When to suspect a diagnosis of lymphoma

Lymphomas are clonal tumours of B-cells, T-cells or natural killer (NK) cells that, in many respects, correlate to malignant growth of cells at various stages of normal B-cell or T-cell differentiation. Traditionally, lymphomas have been divided into Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), although, since the 1990s, it has been established that the typical mononucleated and multinucleated giant Hodgkin and Reed-Sternburg cells in HD are, in fact, clonal B cells.

Over the years, numerous classifications of lymphomas have appeared, reflecting the difficulties in categorising some lymphoma types. The 2008 World Health Organisation (WHO) classification of lymphoid neoplasms is the latest attempt to find consensus amongst clinicians and pathologists.

Despite the complexities of lymphoma classification, the most important practical concerns for clinicians treating lymphoma remain whether the lymphoma is HD or NHL and, if NHL, whether the tumour is high-grade (having an aggressive biology but potentially curable with combination chemotherapy with or without immunotherapy), eg B-cell diffuse large cell NHL, or low-grade (usually indolent with prolonged patient survival but largely incurable), eg follicular B-cell NHL.

Aetiology
HD is uncommon with an annual incidence of 2-3 cases per 100,000 persons. In Western countries, about 50 per cent of all cases of classic HD are Epstein-Barr virus (EBV) positive (ie carry the virus within the tumour cells) and most evidence suggests that EBV is involved in the transformation process in this subset of HD. HIV-positive patients are at increased risk for developing HD, often presenting atypically with extensive subdiaphragmatic and extranodal disease.

NHL represents 5 per cent of all malignancies, with almost all cases arising sporadically without well defined aetiological factors. However, a number of important risk factors have been described, which make certain groups of patients at increased risk of NHL. Immunosuppression, whether congenital or acquired, is a particularly important predisposing factor.

For example, patients on immunosuppressive therapy following solid organ transplantation and patients following haemopoietic stem cell transplantation are at greatly increased risk for developing NHL, with EBV infection commonly the cause of post-transplant lymphoproliferative disorder. In addition, EBV causes endemic Burkitt’s lymphoma in certain parts of Africa.

Apart from EBV, other infections have been implicated in the aetiology of NHL. HIV-positive patients have an up to 100-fold increased risk of developing lymphoma, usually of high-grade type. HTLV-1 and HTLV-2 are viral infections endemic in Japan and parts of the Caribbean, associated with adult T-cell leukaemia/lymphoma.

Hepatitis C is linked to a number of low-grade lymphomas, which often regress with treatment of the underlying infection. Likewise, Helicobacter pylori infection is an important aetiological agent in the development of gastric mucosa-associated lymphoid tissue (malt) lymphoma and eradication of this bacterium can lead to regression of the tumour.

Multiple autoimmune disease, such as rheumatoid arthritis, systemic lupus and Sjogren’s disease, have been associated with an increased incidence of NHL. However, as many of these patients are receiving long-term immunosuppressive therapy, it is difficult to be certain whether the immunosuppression or the underlying disease is the responsible aetiological agent.

Previous chemotherapy is also associated with an increased risk of NHL and, again, immunosupression may be an important underlying mechanism. Coeliac disease is associated with an increased incidence of enteropathy-associated T-cell lymphoma.

Clinical presentation
Approximately 70-80 per cent of patients with classic HD present with primary lymphadenopathy in the cervical or supraclavicular regions or in the mediastinum and two-thirds of newly diagnosed HD patients have radiological evidence of intrathoracic involvement. Bulky lymphadenopathy can cause regional complications such as vascular, tracheal, bronchial or gastrointestinal compesssion or obstruction but, even if large mediastinal masses are present, superior vena cava (SVC) obstruction seldom occurs. The extent of HD involvement can be assessed using the 4 stage Cotswolds modification of the classical Ann Arbor classification, ranging from early, localised disease, involving a single lymphoid structure or single extranodal site (stage I) to widespread disease with diffuse involvement of one or more extralymphatic organs or tissues (stage IV).

In addition, absence (A) or presence (B) of systemic symptoms (fever over 38oC, drenching night sweats, over 10 per cent weight loss) further characterises disease severity.

In fact, some HD patients present with systemic symptoms before the discovery of enlarged nodes. As well as classic B symptoms, including the characteristic intermittent Pel-Ebstein fever, other non-specific symptoms include fatigue, pruritus and pain soon after drinking alcohol.

Lymphadenopathy
Like HD, most NHL patients (about two-thirds) present with lymphadenopathy. If lymphadenopathy is rapidly enlarging, high-grade NHL, such as Burkitt’s lymphoma, should be suspected. However, extranodal disease is more common in NHL than in HD, with possible involvement of nearly any organ, most commonly skin, gastrointestinal tract and bone.

Approximately one-third of all NHL patients will have bone marrow involvement at presentation, although this is even commoner in those with low grade NHL.

Compared to the more common B-cell NHL, T-cell lymphomas are more likely to present with extranodal involvement and severe constitutional symptoms. The extent of NHL involvement may be classified in the same way as for HD.

Asymptomatic
In NHL, symptoms may be non-specific to areas of disease involvement, whilst patients with low grade, indolent lymphoma, who are not at an advanced stage of disease, are often asymptomatic.

However, NHL patients with extensive tumour burden commonly present with B symptoms. Many other patients do present with signs and symptoms related to the specific area(s) of disease involvement. Inter-abdominal lymphadenopathy or direct gastrointestinal tract involvement may produce bowel obstruction whilst retroperitoneal disease can lead to obstructive uropathy. Inguinal lymphadenopathy may cause deep venous thrombosis by venous compression.

Rarely, patients may present with SVC obstruction or with pleural or pericardial effusions, whilst lymphomas presenting in paravertebral areas can cause spinal cord or cauda equina compression.

Patients with central nervous system disease due to primary lymphomatous involvement or secondary dissemination may present with cranial neuropathy or other neurological abnormalities, depending on location of disease.

Laboratory findings
Normochromic or microcytic anaemia with elevated ESR and serum ferritin, suggestive of anaemia of chronic disease, may be one way that HD or NHL might present, although a vast number of other inflammatory, infective or neoplastic conditions could produce similar abnormalities.

Lymphomatous infiltration of the bone marrow, if extensive enough, could manifest as pancytopenia. However, cytopenias may also be autoimmune manifestations of an underlying NHL: for example, any patient presenting with Coombs positive autoimmune haemolytic anaemia requires investigation for an underlying NHL.

In the case of NHL, tumour cells circulating in the peripheral blood (leukaemia) may be suspected by a white-cell count and differential and by blood film examination.

Immunophenotyping of peripheral blood white cells by flow cytometry often confirms a suspected clonal population and may be able to identify the exact type of lymphoma/leukaemia by the pattern of CD antigen expression on the tumour cells.

Liver blood tests
Occasionally, lymphomas may present with abnormalities of electrolytes, including calcium and phosphate, serum creatinine or liver blood tests, due to direct infiltration by tumour. For patients with elevated lactic dehydrogenase (LDH), an important differential is aggressive lymphoma, including transformation of indolent NHL.

The discovery of a monoclonal IgM protein on serum protein electropheresis implies a clonal growth of B-cells and the need to investigate for evidence of NHL by CT scanning of thorax, abdomen and pelvis and by bone marrow examination. The discovery of cryoglobulins requires investigation for lymphoma, in particular hepatitis C associated marginal zone lymphoma, as an underlying cause.

Conclusions
As lymphoma can present in so many different ways, it is important to consider lymphoma in the differential diagnosis of a wide range of patient presentations. Clearly, if the patient presents with one or more suspicious enlarged lymph nodes, especially if immobile and painless, referral for possible excisional biopsy is required.

Likewise, lymphomas may present with oncological emergencies, such as SVC obstruction and spinal cord compression, in which circumstances, urgent hospital admission is mandatory. However, presentation may be less straight foreword and a high index of suspicion is required. In the situation where a patient presents with B symptoms or other non specific symptoms such as unexplained itch without any palpable lymphadenopathy, full blood count, basic biochemistry tests, serum LDH, serum protein electropheresis and CT body scan may uncover some indication of an underling lymphoma. As described above, certain patient groups are at much higher risk of lymphoma than the general population, and if any of these patients were to develop unusual signs or symptoms, a diagnosis of lymphoma would need to be strongly considered. – Irish Medical Times