KSHV-Positive Solid Lymphomas Represent an Extra-Cavitary Variant of Primary Effusion Lymphoma

Abstract

Primary effusion lymphoma (PEL) is a unique form of non-Hodgkin lymphoma (NHL) associated with Kaposi sarcoma-associated herpesvirus (KSHV; HHV-8) that displays a distinct constellation of clinical, morphologic, immunologic, and molecular characteristics. Rare KSHV-containing immunoblastic lymphomas occurring in solid tissues have been described. Whether they represent part of the spectrum of PEL has not been determined. The morphologic, immunophenotypic, and molecular features of KSHV-positive solid lymphomas occurring in 8 HIV+/AIDS patients were systematically investigated and compared with those of 29 similarly analyzed PELs. The 8 KSHV-positive solid lymphomas were virtually indistinguishable from the 29 PELs based on morphology (immunoblastic/anaplastic), immunophenotype (CD45 positive; T cell antigen negative; CD30, EMA, CD138 positive; CD10, CD15, BCL6 negative) and genotype (100% immunoglobulin genes rearranged; no identifiable abnormalities in C-MYC, BCL6, BCL1, BCL2; and uniformly EBV positive). The only identifiable phenotypic difference was that the KSHV-positive solid lymphomas appeared to express B cell-associated antigens (25%) and immunoglobulin (25%) slightly more often than the PELs (<5% and 15%, respectively; P = 0.11 and P = 0.08, respectively). The clinical presentation and course of the patients who develop KSHV-positive solid lymphomas were also similar, except for the lack of an effusion and somewhat better survival (median 11 months vs. 3 months). However, the 3 KSHV-positive solid lymphoma patients alive without disease 11, 25, and 44 months following initial presentation were recently diagnosed patients and, unlike the other patients with KSHV-positive solid lymphomas, received anti-retroviral therapy. These findings strongly suggest that these decidedly rare KSHV-positive solid lymphomas belong to the spectrum of PEL. Therefore, we propose that the KSHV-positive solid lymphomas be designated extra-cavitary PELs.

HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma and HHV8-positive intravascular large B-cell lymphoma

“…22 These 'solid lymphomas' show genetic features similar to those of primary effusion lymphoma, further supporting a close relationship between these two lymphomas. 8,9,20 Variations on the spectrum of changes associated with multicentric Castleman's disease have also been observed. Germinotropic lymphoproliferative disorder has histologic features similar to those of plasmablastic microlymphoma (Tables 1 and 2) but in contrast to multicentric Castleman's disease and its associated plasmablastic proliferations, germinotropic lymphoproliferative disorder affects HIV-negative individuals who present with lymphadenopathy without systemic symptoms and have a good outcome; HHV8-positive cells are coinfected by EBV.…”

“…4,6 Primary effusion lymphoma is a distinctive type of diffuse large B cell initially recognized in HIVpositive patients, characterized by occurrence in a body cavity unassociated with a contiguous solid mass, immunophenotypic and genetic features corresponding to a late postgerminal center B cell in most cases, 2,7-12 a distinctive gene expression profile 13,14 and a poor prognosis. 2,7,8,12,15 Tumor cells are usually coinfected by EBV, a g herpesvirus closely related to HHV8 (Tables 1 and 2). Nearly all cases of multicentric Castleman's disease in HIVpositive patients and a subset of multicentric Castleman's disease in HIV-negative individuals contain HHV8.…”

“…19 In addition, site of disease proved to be somewhat variable: involvement of the subarachnoid space has been described, so that primary effusion lymphoma may arise in spaces lacking a mesothelial lining. 8 In one remarkable case, a woman developed primary effusion lymphoma in an artificial cavity that had formed adjacent to the capsule of silicone breast implant, 19 demonstrating that the body cavity giving rise to primary effusion lymphoma does not even have to be a normal anatomic structure.…”

“…8,16,20,21 These have been called HHV8-positive or KSHV-positive solid lymphomas or extracavitary primary effusion lymphomas, 8,20 or KSHV-positive solid immunoblastic/plasmablastic diffuse large B-cell lymphomas. 22 These 'solid lymphomas' show genetic features similar to those of primary effusion lymphoma, further supporting a close relationship between these two lymphomas.…”

NK/T cell non-Hodgkin lymphoma in a HIV-positive patient

“…The majority are aggressive B cell lymphomas that also occur in immunocompetent patients, i.e., Burkitt lymphoma and diffuse large B cell lymphoma [1]. Additional B cell lymphomas occur predominately in HIV/AIDS patients, but only rarely in immunocompetent patients, and include primary effusion lymphoma (PEL), plasmablastic lymphoma of the oral cavity, and Kaposi sarcoma herpesvirus (KSHV; HHV-8) associated lymphomas arising in the setting of multicentric Castleman disease [1,2]. In contrast to immunocompetent patients, many of the lymphomas in HIV/AIDS patients are associated with herpes viruses, particularly Epstein-Barr virus (EBV) and KSHV.…”