Non-Hodgkin's Lymphoma

Malignant monoclonal proliferation of lymphoid cells in sites of the immune system, including lymph nodes, bone marrow, spleen, liver, and GI tract.

In the USA, the annual age-adjusted incidence of non-Hodgkin's lymphomas (NHLs) ranges from 2.6 to 5.8/100,000. Increasing incidence with age is similar to that of acute leukemia. At age 80, the annual incidence is about 40/100,000.

The NHLs are a heterogeneous group of lymphoid malignancies that share certain features. Classification of NHLs is controversial and has undergone many revisions. Currently, there are two complementary approaches: one based on descriptions of lymph node architecture and histologic features (see Table 74-4) and the other based on the use of immunologic markers. A new classification based on immunologic markers and histologic features is shown in Table 74-5.

Etiology and Pathophysiology

The cause of most NHLs is unknown. However, immunosuppressed patients (eg, renal transplant patients) and patients with abnormally high immune function (eg, those with collagen-vascular disease) are at greater risk, as are those taking hydantoin drugs (eg, phenytoin), suggesting that the immune system plays a role. A virus is involved in at least some cases. Burkitt's lymphoma, endemic in Central Africa, is associated with Epstein-Barr virus infection. An aggressive T-cell leukemia-lymphoma is associated with human T-cell lymphotropic virus type I (HTLV-I) infection in Japan and the Caribbean. Patients with HIV often develop aggressive NHL.

In the pathophysiology of NHL, normal lymphoid tissue is replaced by the malignant lymphoma, resulting in immunodeficiency and infections. The bone marrow may be replaced, resulting in pancytopenia and subsequent bleeding and infection. Tumor bulk may obstruct or invade organs, ultimately causing death.

Symptoms and Signs

NHL appears to be multicentric in origin and is often widespread at presentation. A leukemic phase, detectable by peripheral blood testing, may occur. Most patients initially seek medical care because of cervical or inguinal lymph node enlargement. However, the skin, GI tract, bone, liver, and central nervous system constitute up to 10 to 20% of the primary sites of lymphoma at presentation. Occasionally, splenomegaly, bone marrow failure, autoimmune hemolytic anemia, and autoimmune thrombocytopenia are presenting features. Systemic symptoms (fever, night sweats, loss of weight, pruritus) are not as common as in Hodgkin's disease. Waldeyer's tonsillar lymphatic ring is commonly involved in patients with GI lesions. Hypercalcemia is prominent in HTLV-I-related NHL but is rare in other types. Hypogammaglobulinemia may occur. However, occasionally a monoclonal serum M spike is found on serum protein electrophoresis and on immunoelectrophoresis.

Diagnosis

The diagnosis is made by a biopsy of a lymphatic site revealing the histologic features of malignant lymphoma. Clinical staging of NHL is similar to that of Hodgkin's disease, although a staging laparotomy is rarely required because the illness is usually disseminated when discovered. After a complete physical examination, CBC, blood chemistry profile, bone marrow aspirate, lymph node biopsy, chest x-ray, and abdominal CT scan, about 90% of patients are found to have stage III or IV disease. Other studies (eg, serum protein electrophoresis, skeletal x-rays, IV urography) are sometimes useful.

Prognosis and Treatment

In NHL, indicators of a good prognosis are nodular histologic pattern, limited stage, low number of extranodal sites, and younger age. Marrow involvement is a poor prognostic sign for high-grade lymphomas but not for low- or intermediate-grade lymphomas. Other poor prognostic signs are poor performance status, bulky abdominal disease, Hb < 12 g/dL, and serum LDH > 250 U/L. The rapidity of response to chemotherapy also predicts survival.

Chemotherapy has the potential to cure only patients with intermediate- and high-grade lymphomas. Paradoxically, aggressive therapy does not even prolong survival of patients with low-grade lymphomas, even though these tumors are extremely sensitive to chemotherapy. Therefore, therapy should be minimal with low-grade tumors and aggressive with intermediate- and high-grade tumors. Hemolymphopoietic growth factors may also be used.

Low-grade lymphomas: In stage I or II disease, often no therapy is indicated. The disease at these stages usually is asymptomatic, except in patients with lymphadenopathy. The clinical course of low-grade NHL is identical to that of chronic lymphocytic leukemia. Particularly in the elderly, a practical approach is to withhold treatment and to monitor closely until problems of progressive disabling constitutional symptoms clearly due to the NHL develop (ie, progression to stages III and IV). Regional radiation can be used in stage I or II disease to reduce the local bulky nodes and any resulting compromise of vital organs. Since most of these patients relapse despite regional radiotherapy, chemotherapy may be indicated to prevent relapses and to reduce disabling constitutional symptoms. However, even without chemotherapy, the disease is usually so indolent that it does not recur for 5 to 10 years.

In stages III and IV, most patients experience only lymphadenopathy. Although most patients respond to chemotherapy, the relapse rate is 10 to 20% annually. Even though 80 to 90% of patients with favorable prognostic histologic findings achieve a complete remission, only 10 to 20% are without disease after 10 years. Thus, it seems wise to avoid both the serious systemic toxicity inherent in aggressive combination chemotherapy and the risk of acute nonlymphocytic leukemia caused by chronic low-dose alkylating agents. Chemotherapeutic treatment is reserved for patients with progressive disabling constitutional symptoms. Most oncologists use a single alkylating agent (eg, chlorambucil 0.4 mg/kg as a single dose for 1 day every 28 days). This so-called pulse therapy has less myelotoxicity and, perhaps, less leukemogenic potential. Some physicians use relatively mild combination chemotherapy regimens (see Table 74-6). Local radiation can be used to reduce bulky nodes.

Intermediate- and high-grade lymphomas: These aggressive NHLs are rapidly growing tumors with a short natural history. In elderly patients with intermediate- and high-grade lymphomas who have good functional status and normal organ function, curative combination chemotherapy is generally feasible. In those elderly patients with poor functional status and cardiopulmonary, renal, or central nervous system impairment, chemotherapy is poorly tolerated and rarely successful. Clearly, the physician must weigh all of these factors before recommending chemotherapy.

Regimens developed specifically for the elderly are available. One such regimen, as shown in Table 74-6, uses cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone (CAP/BOP). However, doxorubicin is not well tolerated by the elderly (nor is methotrexate because it causes renal complications). Nearly identical complete remission rates were found for patients > 60 and those < 60 treated with this regimen. The toxicity was the same in both age groups, as was the duration of remission. Overall survival was 62% for those < 60 but only 35% for those > 60. However, most of the excess morbidity was related to factors other than lymphoma.