Lymphoma and Hodgkin’s disease are lymphoid neoplasms that are fascinating and challenging to diagnose and treat because of the diversity of the clinical presentation and tumour behaviour. This unexpected diversity has been clarified by landmark research on normal lymphoid development and biology. The neoplastic clone may arise from and mimic a lymphoid cell at a certain stage of maturation arrest that is associated with characteristic morphological, immunophenotypical, and genetic changes. Once frequently misdiagnosed, lymphomas are now readily diagnosed, and treatment can be potentially curative even for advanced stages of disease.

The age-standardised rates (ASR) of non-Hodgkin’s lymphoma for the total male and female population in Singapore for 1998-99 were 7.5 and 4.5 per 100,000 per year, respectively. At these rates, a general practitioner is likely to have 2 patients per year presenting with a possible diagnosis of lymphoma. The rising incidence of lymphoma and its inclusion in the top three most frequent cancers among Singapore children and young adults give it social and economic prominence.

By contrast, Hodgkin’s disease is far less common, with ASRs of 0.6 for men and 0.5 for women.

The cause of most lymphomas is unknown. However, certain viruses and bacteria (e.g. HIV, HTLV-1, HSV-8, hepatitis C, Epstein-Barr virus, and Helicobacter pylori) have been established as causative agents, and antimicrobials have become part of the treatment options against lymphoma.

One of the major advances in the past decade has been the international consensus on the pathological classification of lymphoma, starting with the Working Formulation Classification, which has become redundant with the advances in molecular biology, which in turn have culminated in the worldwide adoption of the REAL/WHO classification for lymphoid neoplasms. Another advance is the development of prognostic scores and indices that enable prediction of treatment outcomes. Both advances have made multicentered comparative trials possible and allowed a systematic evaluation of different generations of combination chemotherapy, to establish what should be the evidence-based standard treatment. The major therapeutic advance in the past decade has been the development of target-specific therapy to improve treatment response and survival.

Presentations
Lymphoma presents itself in a myriad of ways and diagnosis of malignant lymphoma can sometimes be difficult because it has similar presenting features to those of a wide range of disorders, such as infection and collagen vascular disorders (see Table 1). A careful history and physical examination are the most important aspects of the evaluation. Lymphoma may be present as painless generalised or localised lymphadenopathy. It may also involve extranodal tissues, with presenting symptoms referable to these sites. Some patients may have constitutional symptoms such as fever, weight loss and night sweats. Extranodal presentations may mimic common medical ailments such as ‘gastritis’ in gastric lymphomas, ‘asthma’ in mediastinal lymphomas, and sinusitis in paranasal lymphoma.

Table 1: Evaluation of suspected causes of lympadenopathy

If the diagnosis of lymphoma is suspected, the next step is to obtain a histological diagnosis. Excision biopsy of the lymph node is preferred because a fine-needle aspiration biopsy is often inadequate for making or excluding a diagnosis of lymphoma.

Classification and subtyping of lymphoma

The pathologist classifies lymphoma on the basis of the following:

1. Morphology
This involves the evaluation of the architectural features of the biopsied tissue and the cellular features of the lymphoma cells.

2. Cell-surface-marker analysis or immunophenotyping.
Different subtypes of lymphoma have different surface antigens, which correspond to their normal counterparts at various stages of differentiation. A variety of antibodies are used to detect these cell surface antigens, and these tests are collectively known as immunophenotyping.

3. Gene testing
In some cases, the combination of morphology and cell-marker studies will still not allow the subtyping of the lymphoma or the distinction of benign from malignant lymphoid lesions. In these cases, genetic studies may be necessary. The types of genetic changes that occur include chromosomal translocations, immunoglobulin gene rearrangement, and T-cell-receptor gene rearrangement.

Over the past three decades, knowledge concerning lymphocytes and lymphomas has greatly increased, resulting in the need to continually revise the classification scheme. The current classification system is known as the REAL/WHO classification (see tables 2 and 3). In general, lymphomas are divided into two major groups:

1. Hodgkin’s disease
This entity is characterised by the presence of Reed Sternberg cells and can be further subdivided into 4 subtypes—lymphocyte predominant (LP), nodular sclerotsis (NS), mixed cellularity(MC), and lymphocyte depleted (LP).

2. Non-Hodgkin’s lymphoma (NHL)
This is composed of either B or T cells. NHL is also divided into two groups based on clinical behaviour. The three clinical &groups are:

    · Indolent lymphoma: patients live years without treatment
    · Aggressive lymphomas: patients live months without treatment
    · Highly aggressive lymphomas: patients live weeks without treatment

Table 2: Updated REAL/WHO Classification

B-cell neoplasmas
I.   Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukaemia/lymphoblastic lymphoma (B-ALL, LBL)
II.  Peripheral B-cell neoplasms
   · B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma
   · B-cell prolymphocytic leukaemia
   · Lymphoplasmacytic lymphoma/immunocytoma
   · Mantle-cell lymphoma
   · Follicular lymphoma
   · Extranodal marginal zone B-cell lymphoma of MALT type
   · Nodal marginal zone B-cell lymphoma (+/-monocytoid B-cells)
   · Splenic marginal zone lymphoma(+/-villous lymphocytes)
   · Hairy-cell leukaemia
   · Plasmacytoma/plasma-cell myeloma
   · Diffuse large B-cell lymphoma
   · Burkitt’s lymphoma

T-cell and putative NK-cell neoplasms
I.   Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukaemia/lymphoblastic lymphoma (T-ALL, LBL)
II.  Peripheral T-cell and NK-cell neoplasms
   · T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia
   · T-cell granular lymphocytic leukaemia
   · Mycosis fungoides/Sezary’s syndrome
   · Peripheral T-cell lymphoma, not otherwise characterised
   · Hepatosplenic gamma/delta T-cell lymphoma
   · Subcutaneous panniculitis-like T-cell lymphoma
   · Angioimmunoblastic T-cell lymphoma
   · Extranodal T-/NK cell lymphoma, nasal type
   · Enteropathy-type intestinal T-cell lymphoma
   · Adult T-cell lymphoma/leukaemia (HTLV 1 positive)
   · Anaplastic large-cell lymphoma, primary systemic type
   · Anaplastic, large-cell lymphoma, primary cutaneous type
   · Aggressive NK-cell leukaemia

Hodgkin’s lymphoma (Hodgkin’s disease)
I.   Nodular lymphocyte-predominant Hodgkin’s lymphoma
II.  Classical Hodgkin’s lymphoma
   · Nodular-sclerotic Hodgkin’s lymphoma
   · Lymphocyte-rich classical Hodgkin’s lymphoma
   · Mixed-cellularity Hodgkin’s lymphoma
   · Lymphocyte-depleted Hodgkin’s lymphoma

Blood tests
· Full blood count, erythrocyte sedimentation rate, renal-function test, liver function tests
· Lactate dehydrogenase (LDH)
· Serum calcium – may be elevated in certain T-cell lymphomas. Protein electrophoresis in indolent lymphomas (especially those with plasmacytic features, or in chronic lymphocytic leukaemia (CLL)
· Serological tests — hepatitis B, hepatitis C, and HIV serology

Bone-marrow examination
· Bone-marrow aspirate and trephine biopsy
· Cytogenetics studies only in special circumstances
· CT scan of the thorax, abdomen, pelvis and neck (if indicated).

Cardiac assessment
· 2-D echo or radionuclide scan (MUGA scan)

Other specialised tests such as cytology of the cerebrospinal fluid and gastrointestinal endoscopy are done in certain cases.

The staging of both Hodgkin’s lymphoma and non-Hodgkin’s lymphoma follows the Ann Arbor system

Table 3: Staging of lymphoma

Unlike other cancers, the prognosis of lymphoma does not depend on stage alone. In NHL, an International Prognostic Index (IPI) is frequently used.

The 5 clinical risk factors that independently predict survival in NHL are: age>60, stage III/IV disease, high LDH, more than1 extranodal site, and performance status ECOG>1 (i.e. symptomatic, in bed<50% of the time, occasionally needing nursing care).

Treatment of low-grade lymphoma

Since low-grade NHLs are indolent, decisions on treatment are dependent on the stage of disease and the presence of symptoms. Treatment options include adopting a watch-and-see approach, local radiation, single-agent chemotherapy, combination chemotherapy, or one of the monoclonal antibodies, such as ritiximab.

Treatment of aggressive NHL
In contrast to low-grade lymphomas, aggressive lymphomas are potentially curable. The IPI is very useful in predicting the likely outcome with standard treatment. Studies in progress are looking at tailoring treatment according to the IPI of the patient at presentation. The CHOP (cyclophosphamide, vincristine, adriamycin, and prednisolone) regimen remains the standard treatment for many types of aggressive lymphomas after all these years. In the 1980s, a variety of newer generation regimens for lymphoma were investigated and initial studies showed impressive response rates as high as 70%. These regimens are complex and may contain as many as nine agents. However, when these studies were examined more closely, the high response rates were found to occur mainly in patients with low risk as defined by the IPI. When adjustments were made for prognostic factors, the newer regimens were found to be more toxic and had no survival benefit.

The table below summarises the management of patients with aggressive lymphoma.

Relapse of aggressive lymphoma
After a relapse, patients are treated with salvage chemotherapy (which is a different combination of chemotherapy). Patients who respond well to salvage treatment proceed to receive high-dose chemotherapy with autologous bone-marrow or peripheral stem-cell transplant. This approach is generally considered for younger patients who are fit and without involvement of the central nervous system.