Hodgkin Lymphoma. A Comprehensive Overview [3 ed.] 9783030324810, 9783030324827

Citation preview

Hematologic Malignancies Series Editor: Martin Dreyling

Andreas Engert Anas Younes   Editors

Hodgkin Lymphoma A Comprehensive Overview Third Edition

Hematologic Malignancies Series Editor Martin Dreyling München, Germany

Andreas Engert • Anas Younes Editors

Hodgkin Lymphoma A Comprehensive Overview Third Edition

Editors Andreas Engert Department of Internal Medicine University Hospital Cologne Köln, Nordrhein-Westfalen Germany

Anas Younes Lymphoma Service Memorial Sloan Kettering Cancer Center NY, USA

ISSN 2197-9766     ISSN 2197-9774 (electronic) Hematologic Malignancies ISBN 978-3-030-32481-0    ISBN 978-3-030-32482-7 (eBook) https://doi.org/10.1007/978-3-030-32482-7 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Hodgkin lymphoma has become one of the best curable malignancies in both adult and pediatric patients. More than 80% of all patients can be cured with risk-adapted treatment including chemotherapy and radiotherapy. This progress is largely due to the development of multi-agent chemotherapy and the improvements in radiotherapy. Due to the high cure rate and the young age of most patients affected, Hodgkin lymphoma has also become a model for studying long-term toxicity of radiotherapy and chemotherapy that may impact quality of life and/or survival. Future treatment should continue to balance the need for improving the cure rate while reducing treatment-related side effects. In addition, there are a number of relevant physical and psychosocial issues including infertility and fatigue that need to be further exploited. Monoclonal antibodies against this antigen were successfully used for diagnostic immunophenotyping and exploited therapeutically. This strategy has come full circle with the advent of the anti-CD30 antibody drug conjugate Brentuximab Vedotin. This drug has shown remarkable responses in relapsed and refractory classical Hodgkin lymphoma and is also being used in combination with chemotherapy. The development of targeted treatment for patients with Hodgkin lymphoma is rapidly evolving. The recent approval of checkpoint inhibitors has added an additional treatment option for patients with relapsed cHL, opening the door for new developments including new combinations of chemotherapy or radiotherapy being evaluated in first line. This book should give you a comprehensive overview of the most relevant biology, diagnostic and clinical aspects of Hodgkin lymphoma. We would like to express our sincere gratitude to all those who have contributed to this project. Cologne, Germany New York, NY, USA 

Andreas Engert Anas Younes

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Contents

Part I Epidemiology and Pathogenesis 1 Epidemiology of Hodgkin Lymphoma ���������������������������������������������� 3 Henrik Hjalgrim and Ruth F. Jarrett 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma���������� 25 Ruth F. Jarrett, Henrik Hjalgrim, and Paul G. Murray 3 Pathology and Molecular Pathology of Hodgkin Lymphoma�������� 47 Andreas Rosenwald and Ralf Küppers 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms��������������������������������������������������������������������������������������  69 Lydia Visser, Johanna Veldman, Sibrand Poppema, Anke van den Berg, and Arjan Diepstra 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma������������������������������������������������������  87 Davide Rossi and Christian Steidl Part II Diagnosis and First-Line Treatment 6 Clinical Evaluation��������������������������������������������������������������������������  99 James O. Armitage and Jonathan W. Friedberg 7 Functional Imaging in Hodgkin Lymphoma �������������������������������� 113 Andrea Gallamini, Bruce Cheson, and Martin Hutchings 8 Prognostic Factors���������������������������������������������������������������������������� 145 Paul J. Bröckelmann and Lena Specht 9 Principles of Radiation Therapy for Hodgkin Lymphoma���������� 171 Joachim Yahalom, Bradford S. Hoppe, Joanna C. Yang, and Richard T. Hoppe 10 Principles of Chemotherapy in Hodgkin Lymphoma������������������ 199 David Straus and Mark Hertzberg 11 Treatment of Early Favorable Hodgkin Lymphoma�������������������� 219 Wouter Plattel and Pieternella Lugtenburg

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12 Treatment of Early Unfavorable Hodgkin Lymphoma���������������� 237 Marc P. E. André and Andreas Engert 13 Treatment of Advanced-Stage Hodgkin Lymphoma�������������������� 249 Alexander Fosså, René-Olivier Casasnovas, and Peter W. M. Johnson 14 Optimizing Decision Making in Hodgkin Lymphoma������������������ 265 Susan K. Parsons, Joshua T. Cohen, and Andrew M. Evens Part III Special Clinical Situations 15 Pediatric Hodgkin Lymphoma�������������������������������������������������������� 277 Georgina W. Hall, Cindy Schwartz, Stephen Daw, and Louis S. Constine 16 The Management of Older Patients with Hodgkin Lymphoma���������������������������������������������������������������������������������������� 297 Boris Böll and Andrew M. Evens 17 Nodular Lymphocyte-Predominant Hodgkin Lymphoma ���������� 317 Dennis A. Eichenauer and Ranjana H. Advani 18 The Management of Hodgkin Lymphoma During Pregnancy���������������������������������������������������������������������������� 325 Veronika Bachanova and Joseph M. Connors 19 The Management of HIV-Hodgkin Lymphoma���������������������������� 335 Marcus Hentrich and Michele Spina Part IV Relapsed and Refractory Disease 20 Relapsed and Refractory Hodgkin Lymphoma���������������������������� 351 Bastian von Tresckow and Craig Moskowitz 21 Allogeneic Transplantation for Relapsed Hodgkin Lymphoma���������������������������������������������������������������������������������������� 365 Anna Sureda, Martina Pennisi, and Paolo Corradini 22 Targeting CD30 in Patients with Hodgkin Lymphoma���������������� 381 Anita Kumar, Stefano Pileri, Anas Younes, and Andreas Engert 23 Hodgkin Lymphoma and PD-1 Blockade�������������������������������������� 395 Reid Merryman, Philippe Armand, and Stephen Ansell 24 Other New Agents for Hodgkin Lymphoma���������������������������������� 411 Alison J. Moskowitz and Anas Younes Part V Survivorship 25 Quality of Life in Hodgkin Lymphoma������������������������������������������ 419 Stefanie Kreissl, Hans-Henning Flechtner, and Peter Borchmann

Contents

Contents

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26 Second Malignancy Risk After Treatment of Hodgkin Lymphoma���������������������������������������������������������������������������������������� 429 Michael Schaapveld, David C. Hodgson, and Flora E. van Leeuwen 27 Cardiovascular and Pulmonary Late Effects�������������������������������� 465 Berthe M. P. Aleman and David J. Cutter 28 Gonadal Dysfunction and Fertility Preservation in Hodgkin Lymphoma Patients ���������������������������������������������������� 485 Karolin Behringer and Michael von Wolff 29 Cancer-Related Fatigue in Hodgkin Lymphoma�������������������������� 501 Stefanie Kreissl, Anton Hagenbeek, Hans Knoop, and Peter Borchmann

Part I Epidemiology and Pathogenesis

1

Epidemiology of Hodgkin Lymphoma Henrik Hjalgrim and Ruth F. Jarrett

Contents 1.1

Introduction 

 4

1.2

Definition and Histological Classification (WHO) 

 4

1.3 1.3.1 1.3.2 1.3.2.1  1.3.2.2  1.3.2.3  1.3.3 1.3.4 1.3.5

Hodgkin Lymphoma Occurrence  Overall Incidence  Age-Specific Incidence Patterns Vary Geographically  Historical Patterns  Modern Age-Specific Incidence Patterns  Age-Specific Incidence Patterns for Hodgkin Lymphoma Subtypes  Incidence Trends  Classifications for Epidemiological Studies: Multi-disease Models  Classifications by Age at Diagnosis, Histology and Tumour Epstein-Barr Virus Status  Overlap Between Epidemiological Classifications of Hodgkin Lymphoma 

1.3.6

 amilial Accumulation of Hodgkin Lymphoma: F Genetic Predisposition  1.4.1 Genetic Studies: Genome-­Wide Association Studies  1.4.1.1  Hodgkin Lymphoma Subtype-­Specific Associations in Genetic Analyses 

 5  5  5  5  6  7  7  10  10  11

1.4

1.5 1.5.1 1.5.1.1  1.5.2

Risk Factors  Prevailing Hypotheses in Hodgkin Lymphoma Epidemiology  Childhood Socio-Economic Environment  Anthropometry 

 12  12  12  13  13  13  14

H. Hjalgrim (*) Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: [email protected] R. F. Jarrett MRC-University of Glasgow Centre for Virus Research, Glasgow, UK © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_1

3

H. Hjalgrim and R. F. Jarrett

4 1.5.3 1.5.3.1  1.5.3.2  1.5.3.3  1.5.3.4  1.5.4 1.5.4.1  1.5.4.2  1.5.4.3 

Medical History  Infections  Primary and Secondary Immune Deficiencies  Autoimmune and Allergic Disorders  Medications  Environmental Exposures  Ultraviolet Light  Tobacco  Alcohol 

 15  15  16  17  17  18  18  18  18

1.6

Conclusion 

 19

References 

1.1

Introduction

The treatment of Hodgkin lymphoma has become one of the great successes in modern oncology with cure rates exceeding 90% for patients with early-stage disease and approaching the same level for patients with advanced disease [1, 2] (see also elsewhere in this book). Although Hodgkin lymphoma was among the first haematological malignancies described in the literature in 1832 [3], the advances made in the understanding of the natural history of Hodgkin lymphoma and its causes are less impressive. It might be ventured that the impressive treatment results leave this to be of little consequence; however, efforts in this regard are continuously worthwhile. Accordingly, the good prognosis for Hodgkin lymphoma is entirely dependent on modern care which is inaccessible in many parts of the world, where the disease still carries considerable mortality. Moreover, as highlighted by a growing literature, the high cure rates have been achieved at the cost of a high frequency of late and often severe adverse treatment effects among Hodgkin lymphoma survivors [4]. Consequently, if better understanding of Hodgkin lymphoma aetiology could help identify means to its prevention, e.g. through vaccination [5], much could be gained. The present chapter gives an overview of the epidemiology of Hodgkin lymphoma and summarizes current understanding of its risk factors. For a more detailed review, please be referred to [6].

 19

1.2

Definition and Histological Classification (WHO)

Hodgkin lymphoma is a malignancy which in the vast majority of cases is derived from germinal centre B-lymphocytes, with odd cases (possibly) being of T-cell origin [7]. The current WHO classification recognizes two main variants of Hodgkin lymphoma, specifically classic Hodgkin lymphoma and nodular lymphocytic predominant Hodgkin lymphoma [8, 9]. The two variants of Hodgkin lymphoma display different clinical, morphological, immunological and molecular characteristics, allowing them to be distinguished with reasonable precision [10, 11]. Because the two variants are also believed to have different natural histories, they are conventionally considered separately in epidemiological investigations whenever possible. This is also the case in the present chapter, which for all practical purposes will focus on classic Hodgkin lymphoma. Classic Hodgkin lymphomas make up around 95% of all cases and are further divided into four subtypes referred to as nodular sclerosis (70% of all classic Hodgkin lymphomas), mixed cellularity (20–25% of classic Hodgkin lymphomas), lymphocyte-rich, and lymphocyte-depleted classic Hodgkin lymphoma, respectively [12, 13]. Because the distinction between the classic Hodgkin lymphoma subtypes relies entirely on a subjective interpretation of the histological presentation of the tumour lesion, it is subject to

1  Epidemiology of Hodgkin Lymphoma

5

both inter- and intra-observer variation [10, 11]. While classic Hodgkin lymphoma subtype may previously have had clinical relevance, this is no longer the case with modern imaging tools aiding diagnosis [14]. Importantly, because of the distribution of the Hodgkin lymphoma variants and classic Hodgkin lymphoma subtypes, investigations reporting associations of one kind or another for Hodgkin lymphoma overall will still be epidemiologically informative.

As already alluded to the discordant incidence and mortality patterns reflect that modern therapy can cure most Hodgkin lymphoma patients and that access to such therapy is dependent on the level of socio-economic development [16]. Of note, similar socio-economically dependent variation in Hodgkin lymphoma mortality can also be observed in affluent countries [17] and underscores the continued need for epidemiological investigations to promote preventive interventions.

1.3

1.3.2 Age-Specific Incidence Patterns Vary Geographically

Hodgkin Lymphoma Occurrence

1.3.1 Overall Incidence The International Agency for Research on Cancer estimates that world-wide close to 80,000 individuals (33,431 women and 46,559 men) were diagnosed with Hodgkin lymphoma in 2018 and that slightly more than 26,000 individuals (10,397 women and 15,770 men) succumbed to the disease the same year [15]. This places Hodgkin lymphoma as the 27th commonest cancer diagnosed and the 27th commonest cancer-specific cause of death [15]. Both Hodgkin lymphoma incidence and mortality display considerable geographic variation. Overall, Hodgkin lymphoma incidence is higher in Western world industrialized countries than in Asian and developing countries (Fig. 1.1). In the USA, for instance, age-standardized (world population) incidence rates were of the order 2.8 and 2.2 per 100,000 per year in men and women, respectively, whereas the corresponding figures for Indian men and women were 0.79 and 0.58 per 100,000 per year, respectively [15]. Hodgkin lymphoma mortality, conversely, is higher in some developing countries than in industrialized countries (Fig.  1.2). Accordingly, age-standardized mortality rates (world) were 0.25 and 0.14 per 100,000 per year for US men and women, respectively, and 0.53 and 0.35 per 100,000 per year for Indian men and women, respectively [15].

1.3.2.1 Historical Patterns Hodgkin lymphoma occurs at all ages, but among populations, age-specific incidence distributions tend to vary with their ethnic and socio-economic make-up. This variation was summarized into four prototypical incidence patterns (numbered I through IV) in studies in the 1950s, 1960s and 1970s [18–20]. Because they have permeated Hodgkin lymphoma epidemiological thinking for decades, the four patterns are briefly described for the sake of completeness. Pattern I was observed in developing countries and comprised an accumulation of Hodgkin lymphoma cases—predominantly mixed cellularity— among young boys, low incidence throughout the second and third decades of life and increasing incidence with age among older adults. Pattern III was seen in affluent Western countries and demonstrated low incidence in childhood, a marked accumulation of cases—typically nodular sclerosis—in adolescents and younger adults (AYA), a lower incidence in middle-aged adults and an increasing incidence with age among older adults. Pattern II was observed in rural areas of affluent countries and perceived as an intermediate between patterns I and III. Finally, a pattern IV prevailed in Asian countries and featured low incidence rates throughout the first four decades of life followed by increasing incidence with age among older adults.

H. Hjalgrim and R. F. Jarrett

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Estimated age-standardized incidence rates (World) in 2018, Hodgkin lymphoma, both sexes, all ages

ASR (World) per 100 000 ≥ 2.1 1.5-2.1 0.78-1.5 0.39-0.78 < 0.39

Not applicable No data

Fig. 1.1  Estimated age-standardized incidence rates of Hodgkin lymphoma for both sexes combined (Data from [15])

Estimated age-standardized mortality rates (World) in 2018, Hodgkin lymphoma, both sexes, all ages

ASR (World) per 100 000 ≥ 0.53 0.33-0.53 0.23-0.33 0.08-0.23 Not applicable < 0.08 No data

Fig. 1.2  Estimated age-standardized mortality rates of Hodgkin lymphoma for both sexes combined (Data from [15])

1.3.2.2 Modern Age-Specific Incidence Patterns The main features of the prototypical Hodgkin lymphoma incidence patterns, i.e. incidence peaks in boys, AYAs and older adults, are still recognizable. In Chennai, India, for instance, the age-­ specific Hodgkin lymphoma incidence pattern

for the period 1993–2012 displayed a type I-like pattern with a peak in boys less than 10 years of age, no incidence peak among adolescents and younger adults and increasing incidence with age among older adults (Fig.  1.3), even if a transition towards a type II-like pattern can be observed in the more recent of these data [15].

1  Epidemiology of Hodgkin Lymphoma

Of note, an incidence peak among boys can also be demonstrated within European populations when more granular data are available for analysis [21, 22]. In the USA, conversely, Hodgkin lymphoma incidence follows a type III-like pattern with incidence peaks among AYAs and older adults, respectively (Figs. 1.3 and 1.4). Even within the US age-specific incidence patterns adhere to the correlation with socio-­ economic level. In California, a survey of cases diagnosed 1988–1992 showed higher Hodgkin lymphoma incidence among adolescents and younger adults in the highest compared with the lowest tertile of socio-economic status (Fig. 1.4) [23].

7

Although it correlates with the level of socio-­ economic development, the geographical variation in Hodgkin lymphoma incidence likely also reflects an association with ethnicity (Fig.  1.6). Thus, in a Californian survey, variation in Hodgkin lymphoma incidence rates between ethnic/racial groups was apparent even within strata of socio-economic status [23].

1.3.3 Incidence Trends

Changes to Hodgkin lymphoma classification systems have not been substantial in principle allowing analyses of incidence over longer time periods. However, considerable misclassification between Hodgkin and non-Hodgkin lym1.3.2.3 Age-Specific Incidence Patterns phomas in the older age groups (see [10, 11, 24] for Hodgkin Lymphoma and references therein) resulted in inflated Subtypes Hodgkin lymphoma incidence rates in these age The bimodal age distribution of Hodgkin lym- groups in earlier studies. Improvement of diagphoma incidence overall in affluent populations nostic precision may, therefore, contribute to the is largely mirrored by the corresponding distribu- decreasing Hodgkin lymphoma incidence rates tion of the classic Hodgkin lymphoma variants that have been reported in older age groups (e.g. (Fig. 1.5). [24–26]). Both nodular sclerosis and mixed cellularity The misclassification vis-à-vis non-Hodgkin classic Hodgkin lymphoma display bimodal age lymphoma has been less for Hodgkin lymphoma distributions with incidence peaks in AYA and among younger patients, rendering incidence older adult age groups, respectively (Fig.  1.5). trend analyses more meaningful. The correlation Mixed cellularity classic Hodgkin lymphoma between age-specific incidence patterns and level may be the most common subtype among the of socio-economic development in the underlyyoungest children [21], but otherwise nodular ing population strongly suggests that Hodgkin sclerosis classic Hodgkin lymphoma is the most lymphoma occurrence (and risk) is influenced by common subtype in all age groups. environmental factors. More specifically, it indiWhile the age-specific incidence patterns for cates that Hodgkin lymphoma incidence in nodular sclerosis and mixed cellularity Hodgkin ­childhood and in adolescence and early adultlymphoma overall are similar for the two sexes hood is determined by correlates of socio-ecoand Hodgkin lymphoma incidence overall is nomic status or, alternatively, Westernized higher in men than in women, the incidence of living. classic Hodgkin lymphoma—in effect the noduTherefore, it is perhaps of little surprise that lar sclerosis subtype—may be higher in women increasing incidence of Hodgkin lymphoma has than in men in adolescence and early adulthood been described among adolescents and younger (Fig. 1.3). adults in conjunction with continued improveFor lymphocyte-depleted and lymphocyte-­ ments in living standards in both industrialized rich classic Hodgkin lymphoma, incidence rates and developing countries (e.g. [25–29]). generally increase with age (Fig. 1.5). Interestingly, the rate of increase appears to have

H. Hjalgrim and R. F. Jarrett

8 Fig. 1.3 Age-specific incidence rates for Hodgkin lymphoma in Chennai, India, and in the USA in the period 1993–2012 (Data from Bray F, Colombet M, Mery L, Piñeros M, Znaor A, Zanetti R and Ferlay J, editors (2017) Cancer Incidence in Five Continents, Vol. XI (electronic version) Lyon, IARC. http://ci5. iarc.fr last accessed on [25 March 2019])

Hodgkin Iymphoma (1993-2012) 6.5 6.0 5.5 5.0 4.5

rate per 100,000

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0-

10-

20-

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4050age

60-

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International Agency for Research on Cancer (IARC) - 25.3.2019 USA, SEER (9 registries) : Male USA, SEER (9 registries) : Female India, Chennai : Male India, Chennai : Female

been more pronounced among AYA women than among AYA men. Because diagnostic misclassification also extends to subtypes of classic Hodgkin lymphoma [10, 11] and because the increasing use of

non-excisional biopsies for lymphoma diagnosis limits the tumour material available for diagnostic purposes [30], changes in classic Hodgkin lymphoma subtype-specific trends are also difficult to interpret.

1  Epidemiology of Hodgkin Lymphoma 7 6 5 Rate/100,000

Fig. 1.4 Age-specific incidence rates of Hodgkin lymphoma by tertile of neighbourhood socio-economic status, California, 1988–1992 (Figure reproduced from [23])

9

4 3 2 1 0 0-4

10-14

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30-34

40-44

50-54

60-64

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80-84

Age at diagnosis Medium

High

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3.5

Incidence per 100,000 per year

3

2.5 2

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80+ yr

Age group Nodular sclerosis

Mixed cellularity

Lymphocyte depleted

Lymphocyte rich

Not otherwise specified

Fig. 1.5  Age-specific incidence rates of classic Hodgkin lymphoma in both sexes combined by histological subtype in the USA (2000–2011) (Data from US SEER 18. This Figure was reproduced from [6])

H. Hjalgrim and R. F. Jarrett

10 7 Whites

Blacks

Hispanics

Asian/Pacific Islanders

Incidence per 100,000 per year

6

5 4

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1

0

00–09 yr

10–19 yr

20–29 yr

30–39 yr

40–49 yr

50–59 yr

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Age group

Fig. 1.6  Age-specific incidence rates of classic Hodgkin lymphoma overall in both sexes combined by race/ethnicity in the USA (2008–2012) (Data from US SEER 18. Figure reproduced from [6])

1.3.4 Classifications for Epidemiological Studies: Multi-disease Models Efforts to unravel causes of Hodgkin lymphoma have been complicated by the strong suspicion that several epidemiologically and etiologically distinct Hodgkin lymphoma variants exist and because efforts to define these have proven exceedingly difficult.

1.3.5 C  lassifications by Age at Diagnosis, Histology and Tumour Epstein-Barr Virus Status Intrigued by the bimodal age distribution and by corresponding epidemiological and clinical variation between cases within the age-specific incidence peaks, MacMahon in 1966 [19] proposed that three etiologically heterogeneous Hodgkin lymphoma types existed and that age at diagnosis, specifically 0–14  years, 15–34  years and 50+ years, could be used as a proxy to distinguish between them.

MacMahon, moreover, suggested that Hodgkin lymphoma in young adults had an infectious aetiology [19]. As information on Hodgkin lymphoma subtypes, classified using modern criteria, became available for larger patient series, the composition of cases within the incidence peaks (Fig. 1.6) led to the proposal that nodular sclerosis and mixed cellularity Hodgkin lymphoma each ­captured one of the supposedly etiologically distinct variants. In 1985, Poppema and colleagues were the first to report the presence of Epstein-Barr virus genome products in the malignant Hodgkin/Reed-Sternberg cells in a patient with Hodgkin lymphoma [31]. Nearly 35 years later, we now know that some 30% of Hodgkin lymphomas among adults in affluent Western populations and even more in African and Asian countries are positive for Epstein-Barr virus [32]. We also know that epidemiologically Epstein-Barr virus-­ positive and Epstein-Barr virus-negative Hodgkin lymphomas differ (reviewed in [33], and further discussed in Chap. 2). Consequently, tumour Epstein-Barr

1  Epidemiology of Hodgkin Lymphoma

11

virus status offers itself as a third way to group classic Hodgkin lymphoma into epidemiologically distinct entities.

miologically specific entities has empirical merit, as will be discussed in the sections below. However, they are sufficiently incongruent to reflect the same phenomenon or subtype. Age at diagnosis displays some overlap with both histology (Fig.  1.5) and tumour Epstein-­ Barr virus status (Fig.  1.7). However, there is less overlap between tumour Epstein-Barr virus status and histological subtype. While most mixed cellularity classic Hodgkin lymphomas are Epstein-Barr virus-positive and most nodular

1.3.6 O  verlap Between Epidemiological Classifications of Hodgkin Lymphoma Each of the three proposed means to stratify Hodgkin lymphoma into etiologically and epidea

6

5

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0

20

30

40

50

60

70

Age (years)

b

2.5

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Fig. 1.7 Age-specific incidence rates for classic Hodgkin lymphoma overall (dotted line), Epstein-­ Barr virus-negative (squares) and virus-­ positive (triangles) classic Hodgkin lymphomas. Panel b: Age-specific Epstein-­ Barr virus-positive classic Hodgkin lymphoma among men (squares) and women (triangles) (Figure reproduced from [10])

1.5

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H. Hjalgrim and R. F. Jarrett

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sclerosis classic Hodgkin lymphomas are Epstein-Barr virus-negative, nodular sclerosis classic Hodgkin lymphomas still make up more than half of all Epstein-Barr virus-positive cases [33]. Because Epstein-Barr virus remains the most plausible causal candidate for Hodgkin lymphoma, its incongruence with the tumour histology classification is insufficient grounds for its dismissal. Therefore, age at diagnosis, tumour histology and tumour Epstein-Barr virus status likely represent different elements of Hodgkin lymphoma natural history, emphasizing its complexity.

1.4

Familial Accumulation of Hodgkin Lymphoma: Genetic Predisposition

It has been known for more than half a century that Hodgkin lymphomas cluster within families, the earliest investigation indicating an approximately threefold increased risk among Hodgkin lymphoma patients’ first-degree relatives [34]. Subsequent studies with access to larger and even register-based data have largely confirmed this association. The hitherto largest investigation, a Nordic register-based investigation of 57,475 first-degree relatives of 13,922 classic Hodgkin lymphoma patients, yielded an overall standardized incidence ratio of 3.3 (95% confidence interval 2.8–3.9) for familial recurrence, corresponding to a 0.6% lifetime risk of classic Hodgkin lymphoma among patient relatives [35]. Owing to its magnitude, the Nordic study allowed for stratification of analyses by type of family relation and found a standardized incidence ratio of 2.1 (95% confidence interval 1.6–2.6) for the combined group of patient parents and offspring, but 6.0 (95% confidence interval 4.8–7.4) among patient siblings [35]. Even more extremely increased risks were observed for same-sex twins (standardized incidence ratio 57 (95% confidence interval 21–125)), consistent with the results of a previous American twin study [36]. Hodgkin lymphoma also clusters with other haematological malignancies, notably chronic

lymphocytic leukaemia [37] and diffuse large B-cell lymphoma [38], with relative risks for these malignancies being slightly less increased— twofold—than for classic Hodgkin lymphoma.

1.4.1 G  enetic Studies: Genome-­ Wide Association Studies The accumulation of Hodgkin lymphomas among relatives must reflect shared environmental and constitutional risk factors. Both candidate gene investigations and genome-wide association studies confirm the suspicion that genetic predisposition is important to Hodgkin lymphoma risk. The histological presentation of Hodgkin lymphoma is dominated by admixture of accessory and inflammatory cells indicating that immune function is important to the disease. Early research, therefore, focused on the association between tissue type, i.e. HLA, and Hodgkin lymphoma risk. Indeed, Hodgkin lymphoma was among the first diseases linked with markers of specific HLA types [39, 40]. Genotyping of more than 5000 patients with Hodgkin lymphoma has identified a total of 18 genetic loci associated with Hodgkin lymphoma risk. Based on these loci, Sud and colleagues point to three key biological processes underlying Hodgkin lymphoma susceptibility. These are (1) the germinal centre reaction (2p16.1, REL; 3q28, BCL6 and mir-28; 6p21, HLA; 6q23.3, MYB; 8q24.21, MYC; 11q23.1, POU2AF1; 16p11.2, MAPK3; 19p13.3, TCF3; 20q13.12, CD40), (2) T-cell differentiation and function (3p24.1, EOMES; 5q31,1, IL13; 6q22.33, PTPRK and THEMIS; 6q23.3, MYB; 6q23.3, AHI1; 10p14, GATA3; 16p13.1, SOCS1 and CLEC16A; 16p11.2, MAPK3 and CORO1A) and (3) constitutive NF-kB activation (2p16.1, REL; 3p24.1, AZI2; 6q23.3, TNFAIP3; 20q13.12, CD40) [41].

1.4.1.1 Hodgkin Lymphoma Subtype-­ Specific Associations in Genetic Analyses In addition to shedding light on possible mechanisms underpinning Hodgkin lymphoma pathogenesis in general (discussed in the following

1  Epidemiology of Hodgkin Lymphoma

chapter (The Role of Viruses in the Genesis of Hodgkin Lymphoma)), the genetic investigations also add further credence to the notion of etiological heterogeneity between classic Hodgkin lymphoma subtypes. Accordingly, as discussed in the following chapter, evidence is mounting that risk of EpsteinBarr virus-positive Hodgkin lymphoma is strongly associated with alleles in the HLA class I region (e.g. rs2734986, HLA-A; rs6904029, HCG9), whereas risk of Epstein-Barr virus-negative disease is more strongly associated with alleles within the HLA class II region (e.g. rs6903608, HLA-DRA) [42]. The variation in genetic associations underscores the importance of detailed phenotyping in genome-wide association as well as other types of studies of Hodgkin lymphoma. Thus, in the absence of information on either tumour histology or tumour Epstein-Barr virus status, neither the presence nor absence of associations can be fully interpreted. This is illustrated by an extended analysis of the HLA region in the first GWAS to stratify cases by EBV status [42, 43]. This study revealed a single nucleotide polymorphism near the HLA-­DPB1 gene (rs6457715) which was associated with Epstein-Barr virus-positive (odds ratio 2.33 (95% confidence interval 1.83– 2.97; P 10–12)), but not with Epstein-Barr virus-negative Hodgkin lymphoma risk (odds ratio 1.06 (95% confidence interval 0.92–1.21); Phom = 10−8), a difference that was present even within strata defined by classic Hodgkin lymphoma histology [43]. With that reservation, the association with class I alleles for Epstein-Barr virus-positive Hodgkin lymphomas or with mixed cellularity Hodgkin lymphoma suggests that cytotoxic T-cells’ control of virally infected lymphocytes whether before or after malignant transformation is significant to the risk of the lymphoma. Epstein-Barr virus-negative Hodgkin lymphoma’s association with HLA class II alleles may reflect a similar role of immune control of an infectious agent in the pathogenesis of this Hodgkin lymphoma subtype. Alternatively, it may also be indicative of the involvement of

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CD4-positive T follicular helper cells in Hodgkin lymphoma pathogenesis [44]. For further discussion, please be referred to Chap. 2.

1.5

Risk Factors

1.5.1 Prevailing Hypotheses in Hodgkin Lymphoma Epidemiology As already mentioned, for more than half a century, it has been assumed that Hodgkin lymphomas in children, AYA and older adults differ epidemiologically—possibly aetiologically— from one another [19]. Therefore, epidemiological investigations have conventionally considered risk factors for Hodgkin lymphoma for the three age groups separately, when practically possible. Owing to the bimodal age distribution of Hodgkin lymphoma in affluent populations, the epidemiology of AYA Hodgkin lymphoma has been the most studied.

1.5.1.1 Childhood SocioEconomic Environment The correlation between age-specific Hodgkin lymphoma incidence patterns and level of socio-­economic development in the underlying population led to the formulation of the socalled late infection model for Hodgkin lymphoma [45, 46]. This model suggests that Hodgkin lymphoma among children, adolescents and younger adults is caused by an infectious agent and that lymphoma risk increases with increasing age at primary infection [45, 46]. Early studies supported this understanding of AYA Hodgkin lymphoma indirectly by reporting that correlates of childhood socio-economic affluence, which are thought to be associated with low childhood infectious disease pressure, such as length of maternal education, home ownership and being a member of a small sibship, were associated with increased risk of AYA Hodgkin lymphoma [47]. Moreover, within sib-

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ships, Hodgkin lymphoma risk correlated inversely with number of older siblings, i.e. birth order [47]. Mack and colleagues recently (2015) reported the results of a register-based case-control study nested in a cohort of US army conscripts in the period 1950–1968. The study included 656 men diagnosed with Hodgkin lymphoma at ages 17–32  years and individually matched controls. In univariate analyses, they found increased Hodgkin lymphoma risk with small sibship size (odds ratio 1.4 (95% confidence interval 1.1–1.9) for 2–3 vs. >3 children), birth order (odds ratio 1.9 (95% confidence interval 1.4–2.6) for first vs. middle born) and short age gap to nearest sibling (odds ratio 2.1 (95% confidence interval 1.5–3.1) for more vs. less than 5 years) [48]. Information on histological subtype was available for a subset of the cases in the study of US conscripts, but analyses did not point to different associations for nodular sclerosis and mixed cellularity Hodgkin lymphoma. No information on tumour Epstein-Barr virus status was available for analyses [48]. In later investigations—that is, studies of patients diagnosed in more recent years—the association between traditional measures of childhood socio-economic affluence and AYA Hodgkin lymphoma risk in Western countries has been less compelling or even absent [49–54]. This change in the epidemiology of Hodgkin lymphoma in AYA may suggest that family or rather sibship structure no longer reflects the early life exposures associated with the disease [51]. Of note in this regard, in two case-control investigations, one American and one Scandinavian, kindergarten attendance was associated with reduced Hodgkin lymphoma risk in AYAs (odds ratio 0.64 (95% confidence interval 0.45–0.92) and odds ratio  =  0.78 (95% confidence interval 0.56–1.09)) [49, 52]. Information on tumour Epstein-Barr virus status was available in both investigations, and while no differences in association with nursery school attendance were observed in the American investigation, it tended to be stronger for virus-­negative Hodgkin lymphoma in the Scandinavian study [49, 52]. This contrast highlights that varying

H. Hjalgrim and R. F. Jarrett

associations may simply result from the subtype composition of the studied Hodgkin lymphomas. The evidence supporting the idea that childhood socio-economic environment influences Hodgkin lymphoma risk in childhood is also insubstantial. One Danish register cohort study found that risk of Hodgkin lymphoma before age 15  years increased with sibship size and birth order [55]. This association was reproduced in neither Swedish [56] nor American data [57]. However, a large North American case-control investigation reported findings similar to the Danish study: increasing sibship size was positively and increasing maternal education and household income inversely associated with Hodgkin lymphoma risk before age 15 years [58].

1.5.2 Anthropometry Hodgkin lymphoma risk up to the age of early adulthood in some investigations (though not all) associates with increasing birth weight (e.g. [53, 54]). In a Californian register-based investigation, Hodgkin lymphoma risk in the age group 0–19  years was found to increase by 16% (95% confidence interval 1.03–1.30) per kilogram increase in birth weight [54]. While in this investigation the association appeared specific to nodular sclerosis classic Hodgkin lymphoma [54], it applied to both nodular sclerosis and mixed cellularity classic Hodgkin lymphoma in the other [53]. Like reports of association between stature late in childhood/in early adolescence and subsequent risk of Hodgkin lymphoma [59, 60], the association with birth weight may at least in part reflect Hodgkin lymphomas association with childhood socio-economic affluence. A number of prospective investigations have pointed to an association between obesity and Hodgkin lymphoma risk [61–63]. For example, in the UK Million Women Study, body mass index correlated with Hodgkin lymphoma risk (hazard ratio 1.64 (95% confidence interval 1.21– 2.21) per 10 kg per square meter increase)) [63]. If true, the association between obesity and Hodgkin lymphoma risk could reflect obesity-­ related inflammation references.

1  Epidemiology of Hodgkin Lymphoma

1.5.3 Medical History

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extension of the Scandinavian cohort study mentioned above, according to which infectious mononucleosis was associated with an increased 1.5.3.1 Infections The late infection model fostered much interest risk of Epstein-Barr virus-positive classic in the search for infectious agents that might Hodgkin lymphomas (standardized incidence cause Hodgkin lymphoma. Among suspected ratio 4.0 (95% confidence interval 3.4–4.5)) and organisms, the human herpesvirus Epstein-Barr not Epstein-Barr virus-negative classic Hodgkin virus, first isolated from Burkitt lymphoma tissue lymphoma (standardized incidence ratio 1.5 [64] and soon after established as the cause of (95% confidence interval 0.9–2.5)) [68]. While similar subtype-specific observations infectious mononucleosis [65], has long been the were also made in British and Scandinavian case-­ centre of attention. control investigations [49, 69], other studies have reported increased risks for both Epstein-Barr Epstein-Barr Virus Infection: Infectious virus-positive and Epstein-Barr virus-negative Mononucleosis Epidemiological, serological and molecular-­ Hodgkin lymphomas [70] or no associations at biological (i.e. the presence of Epstein-Barr virus all [50, 52]. genome products in the malignant cells) evidence link Epstein-Barr virus infection to Hodgkin Epstein-Barr Virus Infection: Serological lymphoma development. Here, only the epide- Evidence miological and serological evidence will be pre- Support for the association between Epstein-Barr sented; for the presence and role of Epstein-Barr virus infection and Hodgkin lymphoma risk also comes from serological investigations [71, 72]. virus in the malignant cells, please see Chap. 2. In 1989 Nancy Mueller and colleagues in a Infectious mononucleosis is rarely seen prospective nested case-control study found that among children but is a common presentation of primary infection with the Epstein-Barr virus aberrant patterns of anti-Epstein-Barr virus antiwhen it is delayed until adolescence [66]. bodies were associated with overall Hodgkin Numerous investigations have assessed the asso- lymphoma risk [73]. Three decades later this study was replicated ciation between infectious mononucleosis and Hodgkin lymphoma, and most have reported only this time with information on tumour increased Hodgkin lymphoma risk in the wake of Epstein-Barr virus status. Comparing pre-­ diagnostic antibody patterns in 40 and 88 infectious mononucleosis (reviewed in [33]). The largest of these was a Scandinavian patients with Epstein-Barr virus-positive and Barr virus-negative classic Hodgkin register-­based cohort study of more than 40,000 Epstein-­ patients with infectious mononucleosis followed lymphomas with those in matched controls, for the occurrence of Hodgkin lymphoma. Levin and colleagues showed that an inverted EBNA2 antibody level ratio Compared with the general population, the infec- anti-EBNA1/anti-­ tious mononucleosis patients were at a 2.55 (95% (≤1) consistent with impaired control of confidence interval 1.87–3.40)-fold increased Epstein-Barr virus infection was associated with Hodgkin lymphoma risk. The risk increase was a 4.7 (95% confidence interval 1.6–13.8)-fold particularly high shortly after the Epstein-Barr increased risk of Epstein-Barr virus-positive virus infection but remained increased for up to Hodgkin lymphoma, whereas no association negative 20  years of follow-up [67]. Because infectious was observed for Epstein-Barr virus-­ mononucleosis typically occurs in adolescence, Hodgkin lymphoma [74]. the increased Hodgkin lymphoma risk tended to Epstein-Barr Virus Infection: Variation present in younger adults. In a few investigations, information on in Tumour Prevalence Hodgkin lymphoma Epstein-Barr virus status has Epstein-Barr virus can, as already mentioned, be been available for analyses. One such was an demonstrated in the malignant cells in a proportion

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of classic Hodgkin lymphomas [32]. Importantly, however, its presence is non-­randomly distributed between cases and tends to reflect ethnic, sociodemographic, age, sex and disease-specific circumstances, adding further support to the suspicion of a causal relation. This variation was most eloquently demonstrated by Glaser and colleagues in a pooled analysis of 1546 patients [75]. The analysis showed that irrespective of age at diagnosis, Epstein-Barr virus could more often be demonstrated in mixed cellularity than in nodular sclerosis Hodgkin lymphoma, in children from deprived rather than affluent settings and in male than in female patients, except among older adults. At the same time, compared with adolescents and younger adults, Hodgkin lymphomas in children and older adults were more often Epstein-Barr virus-­ positive [75]. The seminal paper by Glaser and colleagues once again underscores the importance of information on histological subtype and tumour Epstein-Barr virus status in epidemiological investigations.

H. Hjalgrim and R. F. Jarrett

phoma has so far been in vain (see also Chap. 2). Indeed, direct support for the decreased infectious disease load in early childhood among adolescent and younger adult Hodgkin lymphoma patients implied by the late infection hypothesis is scarce. Even if in interview-based case-control studies self-reported history of infections such as measles, mumps and rubella have been associated with reduced risk of Hodgkin lymphoma in adolescence and early adulthood [50, 69, 77, 78], the validity of such recalled childhood health history may be questioned. Still, in Mack and colleagues’ prospective study of army conscripts, history of mumps ascertained at the start of follow-­up also was associated with reduced Hodgkin lymphoma risk [48]. Cozen and colleagues retrospectively assessed childhood exposures likely to produce oral exposure to microbes among 188 sets of twins discordant for Hodgkin lymphoma diagnosed at ages 13–50  years. Most interestingly, their study showed that Hodgkin lymphoma risk was lower for the twins whose behaviour mostly likely led to oral microbial exposure [79].

A Four-Disease Model for Hodgkin 1.5.3.2 Primary and Secondary Immune Deficiencies Lymphoma The age-dependent variation in prevalence of Similar to non-Hodgkin lymphomas, Hodgkin Epstein-Barr virus-positive Hodgkin lymphomas lymphomas also occur excessively among along with its association with infectious mono- patients suffering from (certain) primary and secnucleosis has given rise to the four-disease model, ondary immune deficiencies (reviewed in [80]). according to which Epstein-Barr virus-positive Risk of Hodgkin lymphoma is between 4- and and Epstein-Barr virus-negative Hodgkin lym- 16-fold increase in cohort studies of HIV-infected phomas are etiologically separate entities [76]. people and between 2- and 7-fold increase in The model is further discussed in Chap. 2, but in cohort studies of solid organ transplant recipients summary suggests that Epstein-Barr virus-­ (reviewed in [80]). positive Hodgkin lymphoma develops in conMost Hodgkin lymphoma occurring in the setjunction to primary infection with the virus ting of immune deficiency is Epstein-Barr virus-­ (children and adolescents) or because of subse- positive [80]. Correspondingly, in one cohort quent loss of control with the viral infection in its study of people with AIDS-related immune defichronic phase owing to immune impairment for a ciency, risk was more increased for mixed celluvariety of reasons, while no causes for Epstein-­ larity (rate ratio 18.3 (95% confidence interval Barr virus-negative Hodgkin lymphoma are 15.9–20.9)) and lymphocyte-depleted (rate ratio suggested. 35.3 (95% confidence interval 24.7–48.8)) Hodgkin lymphoma subtypes than for nodular Other Childhood Infections sclerosis Hodgkin lymphoma [81]. The search for other specific childhood infections There is (some) evidence that Hodgkin lymcausally associated with classic Hodgkin lym- phoma risk correlates inversely with degree of

1  Epidemiology of Hodgkin Lymphoma

immune suppression as measured by CD4-­ lymphocyte count among HIV-infected people, but the correlation is less strong than for non-­ Hodgkin lymphoma and, in contrast to the latter, risk does not correlate with measures of HIV load [82, 83]. These differences between Hodgkin and non-­ Hodgkin lymphoma may explain why the overall incidence of Hodgkin lymphoma has not decreased to the same extent as non-Hodgkin lymphoma following the introduction of highly active antiviral therapy (see [82] and references therein).

1.5.3.3 Autoimmune and Allergic Disorders Autoimmune and Allergic/Atopic Diseases Several studies have reported an increased risk of Hodgkin lymphoma among patients with autoimmune diseases (see reviews [80, 84]). A large Swedish investigation reported a twofold increased risk of Hodgkin lymphoma risk among 878,000 patients registered with any of 33 autoimmune conditions in the Swedish inpatient register [85]. Temporal variation in relative risk of Hodgkin lymphoma suggested that the increased risk was partially explained by reversed causality; specifically, that incipient (undiagnosed) Hodgkin lymphoma led to autoimmune disease diagnosis. Thus, the standardized incidence ratio (SIR) for Hodgkin lymphoma decreased with time since autoimmune disease diagnosis from 5.2 (95% confidence interval 4.2–6.3) in the first year of follow-up to 2.0 (95% confidence interval 1.7– 2.4) in the period 1–4 years after autoimmune disease diagnosis and to 1.5 (1.2–1.7) at 5 or more years after autoimmune disease diagnosis [85]. Accordingly, when the first 5 years after autoimmune diagnosis was disregarded, statistically significantly increased risk of Hodgkin lymphoma was observed for patients with rheumatoid arthritis (SIR = 2.0 (95% confidence interval 2.1–3.7)), autoimmune haemolytic anaemia (SIR = 16.6 (95% confidence interval 3.1–49.2)), Behcet disease (SIR = 4.0 (95% confidence interval 1.3–9.3)) and systemic lupus erythematosus (SIR  =  4.1 (95% confidence interval 1.5–9.0)). Elevated risk estimates, albeit not statistically

17

significant, were still observed for various other autoimmune diseases [85]. The mechanisms underlying the association between Hodgkin lymphoma and autoimmune diseases have remained elusive. Interestingly, in another register-based study from Sweden, reduced risk of Hodgkin lymphoma was observed in families of patients with acute glomerular nephritis, ankylosing spondylitis and Graves disease and increased in family members of patients with pemphigus. In first-degree relatives of Hodgkin lymphoma patients, several autoimmune diseases occurred in excess (Behcet disease, dermatitis herpetiformis, multiple sclerosis, primary biliary cirrhosis and rheumatoid arthritis) or in deficit (celiac disease and psoriasis) pointing to some form of shared risk between the two disease groups [86], which to some extent could be genetic in nature [87]. Multiple sclerosis stands out from other autoimmune diseases in this regard. Thus, studies have shown that Hodgkin lymphoma in young adults and multiple sclerosis clusters mutually within individuals [88] and within families [86, 89]. Moreover, the two conditions have also been found to share genetic risk profiles to the extent that polygenic risk scores for either of the two diseases are associated with risk of the other [87]. Interestingly, these two disparate conditions both share the association with infectious mononucleosis, raising the possibility that the three conditions are somehow immunologically related. Few studies have examined the association between allergic/atopic diseases and Hodgkin lymphoma risk ([90], review in [91]). Methodological issues aside, the results of the analyses are too heterogeneous to preclude conclusions other than that the current evidence does not support any association between the two. In agreement with this, Levin and colleagues found no evidence of an association between pre-­ diagnostic titres of IgE and Hodgkin lymphoma risk in a prospective serological investigation [92].

1.5.3.4 Medications Regular use of aspirin has been suggested to be associated with reduced Hodgkin lymphoma risk in one American [93] and in two partly

18

overlapping Danish studies [94]. Combining the two sets of results in a meta-analysis, long-term use of aspirin was associated with an odds ratio of 0.62 (95% confidence interval 0.46–0.82) for Hodgkin lymphoma [94]. Aspirin’s interference with inhibition of NF-κB which is constitutively active in the malignant Hodgkin/Reed-Sternberg cells and its binding to cyclooxygenase (COX)-1 and cyclooxygenase-2, which are overexpressed in Hodgkin lymphoma, both lend biological plausibility to the observed association [93, 94]. Of note, the same investigations also reported increased Hodgkin lymphoma risk among users of other nonsteroidal anti-inflammatory drugs such as selective Cox-2 inhibitors or acetaminophen. However, temporal variation in the risk increase suggested that reverse causality—confounding by indication—most likely accounted for the observed association [93, 94].

1.5.4 Environmental Exposures 1.5.4.1 Ultraviolet Light Recent decades have witnessed considerable epidemiological interest in the possible association between vitamin D and cancer because of the vitamin’s potential anticarcinogenic effects [95]. Because ultraviolet light radiation is critical to vitamin D production, studies have typically focused on this exposure, as is also the case for Hodgkin lymphoma investigations. An association between ultraviolet radiation exposure and Hodgkin lymphoma risk is supported by two types of evidence. Firstly, according to ecological studies, Hodgkin lymphoma incidence rates and ambient levels of ambient ultraviolet radiation correlate inversely [96, 97]. Secondly, according to a pooled analysis of data from four case-control studies including a total of 1320 patients with Hodgkin lymphoma and 6381 controls, history of sunburn (odds ratio = 0.77 (95% confidence interval 0.63–0.95)) and sunlamp use (odds ratio = 0.81 (95% confidence interval 0.69–0.96)) and cumulative lifetime exposure to ultraviolet radiation were each associated with statistically significantly decreased risk of Hodgkin lymphoma [98]. The

H. Hjalgrim and R. F. Jarrett

observed associations tended to be stronger for Epstein-Barr virus-positive than for Epstein-Barr virus-­negative Hodgkin lymphomas [98]. Both the ecological and the analytical epidemiological data are compatible with ultraviolet radiation exposure in some way or other preventing Hodgkin lymphoma pathogenesis.

1.5.4.2 Tobacco Considering tobacco’s many effects on the human immune system, it is conceivable that it is also associated with Hodgkin lymphoma risk [99]. Support for this notion comes from two meta-­ analyses and a pooled analysis of several large datasets. The meta-analyses both conclude that current smoking carries a statistically significant 30–40% increased risk of Hodgkin lymphoma [100, 101], whereas the pooled analyses suggest a statistically nonsignificant 16% increased risk [102]. Both meta-analyses also find evidence of doseresponse associations between Hodgkin lymphoma risk and current cigarette smoking measured as number of cigarettes smoked, years smoked and pack-years [100, 101]. The pooled analysis, in contrast, found no evidence of a dose-­response pattern in the association between Hodgkin lymphoma risk and cigarette smoking [102]. In stratified analyses, the association with current smoking was stronger for mixed cellularity than for nodular sclerosis Hodgkin lymphoma [100] and correspondingly also stronger for Epstein-Barr virus-positive than for Epstein-Barr virus-negative Hodgkin lymphoma [101, 102]. 1.5.4.3 Alcohol A reduced Hodgkin lymphoma risk with alcohol intake has been suggested by most investigations of the topic, even if observed associations do not always reach statistical significance and rarely display dose-response patterns [103–112]. In a recent meta-analysis of available cohort studies, ever drinking alcohol was associated with a statistically nonsignificant reduced Hodgkin lymphoma risk (relative risk  =  0.74 (95% confidence interval 0.52–1.05)) [113]. Although results vary between studies, the reported inverse association has been reported for

1  Epidemiology of Hodgkin Lymphoma

19

all Hodgkin lymphoma subgroups, i.e. for both perspective of the understanding of what drives younger and older adult patients, for Epstein-­ Hodgkin lymphoma development, this represents Barr virus-positive and Epstein-Barr virus-­ a field of research that has only been little explored negative Hodgkin lymphoma, as well as for in Epstein-Barr virus status-­specific contexts. nodular sclerosis and mixed cellularity Hodgkin The favourable prognosis of Hodgkin lymlymphoma alike. phoma achievable with modern therapy is One caveat to the interpretation of the observed unlikely to foster clinical interest into the clinical reduced Hodgkin lymphoma risk is that the lym- significance of tumour Epstein-Barr virus status phoma may be accompanied by alcohol intoler- or other (potential) markers of baseline treatment ance [114]. Consequently, reduced alcohol intake needs. Accordingly, though it could further could result from early Hodgkin lymphoma man- access to large dataset amenable for research, the ifestations. An attempt to mitigate this problem motivation to determine epidemiologically relewas introduced in the UK Million Study in which vant markers in clinical trials is modest. an increased risk of Hodgkin lymphoma among never drinkers (hazard rate ratio  =  1.70 (95% confidence interval 1.27–2.26)) compared with References occasional drinkers (0.5–3 drinks weekly) was unaffected when the first 3  years of follow-up 1. Engert A, Haverkamp H, Kobe C et al (2012) Reduced-intensity chemotherapy and PET-guided was disregarded [112]. Still, this study also radiotherapy in patients with advanced stage showed no dose-response pattern between alcoHodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet hol consumption and Hodgkin lymphoma risk. 379(9828):1791–1799 2. Engert A, Plütschow A, Eich HT et  al (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 1.6 Conclusion 363(7):640–652 3. Hodgkin T (1832) On some morbid appearances of Studies have demonstrated that Hodgkin lymthe absorbent glands and spleen. Med Chirurg Trans 17:68–114 phomas occurring at different ages have different epidemiologic profiles. This variation is com- 4. Ng AK, van Leeuwen FE (2016) Hodgkin lymphoma: late effects of treatment and guidelines for monly interpreted as evidence that Hodgkin lymsurveillance. Semin Hematol 53(3):209–215 phoma comprises two or more aetiologically 5. Cohen JI (2018) Vaccine development for Epstein-­ Barr virus. Adv Exp Med Biol 1045:477–493 heterogeneous conditions. 6. Hjalgrim H, Chang ET, Glaser SL (2018) Hodgkin Age, histological presentation and tumour lymphoma. Schottenfeld and Fraumeni Cancer Epstein-Barr virus status have been suggested to Epidemiology and Prevention. Oxford University identify unique classic Hodgkin lymphoma entiPress:745–766 ties. Evidence is strong that Epstein-Barr virus-­ 7. Stein H (2001) Hodgkin lymphomas: introduction. WHO Classif Tumours Tumours Haematop positive Hodgkin lymphomas are aetiologically Lymphoid Tissues 8:239 different from their Epstein-Barr virus-negative 8. Stein H, Delsol G, Pileri S et  al (2001) Nodular counterparts. There is also good evidence that the lymphocyte predominant Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic risk of Epstein-Barr virus-positive Hodgkin lymLymphoid Tissues:240–243 phoma at different ages to a large extent is influ 9. Stein H, Delsol G, Pileri S et  al (2001, 2001) enced by circumstances influencing age at primary Classical Hodgkin lymphoma. WHO Classif infection and immunological response to or conTumours Tumours Haematopoietic Lymphoid Tissues:244–253 trol of the infection, whether in its acute or chronic phases. Meanwhile, the causes of Epstein-Barr 10. Jarrett RF, Krajewski AS, Angus B et al (2003) The Scotland and Newcastle epidemiological study of virus-negative Hodgkin lymphoma have remained Hodgkin’s disease: impact of histopathological elusive and call for continued research. review and EBV status on incidence estimates. J Clin Pathol 56(11):811–816 Both Epstein-Barr virus-positive and Epstein-­ 11. Glaser SL, Dorfman RF, Clarke CA (2001) Expert Barr virus-negative Hodgkin lymphoma can have review of the diagnosis and histologic classification

different histopathological presentations. From the

20 of Hodgkin disease in a population-based cancer registry: interobserver reliability and impact on incidence and survival rates. Cancer 92(2):218–224 12. Stein H, von Wasielewski R, Poppema S, MacLennan K, Guenova M (2008) Nodular sclerosis classical Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues 2008:330 13. Weiss LM, von Wasielewski R, Delsol G, Poppema S, Stein H (2008) Mixed cellularity classical Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues 2008:331 14. Ansell SM (2015) Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc 90(11):1574–1583 15. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today, accessed [25 March 2019]. 16. Chatenoud L, Bertuccio P, Bosetti C et  al (2013) Hodgkin’s lymphoma mortality in the Americas, 1997–2008: achievements and persistent inadequacies. Int J Cancer 133(3):687–694 17. Keegan THM, DeRouen MC, Parsons HM et  al (2016) Impact of treatment and insurance on socioeconomic disparities in survival after adolescent and young adult Hodgkin lymphoma: a population-­ based study. Cancer Epidemiol Biomark Prev 25(2):264–273 18. Macmahon B (1958) Epidemiological evidence of the nature of Hodgkin’s disease. Cancer 10(5):1045–1054 19. MacMahon B (1966) Epidemiology of Hodgkin’s disease. Cancer Res 26(6):1189–1201 20. Correa P, O’Conor GT (1971) Epidemiologic patterns of Hodgkin’s disease. Int J Cancer 8(2):192–201 21. Clavel J, Steliarova-Foucher E, Berger C, Danon S, Valerianova Z (2006) Hodgkin’s disease incidence and survival in European children and adolescents (1978–1997): report from the automated Cancer information system project. Eur J Cancer 42(13):2037–2049 22. Hjalgrim LL, Rostgaard K, Engholm G et al (2016) Aetiologic heterogeneity in pediatric Hodgkin lymphoma? Evidence from the Nordic countries, 1978– 2010. Acta Oncol (Stockholm) 55(1):85–90 23. Clarke CA, Glaser SL, Keegan THM, Stroup A (2005) Neighborhood socioeconomic status and Hodgkin’s lymphoma incidence in California. Cancer Epidemiol Biomark Prev 14(6):1441–1447 24. Glaser SL, Swartz WG (1990) Time trends in Hodgkin’s disease incidence. The role of diagnostic accuracy. Cancer 66(10):2196–2204 25. Hjalgrim H, Askling J, Pukkala E et  al (2001) Incidence of Hodgkin’s disease in Nordic countries. Lancet 358:297–298 26. van Leeuwen MT, Turner JJ, Joske DJ et al (2014) Lymphoid neoplasm incidence by WHO subtype in Australia 1982–2006. Int J Cancer 135(9):2146–2156

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1  Epidemiology of Hodgkin Lymphoma lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 104(3):240–253 43. Delahaye-Sourdeix M, Urayama KY, Gaborieau V et al (2015) A novel risk locus at 6p21.3 for Epstein-­ Barr virus-positive Hodgkin lymphoma. Cancer Epidemiol Biomark Prev 24(12):1838–1843 44. Sud A, Thomsen H, Law PJ et  al (2017) Genome-­ wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nat Commun 8(1):1–11 45. Newell GR (1970) Etiology of multiple sclerosis and Hodgkin’s disease. Am J Epidemiol 91(2):119–122 46. Gutensohn N, Cole P (1977) Epidemiology of Hodgkin’s disease in the young. Int J Cancer 19:595–604 47. Gutensohn N, Cole P (1981) Childhood social environment and Hodgkin’s disease. N Engl J Med 304(3):135–140 48. Mack TM, Norman JE, Rappaport E, Cozen W (2015) Childhood determination of Hodgkin lymphoma among U.S. servicemen. Cancer Epidemiol Biomark Prev 24(11):1707–1715 49. Hjalgrim H, Ekström Smedby K, Rostgaard K et al (2007) Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res 67(5):2382–2388 50. Glaser SL, Keegan THM, Clarke CA et  al (2005) Exposure to childhood infections and risk of Epstein-Barr virus-defined Hodgkin’s lymphoma in women. Int J Cancer 115(4):599–605 51. Glaser SL, Clarke CA, Nugent RA, Stearns CB, Dorfman RF (2002) Social class and risk of Hodgkin’s disease in young-adult women in 1988– 94. Int J Cancer 98(1):110–117 52. Chang ET, Zheng T, Weir EG et  al (2004) Childhood social environment and Hodgkin’s lymphoma: new findings from a population-based casecontrol study. Cancer Epidemiol Biomark Prev 13(8):1361–1370 53. Crump C, Sundquist K, Sieh W, Winkleby MA, Sundquist J (2012) Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood. Am J Epidemiol 176(12):1147–1158 54. Triebwasser C, Wang R, DeWan AT et  al (2016) Birth weight and risk of paediatric Hodgkin lymphoma: findings from a population-based record linkage study in California. Eur J Cancer 69:19–27 55. Westergaard T, Melbye M, Pedersen JB et al (1997) Birth order, sibship size and risk of Hodgkin’s disease in children and young adults: a population-­ based study of 31 million person-years. Int J Cancer 72(6):977–981 56. Chang ET, Montgomery SM, Richiardi L et al (2004) Number of siblings and risk of Hodgkin’s lymphoma. Cancer Epidemiol Biomark Prev 13(7):1236–1243 57. Von Behren J, Spector LG, Mueller BA et  al (2011) Birth order and risk of childhood cancer: a pooled analysis from five US states. Int J Cancer 128(11):2709–2716

21 58. Linabery AM, Erhardt EB, Fonstad RK et al (2014) Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: a Children’s oncology group study. Int J Cancer 135(6):1454–1469 59. Isager H, Andersen E (1978) Pre-morbid factors in Hodgkin’s disease. I. Birth weight and growth pattern from 8 to 14 years of age. Scand J Haematol 21(3):250–255 60. Keegan THM, Glaser SL, Clarke CA et  al (2006) Body size, physical activity, and risk of Hodgkin’s lymphoma in women. Cancer Epidemiol Biomark Prev 15(6):1095–1101 61. Larsson SC, Wolk A (2011) Body mass index and risk of non-Hodgkin’s and Hodgkin’s lymphoma: a meta-analysis of prospective studies. Eur J Cancer 47(16):2422–2430 62. Engeland A, Tretli S, Hansen S, Bjørge T (2007) Height and body mass index and risk of lymphohematopoietic malignancies in two million Norwegian men and women. Am J Epidemiol 165(1):44–52 63. Murphy F, Kroll ME, Pirie K et al (2013) Body size in relation to incidence of subtypes of ­haematological malignancy in the prospective million women study. Br J Cancer 108(11):2390–2398 64. Epstein MA, Achong BG, Barr YM (1964) Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1:702–703 65. Henle G, Henle W, Diehl V (1968) Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci U S A 59(1):94–101 66. Odumade OA, Hogquist KA, Balfour HH (2011) Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev 24(1):193–209 67. Hjalgrim H, Askling J, Sørensen P et  al (2000) Risk of Hodgkin’s disease and other cancers after infectious mononucleosis. J Natl Cancer Inst 92(18):1522–1528 68. Hjalgrim H, Askling J, Rostgaard K et  al (2003) Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349(14):1324–1332 69. Alexander FE, Jarrett RF, Lawrence D et al (2000) Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer 82(5):1117–1121 70. Alexander FE, Lawrence DJ, Freeland J et  al (2003) An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin’s disease (HD): evidence for a specific association with EBV +ve HD in young adults. Int J Cancer 107(2):298–302 71. IARC (1997) IARC monographs on the evaluation of carcinogenic risks to humans: tobacco smoke and involuntary smoking. IARC, Lyon, p 83 72. Coghill AE, Hildesheim A (2014) Epstein-Barr virus antibodies and the risk of associated malig-

22 nancies: review of the literature. Am J Epidemiol 180(7):687–695 73. Mueller N, Evans A, Harris NL et  al (1989) Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med 320(11):689–695 74. Levin LI, Chang ET, Ambinder RF et  al (2012) Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. Blood 120(18):3750–3755 75. Glaser SL, Lin RJ, Stewart SL et al (1997) Epstein-­ Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70(4):375–382 76. Viruses JRF (2002) Hodgkin’s lymphoma. Ann Oncol 13(Suppl 1):23–29 77. Monnereau A, Orsi L, Troussard X et  al (2007) History of infections and vaccinations and risk of lymphoid neoplasms: does influenza immunization reduce the risk? Leukemia 21(9):2075–2079 78. Montella M, Maso LD, Crispo A et  al (2006) Do childhood diseases affect NHL and HL risk? A case-­ control study from northern and southern Italy. Leuk Res 30(8):917–922 79. Cozen W, Hamilton AS, Zhao P et  al (2009) A protective role for early oral exposures in the etiology of young adult Hodgkin lymphoma. Blood 114(19):4014–4020 80. Engels EA, Hildesheim A (2018) Immunologic factors. In: Schottenfeld and Fraumeni cancer epidemiology and prevention. Oxford University Press, Oxford 81. Frisch M, Biggar RJ, Engels EA et  al (2001) Association of cancer with AIDS-related immunosuppression in adults. JAMA 285(13):1736 82. Shepherd L, Ryom L, Law M et  al (2018) Differences in virological and immunological risk factors for non-Hodgkin and Hodgkin lymphoma. J Natl Cancer Inst 110(6):598–607 83. Grulich AE, Vajdic CM (2015) The epidemiology of cancers in human immunodeficiency virus infection and after organ transplantation. Semin Oncol 42(2):247–257 84. Landgren O, Caporaso NE (2007) New aspects in descriptive, etiologic, and molecular epidemiology of Hodgkin’s lymphoma. Hematol Oncol Clin North Am 21(5):825–840 85. Fallah M, Liu X, Ji J et  al (2014) Hodgkin lymphoma after autoimmune diseases by age at diagnosis and histological subtype. J Eur Soc Med Oncol 25(7):1397–1404 86. Hemminki K, Försti A, Sundquist K, Sundquist J, Li X (2017) Familial associations of lymphoma and myeloma with autoimmune diseases. Blood Cancer J 7(1):e515–e515 87. Khankhanian P, Cozen W, Himmelstein DS et al (2016) Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis. Int J Epidemiol 45(3):728–740 88. Montgomery S, Hajiebrahimi M, Burkill S et  al (2016) Multiple sclerosis and risk of young-adult-­

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2

The Role of Viruses in the Genesis of Hodgkin Lymphoma Ruth F. Jarrett, Henrik Hjalgrim, and Paul G. Murray

Contents 2.1

Introduction 

 26

2.2 2.2.1  2.2.2  2.2.3  2.2.4 

Hodgkin Lymphoma and Epstein-Barr Virus   pstein-Barr Virus and the Pathogenesis of Hodgkin Lymphoma  E Risk Factors for Epstein-Barr Virus-Associated Hodgkin Lymphoma  Epstein-Barr Virus and Hodgkin Lymphoma: A Causative Association?  Epstein-Barr Virus and the Clinicopathological Features of Hodgkin Lymphoma 

 26  27  29  32

2.3 2.3.1  2.3.2  2.3.3  2.3.4 

Epstein-Barr Virus-Negative Hodgkin Lymphoma Cases   odgkin Lymphoma and Herpesviruses Other Than Epstein-Barr Virus  H Polyomaviruses and Hodgkin Lymphoma  Measles Virus and Hodgkin Lymphoma  The Virome, Anelloviruses, and Hodgkin Lymphoma 

 34  34  36  37  37

2.4

Conclusions 

 38

References 

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 38

Abbreviations R. F. Jarrett (*) MRC-University of Glasgow Centre for Virus Research, Glasgow, UK e-mail: [email protected] H. Hjalgrim Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: [email protected] P. G. Murray Bernal Institute, Limerick, Ireland Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK e-mail: [email protected]

BARTs BamHI fragment A rightward transcripts BHRF1 BamHI-H rightward open reading frame 1 cHL Classic Hodgkin lymphoma DDR1 Discoidin domain receptor 1 EBER EBV-encoded small RNAs EBNA EBV nuclear antigen EBV Epstein-Barr virus HHV Human herpesvirus HL Hodgkin lymphoma HLA Human leukocyte antigen HPyV Human polyomavirus HRS Hodgkin and Reed-Sternberg

© Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_2

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R. F. Jarrett et al.

26

IHC Immunohistochemistry LMP Latent membrane protein MCHL Mixed cellularity Hodgkin lymphoma MCPyV Merkel cell polyomavirus miRNAs MicroRNAs MV Measles virus NSHL Nodular sclerosis Hodgkin lymphoma ORF Open reading frame PyV Polyomavirus SNP Single nucleotide polymorphism TSPyV Trichodysplasia spinulosa polyomavirus TTMDV Torque teno midi virus TTMV Torque teno mini virus TTV Torque teno virus

2.2

Hodgkin Lymphoma and Epstein-Barr Virus

EBV is a herpesvirus with a worldwide distribution [10–13]. Over 90% of healthy adults are infected by EBV, and, following primary infection, the virus establishes a persistent infection with a reservoir in memory B-cells [14]. Although EBV is an extremely efficient transforming agent, the virus is kept under tight control by cell-­ mediated immune responses, and both primary and persistent infections are usually asymptomatic [10, 15]. EBV infection can be lytic or latent. Lytic infection is associated with expression of a large number of viral genes, production of progeny virus, and death of the infected cell; in contrast, latent infection is associated with expression of a small number of EBV genes, persistent infection, and growth transformation [10]. In B-cells trans2.1 Introduction formed by EBV in  vitro, six EBV nuclear antigens (EBNA1, 2, 3A, 3B, 3C, and LP, also called Hodgkin lymphoma (HL) is a heterogeneous con- EBNA1–6) and three latent membrane proteins dition. Seminal papers published in 1957 and (LMP1, LMP2A, and LMP2B) are expressed 1966 suggested that HL in younger and older [10]. In addition, noncoding viral RNAs are tranadults had different etiologies and further sug- scribed in latently infected cells [16]. These gested an infectious etiology for young adult HL include two small non-polyadenylated tran[1, 2]. Subsequent epidemiological studies pro- scripts, the EBERs, and over 44 viral microRNAs vide broad support for these hypotheses [3, 4]. (miRNAs) located within introns of the BARTs Data linking young adult HL with a high standard (BamHI fragment A rightward transcripts) or of living in early childhood and lack of child-­child around the coding region of the BHRF1 contact suggest that delayed exposure to common (BamHI-H rightward open reading frame 1) gene childhood infections may be involved in the etiol- [16–22]. Expression of the full set of latent genes ogy of these cases [5, 6]. There is now compelling is known as latency III [10, 13]. EBV gene evidence that a proportion of cases of HL are expression in EBV-positive lymphomas occurassociated with the Epstein-Barr virus (EBV). ring in the context of immunosuppression freParadoxically, older adult and childhood cases of quently follows this pattern, but more restricted HL are more likely to be EBV-associated than patterns of EBV gene expression are observed in young adult cases [7–9]. In this article, we review other malignancies, including cHL [10, 12, 13]. studies on viral involvement in HL with a focus The EBNA3 family proteins are immunodomion classic HL (cHL), since nodular lymphocyte-­ nant, and the other latent antigens elicit only subpredominant HL is considered a separate disease dominant or weak cell-mediated immune entity. The association with EBV will be dis- responses [23, 24]. The pattern of gene exprescussed with an emphasis on findings that support sion in EBV-associated malignancies most proba causal role for EBV in this malignancy. Studies ably depends on both the lineage and stage of investigating the direct involvement of other differentiation of the infected tumor cells and the exogenous viruses will be summarized. host EBV-specific immune response.

2  The Role of Viruses in the Genesis of Hodgkin Lymphoma

In EBV-associated cHL (also referred to as EBV-positive cHL), all of the tumor cells, the Hodgkin and Reed-Sternberg (HRS) cells, are infected by EBV [25–27]. The EBV infection within tumors is also clonal suggesting that all of the tumor cells are derived from a single infected cell [28, 29]. The HRS cells express EBNA1, LMP1, LMP2A, and 2B, but the remaining EBNAs are downregulated (Fig.  2.1); the noncoding EBER RNAs and BART miRNAs are also expressed [25, 26, 30–33]. This pattern of gene expression is referred to as latency type II [10]. EBV infection of HRS cells can be readily demonstrated in sections of routinely fixed, paraffin-­embedded material using either EBER in situ hybridization or LMP1 immunohistochemistry (IHC) (Fig. 2.1) [25, 26]. Reagents for both assays are commercially available.

2.2.1

27

35]. A pathognomonic feature of these cells is the global suppression of B-cell signature genes and inappropriate expression of genes associated with other hematopoietic lineages [36, 37]. Importantly, HRS cells do not express B-cell receptors (BCRs). Survival of germinal center B-cells normally requires signaling through both BCRs and CD40; HRS cells must, therefore, have acquired a nonphysiological survival mechanism(s). Functional studies of EBV, and LMP1 and LMP2A, support a role for the virus in HRS cell survival, transcriptional reprogramming, and immune evasion, as summarized below (Fig. 2.2).

Epstein-Barr Virus and the Pathogenesis of Hodgkin Lymphoma

The molecular pathogenesis of cHL and the origin of the HRS cell are described in detail in Chap. 3. Briefly, HRS cells have clonally rearranged immunoglobulin genes with evidence of somatic hypermutation, indicating a derivation from B-cells that have participated in a germinal center reaction [34,

Fig. 2.2  EBV EBER in situ hybridization staining of EBV-positive Hodgkin and Reed-Sternberg cells. The characteristic staining pattern is observed in the nuclei of Hodgkin and Reed-Sternberg cells LMP2A

LMP1

C-terminus activates signalling pathways e.g. NF-ĸB, JAK/STAT, PI3-K/Akt Induces chemokine/cytokine secretion that promotes tumour microenvironment

Fig. 2.1  The latent membrane proteins of EBV contribute to the pathogenesis of classic Hodgkin lymphoma. Schematic diagram of LMP1 (left) and LMP2A (right) proteins in the cell membrane (gray bar). Both are transmembrane proteins that signal constitutively through the C-terminus in the case of LMP1 and the N-terminus in the

LMP1 LMP2

N-terminus activates signalling pathways e.g. PI3-K/Akt Contributes to survival of BCR-negative B-cells

case of LMP2A. The photomicrograph in the center shows the co-expression of LMP1 (red) and LMP2A (green) in the same Hodgkin and Reed-Sternberg cell in a tissue section of classic Hodgkin lymphoma. The nucleus of the Hodgkin and Reed-Sternberg cell stained blue with DAPI is arrowed

28

In 2005, three independent groups published data showing that germinal center B-cells lacking BCRs could survive and be immortalized by EBV [38–40]. In elegant experiments, Mancao and Hammerschmidt later showed that this survival function was dependent on LMP2A expression [41]. A series of in vivo and in vitro studies from the Longnecker laboratory further defined LMP2A function and showed that this viral protein could mimic an activated BCR and provide a survival signal to BCR-negative B-cells [42–44]. LMP2A expression in B-cells also results in downregulation of B-cell-specific genes and induction of genes associated with proliferation and inhibition of apoptosis, a gene expression profile similar to that seen in cHL-derived cell lines [45]. Constitutive activation of Notch1 by LMP2A, and subsequent inhibition of E2A and downregulation of EBF, two transcription factors that regulate B-cell development, appears to be involved in both survival signaling and transcriptional regulation [44]. Although these data suggest a role for LMP2A in the survival and reprogramming of HRS cells, many of the intracellular molecules involved in BCR signaling are downregulated in HRS cells, and therefore the precise contribution of LMP2A in cHL is not clear. CD40 signaling plays a critical role in the positive selection of germinal center B-cells expressing high-affinity immunoglobulin and their subsequent exit from the germinal center [46]. EBV LMP1 is an integral membrane protein which interacts with several signal transduction pathways to activate NF-κB, Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase [47–51]. In this way, LMP1 mimics a constitutively active CD40 molecule, although it provides a more potent and sustained signal. Many of the genes that are transcriptionally regulated by LMP1  in germinal center B-cells are also CD40 and NF-κB targets [52]. Activation of the NF-κB pathway, which is a feature of both EBV-­ positive and EBV-negative HRS cells, leads to upregulation of anti-apoptotic genes and is thought to play a key role in HRS cell survival [53–55]. LMP1 expression in germinal center B-cells also leads to increased expression of Id2,

R. F. Jarrett et al.

an inhibitor of the E2A transcription factor mentioned above, and repression of B-cell signature genes [52]; therefore, LMP1 may also contribute to transcriptional reprogramming. The EBV genome is maintained as an episome in infected cells; i.e., it does not normally integrate. The EBNA1 protein is responsible for maintenance of the genome in episomal form, genome replication, and genome partitioning during mitosis [10, 56]. EBNA1 can also influence both viral and cellular gene expression and appears to confer a B-cell survival advantage, although the impact of EBNA1 on oncogenesis in vivo is controversial [10, 57–60]. Interestingly, in the context of cHL, overexpression of EBNA1 in vitro leads to the appearance of multinucleated cells [57]. The EBV EBER RNAs are two small, non-­ polyadenylated RNA pol III transcripts that are stably expressed in the nuclei of all latently infected cells, including HRS cells. The precise function of the EBERs remains unclear, and, although not essential for transformation, expression of these small RNAs is required for efficient EBV-induced B-cell growth and transformation [16, 61–63]. EBV-encoded miRNAs were identified first in 2004, and their important role in EBV biology and oncogenesis is an area of intense study [16, 17, 22, 64, 65]. Functional analysis of the BHRF1 and BART miRNAs suggests roles in evading the immune response, promoting cell survival and proliferation, inhibiting viral reactivation, and fine-tuning gene expression [16, 22, 64, 65]. EBV-associated malignancies, including cHL, express BART miRNAs, but the BHRF1 miRNAs, which are associated with latency type III, are not expressed [33]. In vitro studies of knockout viruses lacking some or all of the miRNAs suggest that they have an important role in the initial stages of B-cell transformation by EBV; BHRF1 miRNAs play the predominant role with some contribution from BART miRNAs at low multiplicity of infection [22]. In contrast, in vivo studies in a murine huNSG model suggest that the main function of these miRNAs is to attenuate the antiviral T-cell-mediated immune response, leading to increased numbers of EBV-­

2  The Role of Viruses in the Genesis of Hodgkin Lymphoma

infected B-cells at later time points [66]. Again, these effects appear to be mediated by the BHRF1 miRNAs, as viruses deficient in only the BART miRNAs produced similar results to wild-type virus in this model system [66]. Ross et  al. reported that miRNA BART11-5p downregulates the B-cell transcription factor EBF1, suggesting a plausible role for this miRNA in cHL [67]. EBV also regulates the expression of host miRNAs; infection of primary B-cells leads to a conspicuous downregulation of many miRNAs with the notable exception of mIR-155, which is highly expressed by both EBV-positive and EBV-­ negative HRS cells [68, 69]. Analysis of host miRNAs in cHL is described in more detail in Chap. 4, but it has been reported that EBV status of tumors is associated with differences in expression pattern [70]. While most studies have investigated the effects of the latent genes in isolation, there is evidence that co-expression of the EBV latent genes is important. For example, it has been shown that LMP1 is transforming when expressed alone in transgenic mouse B-cells [71]. However, when LMP2A is expressed together with LMP1, the resulting mouse B-cells are normal [71]. Comparison of LMP1 and LMP2A in B-cells confirms they have both synergistic and counteracting transcriptional effects [72]. Furthermore, in another study it was shown that LMP1 and LMP2A co-expression in mouse B-cells resulted in tumors, but only if the animals were immunosuppressed suggesting that the combined expression of these latent genes is immunogenic in vivo [73]. There is evidence that the tumor microenvironment in EBV-positive and EBV-negative cHL is different. Thus, the T-helper cells present in EBV-positive cHL are enriched for functional Th1 cells [74]. EBV-positive cHL is also preferentially infiltrated by regulatory Type 1 cells (Tr1), which express ITGA2, ITGB2, and LAG3 and secrete IL-10 [75]. This Th1-biased infiltrate is consistent with previous reports of higher numbers of activated CD8+ T-cells in EBVpositive cHL [76] and is also associated with the presence of predominantly M1-polarized macrophages [77]. There is evidence that the EBV

29

latent genes are responsible, at least in part, for the recruitment and modification of this tumor microenvironment. LMP1, in particular, has been shown to induce expression of many of the chemokines and cytokines secreted by EBV-infected HRS cells [78, 79]. The cHL tumor microenvironment also contributes to the suppression of host anti-­ EBV-­ specific immunity. Thus, while LMP1 and LMP2A proteins are targets of CD8+ cytotoxic T lymphocytes, it is clear that immune effectors present in the tumor tissues of EBVpositive cHL cannot kill the virus-infected cells [80, 81]. LMP1 probably also contributes to the suppression of EBV-specific immunity through its ability to induce expression of the immunosuppressive cytokines, including IL-10, and upregulate the immune checkpoint ligand, PD-L1 [82, 83]. LMP1 also upregulates the collagen receptor, discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase expressed by HRS cells [84]. Engagement of DDR1 by collagen leads to the increased survival of lymphoma cells, thus providing a link between the expression of LMP1 and pro-survival signaling from the tumor microenvironment.

2.2.2 R  isk Factors for Epstein-Barr Virus-Associated Hodgkin Lymphoma It is clear that EBV is associated with only a proportion of cHL cases. In industrialized countries around one third of cases are EBV-associated, whereas in Africa and Central and South America, this proportion is significantly higher [8, 9, 85, 86]. EBV-associated cHL cases are not randomly distributed among all cHL cases, and the demographic features and risk factors for the development of EBV-positive and EBV-negative cHL show distinctive features [8, 9, 86]. Childhood (2-log drop in lished as a source of tumor DNA for cHL muta- ctDNA, while relapsing patients who are incontional profiling. By overcoming the major sistently judged as interim PET/CT negative technical hurdles that have so far limited cHL have a 225ml 20

TMTV0 ≤225ml

80 60 40

TMTV0 >225ml

20

P= 0.001

P= 0.0015 0

0 0

10

20

30 40 50 Time (months)

60

70

Fig. 8.2  Progression-free (PFS) and disease-specific survival (DSS) for 59 patients with all stages of HL divided into low and high total metabolic tumour volume, i.e. < or

0

10

20

30 40 50 Time (months)

60

70

>225 ml (Reprinted with permission from Kanoun et al. 2014 [49])

P. J. Bröckelmann and L. Specht

150

prognostic factors in early-stage HL.  Based on the most important factors, different centres and groups divided early-stage patients into favourable and unfavourable. Table 8.2 shows the factors and risk groups defined by some of the major groups. Although the factors included in these risk group definitions are fairly similar, the risk group definitions vary making comparisons between patient materials difficult. Treatment of early-stage patients is tailored according to prognostic subgroups. Thus, in many studies patients are selected, making the detection of prognostic factors difficult. Most of the important prognostic factors are correlated providing indirect measures of the patient’s total tumour burden [36, 39, 62]. Functional imaging with FDG-PET has become an important part of staging and treatment evaluation of lymphomas. An early interim FDG-PET scan after one or two cycles of chemotherapy has been shown to be highly predictive of outcome after combined modality treatment [66–71]. However, in early-stage disease, there are many false-positive results, the predictive value depends on the chemotherapy regimen used, and the majority of the patients with interim PET positivity were cured with combined modality therapy, yielding a positive predictive value of only 15% [72]. The negative predictive value is very high in earlystage disease, which would be expected in a disease with a very good prognosis. In fact, because over 90% of patients with early-­stage disease are cured with standard treatment, the added information from a negative interim PET scan is actually very limited [73, 74]. The early interim FDG-PET scan may be regarded as an in vivo test of the chemosensitivity of disease. As the result of the scan is not known at the outset, there is a methodological problem with this test. Strictly speaking, outcome according to the result of an early interim FDG-PET scan should only be measured from the time when it is available, and it should be regarded more as a predictive factor indicating the sensitivity to a particular treatment rather than as a usual prognostic factor. From a clinical point of view, it would be better to predict the outcome with a given regimen up front rather than having to initially administer

possibly ineffective or too intensive treatment. The total metabolic tumour volume (MTV) as a surrogate for the total tumour burden seems promising in this respect. Furthermore, recent research into molecular abnormalities in either tumour cells or non-malignant background cells has demonstrated numerous biomarkers, some of which will hopefully allow individualization of treatment up front [75–91]. However, for a new prognostic factor to be proven useful, it needs to be demonstrated to show independent significance when the already known factors, in particular the total tumour burden, are taken into account. The standard treatment for early-stage disease is combined modality treatment. Recently, chemotherapy alone has been used, resulting in a moderate increase in the risk of relapse. Prognostic factors in this group of patients have not been analysed in detail as large cohorts of patients with reasonable follow-up are not yet available.

8.5

Advanced-Stage Hodgkin Lymphoma

Patients presenting in stage III/IV are universally considered as advanced-stage requiring systemic treatment, eventually followed by consolidative RT in selected cases. Patients with stage IIB and additional risk factors such as extranodal disease (EN) or a large mediastinal mass (LMM) are additionally regarded advanced-stage by some study groups or centres for the purpose of first-­ line therapy. Large data sets are important to reliably assess the independent contributions of single routinely documented clinical prognostic factors and two very large data sets resulted from international cooperation: The International Database on Hodgkin’s Disease set up in 1989 combined >14,000 individual patient data across all stages from 20 study groups in the MOPP era [14]. In 1995, the International Prognostic Factors Project on advanced Hodgkin lymphoma combined data of 5141 advanced-stage patients mainly treated with doxorubicin-containing regimen [92]. More

CS I or CS IIA with ≥1 risk factors CS IIB with (c) or (d) but without (a) and (b)

GHSG (a) Large mediastinal mass (b) Extranodal disease (c) ESR ≥ 50 without B symptoms or ≥30 with B symptoms (d) ≥3 nodal areas CS I–II without risk factors

EORTC (a) Large mediastinal mass (b) Age ≥ 50 years (c) ESR ≥ 50 without B symptoms or ≥with B symptoms (d) ≥4 nodal areas CS I–II (supradiaphragmatic) without risk factors CS I–II (supradiaphragmatic) with ≥1 risk factors

NCI-C and ECOG (a) Histology other than LP/NS (b) Age ≥ 40 years (c) ESR ≥ 50 (d) ≥4 nodal areas CS I–II without risk factors CS I–II with ≥1 risk factors

CS I–II without risk factors CS I–II with ≥1 risk factors

Stanford (a) B symptoms (b) L  arge mediastinal mass

GHSG German Hodgkin Study Group, EORTC European Organization for Research and Treatment of Cancer, NCI-C National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology Group

Unfavourable

Favourable

Risk factors

Table 8.2  Criteria for favourable vs. unfavourable early-stage HL as defined by different centres and cooperative study groups

8  Prognostic Factors 151

152

recent studies focussed on disease activity measured by interim and/or end-of-treatment PET to further individualize treatment.

8.5.1 Pretreatment Prognostic Factors in Advanced-Stage Hodgkin Lymphoma The most important patient-related prognostic factor for overall survival (OS) in advanced-stage HL is age [93–97]. Elderly patients (>60  years) are often excluded from clinical trials [98]. Prevalence of co-morbidity is associated with age and treatment-related mortality is increased [99]. In patients up to 65  years, age >45  years is an independent prognostic factor for freedom from progression. The impact of age is amplified in overall survival as compared to progression-free survival due to compromised results of salvage treatment in elderly relapsed patients [100]. Male gender is another independent, although quantitatively moderate, adverse patient-related prognostic factor within advanced stages [14, 92, 101, 102]. In terms of disease-related factors, tumour burden either quantified from conventional or PET imaging is a main determinant of prognosis [39–41, 62, 103]. As previously outlined, MTV is increasingly being recognised as pre-therapeutic prognostic factor but still rarely measured routinely. Stage IV marks dissemination of the disease to extranodal sites and is independently prognostic within advanced-stage disease [14, 92]. A particularly bad prognosis for bone marrow, lung, or liver involvement could not be confirmed. It thus remains controversial whether certain disease locations or the number of involved extranodal sites carries independent prognostic value within stage IV disease. Several haematological and biochemical laboratory parameters form a cluster of interrelated prognostic indicators that mirror both tumour burden and inflammatory processes [75]. These factors include decreased serum albumin and haemoglobin levels as well as an elevated ESR, LDH, C-reactive protein (CRP), and alkaline phosphatase, which are correlated with one other as well as with the presence of B symptoms and

P. J. Bröckelmann and L. Specht

tumour burden. Leukocyte and lymphocyte counts form a second correlation cluster of laboratory parameters; in addition, leucocytosis and lymphocytopenia have an independent prognostic impact [92]. A plethora of biological parameters such as levels of cytokines released by HRS cells, soluble forms of membrane-derived antigens, and cell-­ free tumour DNA have been investigated for prognostic value not confined to advanced-stage disease. Many of these studies were done in rather small data sets, and findings are often not yet integrated with other clinical or imaging factors in multivariate analysis. The soluble form of the CD30 molecule (sCD30) is released by HRS cells and is detectable in the serum of virtually all untreated patients. It maintains independent prognostic significance in multivariate analysis in moderately sized data sets [78, 104–106]. The thymus and activation-regulated chemokine (TARC or CCL117) plays a role in the pathogenesis of HL and correlates with disease burden and outcome [107]. A correlative analysis of the recent randomized phase III ECHELON-1 trial comparing ABVD and BV-AVD could not confirm a prognostic role for sCD30 or TARC since neither of the two parameters correlated with early or end-of-treatment response nor PFS [108]. The relevance of cytokine levels such as IL-1RA, IL-2R, IL-6, IL-10, or tumour necrosis factor (TNF) requires further investigation [78, 109, 110] as does the role of elevated β2-­ microglobulin [111]. Circulating cell-free tumour DNA (cfDNA) recently gained attention across various tumour types since it potentially allows minimally invasive monitoring of disease activity over the course of treatment as well as genetic assessment of the malignancy [112]. After a proof-of-concept study for HL was published [113], very recent studies highlight the prognostic potential of cfDNA, especially in correlation with disease status by PET [114, 115]. Focussing on tumour architecture and composition, several histopathological markers in tumour tissue either expressed by HRS or reactive bystander cells were identified. High density of CD68+ macrophages has been shown to be adversely prognostic with ABVD treatment [89,

8  Prognostic Factors

153

116]. Tumour-associated macrophages (TAM) together with cells involved in a TH1 immune response possibly create an inflammatory ­environment favouring rapid lymphoma proliferation. A recent analysis revealed frequent 9p24.1 amplifications in advanced-stage cHL which were associated with poorer PFS in ABVD-­ treated patients [117]. In order to obtain a method usable in clinical practice, a 23-gene expression signature was shown to be predictive in advanced-­ stage ABVD-treated patients [88]. However, further validation in clinical trials including PET-adapted or BEACOPP-based therapy is required.

8.5.2 I nterim PET as Prognostic Factor in Advanced-Stage Hodgkin Lymphoma An early interim FDG-PET scan after two cycles of chemotherapy (PET-2) has been shown to be highly predictive of outcome in advanced-stage HL a decade ago [68, 118–120]. In a large study of advanced-stage patients treated with ABVD, the prognostic value of PET-2 completely overshadowed the role of the International Prognostic Score (IPS) [121]. Figure 8.3 shows PFS according to the IPS and the PET-2 result. Within the last years, individualized treatment guided by PET-2 was investigated in several phase III trials. Within the UK-led RATHL trial,

8.5.3 Prognostic Indices in Advanced-Stage Hodgkin Lymphoma

Progression-Free Survival

1.0 0.8 0.6

IPS 0-2, PET2 negative IPS 0-2, PET2 positive IPS 3-7, PET2 negative IPS 3-7, PET2 positive

0.4 0.2

Log-rank P = ≈ 0

0

PFS and OS were superior in PET-2-negative patients as compared to PET-2-positive patients, despite de-escalation from ABVD to AVD or escalation from ABVD to BEACOPPescalated, respectively [122]. In PET-2-negative patients, only stage IV disease and the IPS but no other factors such as bulky disease, PET score by Deauville, or B symptoms retained prognostic significance for PFS.  In contrast, PET-2 status was not prognostic for PFS in the GHSG HD18 trial [123] as shown in Fig. 8.4. Neither addition of rituximab to BEACOPPescalated in the PET-2-positive patient nor reduction from 6–8×BEACOPPescalated to 4×BEACOPPescalated did relevantly change PFS or OS for these different treatment arms (Fig. 8.5) [123]. Similar observations were made in the French AHL2011 trial, which investigated de-­ escalation to 4xABVD in PET-2-negative patients after 2×BEACOPPescalated [124]. These findings underline the poor positive predictive value of a positive PET-2  in patients initially treated with BEACOPPescalated. On the other hand, the improved negative predictive value of a negative PET-2  in this group of patients has to be compared to those initially treated with ABVD. Of note, post-hoc analyses of the UK RATHL trial showed very good inter-observer comparability, highlighting the feasibility of utilizing PET-2-guided therapy in routine clinical care [125] .

1

2

3

4

5

Time (years)

Fig. 8.3  PFS in 260 patients with advanced-stage disease according to the IPS and PET-2 status after 2×ABVD (Reprinted with permission from Gallamini et al. [121])

Prognostic indices for advanced HL are clinically important to select patients prior to initiation of first-line treatment who may be over- or undertreated by standard therapeutic approaches. Over the last decades, several groups developed prognostic indices or scores based on a few hundred cases trying to define high-risk groups. Most scores combined age, disease extent, and laboratory markers, but only a prognostic model for OS developed by Gobbi et al. based on the following seven factors received

P. J. Bröckelmann and L. Specht

154 PET-2 negative

PET-2 positive

Non-randomised

100

Progression-free surival (%)

90 80 70 60

3-year estimate (95% CI)

50

PET-2 negative

40

5-year estimate (95% CI)

93·5% (91·9–95·1)

91·4% (89·5–93·4)

92·5% (90·7–94·3)

88·3% (85·8–90·8)

30

Non-randomised 77·6% (68·6–86·6)

77·6% (68·6–86·6)

20

Overall

92·3% (91·1-93·5)

89·4% (87·9-91·0)

10

Median observation time 52 months (IQR 32–67)

PET-2 positive

0

0 Number at risk (number censored) PET-2 negative 1010 (0) PET-2 positive 948 (0) Non-randomised 115 (0)

12

24

36

48

60

921 (63) 854 (62) 72 (31)

845 (118) 766 (131) 61 (37)

685 (265) 600 (284) 47 (49)

548 (396) 476 (398) 35 (61)

385 (553) 276 (588) 24 (72)

Fig. 8.4  PFS according to PET-2 status after 2×BEACOPPescalated in 2073 patients with advanced-stage treated within the HD18 trial (Reprinted with permission from Borchmann et al. [123])

8×eBEACOPP or 6xeBEACOPP

4×eBEACOPP

100

Progression-free surival (%)

90 80 70 60 3-year estimate (95% CI)

50 40 30

8×eBEACOPP or 6×eBEACOPP

91·7% (89·0 to 94·4)

90·8% (87·9 to 93·7)

4×eBEACOPP

95·3% (93·3 to 97·3)

92·2% (89·4 to 95·0)

3·6% (−0·2 to 6·9)

−1·4% (−2·7 to 5·4)

Difference

20

Hazard ratio (95% CI)

10

5-year estimate (95% CI)

0·79% (0·50 to 1·24)

Median observation time 55 months (IQR 36–70)

0 0

12

24

36

48

60

411 (21) 444 (22)

378 (45) 412 (43)

310 (102) 334 (119)

247 (164) 269 (180)

164 (246) 198 (246)

Number at risk (number censored) 8×eBEACOPP or 6×eBEACOPP 446 (0) 4×eBEACOPP 474 (0)

Fig. 8.5  PFS in 920 PET-2-negative patients treated with a total of 6–8× vs. 4×BEACOPPescalated in the HD18 trial (Reprinted with permission from Borchmann et al. [123])

8  Prognostic Factors

general acceptance: stage, age, histology, B symptoms, serum albumin, sex, and involved area distribution (infradiaphragmatic disease or >3 supradiaphragmatic areas) [101]. Some years later, the International Prognostic Factors Project on advanced-stage HL focussed on FFP [92]. Individual patient data were collected from 23 centres and study groups including 5141 advanced-stage HL patients who were treated mainly with doxorubicin-containing chemotherapy with and without radiotherapy. A prognostic score was developed from this data set in patients up to 65 years of age. The score is a simple count of seven binary adverse prognostic factors (Table 8.3): This prognostic model, termed the “International Prognostic Score” (IPS), predicts 5-year tumour control rates in the range of 45–80%. Each additional factor reduces the prognosis by about 8%. Figure  8.6 shows the FFP according to the number of adverse prognostic factors. Since its publication, the IPS has performed reasonably well in independent data sets [126– 131], including patients treated with intensified BEACOPP chemotherapy, where outcome uniformly improved in all IPS groups with persisting but quantitatively reduced differences [126, 130]. Comparison of several prognostic models [94, 128] revealed that none of the models including the IPS are able to select either a very low-risk group (e.g. 50%). The prognostic models thus discriminate only between low-risk and high-risk patients (e.g. IPS ≤2 vs. IPS >2). A more recent analysis verified the prognostic value Table 8.3  Adverse prognostic factors incorporated in the International Prognostic Factors Project score for FFP in advanced-stage HL Age ≥ 45 years Male sex Stage IV disease Haemoglobin