Update on Cholangiocarcinoma

Cholangiocarcinoma is a highly lethal hepatobiliary cancer with features of biliary epithelial cell differentiation. Cholangiocarcinoma can be divided into three subtypes anatomically. Intrahepatic cholangiocarcinoma (iCCA) which are mass forming lesions within the hepatic parenchyma. Perihilar cholangiocarcinoma (pCCA) which originates between the insertion of the cystic duct into the common bile duct and secondary bifurcation of the left and/or right hepatic ducts. Distal cholangiocarcinoma (dCCA) originates below the level of the cystic duct insertion and involve the distal common bile duct. Each of the three anatomic subtypes differs in pathology, genetics, and treatment approaches. iCCA and dCCA are amenable to biopsies to ensure the correct diagnosis. pCCA can be difficult to biopsy and diagnose; advanced biliary cytology and genetic approaches aid in the diagnosis of this cancer subtype. Where feasible, these cancers are resected; if unresectable a select group are candidates for liver transplantation (unicentric, moderately differentiated iCCA < 3m in size in the context of cirrhosis without intrahepatic or extrahepatic metastasis) and unresectable pCCA without intrahepatic or extrahepatic metastasis. Neoadjuvant therapy has not been shown to be beneficial for any of the three anatomic subtypes. The only adjuvant therapy which is shown to be beneficial is Capecitabine. If unresectable, the standard of care is Gemcitabine, Cisplatin, plus Durvalumab; of which the latter agent is a checkpoint inhibitor. For patients who fail standard of care systemic therapy, targeted therapy is available but mainly for iCCA. Targeted therapy is available for patients with FGFR2 fusion aberrations, isocitrate dehydrogenase gain of function mutations, and Braf and NTRK kinase mutations. KRAS are mutations, which were previously thought to be nontargetable, are now being targeted by small molecules which are in clinical trials. The overall benefits of these agents in treating cholangiocarcinoma are unknown. Chemoprevention strategies are being examined in patients at high-risk for cholangiocarcinoma, namely those patients with Primary Sclerosing Cholangitis. Statins in large population databases are associated with a lower incidence of cholangiocarcinoma. Trials are ongoing in Scandinavia to determine whether statins may be beneficial in chemoprophylaxis of cholangiocarcinoma in PSC. Future studies are focused on enhancing imaging of these patients using artificial intelligence, unique PET scan technology to identify the cancer associated fibroblast which are prevalent in these lesions, and enhanced immunotherapy approaches.