Challenges in the diagnosis and classification of cholangiocarcinoma have made it difficult to quantify the true incidence of this highly aggressive malignancy.

We analyzed the Surveillance, Epidemiology, and End Results data to assess long-term trends in the age-standardized incidence of intrahepatic and extrahepatic cholangiocarcinoma between 1973 and 2012, correcting for systematic coding errors. Because intrahepatic cholangiocarcinoma (ICC) may frequently be misdiagnosed as cancer of unknown primary (CUP), we also analyzed trends in the incidence of CUP.

Between 1973 and 2012, the reported U.S. incidence of ICC increased from 0.44 to 1.18 cases per 100,000, representing an annual percentage change (APC) of 2.30%; this trend has accelerated during the past decade to an APC of 4.36%. The incidence of extrahepatic cholangiocarcinoma increased modestly from 0.95 to 1.02 per 100,000 during the 40-year period (APC, 0.14%). The incidence of CUP with histologic features potentially consistent with cholangiocarcinoma decreased by 51% between 1973 and 2012 (APC, −1.87%), whereas the incidence of CUP with squamous or nonepithelial histologic features increased modestly (APC, 0.42%).

The recognized incidence of ICC in the U.S. continues to rise, whereas the incidence of ECC is stable. The incidence of CUP has fallen dramatically during the same time period.