Among the most common HIV-associated lymphomas are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with immunoblastic-plasmacytoid differentiation (also involving the central nervous system). Lymphomas occurring specifically in HIV-positive patients include primary effusion lymphoma (PEL) and its solid variants, plasmablastic lymphoma of the oral cavity type and large B-cell lymphoma arising in Kaposi sarcoma herpesvirus (KSHV)–associated multicentric Castleman disease. These lymphomas together with BL and DLBCL with immunoblastic-plasmacytoid differentiation frequently carry EBV infection and display a phenotype related to plasma cells. EBV infection occurs at different rates in different lymphoma types, whereas KSHV is specifically associated with PEL, which usually occurs in the setting of profound immunosuppression. The current knowledge about HIV-associated lymphomas can be summarized in the following key points: (1) lymphomas specifically occurring in patients with HIV infection are closely linked to other viral diseases; (2) AIDS lymphomas fall in a spectrum of B-cell differentiation where those associated with EBV or KSHV commonly exhibit plasmablastic differentiation; and (3) prognosis for patients with lymphomas and concomitant HIV infection could be improved using better combined chemotherapy protocols in-corporating anticancer treatments and antiretroviral drugs.

AIDS-related primary effusion lymphoma (PEL) is an HIV-associated malignancy characterized by the ability of the tumor cells to specifically home in the serous body cavities. Here we used gene expression profile analysis (about 12 000 genes) to further define the phenotype of PEL and to investigate the lymphoma relationship to normal B cells and to other tumor subtypes, including non-Hodgkin lymphomas (NHLs) of immunocompetent hosts and AIDS-associated NHL (AIDS-NHL). The results showed that PEL displayed a common gene expression profile that is clearly distinct from all NHLs of immunocompetent hosts and AIDS-NHL subtypes and, in contrast to those, is not related to germinal center (GC) or memory B cells. The gene expression profile of PEL was defined as plasmablastic because it showed features of both immunoblasts identified by Epstein-Barr virus (EBV)–transformed lymphoblastoid cell lines and AIDS immunoblastic lymphoma, and plasma cells, as defined by multiple myeloma cell lines. Finally, our results identify a set of genes specifically expressed in PEL tumor cells. Their expression was validated at the protein level, suggesting their potential pathogenetic and clinical significance.

Background: The gene encoding the DNA repair enzyme O⁶-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents. Methods: In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan–Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided. Results: Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P = .01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P = .02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status. Conclusion: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.

Angioimmunoblastic lymphoma (AILT) is the second most common subtype of peripheral T-cell lymphoma (PTCL) and is characterized by dismal prognosis. Thus far, only a few studies have dealt with its molecular pathogenesis. We performed gene expression profile (GEP) analysis of six AILT, six anaplastic large cell lymphomas (ALCL), 28 PTCL-unspecified (PTCL/U), and 20 samples of normal T lymphocytes (including CD4⁺, CD8⁺, and activated and resting subpopulations), aiming to (a) assess the relationship of AILT with other PTCLs, (b) establish the relationship between AILT and normal T-cell subsets, and (c) recognize the cellular programs deregulated in AILT possibly looking for novel potential therapeutic targets. First, we found that AILT and other PTCLs have rather similar GEP, possibly sharing common oncogenic pathways. Second, we found that AILTs are closer to activated CD4⁺, rather than to resting or CD8⁺ lymphocytes. Furthermore, we found that the molecular signature of follicular T helper cells was significantly overexpressed in AILT, reinforcing the idea that AILT may arise from such cellular counterpart. Finally, we identified several genes deregulated in AILT, including PDGFRA, REL, and VEGF. The expression of several molecules was then studied by immunohistochemistry on tissue microarrays containing 45 independent AILT cases. Notably, we found that the vascular endothelial growth factor (VEGF) was expressed not only by reactive cells, but also by neoplastic cells, and that nuclear factor-κB (NF-κB) activation is uncommon in AILT, as suggested by frequent exclusively cytoplasmic c-REL localization. Our study provides new relevant information on AILT biology and new candidates for possible therapeutic targets such as PDGFRA (platelet-derived growth factor α) and VEGF. [Cancer Res 2007;67(22):10703–10]

Learning Objectives: After completing this course, the reader will be able to: Assess patients with EBV-associated lymphoproliferative disorders.Describe the pathogenesis of the lymphoproliferative disorders linked to EBV infection.Evaluate EBV cell–based immunotherapy for use in patients with EBV-associated lymphoproliferative disorders. CME This article is available for continuing medical education credit at CME.TheOncologist.com Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt's lymphoma, classic Hodgkin's lymphoma, and lymphomas arising in immunocompromised individuals (post-transplant and HIV-associated lymphoproliferative disorders). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal type natural killer/T-cell lymphoma, and other rare histotypes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation. However, the exact mechanism by which EBV promotes oncogenesis is an area of active debate. The focus of this review is on the pathology, diagnosis, classification, and pathogenesis of EBV-associated lymphomas. Recent advances in EBV cell–based immunotherapy, which is beginning to show promise in the treatment of EBV-related disorders, are discussed.