Cholangiocarcinoma: preventing invasion as anti-cancer strategy

Abstract

Cholangiocarcinomas are adenocarcinomas arising from cholangiocytes, the epithelial cells lining the bile duct apparatus. Because the biliary tree is both intra- and extrahepatic, cholangiocarcinomas likewise may arise within the liver parenchyma or from the extrahepatic bile ducts. Cholangiocarcinomas arising within the hepatic parenchyma often present as intrahepatic mass lesions whereas cancers developing along the extrahepatic ducts cause mechanical biliary obstruction with jaundice, pruritus, acholic stools, and weight loss. For reasons unexplained, the extrahepatic ductal cholangiocarcinomas frequently involve the hilum of the liver, the junction of the right and left hepatic ducts. These perihilar ductal cholangiocarcinomas, therefore, frequently present with biliary obstruction of one or both lobes of the liver. Several epidemiologic studies have now demonstrated an increase in the incidence of cholangiocarcinoma in Western countries [1–4]. Because the incidence of cholangiocarcinoma is increasing, most hepatologists now frequently encounter this disease. Many patients with cholangiocarcinoma do not have identified risk factors for this disease. However, established risk factors include primary sclerosing cholangitis, biliary-enteric drainage procedures associated with cholangitis, Caroli’s disease, congenital choledochal cysts, chronic hepatic lithiasis, and liver fluke infestations (Clonorchis sinsesis and Opithorchis viverrini infections) [5]. In primary sclerosing cholangitis the risk of developing cholangiocarcinoma is approximately 0.5–1.5% per year [6]. The common link between these risk factors and cholangiocarcinoma is chronic inflammation. Like other organs in the gastrointestinal tract, chronic inflammation of the biliary tree predisposes to carcinogenesis. Chronic inflammation is associated with inflammatory cytokines which serve as cholangiocyte mitogens (interleukin6), nitrosative and oxidative stress causing DNA damage, and the induction of tumor promoting proteins (i.e. cyclooxygenase-2) [7–10]. These concomitant processes likely promote initiation, promotion and progression of these neoplasms. Therapy for cholangiocarcinoma is limited. Surgical extirpation is thought to be the treatment of choice, but resection for cure is often not feasible due to: (i) anatomic location of the cancer (spread to the secondary bifurcations of both the right and left hepatic ducts or involvement of the contralateral lobar vessels with ipsilateral extension into the secondary duct bifurcations of the primarily affected lobe); and/or (ii) the presence of extra- or intrahepatic metastases