma (AIL), 62-3, 327 angiotropic large cell lymphoma, 86, 87 Ann Arbor staging system Hodgkin's disease, 184,191-2,196, 225 pediatric, 377-8 stage III, 236 lymphoblastic lymphoma, 300 non-Hodgkin's lymphoma, 196,197,248, 289 antibody therapy, 279, 315, 340, 365 anti-B4 (CD 20), 356 antimetabolites see fludarabine; methotrexate antimicrobial therapy, 404-12 combined, 406 duration and modification, 406 H. pylori eradication, 253-4, 326 pediatric, 379 postsplenectomy, 422 prophylaxis herpes virus infections, 407-9 in neutropenic patients, 406-7 and treatment of fungal, 409-10 single-agent, 406 use in febrile neutropenic patients, 404 antisense therapy, 315 hRLsee acquired immune deficiency syndrome, (AIDS)-related lymphomas ataxia-telangiectasia, 56 ATLL see adult T cell leukemia/lymphoma ATM tumor suppressor gene, 56, 58 autologous bone marrow transplantation see bone marrow transplantation, autologous (ABMT) axillary lymphadenopathy, 214 BACT (carmustine, cytarabine, cyclophosphamide, 6-thioguanine), 331 bacterial infections, 401-2 Bcell centroblast and centrocyte, 4, 21, 22, 27, 29 centrocyte-like (CCL), 73 disruption in angioimmunoblastic T cell lymphoma, 62 germinal centre-derived, 10-11, 21,22, 33, 34 immunocytochemistry, 11, 31 infiltration of bone marrow in follicular lymphoma, 23 lymphocytic lymphoma phenotypes, 33 in mucosa-associated lymphoid tissue (MALT), 72-3

440 Index

B cell chronic lymphocytic leukemia (B-CLL) (small lymphocytic lymphoma), 43-4,45, 325 B cell lymphomas aerodigestive tract, 82 AIDS-related, 351 associated viruses, 119-21 bladder, 85 breast, 86 classification ILSG, 6 Lukes and Collins, 4 updated Kiel, 5 WHO, 7 cutaneous, 81, 261, 359, 367-8 diffuse aggressive, 49-54 diffuse indolent (low-grade), 43-7 diffuse large B cell lymphoma (DLBCL), 50, 61 follicular, 21-2 marginal zone, 326-7 non-Hodgkin's lymphoma, 5, 11-12 pediatric, 372-3 pulmonary, 79 splenic, 84 T cell-rich, 51 testicular, 85 thymic, 51, 83-4, 262 bcl-1/PRAD-1 gene rearrangement, 31-2, 135-7 bcl-2 oncogene, 137-40, 315 bcl-3 and REL/NF kappa B transcription factors, 144 bc/-6/laz-3 gene rearrangements, 140-1 bc/-10 and mucosa-associated lymphoid tissue (MALT) lymphoma, 74, 142 B-CLL see B cell chronic lymphocytic leukemia BCNUseecarmustine biological therapy, 314-15, 365-6 infection prevention, 411-12 biopsy CT-guided, 207, 210, 215, 217 lymph node, 184 nasopharangeal, 211 bladder involvement, imaging, 209 bladder lymphomas, 85 non-Hodgkin's lymphoma, 257 bleomycin, 271, 272 pulmonary effects, 379, 389 seeo/soABVD; CHVmP/VB; MACOP-B; m-BACOD; PACEBOM; P-VEBEC P microglobulin, 190 BNLI see British National Lymphoma Investigation bone imaging marrow involvement, 210, 211 osseous involvement, 210, 211 bone involvement, Hodgkin's disease, 187, 239 bone lymphomas, primary, 85-6 non-Hodgkin's lymphoma, 258-9 bone marrow imaging, 210, 211 bone marrow infiltration angioimmunoblasticTcell lymphoma, 63 B cell chronic lymphocytic leukemia, 44 follicular lymphoma, 23, 310, 311 Hodgkin's disease, 187-8 lymphoplasmacytic lymphoma, 45 mantle cell lymphoma, 29-30, 34-5 marginal zone lymphoma, 45 bone marrow transplantation allogeneic, 302, 3 0 3 - , 341-2 cytomegalovirus infection risk, 408-9 versus autologous (ABTM), 342-3

autologous (ABTM), 302-3 versus peripheral blood, 303, 304, 313-14, 331, 340-2 Borrelia burgdorferi, 261 brain lymphomas, 259-60 breast cancer, secondary, 239, 428, 429 breast lymphomas, 86 imaging, 214 non-Hodgkin's lymphoma, 258 British National Lymphoma Investigation (BNLI), 10, 14 grading system, 12, 14 nodular sclerosis, 12, 13 Burkitt's-like lymphoma, 49-50, 76, 87 Burkitt's lymphoma, 49, 76, 288 chromosomal translocation, 94-4 and c-myc oncogene, 134-5 endemic, 49, 86 Epstein-Barr virus (EBV), 118-19, 172 p53 mutations, 143 pediatric, 49,170,288,373 treatment, 376 sporadic, 86 cardiac failure, Hodgkin's disease, 431 cardiovascular dysfunction, iatrogenic, 423 chemotherapy, 379, 423 radiation therapy, 238 carmustine (BCNU), 260, 270, 272 topical, 364 see also BACT Castleman's disease, 14, 33, 117, 262 causes of death, 430-1 CBCLsee cutaneous B cell lymphomas CCL cells see centrocyte-like (CCL) cells CD 2, 22, 56-7 CD 3, 13,22 CD 3/TCR alpha/beta, 58, 59, 85 CD 4, 13, 22, 56, 58, 59, 62, 63 AIDS-related lymphomas, 351, 355 CD 5, 22, 31, 33, 34, 44, 50, 56 CD 8, 13,56,58,59,62 CD 10, 22, 31, 34, 49, 50, 57 CD 15, 11,13, 109 CD 19, 19, 22, 44, 45, 49, 50, 51 CD 20, 11, 22, 31, 44, 45, 49, 50, 51, 57 anti-B 4 monoclonal antibody, 356 CD 21, 11,74 CD 22, 22, 31, 45, 50 CD 23, 22,31,44 CD 30, 11, 13, 23, 60, 81, 96, 109, 368, 373 ligand interaction, 111 CD 35, 11, 74 CD 38, 44, 58, 59 CD 43, 22, 31, 33 CD 45RO, 13, 58, 59, 62, 63 CD 57, 11, 22, 58 CD 71, 61, 109 CD 79a, 11, 45, 49, 50 CDE infusional chemotherapy (cyclophosphamide, doxorubicin, etoposide), 354-5 celiac disease, 76-7 central nervous system (CNS) lymphomas, 83 AIDS-related, 215, 353, 356 angiotropic large cell, 86, 87 Hodgkin's disease, 187 imaging, 213-14, 215 immunodeficiency-associated, 87, 215, 353, 356 non-Hodgkin's lymphoma, 259-61 centrocyte and centroblast cells, 4, 21, 22, 27, 29

Index 441 centrocyte-like (CCL) cells, 73 centrocytic lymphoma see mantle cell lymphoma cephalosporins/glycopeptide combinations, 406 cerebral spinal fluid analysis, 289 cervix uteri, 258 chemotherapy acronyms, 277,297 blood-brain barrier penetrating, 260 infusional, 354-6 metabolism in elderly, 388-9 in pregnancy, 195 relapse after initial, 277-8 and secondary malignancies, 426, 428 versus combined modality, 235-6,250 versus radiation therapy, 235 see also combined modality therapy; high-dose chemotherapy/stem cell transplantation; salvage therapy chest, imaging, 206-7 chlorambucil, 312, 389 ChlVPP (chlorambucil, vincristine, procarbazine, prednisolone), 378, 379 ChlVPP/EVA (chlorambucil, vinblastine, procarbazine, prednisolone, doxorubicin, vincristine, etoposide), 425 CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), 297, 295-6, 354, 356 adult T cell leukemia/lymphoma (ATLL), 58 and autologous transplantation, 339 in elderly, 389, 390, 391, 392 follicular lymphoma, 313 mantle cell lymphoma, 35-6 and radiotherapy, 250 testicular lymphoma, 257 versus MACOP-B, 295 versus ProMACE-CytaBOM versus MACOP-B, 295 versus m-BACOD, 294-5 versus PACEBOM, 295 chromosomal abnormalities, 133-4 11q23, 142 anaplastic large cell lymphoma, 61 clonal rearrangements t(14)(q11) lesions, 96, 98 mucosa-associated lymphoid tissue (MALT), 74, 142 non-Hodgkin's lymphoma, 97-9 'primary'acquired, 92 probable 'secondary' acquired, 92 t(2;5)(p23;q35), 96, 97,141-2 t(3;14)(q27;q32), 94, 95,140 t(3;22)(q27;q11), 140-1 t(8;14)(q24;q32), 93-4 t(9;14)(p13;q32), 96 t(11;14)(q13;q32), 94-6, 135-7 t(11;18)(q21;q21), 96,97 t(14;18)(q32;q21), 94,99,137-40 T cell acute lymphoblastic leukemia, 57 CHVmP/VB (cyclophosphamide, doxorubicin, teniposide, prednisolone, vincristine, bleomycin), 392 classification systems, 3-8 extranodal lymphomas, 71-2 pediatric non-Hodgkin's lymphoma, 372 see also specific classification systems ClUPLsee prolymphocytoid transformation CMV see cytomegalovirus c-myc oncogene, 22, 51, 93-4 and Burkitt's lymphoma, 134-5 CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisolone), 391 CODOX-M (cyclophosphamide, vincristine, doxorubicin, methotrexate), 376 combined modality therapy

brain lymphoma, 260 gastric lymphoma, 253 Hodgkin's disease advanced, 275-6 in elderly, 393 localized, 236 pediatric, 378-9 stage IMA, 237 intestinal lymphoma, 254 lymphoblastic lymphoma, 300-2 mycosis fungoides, 366 non-Hodgkin's lymphomas, 250 in elderly, 390-2 testes, 257 versus chemotherapy, 235-6, 250 versus radiation therapy, 234-5 co-morbidity in elderly, 390 COMP (cyclophosphamide, oncovin, methotrexate, prednisolone), 376 computed tomography (CT) abdomen and pelvis, 207-8, 209-10, 211 AIDS-related lymphoma, 215, 216 central nervous system, 213-14 chest, 206-7 follow-up, 216 -guided biopsy, 207, 210, 215 head and neck, 211,212-13 lymph nodes, 205-6 skeletalsystem, 210, 211 COPP (cyclophosphamide, vincristine, procarbazine, prednisolone), 425 cotrimoxazole, 407, 410 Cotswold staging system, Hodgkin's disease, 184, 785 pediatric, 377-8 cutaneous lymphomas, 80-1, 359-70 anaplastic large cell lymphoma (ALCL) of T cell lineage (CD30/Ki-1), 80-1,261-2,368 B cell lymphomas (CBCL), primary, 81,261, 367-8 Hodgkin's disease, 188 large cell lymphomas of T cell phenotype (T-LCL), primary, 261 non-Hodgkin's lymphoma, 261-2 CVP (cyclophosphamide, vincristine, prednisolone), 327 in elderly, 36 follicular lymphoma, 372, 313 CVPP (cyclophosphamide, vinblastine, procarbazine, prednisolone), 235-6 cyclin 01,32,117,136-7 cyclophosphamide, 260,271, 272, 312, 314, 376 metabolism in elderly, 389 see also BACT; CDE; CHOP; CHVmp/VB; CNOP; CODOX-M; COMP; COPP; CVP; CVPP; EPOCH; PACEBOM; P-VEBEC cytarabine, 260, 376 cytogenetics, 91-103 clinical and prognostic correlations, 99 Hodgkin's disease, 92-3,108-9 mantle cell lymphoma (MCL), 31-3 methods, 91-2 non-Hodgkin's lymphoma, 93-9 pediatric lymphomas, 372 cytomegalovirus (CMV), 403 prevention, 408-9 treatment, 409 dexamethasone, 260 DHAP (dexamethasone, cytarabine, cisplatin), 336 diaphragmatic invasion, 206,207, 231 didanosine, 355 diffuse immunoblastic lymphoma, 288

442 Index

diffuse large B cell lymphoma (DLBCL), 50-1, 61 morphology, 50 pediatric, 372-3 phenotype, 50 rare subtypes, 51 diffuse large cell non-Hodgkin's lymphoma, 287-8 treatment in elderly, 390-2 diffuse small non-cleaved cell lymphoma see Burkitt's lymphoma digestive system see gastrointestinal tract DLBCL see diffuse large B cell lymphoma doxorubicin, 272-3 age-specific considerations, 389 bladder lymphoma, 257 cardiotoxicity, 423 secondary malignancy, 426 see also ABVD; CDE; ChlVPP/EVA; CHOP; CHVmP/VB; CODOX-M; EPOCH; MACOP-B; m-BACOD; PACEBOM dysphagia, 237-8 EATL see enteropathy-associated T cell lymphoma EBNAssee Epstein-Barr nuclear antigens EBT see electronic beam therapy ECPPsee photopheresis, extracorporeal elderly, 385-97 advanced age as prognostic factor, 386-8 age-specific treatment considerations, 36, 388-90 Hodgkin's disease, 110, 226, 386, 387-8, 392-3 incidence of lymphoma in population, 385-6 manifestations of lymphoma, 386 non-Hodgkin's lymphoma, 385-7, 390-2 treatment strategies, 390-3 advanced disease, 390-2 localized disease, 390 electron beam therapy (EBT), 364-5, 366, 367 emesis, 237, 238 enteropathy-associated T cell lymphoma (EATL), 76-7 EORTC see European Organisation for Research and Treatment of Cancer (EORTC) eosinophilia, 189 epidermotropic small cerebriform cell lymphomas see mycosis fungoides EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisolone), 355-6 Epstein-Barr nuclear antigens (EBNAs), 117,118 Epstein-Barr virus (EBV), 117-18 angioimmunoblastic T cell lymphoma, 62 Burkitt's lymphoma, 118-19,172 Hodgkin's disease, 110-11, 164-5 pediatric, 372 immunodeficiency-associated lymphomas, 87 B cell, 119-20 HIV, 196 nasal lymphoma, 252, 255 primary effusion lymphoma (PEL), 51 T/natural killer cell lymphomas, 121-2 types A and B, 118, 120, 121 European Organisation for Research and Treatment of Cancer (EORTC), 10, 224, 234 extracorporeal photopheresis (ECPP), 366 extradural lymphoma, 260-1 extranodal lymphomas classification, 71-2 sites, 71, 196-8 Hodgkin's disease, 186-8 non-Hodgkin's lymphoma, 251-62 extranodal marginal zone lymphoma of MALT type, 326-7 eye lymphomas see ocular adnexa and eye lymphomas

FDC see follicular dendritic cells female genital tract lymphomas, 85, 258 fertility, treatment effects, 195, 239, 380, 424-6 fine-needle aspiration biopsy (FNAB), 210, 217 FISH see fluorescence In situ hybridization FLsee follicular lymphoma fluconazole, 410 flucytosine, 410 fludarabine, 313, 314, 327-8, 389 fluorescence In situ hybridization (FISH), 92, 99-100 FNAB see fine-needle aspiration biopsy follicular dendritic cells (FDC), 11, 22, 23 follicular lymphoma (FL), 21-6, 309-24 diagnosis, 311 extranodal disease, 23, 76 immunophenotype, 22 investigation, 311 management, 311-16 morphology, 21-2 pathology, 309-10 presentation features, natural history and clinical course, 310-11 transformation, 22-3 treatment options, 312-15 biological therapy, 314-15 chemotherapy, 312-13 high dose therapy/stem cell rescue, 313-14 radiotherapy, 312 treatment strategy, 311-12, 315-16 fungal infections, 402 prevention and treatment, 409-10 gallium-67 scanning, 206 withSPECT, 207, 216-17 ganciclovir, 407 gastric lymphomas mucosa-associated lymphoid tissue (MALT), 75 therapeutic strategies, 253 gastric wall thickening, 270 gastrointestinal tract B cell nodal lymphomas, 76 Burkitt's and Burkitt-like lymphoma, 76 complications, long-term, 424 enteropathy-associated T cell lymphoma (EATL), 76-7 Hodgkin's disease, 188 imaging, 209-10 immunodeficiency-associated lymphomas, 87 immunoproliferative small intestinal disease (IPSID), 76,254,326-7 mantle cell lymphoma (MCL), 30-1, 34, 35, 76 mucosa-associated lymphoid tissue (MALT) lymphomas, 74-7, 253-1, 326-7 non-Hodgkin's lymphomas, 75, 253-4, 326-7 radiation therapy side-effects, 238 G-banding methods, 92 G-CSF see granulocyte colony stimulating factor gender female predominance, 51 Hodgkin's disease, 161, 762 prognostic factor in, 191 male predominance, 76, 299, 367 gene amplification, 144 gene mutations, 142-4 genes see bdl; c-myc oncogene; latent membrane protein (LMP), gene deletion; p53 gene; PRAD-1 gene; TAL-1 gene; TCR gene gene sequences, non-Hodgkin's lymphoma, 172 gentamicin/carbenicillin combination, 406 GM-CSF see granulocyte-macrophage colony stimulating factor gonadal dysfunction, 424-6 MOPP in children, 380

Index 443

see also fertility; ovaries; testes 'graft versus lymphoma effect', 341-3 granulocyte colony stimulating factor (G-CSF) in elderly, 389, 392 in neutropenic patients, 411, 412 granulocyte-macrophage colony stimulating factor (GM-CSF) AIDS-related lymphoma, 354 in elderly, 389 follicular lymphoma, 315 in neutropenic patients, 411, 412 granulocytopenic lymphoma patient, 400-1 HAART see highly active antiretroviral therapy Haemophilus influenzae type b, 399, 400,401 vaccination, 379, 399 'hallmark' cell, 60-1 Hashimoto's disease, 79,252, 255 HCV see hepatitis C HD see Hodgkin's disease head and neck cutaneous B cell lymphomas, 367 imaging, 211-13 somatostatin receptor scintigraphy, 218 non-Hodgkin's lymphoma, 212-13 pediatric, 373 Helkobacter pylori, 75, 252, 253-4, 326 hemopoietic growth factors, infection prevention, 411-12 hepatitis C (HCV), 124 herpes viruses, 402 herpes simplex virus (HSV), 403 prevention and treatment, 408 human herpes virus 6 (HHV-6), 123-4, 403 human herpes virus 8 (HHV-8), 51 Kaposi's sarcoma-associated (KSHV), 116-17,173 prevention of infection, 407-9 high-dose therapy/stem cell transplantation, 331-50 comparison of rescue sources, 340-3 current status, 344 in first remission, 302^1 source of stem cells, 303-4 future directions, 344 preparative regimens, 339-40 prospects for pediatric treatment, 380 purging, 343 results, 313-14, 328, 332-5 comparison with conventional salvage therapy, 304-5, 335-7 early transplantation, 337-9 Hodgkin's disease, 334-5 non-Hodgkin's lymphoma, 332-4 highly active antiretroviral therapy (HAART), 351, 354, 355 hilar adenopathy, 231-2 HIV see human immunodeficiency virus Hodgkin-cell leukemia, 188 Hodgkin's disease (HD), 9-19, 107-14, 161-7, 181-204, 221-45, 269-85 age factors, 161-3, 164, 181, 191 familial longevity, 193 and incidence, 385-6 as prognostic factor, 387-8 in AIDS/HIV, 195-6, 215 and anaplastic lymphoma of T cell lineage (ALCL), 61 atypical immune reaction, 110-12,165 EBV infection, 110-11, 164-5 H-RS as antigen-presenting cells, 111 causes of death, 430-1 cell of origin, 10 classification systems, 9-10 ILSG, 6 Lukes and Collins, 4, 9

WHO, 7 clinical approach to patient, 188-94 clinical significance of morphological pattern, 14 contrasts with non-Hodgkin's lymphoma, 196-8 cytogenetics, 92-3 diagnosis and staging, 184-8, 190-1, 222-6 extranodal, 186-8 lymphatic, 185-6 in elderly age as prognostic factor, 387-8 manifestations, 386 treatment strategies, 392-3 epidemiology, 110, 161-7 analytical, 163-5 descriptive, 161-3 Epstein-Barr virus association, 110-11,164-5 fertility in, 195 histological morphology, 11, 12, 13-14 as prognostic factor, 14, 192 HIV/AIDS-related, 195-6, 215 immunocytochemistry, 11,13 incidence and age factors, 385-6 and mortality, 221-2 infection risks, 399^100 investigations, 189-91 alternative markers of disease severity, 190 biochemistry, 189-90 hematological, 189 staging, 190-1,222-6 lymphocyte-depleted, 13 lymphocyte-predominant, 10-12 lymphocyte-rich classical (LRCHD), 14 mixed cellularity, 13-14,107,108 naming of, 3, 9 nodular, 10-12 nodular sclerosis (NS), 12-13, 107, 183, 184 paraneoplastic manifestations, 188 patient history, 188 patterns of recurrence, 194 physical examination, 188-9 in pregnancy, 195,279 presenting features, 181-4 prognostic factors, 191-4 advanced age, 387-8 definition of, 224-6 individual patient, 191-3 multivariate analysis and models, 193-4 transplantation, 334-5 quality of life, long-term survivors, 429-30 secondary ANLL and myelodysplastic syndrome, 426-7 secondary non-Hodgkin's lymphoma after, 427 secondary solid tumors, 427-8 stage MIA, 236-7, 270 staging see diagnosis and staging of thymus, 83 treatments, advanced stage initial therapy, 270-7 salvage therapy, 277-6 treatments, high dose chemotherapy/stem cell transplantation, 334-5, 336-7 treatments, localized disease radiation therapy, 226-34 systemic, 234-6 treatments, stage MIA, 236-7, 270 variant of Richter's syndrome, 44 see also Hodgkin's and Reed-Stern berg cells; pediatric lymphomas, Hodgkin's disease

444 Index Hodgkin's and Reed-Stern berg (RS/H-RS) cells as antigen-presenting cells, 111 in B cell chronic lymphocytic leukemia, 44 cell lines and animal models, 109 detection of chromosome abnormalities in, 93 Epstein-Barr virus, 12,110,123 genetic aberations, 108-9 lineage origin and clonality, 107-9 malignant proliferation of, 107-9 in mixed cellularity HD, 14 in nodular sclerosis, 13 p53 mutations, 143-4 in reticular lymphocyte-depleted HD, 13 variants, 11,12 H-RS cell see Hodgkin's and Reed-Stern berg (H-RS/RS) cell HSV see herpes simplex virus under herpes viruses HTVL-1 see human T cell leukemia virus type 1 human herpes virus 6 (HHV-6), 123-4,403 human herpes virus 8 (HHV-8), 51 human immunodeficiency virus (HIV), 172-3, 351 Epstein-Barr-positive lymphocytes, 120,165 Hodgkin's disease, 195-6, 215 Kaposi's sarcoma-associated herpes virus (KSHV), 116-17 primary effusion lymphoma (PEL), 51 see also acquired immune deficiency syndrome (AIDS)-related lymphomas human T cell leukemia virus type 1 (HTLV-1), 58-9,115-16,173, 288 p53 mutations, 143 IFN see interferon therapy IL-1, 59,111 IL-2, 111 IL-2-diphtheria toxin fusion protein, 365-6 IL-2R, 59 IL-4, 59 IL-6, 62,190,352 IL-10, 59,190,352 ILSG see International Lymphoma Study Group imaging, 205-20 abdomen and pelvis, 207-10 AIDS-related lymphomas, 214-16 breast, 214 central nervous system (CMS), 213-14 chest, 206-7 children, 216 clinical staging, 222 follow-up, 216-17 assessment of residual mass, 216-17 assessment of response to treatment, 216 detection of late relapse, 217 head and neck, 211-13 new techniques, 217-18 in pregnancy, 195, 279 skeletalsystem, 210-11 immunoblastic lymphoma, diffuse, 288 immunocytochemistry, Hodgkin's disease, 11,13 immunocytomassee lymphoplasmacytic lymphomas immunodeficiency, 399-401 associated pathogens, 401-3 B cell lymphomas, 119-20 due to past medical history, 172 extranodal lymphoma associated with, 86-7 as long-term complication, 421-2 immunoglobulin G (IgG), 21-2, 31,44 immunoglobulin M (IgM), 21-2, 31, 44,45,49 postsplenectomy, 422 immunophenotypes B cell chronic lymphocytic leukemia (B-CLL), 44

diffuse large B cell lymphoma (DLBCL), 50 follicular lymphoma (FL), 22 large granular lymphocytosis (LGL), 58 lymphoplasmacytic lymphoma, 45 mantle cell lymphoma (MCL), 31 mucosa-associated lymphoid tissue (MALT), 74 pediatric lymphomas, 372, 373 T cell acute lymphoblastic leukemia (T-ALL), 56-7 immunoproliferative small intestinal disease (IPSID), 76, 254, 326-7 immunosuppression drug therapy, 172,401 lifestyle and other exposures, 174 occupational links, 173 viral, 172-3 infections, 422 as cause of death, 431 of 'childhood' in adult life, 163-4 common pathogens, 401-3 factors underlying, 399-401 reactivation of latent, 402-3 treatment and prevention see antimicrobial therapy; hemopoietic growth factors infectious mononucleosis, 58, 110, 122, 123, 164 inherited syndromes, 172 interferon (IFN) therapy, 314, 365, 367 International Lymphoma Study Group (ILSG), 5-6, 44, 45 intestinal lymphomas, 76-7, 254 intraocular lymphoma, 80 intravascular large cell lymphoma, 51 iodine-131,315 IPSID see immunoproliferative small intestinal disease jaw involvement, Burkitt's lymphoma, 49, 86 Kaposi's sarcoma-associated herpes virus (KSHV), 116-17, 173 Ki-1 lymphoma see anaplastic large cell lymphoma (ALCL), of T cell lineage (Ki-1) Kiel classification, 4, 44, 55, 372 mantle cell lymphoma, 36 revised, 5-6 low grade non-Hodgkin's lymphomas, 325-6, 327 L&H cells see lymphocytic and histiocytic cells lamina propria, 72 Langerhans cells, intradermal, 80 laparotomy, staging, 190-1, 222-4 pediatric, 377, 379 large cell anaplastic lymphoma (LCAL), 51 large granular lymphocytosis (LGL), 57-8 latent membrane protein (LMP), 110 gene deletion, 117-18, 119, 122 LBL see lymphoblastic lymphoma Lennert's lymphoma (lymphoepithelioid lymphoma), 63 leucocytosis, 189 leucopenia, 189 leukemia see acute lymphoblastic leukemia (ALL), B and T lineage; ANLL, secondary; B cell chronic lymphocytic leukemia (B-CLL); Hodgkin-cell leukemia; peripheral T cell lymphoproliferative disorders, predominantly leukemic LGL see large granular lymphocytosis liver involvement, Hodgkin's disease, 786,187 liver lymphomas, 86 AIDS-related, 215 imaging, 209 LMP see latent membrane protein LRCHD see lymphocyte-rich classical Hodgkin's lymphoma LSA2-L2 (10 drug leukemia-like regimen), 376 Lukes and Collins classification, 4, 9,21

Index 445 lung cancer, 428 lymph nodes B cell chronic lymphocytic leukemia (B-CLL), 43, 44 biopsy, 34 imaging characteristics, 205-6 lymphoplasmacytic lymphoma, 44-5 mantle cell lymphoma (MCL), 27-9 marginal zone lymphoma (MZL), 45 lymphoblastic lymphoma (LBL), 299-307 clinicopathological features, 299-300 pediatric, 372, 373 prognostic factors, 302 treatments, 300-5 combined modality, 300-2 high-dose therapy in first remission, 302-4 salvage therapy, 304-5 lymphocyte-depleted Hodgkin's disease, 13,107,108 lymphocyte-predominant Hodgkin's disease, 10-12 immunocytochemistry, 11 morphologic features, 11 non-Hodgkin's lymphoma arising in patients with, 11-12 lymphocyte-rich classical Hodgkin's lymphoma (LRCHD), 14 lymphocytic and histiocytic (L&H) cells, 10 morphology and immunocytochemistry, 11, 107, 108 lymphoepithelioid lymphoma (Lennert's lymphoma), 63 lymphomatoid granulomatosis, 78 lymphomatoid papulosis, 61, 81, 368 lymphopenia, 189 lymphoplasmacytic lymphomas, 44-5, 325 of central nervous system, 83 MACOP-B (methotrexate, Adriamycin (doxorubicin); cyclophosphamide; Oncovin; prednisolone; bleomycin), 297, 293-4, 425 and autologous transplantation, 339 versus CHOP, 295 versus ProMACE-CytaBOM versus MACOP-B, 295 versus ProMACE-MOPP, 294 macrophages, epithelioid, 63 magnetic resonance imaging (MRI) abdomen, 208-9, 210 central nervous system, 213-14, 216 chest, 207 follow-up, 217 head and neck, 211,212-13 lymph nodes, 206 skeletalsystem, 210, 211,259 MAI see Mycobacterium avium intracellulare MALT see mucosa-associated lymphoid tissue mantle cell lymphoma (MCL), 11,27-41, 325-6 clinical features, 34-5 cytogenetic and molecular genetic features, 31-3 differential diagnosis, 33-4 immunological features, 31 and mucosa-associated lymphoid tissue (MALT), 76 normal cellular counterpart, 33 pathological features, 27-31 cytology, peripheral blood and bone, 29-30 gastrointestinal tract, 30-1 lymph nodes, 27-9 spleen, 30 Waldeyer's ring, 30 prognostic factors, 35-6 treatments stem cell rescue, 328 and survival, 35-6 tumor grade, 36-7 mantle zone hyperplasia, 33

marginal zone lymphoma (MZL), 45, 326 cutaneous, 81 extranodal, of MALT type, 326-7 m-BACOD (methotrexate; bleomycin; adriamycin (doxorubicin); cyclophosphamide; oncovin; decadron), 297, 292-3 modified, AIDS-related lymphoma, 353-4, 356 versus CHOP, 294-5 versus ProMACE-CytaBOM versus MACOP-B, 295 mediastinal disease Hodgkin's disease, 193 radiotherapy, 231-2 lymphoblastic lymphoma, 299 non-Hodgkin's lymphoma, 262 pediatric, 373 mediastinal large B cell lymphomas, 51 thymic origin, 83-4,262 mediastinal nodes, 206, 216 mediastinal radiotherapy, 231-2 and cardiac dysfunction, 423 MESA see myoepithelial sialadenitis methotrexate, 260, 292-3, 376 seeo/soCODOX-M; COMP; MACOP-B; m-BACOD; PACEBOM MF see mycosis fungoides mixed cellularity Hodgkin's disease, 13-14,107,108 monoclonal antibodies see antibody therapy monocytoid lymphoma, 327 MOPP (mustine, vincristine, procarbazine, prednisolone) alternatives, 272-3 combined therapy, long-term side-effects, 423, 424 Hodgkin's disease, 234, 235, 236 elderly, 393 fertility, 380 pediatric, 378, 379, 380, 381 -like regimens, 271-2 secondary malignancies, 426 mucosa-associated lymphoid tissue (MALT) lymphomas, 71, 72-6, 248,252, 255, 256 acquired, 72 fccMOgene, 74,142 bladder lymphomas, 85 breast lymphomas, 86 clinical presentation, 73 extranodal marginal zone B cell lymphoma, 326-7 female genital tract lymphomas, 85 functional properties, 72 gastrointestinal tract, 74-7 high-grade B cell lymphoma, 74 high-grade gastric lymphoma, 75 histology of, 72 liver lymphomas, 86 low-grade B cell lymphomas gastrointestinal tract, 74 thymus, 83 Waldeyer's ring, 82 low-grade gastric lymphoma, 75 low-grade lymphomas, 73-4 clinical behaviour, 74 histopathology, 73 immunophenotype, 74 lymph node involvement and distant spread, 74 molecular genetics, 74 lymphomas of the intestine, 76 MALT lymphoma concept, 72-3 ocular adnexa and eye, 79-80 pulmonary lymphomas, 77-9 salivary glands, 77 thyroid, 79 mucositis, 237-8

446 Index MVPP (mechlorethamine, vinblastine, procarbazine, prednisole), 425 mycobacterial infections, 403 Mycobacterium avium intracellulare (MAI), 215, 403 mycosis fungoides (epidermotropic small cerebriform cell lymphoma) (MF), 80, 359-67 clinical presentation and natural history, 360-1 etiology and epidemiology, 359-60 HTLV-1 infection, 59, 115, 116 pathology, 360 staging, 361-3 treatments, 363-7 biological agents, 365-6 chemotherapy, 365 combined modality, 366 guidelines, 366-7 photopheresis, 366 phototherapy, 363 radiation, 364-5 systemic, 365-6 topical, 363-4 see also Sezary syndrome myelodysplastic syndrome, 334, 426-7 myoepithelial sialadenitis (MESA), 77, 255 MZLsee marginal zone lymphoma nasal lymphomas non-Hodgkin's lymphoma, 254-5 pediatric, 373,374 T/natural killer cell, 121, 252, 255 nasopharangeal biopsy, 211 National Cancer Institute (NCI) lymphoma classification project, 4-5, 55 see also Working Formulation natural killer (NK) cell lymphomas, 6 angiocentric T and/or, 82 associated viruses, 121-2 large granular lymphocytosis (LGL), 57, 58 nausea, 237, 238 MOPP therapy in children, 378 Neisseria meningitidis, 399, 400 neutropenia, 58, 355, 399, 400 febrile patients antibiotic therapy, 404 antifungal therapy, 410 prevention of infection, 406-7, 409 and treatment, hemopoietic growth factors, 411-12 NHL see non-Hodgkin's lymphomas nitrogen mustard, 363, 364, 365, 366, 367 secondary malignancy, 426 NK see natural killer (NK) cells nodal-based peripheral T cell lymphomas, 60-3 nodal marginal zone B cell lymphoma, 327 nodular Hodgkin's disease, 10-12 nodular sclerosis (NS), 12-13, 107, 183, 184 immunocytochemistry, 13 morphological features, 12 non-epidermotropic pleomorphic large T cell lymphoma, 80 non-epidermotropic small cerebriform cell lymphoma, 80 non-Hodgkin's lymphoma (NHL), 21-6, 27-41, 43-7, 49-54, 55-69, 71-90,169-77, 247-68, 287-98, 299-307, 309-24 aggressive, 287-98 advanced stage chemotherapy, 292-5 clinical features and staging, 289-90 early stage chemotherapy, 290-2 transformation of follicular into, 22-3 types, 287-8 in AIDS patients, 215 chemotherapy

aggressive disease, 290-6 localized disease, 250 low-grade disease, 327-8 see also high dose chemotherapy/stem cell transplantation classification, 3 ILSG, 6 Kiel, revised, 5-6 problems, 169 contrasts with Hodgkin's disease, 196-8 cytogenetics, 93-9 chromosomal translocations, 93-6 other chromosomal abnormalities, 97-9 in elderly age and incidence, 385-6 age as prognostic factor, 386-7 manifestations, 386 treatment strategies, 390-2 epidemiology, 169-77 analytical, 172-4 descriptive, 170-2 extranodal see under specific sites follicular see follicular lymphoma (FL) high dose chemotherapy/stem cell transplantation, 332^1 early treatment, 337-9 preparative regimens, 340 versus conventional salvage chemotherapy, 336 infection risks, 399 localized management, 247-51 see also non-Hodgkin's lymphoma under specific sites low grade not follicular, 325-30 transplantation results, 333-4 treatment, 327-8 treatment strategies in elderly, 392 types, 32S-7 lymphoblastic see lymphoblastic lymphoma (LBL) p53 mutations, 143 principles of treatment, 249 assessment of response and follow-up, 251 prognostic factors, 247-8 and patterns of failure, 248-9 transplantation results, 332-4 radiation therapy, 249-50 secondary, after Hodgkin's disease, 427 secondary malignancies after, 429 staging classification, 248 surgery, 249 working formulation for clinical usage, 5 see also pediatric lymphomas, non-Hodgkin's lymphoma (NHL) non-malignant complications, 421-6 NS see nodular sclerosis occupational factors, 165,173 ocular adnexa and eye lymphomas, 79-80 non-Hodgkin's lymphoma, 212,255-6, 260 OPSI see overwhelming postsplenectomy infections organ transplantation, 172 osteonecrosis, 239 ovaries non-Hodgkin's lymphoma, 257-8 radiotherapy to, 239 overwhelming postsplenectomy infections (OPSI), 422,424 p53 gene, 32, 142-4, 352 PACEBOM (prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate) versus CHOP, 297,295 pancreas, 209 paranasal sinuses, 81-2, 212, 254-6

Index 447 parotid gland, 77, 237 PBPCs see peripheral blood progenitor/stem cells (PBPCs) PCR see polymerase chain reaction pediatric lymphomas, 371-84 biology cytogenetics, 372 immunophenotyping, 372 Burkitt's lymphoma, 49,170, 288, 373 treatment, 376 epidemiology, 371-2 Hodgkin's disease (HD), 376-80 clinical presentation, 376-7 diagnosis and staging, 377-8 epidemiology, 161, 163, 164, 372 long-term effects of therapy, 379-80 secondary malignancies, 428-9 treatment, 378-9, 380, 381 imaging, 216 non-Hodgkin's lymphoma (NHL), 372-6 chemotherapy, 375-6 classification, 372-3 clinical features, 373 diagnosis and staging, 373-4, 375 epidemiology, 371-2 prospects for therapy, 380-1 secondary malignancy, 380 treatments, 375-6 siblings, 165 T cell acute lymphoblastic leukemia (T-ALL), 56, 57 PEL see primary effusion lymphoma pericardial invasion, 206 Hodgkin's disease, 188 non-Hodgkin's lymphoma, 262 peripheral blood progenitor/stem cells (PBPCs) versus bone marrow transplantation, 303, 304, 313-14, 331, 340-2, 412 peripheral T cell lymphoma, common type, 63 peripheral T cell lymphoproliferative disorders, predominantly leukemic, 57-60 personality factors, Hodgkin's disease, 193 PET see positron emission tomography petrochemical industry, 173 Peyer's patches, 72, 76, 82 phosphocholines, 364 photopheresis, extracorporeal (ECPP), 366 phototherapy (PUVA), 363, 364, 365, 366, 367 plain radiographs, 211 pleural effusions, 206 Hodgkin's disease, 186 non-Hodgkin's lymphoma, 262 pleural lymphoma, 79 pneumococcal vaccination, 328, 379, 424 Pneumocystis carinii infection, 401, 410 prevention, 410 treatment, 410-11 pneumonia, 401, 410-11,422 polymerase chain reaction (PCR), 32, 55, 62 polymorphic immunoblastic B lymphoproliferations, 87 popcorn cell see lymphocytic and histiocytic (L&H) cells positron emission tomography (PET), 217 bone marrow disease, 211 PRAD1 gene, 37, 32, 32-3, 94,136-7 precursor B lymphoblastic lymphoma, 372 precursor T cell lymphoblastic lymphoma, 56-7 pediatric, 373 prednisolone (prednisone), 271,272 see also ChlVPP; ChlVPP/EVA; CHOP; CHVmP/VB; CNOP; COMP; COPP; CVP; CVPP; EPOCH; MACOP-B; MOPP; PACEBOM; P-VEBEC; VEEP

pregnancy, 195, 279 primary effusion lymphoma (PEL), 51 procarbazine, 260,426 see also ChlVPP; ChlVPP/EVA; COPP; CVPP; MOPP; MVPP prolymphoblasts, 43 prolymphocytic leukemia, 325 Tcell(T-PLL),56, 58 prolymphocytoid transformation (CLL/PL), 44 ProMACE see under MACOP-B protozoan infections, 402 pseudofollicles, 43 pseudo-T cell lymphoma, 51 psychosocial and psychosexual function, 239, 430 pulmonary dysfunction, iatrogenic bleomycin, 379, 389 radiation, 238, 239, 423-4 pulmonary fibrosis, 379, 424 pulmonary lymphomas, 77-9 Hodgkin's disease, 186 imaging, 206 non-Hodgkin's lymphoma, treatment, 259 PUVA see phototherapy P-VEBEC (prednisolone, vinblastine, etoposide, bleomycin, epirubicin, cyclophosphamide), 392 quality of life, long-term survivors, 429-30 quinolone antibiotics, 406, 407 race, 161,170 radiation pneumonitis, 423-4 radiolabeled antibodies, 279, 315, 340, 365 radiotherapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), 250 and fertility, 195 follicular lymphoma, 312 Hodgkin's disease (HD), localized, 226-34 dose, fractionation and tumor control, 226 field size (radiation volume), 227-32 relapse rates, 227, 228, 229, 230 salvage of recurrent disease, 233-4 technical aspects, 232-3 mycosis fungoides, 364-5 non-Hodgkin's lymphomas (NHL), 249-50, 328 bladder, 257 bone, 259 orbital, 256 pediatric, 375 relapse after initial, 277 shielding, 232, 233, 238, 256, 364, 425 side effects acute, 237-8 chronic, 238-9, 422, 423-4, 426, 428, 429 targeted therapy, 315 testes, 256-7 total body irradiation (TBI), 314, 339-40 versus chemotherapy, 235 versus combined modality, 234-5 see also combined modality Rappaport classification, 3-4 REAL classification see Revised European-American Lymphoma classification Reed-Sternberg cells see Hodgkin's and Reed-Stern berg (RS/H-RS) cells REL/NF kappa B transcription factors and bcl-3,144 renal function, 189, 239 renal lymphoma, 209, 215 retinoids, 366

448 Index

Revised European-American Lymphoma (REAL) classification, 6-7, 12, 14, 45,49, 71-2, 368 non-Hodgkin's lymphoma, 325-7 pediatric B neoplasms, 372-3 T cell and natural killer (NK) cell lymphomas, 55-6 rheumatoid disease, 57-8, 172 Richter's syndrome, 44, 325 RS see Hodgkin's and Reed-Sternberg (RS/H-RS) cell salivary glands, 212-13, 255 mucosa-associated lymphoid tissue (MALT) lymphoma, 77, 78 parotid, 77, 237 salvage therapy, 277-8, 304-5, 356 chemotherapy versus transplantation results, 336 secondary malignancies, 426-9 as cause of death, 431 in children, 380 following radiotherapy, 239 Sezary syndrome, 60, 80 siblings, 165 single photon emission computed tomography (SPECT), 207, 216-17 Sjogren's syndrome, 77, 255, 327 skin lymphomas see cutaneous lymphomas skin reactions phototherapy, 363 radiotherapy, 237, 364 small bowel lymphoma see intestinal lymphoma small lymphocytic lymphoma (B cell chronic lymphocytic leukemia),

43-4, 45, 325 socioeconomic status, Hodgkin's disease, 163-4 soft tissue lymphomas, 86 solid tumors, secondary, 427-8 somatostatin receptor scintigraphy, 218 Southern blotting, 55 spinal cord compression, Hodgkin's disease, 187 spinal lymphoma see extradural lymphoma spleen, 84-5 AIDS-related lymphoma, 215 in follicular lymphoma, 23 in lymphoplasmacytic lymphoma, 45 in mantle cell lymphoma, 30,35 in marginal zone lymphoma, 45 secondary malignancy, 239, 428 splenectomy staging, 222-3, 224 as treatment, 328 impaired immunity, 399, 422, 424 pediatric, 377, 379, 380 secondary malignancy, 239, 428 splenic gamma/delta T cell lymphoma, 85 splenic marginal zone lymphoma, 34, 45, 84-5 with or without villous lymphocytes, 327 splenomegaly, imaging, 207-8 staging abdominal lymphoma, 210 AIDS-related lymphoma, 215 central nervous system lymphoma, 213-14 Hodgkin's disease early, 222-4 pediatric, 377-8 lymphoblastic lymphoma, 300 non-Hodgkin's lymphomas (NHL), 289-90 classification, 248 head and neck, 213 investigations, 247-8 pediatric lymphomas, 216, 377-8 skeletal,211 testicular lymphoma, 209

thoracic lymphoma, 207 see also Ann Arbor staging system; Cotswold staging system; laparotomy, staging stem cell transplantation see high-dose therapy/stem cell transplantation superior vena caval obstruction, 186-7 surgery gastric lymphoma, 253 intestinal lymphoma, 254 non-Hodgkin's lymphomas (NHL), 249 pediatric, 375 see also laparotomy, staging; splenectomy TAL-1 gene, 57 T-ALL see T cell acute lymphoblastic leukemia taste perception, altered, 237 Tcell bone marrow infiltration in follicular lymphoma, 23 immunocytochemistry, 11, 13, 22, 31 -rich B cell lymphoma, 51 Tcell acute lymphoblastic leukemia (T-ALL), 56-7 T cell lymphomas, 4, 5, 55-69 AIDS-related, 352-3 associated viruses, 121-2 classification ILSG, 6 WHO, 7 cutaneous, 80-1, 261-2, 359, 368 non-Hodgkin's lymphomas, 12, 288, 327 pediatric, 373-6 pulmonary, 78-9 splenic, 84, 85 thymic, 83 T cell prolymphocytic leukemia (T-PLL), 56, 58 T cell receptor see TCR TCR alpha/beta/CD 3, 58, 59, 85 TCR gene, 96, 98 rearrangements, 10 testes, radiotherapy to, 239 testicular lymphomas high-grade B, 85 imaging, 209 non-Hodgkin's lymphoma, 256-7 thymus enlargement, 206 primary lymphomas, 51, 83-4, 262 thyroid cancer, 428 thyroid dysfunction, 238-9, 379-80,422-3 thyroid involvement, Hodgkin's disease, 188 thyroid lymphomas, 79, 252, 255 TIB see total body irradiation T-LCLsee cutaneous large cell lymphomas of T cell phenotype, primary tonsillar lymphoma, 212 total body irradiation (TIB), 314, 339-40 toxoplasmosis, 45 T-PLL see T cell prolymphocytic leukemia transgenic mouse models, 32-3, 134-5, 137 tumor bulk, 251 upper aerodigestive tract lymphomas, 81-2 urogenital tract lymphomas, 85 uterus, 258 vaccination DNA, 315 Haemophilus B, 379, 399 meningococcal, 399

Index 449

pneumococcal, 328, 379, 424 vagina, 258 varicella-zoster virus (VZV), 403 prevention and treatment, 408 VEEP (vincristine, etoposide, epirubicin, prednisolone), 381 venous catheters, 407 vinblastine, 271, 272, 389 see also ABVD; ChlVPP/EVA; CVPP; MVPP; P-VEBEC vinca alkaloids, metabolism in elderly, 389 vincristine, 260, 271,272, 312, 389 see also ChlVPP; ChlVPP/EVA; CHOP; CHVmP/VB; CNOP; CODOX-M; COPP; CVP; EPOCH; MOPP; PACEBOM; VEEP viruses, 115-31,402 immunosuppression, 172-3

reactivation of latent, 403 see also specific viruses VZV see varicella-zoster virus Waldeyer's ring, 71, 81-2,254 mantle cell lymphoma (MCL), 30, 35 weight loss, 237, 238 'western-type' intestinal MALT lymphoma, 76 Working Formulation classification, 36, 93, 287, 288, 372 World Health Organisation (WHO) classification, 7-8,14, 36 Ytrium-90, 315 zidovudine, 351, 354

Malignant Lymphoma

Malignant Sadness

Malignant Mesothelioma

Hodgkin Lymphoma

Primary Intraocular Lymphoma

Pathology of Malignant Mesothelioma

Textbook of Malignant Hematology

The Malignant Entity

Clinical Malignant Hematology

Radiotherapy for Hodgkin Lymphoma

Pocket Guide to Malignant Melanoma

TNM Classification of Malignant Tumours

Dead City, or, Malignant Marauder

Malignant Self Love - Narcissism Revisited

Lymphoma (Methods in Molecular Medicine)

Lymphoma: Pathology, Diagnosis and Treatment

Lymphoma Research Foundation Patient Booklets 2010

Malignant Liver Tumors: Current and Emerging Therapies

Malignant Sadness: The Anatomy of Depression

Neuroleptic Malignant Syndrome and Related Conditions

Johns Hopkins Patients' Guide to Lymphoma

An Illustrated Guide to Skin Lymphoma

Malignant Mesothelioma: Pathogenesis, Diagnosis, and Translational Therapies

Transcription Factors: Normal and Malignant Development of Blood Cells

Allogeneic Immunotherapy for Malignant Diseases (Basic and Clinical Oncology)

Malignant Liver Tumors, Third Edition: Current and Emerging Therapies

Malignant mesothelioma: advances in pathogenesis, diagnosis, and translational therapies

Malignant Lymphoma

Malignant Sadness

Malignant Mesothelioma

Hodgkin Lymphoma

Primary Intraocular Lymphoma

Pathology of Malignant Mesothelioma

Textbook of Malignant Hematology

The Malignant Entity

Clinical Malignant Hematology

Radiotherapy for Hodgkin Lymphoma

Pocket Guide to Malignant Melanoma

TNM Classification of Malignant Tumours

Dead City, or, Malignant Marauder

Malignant Self Love - Narcissism Revisited

Lymphoma (Methods in Molecular Medicine)

Lymphoma: Pathology, Diagnosis and Treatment

Lymphoma Research Foundation Patient Booklets 2010

Malignant Liver Tumors: Current and Emerging Therapies

Malignant Sadness: The Anatomy of Depression

Neuroleptic Malignant Syndrome and Related Conditions

Johns Hopkins Patients' Guide to Lymphoma

An Illustrated Guide to Skin Lymphoma

Malignant Mesothelioma: Pathogenesis, Diagnosis, and Translational Therapies

Transcription Factors: Normal and Malignant Development of Blood Cells

Allogeneic Immunotherapy for Malignant Diseases (Basic and Clinical Oncology)

Malignant Liver Tumors, Third Edition: Current and Emerging Therapies

Malignant mesothelioma: advances in pathogenesis, diagnosis, and translational therapies

Recommend Documents