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Non-Hodgkin lymphoma

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DOI: 10.1016/j.mpmed.2017.02.008

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 LYMPHOPROLIFERATIVE DISORDERS
Non-Hodgkin lymphoma
Slavisa Ninkovic
Jonathan Lambert
Abstract
Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the
UK and represents a heterogenous group of malignancies. This article
gives a brief overview of current classification of B and T cell NHL, the
increased understanding of molecular and cytogenetic abnormalities
associated with their pathogenesis, as well as current management
principles. Although advances in immuno-chemotherapy and support-
ive care have resulted in better patient outcomes, many challenges
remain, especially with relapsed and refractory disease. The recent
introduction of novel agents in the treatment of lymphoma has resulted
in some promising outcomes.
Keywords Aggressive; Classification; immuno-chemotherapy;
indolent; non-Hodgkin lymphoma; novel agents; prognosis
Introduction
Lymphomas are a heterogeneous group of malignancies arising
from lymphocytes. Over recent years, improved clinical, patho-
logical and molecular data have helped guide an evolution in the
classification of lymphomas that is reflected in the 2016 revision of
the World Health Organization (WHO) classification. This recog-
nizes >40 mature B cell neoplasms and >25 mature T and NK
(natural killer) cell neoplasms.1 Approximately 15% of lymphomas
are classified as Hodgkin lymphoma; the remainder are classed as
non-Hodgkin lymphoma (NHL) and are the focus of this review.
Common lymphoid progenitors, with both B and T cell po-
tential, originate in bone marrow; their site of initial maturation
varies according to their subtype. Early T cell progenitors migrate
to the thymus, where they undergo T cell receptor rearrangement
and a process of positive and negative selection to eliminate
autoreactive clones. B lymphocytes develop in bone marrow into
naive mature B lymphocytes, which migrate to secondary
lymphoid tissues such as the lymph nodes, mucosa-associated
lymphoid tissue (MALT) and spleen. Here, antigenic exposure
stimulates them to proliferate and differentiate into activated B
lymphocytes, which undergo somatic hypermutation of the
immunoglobulin genes and immunoglobulin class switching.
They can then terminally differentiate into plasma cells, which
secrete antibodies, or memory B cells, which are involved in
subsequent, secondary immune responses. NK cells are cytotoxic
Slavisa Ninkovic MB BS (Hons) FRACP FRCPA is Clinical Fellow in
Haematology at University College London Hospitals, London, UK.
Competing interests: none declared.
Jonathan Lambert BM BS PhD FRCP FRCPath is Consultant
Haematologist at University College London Hospitals and Mount
Vernon Cancer Centre, Department of Haematology, UCL Hospitals,
London, UK. Competing interests: JL has received speaker fees and
reimbursement of conference expenses from Roche and Gilead.
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Key points
C Non-Hodgkin lymphomas (NHLs) are a diverse group of ma-
lignancies arising from lymphocytes; they represent the sixth
most common cancer in the UK. There are >40 types of mature
B cell lymphoma and >25 types of mature T and natural killer
(NK) cell lymphomas
C B cell NHL can be broadly divided into low-grade (histologi-
cally indolent) and high-grade (histologically aggressive)
subtypes. Low-grade B cell NHL usually grow relatively slowly
and may not immediately need treatment. They follow a re-
lapsingeremitting course and are mostly incurable. High-grade
B cell NHL usually grow relatively quickly and can be rapidly
fatal if left untreated; with prompt treatment, however, they
are often curable
C T cell and NK cell NHL can be divided into peripheral (systemic)
and cutaneous subtypes. Most peripheral T cell and NK cell
NHL carry a poorer prognosis than B cell NHL
C Individuals with NHL typically present with painless, progres-
sive lymphadenopathy, sometimes accompanied by B symp-
toms (fevers, drenching night sweats, weight loss),
compressive symptoms and features of extranodal involve-
ment (hepatosplenomegaly, cytopenias, organ dysfunction)
C Diagnosis is usually made by excisional or core biopsy of an
enlarged lymph node. Fine needle aspiration is not suitable for
diagnostic purposes in NHL
C NHL are staged using the 2014 Lugano Modification of the Ann
Arbor system, based on cross-sectional body imaging, using
either contrast-enhanced CT or PET-CT. Bone marrow biopsy is
usually required in staging low-grade NHL and in some cases
of high-grade NHL
C In all cases, relevant clinical details, diagnostic pathology and
imaging should be reviewed in a multidisciplinary team
meeting
C Patient fitness for therapy should be evaluated before starting
treatment. Patients should also be considered for fertility
preservation
C Management may consist of watchful waiting, chemotherapy,
immunotherapy (e.g. rituximab), targeted agents (e.g. tyrosine
kinase inhibitors), radiotherapy and stem cell transplantation
lymphocytes that do not express T cell receptors; they primarily
serve to kill virally infected cells and tumour cells without further
differentiation.
Maturation arrest at any stage of lymphocyte development, or
the gain of a proliferative or anti-apoptotic abnormality, can lead
to a lymphoid neoplasm, whose precise phenotype depends on
the developmental stage at which the lymphocyte is affected. If
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 LYMPHOPROLIFERATIVE DISORDERS

arrest occurs at the early lymphocyte progenitor stage, acute

lymphoblastic leukaemia or lymphoblastic lymphoma can result; Modified 2016 WHO classification of B cell lymphoid
if intermediate stages are involved (mature lymphocytes), lym- neoplasms1
phoma can result; and if the terminal stages (plasma cells) are Indolent B cell NHL Aggressive B cell NHL
involved, myeloma can ensue.
Lymphoplasmacytic lymphoma, DLBCL NOS, DLBCL germinal
Epidemiology and risk factors Waldenstro€m’s centre B-type, and DLBCL
macroglobulinaemia activated B-cell type
In 2013, 13,413 new cases of NHL were diagnosed in the UK,
Splenic marginal zone Primary DLBCL of the central
making it the sixth most common cancer in men and seventh
lymphoma nervous system
most common in women.2 The incidence of NHL appears to have
Extranodal marginal zone Primary mediastinal (thymic)
increased by almost 18% over the last decade, at least partly
lymphoma of mucosa- large B cell lymphoma
because of a combination of an ageing population and better
associated lymphoid tissue High-grade B cell lymphoma,
reporting. Table 1 summarizes NHL incidence by subtype.
(MALT lymphoma) NOS
Most lymphomas have no single identifiable cause, although
Nodal marginal zone lymphoma Burkitt’s lymphoma
there are several well-defined associations, for example between
Helicobacter pylori infection and gastric MALT lymphoma; Follicular lymphoma Mantle cell lymphoma
EpsteineBarr virus (EBV) infection and Burkitt’s lymphoma Mantle cell lymphoma
(BL); human T-lymphotropic virus 1 and adult T cell leukaemia/ DLBCL, diffuse large B cell lymphoma; NOS, not otherwise specified.
lymphoma; and poorly-controlled coeliac disease and
enteropathy-associated T cell lymphoma. Immunodeficiency, Table 2
such as HIV and post-transplant immunosuppression, also con-
fers an increased risk of many lymphomas.
Presentation, diagnostic work-up and patient evaluation

Aggressive versus indolent NHL Presentation

NHLs can be divided into two main histological subgroups:
aggressive and indolent (often called high- and low-grade,
respectively). Aggressive lymphomas, if untreated, lead fairly
rapidly to death, but many cases are potentially curable with
prompt immuno-chemotherapy. In these patients, treatment is
therefore aimed at curing the disease, and can comprise relatively
intensive chemotherapy, sometimes causing significant short-term
toxicity. By contrast, indolent lymphomas are generally incurable:
although they are usually very responsive to initial therapy, they
follow a relapsingeremitting course, generally characterized by
increasing resistance to therapy and a shorter duration of response
with each successive treatment. Treatment of these patients aims
to control the disease in order to improve life expectancy and
symptoms, while minimizing adverse effects. Mantle cell lym-
phoma (MCL) often behaves aggressively but is usually incurable;
it is sometimes considered to be intermediate between aggressive
and indolent NHL (Table 2).
Indolent lymphomas usually present with widespread, slowly
progressive disease, generally without systemic symptoms. By
contrast, aggressive lymphomas typically present with rapidly
enlarging lymph nodes, often accompanied by B symptoms
(fever 38 C, drenching night sweats, 10% loss of body weight
in the previous 6 months) and extranodal involvement.
Diagnosis
Excisional tissue biopsy is the gold standard diagnostic investiga-
tion to facilitate examination of tissue microarchitecture, immu-
nohistochemistry, flow cytometry, fluorescence in situ
hybridization (FISH) studies and molecular studies. If patient co-
morbidities or site of disease precludes excisional biopsy, core bi-
opsy is acceptable. In this setting, multiple 10e15 mm tissue cores
should be assessed. Fine needle aspiration is not suitable for
diagnosis. Corticosteroid therapy can lead to rapid tumour degen-
eration and should if possible be avoided before biopsy. Diagnostic
samples should be reviewed by an experienced haematopatholo-
gist and discussed at a multidisciplinary team meeting.

Staging
UK incidence of NHL by subtype2 The Ann Arbor staging system has for many years been widely
used for staging patients with NHL It relies on aspects of the
NHL Annual Sex Age at 5-year Estimated
clinical history (presence or absence of B symptoms), bone
subtype rate/ (M:F) diagnosis relative number/year
marrow biopsy findings and the results of computed tomography
100,000 (years) survival (%) in UK
(CT) of the neck, chest, abdomen and pelvis, to guide manage-
DLBCL 8.4 1.3 69.9 56.7 4910 ment and predict outcome.
MCL 0.8 1.9 73.5 30.2 510 Positron emission tomography (PET) combined with CT using
18
FL 3.2 0.9 64.9 86.5 1890 F-fluorodeoxyglucose (FDG) as a tracer (PET-CT) has, howev-
Splenic 2.7 1.4 72.9 75.8 1580 er, been shown to be more sensitive than contrast-enhanced CT
MZL in many lymphoma subtypes, especially for extranodal disease.
Extranodal 0.7 1.0 68.5 86.4 430 In addition, the presence of B symptoms appears not to affect
MZL prognosis in NHL. To reflect these developments, the 2014
Lugano Classification proposes changes to the original Ann
Table 1 Arbor system (Table 3).3 For instance, PET-CT rather than

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 LYMPHOPROLIFERATIVE DISORDERS

conventional CT should be used for imaging patients with FDG-
avid lymphoma, the presence of B symptoms should not be
included in the staging of NHL, and bone marrow biopsy is not
always needed. It also emphasizes that Ann Arbor staging pri-
marily describes the anatomical extent of the disease and should
be evaluated alongside subtype-specific prognostic scores when
assessing prognosis or planning management.
In addition to these tests, magnetic resonance imaging and
cerebrospinal fluid examination (cytology, flow cytometry) are
essential for patients with clinical features of central nervous
system (CNS) involvement.
Patient evaluation
Additional investigations before starting immuno-chemotherapy
focus on assessing the patient’s fitness for treatment, both clin-
ically and using relevant investigations (e.g. echocardiography
before anthracycline use, pulmonary function testing before
bleomycin). Lymphoma can arise in patients with previously
undiagnosed HIV: prompt diagnosis and treatment of the HIV, as
well as the lymphoma, is crucial to achieving optimal outcomes.
Furthermore, reactivation of hepatitis B can occur in chronic
carriers after anti-lymphoma therapy. For this reason, it is
essential to screen for these viruses in all new cases of lym-
phoma. In addition, fertility preservation (sperm cryopreserva-
tion in men, egg/embryo cryopreservation in women) should be
considered before starting treatment.
Aggressive B cell NHL
Diffuse large B cell lymphoma (DLBCL)
DLBCL is the most common NHL subtype, accounting for 30
e40% of all cases. Complete remission is achieved in approxi-
mately 65e85% of patients following first-line immuno-
NHL staging of primary nodal lymphomas e the 2014
Lugano Classification3
Stage Involvement Extranodal status (E)
chemotherapy, of whom 20e30% relapse within 5 years of
treatment. Outcome can be predicted using the International
Prognostic Index (IPI; Table 4). More recently, gene expression
profiling identified two main DLBCL subtypes: germinal centre B
cell and activated B cell, the latter being associated with a worse
prognosis. The presence of ‘double-hit’ chromosomal rear-
rangements (involving the MYC (v-myc avian myelocytomatosis
viral oncogene homolog) gene and either BCL2 (BCL2, apoptosis
regulator) or BCL6 (B-cell CLL/lymphoma 6)) as detected by
FISH also confers a relatively poor prognosis.
Initial therapy: the mainstay of therapy in DLBCL is immuno-
chemotherapy, most commonly R-CHOP (cyclophosphamide,
doxorubicin, vincristine and prednisolone, plus rituximab, a
chimeric humanized anti-CD20 antibody), conventionally given
in 21-day cycles.4
Stage I and contiguous stage II disease e if the tumour is
amenable to radiotherapy and non-bulky, the standard of care is
three cycles of R-CHOP followed by 30 Gy of involved field
radiotherapy (IFRT), resulting in a 4-year progression-free sur-
vival (PFS) and overall survival (OS) of 88% and 92%,
respectively.
Stage II (non-contiguous)eIV disease e the standard of care is
6e8 cycles of R-CHOP followed by IFRT to sites of bulk and
extranodal disease on completion of immuno-chemotherapy.
More aggressive treatment regimens for patients with high-risk
(IPI score 3e5) disease include R-CHOEP-14 and the dose intense
R-CODOX-M/R-IVAC. Although these have not been directly
compared with R-CHOP in a randomized trial, these show
promising results.
CNS prophylaxis e CNS relapse is a rare but devastating form
of treatment failure, and the addition of up-front CNS prophy-
laxis (intrathecal methotrexate, intravenous high-dose metho-
trexate) is recommended in patients with high-risk features such
as a high lactate dehydrogenase (LDH) and 2 extranodal sites of
disease, or who have epidural, testicular, breast, renal or adrenal
involvement.5

Limited
I Single node or a group Single extranodal lesion DLBCL prognostic score e IPI
of adjacent nodes without nodal involvement
Parameter Adverse factors
II Two or more nodal groups Stage I or II by nodal
on the same side of the extent with limited Age >60
diaphragm contiguous extranodal Stage IIIeIV
involvement Eastern Cooperative Oncology 2
II bulkya II as above with bulky N/A Group performance status
disease Serum LDH > ULN
Advanced Number of nodal areas involved >1
III Nodes on both sides N/A
IPI score 5-year 5-year overall
of the diaphragm; nodes
progression-free survival (%)
above the diaphragm
survival (%)
with spleen involvement
IV Additional non-contiguous N/A 0e1 87 91
extralymphatic involvement 2 75 81
a
Whether stage II bulky disease is treated as limited or advanced disease 3 59 65
can be determined by histology and a number of prognostic factors. 4e5 56 59

Table 3 Table 4

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 LYMPHOPROLIFERATIVE DISORDERS
Relapsed and refractory disease: in patients who are sufficiently
fit, relapse is initially treated with salvage chemotherapy, such as
R-ESHAP, R-DHAP, R-IVE, and R-ICE. There is no evidence that
one is superior to the others. The novel regimen R-GDP has
recently been shown to be as effective as R-DHAP, and less toxic.
Responders should proceed to consolidation with high-dose
chemotherapy and autologous stem cell transplantation
(ASCT). Patients who fail first-line salvage have a very poor
prognosis (<10% 3-year survival), and should be considered for
novel therapies. Reduced-intensity allogeneic SCT (allo-SCT)
should be considered in patients who relapse after ASCT or fail to
mobilize autologous stem cells.
Other DLBCL subtypes: Primary mediastinal B cell lym-
phoma (PMBL) e PMBL accounts for <10% of DLBCL, is more
common in younger women and is biologically related to nodular
sclerosing Hodgkin lymphoma. Optimal treatment is currently
uncertain. R-CHOP therapy alone may be insufficient in some
patients, and consolidative radiotherapy is frequently offered to
patients in first remission following R-CHOP. Dose-adjusted
EPOCH plus rituximab, a more intensive regimen than R-
CHOP, can obviate the need for radiotherapy, although the two
have not been compared in a randomized study.
Primary DLBCL of the CNS (PCNSL) e PCNSL is rare, accounting
for 4% of intracranial malignancies; it carries a poorer prognosis
than other forms of aggressive lymphoma. Patients generally present
with neurological dysfunction and poor performance status.
Chemotherapy agents used to treat PCNSL must cross the blood
ebrain barrier: high-dose methotrexate and cytarabine therefore
constitute the backbone of most anti-PCNSL regimens, most recently
with the addition of rituximab and thiotepa (MATRIX).
Burkitt’s lymphoma
BL is a highly aggressive B cell lymphoma that is almost uni-
formly associated with translocations involving the MYC gene,
usually with the immunoglobulin heavy chain (t(8;14)). The
tumour cells have a very high proliferation rate (virtually 100%
of the tissue stains positively with the Ki67 monoclonal anti-
body), with a classic ‘starry sky’ histological appearance, repre-
senting macrophages ingesting apoptotic tumour cells.
The endemic form of BL is most common in equatorial Africa,
typically presenting as rapidly enlarging EBV-positive jaw or
facial bone tumours in children. In other parts of the world,
sporadic BL is more common than endemic BL. Patients can
present in extremis, with rapidly enlarging cervical lymphade-
nopathy, bowel obstruction caused by abdominal masses, or
spontaneous tumour lysis. They therefore require prompt diag-
nosis and treatment initiation. Very intensive regimens such as
R-CODOX-M/R-IVAC are the current gold standard, with gener-
ally good outcomes (3-year PFS 74%).
Indolent B cell NHL
Follicular lymphoma (FL)
FL is the most common indolent NHL in the UK and is charac-
terized by neoplastic proliferation of centrocytes and centroblasts:
the higher the proportion of centroblasts, the higher the grade
(range grade 1e3B) and the more aggressive the disease course
(Table 5). Grade 3B FL, characterized by solid sheets of centro-
blasts, clinically resembles DLBCL and is managed similarly.
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The development of FL usually depends on overexpression of
the anti-apoptotic protein BCL2 in the malignant cells, most often
resulting from the t(14;18) translocation. FL cells typically
harbour other genetic abnormalities, such as inactivating muta-
tions in the KMT2D (lysine methyltransferase 2D) gene (formerly
known as MLL2) and rearrangements of the BCL6 gene.
The typical presentation is with asymptomatic lymphadenopa-
thy, which can fluctuate in size over many years. Most patients
present with advanced stage (III, IV) disease, often with bone
marrow involvement. Prognostic scores including the Follicular
Lymphoma International Prognostic Index (FLIPI; derived in the
pre-rituximab era) and the FLIPI-2 (derived in the rituximab
chemotherapy era) are used to risk-stratify patients at diagnosis
(Table 5). Integrated clinicogenetic risk models such as m7-FLIPI
are undergoing prospective validation. The strongest prognostic
factor is duration of response following first-line chemo-immuno-
therapy: progression within 2 years of treatment is associated with
50% 5-year OS, compared with 90% in patients who progress later.
Localized (limited stage) FL: localized FL (stage I, contiguous
stage II) is uncommon, and should be confirmed using FDG-PET-
CT and bone marrow biopsy. IFRT to the site of disease usually
results in prolonged disease-free progression (10 years or more),
and is curative in some cases.
Advanced-stage FL: using the Groupe d’Etude des Lymphomes
Folliculaires (GELF) criteria (Table 5), patients with advanced-stage
FL can be divided into two main groups: asymptomatic with low
tumour burden, and symptomatic with high tumour burden.
Asymptomatic, low tumour burden FL e immediate treatment
with cytotoxic chemotherapy does not afford these patients any
survival benefit compared with watchful waiting. Similarly,
although up-front rituximab monotherapy typically delays the
need to start cytotoxic chemotherapy and can improve quality of
life compared with watchful waiting, it has no effect on OS. The
option of initial rituximab monotherapy should therefore be
discussed with asymptomatic patients, but many opt for watchful
waiting. If they do, the median interval between diagnosis and
needing chemotherapy is 31 months, and nearly 20% do not
need any chemotherapy for a decade after diagnosis.
Symptomatic, high tumour burden FL e these patients should
be offered therapy, usually with immuno-chemotherapy,
combining rituximab with various chemotherapy backbones,
including CVP (cyclophosphamide, vincristine, prednisolone),
CHOP and fludarabine. Latterly, bendamustine has entered
widespread clinical practice: a recent Phase III study demon-
strated that bendamustineerituximab therapy resulted in longer
median PFS (not reached versus 40.9 months) with less serious
toxicity (and no alopecia) than R-CHOP. There was no difference
in OS between the two groups. Continuing with maintenance
rituximab treatment for 2 years after initial R-CHOP improves PFS
but not OS, at the cost of a small increase in serious infections.
Relapsed and refractory disease e most patients with advanced
FL relapse after initial therapy. Patients with symptomatic or high
tumour burden disease at relapse should be offered treatment with
either a different first-line chemotherapy combination from that
originally used, or a salvage regimen (similar to DLBCL). Patients
who respond inadequately to conventional regimens should be
considered for treatment with new, targeted agents. These include
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 LYMPHOPROLIFERATIVE DISORDERS

Follicular lymphoma
WHO grading of FL
Grade Centroblasts per high-power field Interpretation

1e2 0e15 Low-grade FL

3A >15 Centrocytes present; histologically higher
grade FL
3B >15 No centrocytes; sheets of
centroblasts e classed as large cell lymphoma

FLIPI
Parameter Adverse factors

Age >60 years

Stage IIIeIV
Haemoglobin <120 g/litre
Serum LDH >Upper limit of normal
Number of nodal areas involved >4
Risk groups Number of adverse 5-year OS (%)
factors

Low 0e1 90.6

Intermediate 2 77.6
High 3 52.5

GELF criteria: presence of ‡1 is indicative of high tumour burden

C Any nodal or extranodal tumour mass >7 cm in diameter

C Involvement of at least >2 nodes, in three nodal sites, each >3 cm
C Presence of any systemic or B symptoms (Eastern Cooperative Oncology Group performance status >1)
C Symptomatic splenomegaly
C Organ compression
C Pleural or peritoneal serous effusion (irrespective of cell content)
C Serum LDH or b2-microglobulin concentration above normal

Table 5

novel anti-CD20 monoclonal antibodies (e.g. obinutuzumab),
immunomodulatory agents (e.g. lenalidomide) and small-
molecule inhibitors (e.g. ibrutinib, a Bruton’s tyrosine kinase in-
hibitor; venetoclax, a BCL2 inhibitor; idelalisib, a phosphoinosi-
tide 3 kinase inhibitor). For instance, patients refractory to both
rituximab and alkylating agents achieved a 57% response rate
following idelalisib therapy, with a median response duration of
12.5 months. Radio-immunotherapy (e.g. 90Y-ibritumomab) is
now rarely used.
If patients achieve remission after second-line or subsequent
therapy, stem cell transplantation should be considered in pa-
tients who are fit enough, typically with ASCT, which usually
prolongs PFS but is not generally considered curative. The role of
allo-SCT in this setting is still being defined, but this potentially
curative approach should be considered in patients with poor-
prognosis FL.
Transformed disease: rapidly enlarging lymph nodes, elevated
LDH and extra-nodal involvement raise the suspicion of
transformation to large cell lymphoma, a phenomenon seen in 2
e3% of FL patients per year. In this setting, histological confir-
mation should be sought and DLBCL-type therapy, often fol-
lowed by ASCT, offered to patients who are sufficiently fit.
Lymphoplasmacytic lymphoma and Waldenstro € m’s
macroglobulinaemia (WM)
Lymphoplasmacytic lymphoma is an indolent B cell neoplasm
composed of small lymphocytes, plasmacytoid lymphocytes and
plasma cells, typically involving the bone marrow. If, as is
common, there is associated IgM paraproteinaemia, the condi-
tion is termed WM. Somatic mutations of MYD88 (myeloid dif-
ferentiation primary response 88) and CXCR4 (C-X-C motif
chemokine receptor 4) are commonly present. WM primarily
affects older patients. Symptoms can be caused by tumour
infiltration (marrow, spleen, liver, lymph nodes), circulating IgM
paraprotein (hyperviscosity, cryoglobulinaemia, cold agglutinin
haemolytic disease) or tissue deposition of IgM paraprotein
(neuropathy, renal disease, amyloidosis).

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 LYMPHOPROLIFERATIVE DISORDERS
Asymptomatic patients can be observed. If therapy is neces-
sary, options include rituximab as monotherapy or combined
with corticosteroids and cytotoxic agents such as cyclophos-
phamide and bendamustine. Plasmapheresis is recommended for
patients with symptomatic hyperviscosity.
Marginal zone lymphoma
Marginal zone lymphoma (MZL) can be divided into three sub-
types: extranodal MZL or MALT, nodal MZL and splenic MZL.
MZLs often show an association with chronic antigenic stimu-
lation by microbial pathogens or autoantigens.
MALT lymphoma: MALT lymphomas are the most common
MZLs; 30e40% are gastric/intestinal in origin. Most gastric
MALT lymphomas are associated with H. pylori infection, and H.
pylori eradication therapy often induces a complete response;
however, the presence of t(11;18), seen in 20e30% of cases, is
associated with non-response to H. pylori eradication. Treatment
of advanced-stage disease is similar to treatment for FL. Non-
gastric MALT lymphomas most commonly involves the small
bowel, skin and ocular adnexae, which are associated with
Campylobacter jejuni, Borrelia burgdorferi and Chlamydia psit-
taci, respectively. They are generally indolent, and treatment
consists of radiotherapy, rituximab or chemotherapy.
Nodal MZL: Nodal MZL is uncommon (<10% of MZLs). Patients
usually present with widespread non-bulky nodal disease, a good
performance status, no B symptoms, and bone marrow
involvement in one-third of patients. Hepatitis C infection is
present in 25% of cases. Therapy resembles that for FL.
Splenic MZL: splenic MZL is very rare and typically presents
with symptomatic splenomegaly. It is characterized by the
presence of villous lymphocytes in the peripheral blood and/or
bone marrow. First-line therapy includes rituximab monotherapy
or splenectomy while some patients respond to hepatitis C virus
eradication alone.
Mantle cell lymphoma
MCL accounts for 6% of NHLs, with a median age at presentation
of 60e70 years, and a marked male predominance. Stage III/IV
disease with extranodal involvement (especially bone marrow
and bowel) is typical at presentation. The molecular hallmark is
t(11;14), leading to constitutive overexpression of cyclin D1.
Presentation with isolated bone marrow or splenic involve-
ment is associated with a relatively indolent disease course.
These patients, and those with asymptomatic small-volume
nodal disease, can initially be observed, but most patients need
treatment soon after diagnosis. Overall, MCL has a significantly
worse prognosis than other indolent lymphomas.
Initial treatment: if sufficiently fit, patients should be offered
intensive treatment containing high-dose cytarabine (HDAC), such
as the Nordic Lymphoma Group MCL2 regimen (R-maxi-CHOP
alternating with HDAC) followed by high-dose chemotherapy and
ASCT. Less fit patients can be offered rituximab with
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bendamustine or CHOP. Maintenance rituximab prolongs duration
of response and OS after rituximab-based chemotherapy.
Relapsed disease: almost all patients with MCL relapse after
initial treatment. Conventional immuno-chemotherapy typically
results in short second and subsequent remissions. Novel agents
including bortezomib, lenalidomide and ibrutinib show more
promise, either as monotherapy, with overall response rates
ranging from 22% to 68%, or in combination with one another;
they can offer a ‘bridge to transplant’ in suitable patients.
T cell non-Hodgkin lymphoma
T cell lymphomas account for approximately 15% of all NHL.
There are 28 different established and provisional mature T cell/
NK cell entities in the 2016 WHO classification of lymphoid
neoplasms, broadly subdivided into two groups: peripheral
(PTCL) and cutaneous (CTCL).1 PTCLs are primarily a systemic
disease but can sometimes present with, or evolve to, skin
involvement. CTCLs initially present with skin involvement and
can progress to systemic disease. Making the diagnosis of a T cell
lymphoma is often not straightforward, so a histopathology re-
view by an experienced haematopathologist is critical.
Peripheral T cell lymphoma
The three most common subtypes of PTCL are angioimmunoblastic
T cell lymphoma, anaplastic large cell lymphoma, and PTCL not
otherwise specified. The prognosis for most patients with PTCL is
poor (5-year OS 32e49%), with the exception of patients with
anaplastic large cell lymphoma expressing anaplastic lymphoma
kinase, whose median 5-year OS approaches 70%.
Initial treatment for PTCL is usually with CHOP-based
chemotherapy. Addition of etoposide and alemtuzumab (an
anti-CD52 antibody) to CHOP seems not to significantly enhance
OS. Patients who are sufficiently fit and achieve remission
following initial therapy should be offered consolidation with
high-dose chemotherapy and ASCT.
Treatment of relapse is challenging, and patients should be
considered for clinical trials of novel agents including the histone
deacetylase inhibitors romidepsin and belinostat, and the antime-
tabolite pralatrexate. Brentuximab vedotin, a monoclonal anti-CD30
antibody conjugated to a potent anti-tubule agent, has proven
particularly effective for treating relapsed CD30-positive PTCL.
Cutaneous T cell lymphoma
Mycosis fungoides is the most common type of CTCL. It has a
generally indolent course and little progression for several years
or decades. Because of its heterogeneous presentation, ranging
from patches and plaques to fungating tumours, the diagnosis is
often significantly delayed. The leukaemic variant of CTCL,
Sezary syndrome, is characterized by rapid progression and a
median survival of <3 years. It can present with erythroderma,
recurrent opportunistic infections, generalized lymphadenopathy
and circulating tumour cells.
Treatment choices depend on stage of disease, with skin-
directed therapy (e.g. topical corticosteroids, topical
302 Ó 2017 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS
chemotherapy) alone or in combination, with phototherapy or
radiotherapy for localized disease. Those with recalcitrant early-
stage or advanced disease usually require the addition of sys-
temic chemotherapy, transplantation or extracorporeal
photopheresis.
Special circumstances
Older patients e chemotherapy in older, frail patients and those
with co-morbidities can produce excessive adverse effects, and
such patients should be carefully evaluated before treatment.
Specialist input to optimize cardiorespiratory function, adminis-
tering corticosteroids before chemotherapy to improve perfor-
mance status, growth factor support to minimize neutropenia, and
consideration of dose reduction (e.g. R-mini-CHOP) or targeted
therapies are options to deliver effective treatment in this age group.
HIV e HIV infection increases the risk of developing lym-
phoma. Effective anti-HIV treatment in addition to standard
immuno-chemotherapy (e.g. R-CHOP in DLBCL) results in sur-
vival rates comparable to those of HIV-negative patients.
Pregnancy e chemotherapy and radiotherapy should be
avoided in the first trimester because of the high risk of
congenital malformations. If urgent treatment is required,
termination of pregnancy should be advised first. After the first
trimester, there is limited evidence suggesting that R-CHOP can
be given safely, with specialist supervision, or treatment can be
TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.
Question 1
A 34-year-old woman presented with a painless lump in the neck
that was slowly enlarging. She had no other symptoms.
Clinical examination showed cervical lymphadenopathy.
Investigations
Excisional biopsy of the node showed follicular lymphoma.
Which of the following is the most appropriate next
investigation?
A. CT of her neck and chest, and lumbar puncture
B. Whole-body PET-CT and bone marrow biopsy
C. CT of her neck, chest, abdomen and pelvis
D. Echocardiogram and lung function studies
E. Whole-body PET-CT and lumbar puncture
Question 2
A 65-year-old man was treated for relapsed diffuse large B cell
lymphoma (DLBCL). He had originally received six cycles of
induction treatment (R-CHOP chemotherapy) for stage IIIA
DLBCL, going into complete remission. Two years later, he
relapsed with biopsy-proven DLBCL and received two cycles of
second-line treatment (GDP chemotherapy). Following this
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delayed until after the baby has been born if the mother’s con-
dition is stable. Breastfeeding should be avoided while the
mother is receiving chemotherapy. A
KEY REFERENCES
1 Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the
World Health Organization classification of lymphoid neoplasms.
Blood 2016; 127: 2375e90.
2 Patmore R, Roman E, Smith A, Apleton S, Bagguley T, Blase  J.
Patient’s age and treatment for haematological malignancy: a
report from the Haematological Malignancy Research Network.
York: Leukaemia and Lymphoma Research & Association of the
British Pharmaceutical Industry, 2014.
3 Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for
initial evaluation, staging, and response assessment of Hodgkin
and non-Hodgkin lymphoma: the Lugano classification. J Clin
Oncol 2014; 32: 3059e68.
4 Chaganti S, Illidge T, Barrinton S, et al. British Committee for
Standards in Haematology. Guidelines for the management of
diffuse large B-cell lymphoma. Br J Haematol 2016; 174: 43e56.
5 National Institute for Health and Care Excellence. Clinical guide-
lines, non-Hodgkin’s lymphoma: diagnosis and management.
London: NICE, 2016.
chemotherapy, he was generally well, with a performance score
of 0, and had no co-morbidities.
Investigations
A PET-CT after the GDP chemotherapy scan confirmed he was in
complete remission.
Which of the following was the most appropriate next step in
his management?
A. Rituximab maintenance therapy every 2 months for 2 years
B. Watchful waiting
C. Autologous stem cell transplantation
D. Unrelated donor search followed by allogeneic stem cell
transplantation
E. Consolidation radiotherapy to the original site of disease
Question 3
A 73-year-old man presented with night sweats and swelling of
the abdomen. He had a history of exertional angina and well-
controlled type 2 diabetes, but was independent and had a per-
formance score of 1.
On clinical examination, there was a palpable abdominal mass
and ascites. He was found to have a stage 4B mantle cell
lymphoma.
303 Ó 2017 Elsevier Ltd. All rights reserved.
 LYMPHOPROLIFERATIVE DISORDERS

What is the most appropriate option and advice to recommend C. Immuno-chemotherapy followed by autologous stem cell
at this stage? transplantation, with curative intent
A. Immuno-chemotherapy, with curative intent D. Radiotherapy, with palliative intent
B. Immuno-chemotherapy to induce a response, but unlikely E. Corticosteroids, with palliative intent
to be curative

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