The AIDS-associated lymphomas represent a heterogeneous set of disease processes. The largest histologic subset of lymphomas is the large-cell lymphomas, which represent a spectrum of disease processes ranging from monomorphic monoclonal B-cell proliferations to very polymorphic and polyclonal mixtures of B cells, T cells and macrophages. The next most frequent class of systemic lymphoma are the small non-cleaved cell or Burkitt's-like lymphomas. These are relatively monomorphic, monoclonal malignant B-cell proliferations. The final subset of lymphomas, which are likely to become more common as the AIDS epidemic progresses, are the primary CNS lymphomas, which are expansions of EBV-immortalized B cells. The high incidence of tumor-associated EBV in the CNS lymphomas makes these lesions somewhat analogous to an opportunistic EBV infection. In HIV disease there is a long lag after infection before the appearance of clinical manifestations of impaired T-cell immunity. During this period, both appropriate B-cell proliferation in response to antigen (including the ubiquitous HIV) and abnormal B-cell proliferation (autoimmune, dysregulated) occur as the follicular architecture is disrupted by the virus and potential APC are exposed and/or infected with HIV. The destruction of FDC or the involution of their processes could interfere with the elimination by apoptosis of low-avidity B-cell clones. Antigen-competent B cells with pre-existing chromosomal translocations such as the t(8;14) (c-myc, IgH) would have a selective growth advantage in this setting. Figure 9 shows a schematic representation of pre-lymphomatous and lymphomagenic events as they are projected to occur. A similar pathogenetic scheme has been postulated for follicular B-cell lymphomas: PCR studies have demonstrated that a pool of t(14;18) (IgH;bcl-2) B-cells are present in lymph nodes featuring follicular hyperplasia. In response to antigen (the evidence favoring antigen drive is extensive hypersomatic mutation in sequences related to binding sites), B cells with the t(14;18) translocation have a selective advantage because the bcl-2 oncogene confers a resistance to apoptosis. Burkitt's lymphomas, particularly sporadic or HIV variants, fulfill at least the key criteria for antigen competence, mainly the presence of surface Ig. The c-myc-associated chromosomal translocational events are likely to occur early during the enzymatic machinations of gene rearrangement. Such B cells would be in the dysregulated cytokine and antigen milieu of HIV disease and ultimately could have a selective advantage. EBV infection of B cells probably requires activation and expression of the CD21 receptor. Furthermore, CD5+ B cells of CLL are refractory to EBV infection. Table 3 illustrates a possible high prevalence of this type of B cell in HIV-associated lymphomas. EBV infection of B cells is likely to occur after gene rearrangement and presumably after translocation. The combination of a lack of CD21 receptor and presence of CD5 may partially explain the low incidence of EBV in peripheral HIV lymphomas. EBV, after superinfection of a tumor B cell, undoubtedly affects growth. (This latter part is by inference if the final tumor is monoclonal and EBV-positive.) Such a hit could occur in later stages of oncogenesis after as yet undefined immunological events and t(8;14) translocation. The studies of Birx and colleagues demonstrated an increase in infectious EBV virions as the course of HIV disease progressed. Such virions are the candidates for tumor superinfection. Figure 9 represents immunerelated processes emphasized in this review that should be included in pathogenetic schemes involving chromosomal abnormalities and EBV. Research and speculation on the timing of c-myc translocations, p53 inactivation, Ig rearrangements and EBV infection in the context of endemic, sporadic and HIV-associated Burkitt's lymphoma are contentious and need further definition. These controversies, coupled with the complex, ill-understood immune dysregulation of HIV infection and the heterogeneous biology of the large-cell lymphomas described in this review, make it clear that the pathogenesis of AIDS lymphomas and Hodgkin's disease should be approached with an open mind. The ultimate goal of further research is to find rational therapies of these devastating complications of HIV disease.
