General Information About AIDS-Related Lymphoma
Background and Definitions
The AIDS was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicenter study described the clinical spectrum of non-Hodgkin lymphomas (NHLs) in the populations at risk for AIDS. In 1985 and 1987, the Centers for Disease Control and Prevention (CDC) revised the definition of AIDS to include human immunodeficiency virus (HIV)-infected patients who had aggressive B-cell NHL. The incidence of NHL has increased in an almost parallel course with the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases.
Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include the following:
- Diffuse large B-cell lymphoma.
- B-cell immunoblastic lymphoma.
- Small noncleaved lymphoma, either Burkitt or Burkitt-like.
The HIV-associated lymphomas can be categorized into the following:
- Aggressive B-cell lymphoma.
- Primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients.
- Primary effusion lymphoma.
- Plasmablastic multicentric Castleman disease.
- Hodgkin lymphoma.
Primary effusion lymphoma
Primary effusion lymphoma has been associated with Kaposi sarcoma-associated herpes-virus/human herpes virus type-8 (KSHV/HHV-8).[3,4] Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy. In addition to HHV-8, many cases are also associated with Epstein-Barr virus. Extension of lymphoma from the effusion to underlying tissue may occur. Plasmablastic multicentric Castleman disease is also associated with a coinfection of KSHV/HHV-8 and HIV.[5,6] Patients typically present with fever, night sweats, weight loss, lymphadenopathy, and hepatosplenomegaly. Patients may progress to primary effusion lymphoma or to plasmablastic or anaplastic large cell lymphoma. Anecdotal responses to rituximab, an anti-CD20 monoclonal antibody, have been reported.[Level of evidence: 3iiiDiv]
Incidence and Prevention
An international database of 48,000 HIV-seropositive individuals from the United States, Europe, and Australia found a 42% decline in the incidence of NHLs from 1997 to 1999 compared with 1992 to 1996, both for PCNSL and for systemic lymphoma. The introduction of highly active antiretroviral therapy (HAART) is the proposed explanation for this decline. The diagnosis of AIDS precedes the onset of NHL in approximately 57% of the patients, but in 30% of the patients the diagnosis of AIDS is made at the time of the diagnosis of NHL and HIV positivity. The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi sarcoma, which has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of NHLs; these risk groups include intravenous drug users and children of HIV-positive individuals.
In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from that of the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.
Common extranodal sites include the following:
- Bone marrow.
- Gastrointestinal tract.
Very unusual sites are also characteristic and include the following:
- Bile duct.
The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Treatment of the malignancy increases the risk of opportunistic infections that, in turn, further compromise the delivery of adequate treatment.
Prognosis and Survival
Prognoses of patients with AIDS-related lymphoma have been associated with the following:
- Stage (i.e., extent of disease, extranodal involvement, lactate dehydrogenase level, and bone marrow involvement).
- Severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood).
- Performance status.
- Prior AIDS diagnosis (i.e., history of opportunistic infection or Kaposi sarcoma).
Patients with AIDS-related PCNSL appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this severity was evidenced by patients with PCNSL having a higher incidence of prior AIDS diagnoses (73% vs. 37%), lower median number of CD4 lymphocytes (30/dL vs. 189/dL), and a worse median survival time (2.5 months vs. 6.0 months). This report also showed that patients with poor risk factors—defined as Karnofsky performance status less than 70%, history of prior AIDS diagnosis, and bone marrow involvement—had a median survival time of 4.0 months compared with a good prognosis group without any of these risk factors, who had a median survival time of 11.3 months.
In another report (NIAID-ACTG-142), prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomly assigned to receive either low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) or standard dose m-BACOD with granulocyte-macrophage colony-stimulating factor. No differences existed between these two treatments in terms of efficacy for disease-free survival, median survival, or risk ratio for death.[Level of evidence: 1iiA] On multivariate analysis, factors associated with decreased survival included age older than 35 years, history of intravenous drug use, stage III or stage IV disease, and CD4 counts of less than 100 cells/mm3. The median survival rates were 46 weeks for patients with one or no risk factors, 44 weeks for patients with two risk factors, and 18 weeks for patients with three or more risk factors. The International Prognostic Index may also be predictive for survival.[14-16] In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to HAART was independently associated with prolonged survival (relative hazard = 0.32; 95% confidence interval, 0.16–0.62).[Level of evidence: 3iiiDii]
HIV-associated Hodgkin lymphoma
Multiple reviews of Hodgkin lymphoma occurring in patients at risk for AIDS have been done;[18,19] however, Hodgkin lymphoma is still not part of the CDC definition of AIDS because of no clear demonstration of its increased incidence in conjunction with HIV, as is the case for aggressive NHL. The CDC, in conjunction with the San Francisco Department of Public Health, has reported a cohort study in which HIV-infected men had an excess risk that was attributable to the HIV infection of 19.3 cases of Hodgkin lymphoma per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although an excess incidence of Hodgkin lymphoma was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin lymphoma as an HIV-associated malignancy.
HIV-associated Hodgkin lymphoma presents in an aggressive fashion, often with extranodal or bone marrow involvement.[18,19,21] A distinctive feature of HIV-associated Hodgkin lymphoma is the lower frequency of mediastinal adenopathy compared with non-HIV-associated Hodgkin lymphoma. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin lymphoma, expression of Epstein-Barr virus-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or less. In a retrospective multicenter review of 62 patients, those receiving HAART with chemotherapy had a 74% 2-year overall survival (OS) versus a 30% OS for those not receiving HAART (P < .001).[Level of evidence: 3iiiA]
Note: Other PDQ summaries containing information about AIDS-related lymphoma include the following:
- Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311 (9): 565-70, 1984. [PUBMED Abstract]
- Rabkin CS, Yellin F: Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst 86 (22): 1711-6, 1994. [PUBMED Abstract]
- Simonelli C, Spina M, Cinelli R, et al.: Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 21 (21): 3948-54, 2003. [PUBMED Abstract]
- Nador RG, Cesarman E, Chadburn A, et al.: Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 88 (2): 645-56, 1996. [PUBMED Abstract]
- Goedert JJ: Multicentric Castleman disease: viral and cellular targets for intervention. Blood 102 (8): 2710-11, 2003.
- Marcelin AG, Aaron L, Mateus C, et al.: Rituximab therapy for HIV-associated Castleman disease. Blood 102 (8): 2786-8, 2003. [PUBMED Abstract]
- International Collaboration on HIV and Cancer: Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 92 (22): 1823-30, 2000. [PUBMED Abstract]
- Stebbing J, Gazzard B, Mandalia S, et al.: Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 22 (11): 2177-83, 2004. [PUBMED Abstract]
- Knowles DM, Chamulak GA, Subar M, et al.: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). The New York University Medical Center experience with 105 patients (1981-1986). Ann Intern Med 108 (5): 744-53, 1988. [PUBMED Abstract]
- Sparano JA: Clinical aspects and management of AIDS-related lymphoma. Eur J Cancer 37 (10): 1296-305, 2001. [PUBMED Abstract]
- Bower M, Gazzard B, Mandalia S, et al.: A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med 143 (4): 265-73, 2005. [PUBMED Abstract]
- Levine AM, Sullivan-Halley J, Pike MC, et al.: Human immunodeficiency virus-related lymphoma. Prognostic factors predictive of survival. Cancer 68 (11): 2466-72, 1991. [PUBMED Abstract]
- Kaplan LD, Straus DJ, Testa MA, et al.: Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med 336 (23): 1641-8, 1997. [PUBMED Abstract]
- Navarro JT, Ribera JM, Oriol A, et al.: International prognostic index is the best prognostic factor for survival in patients with AIDS-related non-Hodgkin's lymphoma treated with CHOP. A multivariate study of 46 patients. Haematologica 83 (6): 508-13, 1998. [PUBMED Abstract]
- Rossi G, Donisi A, Casari S, et al.: The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related systemic non-Hodgkin lymphoma. Cancer 86 (11): 2391-7, 1999. [PUBMED Abstract]
- Straus DJ, Huang J, Testa MA, et al.: Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: analysis of AIDS Clinical Trials Group protocol 142--low-dose versus standard-dose m-BACOD plus granulocyte-macrophage colony-stimulating factor. National Institute of Allergy and Infectious Diseases. J Clin Oncol 16 (11): 3601-6, 1998. [PUBMED Abstract]
- Hoffmann C, Wolf E, Fätkenheuer G, et al.: Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 17 (10): 1521-9, 2003. [PUBMED Abstract]
- Spina M, Vaccher E, Nasti G, et al.: Human immunodeficiency virus-associated Hodgkin's disease. Semin Oncol 27 (4): 480-8, 2000. [PUBMED Abstract]
- Thompson LD, Fisher SI, Chu WS, et al.: HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol 121 (5): 727-38, 2004. [PUBMED Abstract]
- Hessol NA, Katz MH, Liu JY, et al.: Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Intern Med 117 (4): 309-11, 1992. [PUBMED Abstract]
- Re A, Casari S, Cattaneo C, et al.: Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer 92 (11): 2739-45, 2001. [PUBMED Abstract]
- Dolcetti R, Boiocchi M, Gloghini A, et al.: Pathogenetic and histogenetic features of HIV-associated Hodgkin's disease. Eur J Cancer 37 (10): 1276-87, 2001. [PUBMED Abstract]
- Hentrich M, Maretta L, Chow KU, et al.: Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin's disease: results of a multicenter study. Ann Oncol 17 (6): 914-9, 2006. [PUBMED Abstract]