Aetiology
There is a close association between infection, inflammation, and cancer. Multiple risk factors, particularly those linked to chronic biliary inflammation, are associated with cholangiocarcinoma.[7][8] Some risk factors are relevant to all types of cholangiocarcinoma, while others are specific to different subtypes of the disease. For example, conditions that are associated with an increased risk of developing intrahepatic cholangiocarcinoma include chronic liver disease due to hepatitis B or C leading to cirrhosis, alcoholic liver disease, non-specific cirrhosis, bile duct diseases (e.g., bile duct adenoma, biliary papillomatosis, and congenital liver abnormalities such as choledochal cyst and Caroli’s disease), choledocholithiasis, cholecystolithiasis, ulcerative colitis, and HIV.[7][9][10][11][12][13]
Primary sclerosing cholangitis (PSC) has also been associated with high risk of cholangiocarcinoma, with a prevalence in patients with PSC ranging from 7% to 13%.[14] The risk of cholangiocarcinoma in patients with PSC increases with older age.[7]
Risk factors for both intra- and extrahepatic cholangiocarcinoma include chronic typhoid carriers, infection with liver flukes (Clonorchis sinensis and Opisthorchis), heavy drinking (>80 g of ethanol per day), exposure to certain toxins/medications (e.g., polychlorinated biphenyls [PCBs], isoniazid, and oral contraceptive pills), and the use of radionuclides (thorium dioxide, a radioactive contrast agent used until the 1950s).[15][16][17][18]
Pathophysiology
Cholangiocarcinomas are uncommon and, depending on the site of the cancer, the aetiological risk factors, patient characteristics, and molecular biology of the tumour vary. Despite the remarkable advances that have occurred in the understanding of cancer biology and genetics, little is known about the molecular biology of biliary tract cancers. Reports have associated genetic mutations with the cellular mechanisms that have an important role in the development of these tumours. Point mutations of K-ras and beta-catenin proto-oncogenes, and alterations of p53, p16, APC, and DPC4 tumour suppressor genes by a combination of chromosomal deletion, mutation, or methylation have been associated with biliary tract tumours.[19]
More than 95% of biliary tract cancers are adenocarcinomas. Most are of the infiltrating nodular or diffusely infiltrating type. Purely nodular or papillary are less frequent subtypes. These tumours produce a desmoplastic reaction resulting in a low neoplastic cellularity. This makes establishing a diagnosis difficult with small biopsies. Staining for carcinoembryonic antigen (CEA), CA 19-9, or CA-50 aids in making a pathological diagnosis.[6][12][14][20]
Signalling pathways, drivers of carcinogenesis, and potential targets for therapies include KRAS/MAPK, EGFR, IL-6/STAT, IDH1/2, FGFR2, and MET signalling.[1] No oncogenic addiction loops have been described so far. Molecular classification of iCCA based on gene signatures or molecular abnormalities is not ready for clinical application.
Classification
International Liver Cancer Association[1]
Guidelines from the International Liver Cancer Association recommend that cholangiocarcinoma should be sub-classified as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), where iCCA arises within the liver parenchyma. The terms 'Klatskin's tumour' and 'extrahepatic tumour' are discouraged.
American Joint Committee on Cancer TNM staging system (8th Edition)[2]
The American Joint Committee on Cancer (AJCC) staging system describes the extent of disease based on the following anatomic factors: size and extent of the primary tumour (T); regional lymph node involvement (N); and presence or absence of distant metastases (M). Nonanatomic prognostic factors (e.g., tumour grade, biomarkers) may be used to supplement the staging of certain cancers.
Bismuth-Corlette: hilar cholangiocarcinoma[3]
The extent of duct involvement by perihilar tumours can be classified as suggested by Bismuth:
Type 1 - tumours below the confluence of the left and right duct
Type 2 - tumours reaching the confluence but not involving the left or right hepatic ducts
Type 3 - tumours occluding the common hepatic duct and either the right (3a) or left (3b) hepatic duct
Type 4 - tumours that are multi-centric or that involve the confluence and both the right and left hepatic ducts.
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