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Lymphoma 

Lymphoma

Chapter:
Lymphoma
Author(s):

James O. Armitage

DOI:
10.1093/med/9780199204854.003.220403_update_002

Update:

Treatment—updated information on use of biological agents.

Mature B cell lymphomas—new discussion of management of various subtypes of this disease.

Updated on 28 Nov 2012. The previous version of this content can be found here.
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date: 30 March 2017

Lymphomas are malignancies of lymphoid cells. Genetic abnormalities determine the nature of a lymphoma by leading to the overexpression, underexpression, or abnormal expression of specific genes (‘oncogenes’), which are typically those that regulate cell cycle differentiation, rate of proliferation, and apoptosis.

Clinical features—the usual manifestation is with palpable nontender lymphadenopathy. Symptoms from a large mediastinal mass are a common initial presentation. A significant minority of patients present with fevers, night sweats and/or weight loss. Manifestations due to bone marrow or gastrointestinal tract involvement are seen frequently in some subtypes of disease.

Diagnosis—this should always be based on evaluation by an expert haematopathologist of (preferably) an adequate biopsy of a lymph node, or of an extranodal tumor mass if lymph nodes are unavailable. Expression of surface proteins involved in cell recognition and intracellular signalling are important in diagnosis, predicting clinical course, and therapy, as are the presence or absence of specific chromosomal translocations. Various types of lymphoma are recognized, with initial division into Hodgkin’s disease and non-Hodgkin’s lymphomas.

Clinical approach to the patient—after the diagnosis of lymphoma is established, studies should be carried out to determine the extent of disease. The Ann Arbor Staging system defines (1) Stage I—one nodal site involved (IE if one site of localized extranodal involvement); (2) Stage II—two or more nodal sites involved, but only on one side of the diaphragm (IIE if one site of localized extranodal involvement plus regional nodes involved, but all on one side of the diaphragm); (3) Stage III—nodal involvement (including spleen) on both sides of the diaphragm; (4) Stage IV—bone marrow, liver, or other extensive extranodal involvement; with each stage being classified A (absence) or B (presence) of unexplained fever (i.e. >38 °C), drenching night sweats, or weight loss (≥10% in 6 months). The Ann Arbor staging, along with other factors, is used to determine a prognostic index for each patient, which informs decisions about management.

General approach to treatment—for most patients, the goal of therapy is to achieve a complete remission. Most cases are treated with cytotoxic chemotherapy, often in association with therapeutic antibodies, sometimes with radiotherapy, and sometimes with bone marrow transplantation. Decisions should be made in conjunction with the patient, and require good judgement in addition to technical knowledge.

Hodgkin’s disease

The incidence of Hodgkin’s disease is about 3 per 100 000 per year in Western countries. Its cause is unknown.

Diagnosis and classification—this requires the identification of Reed–Sternberg cells (which are of B-cell origin and typically CD15 and CD30 positive, but CD20 negative) in a characteristic cellular background, with subclassification into (1) classical Hodgkin’s disease—95% of cases; subdivided into (a) nodular sclerosis, (b) mixed cellularity, (c) lymphocyte depletion, and (very rarely) (d) lymphocyte-rich/predominant; (2) nodular lymphocyte predominant Hodgkin’s disease—5% of cases.

Prognostic factors—adverse prognostic factors at presentation include age over 45 years, Ann Arbor stage IV disease, male gender, white cell count over 15 × 109/litre, lymphocyte count less than 0.6 × 109/litre or less than 8% of all white cells, albumin less than 40 g/litre, and haemoglobin less than 10.5 g/dl. Patients with no adverse factors have a 5-year freedom from progression of over 80%, compared with about 40% for those with four or five factors. However, the most important factor in predicting outcome is response to therapy.

Treatment—(1) Primary therapy—patients with localized Hodgkin’s disease (i.e. stage I or nonbulky stage II) are usually treated with combined chemotherapy and radiotherapy or chemotherapy alone. Patients who present with B-symptoms or stage III or IV disease are best treated initially with a combination-chemotherapy regimen, with the most popular currently being ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine). (2) Relapse—25 to 35% of patients treated with chemotherapy for stage III or IV Hodgkin’s disease will suffer relapse after achieving a remission, and a few patients will fail to enter initial complete remission; autologous bone marrow transplantation can be curative in 25 to 50% of such patients.

Complications of treatment—(1) Short-term complications—these include hair loss, emesis, fatigue, anaemia, and infection due to chemotherapy-induced neutropenia. (2) Longer term complications—these are a major problem for young patients who are cured of their lymphoma; indeed, for patients with good-prognosis Hodgkin’s disease they might lead to a higher mortality rate than the Hodgkin’s disease itself. Radiotherapy can cause delayed pulmonary fibrosis, accelerated coronary artery disease, and the development of secondary cancers (particularly lung and breast). Complications of chemotherapy include treatment-related leukaemia, infertility, pulmonary fibrosis, heart failure, and aseptic necrosis of bone.

Non-Hodgkin’s lymphoma

The incidence of non-Hodgkin’s lymphoma varies from about 2 cases per 100 000 per year in East Asia to more than 15 per 100 000 peryear in the United States of America. The aetiology of most cases is unknown, but increased risk is associated with immune deficiencies (e.g. immunosuppression following organ transplantation, various hereditary immune deficiencies), agricultural chemicals, autoimmune disorders, treated Hodgkin’s disease, and some infectious agents (e.g. Helicobacter pylori, HTLV-1, HIV, EBV, HHV-8).

Classification—the World Health Organization (WHO) histological classification divides non-Hodgkin’s lymphomas into the following subtypes: (1) precursor B-cell and T-cell neoplasms; (2) mature B-cell neoplasms—including chronic lymphocytic leukaemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), mantle cell lymphoma, follicular lymphoma (22% of all cases), diffuse large B-cell lymphoma (31% of all cases); (3) mature T-cell and NK-cell neoplasms—including leukaemic/disseminated, cutaneous (e.g. mycosis fungoides, Sezary syndrome), other extranodal, nodal, and neoplasms of uncertain lineage and stage of differentiation.

Prognostic factors—these include the specific subtype of non-Hodgkin’s lymphoma and individual patient characteristics, with adverse factors including age over 60 years, Ann Arbor stage III/IV disease, serum lactate dehydrogenase level greater than normal, reduced performance status, and multiple extranodal sites of involvement by lymphoma.

Treatment—(1) Diffuse large B-cell lymphoma—all regimens will include rituximab unless the particular patient’s tumor has been shown to be CD20 negative; the most popular regimen is CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) plus rituximab, but other regimens including ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) plus rituximab, and EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab are at least as efficacious. Local radiotherapy is sometimes added to very bulky (i.e. >10 cm) sites of disease. About 80% of patients with localized disease and 50% of those with disseminated disease can be cured, and those who relapse from complete remission can sometimes be cured with autologous haematopoietic stem cell transplantation. (2) Follicular lymphoma—asymptomatic patients may initially be managed by ‘watchful waiting’, but almost all patients will progress and require therapy. There is no ‘standard’ treatment: the most often utilized initial treatments are single-agent chemotherapy, CVP (cyclophosphamide, vincristine, and prednisone), CHOP, and bendamustine or fludarabine-containing regimens, each usually combined with rituximab. Maintenance rituximab is often given for patients achieving a remission. An increasingly popular approach, and one that is sometimes utilized instead of watchful waiting, is single-agent therapy with rituximab. Most patients will eventually fail their initial treatment regimen, in which case a wide variety of treatments are used, including autologous and allogeneic haematopoietic stem cell transplantation. (3) Other subtypes of lymphoma—a wide variety of chemotherapeutic regimen are employed, depending on subtype of disease and the patient’s performance status. Eradication of Helicobacter pylori can cure some patients with gastric MALT lymphoma.

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