AIDS-Related Lymphoma

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of AIDS-Related Lymphoma.

AIDS-Related Lymphoma

General Information

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The acquired immunodeficiency syndrome (AIDS) was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi’s sarcoma, and central nervous system (CNS) lymphomas. (Refer to the PDQ summaries on Kaposi’s Sarcoma Treatment and Primary CNS Lymphoma Treatment for more information.) In 1984, a multicenter study described the clinical spectrum of non-Hodgkin’s lymphomas (NHLs) in the populations at risk for AIDS.¹ 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.²

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:

• 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:

• Aggressive B-cell lymphoma.
• Primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
• Primary effusion lymphoma.
• Plasmablastic multicentric Castleman disease.
• Hodgkin's lymphoma.

Primary effusion lymphoma has been associated with Kaposi’s 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.³ 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.^5,[Level of evidence: 3iiiDiii]

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.⁷ The introduction of highly active antiretroviral therapy (HAART) is the proposed explanation for this decline.⁸ 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.⁹ The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi’s 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.¹⁰ Common extranodal sites include bone marrow, liver, meninges, and gastrointestinal tract, while very unusual sites are also characteristic, including anus, heart, bile duct, gingiva, and muscles. 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.

Prognoses of patients with AIDS-related lymphoma have been associated with stage (extent of disease, extranodal involvement, lactate dehydrogenase level, and bone marrow involvement), age, severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood), performance status, and prior AIDS diagnosis (history of opportunistic infection or Kaposi’s sarcoma).¹¹ 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 a 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).¹² This report also showed that patients with poor risk factors (defined as Karnofsky performance status <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, prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomized 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.¹³ No differences existed between these two treatments in terms of efficacy for disease-free survival, median survival, or risk-ratio for death.^13,[Level of evidence: 1iiA] On multivariate analysis, factors associated with decreased survival included age older than 35, history of intravenous drug use, stage III or stage IV disease, and CD4 counts of <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.^14,15,16, 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).¹⁷ [Level of evidence: 3iiiDi]

HIV-associated Hodgkin's lymphoma

Since 1984, several series of cases of Hodgkin’s lymphoma occurring in patients at risk for AIDS have been reviewed;^18,19 however, Hodgkin’s 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’s lymphoma per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although an excess incidence of Hodgkin’s lymphoma was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin’s lymphoma as an HIV-associated malignancy.^20,

HIV-associated Hodgkin’s lymphoma presents in an aggressive fashion, often with extranodal or bone marrow involvement.^18,19,21 A distinctive feature of HIV-associated Hodgkin’s lymphoma is the lower frequency of mediastinal adenopathy compared with non-HIV-associated Hodgkin’s lymphoma. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin’s 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.²² 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).^23,[Level of evidence: 3iiiA]

¹ 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.

² 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.

³ 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.

⁴ 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.

⁵ Goedert JJ: Multicentric Castleman disease: viral and cellular targets for intervention. Blood 102 (8): 2710-11, 2003.

⁶ Marcelin AG, Aaron L, Mateus C, et al.: Rituximab therapy for HIV-associated Castleman disease. Blood 102 (8): 2786-8, 2003.

⁷ 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.

⁸ 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.

⁹ 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.

¹⁰ Sparano JA: Clinical aspects and management of AIDS-related lymphoma. Eur J Cancer 37 (10): 1296-305, 2001.

¹¹ 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.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ 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.

¹⁸ Spina M, Vaccher E, Nasti G, et al.: Human immunodeficiency virus-associated Hodgkin's disease. Semin Oncol 27 (4): 480-8, 2000.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² 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.

²³ 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.

Cellular Classification

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:

• Diffuse large B-cell lymphoma.
• B-cell immunoblastic lymphoma.
• Small noncleaved lymphoma, either Burkitt or Burkitt-like.

All three pathologic types are equally distributed and represent aggressive disease.

AIDS-related lymphomas, though usually of B-cell origin as demonstrated by immunoglobulin heavy-chain gene rearrangement studies, have also been shown to be oligoclonal and polyclonal as well as monoclonal in origin. Although HIV does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T lymphocytes whose loss of regulation function leads to hypergammaglobulinemia and polyclonal B-cell hyperplasia. B cells are not the targets of HIV infection. Instead, Epstein-Barr virus (EBV) is thought to be at least a cofactor in the etiology of some of these lymphomas. The EBV genome has been detected in varying numbers of patients with AIDS-related lymphomas; molecular analysis suggests that the cells were infected before clonal proliferation began.¹ EBV is detected in 30% of patients with small, noncleaved lymphomas and in 80% of patients with diffuse, large cell lymphomas. The rare, primary effusion lymphoma consistently harbors human herpes virus type-8 and frequently contains EBV.² HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.^3,

¹ Thorley-Lawson DA, Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350 (13): 1328-37, 2004.

² 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.

³ Thomas JA, Cotter F, Hanby AM, et al.: Epstein-Barr virus-related oral T-cell lymphoma associated with human immunodeficiency virus immunosuppression. Blood 81 (12): 3350-6, 1993.

Stage Information

Although stage is important in selecting the treatment of patients with non-Hodgkin’s lymphoma (NHL) who do not have acquired immunodeficiency syndrome (AIDS), the majority of patients with AIDS-related lymphomas have far-advanced disease. In general, the staging system used is the Ann Arbor system, which is identical to that used for non-AIDS-related NHLs.

Staging Subclassification System

Stages I, II, III, and IV NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:

• Unexplained loss of >10% of body weight in the 6 months before diagnosis.
• Unexplained fever with temperatures higher than 38° C.
• Drenching night sweats.

The designation “E” is used when extranodal lymphoid malignancies arise in tissues away from the major lymphatic aggregates. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation:

Notation for identification of sites

N = nodes H = liverL = lung M = marrowS = spleen P = pleura O = bone D = skin

Stage I

Stage I NHL means involvement of a single lymph node region (I), or localized involvement of a single extralymphatic organ or site (IE).^1,2,

Stage II

Stage II NHL means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE).^1,2,

Stage III

Stage III NHL means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIS+E).^1,2,

Stage IV

Stage IV NHL means disseminated (multifocal) involvement of one or more extralymphatic organs with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.^1,2,

A number of factors that are important for determining prognosis are not included in the staging system for NHLs. All of these factors should be considered when selecting treatment. Prognosis is related to the severity of the underlying immune deficiency (CD4 lymphocyte count), the presence or history of opportunistic infections (prior AIDS-defining illness), bone marrow involvement, performance status, and presence of extranodal disease.³ Typically, AIDS-related lymphomas are widespread with extranodal disease at the time of presentation. The most common extranodal sites are the gastrointestinal (GI) tract, central nervous system, bone marrow, and liver. In one series, the largest group of patients had both extranodal and nodal disease (43%), but 33% of the patients presented with extranodal disease only.⁴ In a second series, 87% of the patients had extranodal disease at presentation.^5,

At diagnosis, 66% of the patients have stage IV disease. In addition, unusual presentations include involvement of the rectum, heart, pericardium, pulmonary parenchyma, bile ducts, mouth, and subcutaneous and soft tissues. The clinical features of AIDS-related lymphomas correlate with histopathology. The majority of patients with small noncleaved cell (Burkitt) lymphomas present with stage IV disease, mostly because of bone marrow involvement. This compares with an approximately 40% stage IV presentation by those with immunoblastic and large cell lymphomas. A particular prevalence for GI involvement has been noted in patients who have immunoblastic and large noncleaved cell lymphoma types.⁶ While high-risk behavior should be looked for in every patient, HIV testing should probably be done for any patient who has Burkitt lymphoma or the atypical presentation of extranodal lymphoma that involves rare sites, i.e., rectum, GI tract, bone, or orbit. Similarly, malignant lymphoma should be considered in any HIV-infected patient who has progressive lymphadenopathy, tumors at any site, central nervous system symptoms, or unexplained wasting, fever, or abdominal pain.

¹ Lymphoid neoplasms. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 393-406.

² National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982.

³ Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Semin Oncol 27 (4): 442-53, 2000.

⁴ Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. JAMA 261 (5): 719-24, 1989.

⁵ 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.

⁶ Raphael BG, Knowles DM: Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. Semin Oncol 17 (3): 361-6, 1990.

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The treatment of patients with acquired immunodeficiency syndrome (AIDS)-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by HIV infection, which to date is a chronic incurable illness.¹ In addition to antitumor therapy, essential components of an optimal non-Hodgkin’s lymphoma treatment strategy include highly active antiretroviral therapy, prophylaxis for opportunistic infections, and rapid recognition and treatment of intercurrent infections.² Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, which compromises the potential for drug dose intensity. Intercurrent opportunistic infection is a risk that may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system and increases the likelihood of opportunistic infection.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

¹ Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Semin Oncol 27 (4): 442-53, 2000.

² Tirelli U, Bernardi D: Impact of HAART on the clinical management of AIDS-related cancers. Eur J Cancer 37 (10): 1320-4, 2001.

AIDS-Related Peripheral/Systemic Lymphoma

The treatment of acquired immunodeficiency syndrome (AIDS)-related lymphomas involves overcoming several problems. These are all aggressive lymphomas, which by definition are diffuse large cell/immunoblastic lymphoma or small noncleaved cell lymphoma. These lymphomas frequently involve the bone marrow and central nervous system and, therefore, are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia that is commonly seen with HIV infection makes the use of immunosuppressive chemotherapy difficult.

A large number of retrospective studies and several prospective studies have been reported using regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD), and infusional cyclophosphamide, doxorubicin, and etoposide.^1,2,3,4 The patients who go into remission are more likely to have less disease, no bone marrow or central nervous system (CNS) involvement, no prior AIDS-defining illness, and a better performance status. Patients at risk for subsequent CNS involvement include those with bone marrow involvement or those with Epstein-Barr virus identified in the primary tumor or in the cerebrospinal fluid (by polymerase chain reaction).^5,6,7 Intrathecal chemotherapy is usually considered for those patients at higher risk for CNS involvement.

In the pre-highly active antiretroviral therapy (HAART) era, a randomized trial of patients with HIV and either Burkitt's lymphoma (BL) or diffuse large B-cell lymphoma (DLBCL) compared standard dose chemotherapy and growth factor support with reduced-dose chemotherapy.¹ No difference was found in overall survival (OS) between the two dose levels, and no difference was observed between the historic groups (BL and DLBCL); however, the median survival was equally poor at 6 to 7 months.^1,[Level of evidence: 1iiA] The introduction of HAART has led to a marked reduction in opportunistic infections, prolonged survival with HIV infection, and a median OS for patients with AIDS-related lymphoma, which is comparable to the outcome in the nonimmunosuppressed population.^{4,8,9,10,11,12,13,14,}[Level of evidence: 3iiiDiii] The use of HAART has also allowed the use of standard dose and even intensive chemotherapy regimens to be given with reasonable safety to patients with AIDS-related lymphomas, which is comparable to the outcome in non-HIV patients.^{3,4,13,14,15,16} In a retrospective review of 363 patients with HIV-associated lymphoma, survival of patients with HIV-DLBCL improved in the HAART era, but survival of similarly treated patients with HIV-BL remained poor.^17,[Level of evidence: 3iiiDiii] Future studies will evaluate if more intensive chemotherapy appropriate for non-HIV patients with BL results in better outcomes for patients with HIV-BL.¹⁷ A prospective randomized comparison of rituximab plus CHOP (R-CHOP) versus CHOP in 150 patients with HIV-DLBCL and HIV-BL showed no difference in (OS); treatment-related infectious deaths occurred in 14% of patients who received R-CHOP versus 2% of patients who received CHOP alone (P = .035).^18,[Level of evidence: 1iiA]

Highly selected patients with resistant or relapsed lymphoma after first-line chemotherapy and with continued responsiveness to HAART underwent second-line chemotherapy followed by high-dose therapy and autologous peripheral stem cell transplantation. Long-term survivors have been reported anecdotally for these highly selected patients who relapsed.^19,20,21,[Level of evidence: 3iiiDiii]

¹ 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.

² Sparano JA, Lee S, Chen MG, et al.: Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 22 (8): 1491-500, 2004.

³ Ratner L, Lee J, Tang S, et al.: Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 19 (8): 2171-8, 2001.

⁴ Levine AM, Tulpule A, Espina B, et al.: Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response. J Clin Oncol 22 (13): 2662-70, 2004.

⁵ Gill PS, Levine AM, Krailo M, et al.: AIDS-related malignant lymphoma: results of prospective treatment trials. J Clin Oncol 5 (9): 1322-8, 1987.

⁶ Cingolani A, Gastaldi R, Fassone L, et al.: Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin's lymphomas. J Clin Oncol 18 (19): 3325-30, 2000.

⁷ Scadden DT: Epstein-Barr virus, the CNS, and AIDS-related lymphomas: as close as flame to smoke. J Clin Oncol 18 (19): 3323-4, 2000.

⁸ Palella FJ Jr, Delaney KM, Moorman AC, et al.: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338 (13): 853-60, 1998.

⁹ Antinori A, Cingolani A, Alba L, et al.: Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 15 (12): 1483-91, 2001.

¹⁰ 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.

¹¹ Tam HK, Zhang ZF, Jacobson LP, et al.: Effect of highly active antiretroviral therapy on survival among HIV-infected men with Kaposi sarcoma or non-Hodgkin lymphoma. Int J Cancer 98 (6): 916-22, 2002.

¹² Vaccher E, Spina M, Talamini R, et al.: Improvement of systemic human immunodeficiency virus-related non-Hodgkin lymphoma outcome in the era of highly active antiretroviral therapy. Clin Infect Dis 37 (11): 1556-64, 2003.

¹³ Mounier N, Spina M, Gabarre J, et al.: AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood 107 (10): 3832-40, 2006.

¹⁴ Weiss R, Mitrou P, Arasteh K, et al.: Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival--results of the German Multicenter Trial. Cancer 106 (7): 1560-8, 2006.

¹⁵ Wang ES, Straus DJ, Teruya-Feldstein J, et al.: Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer 98 (6): 1196-205, 2003.

¹⁶ Cortes J, Thomas D, Rios A, et al.: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 94 (5): 1492-9, 2002.

¹⁷ Lim ST, Karim R, Nathwani BN, et al.: AIDS-related Burkitt's lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol 23 (19): 4430-8, 2005.

¹⁸ Kaplan LD, Lee JY, Ambinder RF, et al.: Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 106 (5): 1538-43, 2005.

¹⁹ Re A, Cattaneo C, Michieli M, et al.: High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol 21 (23): 4423-7, 2003.

²⁰ Krishnan A, Molina A, Zaia J, et al.: Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Blood 105 (2): 874-8, 2005.

²¹ Costello RT, Zerazhi H, Charbonnier A, et al.: Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 100 (4): 667-76, 2004.

AIDS-Related Primary Central Nervous System Lymphoma

Until the 1980s, primary central nervous system lymphoma (PCNSL) was a rare disease. PCNSL has increased dramatically in association with acquired immunodeficiency syndrome (AIDS).¹ PCNSL accounts for approximately 0.6% of initial AIDS diagnoses and is the second most frequent central nervous system (CNS) mass lesion in adults with AIDS. As with other AIDS-related lymphomas, these are usually aggressive B-cell neoplasms, either diffuse large cell or diffuse immunoblastic non-Hodgkin’s lymphoma. Unlike AIDS-related systemic lymphomas, in which 30% to 50% of tumors are associated with Epstein-Barr virus (EBV), AIDS-related PCNSL has been reported to have a 100% association with EBV.² This percentage indicates a pathogenetic role for EBV in this disease. These patients usually have evidence of far-advanced AIDS, are severely debilitated, and present with focal neurologic symptoms such as seizures, changes in mental status, and paralysis.

Computed tomographic scans show contrast-enhancing mass lesions that may not always be distinguished from other CNS diseases, such as toxoplasmosis, that occur in AIDS patients.³ Magnetic resonance imaging studies using gadolinium contrast may be a more useful initial diagnostic tool in differentiating lymphoma from cerebral toxoplasmosis or progressive multifocal leukoencephalopathy. Lymphoma tends to present with large lesions, which are enhanced by gadolinium. In cerebral toxoplasmosis, ring enhancement is very common, lesions tend to be smaller, and multiple lesions are seen.^4,5,6 Use of positron emission scanning has demonstrated an improved ability to distinguish PCNSL from toxoplasmosis.^7,8 PSNCL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful because the vast majority of cerebral toxoplasmosis occur as a consequence of reactivity of a previous infection. If the IgG titer is <1:4, the disease is unlikely to be toxoplasmotic. A lumbar puncture may be useful to detect as many as 23% of patients with malignant cells in their cerebrospinal fluid (CSF). Evaluating the CSF for EBV DNA may be a useful lymphoma-specific tool since EBV is present in all patients with PCNSL. Despite all of these evaluations, however, the majority of patients with PCNSL require a pathologic diagnosis.^9,10,11 Diagnosis is made by biopsy. Sometimes, a biopsy is attempted only after failure of antibiotics for toxoplasmosis, which will produce clinical and radiographic improvement within 1 to 3 weeks in patients with cerebral toxoplasmosis.¹² PCNSL is often identified as a terminal manifestation of AIDS or on postmortem examination.

Radiation therapy alone has usually been used in this group of patients. With doses in the 3,500 to 4,000 cGy range, median duration of survival has been only 72 to 119 days.^3,13,14 Survival is longer in younger patients with better performance status and the absence of opportunistic infection.¹⁵ Most patients respond to treatment by showing partial improvement in neurologic symptoms. Autopsies have revealed that these patients die of opportunistic infections as well as tumor progression. Treatment of these patients is also complicated by other AIDS-related CNS infections, including subacute AIDS encephalitis, cytomegalovirus encephalitis, and toxoplasmosis encephalitis. Spontaneous remissions have been reported after highly active antiretroviral therapy.^16,

¹ 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.

² MacMahon EM, Glass JD, Hayward SD, et al.: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338 (8773): 969-73, 1991.

³ Goldstein JD, Dickson DW, Moser FG, et al.: Primary central nervous system lymphoma in acquired immune deficiency syndrome. A clinical and pathologic study with results of treatment with radiation. Cancer 67 (11): 2756-65, 1991.

⁴ Nyberg DA, Federle MP: AIDS-related Kaposi sarcoma and lymphomas. Semin Roentgenol 22 (1): 54-65, 1987.

⁵ Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.

⁶ Ciricillo SF, Rosenblum ML: Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 73 (5): 720-4, 1990.

⁷ Hoffman JM, Waskin HA, Schifter T, et al.: FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS. J Nucl Med 34 (4): 567-75, 1993.

⁸ Pierce MA, Johnson MD, Maciunas RJ, et al.: Evaluating contrast-enhancing brain lesions in patients with AIDS by using positron emission tomography. Ann Intern Med 123 (8): 594-8, 1995.

⁹ Cinque P, Brytting M, Vago L, et al.: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342 (8868): 398-401, 1993.

¹⁰ Cingolani A, De Luca A, Larocca LM, et al.: Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 90 (5): 364-9, 1998.

¹¹ Yarchoan R, Jaffe ES, Little R: Diagnosing central nervous system lymphoma in the setting of AIDS: a step forward. J Natl Cancer Inst 90 (5): 346-7, 1998.

¹² Mathews C, Barba D, Fullerton SC: Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis. AIDS 9 (11): 1243-50, 1995.

¹³ Baumgartner JE, Rachlin JR, Beckstead JH, et al.: Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 73 (2): 206-11, 1990.

¹⁴ Remick SC, Diamond C, Migliozzi JA, et al.: Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome. A retrospective analysis and review of the literature. Medicine (Baltimore) 69 (6): 345-60, 1990.

¹⁵ Corn BW, Donahue BR, Rosenstock JG, et al.: Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience. Cancer J Sci Am 3 (1): 52-6, 1997 Jan-Feb.

¹⁶ McGowan JP, Shah S: Long-term remission of AIDS-related primary central nervous system lymphoma associated with highly active antiretroviral therapy. AIDS 12 (8): 952-4, 1998.

Changes to This Summary (12/14/2006)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Added text about a multicenter review of patients receiving HAART with chemotherapy who had a greater rate of overall survival than those who did not receive HAART (cited Hentrich et al. as reference 23).

Aids-Related Peripheral/Systemic Lymphoma

Added Mounier et al. and Weiss et al. as references 13 and 14, respectively.

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