Exploring the Association Between Hepatitis C and Lymphoma

Patients with chronic hepatitis C virus have an increased risk of developing B-cell lymphomas.

The liver is not the only organ impacted by hepatitis C virus (HCV). The most common extrahepatic manifestation is type II mixed cryoglobulinemia (MC) and approximately 80 to 90% of patients with MC also have HCV.

Lesions of MC are related to vasculitis, which is caused by the deposit of immune complexes in the wall of small vessels. These immune complexes are typically highly enriched in HCV-RNA.

Some studies have found a predisposition of HCV to select a restricted B-cell repertoire in response to chronic antigenic stimulation. Prior research has also revealed the presence of monoclonal B lymphocytes in the liver, bone marrow, and peripheral blood of patients with MC, according to the study.

Approximately 5 to 10% of patients with MC develop non-Hodgkin’s lymphoma (NHL).

Though previous studies reported an epidemiological association between HCV and lymphoproliferative disorders, researchers said the data shows little to no risk of T-cell NHL and Hodgkin’s lymphoma.

An association between HCV and B-cell NHL shows strong evidence, but varies by geographical region. In the study EPILYMPH, researchers found that patients from northern Europe have an estimated 2-fold global risk of developing lymphoma.

In most low HCV prevalence areas, there was little to no correlation between the diseases.

Other studies have found a higher a prevalence of certain subtypes of B-cell NHL subtypes, such as diffuse large B-cell lymphomas (DLBCLs), lymphoplasmacytic lymphomas (LPLs), and marginal zone lymphomas (MZLs).

A relationship between HCV and NHL is potentially based on the direct oncogenic effect or an indirect mechanism, according to the study.

The most direct link is said to be an indirect mechanism presented in the form of an antigen-driven lymphocyte proliferation, analogous to Helicobacter pylori-associated gastric MZL.

Diverse oncogenic stimuli do not necessarily have to be exclusive, but the accumulation of at least 2 oncogenic signals could potentially dictate lymphoma occurrence.

It has also been confirmed in many studies that HCV has the ability to stimulate B-cell proliferation. Researchers believe that chronic antigenic stimulation can help the development of polyclonal B-cell expansion and predispose people to genetic abnormalities.

Patients with HCV also tend to have high levels of induced cytidine deaminase (AID) in B-cells, which can lead to DNA mutation that results in genetic susceptibility to mutagenesis, according to the study.

Researchers said that immune system deregulation from HCV could be involved in the development of lymphoma. Also, different signaling pathways have shown the potential to increase HCV-induced lymphoma, though the data is mainly from in vitro models.

Association between the 2 diseases has been shown in many case-control studies with varying strength due to either methodological differences or the heterogeneity of the populations studied.

According to the study, the possible causative role of HCV in lymphogensis can be most clearly seen through the response of NHL to an HCV treatment.

In a previous study, researchers found that patients with splenic lymphoma who did not receive antiviral treatment achieved lymphoma regression, while those who did receive antiviral treatment did not.

Another study from Japan found that patients treated with interferon α for an HCV infection had lower rates of lymphoma compared with those who were not treated.

The management of HCV and NHL depends primarily on the aggressiveness of the cancer and remains related to the lymphoma histological type, according to the study.

Hematological responses to antiviral therapy have been seen in both marginal zone lymphomas, as well as follicular lymphoma and lymphoplasmacytic lymphoma.

Researchers also said that HCV-RNA clearance is needed to attain lymphoma response and patients should be treated with pegylated interferon α and ribavirin prior to receiving antilymphoma treatment, if possible.

Patients resistant to interferon treatments should receive newer interferon-free treatments, which have a higher efficacy than older treatments, the study noted.

Diffuse large B-cell lymphoma is the most common and aggressive form of lymphoma in patients with HCV and currently, there are no data to suggest whether HCV-positive patients fair better or worse than HCV-negative patients.

However, some studies suggest a benefit from initiating HCV treatment after chemotherapy and studies have found that simultaneous treatment increases hematological toxicity.

In addition to lymphomas, researchers said that HCV-positive patients often have a GB virus C coinfection (GBV-C). GBV-C replicates in B and T lymphocytes and is said to have an association with lymphomas, but conclusive evidence has not been found yet.

New HCV treatments have been reported with certain extrahepatic manifestations, but the safety of antiviral therapy concomitant with chemotherapy is unknown and an expert hepatologist/gastroenterologist should decide appropriate treatment, the study found.

Researchers concluded that HCV therapy should be administered to all patients with B-NHL who do not need to start chemotherapy immediately, but other patients, such as those with DLBCL, should undergo chemotherapy immediately. However, more research is needed to find the appropriate timing for interferon-free drugs in lymphoma treatment, according to the study.