Chronic hepatitis C virus (HCV) infection has been associated with liver cancer and cirrhosis, autoimmune disorders such as thyroiditis and mixed cryoglobulinema, and alterations in immune function and chronic inflammation, both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma (NHL). HCV bound to B cell surface receptors can induce lymphoproliferation, leading to DNA mutations and/or lower antigen response thresholds. These findings and epidemiological reports suggest an association between HCV infection and NHL. We performed a systematic review of the literature to clarify this potential relationship. We searched the English-language literature utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews, with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases. References were screened to further identify relevant studies and literature in the basic sciences. A total of 62 reports discussing the relationship between HCV, NHL, and lymphoproliferative diseases were identified. Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV, particularly in areas with high HCV prevalence. Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size, short follow-up periods, and database limitations. The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases. Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear. Lymphomagenesis is a multifactorial process involving genetic, environmental, and infectious factors. HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted.

A high prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (B-NHL) has been reported in some, but not all, studies, and the association showed a strong regional variation. We conducted a systematic review of the prevalence of HCV infection in case series of B-NHL and, when an appropriate control group was available, of the odds ratio of B-NHL associated with HCV infection. A high HCV prevalence in B-NHL was found in southern and eastern Europe, Japan and the southern United States, but not in central and northern Europe, Canada, northern United States, or a few Asian countries. Possible sources of heterogeneity and bias are discussed. The odds ratio of B-NHL for HCV infection was relatively weak, ranging from 2 to 4 in most studies. Thus, even if the observed association were causal, the percentage of cases of B-NHL attributable to HCV infection would be relatively low (10%) also in countries with a high prevalence of HCV infection in the general population, and extremely low in other countries. This may explain apparent inconsistencies between studies. Potential mechanisms of action are also discussed.