Many environmental risk factors for hepatobiliary cancers are known but whether they are associated with specific cancer types is unclear. We present here a novel approach of assessing standardized incidence ratios (SIRs) of previously diagnosed comorbidities for hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cholangiocarcinoma (CCA) and ampullary cancer. The 13 comorbidities included alcohol and nonalcohol related liver disease, chronic obstructive pulmonary disease, gallstone disease, viral and other kinds of hepatitis, infection of bile ducts, hepatic and other autoimmune diseases, obesity and diabetes. Patients were identified from the Swedish Inpatient Register from 1987 to 2018, and their cancers were followed from 1997 onwards. SIRs for HCC were 80 to 100 in men and women diagnosed with hepatitis C virus and they were also >10 in patients diagnosed with hepatitis B virus, other kind of hepatitis, hepatic autoimmune disease and nonalcohol related liver disease. Many of these risks, as well as alcohol related liver disease, were either specific to HCC or were shared with intrahepatic CCA. For GBC, CCA and ampullary cancer infection of bile ducts was the main risk factor. Gallstone disease, nonhepatic autoimmune diseases and diabetes were associated with all hepatobiliary cancers. The limitations of the study include inability to cover some rare risk factors and limited follow-up time. Many of the considered comorbidities are characterized by chronic inflammation and/or overt immune disturbance in autoimmune diseases. The results suggest that local chronic inflammation and a related immune disturbance is the carcinogenic trigger for all these cancers.

Cancer Gene Therapy Group Translational Immunology Research Program University of Helsinki Helsinki Finland

Center for Primary Health Care Research Lund University Malmö

Comprehensive Cancer Center Helsinki University Hospital Helsinki Finland

Department of Family Medicine and Community Health Icahn School of Medicine at Mount Sinai Mount Sinai New York USA

Department of Functional Pathology Center for Community Based Healthcare Research and Education School of Medicine Shimane University Shimane Japan

Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai Mount Sinai New York USA

Department of Surgery University Hospital School of Medicine in Pilsen Pilsen Czech Republic

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Biomedical Center Charles University Prague Pilsen

Hopp Children's Cancer Center Heidelberg Germany

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