Hepatitis C virus-associated B-cell non-Hodgkin lymphomas

Abstract

Epidemiological studies have demonstrated an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence. It remains unclear whether additional environmental and genetic factors are involved or if the international variability is simply a consequence of the variable infection prevalence. Therefore, a causal relationship remains controversial. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used, and the year of publication. The most convincing proof is the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after HCV eradication with IFN and ribavirin. However, the molecular mechanisms of the HCV-induced lymphomagenesis are mainly hypothetical. According to the model considered to be most plausible, lymphoma growth is a consequence of the continuous antigenic stimulation of the B-cell immunologic response induced by the chronic viral infection. This review summarizes the current epidemiological and biological evidence of a role of HCV in lymphomagenesis, describing the putative mechanisms for a causative relationship. The clinical characteristics and management difficulties of the HCV-associated lymphomas are also discussed. HCV treatment with IFN cannot be given safely in concomitance with cytotoxic lymphoma treatment because of hematological and liver toxicity. However, novel and better tolerated antiviral regimens are under development and will hopefully make the treatment of both lymphoma and hepatitis easier in the future. Learning Objectives• To understand the current lines of evidence linking HCV infection and lymphomagenesis • To review the specific problems of the clinical management of patients with chronic HCV infection

Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

“…Epidemiological studies have demonstrated an increased risk of developing B‐NHL in patients with chronic HCV infection . B‐NHL subtypes frequently associated with HCV are marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B‐cell lymphoma.…”

“…B‐NHL subtypes frequently associated with HCV are marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B‐cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B‐NHL regression after HCV eradication with interferon‐α monotherapy or in combination with ribavirin . However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence.…”

“…Three general hypotheses have been proposed to elucidate HCV‐induced lymphomagenesis: (1) continuous external stimulation of lymphocyte receptors by viral antigens throughout persistent infection, (2) HCV replication in B cells with an oncogenic effect mediated by intracellular viral proteins, and (3) permanent B‐cell damage by mutation of tumor suppressor genes caused by a transiently present intracellular virus . The lymphoma subtypes associated with HCV infection originate from germinal center or post‐germinal center lymphocytes, suggesting a possible antigen‐driven proliferation . Indeed, a monoclonal/oligoclonal B‐cell expansion has been shown in circulating B cells as well as in the bone marrow or intrahepatic B cells of chronic HCV patients .…”

The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance

“…36,66,67 The association with HCV, however, shows considerable and not entirely explained geographic discrepancies. 68 These site-specific biological differences might influence outcome, and recognition of the driving source of the antigenic stimulation in different tissues may have important therapeutic implications. Although antibiotic therapy is nowadays well established for primary gastric MALT lymphoma, much less is known about the value of anti-infectious therapy in other MALT lymphomas (Table 3 69-72 ).…”

“…Importantly, the strongest evidence for a causal relationship between HCV and lymphoma comes again from the observation of lymphoma regression after antiviral treatment. 68,105,106 Several potential pathogenic mechanisms have been advanced to explain a causative link with lymphoma growth 68,107 : a nondirect antigen-driven stimulation; a direct oncogenic role of HCV; a viral immunosuppressive effect on the tumor cells; and the co-infection by another unknown oncogenic virus.…”