MOLECULAR PATHOLOGY OF AIDS-RELATED LYMPHOMAS - BIOLOGIC ASPECTS AND CLINICOPATHOLOGICAL HETEROGENEITY

A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immun odeficiency syndrome (AIDS) epidemic in 1982. AIDS-associated non-Hodg kin's lymphoma (AIDS-NHL) is almost invariably derived from B cells an d is classified as high- or intermediate-grade NHL, according to the w orking formulation. Two main histologic types are recognized, includin g small noncleaved cell lymphoma (SNCCL) and diffuse large cell lympho ma (DLCL). Pre-existing host factors putatively involved in lymphoma d evelopment include disrupted immunosurveillance, deregulated cytokine production, chronic antigen stimulation, and infection by Epstein-Barr virus (EBV). These alterations are associated with the development of multiple oligoclonal expansions which correspond to the clinical phas e known as persistent generalized lymphadenopathy (PGL). The appearanc e of a true AIDS-NHL is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monocl onal EBV infection, c-MYC and BCL-6 rearrangements, RAS mutations, p53 inactivation, and 6q deletions. These genetic lesions cluster into tw o distinct molecular pathways, which specifically associate with the d ifferent histologic subtypes of AIDS-NHL, i.e., AIDS-SNCCL and AIDS-DL CL. The presence of distinct genetic pathways for AIDS-SNCCL and AIDS- DLCL correlate with a number of clinical features which distinguish th ese two groups of tumors, including differences in the age of onset, C D4 counts at the time of presentation, time elapsed since HIV infectio n, and clinical outcome.