Aspects of biliary tract cancer : incidence and reproductive risk factors

Abstract: Biliary tract cancer, including cancer of the extra-hepatic bile ducts, cancer of the Ampulla of Vater and gallbladder cancer, is a devastating disease with poor prognosis. The incidence of biliary tract cancer is decreasing worldwide, for unknown reasons. One of two aims of this thesis was to evaluate the Swedish Cancer Register regarding biliary tract cancer and to assess the incidence of biliary tract cancer in Sweden. Secondly, an association between sex hormone exposure, particularly estrogen, and biliary tract cancer has been suggested. Thus, the second aim of this thesis was to evaluate the effect of sex hormone exposure on biliary tract cancer risk. Study I and II were based on data from the Swedish Cancer Register, the Swedish Patient Register and the Swedish Causes of Death Register. Study I was a validation study of biliary tract cancer diagnoses in the Cancer Register, using data from the Patient Register and the Cause of Death Register as comparison. Overall, 44% of patients diagnosed with biliary tract cancer between 1990 and 2009 were not found in the Cancer Register. The underreporting increased with increasing patient age and later time period. Study II indicated a decreasing incidence trend of biliary tract cancer. However, the mortality rates were higher than the incidence rates after the mid 1980’s and onwards. Moreover, the incidence trends based on data from the Patient Register suggested a more stable or only slightly decreasing trend. Thus, even though the incidence of biliary tract cancer may be decreasing, the extent of the decline is likely over-estimated. Study III investigated the association between reproductive factors and biliary tract cancer. Women and men were included in the study, but analyzed separately, to enable differentiation between hormone exposure and other factors. The risk of cancers of the extrahepatic bile ducts (including the Ampulla of Vater) is likely not influenced by reproductive factors because similar associations were seen in women and men. However, an association between reproductive factors and gallbladder cancer was observed in women, but not as clearly in men. Study IV investigated the risk of biliary tract cancer in a cohort of men with prostate cancer, a proxy for estrogen exposure (prostate cancer treatment). There was no clear association, although a slightly decreased risk was indicated. However, men with the highest presumed estrogen exposure had an increased risk of biliary tract cancer, though the association was not statistically significant. Study V investigated the association between menopausal hormone therapy and biliary tract cancer. A slightly reduced risk of gallbladder cancer was suggested for users of menopausal hormone therapy compared to non-users, but the association was not statistically significant. However, an increased risk of gallstone disease was noted however. In conclusion, there is substantial under-reporting of biliary tract cancer to the Swedish Cancer Register, especially in the elderly and in the later time period. The decreasing incidence trends of biliary tract cancer in Sweden are likely over-estimated, as a consequence of under-reporting. Furthermore, the role of sex hormones in the etiology of biliary tract cancer is uncertain. Sex hormone exposure may influence the risk of gallbladder cancer specifically but not biliary tract cancer as a whole. Future etiological research should separate gallbladder cancer from other extra-hepatic cancers