EBV-Associated Tumors: Pathogenetic Insights for Improved Disease Monitoring and Treatment

Epstein-Barr virus (EBV) is a ubiquitous gamma-herpes virus that is a well-established risk factor for Hodgkin's lymphoma, Burkitt's lymphoma, a subset of T cell lymphomas and various tumors of epithelial cell origin with nasopharyngeal carcinoma as the most representative. Furthermore, EBV-associated lymphoproliferative disorders are a well recognized major complication of immune suppression. EBV generally establishes a life-long asymptomatic infection in memory B lymphocytes, by mimicking cellular signaling pathways that regulate antigen-dependent B cell differentiation. In the long-lived memory B lymphocyte pool, the virus is almost completely silent or expresses a very restricted set of latent proteins, evading thus the immune control by EBV-specific effectors. EBV-associated lymphoid and epithelial malignancies are characterized by a peculiar geographic distribution and distinctive epidemiologic and histopathologic and histogenetic features. Moreover, new histogenetic and molecular features have contributed to the recognition and the diagnosis of specific disease categories. The ability of the virus to establish life-long persistent infections in humans and to contribute to cell transformation is related to the biologic properties of a set of EBV-encoded proteins, differently expressed in both normal and transformed cells. In the last decade, our understanding of the latency programs activated by EBV in cellular backgrounds and the function of EBV-encoded proteins has considerably improved. The emerging picture indicates that EBV proteins are able to hijack critical cellular pathways to promote the proliferation and survival of infected cells, while impairing anti-viral immune responses. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion help to design novel treatment approaches for EBV-related malignancies. Moreover, it has been clearly shown that the quantification of circulating EBV DNA is a valuable tool in the diagnosis, clinical monitoring and prognosis of some EBV-associated tumors.