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Pathogenesis:
AIDS NHL is primarily of B-cell origin and occurs in 5% to 10% of individuals with HIV infection. Several mechanisms are likely to be involved in the etiology of AIDS NHL though the cause still remains unknown. NHL is frequently associated with Epstein-Barr virus (EBV), a herpesvirus that infects B lymphocytes and stimulated their proliferation. EBV genomes can be detected in about 50% of AIDS-related lymphomas. Some cytokines such as interleukin 6 (IL-6), IL-10 and tumor necrosis factor (TNF), which enhance HIV-replication and are elevated during HIV-infection, are known to induce B-cell differentiation and may also be a factor in the development of NHL.
Cesarman et al. recently identified herpesvirus-like DNA (HHV8) in tissue samples from eight HIV-positive patients with an unusual form of NHL, so-called body-cavity-based, B-cell lymphomas. The herpesvirus-like DNA was identical to that recently found in KS lesions; however were 40 to 80 times more abundant in B-cell lymphomas.
Shiramizu B et al. have identified 4 cases of non-B cell NHL in which HIV was inserted near a known oncogene indicating a pathway for HIV-induced lymphoma.
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Site of Disease:
Common extra-nodal sites of AIDS NHL include the central nervous system, bone marrow, gastrointestinal tract, meninges, and liver. Less common sites include the mouth, rectum, heart and pericardium, and common bile duct.
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Symptoms:
NHL should be considered in patients presenting with a mass lesion at any site. Symptoms include enlarged spleen, hepatic obstruction, rectal pain, cardiac arrhythmia, unexplained gastrointestinal symptoms or GI bleeding. Constitutional symptoms included elevated fever, unexplained weight loss, and night sweats.
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Diagnosis:
Diagnosis of NHL is made by biopsy or examination of bone marrow, spinal fluid or other body fluids. X-rays, whole-body gallium scanning, computerized tomography (CAT) scans, magnetic resonance imaging MRI and bone marrow biopsies are used to stage NHL lymph node biopsy is often performed in patients with asymmetrical lymphadenopathy and rapidly enlarging or bulky nodes. Elevated uric acid and lactate dehydrogenase may indicate the need for further evaluation.
EBV sequences are consistently found in primary CNS lymphomas. This suggests that EBV might have a role as a marker in its diagnosis.
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Treatment:
Treatment of AIDS NHL normally involves cytotoxic chemotherapy. Combinations include mBACOD, COMP, COMP, NHL-7 and PRO-MACE/MOPP and an oral combination regimen. For individuals with poor immune function, evidence indicates that less aggressive regimens in combination with antiretroviral therapy may improve survival. The addition of growth factors such as G-CSF and GM-CSF may facilitate the administration of chemotherapy by reducing blood cell toxicity.
Sparano et al. have reported success using a combination of cyclophosphamide, doxorubicin, and etoposide (CDE) for the treatment of NHL. CDE was administered at a continuous rate over 96 hours every 28 days to 21 patients. Nineteen patients (90%) had extra-nodal disease and the mean CD4+ count of all patients was 87 cells/mm3. Patients were followed for a median on 21 months. 13 (62%) achieved a complete response and 5 (24%) achieved a partial response. Grade IV neutropenia was reported in 38% of the cycles; fevers were associated with 21% of the cycles. The median survival was 18 months.
The Eastern Cooperative Oncology Group of the National Cancer Institute is conducting a phase II trial of CDE in HIV-positive patients with NHL.
Investigational treatment approaches that may also be less immunosuppressive include monoclonal antibodies, clones of a single immune cell which can either destroy cancer cells themselves or carry toxins directly to the target site. Trials involving OK-B7, a monoclonal antibody attached to radioactive iodine, immunotoxin therapy, anti-CD19, anti-CD22, and anti-B4 attached to a potent immunotoxin, ricin, are underway. Cytokines such as interleukin 2 (IL-2) and IL-4, which inhibit tumor growth in vivo are currently under evaluation in several clinical trials.
Clinical trials are also underway for refractory AIDS-associated NHL using MGBG [methylglyoxal(bis)guanylhydrazone]. The activity of this compound is believed to result from the inhibition of polyamine synthesis. Results from a trial in 31 patients with relapsed or refractory NHL have been reported (Levine et al.). Of 25 evaluable patients, 2 complete responses were reported; 5 partial responses were reported and one patient had stable disease at 10 months of treatment. Clinical benefit was observed in terms of weight gain (43% of patients) and improved performance status (33% of patients).
A clinical trial of topotecan, a topoisomerase 1 inhibitor, is currently underway. Topotecan has been reported to be an effective anti-tumor treatment in a number of non-AIDS related neoplastic diseases.
Intirathecal prophylaxis against meningeal lymphoma with ara-C (cytosine arabinoside) or methotrexate is used in patients with systemic NHL to prevent relapse of disease within the meninges. It is also used as treatment when the lymphoma cells are present in the spinal fluid (lymphomatous meningitis).
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REFERENCES:
Cesarman E et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS related body-cavity-based lymphomas. NEJM 332:1181-5, 1995.
Gill PS et al. HIV-related malignant lymphoma: clinical aspects, treatment, and pathogenesis. Canc Invest 6: 413-6, 1988.
Hessol NA et al. Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Int Med 117:309-11, 1992.
Hernier BG at al. Pathogenesis of AIDS lymphomas. AIDS 8: 1025-1049, 1994.
MacMahon EME et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969-73, 1991.
Schiramizu B et al. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas. Cancer Res
54: 2069-72,1994.
So Y et al. Primary central nervous system lymphoma in AIDS: a clinical and pathological study. Ann Neurol 20: 566-72, 1986.
OTHER REPORTS:
Galleto G and Levine A. AIDS-associated primary central nervous system lymphoma (commentary). JAMA 269:92-3, 1993.
Leven A et al. Multicenter phase II study of mitoguazone (MGBG) in relapsed or refractory AIDS-lymphoma. Proc Am Soc Clin Oncol, 1995.
Levine A. Lymphoma in acquired immunodeficiency syndrome. Sem in Oncol 17(l):
104-112,1990.
Levine A et al. Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. JAMA 266: 84-8, 1991.
Marco M. The lymphoma project report: current issues in research and treatment of AIDS associated lymphoma. Treatment Action Group, 1995.
Remick SC et al. Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphomas. J Clin Onc 11: 1691-1701, 1993.
Urba WJ and Longo DL. Hodgkin's disease (review article). NEJM 326: 678-87, 1992.
Baumgartner J et al. Primary central nervous system lymphoma: Natural history and response to radiation therapy in 55 patents with acquired immunodeficiency syndrome. J Neurosurg 73:206-211, 1990.
Canellos GP et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. NEJM 327:1478-84,1992.
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