Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-drivenpathological process

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis characterized by the presence in the serum of a monoclonal cryoprecipitable IgM with rheu matoid factor (RF) activity. Hepatitis C virus (HCV) has been recognized as its major etiologic factor. Because MC frequently evolves into overt B-cel l non Hodgkin's lymphoma (NHL), chronic HCV infection is hypothesized to le ad to both benign and malignant lymphoproliferative disease. In this study, we investigated mutations in the V-H and V-K genes of the B-cell clone ori ginating the overt B-cell lymphoma in a subject with MC. Mutational pattern s were analyzed longitudinally in two bone marrow biopsies obtained at the stage of MC, as well as in multiple involved tissues (bone marrow, liver, a nd peripheral blood cells) at the stage of overt NHL, Hybridization of vari able-diversity-joining (VDJ) PCR products with a probe specific for the neo plastic clone indicated that the lymphoma originated from one of the clones over-stimulated during MC. This clone producing an IgM highly homologous t o a protein with RF specificity may explain the MC syndrome in the patient. Moreover, the presence of an IgH ongoing mutation process and the expressi on of an Ig antigen receptor significantly homologous to an anti-HCV protei n support the hypothesis that the MC syndrome and the subsequent evolution to NHL are antigen-driven lymphoproliferative processes possibly sustained by HCV. Furthermore, the marked reduction in intra-clonal diversity in the last bone marrow biopsy obtained at the stage of overt NHL points out a min or dependence of the cells on the antigen-driven mechanism, although an int rinsic propensity of the neoplastic cell to undergo replacement mutations c annot be excluded. Int. J. Cancer 87:211-216, 2000. (C) 2000 Wiley-Liss, In c.