NHL

These are malignant tumours of the lymphoid system classified separately from Hodgkin’s lymphoma. Most (70%) are of B cell origin with 30% of T cell origin.


The cause is unknown. A number of infective agents are associated with the development of NHL.
-EBV virus DNA is observed in between 10% and 30% of tumours and is strongly associated with endemic
Burkitt’s lymphoma of sub-Saharan Africa.
-The human T cell lymphotropic virus which is prevalent in Japan, Africa, South America and the Caribbean is a major risk factor for adult T cell lymphoma/leukaemia.
-Herpesvirus 8 is associated with primary effusion lymphomas and Castleman’s disease.
-There is an increase in lymphoma in patients with HIV infection and more specifically primary brain lymphoma, immunoblastic diffuse large B-cell lymphoma and Burkitt’s lymphoma are AIDS defining illnesses.
-Helicobacter pylori is an aetiological factor in gastric MALT lymphoma.


Epidemiological studies have documented an association between farming and NHL which may be a result of pesticide exposure.
In addition organic solvents and hair dyes used prior to 1980 have been implicated.

Lymphomas also occur in a number of congenital immunodeficiency states. Acquired immunodeficiency, as a result of organ transplantation, is strongly associated with NHLs.
These are commonly extranodal and most frequently occur in the first year after transplantation. In autoimmune disorders an elevated risk of NHL is reported, attributed to disturbances in immune function (e.g. Sjögren’s syndrome and extranodal marginal zone lymphoma).
A number of familial cancer syndromes are also associated with NHL.




Pathogenesis
There is a malignant clonal expansion of lymphocytes which occurs at different stages of lymphocyte development. In general, neoplasms of non-dividing mature lymphocytes are indolent whereas those of proliferating cells (e.g.lymphoblasts, immunoblasts) are much more aggressive.
This malignant transformation is usually due to errors in gene rearrangements which occur during the class switch, or gene recombinations for immunoglobulins and T cell receptors. Thus, many of the errors occur within immunoglobulin loci or T cell receptor loci. For example, an abnormal gene translocation may lead to the activation of a proto-oncogene next to a promoter sequence for the immunoglobulin heavy chains
(Ig-H).



Cytogenetic features 
Burkitt’s lymphoma was the first tumour in which a cytogenetic change was shown to involve the translocation of a specific gene.

The most frequent change is a translocation between chromosomes 8 and 14 in which the myc oncogene
moves from chromosome 8 to a position near the constant region of the immunoglobulin heavy chain gene on chromosome 14, resulting in upregulation of myc.

Similar rearrangements involving the light chain loci are seen in the alternative Burkitt’s lymphoma translocations between chromosome 8 and either chromosome 2 or 22.

Other somatic cytogenetic abnormalities associated with human lymphoma are the t(14;18) in follicular lymphoma, involving upregulation of the Bcl-2 gene, or the upregulation of the cell cycle regulator cyclin D1 as a result of t(11;14) in mantle cell lymphoma.

Gene expression profiling and other molecular techniques are increasingly revealing aberrations or patterns of aberration which are associated specifically with one or other subtype of lymphoma and have led to the identification of new molecular subclasses of lymphoma.


Immunophenotypes
All NHL B cells express CD20 and surface immunoglobulin.

Individual lymphomas vary in their expression, e.g. follicular lymphomas express CD10, mantle cell CD43, while the diffuse large B cell lymphoma expresses both CD10 and CD43.

They can be used in the classification. T cell lymphomas do not express CD20 but variably express CD3, 4, 8 and 30.


Investigations
■ Full blood count. Normochromic, normocytic anaemia, an elevated white cell count or neutropenia and
thrombocytopenia are suggestive of bone marrow infiltration.
■ ESR may be elevated.
■ Urea and electrolytes. Patients may have renal impairment as a consequence of ureteric obstruction
secondary to intra-abdominal or pelvic lymph node enlargement.
■ Serum uric acid level may be raised.

■ Liver biochemistry. This may be abnormal if there is hepatic involvement.
■ Serum lactate dehydrogenase and b2-microglobulin are prognostic indicators.
■ Serum immunoglobulins. Decreased levels may occur with paraproteinaemia.
■ Chest X-ray, CT scans of chest, abdomen and pelvis. PET and gallium scans help in staging.
■ Bone marrow aspirate and trephine biopsy are always performed.
■ Lymph node biopsy (or Trucut needle biopsy, often under radiological guidance, in the case of surgically
inaccessible nodes). Immunophenotyping and cytogenetic/molecular analysis (DNA microarray
analysis), to distinguish type of NHL.






Prognostic factors in non-Hodgkin’s lymphoma

Adverse factors:
■ Age > 60 years
■ Stage III or IV, i.e. advanced disease
■ High serum lactate dehydrogenase level
■ Performance status (ECOG 2 or more)
■ More than one extranodal site involved

ECOG, Eastern Cooperative Oncology Group.


Follicular lymphoma


These comprise 20% of all B cell lymphomas. Most patients with follicular lymphoma present feeling well but with painless lymphadenopathy.

Investigation usually reveals multiple sites of disease: involvement of the bone marrow is common.

Managed conservatively it is a remitting and recurring disease with a clinical course running over a median of 10 (1–20 years) years during which there will be about three ‘episodes’of relapse.

Death occurs because of resistant disease, transformation to diffuse large B cell lymphoma (LBCL) or the
effects of therapy.
The ‘well’ patient should be managed with no specific therapy until progression is documented. Repeat biopsy should be performed at this time in case there has been histological transformation to LBCL as this has specific implications for therapy and prognosis.

The indications for the initiation of therapy are:

■ Stage I presentation single lymph node field (10–15%). This is treated with ‘involved’ field mega voltage
irradiation, which almost invariably induces ‘complete remission’. The median time to progression is 10–15
years. Some patients may be cured. The therapy has a low morbidity and mortality.
■ Advanced disease with:
– constitutional ‘B’ symptoms
– ‘organ impairment’, i.e. bone marrow failure
– ‘bulky’ disease, i.e. lymph node mass > 10 cm
– progressive disease after expectant management, documented if necessary on two scans 3 months apart
– histological transformation.




Management
Follicular lymphoma has been a recurring remitting disease, treated intermittently, but with a high risk over time of transformation to diffuse large B-cell lymphoma, the median survival being about 10 years.

An increase in the therapeutic options has coincided over the past 10 years with an apparent improvement in the prognosis. There is now a possibility of cure, particularly after allogeneic stem cell haematopoietic
transplantation.




TREATMENT

Chemo-immunotherapy


This has become the treatment of choice for follicular lymphoma since the demonstration in large randomized
phase II clinical trials that the anti-CD20 antibody, rituximab, added to cyclical combination chemotherapy, improves the response rate, freedom from progression and overall survival.
There is only circumstantial evidence that one chemotherapy combination is better than another. Indeed, for the long term, it has not been shown that there is any advantage of combination over single agent chemotherapy.
The duration of antibody therapy after chemotherapy has been completed remains under investigation.


Other options
■ Rituximab alone. This is being investigated in the setting of the patient ‘not needing therapy’, and may
also be valuable in patients with progressive disease, for whom chemotherapy is inappropriate. It induces
remission, mainly partial, in 30–60% of patients depending on how much previous therapy has been
received.
■ Chemotherapy alone. Both mono- and combination chemotherapy are now only being used alone when
there is evidence that antibody therapy has failed.
■ Myeloablative chemo-(immunotherapy) with peripheral blood progenitor cell rescue. This has
been shown to result in very long freedom from recurrence in phase II trials when performed in second
remission, and to have a survival advantage also in a phase III trial. For many physicians, it is the treatment
of choice in second remission, although there are some alternative compelling data for ‘maintenance
rituximab’.

■ Irradiation for stage 1 disease. Targeted irradiation, 131I or 90Y being delivered with anti-CD20 as a carrier is being used.
■ Allogeneic haematopoietic stem cell transplantation (HSCT). Data suggests that this may be curative.
Reduced intensity conditioning HSCT is the subject of many phase II trials. The design of phase III trials is
difficult.