—  SYMPOSIUM #47  —

The Role of Infectious Agents in B-cell Lymphomas
Moderators: Dr. Miguel A. Piris and Dr. Steven H. Swerdlow

Section 1 - Kaposi's Sarcoma Herpesvirus and Lymphoid Malignancies

Daniel M. Knowles


In 1989, Knowles and colleagues and later other investigators described lymphomatous effusions, usually occurring in the absence of a solid tissue mass, in homosexual men with AIDS. These unusual B cell neoplasms were referred to as "body cavity-based lymphomas" because of their distinctive clinical presentation.

The Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), was identified in 1994 by Chang, Moore, Cesarman, Knowles and co-workers. This virus has been shown to be etiologically related to the development of Kaposi's sarcoma (KS) and also to be associated with multicentric Castleman's disease (MCD). Cesarman, Knowles and colleagues demonstrated that KSHV is preferentially associated with the "body cavity-based lymphomas" and showed that these KSHV-containing "body cavity-based lymphomas" exhibit a unique constellation of clinical, morphologic, immunologic, and molecular characteristics, thus constituting a distinct clinicopathologic entity. Knowles designated these lesions primary effusion lymphomas (PEL) to distinguish them from all other lymphomas occurring in the body cavities.

Primary effusion lymphomas comprise less than 3% of all AIDS-associated non-Hodgkin's lymphomas; they occur even less commonly in the general population. Among HIV-positive individuals, they occur almost entirely in severely immunocompromised homosexual men, median age 40 years. Approximately 60% of HIV-positive individuals who develop PEL have severe opportunistic infections and 40% have KS. These patients also occasionally develop MCD. The tumor initially presents as a lymphomatous effusion in the pleural, abdominal, and/or pericardial cavities and remains restricted to one or more body cavities in more than 80% of cases. Patients in whom PEL presents as a solid lesion usually later develop an effusion. These patients have a poor prognosis with a median survival of approximately five months.

Primary effusion lymphoma occurs very uncommonly in HIV-negative individuals, primarily men, median age 74 years. Most of the HIV-negative individuals who develop PEL hail from a KSHV seroprevalent region; they often have coexisting KS and/or MCD. These individuals are generally less immunocompromised than HIV-positive individuals who develop PEL. The lesion nearly always presents initially as an effusion in one or more body cavities, without extension to solid organs. Some HIV-negative individuals who develop PEL survive several months to years.

In Wright-Giemsa-stained, air-dried cytospin preparations, PEL cells display cytomorphologic features bridging immunoblastic and anaplastic large cell lymphoma. The malignant cells are generally large, sometimes extremely so, and are round or ovoid to polygonal. They contain moderate to abundant amphophilic to deeply basophilic cytoplasm and nuclei which may be large, round and regular or highly irregular and pleomorphic. The nuclei possess coarsely reticular chromatin and one to four large prominent nucleoli. Some of the cells may be bi- or multinucleated and resemble Reed-Sternberg cells; others may possess wreath-like nuclei, reminiscent of anaplastic large cell lymphoma. Mitotic figures are usually numerous. The PEL cells usually appear more uniform in size and shape in cell block preparations. Here, they appear to possess moderate to abundant eosinophilic cytoplasm and round to slightly irregular nuclei which contain one or more prominent nucleoli.

The immunophenotypic and molecular characteristics of PELs occurring in HIV-positive and in HIV-negative patients are essentially the same. One notable distinction is that the EBV genome is present in the majority of PELs occurring in HIV-positive individuals, but not in PELs occurring in HIV-negative individuals. Approximately 90% of the tumors express CD45, 100% express various activation-associated antigens, and 70% lack B cell-associated antigens and/or immunoglobulin. Nearly all PELs exhibit clonal immunoglobulin gene rearrangements, indicative of a clonal B-cell derivation. CD138 expression and evidence of immunoglobulin gene hypermutation suggests that PELs represent a post-germinal center stage of B cell differentiation close to the plasma cell stage. Oncogenes and tumor suppressor genes, i.e., C-MYC, BCL-1, BCL-2, BCL-6, RAS, and p53, which are commonly altered in various categories of non-Hodgkin's lymphoma, remain in the wild type configuration in PELs, although nearly 60% of PELs exhibit BCL-6 gene mutations.

Occasional, primarily HIV-positive, persons develop KSHV-positive solid tissue large cell immunoblastic lymphomas unassociated with a lymphomatous effusion during the course of their disease. Chadburn, Knowles and colleagues found that KSHV-positive solid lymphomas are virtually indistinguishable from PELs based on morphology, immunophenotype, immunogenotype, and molecular characteristics, although they may express B cell-associated antigens and immunoglobulin slightly more often than do PELs. Also, patients with KSHV-positive solid lymphomas may have a better survival. Thus, KSHV-containing solid lymphomas appear to represent a solid variant of PEL; Chadburn and Knowles have designated these lesions extra-cavitary PEL.

The virtually invariable occurrence of KSHV in PELs suggests that this virus is necessary for their development. PELs are latently infected with KSHV; latency allows the virus to remain in the infected cell, ensuring that the cell survives and will not be recognized as infected by the host immune system. KSHV contributes to lymphomagenesis by subverting the host-cell molecular signaling machinery to deregulate cell growth and survival. KSHV expresses a selected repertoire of genes in PEL cells that encode viral proteins which play important roles in lymphomagenesis. Deregulation of the NFK B pathway is an important strategy used by KSHV to promote lymphoma cell survival; the viral protein vFLIP is essential for this process.

Gene expression profiling has demonstrated that gene expression patterns can distinguish KSHV-positive PELs from KSHV-negative malignant lymphomas and have shown that PELs exhibit a profile lying between EBV-associated immunoblastic lymphoma and terminally differentiated multiple myeloma. Cesarman, Chadburn, Knowles and colleagues demonstrated that about 500 genes, including apoptosis regulators, cell cycle regulators, transcriptional factors, and signal transduction regulators are differentially expressed between KSHV-positive PELs and KSHV-negative lymphomatous effusions and 40 genes, four of which are regulators of the mitogen-activated protein kinase pathway, are differentially expressed between KSHV-positive, EBV positive and KSHV-positive, EBV negative PELs. Thus, alterations in the mitogen-activated protein kinase pathway may act as a co-factor in PEL development.

KSHV also has been found in association with plasmablastic lymphoma associated with MCD and germinotropic lymphoproliferative disorders occurring in HIV-negative individuals. The plasmablastic lymphomas differ from PELs in being EBV negative and lacking immunoglobulin gene mutations; they are thought to derive from naïve IgM lambda expressing B cells rather than terminally differentiated B cells.

References
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