Epidemiology

Non-Hodgkin’s lymphoma (NHL) is relatively common (Table 30.1). In the United Kingdom in 2011 there were 12,783 diagnoses and 4646 deaths attributable to NHL. There have been many descriptions of the pathological classification of this disease. Rather than achieving clarity, however, most have tended to confuse the situation further because of their complexity. The current WHO classification lists over 80 different forms of lymphomas! They divide the lymphomas into four groups:

• mature B-cell neoplasms
  
• mature T cell and natural killer (NK) cell neoplasms
  
• Hodgkin lymphoma
  
• immunodeficiency-associated lymphoproliferative disorders

In terms of clinical practice, the most significant divisions are into high- and low-grade lymphoma (Table 30.2). High-grade lymphoma is 3–4 times more common than low-grade lymphoma. About 4000 people are diagnosed in the United Kingdom with low-grade lymphoma each year. Slightly more men are affected than women. Lymphomas arise from lymphoid organs or lymphatic tissue associated with other systems that contain lymphatic tissue. The latter, the so-called extranodal lymphomas, constitute up to 30% of all NHL.

Pathogenesis

There have been extraordinary advances in the molecular biology of lymphoma, and from this we have begun to understand some of the aetiological features involved in this condition. The most prominent factors in the pathogenesis are infections and immune suppression. Viral infection with HIV, EBV, HHV8, HCV and HTLV are all associated with NHL (Table 30.3). Helicobacter infection in the stomach leads to a proliferation of gastric lymphoid tissue and the development of low-grade, mucosa-associated tumours. Such tumours may respond to H. pylori eradication treatment, but unfortunately they may still evolve into classical lymphoma despite eradication.

In addition to infection, immunosuppression increases the risk of lymphoma including HIV infection which increases the risk of NHL by 60 times. By comparison the risk of lung cancer is increased 17 times in smokers. Similarly allograft transplant recipients, who are prescribed immunosuppressants to prevent graft rejection, are also at greatly increased risk of lymphoma. Various autoimmune diseases also raise the risk of lymphoma:

• Sjögren’s syndrome (19-fold increased risk)
  
• systematic lupus erythematosus (sevenfold increased risk)
  
• rheumatoid arthritis (twofold to fourfold increased risk)
  
• coeliac disease (increased risk of enteropathy-associated T-cell lymphoma)

Presentation

Patients present with nodal enlargement which may be accompanied by constitutional symptoms including weight loss, sweating and fever (Figures 30.1 and 30.2). These symptoms – where weight loss is in excess of 10% of pre-morbid weight, sweating is sufficient to drench night clothes and fever exceeds 38°C – are described as “B” symptoms. “B” symptoms are less common in high-grade lymphoma than low-grade malignancies. Patients with such symptoms should be referred to specialist centres where the chance for survival and the quality of survival are significantly better than in peripheral non-specialist centres. The care of patients with lymphoma should be by oncologists or haematologists, depending upon the specialist interests of the clinicians.

Staging and grading

In outpatients, a careful history is obtained from the patient who is then examined. The investigations organized should include a blood count, renal and hepatic function tests, chest X-ray, bone marrow aspiration and trephine, and PET–CT scan of body (Figures 30.3, 30.4, 30.5, 30.6 and 30.7). These investigations are done in order to define the extent of the disease. From these investigations the clinical staging is obtained (Figure 30.8). This is defined as follows:

• Stage I: disease confined to one lymph node or two contiguous lymph node groups
  
• Stage II: disease on one side of the diaphragm in lymph node groups that are separate
  
• Stage III: disease on both sides of the diaphragm
  
• Stage IV: extranodal spread of the lymphoma

Preliminary investigations having been organized, the patient should then proceed to a lymph node biopsy. Lymph node biopsies used to be required to describe the architectural arrangement of the tumour. In modern times, they are no longer always considered to be necessary. Sufficient material can often be obtained from core needle biopsies to define the pathological diagnosis. There are many classification systems for NHL, which include the WHO classification (Table 30.4), the Kiel classification, the Working Formulation and the Revised European and American Lymphoma Classification (REAL).

For the purposes of defining treatment, the most practical classification, however, is to describe the tumour as being low or high grade. A low-grade tumour tends to have a follicular nature and to contain relatively inactive cells. A high-grade tumour contains cells that have a high index of mitotic activity, meaning that many of the cells are actively proliferating, and there is no follicular structure to the lymph node. There are variant lymphomas, such as mantle cell and Burkitt’s lymphomas, which are clinical entities with poor prognosis.

Many modern techniques have been applied to the pathological diagnosis of lymphoma. Immunophenotyping using monoclonal antibodies is the most helpful, firstly, in initially distinguishing between a lymphoma or a carcinoma by using antibodies to the leukocyte common antigen (CD45), and secondly, in defining the lymphoma by using antibodies that are specific for B or T lymphocytes, such as CD20 or CD4, CD2 and CD3. T-cell receptor and immunoglobulin gene rearrangement studies are also carried out, and are helpful in describing tumour clonality. Fluorescent in situ hybridization (FISH) is also useful. This is because the observed cytogenetic abnormalities are relatively specific for subtypes NHL. Some of these are outlined in Table 30.5.

Treatment