Epidemiological studies performed over the last decade have demonstrated a positive association between persistent, hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), with HBV-infected patients having a 2-3-fold higher risk to develop NHL than non-infected patients. Moreover, there is evidence that also occult HBV infection (HBsAg-negative, HBV DNA-positive) associates with NHL. An association with HBV infection may exist also for other hematological malignancies, but available evidence is much less persuasive than for NHL. In this review article we will discuss available results on the association between HBsAg-positive HBV infection and NHL, as well as the significance of other serological markers of HBV infection in these subjects. We will also discuss the possible etiopathogenic role of HBV, and propose a multifactorial model for lymphomagenesis. Experimental evidence for multifactorial etiopathogenesis has been obtained in recent years for HBV-associated hepatocellular carcinoma (HCC), and we suggest that a similar model may apply to HBV-associated lymphoma as well. Eventually, we will also address some unresolved questions. Two of these are of particular relevance. First, do HBV-positive NHL patients show regression of their hematologic malignancy upon antiviral therapy? A positive answer would represent a direct demonstration of the necessary etiological role of the virus in the development of NHL, as has been shown previously for HCV-associated lymphomas. Second, if HBV plays a necessary role in lymphomagenesis, then expansion of HBV vaccination is expected to reduce the number of incident NHL cases, even though this effect might become evident only after a long time interval. Studies in those countries which have introduced universal HBV vaccination about two decades ago, like Italy, may soon provide results on this important point.
Keywords: Hepatitis B virus, occult infection, anti-HBs antibodies, anti-HBe antibodies, anti-HBc antibodies, non-Hodgkin lymphoma, hematologic malignancies, antiviral therapy, multicausal etiology, vaccination