Hepatitis C virus infection and lymphoma

Abstract

Apart from its well known role as an etiological agent for non-A and non-B viral hepatitis, there is growing evidence that hepatitis C virus is associated to B-cell non-Hodgkin lymphoma. The association between HCV and lymphoproliferative disorders has been recently postulated based on epidemiological data, biological studies and clinical observations. Although various subtypes of lymphomas appear to be associated to HCV, diffuse large B-cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia and marginal zone lymphoma appeared to be particularly represented among HCV-positive patients. The causative role of HCV in those disorders has been further supported by the response to antiviral therapy. Despite a better understanding of pathophysiological processes at stake leading from HCV infection to overt lymphoma, many issues still need to be further elucidated. Although HCV has been demonstrated to directly infect peripheral blood mononuclear cells both in vitro and, in some cases, in vivo, a strong body of evidence rather supports the hypothesis of an indirect transformation mechanism by which sustained antigenic stimulation leads from oligoclonal to monoclonal expansion and sometimes to lymphoma, probably through secondary oncogenic events. Here, we review epidemiological and biological studies, as well as clinical data on antiviral therapy, linking HCV-infection to B-cell non-Hodgkin lymphoma.

Figure 1.

Villous lymphocyte. Blood smear showing a villous lymphocyte with conspicuous cytoplasmic villous protrusions from a patient with splenic lymphoma with villous lymphocytes (SLVL). May-Grünwald-Giemsa stain, X1000.

Figure 2.

General models of lymphoid transformation by pathogens. Direct transformation model. Infectious agents such as Epstein-Barr virus directly target resting B-cell and establish latent infection. Transcription of viral latent genes with oncogenic potential leads to immortalization of infected B-cell and proliferation, normally kept in check by the immune system of the host. Under certain circumstances (as immune deficiency) or after additional oncogenic mutations, fully transformed EBV-infected B-cell might lead to malignant lymphoma. Indirect transformation model. Persisting pathogens such as Helicobacter Pylori in chronic infection stimulate antigen-specific B-cell either directly or indirectly through T-cell help. Clonal expansion may develop in responding lymphocytes sometimes ultimately leading to frank lymphoproliferation.

Figure 3.

Hypothetical model of B-cell transformation by HCV. 3A. Direct transformation model. Induction of cellular NO-synthase and subsequent mutations of p53, beta-catenin and Bcl-6 by HCV associated core and NS3/4 proteins may participate in B-cell transformation. According to this hypothesis, HCV would directly infect B cells, possibly through CD81-E2 interaction. 3B. Indirect transformation model. Interaction of E2 and CD81 on the cell surface induces expression of activation-induced deaminase (AID) and somatic hypermutations of immunoglobulin genes and potential proto-oncogenes. This mechanism may participate in B-cell transformation by HCV. B-cell transformation would not need to require direct infection of B-cells by HCV as this interaction takes place between extracellular E2 expressed on the virion and surface CD81.

Figure 4.

Hypothetical model of progression from mixed cryoglobulinemia to lymphoma. Stimulation of auto-reactive, rheumatoid factor producing and HCV-E2 or NS3 cross-reactive specific B cells might lead to a first-step lymphoproliferative development such as in type II mixed cryoglobulinemia (MC). Pro-inflammatory cytokines, such as BAFF (also called B lymphocyte stimulator, BLyS), a potent stimulator of B-cell survival and proliferation, are thought to play an important role in this mechanism. Eradication of the antigenic source at this stage by interferon with or without ribavirin leads to a decrease of the cryoglobulin load and of the clonal population. Additional oncogenic events may occur in the proliferating cryoglobulin-producing population and lead to transformation into NHL such as marginal zone lymphoma with villous lymphocytes (SLVL). Such transformed B cells would still remain dependent upon antigen stimulation as attested by the regression of the tumor after HCV eradication but without full disappearance of the clonal population. Further oncogenic events, such as 2q loss, may lead to transformation into high-grade lymphoma.