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Beyond hepatocellular carcinoma (HCC), epidemiological and mechanistic data indicate a link between HBV and extrahepatic malignancies, including gastric, colorectal, pancreatic, lymphoid, and respiratory cancers. Cohort studies and meta-analyses show increased risk, though causality remains debated due to confounding factors. Proposed mechanisms include viral DNA integration, HBx-driven oncogenic signaling, epigenetic changes, and immune microenvironment alterations. The review consolidates epidemiology, pathophysiology, diagnosis, and treatment strategies, and highlights controversies to guide future research and clinical care.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/chronic-hepatitis-b-virus-infection-and-the-risk-of-extrahepatic-malignancies-an-updated-review-of-epidemiology-mechanisms-and-clinical-implications/349399/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/chronic-hepatitis-b-virus-infection-and-the-risk-of-extrahepatic-malignancies-an-updated-review-of-epidemiology-mechanisms-and-clinical-implications/349399.png","ImageObject",300,407,{"name":92,"@type":93},"Aldword","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Which extrahepatic cancers are discussed as being associated with chronic HBV infection?","Question",{"text":112,"@type":113},"The review cites increased risk for cancers including gastric, colorectal, pancreatic, lymphoid, and respiratory cancers, based on epidemiological and mechanistic evidence.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why is HBV causality for extrahepatic malignancies still controversial?",{"text":117,"@type":113},"Causality is debated because studies may be influenced by confounding factors such as coinfections, lifestyle factors, and genetic susceptibility.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanisms are proposed to explain HBV-related tumor development outside the liver?",{"text":121,"@type":113},"Mechanisms include viral DNA integration into the host genome, HBx activation of oncogenic pathways, epigenetic modifications, and alterations of the immune microenvironment that promote tumor immune evasion.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},349399,1790158219,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},2336478940917,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Chen et al. Virology Journal (2026) 23:166 Virology Journal  \n[https://doi.org/10.1186/s12985-026-03186-2](https://doi.org/10.1186/s12985-026-03186-2)  \nREVIEW Open Access  \nChronic hepatitis B virus infection and the  risk of extrahepatic malignancies: an updated review of epidemiology, mechanisms, and clinical implications  \nZhongda Chen1†, Haiwen Zhuang2†, Jin Zhang1, Yong Zhang1, Sanrong Xu1 and Qing Zhou1*  \nAbstract  \nChronic 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 alterationsin 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.  \nKeywords Hepatitis B virus, Extrahepatic cancer, Molecular mechanism, Diagnosis, Treatment  \n†Zhongda Chen and Haiwen Zhuang contributed equally to this work.  \n*Correspondence: Qing Zhou [zhouqingzy@163.com](zhouqingzy@163.com)  \n1Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China  \n2Division of Gastrointestinal Surgery, Department of General Surgery, Huai’an Second People’s Hospital, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu Province, China  \nIntroduction  \nHepatitis B virus (HBV) infection remains a serious global health problem. Despite the availability of effective vaccines and antiviral therapies, HBV continues to cause significant morbidity and mortality, primarily through progressive liver disease and hepatocellular carcinoma (HCC). The causal relationship between HBV and HCChas been well established for decades, and HBV-related liver disease accounts for a significant proportion of liver cancer deaths worldwide [1].  \nBeyond the liver, accumulating evidence suggests that HBV may also contribute to the development of extrahepatic malignancies. Epidemiological studies in Asia and  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To vi","cbCair67C58OWKid","https://ap.wps.com/l/cbCair67C58OWKid","pdf",1344034,15,"English","# Introduction\n## Hepatitis B virus as a global health problem\n# Epidemiology of chronic hepatitis B\n## Global burden and prevalence patterns\n# Mechanisms and pathophysiology (as reviewed)\n## Viral integration and HBx-mediated signaling\n## Epigenetic and immune microenvironment changes\n# Diagnostic strategies\n# Treatment approaches and clinical implications\n# Controversies and future directions","[{\"question\":\"Which extrahepatic cancers are discussed as being associated with chronic HBV infection?\",\"answer\":\"The review cites increased risk for cancers including gastric, colorectal, pancreatic, lymphoid, and respiratory cancers, based on epidemiological and mechanistic evidence.\"},{\"question\":\"Why is HBV causality for extrahepatic malignancies still controversial?\",\"answer\":\"Causality is debated because studies may be influenced by confounding factors such as coinfections, lifestyle factors, and genetic susceptibility.\"},{\"question\":\"What mechanisms are proposed to explain HBV-related tumor development outside the liver?\",\"answer\":\"Mechanisms include viral DNA integration into the host genome, HBx activation of oncogenic pathways, epigenetic modifications, and alterations of the immune microenvironment that promote tumor immune evasion.\"}]","Chronic hepatitis B virus infection and the risk of extrahepatic malignancies - an updated review of epidemiology, mechanisms, and clinical implications | PDF",1790083149,38]