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Background and Definitions
Acquired immunodeficiency syndrome (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 combined antiretroviral therapy (cART) in the mid-1990s, the incidence of lymphomas has decreased, and outcomes have improved. Higher CD4-positive T-lymphocyte (CD4) counts in the cART 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).[4,5,6] In contrast to less-frequent incidences of all the lymphoproliferative disorders in the cART 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:
The human immunodeficiency virus (HIV)-associated lymphomas can be categorized into the following:
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 cART with chemotherapy had a 74% 2-year overall survival (OS) rate versus a 30% OS rate for those not receiving cART (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 cART, 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 cART 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 herpesvirus 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.
Plasmablastic multicentric Castleman disease
Plasmablastic multicentric Castleman disease is also associated with a coinfection of KSHV/HHV8 and HIV.[19,20] 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, alone or with liposomal doxorubicin (along with cART), have been reported.[19,21][Level of evidence: 3iiiDiv] In a retrospective review of 113 patients, the use of rituximab for HIV-associated plasmablastic multicentric Castleman disease resulted in an 11-fold reduction in risk of developing lymphoma; however, higher rates of KS were seen.
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 cART 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:
Very unusual sites are also characteristic and include the following:
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:
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.[29,30,31] In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to cART was independently associated with prolonged survival (relative hazard, 0.32; 95% confidence interval, 0.16-0.62).[Level of evidence: 3iiiDii]
Other PDQ summaries containing information about AIDS-related lymphoma include the following:
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:
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, polyclonal, and monoclonal in origin. Although human immunodeficiency virus (HIV) does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T lymphocytes with the loss of regulation function that 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 most patients with AIDS-related lymphomas; molecular analysis suggests that the cells were infected before clonal proliferation began. The rare primary effusion lymphoma consistently harbors human herpesvirus type 8 and frequently contains EBV. HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.
Although stage is important in selecting the treatment of patients with non-Hodgkin lymphoma (NHL) who do not have AIDS, most patients with AIDS-related lymphomas have far-advanced disease.
Staging Subclassification System
The Ann Arbor staging system is commonly used for patients with NHL.[1,2] In this system, stage 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:
Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.
The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. 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.
Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.
For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).
A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:
The treatment of patients with AIDS-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by human immunodeficiency virus (HIV) infection. In addition to antitumor therapy, essential components of an optimal non-Hodgkin lymphoma treatment strategy include the following:[2,3]
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 treatment of 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 (Burkitt lymphoma). These lymphomas frequently involve the bone marrow and central nervous system (CNS) and, therefore, are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia that is commonly seen with human immunodeficiency virus (HIV) infection makes the use of immunosuppressive chemotherapy challenging.
The introduction of combined antiretroviral therapy (cART) has led to a marked reduction in opportunistic infections, prolonged survival with HIV infection, and a median overall survival (OS) for patients with AIDS-related lymphoma that is comparable to the outcome in the nonimmunosuppressed population.[1,2,3,4,5,6,7][Level of evidence: 3iiiDiv] The use of cART has also allowed 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.[1,2,3,4,5,6,7,8,9,10]
Several prospective nonrandomized trials and pooled individual data from 19 prospective trials that included 1,546 patients show that the addition of rituximab to combination chemotherapy improves the complete response rate, progression-free survival, and OS.[3,4,5,6][Level of evidence: 3iiiDiv] Several other prospective nonrandomized trials and the pooled individual data from the same 1,546 patients also show that infusional EPOCH (infusional etoposide, infusional vincristine, infusional doxorubicin, cyclophosphamide, and prednisone) produced better outcomes than did CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (OS HR, 0.33; P = .03).[3,6,7][Level of evidence: 3iiiDiv] Concurrent use of cART with the infusional EPOCH regimen is controversial; one group advocated for cART after completion of chemotherapy, while others allowed concurrent therapy.
For patients with Burkitt lymphoma, dose-modified regimens such as R-CODOX (cyclophosphamide, doxorubicin, vincristine, methotrexate, cytarabine and rituximab)-M/IVAC (ifosfamide, etoposide, and high-dose cytarabine) or R-EPOCH (etoposide, prednisone, vincristine, and doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride] in combination with rituximab) have shown good results with concurrent or sequential cART.[7,11,12]
Patients at risk of subsequent CNS involvement include those with bone marrow involvement or those with EBV identified in the primary tumor or in the cerebrospinal fluid (i.e., by polymerase chain reaction).[13,14] Intrathecal chemotherapy is usually considered for patients who are at higher risk of CNS involvement.
Highly selected patients with resistant or relapsed lymphoma after first-line chemotherapy and with continued responsiveness to cART 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.[15,16,17,18][Level of evidence: 3iiiDiv]
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with AIDS-related peripheral/systemic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
As with other AIDS-related lymphomas, primary central nervous system lymphoma (PCNSL) is an aggressive B-cell neoplasm, either diffuse large B-cell or diffuse immunoblastic non-Hodgkin lymphoma (a subtype of diffuse large B-cell lymphoma). AIDS-related PCNSL has been reported to have a 100% association with Epstein-Barr virus (EBV). These patients usually have evidence of low CD4-positive T lymphocyte counts, high human immunodeficiency virus viral load, severe debilitation, and 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. 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.[3,4,5] Use of positron emission scanning has demonstrated an improved ability to distinguish PCNSL from toxoplasmosis.[6,7] PCNSL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful because most cerebral toxoplasmosis occurs as a consequence of reactivity of a previous infection. If the immunoglobulin G titer is less than 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 because EBV is present in all patients with PCNSL. Despite the many evaluations, however, most patients with PCNSL require a pathologic diagnosis.[8,9,10] 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.
Radiation therapy alone has usually been used in this group of patients. With doses in the range of 35 Gy to 40 Gy, median duration of survival has been only 72 to 119 days.[2,12,13] Survival is longer in younger patients with better performance status and the absence of opportunistic infection. In the combined antiretroviral therapy (cART) era, a median survival of 18 months can be seen with radiation therapy alone. 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 cART.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with AIDS-related primary CNS lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of AIDS-related lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for AIDS-Related Lymphoma Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ AIDS-Related Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/aids-related-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389186]
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Last modified on: 8 September 2017