Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphomas (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 FL patients for HBV infection status, clinical features and gene mutational profile. Anti-HBc was detectable in sixteen patients (13.2%), although all had undetectable HBV DNA. Anti-HBc+ cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs. 57.2 years, P=0.007) and higher β2-microglobulin (56.3% vs. 28.9%, P=0.04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV-hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year PFS (12.9% vs 58.3%; P<0.0001) and OS (22.0% vs. 86.2%, P<0.0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, two key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

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