Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and poor outcomes. Specific diagnostic and therapeutic approaches are undertaken for cholangiocarcinomas of different anatomical locations (intrahepatic, perihilar, and distal). Mixed hepatocellular cholangiocarcinomas have emerged as a distinct subtype of primary liver cancer. Clinicians need to be aware of intrahepatic cholangiocarcinomas arising in cirrhosis and properly assess liver masses in this setting for cholangiocarcinoma. Management of biliary obstruction is obligatory in perihilar cholangiocarcinoma, and advanced cytological tests such as fluorescence in-situ hybridisation for aneusomy are helpful in the diagnosis. Liver transplantation is a curative option for selected patients with perihilar but not with intrahepatic or distal cholangiocarcinoma. International efforts of clinicians and scientists are helping to identify the genetic drivers of cholangiocarcinoma progression, which will unveil early diagnostic markers and direct development of individualised therapies.
Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory syndrome involving the biliary tract, often accompanied by inflammatory bowel disease. This syndrome is a prototype disease linking chronic inflammation to carcinogenesis. Indeed, PSC is associated with an increased risk of cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, and colorectal cancer. Herein, we review the risk for these malignancies in PSC and discuss rational cancer surveillance strategies for these patients. Where evidence is limited, we suggest a pragmatic approach. In this regard we recommend interval screening for cholangiocarcinoma with non-invasive imaging modalities and serum carbohydrate antigen 19-9 determinations annually. These imaging studies also serve to screen for gallbladder cancer and hepatocellular carcinoma. Screening for colorectal cancer is more firmly established in PSC patients with inflammatory bowel disease and includes colonoscopy at the time of PSC diagnosis and, thereafter, at 1-2 year intervals. We also highlight areas where more information is required such as management of biliary tract dysplasia and cancer chemoprevention in PSC.
Cholangiocarcinomas (CCAs) are tumors that develop along the biliary tract. Depending on their site of origin, they have different features and require specific treatments. Classification of CCAs into intrahepatic, perihilar, and distal subgroups has helped standardize the registration, treatment, and study of this lethal malignancy. Physicians should remain aware that cirrhosis and viral hepatitis B and C are predisposing conditions for intrahepatic CCA. Treatment options under development include locoregional therapies and a chemotherapy regimen of gemcitabine and cisplatin. It is a challenge to diagnose perihilar CCA, but an advanced cytologic technique of fluorescence in situ hybridization for polysomy can aid in diagnosis. It is important to increase our understanding of the use of biliary stents and liver transplantation in the management of perihilar CCA, as well as to distinguish distal CCAs from pancreatic cancer, because of different outcomes from surgery. We review advances in the classification, diagnosis, and staging of CCA, along with treatment options.
Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.
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