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
sarcoma, and central nervous system (CNS) lymphomas. (Refer to the PDQ summaries on Kaposi Sarcoma Treatment and Primary CNS Lymphoma Treatment for more information.)
In 1984, a multicenter
study described the clinical spectrum of non-Hodgkin 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 lymphoma.
Primary effusion lymphoma has been associated with Kaposi
sarcoma-associated herpes-virus/human herpes virus type-8 (KSHV/HHV-8).[3,4]
Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy.[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: 3iiiDiv]
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 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 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 (NIAID-ACTG-142),
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
less than 100 cells/mm3. The median survival rates were 46
weeks for patients with one or no risk factors, 44 weeks for patients with two risk
factors, and 18 weeks for patients with three or more risk factors. The
International Prognostic Index may also be predictive for survival.[14-16]
In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to HAART was independently associated with prolonged survival (relative hazard = 0.32; 95% confidence interval, 0.16–0.62).[17][Level of evidence: 3iiiDii]
HIV-associated Hodgkin lymphoma
Since 1984, several series of cases of Hodgkin lymphoma occurring in patients
at risk for AIDS have been reviewed;[18,19] however, Hodgkin lymphoma is still
not part of the CDC definition of AIDS because of no clear
demonstration of its increased incidence in conjunction with HIV, as is the
case for aggressive NHL. The CDC, in conjunction with the
San Francisco Department of Public Health, has reported a cohort study in which
HIV-infected men had an excess risk that was attributable to the HIV infection
of 19.3 cases of Hodgkin lymphoma per 100,000 person-years and 224.9 cases of
NHL per 100,000 person-years. Although an excess incidence
of Hodgkin lymphoma was found in HIV-infected homosexual men in this report,
additional epidemiologic studies will be needed before the CDC will reconsider
Hodgkin lymphoma as an HIV-associated malignancy.[20]
HIV-associated Hodgkin lymphoma presents in an aggressive fashion, often with
extranodal or bone marrow involvement.[18,19,21] A distinctive feature of
HIV-associated Hodgkin lymphoma is the lower frequency of mediastinal
adenopathy compared with non-HIV-associated Hodgkin lymphoma. Most patients in
these series had either mixed cellularity or lymphocyte-depleted Hodgkin
lymphoma, expression of Epstein-Barr virus-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or
less.[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]
References
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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.
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