Extra-hepatic manifestations of HCV infection: From pathogenesis to clinical management

Hepatitis C virus is associated with chronic liver disease as well as with lymphoproliferative disorders such as mixed cryoglobulinemia and, likely, nonHodgkin’s lymphomas. The association between Hepatitis C virus infection and B-cell lymphoma shows a strong regional variation and the intimate pathogenetic involved in Hepatitis C virus-related lymphomas remains considerably unknown. Hepatitis C virus may exert its oncogenic potentials via an indirect mechanism or directly utilise other pathways. It is reasonable to assume that several different pathogenetic mechanisms operate in the wide spectrum of Hepatitis C virusrelated lymphoproliferative disorders, which include low and high-grade lymphomas, preceded by long standing or absence of mixed cryoglobulinemia. In this review, the etiopathogenetic role of Hepatitis C virus in lymphoproliferative diseases is discussed on the basis of epidemiological, immunophenotyping, and molecular considerations. A pathogenetic clue of potential relevance for the definition of innovative therapeutic approaches for HCV-related lymphoproliferations came from the molecular characterization of the immunoglobulin genes expressed by clonally expanded B cells, sustaining these disorders. In fact, several studies have consistently demonstrated that the immunoglobulins expressed by HCV-related B-cell lymphoproliferations share a very restricted use of variable region gene segments, particularly of the light chain. These findings provide the rational background apply these clonotypic immunoglobulins for vaccination purposes in this clinical setting.