B-cell lymphoma frequently occurs in immunosuppressed individuals. Genetic disorders of the immune system such as Wiskott-Aldrich syndrome, as well as immunosuppressive therapy used in organ transplantation, are associated with malignant transformation of B cells and an oligoclonal or monoclonal lymphoma. Non-Hodgkin’s B-cell lymphoma is a frequent manifestation of HIV infection, occurring in 4 to 10% of the affected population. The relative risk of lymphoma in HIV-infected individuals compared with matched uninfected controls is 60- to 100-fold. The incidence of B-cell lymphoma in this population appears stable despite the introduction of potent antiretroviral therapy and may increase as survival lengthens and control of opportunistic infections improves.
Causative factors operative in the development of lymphoma in AIDS are likely to be multiple. HIV provides a permissive environment in which lymphoma develops. Lymphoma in this setting may be regarded as an opportunistic neoplasm and is considered an AIDS-defining illness. Proliferative signals to B cells, whether from dysfunctional T cells, aberrant cytokine production, or infections (such as Epstein-Barr virus or HIV-1 itself), may induce polyclonal expansion of the B-cell population. This expanded population may provide targets for genetic abnormalities that lead to malignant transformation and emergence of several dominant clones.
The oligoclonal populations of malignant B cells seen in some HIV-infected individuals with lymphoma support such a model. Ultimately, a single malignant clone may emerge, leading to a monoclonal neoplasm. The chromosomal abnormalities frequently seen in B-cell lymphoma involve translocation of loci encoding the immunoglobulin genes with the c-myc oncogene. Over 75% of AIDS-related lymphomas manifest alterations in at least one proto-oncogene, and a large fraction also have alterations in at least one tumor-suppressor gene. Genetic evidence of Epstein-Barr virus is found in about one half of B-cell lymphomas in AIDS patients and virtually all primary CNS lymphomas in AIDS. A number of interacting factors are likely to be important in the pathogenesis of lymphoma in those patients with HIV infection united by the disorganization of immune function induced by HIV. Recently, KSHV or HHV-8 infection has been associated with a distinct subset of B-cell lymphomas that presents with body cavity effusions. These aggressive lymphomas also frequently have genomic material from Epstein-Barr virus.
Clinically, B-cell lymphoma in AIDS patients tends to be of high-grade histologic pattern and follows an aggressive clinical course. Small, noncleaved or large cell histologies account for nearly all lymphomas in this setting. The low-grade lymphomas are uncommon and may represent background rather than a neoplasm directly associated with immunosuppression. Rarely, B-cell acute lymphoblastic leukemia or T-cell neoplasms have been reported.
Most patients have extranodular disease involving the gastrointestinal tract, CNS, liver, soft tissues, or bone marrow. In one large series, nearly 80% of all patients diagnosed with B-cell lymphoma in AIDS had extra-nodal involvement. Lymphoma strictly confined to lymph nodes is uncommon.
Gastrointestinal lymphoma may occur anywhere from the esophagus to the anus. Primary CNS lymphoma is usually immunoblastic in histologic type. Such patients generally have solitary mass lesions in the parenchyma of the brain, whereas CNS involvement in conjunction with systemic lymphoma is more often meningeal in location. All AIDS patients diagnosed with systemic non-Hodgkin’s lymphoma should undergo careful CNS assessment with computed tomographic (CT) scan or magnetic resonance imaging (MRI) scan, as well as lumbar puncture with cytology.
Most AIDS patients with B-cell lymphoma are classified as having stage III (involving both sides of the diaphragm without visceral involvement) or stage IV (visceral involvement). Systemic “B” symptoms are frequent, but fever should not be immediately ascribed to lymphoma in AIDS patients, and secondary infectious causes need to be ruled out. Staging of patients should follow the approach used in other settings of non-Hodgkin’s lymphoma, with particular attention to the gastrointestinal tract, bone marrow, and CNS.
The major differential diagnosis to be considered with primary CNS lymphoma is Toxoplasma gondii infection or progressive multifocal leukoencephalopathy (PML). PML usually can be distinguished from CNS lymphoma by its lack of enhancement with gadolinium on MRI. CNS lesions due to lymphoma may be isodense or hypodense and contrast-enhancing on CT scan, and enhance on MRI, thereby resembling toxoplasmosis. Nonetheless, toxoplasmosis usually presents with multiple lesions throughout the neuraxis, whereas primary CNS lymphoma tends to be a single lesion located in a paraventricular site. Accessible lesions should be biopsied to distinguish between lymphoma and toxoplasmosis; lesions difficult to approach surgically may be empirically treated with antitoxoplasmal therapy for a limited time, generally 1 to 2 weeks. If no response is seen, lymphoma becomes more likely.
Alternatively, cerebrospinal fluid analysis for Epstein-Barr virus DNA compared with SPECT scanning may help distinguish abscess from non-Hodgkin’s lymphoma. Treatment for primary CNS lymphoma is radiation therapy and steroids, with taper of the steroids as rapidly as tolerated. Approaches are currently in clinical trial for those patients who relapse with reasonable underlying immune function and performance status.
The treatment of AIDS-related B-cell lymphoma pivots on a balance between the poor prognosis of the neoplasm and the limited tolerance of aggressive chemotherapy in this patient population. Both opportunistic infection and bone marrow suppression often limit the delivery of high doses of chemotherapy on schedule. Patients with prior AIDS-defining illness, particularly a history of opportunistic infection, have a poor prognosis compared with patients who present with lymphoma as their initial manifestation of AIDS. Similarly, more severely immunocompromised patients with low CD4 cell numbers have a poor outcome and are less tolerant of chemotherapy than are those patients with more intact immune function.
Among “good prognosis” patients with relatively intact immune function and/or those presenting with lymphoma as their AIDS manifestation, aggressive therapy with combination regimens is indicated. The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (“CHOP”) is most often used, although infusional regimens with etoposide, doxorubicin, and cyclophophamide also have reported good results. Hematopoietic growth factors to ameliorate cytopenias generally are needed. Antiretroviral therapy generally can be sustained, but systematic pharmacokinetic studies are lacking and significant drug-drug interactions may occur. We have noted no undue toxicity when using indinavir, 3TC, and d4T in conjunction with CHOP. For those patients who do not have CNS involvement at the time of presentation, prophylactic therapy to the CNS often is given to prevent CNS relapse. This may be particularly important for patients with small, noncleaved cell histology or bone marrow, or testicular or Waldeyer’s ring involvement. The response rate in patients undergoing systemic chemotherapy is on the order of 50%, but the long-term survival rate is still poor owing to frequent relapse and intervening infections. The potential for eradication of the non-Hodgkin’s lymphoma is real and should be pursued in select patients. Fifty per cent of patients achieve a complete remission and have a median survival of 18 months or longer. For those failing initial therapy, no clear second-line approach has been defined. Patients with this disorder should be treated in clinical trial settings whenever possible.
Patients with poor prognosis based on severe immune suppression and/or complicating opportunistic infections pose a particularly complex treatment dilemma. Some patients have opted for palliative therapy with corticosteroids because intensive chemotherapy may lead to further immune compromise and infection. Yet lymphoma is generally rapidly growing and fatal in patients who are not aggressively treated. Thus, the clinician needs to pursue therapy in such patients only with an informed discussion of the risks and benefits of treatment, honestly emphasizing the poor prognosis with or without chemotherapy.
Revision date: June 11, 2011
Last revised: by Jorge P. Ribeiro, MD