HIVRelated Lymphomas

While many HIV-related lymphomas are obvious highgrade lesions that rarely need molecular confirmation for diagnostic purposes, situations arise when molecular confirmation of the diagnosis is important. Benign lym-phadenopathies associated with HIV infection can be dramatic, with large hyperplastic follicles composed almost entirely of mitotically active centroblasts with only rare centrocytes. Furthermore, these follicles may contain a small number of B-cell clones. When a needle biopsy is performed, often only fragments of germinal centers are obtained without architectural references for histologic evaluation. Without these architectural references, the collections of germinal center cells can be confused with centroblasts of high-grade lymphoma. In addition, immunophenotypic analysis may show that the cells are monotypic. In this setting, analysis of IGH gene rearrangements may be very helpful for diagnosis. This type of clon-ality analysis also can distinguish a recurrence from a second independent lymphoma in patients with lymphoma that responded to therapy.

Molecular testing contributes to the subclassification of AIDS-related lymphomas. The presence of MYC translocations is supportive of BL. Accurate diagnosis of BL is particularly important because the treatment of BL is different from that of DLBCL and usually requires CNS prophylaxis. Identification of KSHV is indicative of a primary effusion lymphoma, or a KSHV-associated (PEL-like) extracavitary lymphoma. In addition, the finding of certain molecular markers is indicative of a particular biologic process and thus is informative. For example, the presence of EBV, and in particular the EBV gene expression profile, is reflective of the immune competence of the host, with patients that are more immunodeficient tend to have lymphomas with a type III latency pattern. As more biological therapies are developed, molecular classification will become increasingly important.

Figure 34-1. Model of tumor progression in EBV-positive solid organ posttransplantation lymphoproliferative disorders (PTLD). An initial step in the development of PTLD is the polyclonal expansion of EBV-infected B cells, as a result of either release from immune surveillance of latently infected cells or de novo infection. This expansion has a histologic appearance of a plasmacytic hyperplasia (PH). Subsequently, some clones with unknown selective advantages outgrow others, leading to oligo-clonal and then monoclonal expansions, which are still responsive to immune responses if restored. Each individual clone is represented by a different color of EBV. These lesions have the histologic appearance of a polymorphic PTLD. However,if genetic alterations in oncogenes or tumor suppressor genes occur, a truly neoplastic process arises, which may no longer be responsive to immune surveillance mechanisms. Mutation in BCL6 (BCL-6) alone does not appear to affect the morphologic features, but cases with structural alterations in TP53 (p53), NRAS (N-ras), or MYC (c-myc), or some combination of these, have the histologic appearance of a monomorphic malignant lymphoma (ML) or, more rarely, a multiple myeloma/plasmacytoma (MM). (Reprinted from Cesarman E. Epstein-Barr virus (EBV) and lymphomagenesis. FrontBiosci. 2002;7:e58-e65.)

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