LYMPHOPROLIFERATIVE DISORDERS
Non-Hodgkin’s lymphoma
Lisa Lowry
David Linch
Abstract
Non-Hodgkin’s lymphoma (NHL) is the fifth most common cancer in the
UK, and represents a heterogeneous group of malignancies. This article
will give an overview of lymphoid neoplasms, concentrating on the com-
mon subtypes of diffuse large B-cell lymphoma (DLBCL) and follicular lym-
phoma (FL). Clinical outcomes in B-cell NHL have significantly improved in
the past decade, largely due to the availability of the monoclonal anti-
body, rituximab. However, some aggressive lymphomas, including many
T-cell disorders, still carry a poor prognosis.
Keywords aggressive; classification; epidemiology; indolent; lym-
phoma; management; prognosis
Introduction
The lymphomas form a group of neoplasms in which the ma-
lignant cells derive from lymphocytes, originating in the bone
marrow. Normally, B lymphocytes mature in the bone marrow,
whereas T-lymphocytes migrate to the thymus to undergo
maturation and selection. Following maturation, lymphocytes
enter the circulation, and congregate in lymphoid tissue. B and T-
cells differentiate further when they encounter antigen, forming
effector and memory lymphocytes. The other type of lympho-
cyte, natural killer (NK) cells, respond rapidly to ‘non-self’
invading pathogens without further differentiation, and also
contribute to adaptive immunity.
Maturation arrest can occur at different stages in lymphoid
development. When early progenitor B- or T-cells are involved,
the patient presents with acute lymphoblastic leukaemia (ALL) or
lymphoblastic lymphoma (see Acute leukaemia on pages 269e274
of this issue). The final stage in B-cell maturation following anti-
gen encounter leads to the production of memory cells and plasma
cells, the cancerous equivalent of which is myeloma (see Myeloma
and MGUS on pages 295e298 of this issue). The lymphomas are
malignancies in which the cell of origin lies between these ex-
tremes of maturation (Figure 1). Approximately 15% of lym-
phomas are termed Hodgkin’s lymphomas (HL), identified on
histopathological grounds. This was the first type of lymphoma to
be deemed curable in selected patients and today has such a good
prognosis in favourable risk groups that much attention is focused
Lisa Lowry MRCP FRCPath is Lymphoma Clinical Fellow at University Col-
lege London, UK. Competing interests: none declared.
David Linch FRCP FRCPath FMedSci is Head of Department of Haematology,
at the University College Hospital, Cancer Institute, London, UK.
Competing interests: none declared.
MEDICINE 41:5
What’s new?
C Increasing use of rituximab in B-cell lymphomas including NICE
approval for maintenance rituximab in first response
C New anti-CD20 antibodies, which may prove to be more
efficacious than rituximab
C New targeted therapies under evaluation, such as anti-CD30
antibodyedrug conjugate (brentuximab vedotin) in certain
T-cell lymphomas
C Emerging signalling inhibitors including Bruton’s tyrosine
kinase (BTK) inhibitors
on reducing late effects of therapy. All other lymphomas are
termed non-Hodgkin’s lymphomas (NHL). They represent a highly
heterogeneous group with around 40 entities recognized in the
most recent World Health Organization (WHO) classification
(Table 1), although a few common types predominate. The
epidemiology, management and prognosis of HL and NHL have
important differences and HL is covered separately (see Hodgkin
lymphoma on pages 290e294 of this issue).
Chronic lymphocytic leukaemia (CLL) and small lymphocytic
lymphoma (SLL) are analogous mature B-cell neoplasms with
involvement primarily of bone marrow and lymph nodes,
respectively. SLL is a type of NHL but will not be further dis-
cussed here as its management mirrors that of CLL, described in
detail on pages 275e281 of this issue. Similarly, lymphoblastic
lymphoma is a neoplasm of immature B- or T-cells analogous to
ALL (see Acute leukaemia on pages 269e274 of this issue).
Epidemiology and risk factors
Around 12,300 new NHL cases were identified in the UK in
2009,1 representing 4% of all cancers. NHL is the fifth most
common cancer in the UK (after breast, lung, colorectal and
prostate) although only the tenth most common cause of cancer
death, and is about six times more common than Hodgkin’s
lymphoma. The incidence increases in the elderly and appears to
have more than doubled in the past 30 years, probably as a result
of the increasing age of the population, the increase in immu-
nodeficiency states and better diagnosis and reporting. Most
subtypes have a male preponderance although follicular lym-
phoma (FL) is more common in females.
The risk of developing NHL is increased in congenital and
acquired immunodeficiency states, including human immuno-
deficiency virus (HIV) infection (approximately 80-fold increased
risk2), other immune disorders, such as rheumatoid arthritis, and
post-transplantation. A rare type of intestinal T-cell lymphoma is
strongly associated with coeliac disease, and strict adherence to a
gluten-free diet greatly reduces the risk.3
Various infectious agents have been associated with lym-
phoma, with chronic antigenic stimulation forming one step in
a multi-step carcinogenic process. A recent study estimates
that 4% of NHL cases in the UK are attributable to infection.4
EpsteineBarr virus (EBV) is associated with Burkitt’s lym-
phoma, prevalent in malarial areas of sub-Saharan Africa but
rare in developed countries, and is present in two-thirds of HIV-
related lymphomas.4 Hepatitis C virus (HCV) infection increases
282 Ó 2013 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS

associated lymphoid tissue (MALT) in the stomach; it is esti-

Frequencies of different lymphoid malignancies as mated that 3% of NHL cases in developed countries are due to
recorded in cancer registration data in England in 2010 infection with H. pylori.4
A variety of chemicals, including pesticides, herbicides and
ALL/CLL DLBCL fNHL hair dyes, have been implicated but not proven to have a role in
(19%) (27%) (11%) lymphoma. A small increased risk of NHL has been reported in
siblings of affected patients6 and in those with high body mass
index.7 In the majority of cases the cause is unknown.

Indolent and aggressive NHL

There are many different subtypes of NHL, but broadly speaking
they are clinically divided into indolent and aggressive types.
Indolent lymphomas often present insidiously, have a long nat-
ural history and have historically been controlled by relatively
modest chemotherapy. However, they are not usually curable
and tend to become more resistant to therapy over the course of
the illness, with progressively shorter durations of response to
Myeloma HL Other NHL TNHL
(20%) (8%) (12%) (3%) therapy. Aggressive lymphomas usually have a more rapid
symptom onset, and without therapy would lead to death fairly
Data derived from Release edition reference tables, Office for National quickly. However, many are curable with prompt chemotherapy.
Statistics. Indolent and aggressive lymphomas are also termed low-grade
and high-grade, respectively, based on histopathological ap-
Figure 1 pearances. Mantle cell lymphoma has features of both and is
sometimes regarded as intermediate in grade.
the risk of NHL 2.5-fold.5 Infection with human T-cell lymphoma
virus 1 (HTLV1) causes a rare type of NHL (ATLL), but only in a Presentation
small minority of chronic carriers.4 There is a strong association
between Helicobacter pylori and lymphomas of mucosa- The most common presenting symptom is painless lymph node
enlargement. Indolent lymphomas classically present with
widespread, slowly progressive lymphadenopathy with little in
the way of constitutional symptoms. Aggressive lymphomas
WHO classification with high-grade lymphomas in red typically present with rapidly enlarging lymph nodes and have
B-Cell neoplasms T-cell and NK-cell neoplasms a higher rate of constitutional (‘B’) symptoms (Table 2).
Aggressive lymphomas are more likely to present with extra-
Precursor B lymphoblastic Precursor T lymphoblastic nodal involvement. However, there is overlap between indo-
leukaemia/lymphoma leukaemia/lymphoma lent and aggressive presentations. The possible presenting
Small lymphocytic lymphoma Blastic NK cell lymphoma features are diverse as masses can arise in virtually any tissue
(chronic lymphocytic leukaemia) or organ.
Lymphoplasmacytic lymphoma Adult T-cell leukaemia/lymphoma
Splenic marginal-zone Extranodal NK/T-cell lymphoma,
lymphoma nasal type
Ann Arbor staging system and Cotswold modifications
Hairy cell leukaemia Enteropathy-type T-cell
for Hodgkin’s lymphoma
lymphoma
Extranodal marginal zone Hepatosplenic T-cell lymphoma Stage
lymphoma I Involvement of one lymph-node region or lymphoid structure
Nodal marginal zone lymphoma Subcutaneous panniculitis-like II Involvement of two or more lymph-node regions on the same
T-cell lymphoma side of the diaphragm
Follicular lymphoma Mycosis fungoides III Involvement of lymph nodes on both sides of the diaphragm
Mantle cell lymphoma Sezary syndrome IV Involvement of extranodal sites other than one contiguous
Diffuse large B-cell lymphoma Primary cutaneous anaplastic or proximal extranodal site
large cell lymphoma Modifying features
Mediastinal (thymic) large B-cell Peripheral T-cell lymphoma, A No symptoms
lymphoma unspecified B Fever
38 C, drenching night sweats, loss of
10% body
Intravascular large B-cell Angioimmunoblastic T-cell weight in previous 6 months
lymphoma lymphoma X Bulky disease (mediastinal mass >1/3 thoracic diameter;
Primary effusion lymphoma Anaplastic large cell lymphoma nodal mass >10 cm diameter)
Burkitt’s lymphoma/leukaemia E Involvement of one contiguous or proximal extranodal site

Table 1 Table 2

MEDICINE 41:5 283 Ó 2013 Elsevier Ltd. All rights reserved.

 LYMPHOPROLIFERATIVE DISORDERS
Investigation
Investigations are aimed at making an accurate diagnosis and
classification, excluding differential diagnoses, and subsequently
staging and assessment of other prognostic factors.
Diagnosis
The most important investigation is tissue biopsy and this should
be arranged as quickly as possible if high-grade lymphoma is
suspected as any delay in diagnosis and treatment might adversely
affect outcome. Corticosteroid therapy should be avoided before
biopsy, as rapid tumour degeneration may occur, making diag-
nosis difficult. Biopsies should be reported by a dedicated hae-
matopathologist and all new diagnoses should be reviewed at a
suitable multidisciplinary team meeting. It is of paramount
importance that the subtype of the lymphoma is established
accurately at diagnosis as the management aims, treatments
available and prognoses vary widely. To that end, where possible,
an entire lymph node should be excised to allow appreciation of
nodal architecture. A core biopsy may be adequate in many cases
but needle aspiration cannot be relied upon. If a choice of nodes is
available to biopsy, inguinal nodes should be avoided.
In addition to standard histopathological examination,
immunohistochemistry techniques are essential for accurate
classification. Some entities have specific chromosomal trans-
locations and cytogenetics may be useful. Clonality studies are
occasionally necessary to establish the presence of a malignant
clone. Kappa and lambda staining is used for B-cell malignancies,
which will be light-chain restricted. Gene rearrangement studies
may be necessary for T-cell malignancies.
Staging
The Ann Arbor staging system, originally developed for HL,
is also used routinely in adults with NHL (Table 2). Staging re-
quires computed tomography (CT) scanning of neck, chest,
abdomen and pelvis, together with bone marrow biopsy. Positron
emission tomography (PET) scanning is being used increasingly.
Cerebrospinal fluid (CSF) examination is required if there are
neurological signs or disease at specific sites (paranasal sinus,
epidural, testicular or breast); otherwise the chance of central
nervous system (CNS) involvement is relatively low. Manage-
ment and prognosis are affected by stage but, unlike many solid
organ malignancies, widespread disease at presentation does not
remove the chance of cure.
Prognostic factors
Defining groups with differing prognoses can help guide man-
agement decisions and provide useful information for the patient.
The international prognostic index (IPI) for aggressive lym-
phomas and the follicular lymphoma international prognostic
index (FLIPI) for FL were both devised in the pre-rituximab era
but their prognostic power has been revalidated in patients
treated with rituximab (Figure 2).
Other baseline investigations
In addition to tests required for diagnosis, accurate classification,
staging and prognostication, patients must be assessed for their
fitness to withstand chemotherapy. This involves clinical exam-
ination and assessment of cardiac, renal and hepatic function.
MEDICINE 41:5
Anthracycline-based chemotherapeutic regimens are the main-
stay of curative therapy in aggressive NHL. However, anthracy-
clines are cardiotoxic and those with poor baseline cardiac status
(ejection fraction less than 50%) are generally deemed unsuit-
able for such therapy.
Patients are also routinely tested for HIV, hepatitis B virus
(HBV) and HCV before the commencement of immunosuppres-
sive NHL treatment, which can exacerbate these conditions.
Treatment and prognosis
The aims of therapy are quite different in aggressive and indolent
lymphomas. In aggressive NHL, treatment is generally aimed at
cure unless patient co-morbidities (not age) prohibit the use
of effective therapies. Indolent lymphomas are generally not
considered curable; historically, fairly gentle chemotherapy was
employed to keep the disease at bay without unacceptable
adverse effects. Indeed, patients who are asymptomatic with no
concerning disease features at diagnosis are typically managed
expectantly (‘watch and wait’) until such a time as disease pro-
gression requires specific therapy. Choice of specific treatment
and prognosis are highly dependent on the type of lymphoma,
and are discussed below.
 Patient information. The diagnosis, treatment and prog-
nosis should be carefully explained, and written informa-
tion provided where possible. Patients should give
informed consent before anti-lymphoma therapy.
 Infections. During periods of neutropenia, care must be
taken to prevent (where possible) and aggressively treat
infections. Granulocyte colony-stimulating factor (GCSF)
may be used to hasten neutrophil recovery.
 Tumour lysis syndrome (TLS). Rapid cell death can lead to
severe metabolic disturbance (hyperkalaemia, hyper-
phosphataemia, hypocalcaemia), renal failure and death.
All patients should be adequately hydrated and treated
with allopurinol, at least for the first cycle of chemo-
therapy. Patients at very high risk (Burkitt’s lymphoma,
large tumour burden, re-existing renal disease) or in whom
there are signs of incipient TLS should receive rasburicase.
 Fertility issues. Men should be offered sperm banking.
Female patients may consider embryo or egg storage, or
ovarian cryopreservation, but such approaches involve
treatment delays that are likely to be unacceptable in
aggressive NHL.
Aggressive NHL
Diffuse large B-cell lymphoma (DLBCL)
DLBCL is the most common subtype, accounting for 50% of NHL
cases in recent registry statistics from England.8 It can present at
any site and more than half have extranodal involvement at the
time of diagnosis. The bone marrow is involved in approximately
15% of cases. The tumours are composed of large cells (nucleus
usually at least twice the size of that of a normal lymphocyte)
growing in a diffuse (i.e. non-follicular) pattern.
DLBCL is thought to derive from antigen driven B-cells, which
have completed immunoglobulin rearrangement. Many cytoge-
netic abnormalities have been reported, commonly affecting
BCL6 and cMYC (encoding transcription factors) and BCL-2
(encoding an anti-apoptotic factor). Even in the absence of a
284 Ó 2013 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS

Calculation and implication of prognostic score in aggressive lymphoma (IPI) and follicular lymphoma (FLIPI).

Revised international prognostic index (IPI)

for aggressive lymphomas Follicular lymphoma international prognostic index (FLIPI)

One point assigned to each of the following:

• Stage III or IV • Stage III or IV

• Age >60 • Age >60
• LDH above upper limit of normal • LDH above upper limit of normal
• >1 extranodal site involved • ≥5 lymph node areas involved
• WHO performance status ≥2 • Hb <12 g/dl

Number of factors present:

0 Very good risk 0 or 1 Low risk

1 or 2 Good risk 2 Intermediate risk
3 or more Poor risk 3 or more High risk

1.0 1.0
Very good
0.9 0.9
Freedom from treatment failure
0.8 Good 0.8

0.7 0.7
Survival (%)

0.6 0.6

0.5 0.5
Poor
0.4 0.4

0.3 0.3
1,2 RF
0.2 0.2 3 RF
4,5 RF
0.1 0.1
P < 0.001 P < 0.001
0.0 0.0
0 1 2 3 4 5 6 0 1 2 3 4

Time (years) Time (years)

Patients with diffuse large B cell lymphoma treated Patients with advanced stage follicular lymphoma
with the rituximab-containing R-CHOP up to 2005 treated up-front with R-CHOP

Originally published in Blood. Sehn LH et al. Revised international
prognostic index (R-IPI) is a better predictor of outcome than the standard
IPI for patients with diffuse large B cell lymphoma treated with R-CHOP.
Blood 2007; 109: 1857–61 © American Society of Hematology
LDH, lactate dehydrogenase; RF, risk factors; WHO, World Health Organization.
Originally published in Blood. Buske et al. The follicular lymphoma
international prognostic index (FLIPI) separates high-risk from intermediate-
or low-risk patients with advanced-stage follicular lymphoma treated
front-line with rituximab and the combination of cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment
outcome. Blood 2006; 108: 1504–08 © American Society of Hematology

Figure 2

discrete cytogenetic anomaly, aberrant expression of these genes
is frequently implicated in pathogenesis.
Treatment:
Immunochemotherapy e historically, CHOP chemotherapy
(cyclophosphamide, doxorubicin, vincristine, prednisolone,
administered every 21 days for six to eight cycles) has been the
standard of care since the 1970s9 and can usually be adminis-
tered on an outpatient basis. Improvements in response and
survival have been seen with the use of rituximab-containing
regimens (Figure 3),10,12 with R-CHOP now representing the
standard of care. Rituximab is a chimeric anti-CD20 human
monoclonal antibody. Importantly, it adds little to the toxicity of
the chemotherapy regimen, save for infusion-related reactions.
Current clinical trials are investigating the use of more intensive
therapy in patients with high IPI scores. However, a recent large
randomized trial comparing R-CHOP administered every 21 days
to the same regimen delivered every 14 days, did not demon-
strate any benefit to dose intensification, even in those with
adverse risk factors.11

MEDICINE 41:5 285 Ó 2013 Elsevier Ltd. All rights reserved.


Event-free survival among 399 patients assigned to
chemotherapy with CHOP alone or with CHOP plus
rituximab (elderly patients, all IPI groups)(10)
1.0
Probability of event-free survival
0.8
0.6
0.4
0.2 P < 0.001
0
0 0.5 1.0
Years after randomization
An update reported 5-year overall survival of 58% vs. 45%(12).
Figure reproduced from Coiffier B, et al. N Engl J Med 2002; 346: 235–42.
C 2002 Massachusetts Medical Society. Reprinted with permission.
Figure 3
CNS prophylaxis e CNS relapse is very difficult to treat and is
associated with a very poor prognosis. Overall, the incidence of
CNS relapse following chemotherapy is around 5%, with
increased risk associated with involvement of certain anatomical
sites (testis, breast, paranasal sinuses, epidural space), raised
lactate dehydrogenase (LDH) or involvement of more than one
extranodal site. Conventional chemotherapy does not effectively
cross the bloodebrain barrier (BBB). In high-risk patients, either
additional systemic drugs that do cross the BBB or small doses of
intrathecal cytarabine or methotrexate should be given.
Radiotherapy e these tumours are usually radiosensitive and
radiotherapy may be used in combination with chemotherapy or
alone to provide local control when treatment is not intended to
be curative.
Refractory/relapsed disease e there is still potential for cure
in primary refractory disease or at first relapse, if responsive to
salvage chemotherapy. Numerous regimens are in use (e.g.
R-ESHAP, R-IVE, R-DHAP, R-ICE, R-mini-BEAM) with no clear
evidence to support one over another. Those responding to
salvage chemotherapy should undergo stem cell mobilization
and collection before myelo-ablative chemotherapy with autol-
ogous stem cell rescue. Reduced-intensity allogeneic stem cell
transplantation may have a role in patients in whom stem cells
can not be harvested or in selected patients relapsing after an
autograft.
Burkitt’s lymphoma (BL)
BL accounts for around 3% of NHL. It is a highly aggressive
disease of children and young adults. There are three clinical
variants, which are particularly interesting in terms of epidemi-
ology and possible aetiology.
MEDICINE 41:5
LYMPHOPROLIFERATIVE DISORDERS
 Endemic BL e the original disease described by Denis
Burkitt,13 who identified a correlation between endemic
regions in equatorial Africa and climatic factors. This re-
gion corresponds to that with endemic malaria. The peak
incidence is between ages 4e7, and children typically
present with rapidly enlarging tumours of the jaw or other
facial bones. Most tumours are EBV-associated (EBV was
originally identified from a biopsy of Burkitt’s lymphoma
from Africa).
CHOP plus rituximab  Sporadic BL e uncommon, but occurs throughout the
world and accounts for a high proportion of childhood
lymphoma. The most common presentation is with an
abdominal mass, especially of the ileo-caecal region. As in
CHOP
endemic BL, other extranodal involvement is frequent,
especially ovaries, kidneys and breasts.
 HIV-associated BL e presentation with nodal disease and
marrow involvement is common.
All three subtypes are at risk from CNS disease. It is postulated
1.5 2.0 2.5 3.0 that HIV infection allows for chronic antigenic stimulation from
opportunistic infections, and defective T-cell regulation of EBV-
infected B-cells (although EBV infection is not essential). It is
thought that malaria infection plays a similar role in endemic BL.
Histopathology and genetics: histological sections show a
monotonous infiltrate of medium-sized cells, with occasional
benign macrophages ingesting apoptotic tumour cells, giving rise
to the classical ‘starry sky’ appearance. On touch imprint,
marrow aspirate or CSF samples, the cells can be seen to have
deeply basophilic cytoplasm with vacuolation. Tumour cells
have a very high proliferation rate (virtually 100% of cells are
positive for Ki-67). The MYC gene is deregulated by translocation
to the immunoglobulin heavy chain region (t(8; 14)), or less
commonly light-chain region (t(2; 8) or t(8; 22)).
Treatment and prognosis: historically, BL had a poor prognosis
with standard therapy. However, with the use of intensive in-
patient chemotherapy regimens the prognosis has improved
markedly.
T-cell NHL
Generally, T-cell lymphomas have a poorer prognosis than B-cell
lymphomas, although there are important differences between
subtypes. Cytological, immunophenotypic and molecular fea-
tures have so far been less useful at providing clinical and
prognostic information compared with B-cell lymphomas.
Peripheral T-cell lymphoma, unspecified e this is the most
common subtype, affecting mainly older adults. It is aggressive
and often presents with advanced stage. The prognosis is poor
with 5-year failure-free survival (FFS) and overall survival (OS)
of 20% and 32% respectively.14 Current regimens aim to inten-
sify therapy compared to CHOP, and strong consideration should
be given to high-dose therapy and an autograft in first CR.
Anaplastic large cell lymphoma (ALCL) e anaplastic lym-
phoma kinase (ALK) positive cases are common in children and
young adults and have a relatively good prognosis (70% 5-year
OS).14 The t(2; 5) translocation fuses the ALK gene with the
nucleophosmin (NPM) gene resulting in a fusion protein with
constitutive tyrosine kinase activity. ALK-negative ALCL is a
separate disease entity, being seen in an older age group and
286 Ó 2013 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS
having a worse prognosis with standard therapy (49% 5-year
OS). Brentuximab vedotin (an anti-CD30 monoclonal antibody
conjugated to a potent anti-tubule agent) has shown promise in
phase II trials of relapsed disease.15
Cutaneous T-cell lymphoma. This section encompasses a va-
riety of clinical and pathological entities. Staging is based on the
TNM (tumour, nodes, metastases) system. Broadly, disease
confined to the skin has a very good long-term prognosis and can
often be controlled with phototherapy, topical drug treatment or
radiation. Systemic therapies are used in more advanced disease.
Adult T-cell leukaemia/lymphoma (ATLL) e this is an aggres-
sive lymphoma with poor prognosis, associated with infection by
human T-cell lymphotrophic virus type 1 (HTLV1). Infection rates,
and ATLL, are high in Japan and the Caribbean. There is a long
latent period between infection and disease, and even after 30
years only about 4% of infected people will develop ATLL.
Enteropathy-type intestinal T-cell lymphoma. This is a rare
lymphoma, often but not exclusively developing on a back-
ground of overt clinical coeliac disease or histological villous
atrophy. It is aggressive, and patients should be considered for
intensive therapy.
Indolent NHL
Follicular lymphoma (FL)
FL is the most common indolent subtype, and the second most
common type overall, accounting for 20% of NHL.8 It is derived
from germinal centre B-cells (centrocytes) with a follicular
pattern and grading is based on the number of larger transformed
centroblasts (Table 3). Most cases exhibit the t(14; 18) trans-
location e over-expression of Bcl-2 results from the juxtaposition
of its gene with that of the immunoglobulin heavy chain
enhancer region.
The typical presentation is with painless, widespread lymph-
adenopathy, which may wax and wane and may have been
present for some time before the patient seeks medical attention.
The majority of patients present with advanced stage disease,
with bone marrow involvement in more than half, although
involvement of other organs at diagnosis is uncommon.
Treatment:
Limited disease e a minority present with stage I or contig-
uous stage II disease and cure may be attempted with radical
radiotherapy.
Grading of follicular lymphoma
Grade Centroblasts per
high power field
1e2 0e15 Low-grade follicular lymphoma (FL)
3A >15 Centrocytes present; histologically
higher-grade FL
3B >15 No centrocytes; sheets of
centroblasts e now classified as
diffuse large B-cell lymphoma
Table 3
MEDICINE 41:5
Watchful waiting e a significant proportion of patients are
asymptomatic at presentation, having been diagnosed incidentally
or following investigation of modest, untroublesome lymphade-
nopathy. In such patients there is no detriment to initial watchful
waiting compared to immediate standard chemotherapy.16 Ther-
apy is commenced when symptoms become troublesome or to
relieve organ impairment; the median treatment delay is around
2.5 years with a significant minority not requiring therapy by 10
years from diagnosis.16 Rituximab monotherapy as an alternative
to watchful waiting is being evaluated in clinical trials.
Immunochemotherapy for advanced disease e for those
requiring therapy, a range of therapeutic drugs is available, given
in combination with rituximab, including CVP (cyclophospha-
mide, vincristine, prednisolone), anthracycline-based therapy,
fludarabine and bendamustine. The pattern is usually of recur-
rent, but progressively shorter, responses. Before the availability
of rituximab the median survival from diagnosis was in the re-
gion of 8 years; rituximab is having a major impact on treatment
outcomes and this prognosis has undoubtedly lengthened.
Maintenance rituximab e in those responding to immu-
nochemotherapy, ongoing therapy with single-agent rituximab
administered once every 2 or 3 months can significantly delay
relapse and the need for further therapy. Rituximab has a very
favourable adverse effect profile so a period of maintenance
usually has low impact on quality of life. However, it is associ-
ated with a small increase in serious infections.
Ibritumomab tiuxetan (ZevalinÒ) e a radioimmunoconjugate
targeted to CD20 that is efficacious in consolidation of therapy
responses.
Stem cell transplantation e autologous transplantation in
remission has been used to good effect to delay relapse; its po-
sition relative to maintenance rituximab is currently not well
defined. Allogeneic transplantation historically carried an unac-
ceptable treatment-related mortality. The use of reduced-
intensity conditioning regimens has opened up this option for
those with sub-optimal response to immunochemotherapy.
Transformation e transformation to more aggressive NHL
subtypes (most commonly DLBCL) occurs at a rate of approxi-
mately 3% per year and carries a poor prognosis relative to de
novo aggressive lymphoma. FL grade 3b e should be regarded
and treated as DLBCL.
MALT lymphoma
Extranodal marginal-zone lymphoma of mucosa-associated
lymphoid tissue (MALT) lymphoma is associated with chronic
antigen stimulation from infective organisms, most commonly
gastric lymphoma associated with H. pylori infection. H. pylori
eradication alone results in regression of lymphoma in the ma-
jority of cases, with 5-year recurrence/progression free survival
around 80%.17 MALT lymphomas, like other B-cell lymphomas,
are usually sensitive to rituximab and chemotherapy is reserved
for a small proportion of patients who progress. Other, rarer sites
for MALT lymphoma include ocular adnexa (associated with
Chlamydia psittaci), small bowel (associated with Campylobacter
jejuni) and skin (associated with Borrelia burgdorferi).
Mantle cell lymphoma (MCL)
MCL, although often grouped with indolent lymphomas, has a
significantly worse 5-year overall survival at around 40%.18 It
287 Ó 2013 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS
typically presents with bulky advanced stage disease and bone
marrow involvement. Gastrointestinal tract involvement, either
symptomatic or occult, is very common. Histologically, the tu-
mours comprise a monomorphic infiltrate of small or medium-
sized cells with expanded mantle zones. The characteristic
immunophenotype includes cyclin D1 over-expression due to a
t(11; 14) translocation involving the cyclin D1 gene on chromo-
some 11 and the immunoglobulin heavy chain locus. Treatment
options are expanding; the addition of rituximab to multi-agent
chemotherapy improves outcomes somewhat,19 and agents
such as thalidomide, proteasome inhibitors and cyclin D1 in-
hibitors show promise. For those patients fit enough to undergo
intensive chemotherapy and stem cell transplantation (NORDIC
II protocol), overall survival greater than 10 years has been re-
ported with the hope that a proportion are being cured of their
disease.20
Special circumstances
 Elderly
Indolent lymphomas can often be managed very effectively in
the elderly, making greater use of radiotherapy and less toxic
drug therapies than may be employed in the younger age
group. For many, an indolent lymphoma diagnosed late in life
will not prove fatal due to the long natural history and
competing causes of death. Patients without significant co-
morbidities (particularly cardiac) can receive standard
R-CHOP chemotherapy for DLBCL with a reasonable chance
of cure. However, more aggressive regimens, such as those
employed in BL, are unlikely to be tolerated, even in the fit
elderly. For those without a curative option, palliative
chemotherapy and radiotherapy may extend life expectancy
as well as providing symptom control.
 Pregnancy
Chemotherapy and radiotherapy in the first trimester are
associated with increased risk of congenital malformations;
and this risk diminishes as pregnancy advances. In the large
majority of cases, when aggressive lymphoma is diagnosed
during the first trimester, treatment with a standard chemo-
therapy regimen following pregnancy termination should be
recommended. Beyond the first trimester, treatment with
R-CHOP may be appropriate although there are limited safety
data compared to ABVD, which is used in Hodgkin’s lym-
phoma. The degree of urgency in treating indolent lym-
phomas must be assessed on a case-by-case basis.
 HIV
DLBC NHL is over 100 times more common in HIV-positive
patients than in the general population. Prognosis depends
on IPI score and CD4 count, and has improved in the HAART
era, although not quite to the level of non-HIV infected pa-
tients. Burkitt’s lymphoma has an even greater increased
incidence in HIV-positive patients, and is not decreasing in the
HAART era. Patients should be strongly considered for
aggressive treatment, even when presenting very unwell, as
predicted outcomes are as good as for non-HIV infected
individuals.
 Primary CNS lymphoma
This is a rare condition (2.8 per million per year) but its
incidence has been increasing. It accounts for 5% of all brain
MEDICINE 41:5
tumours and approximately 20% of HIV-associated lym-
phomas. Survival has improved with the development of
combination chemotherapy regimens containing high-dose
methotrexate and cytarabine,21 but long-term neurotoxicity
remains a problem, particularly in the elderly.
 Post-transplant lymphoproliferative disease (PTLD)
This is a group of EBV-driven conditions resulting from iat-
rogenic immunosuppression. B-cell proliferation may be
polyclonal or monoclonal and there is clinical heterogeneity,
including very aggressive, rapidly growing forms. Some cases
will regress spontaneously with reduction of immunosup-
pression; others require specific treatment.
Summary and future directions
NHL is a highly heterogeneous group of malignancies with very
different prognoses and treatment aims between the indolent and
aggressive subtypes. Clinical outcomes in B-cell NHL have
markedly improved in the past decade due to the use of ritux-
imab; it is hoped that new anti-CD20 antibodies (such as ofatu-
mumab and obinutuzumab) will prove even more efficacious.
Novel therapies that hold promise include antibodies directed at
different targets. A
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Practice points
C Prompt biopsy of adequate material for diagnosis and accurate
classification is essential to guide optimum management
C Prognoses for most types of B-cell non-Hodgkin’s lymphoma
(NHL) have improved in the past decade and continue to show
promise for the future
C Patients suspected to have the most aggressive forms of NHL,
such as Burkitt’s lymphoma, should be admitted to hospital for
emergency diagnostic work-up and treatment
289 Ó 2013 Elsevier Ltd. All rights reserved.