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Lymphoma
Pathology, Diagnosis, and Treatment
Second Edition
Edited by:
Robert Marcus
Department of Haematology, Kings College Hospital, Denmark Hill, London, UK

John W. Sweetenham
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

Michael E. Williams
Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA
University Printing House, Cambridge CB2 8BS, United Kingdom

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.................................................................................................
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every effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors, and publishers can make no warranties that the
information contained herein is totally free from error, not least because clinical
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Contents
Preface to second edition page vii
Preface to first edition ix
List of contributors x

1 Epidemiology 1 11 Burkitt and lymphoblastic lymphoma:

Eve Roman and Alexandra G. Smith clinical therapy and outcome 172
Nirali N. Shah, Alan S. Wayne, and Wyndham
2 Prognostic factors for lymphomas 11
H. Wilson
Guillaume Cartron and Philippe Solal-Céligny
12 Therapy of diffuse large B-cell
3 Imaging 32
lymphoma 191
Heok K. Cheow and Ashley S. Shaw
John W. Sweetenham
4 Clinical trials in lymphoma 45
13 Central nervous system lymphomas 208
Thomas M. Habermann and Matthew Maurer
Andrés J. M. Ferreri and Lisa M. DeAngelis
5 Hodgkin lymphoma 61
14 T-cell non-Hodgkin lymphoma 226
Stephanie Sasse and Andreas Engert
Sheetal M. Kircher, Beverly P. Nelson, Steven
6 Follicular lymphoma 87 T. Rosen, and Andrew M. Evens
Kristian Bowles, Daniel Hodson, and Robert 15 Primary cutaneous lymphoma 254
Marcus
Sean Whittaker
7 MALT and other marginal zone
16 Lymphoma in the immunosuppressed 273
lymphomas 104
Michele Spina, Robert Marcus, Shireen Kassam,
Emanuele Zucca and Francesco Bertoni
and Umberto Tirelli
8 Small lymphocytic lymphoma/chronic
17 Atypical lymphoproliferative, histiocytic,
lymphocytic leukemia 121
and dendritic cell disorders 286
Peter Hillmen
Matthew S. Davids and Jennifer R. Brown
9 Waldenström’s macroglobulinemia/
lymphoplasmacytic lymphoma 138
Steven P. Treon and Giampaolo Merlini
10 Mantle cell lymphoma 155 Index 299
Martin Dreyling and Michael E. Williams

v
Preface to second edition

Since the first edition we have seen a number of impor- and mantle cell lymphoma, and idelalisib in indolent
tant changes in the diagnosis, staging and therapy for B-cell lymphoproliferative disorders. These specifi-
many lymphoma subtypes. We are beginning to cally targeted therapies give us hope that, in the very
observe how molecular and cytogenetic characteristics near future, the management of lymphoma will be
can profoundly influence prognosis and that such tools both more effective and less toxic.
should now be as much a part of our diagnostic arma- In this new edition we have also endeavored to
mentarium as histology and immunophenotyping. rectify some of the omissions in the previous edition;
In the near future we expect that “next generation” in particular, we have now additional chapters on
sequencing will also have a considerable impact not Lymphoplasmacytoid Lymphoma and Atypical
only on our understanding of the pathogenesis of Lymphoproliferative disorders that make the book
lymphoma, but also on our selection of therapy. We more comprehensive.
can also envisage how such techniques will themselves Once again we have incorporated biology,
also lead to less toxic and more targeted therapies. pathogenesis, histopathology, and therapy into each
We have seen the steady increase in the incorpo- disease based chapter, we hope the “joins” do not
ration of PET and PET CT into staging, risk-adapted show too much and are most grateful indeed to
therapy, and reassessment such that the presence of a Drs. Ott, Rosenwald, and Wotherspoon for allowing
PET/CT scanner and radiologic expertise should now their contributions on molecular biology and
be an essential in every major Lymphoma centre. The histopathology, respectively, to be separated and
promise and precautions for this important tool are distributed as before.
summarized within this edition. Our thanks are due too to all the authors and to
In terms of therapy, the steady progress in both the colleagues at CUP for their hard work and forbearance
use of monoclonal antibodies and new treatment regi- in the preparation of this new edition.
mens is reflected in the updated chapters. Lymphoma
specialists are also beginning to see the incorporation Robert Marcus
of agents that block intra-cellular signaling pathways John Sweetenham
into clinical practice, notably ibrutinib in CLL/SLL Michael Williams

vii
Preface to first edition

Why publish a book on lymphoma in 2007? Surely accept that their contributions on histopathology and
there are sufficient reviews, meetings and published molecular cytogenetics would be divided and distrib-
educational symposia to make such a work redundant. uted among the relevant chapters. The editors are most
Furthermore, doesn’t instant access to online informa- grateful for their support.
tion make any work in print out of date before it Each chapter in followed by a select bibliography
appears? rather than an exhaustive list of references. We feel
The editors and authors of this work think not. We that these date very quickly, take up disproportionate
firmly believe that there is still a place for a clear amounts of space and are better found by internet
summary of the diagnosis, staging and therapy of searches or perusal of current journals.
lymphoma in a single volume that reflect the advances This book is intended for senior trainees and
in these areas which have taken place over the past five fellows in hematology and oncology, together with
years. The problem with the plethora of information more experienced practitioners who regularly treat
now available is that it is rarely set in a framework of these disorders. It is not intended for those who may
understanding of the major challenges which still feel they could have written the chapters themselves.
face those involved with the diagnosis and therapy of It is also not a book where the reader will find detailed
non-Hodgkin’s and Hodgkin’s lymphomas. We, and descriptions of rarities seen once in a professional
our patients, are confronted with many facts but lifetime.
little judgment. This work is our modest attempt to The appearance of this volume comes at an oppor-
rectify this. tune time: we have seen over the past five years a
Accordingly the layout of the book should enable profound understanding of the pathology of lym-
the reader to gain an understanding of patterns of phoma, the use of increasingly sophisticated imaging
disease, methods of staging, principles of new techniques, and the integration of monoclonal anti-
approaches to therapy, and interpretation of clinical bodies into standard therapy for NHL. Our hope is
trials and prognostic markers by reading the first part that these radical changes in the way we diagnose and
of the book. In the second part the reader will find treat lymphoma have been reflected in the book and
separate succinct yet comprehensive reviews of the will stand the reader in good stead even when newer
individual disease entities which make up the spectrum data become available.
of diseases comprising the lymphomas. Here we have The editors express their sincere and heartfelt
integrated pathology, molecular biology and therapy thanks to all the authors, who have, in the main,
for each subtype into a single chapter; the reader will responded promptly to our comments and recommen-
not need to flick backwards and forwards to gain dations, and to all those at Cambridge University
a comprehensive understanding of, say, follicular or Press who have helped with this project: Richard
diffuse large B-cell lymphoma. Such an integration Barling, who set the wheels of this vehicle in motion,
has posed significant editorial challenges, and has and especially Betty Fulford and Deborah Russell, who
been made possible by a willingness on the part of kept it moving to its final destination whenever it
Dr Wotherspoon, Dr Rosenwald and co-workers to threatened to stall.

ix
 Contributors

Francesco Bertoni Andrew M. Evens

Lymphoma & Genomics Research Program, Division of Hematology/Oncology, Tufts University
Institute of Oncology Research (IOR), and School of Medicine, and Tufts Cancer Center Boston,
Oncology Institute of Southern Switzerland (IOSI), MA, USA
Bellinzona, Switzerland
Andrés J. M. Ferreri
Kristian Bowles Unit of Lymphoid Malignancies, Medical Oncology
Norwich Medical School, UK Unit, Department of Oncology, San Raffaele Scientific
Institute, Milan, Italy
Jennifer R. Brown
Harvard Medical School, Dana-Farber Cancer Thomas M. Habermann
Institute, Boston, MA, USA Mayo Clinic College of Medicine, Rochester, MN, USA

Guillaume Cartron Peter Hillmen

Department of Haematology University Department of Haematology, Leeds General
Hospital, UMR CNRS 5235 Montpellier, Infirmary, Leeds, UK
France
Shireen Kassam
Heok K. Cheow Department of Haematology, Kings College Hospital,
Department of Radiology, Addenbrooke’s Hospital, Denmark Hill, London, UK
Cambridge, UK
Sheetal M. Kircher
Matthew S. Davids Division of Hematology/Oncology, Department of
Harvard Medical School, Dana-Farber Cancer Medicine, Northwestern University Feinberg School
Institute, Boston, MA, USA of Medicine, Robert H. Lurie Comprehensive Cancer
Center, Chicago, IL, USA
Lisa M. DeAngelis
Department of Neurology, Memorial Sloan-Kettering Robert Marcus
Cancer Center, New York, NY, USA Department of Haematology, Kings College Hospital,
Denmark Hill, London, UK
Martin Dreyling
University Hospital Grosshadern, Department of Matthew Maurer
Internal Medicine III, Ludwig-Maximilians- Mayo Clinic College of Medicine, Rochester, MN, USA
University, Munich, Germany
Giampaolo Merlini
Andreas Engert Department of Biochemistry at the University of
First Department of Internal Medicine, Trial Secretary Pavia, and Biotechnology Research Laboratories,
GHSG, University Hospital Cologne, Cologne, University Hospital Policlinico San Matteo, Pavia,
Germany Italy

x
 List of contributors

Beverly P. Nelson Michele Spina

Department of Pathology, Northwestern Division of Medical Oncology A, National Cancer
University Feinberg School of Medicine, Robert Institute, Aviano, Italy
H. Lurie Comprehensive Cancer Center, Chicago,
IL, USA John W. Sweetenham
Huntsman Cancer Institute, University of Utah, 1950
German Ott Circle of Hope, Salt Lake City, UT, USA
Division of Hematology, Oncology and Blood &
Marrow Transplantation, Children’s Hospital Los Umberto Tirelli
Angeles, Keck School of Medicine, University of Division of Medical Oncology A, National Cancer
Southern California, Los Angeles, CA, USA Institute, Aviano, Italy

Eve Roman Steven P. Treon

Epidemiology & Cancer Statistics Group, Bing Center for Waldenstrom’s Macroglobulinemia,
Department of Health Sciences, University of York, Dana-Farber Cancer Institute, Harvard Medical
York, UK School, Boston, MA, USA

Steven T. Rosen Alan S. Wayne

Robert H. Lurie Comprehensive Cancer Center, Division of Hematology, Oncology and Blood &
Northwestern University Feinberg School of Marrow Transplantation, Children’s Hospital
Medicine, Chicago, IL, USA Los Angeles, Keck School of Medicine,
University of Southern California, Los Angeles,
Andreas Rosenwald CA, USA
Institute of Pathology, University of Wurzburg,
Sean Whittaker
Wurzburg, Germany
St Johns Institute of Dermatology, Guys and St
Stephanie Sasse Thomas’ NHS Foundation Trust, and Division of
First Department of Internal Medicine, University Genetics and Molecular Medicine, Kings College
Hospital Cologne, Cologne, Germany London, UK

Nirali N. Shah Michael E. Williams

Pediatric Oncology Branch, Center Hematology/Oncology Division, University of
for Cancer Research, National Cancer Virginia Health System, Charlottesville, VA, USA
Institute, National Institutes of Health, Bethesda,
Wyndham H. Wilson
MD, USA
Lymphoma Therapeutics Section, Metabolism
Ashley S. Shaw Branch, Center for Cancer Research, National Cancer
Department of Radiology, Addenbrooke’s Hospital, Institute, National Institutes of Health,
Cambridge, UK Bethesda, MD, USA

Alexandra G. Smith Andrew Wotherspoon

Epidemiology & Cancer Statistics Group, Department of Histopathology,
Department of Health Sciences, University of York, Royal Marsden Hospital, Fulham Road,
York, UK London, UK
Emanuele Zucca
Philippe Solal-Céligny
Oncology Institute of Southern Switzerland (IOSI),
Institut de Cancérologie de l’Ouest, Nantes-Angers,
Ospedale San Giovanni, Bellinzona, Switzerland
France

xi
 Chapter

1
Epidemiology
Eve Roman and Alexandra G. Smith

Introduction of modern disease classifications is, however, now

beginning to discriminate between subtypes, reveal-
Epidemiology is the basic quantitative science of ing many features that future etiological hypotheses
public health and, as such, is concerned with the dis- will undoubtedly seek to address. Accordingly, the
tribution, determinants, treatment, management, and next few decades promise to be an exciting time for
potential control of disease. Concentrating on the first epidemiological research into lymphoid, as well as
two of these, this chapter reviews the epidemiology of other hematological, malignancies.
lymphomas – a heterogeneous group of malignancies
that is estimated to account for around 3–4% of can-
cers worldwide. Descriptive epidemiology
Epidemiological reports on lymphomas often In 2001 the World Health Organization (WHO) pro-
begin, and sometimes end, by stating that little is duced, for the first time, a consensus classification that
known about the causes of the cancers under study. defined malignancies of the hematopoietic and lym-
This is slowly changing, as evidence about the patho- phoid systems in terms of their immunophenotype,
logical diversity of the various lymphoma subtypes genetic abnormalities, and clinical features. Up until
accumulates. At present, however, the issue of lym- then, the use of competing classifications had tended
phoma classification continues to permeate much of to make meaningful comparison of results both
the literature, since, in order to originate and test between and within populations virtually impossible.
hypotheses about pathogenesis, it is vitally important For a variety of reasons, although WHO’s 2001 classi-
to describe accurately and understand underlying fication and its successor was adopted into clinical
descriptive disease patterns. Implicit in this is the practice almost uniformly around the world, it did not
need to use appropriate disease classifications; it is have an immediate effect on population-based epide-
this requirement that has beleaguered epidemiological miological research. This is because, unlike many other
research into the lymphoid malignancies. cancers, hematological neoplasms are diagnosed using
In short, the classification of hematological malig- multiple parameters, including a combination of histol-
nancies has changed markedly over recent decades, ogy, cytology, immunophenotyping, cytogenetics,
and will continue to do so as biological understand- imaging, and clinical data. This range and depth of
ing increases and new diagnostic methods and data is difficult for cancer registries and other research-
techniques are developed. One problem for epide- ers to access routinely, forming a barrier both to com-
miological research concerns the use of historical plete ascertainment and to the collection of diagnostic
classifications emanating from the latter half of the data at the level of detail required to implement the
nineteenth century – long before there were any latest classification systematically. Furthermore, in
effective treatments or real understanding of the rela- practice, even within some of the best defined WHO
tionships between lymphoid malignancies, the nor- categories, there is a need to qualify the final diagnosis
mal bone marrow and immune system, and before even further using additional clinical and biological
anything was known about the cellular and genetic prognostic factors before valid outcome comparisons
basis of malignant transformation. The application can be made between clinical centers.

Lymphoma, Second Edition, ed. Robert Marcus, John W. Sweetenham, and Michael E. Williams. Published by 1
Cambridge University Press. © Cambridge University Press 2014.
 Chapter 1: Epidemiology

Gathering accurate information about disease bur- than half of all NHL and HL diagnoses occurred in
dens and patterns is central to any successful cancer the three regions with the highest rates – Northern
information strategy. However, whilst cancer registra- America, Europe, and Oceania (Figure 1.1) – largely
tion has a long history in many countries, particularly reflecting the underlying world population distribution.
those in the more affluent regions of the world, nearly The most striking disparity is seen for Asia, which has
80% of the world’s population is not covered by such the lowest rates but more than a third of all of the
systems (www.globocan.iarc.fr/). Furthermore, in estimated worldwide cases. To some extent these
some of these, even enumerating the population at broad regional differences may well reflect, at least in
risk (denominator) through census counts and vital part, underlying lymphoma subtype variations – with a
registration is challenging. Even so, with a view to relatively high proportion of mature T-/natural killer
characterizing the global burden of disease, the cell neoplasms being reported for several Asian popula-
WHO’s International Agency for Research on Cancer tions. These issues are discussed in more depth in the
(IARC) routinely uses the available data to estimate later section on etiology.
worldwide cancer incidence and mortality levels.
Misdiagnosis and underenumeration are recog-
nized as particularly problematic for hematological can- Age and sex
cers. The acute and rapidly fatal presentation of some That lymphoid malignancies are, overall, generally
patients leads to underenumeration in those countries more common in men than in women in all areas of
with less well-developed health service infrastructures the world is evident from Figure 1.1, where for both
and the intermittent and non-specific nature of symp- NHL and HL the age-standardized rates and numbers
toms associated with others poses problems even in are consistently higher for males than for females.
countries with well-developed health service systems Interestingly, these gender differences appear to be
and cancer registration processes. In addition, slightly more pronounced in less developed regions of
population-based data continue to be reported in the the world (http://globocan.iarc.fr/) – the sex rate ratios
broad anatomical-based categories of non-Hodgkin (M:F) for HL, for example, range from 1.8 and 1.6,
lymphoma (NHL), Hodgkin lymphoma (HL), mye- respectively, in Africa and Asia through to 1.2 and 1.1,
loma, and leukemia since, for reasons outlined above, respectively, in North America and Europe. Whether or
the laboratory data required to classify hematological not these gradations reflect genuine underlying inci-
cancers appropriately are hard for cancer registries to dence differences, either generally or within particular
access in a timely and systematic fashion. subtypes, or are in fact caused by enumeration biases
cannot be investigated further from the available cancer
registration data.
Geographic variation The NHL and HL age-specific incidence patterns
Of the 12.68 million new cancers estimated to have seen in more economically developed regions of the
occurred around the world in 2008, 6.64 were in men world are all broadly similar to the pattern shown in
and 6.04 in women. Combined, hematological malig- Figure 1.2, which presents cancer registration data
nancies (lymphomas, leukemias, and myelomas) com- from the UK. For NHL, the age-specific male and
prised 7.5% of the estimated cancers in males and 6.4% female rates increase with increasing age, the diver-
in females, with lymphomas accounting for around gence between the male and female rates becoming
half of all newly diagnosed hematological neoplasms progressively more marked as age increases, but,
in both men and women. despite this, more women than men are diagnosed
Figure 1.1 shows the estimated global regional rates over the age of 80 years. This apparent discrepancy
and numbers of cases of NHL and HL separately for reflects the fact that the UK, like other economically
men and women (www.globocan.iarc.fr/). In general, developed regions of the world, has an aging popula-
estimated lymphoma rates are higher in more econom- tion structure within which more women than men
ically developed regions of the world – North America, survive to reach old age.
Europe, and Australasia – and lower in less affluent The relationship with age and sex is quite different
regions. This relationship with affluence is seen for for NHL and HL. In more affluent regions of the world
both NHL and HL, with one or two interesting pockets HL tends to have a bimodal age distribution that is
2 such as the consistently low overall rates reported characterized by early age peak, within which females
for Japan (www.globocan.iarc.fr/). Nevertheless, less are often in excess but have a deeper following trough,
 Chapter 1: Epidemiology

A Male rate Female rate

Male cases Female cases Number of Cases
80000 70000 60000 50000 40000 30000 20000 10000 0 10000 20000 30000 40000 50000 60000 70000 80000

NORTHERN NORTHERN
AMERICA AMERICA
OCEANIA OCEANIA

EUROPE EUROPE

LATIN AMERICA LATIN AMERICA

& CARIBBEAN & CARIBBEAN
AFRICA AFRICA

ASIA ASIA

18 16 14 12 10 8 6 4 2 0 2 4 6 8 10 12 14 16 18
B Age Standardized Rate
Male rate Female rate
Male cases Female cases
Number of Cases
20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000

NORTHERN NORTHERN
AMERICA AMERICA
EUROPE EUROPE

OCEANIA OCEANIA

LATIN AMERICA LATIN AMERICA

& CARIBBEAN & CARIBBEAN
AFRICA AFRICA

ASIA ASIA

3 2.5 2 1.5 1 0.5 0 0.5 1 1.5 2 2.5 3

Age Standardized Rate

Figure 1.1 Estimated numbers and age-standardized (world population) incidence rates by region for (A) non-Hodgkin lymphoma and
(B) Hodgkin lymphoma. (Source: GLOBOCAN.)

and a late age peak with a pronounced male excess each year, HMRN comprises an ongoing population-
(Figure 1.2). The earlier age peak is not clearly evident based cohort of all newly diagnosed hematological
in less well developed regions of the world. Inspection malignancies (pediatric and adult). Importantly, as a
of various case-series has revealed that these patterns matter of policy and irrespective of treatment intent,
are the result of differences in the age and gender all diagnoses within HMRN are made and coded to the
frequencies of the various HL subtypes. Likewise, the latest WHO classification by a single specialist hema-
comparatively smooth pattern seen when all NHLs are topathology laboratory.
combined (Figure 1.2) conceals considerable age and HMRN patients newly diagnosed with lymphoma
sex subtype variability. in the 5 years from September 2004 to August 2009 are
The diagnostic challenges posed by hematological proportionately distributed by WHO diagnostic cate-
malignancies means that subtype data can only be gory in Figure 1.3, beginning with the B-cell NHLs,
obtained from specialist registries. Furthermore, moving clockwise through the T-cell NHLs and ending
population-based data with clearly defined numera- with the HLs. Diffuse large B-cell (DLBCL), follicular
tors and denominators (as opposed to hospital-based (FL), and marginal zone lymphomas (MZL) dominate –
case-series) are required for epidemiological research. together accounting for more than 70% of the total. The
One such registry is the UK-based Haematological high proportion of DLBCL and MZL is a common
Malignancy Research Network (www.HMRN.org), feature evident in all reported series, including hospital-
and descriptive age and sex patterns for the lympho- based registers in Asia. By contrast, in certain Asian and
mas diagnosed within HMRN are presented in other population groups, diagnoses of the more indo-
Figures 1.3 and 1.4. Established in 2004 and covering lent FL appear to occur far less frequently, whereas 3
a population of 3.6 million with over 2100 diagnoses diagnoses of T-cell lymphomas are more common.
 Chapter 1: Epidemiology

A Figure 1.2 Numbers of new cases and

800 100 age-specific incidence rates by sex for (A)
non-Hodgkin lymphoma and (B) Hodgkin
90 lymphoma, UK in 2007.

Rate per 100,000 population

80
600
70
Number of cases

60
400 50
40
30
200
20
10
0 0
4
10 9
15 4
20 9
25 24
30 9
35 4
40 9
45 44
50 9
55 54
60 59
65 4
70 9
75 4
80 9
4
+
0–
5–
–1
–1

–2
–3
–3

–4

–6
–6
–7
–7
–8
85
–

–
–

Male cases Female cases

Male rates Female rates

B
120 6

100 5

Rate per 100,000 population

Number of cases

80 4

60 3

40 2

20 1

0 0
4
10 9
15 4
20 9
25 4
30 9
35 4
40 9
45 4
50 9
55 4
60 9
65 4
70 9
75 4
80 9
4
+
0–
5–
–1
–1
–2
–2
–3
–3
–4
–4
–5
–5
–6
–6
–7
–7
–8
85

Male cases Female cases

Male rates Female rates
Age at diagnosis

The corresponding HMRN box-and-whisker age lymphoma shows the least variation. By contrast, with a
distributions and sex rate ratios (male rate:female rate), median diagnostic age approaching 71 years, but with
together with their standard errors, are shown in Figure several sporadic pediatric cases, DLBCL covers the larg-
1.4. Whilst most B-cell NHLs have a median diagnostic est age range – the scatter of outliers at younger ages is
age over 70 years, a significant minority tend to be indicative, perhaps, of diagnostic heterogeneity within
diagnosed at younger ages – follicular, Burkitt, and this subtype category.
mediastinal lymphomas in HMRN having median ages Overall, in agreement with other reports, within
of 65, 52, and 36 years, respectively. Furthermore, some HMRN T-cell NHLs tend to be diagnosed at younger
subtypes have broad age ranges whilst others are narrow; ages than B-cell neoplasms. Nonetheless, within T-cell
4 with no patients diagnosed before the age of 48 years and forms of the disease there is considerable subtype
a median of 74 years, the age distribution of mantle cell heterogeneity – the tight age band for enteropathy