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HBV infection as a risk factor for non-Hodgkin lymphoma - Comment
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The Lancet Oncology, Early Online Publication, 4 August 2010
Sook-Hyang Jeong
Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, South Korea
Hepatitis B virus (HBV) is both a hepatotrophic and a lymphotrophic virus. By contrast with the role of HBV infection in hepatocarcinogenesis, data for the causal association of HBV infection and development of non-Hodgkin lymphoma (NHL) are scarce. Several case-control studies have shown a higher prevalence of chronic HBV infection in patients with NHL than in patients in various control groups (historical controls, blood donors, and hospital controls), with an odds ratio of about 2·5.1 However, there have been few cohort studies. A cohort study from the USA, which included about 210 000 people, with a follow-up of up to 7 years, showed that chronic HBV infection increased risk of development of NHL by almost three times.2 A population-based study of long-term mortality for up to 29 years in blood donors testing positive for serum hepatitis B surface antigen in England and Wales showed that risk of NHL increased after the first decade of follow-up, along with a clear increase in liver-related mortality, although patients co-infected with HIV or hepatitis C virus (HCV) were not excluded from the study.3
In this issue of The Lancet Oncology, a cohort study from South Korea,4 which included more than 600 000 people and had a follow-up of more than 14 years, showed that HBV infection increased the risk of NHL (adjusted hazard ratio 1·74, 95% CI 1·45-2·09), especially diffuse large B-cell lymphoma, suggesting that chronic HBV infection promotes lymphomagenesis. Although the study had some limitations, such as absence of HCV and HIV data and lack of information about replication status of HBV or severity of liver disease, it presented reliable evidence for an important role of HBV infection in lymphomagenesis. If the association is causal, might the globally increasing implementation of universal HBV vaccination and increasing use of antiviral drugs for treatment of chronic HBV-related liver disease reduce development of NHL? Engels and colleagues4 commented that the causal association is small in magnitude, and that HBV infection would account for only a few NHL cases. Thus, those efforts would be expected to have a limited effect on NHL incidence.
Many of the genes involved in B-cell lymphomagenesis are normally regulated by signals from the B-cell antigen receptor, and the infectious agents could play a part by directly inducing polyclonal B-cell hyperactivation or providing a chronic antigenic stimulus.5 Would HBV have a direct role, or an indirect role via an immunological mechanism? How would the gene expression profile of HBV-related NHL differ from that of NHL not related to HBV? Although antiviral therapy for HCV in low-grade NHL could have lead to haematological remission in several case series, similar results from antiviral therapy for HBV have not been reported. Complete remission of splenic marginal zone lymphoma after an acute flare-up of hepatitis B in a hepatitis B carrier was reported, although HBV persisted after the hepatitis flare.6 Thus, the mechanisms involving HBV seem to differ from those involving HCV. Further studies to elucidate the mechanism of lymphomagenesis of HBV infection are warranted.
Another point for oncologists to be aware of is the high prevalence of HBV in NHL, which requires proper evaluation of viral replication status and functional liver status before anticancer chemotherapy, and appropriate use of prophylactic antiviral therapy during and after chemotherapy to prevent HBV reactivation and hepatitis flare, which could lead to liver-related mortality after successful treatment of NHL.
The author declared no conflicts of interest.
References
1 Nath A, Agarwal R, Malhotra P, Varma S. Prevalence of hepatitis B virus infection in non-Hodgkin's lymphoma. A systematic review and meta-analysis. Intern Med J 200910.1111/j.1445-5994.2009.02060.x. published online Oct 7. PubMed
2 Yood M Ulcickas, Quesenberry CP, Guo D, et al. Incidence of non-Hodgkin's lymphoma among individuals with chronic hepatitis B virus infection. Hepatology 2007; 46: 107-112. CrossRef | PubMed
3 Crook PD, Jones ME, Hall AJ. Mortality of hepatitis B surface antigen-positive blood donors in England and Wales. Int J Epidemiol 2003; 32: 118-124. CrossRef | PubMed
4 Engels EA, Cho ER, Jee SH. Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study. Lancet Oncol 201010.1016/S1470-2045(10)70167-4. published online Aug 4. PubMed
5 Rui L, Goodnow CC. Lymphoma and the control of B cell growth and differentiation. Curr Mol Med 2006; 6: 291-308. CrossRef | PubMed
6 Fujimoto K, Endo T, Nishio M, et al. Complete remission of splenic marginal zone lymphoma after an acute flare-up of hepatitis B in a hepatitis B virus carrier. Int J Hematol 2009; 90: 601-604. CrossRef | PubMed
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