Non-Hodgkin's lymphoma

Urgency of referral depends on clinical picture, says Dr Lisa Lowry and Professor David Linch.

Lymphadenopathy is one of the most common presenting symptoms (Photograph: SPL)
Lymphadenopathy is one of the most common presenting symptoms (Photograph: SPL)

Non-Hodgkin's lymphoma (NHL) encompasses a spectrum of disease, from indolent malignancies to those that are highly aggressive. The WHO classification lists more than 40 disease entities, and the presentation, management and prognosis is dependant on the histological type.

Epidemiology
More than 10,000 new NHL cases are diagnosed each year in the UK. NHL is the fifth most common cancer in the UK and is about six times more common than Hodgkin's lymphoma. Incidence increases in the elderly and has doubled in the past 30 years. The risk of developing NHL is increased in immunodeficiency states, including HIV (approximately 80-fold increased risk),1 but also other immune disorders, such as rheumatoid arthritis.

Various infectious agents have been associated with lymphoma. Epstein-Barr virus is associated with Burkitt's lymphoma, prevalent in malarial areas of Africa but rare in developed countries, and is present in two-thirds of HIV-related lymphomas.2

There is a strong association between Helicobacter pylori and lymphomas of mucosa- associated lymphoid tissue (MALT) in the stomach; it is estimated that 4 per cent of NHL cases in developed countries are due to infection with H pylori.2

Hepatitis C virus infection increases risk of NHL (2.5-fold increase).3 Infection with human T-cell lymphoma virus 1 causes a rare type of NHL (adult T-cell leukaemia/lymphoma - ATLL), but only in a minority of chronic carriers.2

A rare type of intestinal T-cell lymphoma is strongly associated with coeliac disease, and a gluten-free diet reduces the risk. A variety of chemicals, including pesticides, herbicides and hair dyes, have been implicated. In the majority of cases the cause is unknown.

Presentation and diagnosis
The most common presenting symptom is painless lymph node enlargement. Indolent lymphomas classically present with widespread, slowly progressive lymphadenopathy with few constitutional symptoms. Aggressive lymphomas typically present with rapidly enlarging lymph nodes and have a higher rate of constitutional symptoms ('B' symptoms - fevers, night sweats, weight loss). Aggressive lymphomas are more likely to present with extranodal involvement.

The urgency of referral is dependent on the clinical picture. In a systemically well patient with small nodes (<2cm) it may be reasonable to reassess in a few weeks, especially if there is a recent infective history. However, patients with large or rapidly progressing masses should be referred urgently. Patients with the most aggressive forms of lymphoma should be admitted to hospital.

The diagnosis relies on adequate biopsy of lymph node or other affected tissue for histological and immunohistochemical examination. It is important to accurately subtype the lymphoma as the management aims, treatments available and prognoses vary widely. Once the diagnosis is confirmed, staging is completed with whole-body CT scanning and bone marrow biopsy. The Ann-Arbor staging system is routinely used.

Treatment and prognosis
The natural history, management and prognosis vary widely according to histological type. Follicular lymphoma accounts for about a quarter of all NHL, and has a natural history characterised by multiple relapses and remissions. The average survival from diagnosis was eight to 10 years, and although this has improved in recent years, the extent of this improvement is not yet clear. In those with stage-1 disease at diagnosis (lymphoma limited to one lymph node region), radical radiotherapy may be curative; however, the majority present with more advanced disease and the majority of patients are not currently curable.

For patients asymptomatic at diagnosis there is no proven long-term benefit to early therapy, and an expectant policy is often adopted.4 For those in need of therapy (due to troublesome lymphadenopathy, B symptoms, cytopenias or patient preference) various regimens may be used; in the UK, chlorambucil monotherapy, CVP (cyclophosphamide, vincristine and prednisolone) or CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) together with rituximab would be considered standard.

Rituximab is a monoclonal antibody directed against CD20, expressed on the majority of B-cell lymphomas. Given together with combination chemotherapy it prolongs both progression-free survival (PFS) and overall survival (OS). Use of maintenance rituximab improves the PFS but it is too soon to evaluate the effect on OS.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL and standard therapy is with R-CHOP immunochemotherapy.

This regimen can usually be administered as an outpatient. For those patients with DLBCL who can tolerate R-CHOP, about two thirds may be cured. Prognosis can be refined to some extent using the International Prognostic Index.5

MANAGEMENT AND PROGNOSTIC IMPLICATIONS FOR COMMON SUBTYPES OF NHL
Subtype
Management options
Prognosis
Follicular NHL
Stage 1: radical radiotherapy
Stage 2-4: if asymptomatic no benefit to up-front chemotherapy.
Expectant management until therapy required. First-line regimens include R-CVP and R-CHOP.
Average OS eight to 10 years. Improvements in PFS seen; due to the long history of the disease, prolonged follow-up is required
Gastric MALT The majority of patients have
localised disease and are likely to respond to H pylori eradication.
For those with widespread
or non-responsive disease,
options include radiotherapy,
immunotherapy, chemotherapy
and surgery.
Excellent long-term outcome for those with limited disease.
DLBCL R-CHOP immunochemotherapy is the international standard. The addition of
rituximab to CHOP chemotherapy has significantly improved cure rates.
Approximately 80 per cent achieve a complete remission with R-CHOP.
Peripheral T-NHL CHOP chemotherapy is standard (without rituximab as the tumours do not express its target CD20) with strong consideration to stem cell transplantation if remission is achieved. Poorer prognosis than aggressive B-cell NHL with five-year OS in 30 per cent.
Burkitt's
lymphoma
Combination immunochemotherapy should
be initiated urgently.
Prognosis is good for those diagnosed and treated promptly.

Long-term management
The initial follow-up phase concentrates on residual side-effects of therapy, detection of recurrence and psychological issues. Indolent lymphomas can recur after very prolonged first remissions and patients need to be aware of this, however, some will still be in remission 10 years from diagnosis.

With the aggressive lymphomas the chance of relapse diminishes as time passes, and patients are generally considered 'cured' if they were alive without lymphoma recurrence after five years. Further follow-up is geared to detecting late effects of therapy, particularly second malignancies.

  • Dr Lowry is a Lymphoma Research Trust clinical fellow and Professor Linch is a consultant haematologist, University College London Hospitals.
TEST YOUR KNOWLEDGE
Question 1: A 45-year-old man, previously fit and well, presented with a left-sided cervical mass and tiredness, although has continued to work full-time.  He has been diagnosed with diffuse large B-cell lymphoma, and staging scans have revealed mediastinal and para-aortic involvement in addition to the cervical mass; the bone marrow biopsy was negative.  His LDH is elevated.  He is due to start multi-agent chemotherapy including rituximab and wishes to discuss his diagnosis with you.  What is his prognosis?
Question2:  The same patient completes a planned course of six cycles of R-CHOP chemotherapy, achieving complete remission.  He is concerned about the possibility of relapse and wants to know what symptoms he should be looking out for.

Question 3: Five years later, there has been no lymphoma recurrence and the patient is to be discharged from routine follow-up in the lymphoma clinic.  In what ways could his treatment adversely affect his long-term health, and what measures can be taken to minimise these adverse effects?

CLICK HERE TO SEE THE ANSWERS

References

1. Grulich AE, van Leeuwen MT, Falster MO, et al. Lancet 2007; 370 (9581): 59-67.

2. Parkin DM. Int J Cancer 2006; 118 (12): 3030-44.

3. Dal Maso L, Franceschi S. Cancer Epidemiol Biomarkers Prev 2006; 15 (11): 2078-85.

4. Feugier P, Van Hoof A, Sebban C, et al. J Clin Oncol 2005; 23: 4117-26.

5. Ardeshna KM, Smith P, Norton A, et al. Lancet 2003; 362; 516-22.

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