Seminar

Non-Hodgkin lymphoma
Kate R Shankland, James O Armitage, Barry W Hancock

Lancet 2012; 380: 848–57 Lymphomas are solid tumours of the immune system. Hodgkin’s lymphoma accounts for about 10% of all
Published Online lymphomas, and the remaining 90% are referred to as non-Hodgkin lymphoma. Non-Hodgkin lymphomas have a
July 25, 2012 wide range of histological appearances and clinical features at presentation, which can make diagnosis difficult.
http://dx.doi.org/10.1016/
Lymphomas are not rare, and most physicians, irrespective of their specialty, will probably have come across a
S0140-6736(12)60605-9
patient with lymphoma. Timely diagnosis is important because effective, and often curative, therapies are available
Academic Unit of Clinical
Oncology, Weston Park for many subtypes. In this Seminar we discuss advances in the understanding of the biology of these malignancies
Hospital, Sheffield, UK and new, available treatments.
(K R Shankland MB ChB,
Prof B W Hancock MD); and
University of Nebraska Medical
Epidemiology
Center, Omaha, NE, USA Since non-Hodgkin lymphoma was last reviewed in
(Prof J O Armitage MD) The Lancet in 2003,1 biological understanding of these
Correspondence to: malignancies has advanced and treatments have im-
Dr Kate R Shankland, Weston proved. Around 12 294 people were diagnosed with
Park Hospital, Whitham Road, non-Hodgkin lymphoma in the UK in 2009, and about
Sheffield S10 2SJ, UK
kate.shankland@sth.nhs.uk
4452 people in the UK died of the disease in 2010.2,3
Corresponding numbers in the USA were 65 540 new
cases (in 2007) and 20 210 deaths (in 2008).4 More than
two-thirds of patients are 60 years and older.2,3 Non-
Hodgkin lymphoma is the fifth most frequently
diagnosed cancer in the UK, with roughly equal numbers
of cases in men and women; however, because the
population contains more women than men, the male
age-standardised incidence per 100 000 men (17·7) is
higher than the female incidence (12·8).2,3,5 The frequency
of specific subtypes of lymphoma varies substantially by
geographic region. For example, adult T-cell lymphoma
associated with infection by human T-cell lymphotropic
virus type 1 is much more frequent in east Asia than in
other regions, as is nasal natural killer (NK)-cell or T-cell
lymphoma associated with Epstein-Barr virus infection,
whereas follicular lymphomas are more frequent in
western Europe and North America.6 Diffuse large B-cell
lymphoma, by contrast, is common worldwide.
The incidence of non-Hodgkin lymphoma is increasing
in many regions. In England, Scotland, and Wales, the
age-standardised incidence has increased by 35% in
30 years (1988–2007).2,3,5 A similar trend has been
recorded in the USA, with a 3·7% yearly percentage
increase in the incidence of non-Hodgkin lymphoma
between 1975 and 1991, and a 0·3% yearly increase from
1992 to 2007.7 The incidence in Brazil, India, Japan,
Singapore, and western Europe has also increased.8–10
The reason for this long-term increase is unclear,
Search strategy and selection criteria
We searched PubMed for articles published in English since
2003, with the search terms “non-Hodgkin lymphoma” and
“pathology”, “staging”, “prognosis”, and “treatment”. We
searched reference lists of publications identified through the
initial search for further citations. Text books were also used,
from which we identified further citations.
although the emergence of HIV caused an additional
increase in the incidence of non-Hodgkin lymphoma.
Survival in England and Wales has improved substantially
during the past four decades, with 50·8% of patients now
expected to survive for longer than 10 years, compared
with only 21·8% of those diagnosed in the early 1970s.11
The most well established risk factor for the
development of non-Hodgkin lymphoma is immuno-
suppression. Patients with HIV have an increased risk of
developing high-grade non-Hodgkin lymphoma. Others
at increased risk include organ-transplant recipients,
patients who have had high-dose chemotherapy with
stem-cell transplantation, and those with inherited
immunodeficiency syndromes or autoimmune disease.
Infection does play a part in development of some
lymphomas, either by inhibition of immune function, or
by other mechanisms, such as induction of chronic
inflammatory response. The Epstein-Barr virus, for
example, has recognised associations with Burkitt’s and
nasal NK-cell or T-cell lymphomas, and Helicobacter pylori
infection is a risk factor for gastric mucosa-associated
lymphoid tissue lymphoma. Other microorganisms
thought to be associated with specific lymphomas
include hepatitis C virus with splenic marginal-zone
lymphoma, Borrelia burgdorferi with cutaneous mucosa-
associated lymphoid tissue lymphoma, and Chlamydia
psittaci with ocular adnexal lymphoma.12
Pathophysiology
Non-Hodgkin lymphomas encompass a heterogeneous
group of cancers, 85–90% of which arise from B lympho-
cytes; the remainder derive from T lymphocytes or NK
lymphocytes. This diverse group of malignancies usually
develops in the lymph nodes, but can occur in almost any
tissue, and ranges from the more indolent follicular
lymphoma, to the more aggressive diffuse large B-cell and
Burkitt’s lymphomas. Several different classification
systems have been proposed that have grouped these
malignancies according to their histological characteristics.
The most recent system is the fourth edition of the WHO
classification of tumours of haemopoietic and lymphoid
tissues, published in 2008 (table 1).13 It built upon the
2001 third edition and applied new findings from clinical
and laboratory research to provide guidance on how to
recognise early or in-situ lesions by assessment of B-cell

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 Seminar

clonal expansion and less often T-cell expansion, which
seem to have a decreased potential for malignant trans-
formation; appreciate patient age as a defining feature of
some subtypes (eg, follicular and nodal marginal-zone
lymphomas have variants that present almost exclusively
in children and are clinically and biologically distinct from
their counterparts affecting adults); and recognise border-
line categories that share common morphological and
immunophenotypical features with other subtypes of
lymphoma—eg, primary mediastinal large B-cell lymph-
oma shares features with mediastinal nodular sclerosing
classic Hodgkin’s lymphoma.
Despite this classification refinement, some groups
remain heterogeneous, such as diffuse large B-cell
lymphoma, not otherwise specified, and peripheral
T-cell lymphoma, not otherwise specified. Further sub-
classification of these entities is a probable focus of
future research.
To understand the mechanisms by which lymphomas
might develop, the events that occur during normal
B-cell maturation should be considered (figure). During
normal B-cell development, cells arise from the central
lymphoid tissues (bone marrow and thymus), where
recombination of gene segments results in the assembly
of immunoglobulin heavy-chain and light-chain genes,
enabled by enzymes that cause breaks in double-stranded
DNA.14 In normal cells, DNA repair processes are
activated, but these strand breaks can contribute to
chromosome translocations in lymphoma.15 Such trans-
locations typically result in proto-oncogene activation.
Once B lymphocytes have matured they migrate into the
peripheral lymphoid tissues (blood, spleen, lymph node,
and mucosa-associated). Normal B-cell activation occurs
in the germinal centre of lymph nodes when antigen in
conjunction with signals from T lymphocytes activates
mature B cells. The germinal centre is thought to be the
source of many types of lymphoma, including diffuse
large B-cell lymphoma, follicular lymphoma, and
Burkitt’s lymphoma.14,16 During the germinal centre
reaction, centroblasts (rapidly dividing B cells with a non-
cleaved nucleus) in the dark zone of the germinal centre
expand rapidly in response to the surrounding antigen-
specific T cells and follicular dendritic cells bearing
antigen. Centroblasts periodically enter the germinal
centre light zone where they become centrocytes (non-
dividing B cells with a cleaved nucleus), which remove
antigen from follicular dendritic cells and present it to
T cells. Centrocytes can revert back to centroblasts, or
differentiate into memory B cells or plasma cells.14
During this germinal centre reaction, cells undergo two
distinct modifications to their DNA: class-switch
recombination, whereby the immunoglobulin heavy-
chain class might change from IgM to IgG, IgA, or IgE;
and somatic hypermutation, in which the variable
immunoglobulin (IgV) light chain mutates, thus
modifying the affinity of a population of B cells for a
particular antigen.14 These normal genetic modifications
are a mechanism by which DNA damage can lead to
lymphoma, and also allow the subtypes of lymphoma to
be divided into non-Hodgkin lymphomas with and
without IgV mutations.
Non-Hodgkin lymphomas without IgV mutations
consist of pregerminal centre-derived non-Hodgkin
lymphomas (eg, most cases of mantle-cell lymphoma)
and other tumours arising from B cells that, although
derived from the germinal centre, have not undergone
somatic hypermutation (applies to about a third of cases
of B-cell chronic lymphocytic leukaemia or small
lymphocytic lymphoma).17 Non-Hodgkin lymphomas
with IgV mutations that arise from germinal centre or
postgerminal-centre B cells include Burkitt’s lymphoma,
follicular lymphoma, lymphoplasmacytic lymphoma,
mucosa-associated lymphoid tissue lymphoma, and
diffuse large B-cell lymphoma.17
The developmental biology of peripheral T-cell lymph-
oma is less well understood, and most subtypes are not

Diseases
B-cell lymphomas
Precursor B cell Precursor B-cell lymphoblastic leukaemia or lymphoma
Mature B cell Chronic lymphocytic leukaemia/small lymphocytic lymphoma; lymphoplasmacytic lymphoma; splenic marginal-zone
lymphoma; extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal-zone
B-cell lymphoma; follicular lymphoma; mantle-cell lymphoma; diffuse large B-cell lymphoma; Burkitt’s lymphoma
B-cell proliferations of uncertain Lymphomatoid granulomatosis; post-transplantation lymphoproliferative disorders (polymorphic)
malignant potential
T-cell and NK-cell lymphomas
Precursor T cell Precursor T-cell lymphoblastic leukaemia or lymphoma
Extranodal mature T cell and NK cell Mycosis fungoides; cutaneous anaplastic large-cell lymphoma; extranodal NK-cell or T-cell lymphoma; enteropathy-type
lymphoma; hepatosplenic lymphoma; subcutaneous panniculitis-like lymphoma; primary cutaneous CD8-positive
lymphoma; primary cutaneous γ/δ T-cell lymphoma; primary cutaneous CD4-positive lymphoma
Nodal mature T cell and NK cell Peripheral T-cell lymphoma, not otherwise specified; angioimmunoblastic lymphoma; anaplastic large-cell ALK-positive
lymphoma; anaplastic large-cell ALK-negative lymphoma; adult T-cell leukaemia/lymphoma

NK=natural killer.

Table 1: Subtypes of non-Hodgkin lymphoma according to the 2008 WHO classification13

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 Seminar

the t(14;18) chromosomal translocation, which causes the

Alemtuzumab Rituximab juxtaposition of the BCL2 gene on chromosome 18 to the
(anti-CD52) (anti-CD20)
transcriptionally active immunoglobulin heavy-chain
region on chromosome 14. This translocation can be
Node
detected in 80–90% of cases, and upregulates BCL2,
Marginal/ Germinal
Bone mantle zone centre which increases the apoptotic threshold and prevents
marrow programmed cell death.14 A similar process occurs in
Burkitt’s lymphoma, which is characterised by the
dysregulation of MYC on chromosome 8, most often by
the juxtaposition of MYC with the immunoglobulin
A 90
Y-Ibritumomab
heavy locus on chromosome 14 via a t(8;14) translocation.
DLBCL
Precursor CLL/SLL MZL and MCL FL Tiuxetan In mantle-cell lymphoma, the cyclin-D1 region of
BCL (anti-CD20)
12I
chromosome 11 translocates to the same immunoglobulin
I-Tositumomab
Extranodal (anti-CD20) heavy locus on chromosome 14.
Ofatumumab tissue
(anti-CD20) Clinical presentation and staging
B
Clinical presentation is dependent on the site of involve-
ment, natural history of the lymphoma subtype, and
Precursor
TCL
presence or absence of B symptoms (weight loss >10%,
PTCL
night sweats, body temperature >38°C). Two-thirds of
ALCL
Node patients present with painless lymphadenopathy, which is
more often generalised than in Hodgkin’s lymphoma.19
Thymus Germinal Low-grade lymphomas typically present with peripheral
centre lymphadenopathy that can vary in size. The more aggres-
Brentuximab
vedotin sive lymphomas can cause fulminant symptoms and
(anti-CD30) signs needing prompt assessment and treatment.
In most solid tumours, advanced stage of disease often
correlates with poor prognosis, but this association is
Figure: Cellular origins and therapeutic targets of representative non-Hodgkin lymphomas not always noted with lymphoma. Non-Hodgkin lymph-
(A) B-cell and (B) T-cell. ALCL=anaplastic large-cell lymphoma (activated). BCL=B-cell lymphoma. CLL/SLL=chronic
oma is staged with the Ann Arbor classification system,
lymphocytic leukaemia/small lymphocytic lymphoma. DLBCL=diffuse large B-cell lymphoma. FL=follicular
lymphoma. MCL=mantle-cell lymphoma (pre-germinal centre). MZL=marginal-zone mucosa-associated lymphoid which was originally designed for Hodgkin’s lymphoma
tissue lymphoma (post-germinal centre). PTLC=peripheral T-cell lymphoma. TCL=T-cell lymphoma. Updated version in 1971 (table 2).20
of figure 1 from Evans’ and Hancock’s Seminar1 on non-Hodgkin lymphoma, published in The Lancet in 2003. CT is the standard means of disease assessment above
and below the diaphragm, replacing chest radiography,
associated with distinct genetic or biological changes. lymphangiography, and staging laparotomy. MRI is better
Nevertheless, angioimmunoblastic T-cell lymphoma bears than CT at detecting CNS and bone diseases.19,21 PET
a close relation to the follicular helper T cell of the scanning with 2-[18F]fluoro-2-deoxy-D-glucose (FDG), a
germinal centre, and the follicular variant of peripheral glucose analogue labelled with a positron emitter, is
T-cell lymphoma, not otherwise specified, shares a similar increasingly being used in the management of lymph-
phenotype, although this subtype differs genetically and omas. Different subtypes of non-Hodgkin lymphoma
clinically. Unlike B-cell lymphomas, recurring trans- exhibit varied avidity for FDG, with the most common
locations that activate specific oncogenes are unusual in subtypes (diffuse large B-cell, follicular, and mantle-cell
T-cell lymphomas, apart from the t(2;5) involving ALK lymphomas) believed to be routinely FDG avid, whereas
seen in anaplastic large cell lymphoma. However, gene extranodal marginal-zone, small lymphocytic, and T-cell
expression profiling of peripheral T-cell lymphomas has non-Hodgkin lymphomas are variably FDG avid.19,22,23 In
shown characteristic patterns of gene expression in the subgroups that are routinely avid, PET scanning detects
major subtypes, with the exception of peripheral T-cell disease with a sensitivity of 80% and a specificity of
lymphoma, not otherwise specified. Most nodal peripheral 90%.19,22,24,25 Pretreatment PET scans can result in upstag-
T-cell lymphomas seem to be related to effector T cells.18 ing; however, PET scans are most widely used to assess
Unlike most solid tumours, which typically have sub- response to therapy.
stantial genetic instability, lymphomas generally have a Any organ can be the primary site of non-Hodgkin
stable genome. Rather, chromosomal translocations, lymphoma. However, the gastrointestinal tract is the most
which typically occur in malignancies of the haemopoietic frequent extranodal site in non-Hodgkin lymphoma, and
system, are implicated.17 These translocations typically the stomach is the most frequently implicated part of the
result in the presence of a proto-oncogene in the gastrointestinal tract. Gastric lymphomas are usually
proximity of the chromosomal recombination sites. For mucosa-associated lymphoid tissue lymphomas, or
example, the genetic hallmark of follicular lymphoma is diffuse large B-cell lymphoma on a background of

850 www.thelancet.com Vol 380 September 1, 2012


mucosa-associated lymphoid tissue lymphoma. Endo-
scopic ultrasound might be used for part of the initial
staging. Lymphoma of the stomach often coexists with
lymphoma of the Waldeyer’s ring, so this association
should also be assessed in patients with gastrointestinal
involvement, and vice versa.26 Mantle-cell lymphomas are
associated with the colon in most cases when masked
biopsies are done, and occasionally present with lymph-
omatous polyposis.27 Non-Hodgkin lymphoma is the
most common testicular tumour in men older than
60 years. These testicular tumours are usually aggressive
B-cell tumours, and sites of other involvement include
the contralateral testis and the CNS.26
The International Prognostic Index (IPI) is the most
widely used prognostic model for patients with non-
Hodgkin lymphoma.28 First introduced for aggressive
non-Hodgkin lymphoma, clinical features indepen-
dently associated with survival were age (≤60 years vs
>60 years), lactate dehydrogenase concentration (normal
vs abnormal), Eastern Cooperative Oncology Group
performance status (<2 vs ≥2), Ann Arbor stage (I/II vs
III/IV), and number of extranodal sites implicated
(≤one vs >one). From this, four risk groups were
delineated: low risk (zero to one clinical feature), low-
intermediate risk (two features), high-intermediate risk
(three features), and high risk (four to five features).
When applied to 2031 patients, these risk groups had
5-year survivals of 73%, 51%, 43%, and 26%, respect-
ively.28 Age is a particularly important prognostic
marker, and has been repeatedly associated with poorer
outcomes.29,30 However, elderly patients who are able to
receive full-dose chemotherapy have survival rates
similar to their younger counterparts.29,31 Since the
advent of the anti-CD20 monoclonal antibody rituximab
(figure), the IPI has been revised for diffuse large B-cell
lymphoma.32 The IPI for this lymphoma is still to be
validated in large prospective trials, but it seems to be a
legitimate prognostic method since the introduction of
rituximab, although it does not identify patients with
low survival prospects.32
Biological heterogeneity within diffuse large B-cell
lymphoma is substantial, and gene expression profiling
has identified two broad subgroups: those of germinal
centre origin, known as germinal centre B cell-like
lymphomas (typically CD10+ and BCL6+); and those
arising from cells resembling activated B-cells (typically
IRF4/MUM1+/– and CD138+).33 This distinction has
clinical relevance, because the 5-year survival for the
germinal centre subgroup was 76% versus 16% for the
activated B-cell group.33 This distinction is still relevant in
the era of rituximab plus cyclophosphamide, vincristine,
doxorubicin, and prednisolone (R-CHOP). An assess-
ment of 153 patients given R-CHOP showed that both
subgroups showed increased survival compared with
historical controls treated with CHOP, but the germinal
centre subgroup had a 3-year overall survival of 86%
compared with 68% in the activated B-cell group.34
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Seminar
Definition
Principal stages
I Involvement of one lymph node or one extranodal organ or site (IE)
II Involvement of two or more lymph node regions on the same side of the diaphragm, or
localised involvement of an extranodal site or organ (IIE) and one or more lymph node regions
on the same side of the diaphragm
III Involvement of lymph node regions on both sides of the diaphragm, which might be
accompanied by localised involvement of an extranodal organ or site (IIIE) or spleen (IIIS) or
both (IIISE); the spleen is regarded as nodal
IV Diffuse or disseminated involvement of one or more distant extranodal organs with or without
associated lymph node involvement
Modifiers
A Absence of B symptoms (listed below)
B Temperature >38°C, night sweats, and weight loss of greater than 10% of bodyweight in the
6 months preceding admission are defined as systemic symptoms
Table 2: Ann Arbor staging system
The IPI is less useful in follicular lymphoma, because
fewer patients present with high-risk disease, thus
prompting the evolution of the Follicular Lymphoma
International Prognostic Index (FLIPI).35 Three of the
five prognostic variables are identical to those in the
IPI—namely, age, Ann Arbor stage, and serum lactate
dehydrogenase concentration. The two other prognostic
markers are haemoglobin concentration (<12 g/L vs
≥12 g/L) and number of nodal sites involved (>four vs
≤four). Patients are thus stratified into one of three
prognostic groups: low (zero to one variable), inter-
mediate (two variables), or high (three or more). These
groups have 10-year survivals of 71%, 51%, and 36%,
respectively.35 The FLIPI has yet to be prospectively
assessed in the rituximab era.
Treatment of B-cell lymphomas
Small B-cell lymphocytic lymphoma and chronic
lymphocytic leukaemia
Historically, small B-cell lymphocytic lymphoma and
chronic lymphocytic leukaemia were believed to be two
distinct diseases, but they are now considered to be
different clinical manifestations of the same disease.
This non-Hodgkin lymphoma is mainly a disease of
elderly people, with a median age of 72 years at diagnosis
of chronic lymphocytic leukaemia in the USA. The
clinical course of this disease often begins with asympto-
matic lymphocytosis, with about a quarter of patients
diagnosed after a routine blood count. Other common
presentations include painless lymphadenopathy and
hepatosplenomegaly. Several randomised trials have
compared the efficacy of chlorambucil with combination
chemotherapy including anthracycline-containing com-
binations, but no survival advantage with combination
treatment was noted.36,37 The purine analogues cladribine
and particularly fludarabine have activity against small
B-cell lymphocytic lymphoma and chronic lymphocytic
leukaemia.38–40 Findings from one large trial showed
an improvement in overall survival in patients with
851
 Seminar
previously untreated chronic lymphocytic leukaemia
given fludarabine, cyclophosphamide, and rituximab
compared with those given fludarabine and cyclophos-
phamide alone.41 Bendamustine is an alternative
first-line treatment option for patients for whom
fludarabine-containing regimens are not appropriate.
Three monoclonal antibody therapies have been ap-
proved for use in small B-cell lymphocytic lymphoma
and chronic lymphocytic leukaemia. Rituximab is one,
but it has shown lower response rates in this disease
than in other B-cell lymphomas.41–43 Alemtuzumab, an
anti-CD52 monoclonal antibody (figure) is approved in
the USA and Europe as third-line therapy for cases of
small B-cell lymphocytic lymphoma and chronic
lymphocytic leukaemia that are fludarabine refractory.44
In 2007, the US Food and Drug Administration (FDA)
also approved alemtuzumab for previously untreated
cases of this disease.45 Ofatumumab, a human mono-
clonal antibody to the CD20 protein, has FDA approval
and conditional approval in Europe for the treatment of
refractory chronic lymphocytic leukaemia.46 Radiotherapy
can be used to palliate symptoms of bulky lymphaden-
opathy in this lymphoma subtype.
Follicular lymphoma
Follicular lymphoma is the second most common lymph-
oma in the USA and western Europe, accounting for
about 20% of all non-Hodgkin lymphomas.47 The median
age at diagnosis is 60 years.48 Follicular lymphoma often
presents with painless peripheral lymphadenopathy,
which may increase and decrease in size. Staging investi-
gations usually identify disseminated disease, with
involvement of the spleen (in 40% of cases), liver (50%),
and bone marrow (60–70%).49 The clinical course can
vary—some patients might not need treatment for several
years, whereas others have massive nodal or organ
involvement needing intervention. Follicular lymphoma
has traditionally been graded between 1 and 3 according
to the proportion of centroblasts present. However, the
clinical significance of the division of grades 1 and 2 is
questionable, because clinical outcomes are similar. The
2008 WHO classification therefore combines cases with
few centroblasts as follicular lymphoma grade 1–2 (low
grade). Grade 3 is subdivided into 3A and 3B according to
whether sheets of centroblasts are present (3B). In clinical
practice, the ability to separate grades 3A and 3B is a
histological challenge. Many oncologists treat all patients
with grade 3 follicular lymphoma in a manner similar to
those with diffuse large B-cell lymphoma with R-CHOP.
However, this method is controversial, and others believe
that all patients with follicular lymphoma should be
treated in the same way irrespective of grade.
Historically, the median survival of patients presenting
with advanced stage follicular lymphoma was 10 years,
although since the inclusion of monoclonal antibody
treatment, survival seems to have increased.50,51 Histo-
logical transformation from follicular to a diffuse
852
aggressive lymphoma occurs in 10–70% of cases, and is
associated with a poor prognosis.49,52
Despite the fact that prognosis is measured in years,
follicular lymphoma is not usually curable with con-
ventional treatment. The exception is the few patients
who present with limited-stage disease (stage I or II),
who can be cured with radiotherapy, a few patients with
exceptional responses to initial chemotherapy regimens,
and some patients after autologous or allogeneic
haemopoietic stem-cell transplantation as second-line
therapy.53–55 When to begin treatment is a matter of
debate, with quality of life being a major determining
factor. No evidence suggests that immediate treatment of
asymptomatic patients improves their survival. Before
the introduction of rituximab, no therapy had been
shown to improve overall survival with advanced disease.
Some patients can be treated with rituximab alone. Other
treatment regimens include oral chlorambucil, fludara-
bine, or bendamustine; or combination chemotherapies
with cyclophosphamide, vincristine, and prednisolone;
or anthracycline-containing regimens such as CHOP. All
patients should receive rituximab as part of their initial
treatment for advanced stage follicular lymphoma, since
findings from phase 3 randomised controlled trials have
shown improved overall survival with the addition of this
agent to chemotherapy.56–58 Maintenance rituximab after
induction prolongs remission duration,59–61 and future
analysis will establish whether this prolonged remission
translates into improved overall survival. Radiolabelled
monoclonal antibodies are being tested as part of
initial treatment regimens for follicular lymphoma.
⁹⁰Y-ibritumomab tiuxetan combines an anti-CD20
monoclonal antibody and localised yttrium-90 radiation
(figure). Its use as consolidation therapy after initial
induction chemotherapy has been favourably compared
with induction chemotherapy alone.62 ¹³¹I-tositumomab
is approved for use in the USA.
No convincing data exist that support myeloablative
chemotherapy and autologous stem-cell transplantation
in follicular lymphoma in first remission.63,64 Palliative
radiotherapy might be useful in advanced disease, par-
ticularly to relieve pressure symptoms from a localised
mass, which might cause spinal cord or nerve root
compression, or other local symptoms.
Mantle-cell lymphoma
The median age at diagnosis of mantle-cell lymphoma
is 58 years. Most patients present with disseminated
lymphadenopathy, although gastrointestinal tract involve-
ment is common and mantle-cell lymphoma is the most
common lymphoma to cause lymphomatous polyposis.
Occasionally patients will present with only blood and
bone marrow involvement, which can be confused with
chronic lymphocytic leukaemia.
Although classified as indolent, mantle-cell lymphoma
has one of the poorest prognoses of the various subtypes
of lymphoma.65 Most patients are symptomatic and need
www.thelancet.com Vol 380 September 1, 2012

treatment at diagnosis, although a few are asymptomatic
and can be observed for a period without treatment.
Standard treatment is combination chemotherapy with or
without rituximab, and median overall survival is around
3 years. Studies assessing the addition of rituximab to
standard chemotherapy have shown significant improve-
ments in complete response rates and time-to-treatment
failure, but disappointingly this addition has not led to an
improvement in overall survival.66,67 Regimens incorp-
orating high-dose cytarabine might lead to improved
outcomes.68 Several studies have assessed the role of high-
dose chemotherapy and autologous stem-cell trans-
plantation in patients with mantle-cell lymphoma. The
extent of benefit varies between studies, and at present
autologous stem-cell transplantation should not be
regarded as curative for mantle-cell lymphoma, because
late relapses are recorded.65 For the rare, young patient
with an HLA-matched donor, allogeneic haemopoietic
stem-cell transplantation can be curative.
Marginal-zone lymphoma
Mucosa-associated lymphoid tissue lymphoma is the
third most common subtype of non-Hodgkin lymph-
oma. The most frequent site is the stomach, but these
extranodal marginal-zone lymphomas can involve
almost any organ. Helicobacter pylori infection is
implicated in the pathogenesis of gastric mucosa-
associated lymphoid tissue lymphoma, and remission
can be achieved with eradication of the bacteria in
many patients, although 30–40% of cases do not respond
to antibiotic therapy.69 Localised mucosa-associated
lymphoid tissue lymphomas at all sites can sometimes
be effectively treated with radiotherapy or surgery.
Patients with disseminated disease usually respond to
rituximab alone or chemotherapy regimens incor-
porating rituximab. Patients with widespread marginal-
zone lymphoma involving the lymph nodes and bone
marrow are usually diagnosed with nodal marginal-
zone lymphoma and treated in a similar manner to
patients with follicular lymphoma. A rare subtype,
splenic marginal-zone lymphoma, involves the spleen,
blood, and bone marrow. This subtype has traditionally
been treated in the past with splenectomy, but rituximab
also seems to be effective.
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma is the most common
subtype of non-Hodgkin lymphoma, representing about a
third of cases. There are many subtypes of diffuse large
B-cell lymphoma recognised in the WHO classification
(panel). Mediastinal diffuse large B-cell lymphoma presents
as a mediastinal mass and most often occurs in young
women. Plasmablastic diffuse large B-cell lymphoma is a
histological variant that is frequently detected in patients
with HIV infection, and involves the head and neck. This
subtype does not usually express CD20 and, thus, does not
benefit from treatment with rituximab.
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Seminar
Diffuse large B-cell lymphoma is localised in about 25%
of patients. Before 1980, radiotherapy was given to the
affected region alone, but several trials in the early 1980s
compared radiation alone with radiation plus combination
chemotherapy with cyclophosphamide, vincristine, and
prednisolone or CHOP.70,71 Findings from these trials
showed an improvement in overall survival for dual
modality therapy, which became the standard treat-
ment.70–72 These studies all took place in the prerituximab
era. The MabThera International Trial of 824 patients
from 18 countries assessed the addition of rituximab to
CHOP chemotherapy versus CHOP chemotherapy alone,
with radiotherapy allowed in both groups. Trial
participants were young with a good disease prognosis,
although not all had localised disease. Patients who
received R-CHOP had an improved 3-year overall survival
compared with those randomly assigned to CHOP (93%
[95% CI 90–95] vs 84% [80–88]; log rank p=0·0001).73
Disseminated disease is the most common presen-
tation of diffuse large B-cell lymphoma, and in the pre-
rituximab era more than a third of patients with this
form of the disease were cured with chemotherapy alone,
most by the CHOP regimen. Again, the most important
advance in treatment was the addition of rituximab to
chemotherapy. Findings from several randomised trials
have shown significant increases in overall survival in
patients who received rituximab plus chemotherapy.73,74
A retrospective study in British Columbia, Canada,
compared outcomes of 140 patients given CHOP-like
chemotherapy in the prerituximab era with outcomes of
152 patients treated in the rituximab era. The addition of
rituximab to CHOP-like chemotherapy improved overall
survival at 2 years from 52% to 78%.75 Data from the
Surveillence, Epidemiology, and End Results (SEER)
registry comparing survival in all patients with diffuse
large B-cell lymphoma from 1973–2004 show that survival
has substantially improved since the advent of rituximab;
median overall survival for 1973–79 was 15 months,
1980–89 was 18 months, 1990–99 was 20 months, and
2000–04 was 47 months.76 The use of rituximab with
increasingly intensive chemotherapy regimens looks
promising and is being assessed in randomised trials.
About 30–40% of patients will relapse after first-line
chemotherapy. Salvage chemotherapy regimens are used
in combination with rituximab, but rarely lead to
longlasting progression-free survival. These salvage
regimens are often used to achieve remission before the
use of high-dose chemotherapy and autologous stem-cell
transplantation. Because this subgroup includes a
heterogeneous mix of diseases with varied natural
histories, the future is likely to include different primary
treatment protocols according to risk of relapse.
Burkitt’s lymphoma
Burkitt’s lymphoma occurs endemically in parts of
Africa, and sporadically around the world. Nowadays,
most patients with Burkitt’s lymphoma can be cured, but
853
 Seminar
Panel: Variants of diffuse large B-cell lymphoma in the
2008 WHO classification13
• Centroblastic
• Immunoblastic
• Anaplastic
• Plasmablastic
• T-cell rich
• Anaplastic lymphoma kinase-positive
• CD5-positive
• Germinal centre B cell
• Non-germinal centre B cell
• Primary CNS
• Primary cutaneous, leg-type
• Mediastinal
• Intravascular
• Primary effusion
• Epstein-Barr virus-positive in elderly people
• With chronic inflammation
• Lymphomatoid granulomatosis
• In human herpes virus-8-associated Castleman’s disease
a shortage of access to health-care resources affects
outcomes in developing countries. Burkitt’s lymphoma
has a very high proliferation index, which makes prompt
diagnosis and initiation of therapy very important to
increase chances of survival. Principles of chemotherapy
delivery for Burkitt’s lymphoma include maintenance of
high dose intensity and the use of alternating non-
crossresistant regimens to prevent the emergence of
drug resistance. Patients are at risk of CNS relapse, and
the use of high-dose methotrexate and cytarabine has
helped to reduce this risk.77
Treatment of T-cell lymphomas and precursor
B-cell or T-cell lymphomas
Lymphomas of mature T cells are much less common
than their B-cell counterparts. A few cutaneous T-cell
lymphomas, including mycosis fungoides, cutaneous
anaplastic large-cell lymphoma, and lymphomatoid
papulosis, are indolent. Other lymphomas of mature
T cells (often referred to as peripheral T-cell lymphomas)
are aggressive disorders. Some subtypes present rare
but interesting clinical syndromes and others (eg, adult
T-cell lymphoma and nasal NK-cell or T-cell lymphoma)
are common in east Asia but rare in western Europe
and North America.78 We discuss three subtypes that
are frequently seen in Europe and America: peripheral
T-cell lymphoma, not otherwise specified; angio-
immunoblastic T-cell lymphoma; and anaplastic large-
cell lymphoma.
Peripheral T-cell lymphoma, not otherwise specified, is
the most common of the peripheral T-cell lymphomas
and is made up of a heterogeneous group of diseases that
are usually aggressive. These diseases often present in a
manner similar to that of diffuse large B-cell lymphoma,
854
and a diagnosis is established only when the haemato-
pathologist reviews the biopsy sample. Peripheral T-cell
lymphomas, not otherwise specified, most commonly
present as nodal disease in elderly people, but can be
extranodal. Combination chemotherapy can achieve
long-term survival in 12–45% of patients.79,80 These neo-
plasms are often refractory to anthracyclines.78
Angioimmunoblastic T-cell lymphoma is the second
largest group of peripheral T-cell lymphomas and usually
presents with generalised lymphadenopathy, hepato-
splenomegaly, skin rash, and constitutional symptoms in
elderly patients. This lymphoma, which seems to arise
from follicular helper T cells, often harbours Epstein-
Barr virus-infected B cells that can become monoclonal,
and occasionally patients develop diffuse large B-cell
lymphoma simultaneously. Combination chemotherapy
with anthracycline-containing regimens has led to long-
term survival in around a third of patients.81,82 Patients
with recurrent disease sometimes respond to immune
manipulations such as ciclosporin, and a few patients
seem to benefit from transplantation.
Anaplastic large-cell lymphoma was first described by
Stein and colleagues in 1985.83 Various subtypes have
subsequently been described, and overall it accounts for
3–8% of all lymphomas and 10–15% of all childhood
lymphomas.84 In North America, treatment is generally
the same as that used for diffuse large B-cell lymphoma,
whereas in Europe, treatment varies, with some centres
mirroring American practice, and others using chemo-
therapy protocols that are longer.85–87 All anaplastic large-
cell lymphomas are CD30 positive. A subset of these
lymphomas harbour the t(2;5) translocation and over-
express anaplastic lymphoma kinase (ALK). These
patients are usually younger and have excellent prognosis
with a greater than 50% cure rate. Patients with so-called
ALK-negative anaplastic large-cell lymphoma have a better
outlook than do those with other subtypes of peripheral
T-cell lymphoma, but fewer than half will be cured.88 The
FDA has approved the antibody–drug conjugate brentuxi-
mab vedotin for the treatment of anaplastic large-cell
lymphoma. This agent combines the anti-CD30 mono-
clonal antibody brentuximab and the antitubulin agent
monomethylauristatin E (vedotin)89 (figure).
Lymphoblastic lymphoma is a precursor B-cell or T-cell
lymphoma and the lymphomatous presentation of acute
lymphoblastic leukaemia. This rare subtype of lymphoma
is most often seen in children and young adults. Treatment
usually includes acute leukaemia-like regimens.90
Reassessment after treatment
PET scanning is more accurate than is CT scanning in
the reassessment of patients after completion of treat-
ment because it can distinguish between residual tumour
and necrosis or fibrosis. Residual masses after therapy—
which are not rare in retroperitoneal and mediastinal
lymphomas—are frequently negative on PET scan.
Guidelines suggest that these patients should be classed
www.thelancet.com Vol 380 September 1, 2012

as being in complete remission.91 Findings from
prospective studies have shown that PET correlates well
with patient outcome.92 PET has a positive predictive
value of around 85% in non-Hodgkin lymphoma.93–95
This value is higher than that for CT, which has a positive
predictive value in aggressive lymphoma of 40–50%.91
The negative predictive value of PET is about 85% across
studies.92–94 In practice, PET is a routine part of post-
treatment assessment of patients with potentially curable
lymphoma because further therapy is often needed if
disease is residual—ideally, 6–8 weeks should pass from
the completion of treatment to the PET scan to reduce
the risk of a false-positive result.96
Future challenges
The opportunities to improve the treatment for patients
with non-Hodgkin lymphoma are encouraging. Improved
use of PET might allow shortening of therapy for patients
with very sensitive lymphomas and changing or
intensification of treatment for those with more resistant
disease. As understanding of the molecules or pathways
that are targeted by both old and new drugs improves,
regimens for individual patients will become available. A
focus of research on T-cell lymphomas, similar to that
applied during the past few decades for B-cell lymphomas,
might yield similar advances. A review of non-Hodgkin
lymphomas in 2022 will probably describe at least as
much improvement as has been seen in the past decade.
Contributors
All authors took part in the review of published work, the writing and
editing of the review, figure creation, and reference selection.
Conflicts of interest
JOA has been a consultant for Ziopharm, Seattle Genetics, Eisai,
GlaxoSmithKline, Allos Therapeutics, Genentech, and Roche.
BWH was, until 2009, taking part in studies done or supported by
Seattle Genetics, Roche, and Genentech. KRS declares that she has no
conflicts of interest.
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