General Information About AIDS-Related Lymphoma
Background and Definitions
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 of AIDS. The incidence of NHL has increased in a course almost parallel to that of the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases. Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the incidence of lymphomas has decreased, and outcomes have improved. Higher CD4-positive T-lymphocyte (CD4) counts in the HAART era have been associated with a shift in histologic diagnoses. The shift is away from primary effusion lymphoma and primary CNS lymphoma, which occur with the lowest CD4 counts, and toward histologies that occur at higher CD4 counts, such as Burkitt lymphoma and Hodgkin lymphoma (HL).[4-6] In contrast to less-frequent incidences of all the lymphoproliferative disorders in the HAART era, the incidence rate of anal cancer has not changed.
Pathologically, AIDS-related lymphomas comprise 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 (including 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 (see above).
- Primary central nervous system lymphoma (PCNSL).
- Primary effusion lymphoma.
- Plasmablastic multicentric Castleman disease.
HIV-associated Hodgkin lymphoma
Multiple reviews of HL occurring in patients at risk of AIDS have been done;[8,9] however, HL is still not part of the Centers for Disease Control and Prevention (CDC) definition of AIDS because no clear demonstration of its increased incidence in conjunction with HIV has been shown, 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 in 19.3 cases of HL per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although this report found an excess incidence of HL in HIV-infected homosexual men, additional epidemiologic studies will be needed before the CDC will reconsider HL as an HIV-associated malignancy.
HIV-associated HL presents in an aggressive fashion, often with extranodal or bone marrow involvement.[8,9,11] A distinctive feature of HIV-associated HL is the lesser frequency of mediastinal adenopathy compared with non–HIV-associated HL. Most patients in these series had either mixed cellularity or lymphocyte-depleted HL, expression of Epstein-Barr virus (EBV)-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or lower. In a retrospective multicenter review of 62 patients, those receiving HAART with chemotherapy had a 74% 2-year overall survival (OS) rate versus a 30% OS rate for those not receiving HAART (P < .001).[Level of evidence: 3iiiA] Among 201 patients with classical HL and HIV positivity, the 2- to 5-year OS rate of 88% to 90% after treatment with ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), or similar regimens, and HAART, was not significantly different from the OS rate of HIV-negative patients with newly diagnosed HL in two uncontrolled comparisons.[14,15][Level of evidence: 3iiiDiv] These studies confirm that patients with HL who were treated with standard regimens and HAART have outcomes that are similar to those of the uninfected population. Furthermore, immune function recovers over the course of 6 to 9 months after completion of chemotherapy.
Primary effusion lymphoma
Primary effusion lymphoma has been associated with Kaposi sarcoma (KS)-associated herpesvirus (KSHV)/human herpes virus type 8 (HHV8).[17,18] Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy. In addition to HHV8, many cases are also associated with EBV. Extension of lymphoma from the effusion to underlying tissue may occur.
Multicentric Castleman disease
The plasmablastic type of multicentric Castleman disease is also associated with a coinfection of KSHV/HHV8 and HIV. 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, the anti-CD20 monoclonal antibody, alone (along with HAART), have been reported.[20-23][Level of evidence: 3iiiDiv] For a prospective cohort of 84 patients treated with rituximab for HIV and HHV8 multicentric Castleman disease, the 5-year rate of relapse-free survival was 82% (95% confidence interval [CI], 72–92), and all patients responded again to rituximab at relapse.[Level of evidence: 3iiiDiii]
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 the same incidences in 1992 to 1996, both for PCNSL and for systemic lymphoma. The introduction of HAART is the proposed explanation for this decline. The diagnosis of AIDS precedes the onset of NHL in approximately 50% of the patients; however, in the other half 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 KS, 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, which 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 KS).
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 who had a higher incidence of previously diagnosed AIDS (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 score lower than 70%, history of previously diagnosed AIDS, and bone marrow involvement—had a median survival time of 4.0 months compared with patients in a good prognosis group who had none of these risk factors, and 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 lower than 100 cells/mm3. The International Prognostic Index may also be predictive for survival.[30-32] 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% CI, 0.16–0.62).[Level of evidence: 3iiiDii]
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]
- Dunleavy K, Wilson WH: How I treat HIV-associated lymphoma. Blood 119 (14): 3245-55, 2012. [PUBMED Abstract]
- Little RF, Wilson WH: Update on the Pathogenesis, Diagnosis, and Therapy of AIDS-related Lymphoma. Curr Infect Dis Rep 5 (2): 176-184, 2003. [PUBMED Abstract]
- Carbone A, Gloghini A: AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol 130 (5): 662-70, 2005. [PUBMED Abstract]
- Gopal S, Patel MR, Yanik EL, et al.: Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst 105 (16): 1221-9, 2013. [PUBMED Abstract]
- Piketty C, Selinger-Leneman H, Bouvier AM, et al.: Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol 30 (35): 4360-6, 2012. [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]
- Montoto S, Shaw K, Okosun J, et al.: HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol 30 (33): 4111-6, 2012. [PUBMED Abstract]
- Hentrich M, Berger M, Wyen C, et al.: Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study. J Clin Oncol 30 (33): 4117-23, 2012. [PUBMED Abstract]
- Kaplan LD: Management of HIV-associated Hodgkin lymphoma: how far we have come. J Clin Oncol 30 (33): 4056-8, 2012. [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]
- Bower M, Newsom-Davis T, Naresh K, et al.: Clinical Features and Outcome in HIV-Associated Multicentric Castleman’s Disease. J Clin Oncol 29 (18): 2481-6, 2011. [PUBMED Abstract]
- Goedert JJ: Multicentric Castleman disease: viral and cellular targets for intervention. Blood 102 (8): 2710-11, 2003.
- Uldrick TS, Polizzotto MN, Aleman K, et al.: Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood 124 (24): 3544-52, 2014. [PUBMED Abstract]
- Marcelin AG, Aaron L, Mateus C, et al.: Rituximab therapy for HIV-associated Castleman disease. Blood 102 (8): 2786-8, 2003. [PUBMED Abstract]
- Pria AD, Pinato D, Roe J, et al.: Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients. Blood 129 (15): 2143-2147, 2017. [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]
- 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]