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Non-Hodgkin's lymphoma
LYMPHOPROLIFERATIVE DISORDERS
Non-Hodgkin’s lymphoma
What’s new?
Lisa Lowry C
David Linch C
C
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 common subtypes of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Clinical outcomes in B-cell NHL have significantly improved in the past decade, largely due to the availability of the monoclonal antibody, rituximab. However, some aggressive lymphomas, including many T-cell disorders, still carry a poor prognosis.
C
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 discussed 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).
Keywords aggressive; classification; epidemiology; indolent; lymphoma; management; prognosis
Introduction The lymphomas form a group of neoplasms in which the malignant 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 Tcells differentiate further when they encounter antigen, forming effector and memory lymphocytes. The other type of lymphocyte, 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 antigen 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 extremes of maturation (Figure 1). Approximately 15% of lymphomas 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
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 immunodeficiency states and better diagnosis and reporting. Most subtypes have a male preponderance although follicular lymphoma (FL) is more common in females. The risk of developing NHL is increased in congenital and acquired immunodeficiency states, including human immunodeficiency 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 lymphoma, 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 lymphoma, prevalent in malarial areas of sub-Saharan Africa but rare in developed countries, and is present in two-thirds of HIVrelated lymphomas.4 Hepatitis C virus (HCV) infection increases
Lisa Lowry MRCP FRCPath is Lymphoma Clinical Fellow at University College 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.
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Increasing use of rituximab in B-cell lymphomas including NICE approval for maintenance rituximab in first response New anti-CD20 antibodies, which may prove to be more efficacious than rituximab New targeted therapies under evaluation, such as anti-CD30 antibodyedrug conjugate (brentuximab vedotin) in certain T-cell lymphomas Emerging signalling inhibitors including Bruton’s tyrosine kinase (BTK) inhibitors
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associated lymphoid tissue (MALT) in the stomach; it is estimated that 3% of NHL cases in developed countries are due to infection with H. pylori.4 A variety of chemicals, including pesticides, herbicides and hair dyes, have been implicated but not proven to have a role in 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.
Frequencies of different lymphoid malignancies as recorded in cancer registration data in England in 2010 ALL/CLL (19%)
DLBCL (27%)
fNHL (11%)
Indolent and aggressive NHL
Myeloma (20%)
HL (8%)
Other NHL (12%)
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 natural 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 therapy. Aggressive lymphomas usually have a more rapid symptom onset, and without therapy would lead to death fairly quickly. However, many are curable with prompt chemotherapy. Indolent and aggressive lymphomas are also termed low-grade and high-grade, respectively, based on histopathological appearances. Mantle cell lymphoma has features of both and is sometimes regarded as intermediate in grade.
TNHL (3%)
Data derived from Release edition reference tables, Office for National Statistics.
Figure 1
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 small minority of chronic carriers.4 There is a strong association between Helicobacter pylori and lymphomas of mucosa-
Presentation 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 typically present with rapidly enlarging lymph nodes and have a higher rate of constitutional (‘B’) symptoms (Table 2). Aggressive lymphomas are more likely to present with extranodal involvement. However, there is overlap between indolent and aggressive presentations. The possible presenting features are diverse as masses can arise in virtually any tissue or organ.
WHO classification with high-grade lymphomas in red B-Cell neoplasms
T-cell and NK-cell neoplasms
Precursor B lymphoblastic leukaemia/lymphoma Small lymphocytic lymphoma (chronic lymphocytic leukaemia) Lymphoplasmacytic lymphoma Splenic marginal-zone lymphoma Hairy cell leukaemia
Precursor T lymphoblastic leukaemia/lymphoma Blastic NK cell lymphoma Adult T-cell leukaemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma
Ann Arbor staging system and Cotswold modifications for Hodgkin’s lymphoma Stage I Involvement of one lymph-node region or lymphoid structure II Involvement of two or more lymph-node regions on the same side of the diaphragm III Involvement of lymph nodes on both sides of the diaphragm IV Involvement of extranodal sites other than one contiguous or proximal extranodal site Modifying features A No symptoms B Fever 38 C, drenching night sweats, loss of 10% body weight in previous 6 months X Bulky disease (mediastinal mass >1/3 thoracic diameter; nodal mass >10 cm diameter) E Involvement of one contiguous or proximal extranodal site
Extranodal marginal zone lymphoma Nodal marginal zone lymphoma Subcutaneous panniculitis-like T-cell lymphoma Follicular lymphoma Mycosis fungoides Mantle cell lymphoma Sezary syndrome Diffuse large B-cell lymphoma Primary cutaneous anaplastic large cell lymphoma Mediastinal (thymic) large B-cell Peripheral T-cell lymphoma, lymphoma unspecified Intravascular large B-cell Angioimmunoblastic T-cell lymphoma lymphoma Primary effusion lymphoma Anaplastic large cell lymphoma Burkitt’s lymphoma/leukaemia
Table 2
Table 1
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Investigation
Anthracycline-based chemotherapeutic regimens are the mainstay of curative therapy in aggressive NHL. However, anthracyclines are cardiotoxic and those with poor baseline cardiac status (ejection fraction less than 50%) are generally deemed unsuitable for such therapy. Patients are also routinely tested for HIV, hepatitis B virus (HBV) and HCV before the commencement of immunosuppressive NHL treatment, which can exacerbate these conditions.
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 diagnosis difficult. Biopsies should be reported by a dedicated haematopathologist 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 translocations 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.
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 progression 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 prognosis should be carefully explained, and written information 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, hyperphosphataemia, hypocalcaemia), renal failure and death. All patients should be adequately hydrated and treated with allopurinol, at least for the first cycle of chemotherapy. 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.
Staging The Ann Arbor staging system, originally developed for HL, is also used routinely in adults with NHL (Table 2). Staging requires 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. Management and prognosis are affected by stage but, unlike many solid organ malignancies, widespread disease at presentation does not remove the chance of cure.
Aggressive NHL
Prognostic factors Defining groups with differing prognoses can help guide management decisions and provide useful information for the patient. The international prognostic index (IPI) for aggressive lymphomas 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).
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 cytogenetic 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
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 examination and assessment of cardiac, renal and hepatic function.
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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 • Age >60 • LDH above upper limit of normal • >1 extranodal site involved • WHO performance status ≥2
• Stage III or IV • Age >60 • LDH above upper limit of normal • ≥5 lymph node areas involved • Hb <12 g/dl Number of factors present:
0 1 or 2 3 or more
Very good risk Good risk Poor risk
0 or 1 2 3 or more
1.0
Low risk Intermediate risk High risk
1.0
Very good 0.9
Freedom from treatment failure
0.9
Good
0.8
Survival (%)
0.7 0.6 0.5
Poor
0.4 0.3 0.2 0.1 0.0
0.8 0.7 0.6 0.5 0.4 0.3
1,2 RF 3 RF 4,5 RF
0.2 0.1
P < 0.001 0
1
P < 0.001
0.0 2
3
4
5
6
0
Time (years)
1
2
3
4
Time (years)
Patients with diffuse large B cell lymphoma treated with the rituximab-containing R-CHOP up to 2005
Patients with advanced stage follicular lymphoma 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
Originally published in Blood. Buske et al. The follicular lymphoma international prognostic index (FLIPI) separates high-risk from intermediateor 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
LDH, lactate dehydrogenase; RF, risk factors; WHO, World Health Organization.
Figure 2
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 demonstrate any benefit to dose intensification, even in those with adverse risk factors.11
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 administered on an outpatient basis. Improvements in response and survival have been seen with the use of rituximab-containing
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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 region 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). 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 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 that HIV infection allows for chronic antigenic stimulation from opportunistic infections, and defective T-cell regulation of EBVinfected B-cells (although EBV infection is not essential). It is thought that malaria infection plays a similar role in endemic BL.
Event-free survival among 399 patients assigned to chemotherapy with CHOP alone or with CHOP plus rituximab (elderly patients, all IPI groups)(10)
Probability of event-free survival
1.0
0.8
CHOP plus rituximab 0.6
0.4
CHOP P < 0.001
0.2
0
0
0.5
1.0
1.5
2.0
2.5
3.0
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.
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)).
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 autologous 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.
Treatment and prognosis: historically, BL had a poor prognosis with standard therapy. However, with the use of intensive inpatient 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 features 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 intensify 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 lymphoma 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
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 epidemiology and possible aetiology.
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Watchful waiting e a significant proportion of patients are asymptomatic at presentation, having been diagnosed incidentally or following investigation of modest, untroublesome lymphadenopathy. In such patients there is no detriment to initial watchful waiting compared to immediate standard chemotherapy.16 Therapy 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 (cyclophosphamide, vincristine, prednisolone), anthracycline-based therapy, fludarabine and bendamustine. The pattern is usually of recurrent, but progressively shorter, responses. Before the availability of rituximab the median survival from diagnosis was in the region 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 immunochemotherapy, 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 associated 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 position relative to maintenance rituximab is currently not well defined. Allogeneic transplantation historically carried an unacceptable treatment-related mortality. The use of reducedintensity 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 approximately 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.
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 variety 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 aggressive 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 background 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) translocation 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 lymphadenopathy, 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 contiguous stage II disease and cure may be attempted with radical radiotherapy.
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 majority 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).
Grading of follicular lymphoma Grade
Centroblasts per high power field
1e2 3A
0e15 >15
3B
>15
Low-grade follicular lymphoma (FL) Centrocytes present; histologically higher-grade FL No centrocytes; sheets of centroblasts e now classified as diffuse large B-cell lymphoma
Mantle cell lymphoma (MCL) MCL, although often grouped with indolent lymphomas, has a significantly worse 5-year overall survival at around 40%.18 It
Table 3
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typically presents with bulky advanced stage disease and bone marrow involvement. Gastrointestinal tract involvement, either symptomatic or occult, is very common. Histologically, the tumours comprise a monomorphic infiltrate of small or mediumsized 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 chromosome 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 inhibitors 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 reported with the hope that a proportion are being cured of their disease.20
tumours and approximately 20% of HIV-associated lymphomas. 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 iatrogenic 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 immunosuppression; 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 rituximab; it is hoped that new anti-CD20 antibodies (such as ofatumumab and obinutuzumab) will prove even more efficacious. Novel therapies that hold promise include antibodies directed at different targets. A
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 comorbidities (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 chemotherapy 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 lymphoma. The degree of urgency in treating indolent lymphomas 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 patients. 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
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18
19 Rule S, Smith P, Johnson PW, et al. The addition of rituximab to fludarabine and cyclophosphamide (FC) improves overall survival in newly diagnosed mantle cell lymphoma (MCL): results of the randomised UK National Cancer Research Institute (NCRI) trial. Blood (ASH Annu Meet Abstr) 2011; 118. abstr 440. 20 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: sixyear follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma, followed by BEAM or BEACþ autologous stem cell support: still very long survival but, late relapses do occur. Br J Haematol 2012; 158: 355e62. 21 Ferreri AJM, Reni M, Foppoli M, et al. High-dose cytarabine plus highdose, methotrexate versus high-dose methotrexate alone in patients with primary CNS, lymphoma: a randomised phase 2 trial. Lancet 2009; 374: 1512e20.
patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. J Clin Oncol 2011; 29 (suppl; abstr 8000). Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the RCHOP study in the treatment of elderly patients with diffuse large Bcell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117e26. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958; 46: 218e23. Savage KJ, Harris NL, Vose JM, et al. ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALKþ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-cell Lymphoma Project. Blood 2008; 111: 5496e504. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012; 30: 2190e6. Ardeshna K, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362: 516e22. Hancock BW, Qian W, Linch D, et al. Chlorambucil versus observation after anti-helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial. Br J Haematol 2009; 144: 367e75. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 2009; 27: 511e8.
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Prompt biopsy of adequate material for diagnosis and accurate classification is essential to guide optimum management 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 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
Ó 2013 Elsevier Ltd. All rights reserved.
Non-Hodgkin’s lymphoma
What’s new?
Lisa Lowry C
David Linch C
C
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 common subtypes of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Clinical outcomes in B-cell NHL have significantly improved in the past decade, largely due to the availability of the monoclonal antibody, rituximab. However, some aggressive lymphomas, including many T-cell disorders, still carry a poor prognosis.
C
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 discussed 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).
Keywords aggressive; classification; epidemiology; indolent; lymphoma; management; prognosis
Introduction The lymphomas form a group of neoplasms in which the malignant 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 Tcells differentiate further when they encounter antigen, forming effector and memory lymphocytes. The other type of lymphocyte, 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 antigen 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 extremes of maturation (Figure 1). Approximately 15% of lymphomas 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
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 immunodeficiency states and better diagnosis and reporting. Most subtypes have a male preponderance although follicular lymphoma (FL) is more common in females. The risk of developing NHL is increased in congenital and acquired immunodeficiency states, including human immunodeficiency 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 lymphoma, 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 lymphoma, prevalent in malarial areas of sub-Saharan Africa but rare in developed countries, and is present in two-thirds of HIVrelated lymphomas.4 Hepatitis C virus (HCV) infection increases
Lisa Lowry MRCP FRCPath is Lymphoma Clinical Fellow at University College 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.
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Increasing use of rituximab in B-cell lymphomas including NICE approval for maintenance rituximab in first response New anti-CD20 antibodies, which may prove to be more efficacious than rituximab New targeted therapies under evaluation, such as anti-CD30 antibodyedrug conjugate (brentuximab vedotin) in certain T-cell lymphomas Emerging signalling inhibitors including Bruton’s tyrosine kinase (BTK) inhibitors
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associated lymphoid tissue (MALT) in the stomach; it is estimated that 3% of NHL cases in developed countries are due to infection with H. pylori.4 A variety of chemicals, including pesticides, herbicides and hair dyes, have been implicated but not proven to have a role in 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.
Frequencies of different lymphoid malignancies as recorded in cancer registration data in England in 2010 ALL/CLL (19%)
DLBCL (27%)
fNHL (11%)
Indolent and aggressive NHL
Myeloma (20%)
HL (8%)
Other NHL (12%)
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 natural 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 therapy. Aggressive lymphomas usually have a more rapid symptom onset, and without therapy would lead to death fairly quickly. However, many are curable with prompt chemotherapy. Indolent and aggressive lymphomas are also termed low-grade and high-grade, respectively, based on histopathological appearances. Mantle cell lymphoma has features of both and is sometimes regarded as intermediate in grade.
TNHL (3%)
Data derived from Release edition reference tables, Office for National Statistics.
Figure 1
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 small minority of chronic carriers.4 There is a strong association between Helicobacter pylori and lymphomas of mucosa-
Presentation 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 typically present with rapidly enlarging lymph nodes and have a higher rate of constitutional (‘B’) symptoms (Table 2). Aggressive lymphomas are more likely to present with extranodal involvement. However, there is overlap between indolent and aggressive presentations. The possible presenting features are diverse as masses can arise in virtually any tissue or organ.
WHO classification with high-grade lymphomas in red B-Cell neoplasms
T-cell and NK-cell neoplasms
Precursor B lymphoblastic leukaemia/lymphoma Small lymphocytic lymphoma (chronic lymphocytic leukaemia) Lymphoplasmacytic lymphoma Splenic marginal-zone lymphoma Hairy cell leukaemia
Precursor T lymphoblastic leukaemia/lymphoma Blastic NK cell lymphoma Adult T-cell leukaemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma
Ann Arbor staging system and Cotswold modifications for Hodgkin’s lymphoma Stage I Involvement of one lymph-node region or lymphoid structure II Involvement of two or more lymph-node regions on the same side of the diaphragm III Involvement of lymph nodes on both sides of the diaphragm IV Involvement of extranodal sites other than one contiguous or proximal extranodal site Modifying features A No symptoms B Fever 38 C, drenching night sweats, loss of 10% body weight in previous 6 months X Bulky disease (mediastinal mass >1/3 thoracic diameter; nodal mass >10 cm diameter) E Involvement of one contiguous or proximal extranodal site
Extranodal marginal zone lymphoma Nodal marginal zone lymphoma Subcutaneous panniculitis-like T-cell lymphoma Follicular lymphoma Mycosis fungoides Mantle cell lymphoma Sezary syndrome Diffuse large B-cell lymphoma Primary cutaneous anaplastic large cell lymphoma Mediastinal (thymic) large B-cell Peripheral T-cell lymphoma, lymphoma unspecified Intravascular large B-cell Angioimmunoblastic T-cell lymphoma lymphoma Primary effusion lymphoma Anaplastic large cell lymphoma Burkitt’s lymphoma/leukaemia
Table 2
Table 1
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Investigation
Anthracycline-based chemotherapeutic regimens are the mainstay of curative therapy in aggressive NHL. However, anthracyclines are cardiotoxic and those with poor baseline cardiac status (ejection fraction less than 50%) are generally deemed unsuitable for such therapy. Patients are also routinely tested for HIV, hepatitis B virus (HBV) and HCV before the commencement of immunosuppressive NHL treatment, which can exacerbate these conditions.
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 diagnosis difficult. Biopsies should be reported by a dedicated haematopathologist 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 translocations 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.
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 progression 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 prognosis should be carefully explained, and written information 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, hyperphosphataemia, hypocalcaemia), renal failure and death. All patients should be adequately hydrated and treated with allopurinol, at least for the first cycle of chemotherapy. 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.
Staging The Ann Arbor staging system, originally developed for HL, is also used routinely in adults with NHL (Table 2). Staging requires 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. Management and prognosis are affected by stage but, unlike many solid organ malignancies, widespread disease at presentation does not remove the chance of cure.
Aggressive NHL
Prognostic factors Defining groups with differing prognoses can help guide management decisions and provide useful information for the patient. The international prognostic index (IPI) for aggressive lymphomas 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).
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 cytogenetic 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
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 examination and assessment of cardiac, renal and hepatic function.
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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 • Age >60 • LDH above upper limit of normal • >1 extranodal site involved • WHO performance status ≥2
• Stage III or IV • Age >60 • LDH above upper limit of normal • ≥5 lymph node areas involved • Hb <12 g/dl Number of factors present:
0 1 or 2 3 or more
Very good risk Good risk Poor risk
0 or 1 2 3 or more
1.0
Low risk Intermediate risk High risk
1.0
Very good 0.9
Freedom from treatment failure
0.9
Good
0.8
Survival (%)
0.7 0.6 0.5
Poor
0.4 0.3 0.2 0.1 0.0
0.8 0.7 0.6 0.5 0.4 0.3
1,2 RF 3 RF 4,5 RF
0.2 0.1
P < 0.001 0
1
P < 0.001
0.0 2
3
4
5
6
0
Time (years)
1
2
3
4
Time (years)
Patients with diffuse large B cell lymphoma treated with the rituximab-containing R-CHOP up to 2005
Patients with advanced stage follicular lymphoma 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
Originally published in Blood. Buske et al. The follicular lymphoma international prognostic index (FLIPI) separates high-risk from intermediateor 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
LDH, lactate dehydrogenase; RF, risk factors; WHO, World Health Organization.
Figure 2
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 demonstrate any benefit to dose intensification, even in those with adverse risk factors.11
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 administered on an outpatient basis. Improvements in response and survival have been seen with the use of rituximab-containing
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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 region 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). 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 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 that HIV infection allows for chronic antigenic stimulation from opportunistic infections, and defective T-cell regulation of EBVinfected B-cells (although EBV infection is not essential). It is thought that malaria infection plays a similar role in endemic BL.
Event-free survival among 399 patients assigned to chemotherapy with CHOP alone or with CHOP plus rituximab (elderly patients, all IPI groups)(10)
Probability of event-free survival
1.0
0.8
CHOP plus rituximab 0.6
0.4
CHOP P < 0.001
0.2
0
0
0.5
1.0
1.5
2.0
2.5
3.0
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.
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)).
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 autologous 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.
Treatment and prognosis: historically, BL had a poor prognosis with standard therapy. However, with the use of intensive inpatient 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 features 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 intensify 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 lymphoma 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
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 epidemiology and possible aetiology.
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Watchful waiting e a significant proportion of patients are asymptomatic at presentation, having been diagnosed incidentally or following investigation of modest, untroublesome lymphadenopathy. In such patients there is no detriment to initial watchful waiting compared to immediate standard chemotherapy.16 Therapy 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 (cyclophosphamide, vincristine, prednisolone), anthracycline-based therapy, fludarabine and bendamustine. The pattern is usually of recurrent, but progressively shorter, responses. Before the availability of rituximab the median survival from diagnosis was in the region 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 immunochemotherapy, 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 associated 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 position relative to maintenance rituximab is currently not well defined. Allogeneic transplantation historically carried an unacceptable treatment-related mortality. The use of reducedintensity 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 approximately 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.
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 variety 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 aggressive 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 background 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) translocation 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 lymphadenopathy, 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 contiguous stage II disease and cure may be attempted with radical radiotherapy.
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 majority 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).
Grading of follicular lymphoma Grade
Centroblasts per high power field
1e2 3A
0e15 >15
3B
>15
Low-grade follicular lymphoma (FL) Centrocytes present; histologically higher-grade FL No centrocytes; sheets of centroblasts e now classified as diffuse large B-cell lymphoma
Mantle cell lymphoma (MCL) MCL, although often grouped with indolent lymphomas, has a significantly worse 5-year overall survival at around 40%.18 It
Table 3
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typically presents with bulky advanced stage disease and bone marrow involvement. Gastrointestinal tract involvement, either symptomatic or occult, is very common. Histologically, the tumours comprise a monomorphic infiltrate of small or mediumsized 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 chromosome 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 inhibitors 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 reported with the hope that a proportion are being cured of their disease.20
tumours and approximately 20% of HIV-associated lymphomas. 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 iatrogenic 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 immunosuppression; 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 rituximab; it is hoped that new anti-CD20 antibodies (such as ofatumumab and obinutuzumab) will prove even more efficacious. Novel therapies that hold promise include antibodies directed at different targets. A
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 comorbidities (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 chemotherapy 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 lymphoma. The degree of urgency in treating indolent lymphomas 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 patients. 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
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19 Rule S, Smith P, Johnson PW, et al. The addition of rituximab to fludarabine and cyclophosphamide (FC) improves overall survival in newly diagnosed mantle cell lymphoma (MCL): results of the randomised UK National Cancer Research Institute (NCRI) trial. Blood (ASH Annu Meet Abstr) 2011; 118. abstr 440. 20 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: sixyear follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma, followed by BEAM or BEACþ autologous stem cell support: still very long survival but, late relapses do occur. Br J Haematol 2012; 158: 355e62. 21 Ferreri AJM, Reni M, Foppoli M, et al. High-dose cytarabine plus highdose, methotrexate versus high-dose methotrexate alone in patients with primary CNS, lymphoma: a randomised phase 2 trial. Lancet 2009; 374: 1512e20.
patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. J Clin Oncol 2011; 29 (suppl; abstr 8000). Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the RCHOP study in the treatment of elderly patients with diffuse large Bcell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117e26. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958; 46: 218e23. Savage KJ, Harris NL, Vose JM, et al. ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALKþ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-cell Lymphoma Project. Blood 2008; 111: 5496e504. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012; 30: 2190e6. Ardeshna K, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362: 516e22. Hancock BW, Qian W, Linch D, et al. Chlorambucil versus observation after anti-helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial. Br J Haematol 2009; 144: 367e75. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 2009; 27: 511e8.
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Prompt biopsy of adequate material for diagnosis and accurate classification is essential to guide optimum management 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 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
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