Our understanding and management of intrahepatic cholangiocarcinoma have evolved substantially over the past 5 years, leading to a new staging system distinct from that used for primary hepatocellular carcinoma (HCC), and identification of prognostic imaging and histologic phenotypes which provide more sophisticated guidance for triage.

While primary liver cancer is recognized as among the most deadly malignancies on the planet, approximately 10% of primary hepatobiliary tumors are cholangiocarcinomas. Ninety percent of these originate in the extrahepatic ducts, leaving about 10% as intrahepatic cholangiocarcinomas. These relatively rare tumors account for less than 10,000 new cancers in the USA annually and about 3% of gastrointestinal cancers worldwide. The incidence appears to be increasing globally; however, this is associated with an improvement in immunohistochemical diagnosis, with more tumors previously categorized as adenocarcinoma of unknown primary now recognized as being of pancreaticobiliary origin, likely cholangiocarcinoma.

Unlike HCC, most patients with intrahepatic cholangiocarcinoma have no known risk factors. Recognized risks include conditions associated with chronic inflammation or infection of the biliary tree, such as sclerosing cholangitis, choledochal cyst, biliary cirrhosis, parasitic infections, and hepatic cirrhosis. However, 90% of patients lack any predisposing condition, so routine surveillance is the exception and diagnosis is often delayed until symptoms develop in advanced stages. Early lymphatic spread, bone metastases, and intrahepatic liver metastases are more common than in HCC. Macrovascular invasion is seen similarly to HCC.

Diagnosis of intrahepatic cholangiocarcinoma can be challenging. Imaging appearance is variable, with three imaging phenotypes described as mass-forming, infiltrative, and intraductal invasion. Tumor vascularity is highly variable, with late enhancement a distinguishing feature from HCC. Thorough diagnostic imaging and endoscopy are necessary to exclude other primaries. Biopsy diagnosis can be difficult due to desmoplastic stroma and poorly differentiated histology. Immunohistochemical stains can suggest a biliary origin, while negative stains help to exclude other tissues of origin such as primary liver or metastasis from pancreas, colon, breast, or lung cancer. Tumor markers can be helpful to distinguish cholangiocarcinoma from HCC. A CA-19-9 level > 100 U/mL (normal up to 37 U/mL) is 68% sensitive and 96% specific for intrahepatic cholangiocarcinoma in patients without sclerosing cholangitis. Less-specific tumor marker elevations include carcinoembryonic antigen, CA-125, and alpha-fetoprotein, with 10% having a mixed hepatocholangiocarcinoma histology.