Chronic hepatitis B virus infection and the risk of extrahepatic malignancies: an updated review of epidemiology, mechanisms, and clinical implications.

Abstract

Chronic hepatitis B virus (HBV) infection affects nearly 300 million people worldwide and remains a leading cause of the global cancer burden. While its causal relationship with hepatocellular carcinoma (HCC) is well established, accumulating epidemiological and mechanistic evidence suggests that HBV may also contribute to the development of extrahepatic malignancies, including gastric, colorectal, pancreatic, lymphoid, and respiratory cancers. Cohort studies and meta-analyses consistently report an increased risk in individuals infected with HBV, but causality remains controversial due to confounding factors such as coinfection, lifestyle factors, and genetic susceptibility. Possible mechanisms include viral DNA integration into the host genome, HBV X protein (HBx)-mediated activation of oncogenic signaling pathways (PI3K-Akt, Wnt), epigenetic modifications, and alterations in the immune microenvironment that promote tumor immune evasion. Advances in biomarker discovery, imaging technologies, and antiviral and targeted therapies offer opportunities for early detection and improved management of HBV-related cancers. This review summarizes the current knowledge on the epidemiology, pathophysiology, diagnostic strategies, and treatment approaches of HBV-related extrahepatic malignancies, as well as the current controversies, with the aim of guiding future research and clinical practice.