Hepatitis C and non-Hodgkin lymphoma: The clinical perspective

Abstract

Hepatitis C virus (HCV) is a commonly transmitted infection that has both hepatic and extrahepatic repercussions. These range from the inflammatory to the oncologic with an undisputed link to hepatitis, liver cirrhosis, and hepatocellular carcinoma. Its role in the development of B cell non-Hodgkin lymphoma (B-NHL) is becoming better understood, leading to opportunities for research, therapy, and even prevention. Research in the field has progressed significantly over the last decade, with the number of patients diagnosed with HCV and B-NHL rising incrementally. It is therefore becoming crucial to fully understand the pathobiologic link of HCV in B cell lymphomagenesis and its optimal management in the oncologic setting. (HEPATOLOGY 2012;55:634-641) O ver 180 million people are infected with hepatitis C virus (HCV), accounting for 3% of the global population.1 HCV is well-recognized as a cause of hepatic disease and hepatocellular carcinoma, while its hematologic manifestations (mixed cryoglobulinemia [MC] and B cell non-Hodgkin lymphoma [B-NHL]) are less appreciated.2 Clarifying the oncogenic role of HCV has been hampered by difficulties in viral culture, the heterogeneity of B-NHL, and the differences between viral genotypes, prevalence, and affected populations. This is further complicated by the host environment and the availability of effective therapy. Nevertheless, a molecular and clinical link between HCV and B-NHL has been made placing an emphasis on cause and effect rather than simple association. Mechanisms of LymphoproliferationSung et al.2 established a flourishing HCV-infected B-NHL line whose virions could infect hepatic cells, peripheral blood mononuclear cells, and B cells in vitro. Indeed, viral replication within ''lymphoid reservoirs'' is thought to be responsible for HCV persistence after apparently successful therapy: these reservoirs potentially function as a viral ''storage facility'' and allow for positive selection of different viral subtypes which may influence the natural history of infection.3,4 Current evidence suggests there may be a predilection for B cells 5 and that different viral strains may be more lymphotropic than others. 6The biologic rationale for a causal relationship between HCV and B-NHL is based upon epidemiologic data and clinical observation. One study showed evidence of oligoclonal and monoclonal B cell expansion in 100% of HCV-infected patients with a mixture of pathologies, including MC, Waldenström's macroglobulinemia (WM), and B-NHL.7 However, the mechanism by which HCV infection leads to B-NHL is still unclear.The proposed mechanisms include direct infection of hematopoietic cells, antigen drive, and the ''hit and run'' hypothesis. Despite evidence that HCV can infect and replicate within lymphoid cells, there are few data demonstrating that HCV can induce malignant lymphoproliferation. For example, active viral replication in the peripheral blood and bone marrow of chronically infected patients with MC or B-NHL could not be demonstrated.8 Also, the identi...

Incidence of Hepatocellular Carcinoma Reduced by Phlebotomy Treatment in Patients with Chronic Hepatitis C

“…However, phlebotomy has been shown to improve the rate of carcinogenesis and prognosis of hereditary hemochromatosis (29,30). In patients with hepatitis C, it is thought that HCV is the cause of hepatic and extrahepatic disease, including HCC and non-Hodgkin's lymphoma (31)(32)(33)(34). Oxidative stress is also considered to be a cause of HCVassociated HCC (35,36).…”

Regression of Hodgkin Lymphoma in Response to Antiviral Therapy for Hepatitis C Virus Infection

“…Previous clinical observations have indicated links between HCV infection and several types of lymphoma, including marginal zone lymphoma, lymphoplasmacytic lymphoma and diffuse large B cell lymphoma (2). Importantly, all of these are categorized as B cell NHL.…”

“…Indeed, NLPHL reportedly overlaps with or progresses to T cell/histiocyte rich B cell lymphoma, a subtype of diffuse large B cell lymphoma (3). Although the mechanisms whereby HCV infection causes B cell malignant lymphoma remain to be clarified, working hypotheses propose that either persistent HCV antigen stimulation results in clonal expansion of B cells that finally leads to the development of lymphoma or that HCV infection itself is directly oncogenic in B cells (2,5). Therefore, considering the resemblance of NLPHL to B cell NHL, it is tempting to speculate that these mechanisms could also be applied to the development of NLPHL.…”

“…Recent epidemiological studies have indicated links between HCV infection and several types of malignant lymphomas (2). Importantly, all of these cases have been categorized as B cell non-Hodgkin lymphomas (NHL).…”

Genotype 2 Patients: What is the Optimum Therapy so Far?

“…However, sudden exacerbations with aminotransferases flares have been described typically in HCV-2 patients and associated with accelerated disease progression [4,5], potentially leading to hepatic decompensation in advanced fibrosis patients. HCV-2 infection has finally been associated with increased incidence of some extrahepatic manifestations, like non-Hodgkin lymphoma [6].…”