Table of Contents Purpose of This PDQ Summary General Information Cellular Classification Stage Information
Treatment Option Overview AIDS-Related Peripheral/Systemic Lymphoma AIDS-Related Primary Central Nervous System Lymphoma Get More Information From NCI Changes to This Summary (09/25/2008) More Information
Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of AIDS-related lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
- Prognostic factors.
- Cellular classification.
- Staging.
- Treatment options by cancer stage.
This summary 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.
Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Back to Top 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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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]
-
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]
-
Goedert JJ: Multicentric Castleman disease: viral and cellular targets for intervention. Blood 102 (8): 2710-11, 2003.
-
Marcelin AG, Aaron L, Mateus C, et al.: Rituximab therapy for HIV-associated Castleman disease. Blood 102 (8): 2786-8, 2003.
[PUBMED Abstract]
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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]
-
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.
[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]
-
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]
Back to Top 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]
References
-
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.
[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]
-
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.
[PUBMED Abstract]
Back to Top Stage Information
Although stage is important in selecting the treatment of patients with
non-Hodgkin 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 more than 10% of body weight in the 6 months before
diagnosis.
- Unexplained fever with temperatures higher than 38° C.
- Drenching night sweats. (Refer to the PDQ summary on Fever, Sweats, and Hot Flashes for more information.)
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 = liver |
L = lung |
M = marrow |
S = 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.
References
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Lymphoid neoplasms. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 393-406.
-
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.
[PUBMED Abstract]
-
Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Semin Oncol 27 (4): 442-53, 2000.
[PUBMED Abstract]
-
Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. JAMA 261 (5): 719-24, 1989.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
Raphael BG, Knowles DM: Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. Semin Oncol 17 (3): 361-6, 1990.
[PUBMED Abstract]
Back to Top Treatment Option Overview
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
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.
References
-
Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Semin Oncol 27 (4): 442-53, 2000.
[PUBMED Abstract]
-
Tirelli U, Bernardi D: Impact of HAART on the clinical management of AIDS-related cancers. Eur J Cancer 37 (10): 1320-4, 2001.
[PUBMED Abstract]
Back to Top AIDS-Related Peripheral/Systemic Lymphoma
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 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.[1-4] 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).[5-7] 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 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.[4,8-14][Level of evidence: 3iiiDiv] 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.[3,4,13-16] 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: 3iiiDiv] 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 (AMC-010) 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.[19-21][Level of evidence: 3iiiDiv]
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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 Web site.
References
-
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]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[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]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
-
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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
Back to Top 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 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.[4-6] 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 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 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. 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 35 Gy to 40 Gy 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]
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
General information about clinical trials is also available from the NCI Web site.
References
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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]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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Nyberg DA, Federle MP: AIDS-related Kaposi sarcoma and lymphomas. Semin Roentgenol 22 (1): 54-65, 1987.
[PUBMED Abstract]
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Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
Back to Top Get More Information From NCI
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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.
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Back to Top Changes to This Summary (09/25/2008)
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.
Stage Information
Editorial changes were made to this section.
Back to Top More Information
About PDQ
Additional PDQ Summaries
Important:
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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