Main effusion lymphoma (PEL) is usually a very rare subgroup of B-cell lymphomas presenting as pleural, peritoneal and pericardial neoplastic effusions in the absence of a solid tumor mass or recognizable nodal involvement. non-AIDS-associated PEL. These KSHV+ EBV+/? cell lines are wellcharacterized, authenticated and mostly available from public biological ressource centers. The PEL cell lines display unique features and are clearly unique from other lymphoma cell lines. PEL cell lines represent an indispensable tool for the understanding of KSHV biology and its impact on the clinical manifestation of PEL. Studies on PEL cell lines have shown that a quantity of viral genes, expressed during latency or lytic life cycle, have effects on cell binding, proliferation, angiogenesis and inflammation. Also PEL cell lines are important model systems for the study of the pathology of PEL including the lack of invasive or destructive growth patterns and the peculiar propensity of PEL to involve body cavity surfaces. proto-oncogene, which segregates with BL , are mutually unique molecular events in the development of these unique malignant effusions . Other subtypes of lymphomas Azacitidine inhibition can present with a main neoplastic effusion. Many of these cases are KSHV-unrelated large B-cell lymphomas, also termed KSHV-unrelated PEL-like lymphomas . In these lymphomas the neoplastic cells do not display evidence of KSHV contamination, but display morphologic, immunophenotypic and genotypic features related to large B-cell lymphoma . PEL and KSHV-unrelated PEL-like lymphomas are different in terms of pathogenesis, morphologic-immunophenotypic features, clinical behaviour and prognosis. KSHV-unrelated PEL-like lymphoma cases, are associated with hepatitis C computer virus (HCV) (30C40%). The most frequently involved sites are peritoneum and pleura. The lymphoma cells usually show large cell morphology and B cell immunophenotype. The outcome of patients with KSHV-unrelated PEL-like lymphomas seems to be better than the one for PEL patients in the HIV + setting [27,31]. PEL as a lymphoma of the serous membranes The basic pathologic feature of PEL is usually a diffuse distributing along the serous membranes without markedly infiltrative or destructive growth patterns [3,14,33]. PEL is usually associated with peculiar imaging features including: a) peritoneal effusion or bilateral/unilateral pleural effusions, usually associated with pericardial effusion, b) normal mediastinal and parenchymal imaging findings and c) diffuse slight thickening of the serous membranes at computed tomography (CT) . As seen at autopsy PEL presents as multiple small tumor foci involving the serous membranes, which appear irregularly thickened [16,24,33]. Furthermore, the lymphomatous infiltration of serosal surfaces is adjacent to the site of primary malignant effusion. Notably, these aspects correlate closely with imaging findings of PEL revealed by CT scan. Overall, these features would indicate a primary serous membrane neoplasm. In the natural history of PEL the disease initially affects one single serous cavity, usually remains localized to body cavities throughout the clinical course of the lymphoma, and occasionally extends into tissues underlying the serous membranes, including the omentum Azacitidine inhibition and the outer parts of the gastrointestinal tract wall. Involvement of mediastinal lymph nodes, visceral lymphatics or other superficial and deep lymph nodes, with or without parenchymal infiltration, has been observed Azacitidine inhibition in some cases [2,3,16,33]. PEL pathogenesis and the role of KSHV on PEL development and progression The exact mechanism by which KSHV promotes oncogenesis in B cells leading is an area of active investigation. infection of B cells with KSHV is ineficient, and does not lead to transformation of these cells . Therefore, cell lines derived from PEL specimens, where natural infection by KSHV occurred is not known. Latent gene products Five latent gene products that are thought Tgfb3 to play significant roles in PEL pathogenesis are LANA (ORF73), viral cyclin (v-Cyc, ORF72), viral FLICE inhibitory protein (v-FLIP, ORF71), viral interferon Azacitidine inhibition regulatory factor 3 (vIRF-3 or LANA-2) and viral interleukin-6 (vIL-6, ORFK2). LANA, encoded by ORF73, is required for the replication of the latent episomal viral DNA; it binds to the latent origin of replication in the terminal repeat subunits of the viral genome. In addition it is a multifunctional protein with the potential to significantly alter cellular physiology by recruiting a large variety of cellular proteins linked to transcriptional regulation or proliferation control, including p53, pRB, c-myc, brd2, brd4, CBP, DNAMt1, DNAMt3, GSK3 [reviewed in 35]. LANA is expressed during latency and represents the most consistently detected viral protein in KSHV-associated tumor cells. V-cyclin (vCYC), encoded by Azacitidine inhibition ORF72, represents another candidate KSHV oncogene because of its homology to the human cyclin-D/Prad oncogene. In general, cyclin-D proteins (D1 D2, D3) associate with specific cyclin-dependent kinases (CDKs) and these complexes phosphorylate Rb family members. vCYC associates with cdk2, cdk4 and cdk6 but appears to promote phosphorylation of its targets mainly in concert.