Pathophysiology

Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic; those occurring in the ducts outside the liver are extrahepatic; and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common bile duct may be referred to eponymously as a Klatskin tumor.^[30]

Although cholangiocarcinoma is known to be an adenocarcinoma of the epithelial cells lining the biliary tract, the actual cell of origin is unknown, although recent evidence has suggested that it may arise from a pluripotent hepatic stem cell.^[31][32][33] Cholangiocarcinoma is thought to develop through a series of stages — from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma — in a process similar to that seen in the development of colon cancer.^[34] Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.^[34][35][36]

Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis.^[37] Most tumors (>90%) are adenocarcinomas.^[38]