This Seminar was written after a systematic review of articles published in English, using the PubMed and Medline search engines. We searched using the key word “cholangiocarcinoma” in association with relevant areas including: reviews, epidemiology, intrahepatic, extrahepatic, aetiology, molecular markers, viral hepatitis, tumour markers, cholangiography, endoscopic ultrasound, biliary stents, PET, staging, surgery, portal vein embolisation, liver transplantation, radiotherapy,
SeminarCholangiocarcinoma
Section snippets
Classification
More than 90% of cholangiocarcinomas are adenocarcinomas.9 60–70% arise at the bifurcation of the hepatic ducts (Klatskin tumours)10 and 20–30% in the distal common bile duct. 5–10% of cholangiocarcinomas are peripheral, arising within intrahepatic ducts of the liver parenchyma itself.10 Intrahepatic cholangiocarcinomas originate in the small bile ducts and tend to be grouped, by international classification of disease (ICD) codes, with hepatocellular carcinoma as primary liver tumours.5, 11 In
Epidemiology
Worldwide, cholangiocarcinoma accounts for 3% of all gastrointestinal cancers13 and is the second commonest primary hepatic tumour.5, 13 The peak age for patients with the disease is the seventh decade and the sex incidence shows a slight male preponderance,4, 11 with 48% of these tumours occurring in men compared with 37% in women in a US study.14 The reported incidence in the USA is 1–2 cases per 100 000 (3500 new cases per year) with no clear racial predisposition.14 Of note, several studies
Cause and risk factors for cholangiocarcinoma
Known risk factors account for only a few cases of cholangiocarcinoma and seem to be associated with chronic inflammation of the biliary epithelium.
Molecular pathogenesis and markers
A number of mutations in oncogenes and tumour suppressor genes have been identified in cholangiocarcinoma,44 suggesting the cancer may arise secondary to cellular, and consequent DNA, injury. Several studies have shown abnormal expression of the K-ras oncogene in 21–100% of cases and the p53 tumour suppressor gene in up to 37% of archival specimens in the largest studies.45 These genetic alterations are associated with a more aggressive phenotype in this cancer.45, 46 K-ras and p53 mutations
Carcinogenesis in cholangiocarcinoma
Development of cholangiocarcinoma, as with most tumours, is probably a multi-step process dependent on an interaction between environmental factors and host genetic factors. Most of the putative environmental risk factors for cholangiocarcinoma cause chronic biliary irritation and can contribute to a promotional stage of carcinogenesis. Several of the potential genetic changes44 in the host that could be implicated in cholangiocarcinogenesis are summarised in figure 2. Genetic polymorphisms in
Clinical features
Cholangiocarcinoma is rare in individuals younger than 40 years. The presenting clinical features depend on tumour location. Lesions at the bifurcation of the hepatic ducts or in the distal common bile duct classically present with the sequelae of biliary obstruction: painless jaundice, pale stools, dark urine, and pruritus.11 Peripheral tumours, arising within intrahepatic ducts of the liver parenchyma itself, tend to present with non-specific symptoms such as malaise, weight loss, and
Diagnosis
Most patients with hilar strictures and jaundice have cholangiocarcinoma.54 However, confirmation of cholangiocarcinoma can be very difficult because of a wide range of alternative diagnoses, including benign strictures (iatrogenic bile duct injuries, primary sclerosing cholangitis, and choledocholithiasis); and other carcinomas, such as gallbladder cancer or metastatic hilar nodal metastases. The diagnosis of cholangiocarcinoma occurring in primary sclerosing cholangitis can be especially
Clinical staging
Cholangiocarcinoma staging is based on the tumour-node-metastasis (TNM) system (panel). Furthermore, the extent of duct involvement by perihilar tumours can be classified according to the Bismuth classification (figure 3), which stratifies patients on location and extent of cancer in the biliary tree.75
Surgical management
A complete surgical resection with histologically negative resection margins is the only cure for cholangiocarcinoma. Unfortunately only a few patients are suitable for surgery and therefore early liaison with a specialist surgical team is recommended.11 The nature and extent of the surgery depends on the site of the cancer within the liver or the biliary tract. For extrahepatic cholangiocarcinoma affecting the common bile duct, the biliary tree and hilar lymphatics are resected.54 Most
Palliation
Palliative treatment to relieve symptoms, treat sepsis, or normalise bilirubin before chemotherapy or radiotherapy, clearly has an important role given that 80% of patients with hilar cholangiocarcinoma are unsuitable for resection and even in those undergoing resection there is a high risk of recurrence.77, 86 Median survival for non-resectable cholangiocarcinomas is about 3 months without and 6 months with biliary drainage.100, 101, 102 Bacterial cholangitis or liver failure often contribute
Photodynamic therapy
In this novel treatment, the photosensitiser sodium porfimer (which localises to mitochondria) is given intravenously and localises preferentially in tumour tissue over 24–48 h. This process is followed by endoscopic direct illumination of the tumour bed with a specific wavelength of light resulting in the activation of the porfimer, generating oxygen free radicals and leading to ischaemic cancer cell death.101 This technique has been shown to regress carcinomas of the skin, lungs, pharynx,
Summary
Cholangiocarcinoma is a predominantly fatal cancer, which can be difficult to diagnose and to treat. The incidence is increasing worldwide and its pathogenesis remains unclear. New imaging and staging techniques help select patients for curative resection and can eventually define patients suitable for liver transplantation within chemoradiotherapy protocols. Chemotherapy and radiotherapy results have so far been disappointing. Palliation involves endoscopic or percutaneous stent placement for
Search strategy and selection criteria
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