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Hepatitis C Virus And Non-Hodgkins Lymphoma: VA Study Confirms Association
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: In a retrospective case-control analysis conducted within the U.S. Veterans Affairs hospitals, the incidence of cryoglobulinemia, Waldenstrom's macroglobulinemia, and non-Hodgkin's lymphoma were each found to be significantly increased in patients with hepatitis-C viral infection.
Source: Giordano TP, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with Hepatitis C Virus. JAMA. 2007;297:2010-2017.
An estimated 4.1 million US residents representing 1.6 percent of the total population are infected with the Hepatitis C Virus (HCV). This prevalence is increased over three fold (approximately 5%) in US military veterans. Many previous studies have suggested an association between the HCV and cancer, particularly hematological malignancies and related lymphoproliferative disorders.1 Furthermore, it has been shown that effective treatment of HCV, for example, with interferon alfa, occasionally results in lymphoma remission for those with coexisting disease.2,3
The current study was designed to test the hypothesis that HCV infection has a role in the pathogenesis of lymphoproliferative malignancies. In a US Veterans Administration-wide study capitalizing on the excellent medical records maintained throughout the 150 hospital system, a retrospective case-control cohort study was conducted. This was a particularly suitable strategy in light of the high prevalence of HCV infection among VA patients.
Data from hospitalization and clinic visits between the years 1997 and 2004 identified 146,394 HCV patients. For comparative purposes, an HCV uninfected control cohort was randomly chosen (4 controls for each HCV patient) who were matched by age, sex, and baseline visit type. There were a total of 572,293 control subjects. Both groups (cases and controls) were predominantly men (97%) and were of the same mean age [52 years; SD, (8 years)]. Individuals infected with HIV were excluded from the analysis. Patients were followed for a mean of 2.3 years.
As expected, the risk for hepatocellular carcinoma was markedly increased, (hazard ratio [HR] 24.15; 95% confidence interval [CI], 20.92-27.88). The risk of NHL was increased by 20-30% (HR 1.21; 95% CI, 1.07-1.37). The risk of Waldenstrom's macroglobulinemia nearly tripled (HR 2.72; 95% CI, 2.00-3.72). In addition, there was an increase in non-malignant plasma cell dyscrasias including MGUS and cyroglobulinemia (HR 3.93; 95% CI 3.32-4.64). The incidence of other hematological malignancies was not increased in HCV patients, nor was the incidence of thyroid cancer, as had been previously reported.4 Curiously, acute lymphoblastic leukemia (ALL) was significantly less common in HCV patients (HR 0.57; 95% CI 0.38-0.85).
This, by far, is the largest study to date assessing the increased risk of hematopoietic malignancies in people with HCV, and the data are quite convincing. HCV confers an increased risk for lymphoproliferative disorders (most notably cryoglobulinemia), Waldenstrom's macroglobulinemia, and non Hodgkin lymphoma (NHL). Now, of course, the issue is what do we do with this information? The findings support a hypothesis that chronic HCV infection serves as an immunological stimulus for progression to hematological malignancy. Whether the virus itself is directly responsible for transforming susceptible lymphoid cells, or the lymphomagenesis is merely the result of a chronic lymphoproliferative response to HCV infection is unclear. However, it seems that HCV patients are particularly susceptible to developing malignancies of B cell lineage. Accordingly, this might be a very suitable population for introducing cancer prevention strategies. At the very least, patients with HCV infection should be scrutinized carefully and regularly for the development of associated lymphoproliferative disorders, and this evaluation might well include serum protein analysis as well as imaging studies to identify autonomous lymphoid tissue proliferation.
1. Zignego AL, et al. Hepatitis C virus-related lymphoproliferative disorders: An overview. World J Gastroenterol. 2007;13:2467-2478.
2. Agnello V, et al. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;327:1490-1495.
3. Mazzaro C, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer. 1996;77:2604-2613.
4. Antonelli A, et al. Thyroid cancer in patients with hepatitis C infection [letter]. JAMA. 1999;281:1588.