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
References (126)
- et al.
Changing international trends in mortality rates for liver, biliary and pancreatic tumours
J Hepatol
(2002) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States
Hepatology
(2001)- et al.
Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study
Gastroenterology
(2005) - et al.
Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?
J Hepatol
(2004) - et al.
Malignancies of the biliary tree
Curr Probl Surg
(1995) - et al.
Bcl-2 is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line
Hepatology
(1997) - et al.
p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma
Gastroenterol
(2002) - et al.
The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis
Am J Gastroenterol
(2000) - et al.
Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis
Gastrointest Endosc
(2002) - et al.
Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis
Gastroenterol
(1995)
Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings
Am J Gastroenterol
A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures
Clin Gastroenterol Hepatol
Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma
J Gastrointest Surg
Role of laparoscopy in the evaluation of biliary tract cancer
Surg Oncol Clin N Am
Changing strategies in diagnosis and management of hilar cholangiocarcinoma
Liver Transpl
Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma
Int J Radiat Oncol Biol Phys
“Natural history” of unresected cholangiocarcinoma: patient outcome after noncurative intervention
Mayo Clin Proc
A review and update on cholangiocarcinoma
Oncology
Histological typing of tumours of the liver. WHO International Histological Classification of Tumours
Liver, gallbladder, extrahepatic bile ducts, and pancreas
Cancer
The epidemiology of cholangiocarcinoma
Semin Liver Dis
Worldwide trends in mortality from biliary tract malignancies
BMC Cancer
Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998
Gut
Histological typing of tumours of the liver. WHO International Histological Classification of Tumours
Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors
Ann Surg
Guidelines for the diagnosis and management of cholangiocarcinoma
Gut
The general rules for the clinical and pathological study of primary liver cancer
Recent advances in the management of cholangiocarcinomas
Semin Liver Dis
New p53 mutations in hilar cholangiocarcinoma
Eur J Clin Invest
Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis
Gut
Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study
Hepatology
Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study
Hepatology
Liver fluke-associated cholangiocarcinoma
Br J Surg
Cholangiocarcinoma in patients with opisthorchiasis
Br J Surg
Liver cancer in Thailand I: a case-control study of cholangiocarcinoma
Int J Cancer
Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters
Cancer Res
Gallbladder and biliary tree: anatomy and structural anomalies
Bile duct carcinoma: a late complication of congenital hepatic fibrosis: case report and review of literature
Am J Gastroenterol
Choledochal cyst disease: a changing pattern of presentation
Ann Surg
Carcinoma arising in choledochocele
Endoscopy
FIC1 disease: a spectrum of intrahepatic cholestatic disorders
Semin Liver Dis
Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases
Semin Liver Dis
BSEP: function and role in progressive familial intrahepatic cholestasis
Semin Liver Dis.
Hepatocellular malignancy in ABCB11/BStP disease (progressive familial intrahepatic cholestasis, type 2): four patients
Hepatology
Hepatolithiasis associated with cholangiocarcinoma
World J Surg
Peripheral cholangiocarcinoma (cholangiocellular carcinoma): clinical features, diagnosis and treatment
J Gastroenterol Hepatol
Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology
J Gastroenterol Hepatol
DNA adducts, detected by 32P postlabelling, in human cholangiocarcinoma
Gut
Thorotrast-induced cholangiocarcinoma: case report
Abdom Imaging
Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria: an epidemiological investigation
Br J Cancer
Cited by (1066)
Germline Genetic Associations for Hepatobiliary Cancers
2024, Cellular and Molecular Gastroenterology and HepatologyMethodical selected coptisine attenuates the malignancy of cholangiocarcinoma through the blockade of EGFR signalling
2024, Journal of Functional Foods