PDQ® Treatment Health Professionals
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. In 1984, a multicentered study described the clinical spectrum of non-Hodgkin's lymphomas in the populations at risk for AIDS. In 1985 and 1987, the Centers for Disease Control (CDC) revised the definition of AIDS to include human immunodeficiency virus (HIV)-infected patients who had aggressive B-cell non-Hodgkin's lymphoma. The incidence of non-Hodgkin's lymphoma 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 diffuse large cell lymphoma; B-immunoblastic; and small non-cleaved, either Burkitt's or Burkitt's like. The HIV-associated lymphomas can be categorized into: 1) primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients; 2) systemic lymphoma; and 3) primary effusion lymphoma, also called body cavity-based lymphoma (BCBL). The latter has been associated with co-infection by the 1994 discovery of human herpes virus type-8 (HHV-8).[3,4] All of these lymphomas differ from non-HIV-related lymphomas in their molecular characteristics, presumed mechanism of pathogenesis, treatment, and clinical outcome. All 3 pathologic types are equally distributed and represent aggressive disease. In addition, there appears to be a marked increase in the incidence of lymphoma in patients with previously diagnosed AIDS or AIDS-related complex that, because these are secondary diagnoses, are not included in the CDC statistics. Reports from the National Cancer Institute have estimated the probability of developing a high-grade non-Hodgkin's B-cell lymphoma in this group of patients to be as high as 19.4% by 36 months after starting antiretroviral therapy. Other reports suggest a relatively constant rate of risk for the development of non-Hodgkin's lymphoma of 1.6% to 2.0% per year in a population with AIDS or AIDS-related complex.[6-8] The diagnosis of AIDS precedes the onset of non-Hodgkin's lymphoma in approximately 57% of the patients, but in 30%, the diagnosis of AIDS is made at the time of the diagnosis of non-Hodgkin's lymphoma and HIV positivity. The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi's sarcoma, that 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 non-Hodgkin's lymphomas; 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 the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal. 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. Therefore, 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, and bone marrow involvement), 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). Patients with AIDS-related primary CNS lymphoma 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 primary CNS lymphoma having a higher incidence of a prior AIDS diagnoses (73% versus 37%), lower median number of CD4 lymphocytes (30/dL versus 189/dL), and a worse median survival time (2.5 months versus 6.0 months). This same report 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, 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. There were no differences 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 IV disease, and CD4 counts of less than 100 cells per cubic millimeter. The median survival rates were 46 weeks for patients with 1 or no risk factors, 44 weeks for patients with 2 risk factors, and 18 weeks for patients with 3 or more risk factors.
Since 1984, several series of cases of Hodgkin's disease occurring in patients at risk for AIDS have been published.[12-14] However, Hodgkin's disease is still not part of the CDC definition of AIDS because there has been no clear demonstration of its increased incidence in conjunction with HIV, as is the case for aggressive non-Hodgkin's lymphoma. 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 disease per 100,000 person-years and 224.9 cases of non-Hodgkin's lymphoma per 100,000 person-years. Although an excess incidence of Hodgkin's disease was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin's disease as an HIV-associated malignancy.
The series referenced above are consistent in identifying several features of HIV-associated Hodgkin's disease. Specifically, HIV-associated Hodgkin's disease presents in a more aggressive fashion, often with extranodal or bone marrow involvement. A distinctive feature of HIV-associated Hodgkin's disease is the lower frequency of mediastinal adenopathy compared to non-HIV-associated Hodgkin's disease. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin's disease, B symptoms, and a median CD4 lymphocyte count of 300/dL or less. Median survival time ranges from 8 to 20 months, which is much poorer than the survival expected in patients with non-HIV-associated Hodgkin's disease. Potential causes of decreased survival include early death from other AIDS-related diseases, decreased efficacy of standard therapies, and/or increased toxic effects of treatment.
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-cell, B-immunoblastic, and small non-cleaved, either Burkitt's or Burkitt's like. All 3 pathologic types are equally distributed and represent aggressive disease.
AIDS-related lymphomas, although 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 target 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. EBV is detected in 30% of patients with small, non-cleaved and in 80% of patients with diffuse large cell lymphomas. The rare primary effusion lymphoma consistently harbors HHV-8, and frequently contains EBV. Other genetic lesions commonly detected in AIDS-related lymphomas are not seen. 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's lymphoma 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 non-Hodgkin's lymphomas.
Stages I, II, III, and IV non-Hodgkin's disease 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:
N = nodes H = liver L = lung M = marrow S = spleen P = pleura O = bone D = skin
Stage II non-Hodgkin's lymphoma 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 non-Hodgkin's lymphoma 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 non-Hodgkin's lymphoma 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 non-Hodgkin's lymphomas. 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. 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 one third of the patients presented with extranodal disease only. In a second series, 87% of the patients had extranodal disease at presentation. Two thirds of patients have stage IV disease at diagnosis. 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's) lymphomas present with stage IV disease, mostly because of bone marrow involvement. This compares with approximately a 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. While high-risk behavior should be looked for in every patient, HIV testing should probably be done for any patient who has Burkitt's 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.
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 levels of evidence summary for more information.
The treatment of 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, to date an incurable illness. In addition to antitumor therapy, essential components of an optimal non-Hodgkin's lymphoma treatment strategy include antiretroviral therapy, prophylaxis for opportunistic infections, and rapid recognition and treatment of intercurrent infections. Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, thereby compromising the potential for drug dose intensity. There is a risk of intercurrent opportunistic infection, which may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system thus increasing the likelihood of opportunistic infection. In general, response rates are lower than for a non-HIV population. Complete responses occur but tend to be of shorter duration with frequent relapses. The question is whether the curative potential of high-dose chemotherapy is so compromised by the treatment-related morbidity and mortality that low-dose chemotherapy should be used. Most studies have used a lower dose intensity, and delays in treatment have been common. Several investigators have attempted to use intensive chemotherapy regimens, with a median overall survival time for treated patients of approximately 6 to 9 months.[1-4] The patients with the more favorable prognoses and prolonged survival tend to have CD4 lymphocyte counts greater than 100/microliter, less disease (stage I or II), no systemic symptoms, good performance status, and no central nervous system or bone marrow involvement. The optimal dose intensity of chemotherapy in these patients is under clinical evaluation. In a randomized prospective trial, 198 HIV-seropositive patients with previously untreated, aggressive lymphoma received standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) or reduced-dose m-BACOD with GM-CSF only if needed. There were no differences in complete response rates, disease-free survival, or overall survival (median survival was 8 months).[Level of evidence: 1A] Reduced doses of m-BACOD caused fewer hematologic toxic effects and days of hospitalization with no loss of efficacy. Outside the context of a clinical trial, low-dose chemotherapy should be considered for most patients with HIV infection and a CD4 lymphocyte count under 200. Although m-BACOD was used in the randomized trial, many clinicians now employ half-dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Patients with HIV and CD4 lymphocyte counts over 200 may tolerate full-dose chemotherapy with fewer complications; it is unclear whether efficacy in this group of patients would be compromised with low-dose therapy.
As noted above, 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 to use regimens such as the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and the combination of intermediate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD), as commonly used with non-AIDS aggressive lymphomas.[1-3] In general, these studies have combined the various histologic subsets of AIDS-related systemic peripheral lymphomas. Unlike the non-HIV-related lymphomas, investigators have treated diffuse large cell/immunoblastic lymphoma as they have small noncleaved cell lymphoma. These studies have shown that complete remissions are possible, although the responses are often of short duration and relapses are frequent. 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. Relapses in the CNS are so common that the use of prophylactic intrathecal chemotherapy is considered standard for patients with bone marrow involvement. Overall complete responses have been seen in approximately 50% of patients. The complete response rate and survival time is greater in patients with diffuse large cell lymphoma. Whether patients with small noncleaved cell and immunoblastic lymphoma have a worse prognosis is unclear and varies from one series to another. The most appropriate treatment regimen for patients with AIDS-related lymphoma is not known. Delays in therapy and dose reductions are often necessary, and some investigators have advocated using lower-dose chemotherapeutic regimens. Since myelosuppression and opportunistic infections are the predominant toxic effects, effort has focused on combining combination chemotherapy with colony stimulating factors and antiretroviral therapy. Less myelosuppression was seen when a 96 hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE) was combined with filgrastim (G-CSF) and didanosine (ddI).
Until the 1980s, primary central nervous system (CNS) lymphoma was a rare disease. There has been a dramatic increase in primary CNS lymphoma in association with acquired immunodeficiency syndrome (AIDS). Primary CNS lymphoma accounts for approximately 0.6% of initial AIDS diagnoses and is the second most frequent 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. However, unlike AIDS-related systemic lymphomas in which 30% to 50% of tumors are associated with Epstein-Barr virus (EBV), AIDS-related primary CNS lymphoma has been reported to have a 100% association with EBV. 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 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.[4-6] Use of positron emission scanning has demonstrated an improved ability to distinguish primary central nervous system lymphoma (PCNSL) from toxoplasmosis.[7,8] PSNCL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful, since the vast majority of cerebral toxoplasmosis occur as a consequence of reactivity of a previous infection. If the IgG titer is less than 1:4, the disease is unlikely to be toxoplasmotic. A lumbar puncture may be useful to detect the up to 23% of patients with malignant cells in their cerebral spinal 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.[9-11] Diagnosis is made by biopsy. Primary CNS lymphoma 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 3500 to 4000 cGy range, median duration of survival has been only 72 to 119 days.[3,12,13] Survival is longer in younger patients with better performance status and absence of opportunistic infection. 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.
Date Last Modified: 06/1999