Synonym: Klatskin tumour

Cholangiocarcinoma is a carcinoma arising in any part of the biliary tree from the small intrahepatic bile ducts to the ampulla of Vater at the distal end of the common bile duct.

• Most commonly they occur in the perihilar region (classical Klatskin tumour) near the bifurcation of right and left hepatic ducts.
• Tumours occurring between the upper border of the pancreas and ampulla of Vater are the next most common and are classified as distal extrahepatic tumours.
• Also, it can occur (least commonly) as an intrahepatic tumour.

More than 90% of cholangiocarcinomas are ductal adenocarcinomas and the remainder are squamous cell tumours.¹

Epidemiology

• Incidence is 1-2 per 100,000 population per year in the UK and the USA.¹
• Most cases occur in those aged over 60 years.
• There is a high incidence of cholangiocarcinoma in Southeast Asian countries due to chronic endemic parasite infection with liver flukes.
• In Japan and Israel the incidence is much higher at 5.5 and 7.3 cases per 100,000 people per year.¹
• There appears to have been a significant increase in the incidence of cholangiocarcinoma in the UK over recent years (a fifteen-fold increase in age-specific mortality rates for those aged >45 from 1968 to 1998).² This may be due to better diagnosis or a true increase in the disease's incidence due to unknown mechanisms.²

Risk factors

• Patients with chronic ulcerative colitis who develop primary sclerosing cholangitis are prone to cholangiocarcinoma. The lifetime risk of developing this cancer is 10-20% with primary sclerosing cholangitis. Some patients with Crohn's disease may also be at risk.
• Infection with the liver flukes Clonorchis sinensis and Opisthorchis viverrini have been causally linked. Ascaris lumbricoides infection has also been implicated.¹
• Industrial chemical exposure: chemicals used in the aircraft, rubber and wood-finishing industries have been implicated.¹
• Thorium exposure is associated with an increase in cases of cholangiocarcinoma.³
• Congenital abnormalities of the bile ducts, e.g. choledochal cysts.
• Caroli's disease (a rare congenital disorder of the intrahepatic bile ducts associated with autosomal recessive polycystic kidney disease where the bile ducts become chronically dilated).⁴
• Recently implicated potential risk factors for the intrahepatic form include hepatitis C, HIV, cirrhosis and diabetes.⁵

Presentation

• Jaundice is an early feature in perihilar tumours, usually with hepatomegaly.
• Abdominal pain, localised to the right upper quadrant, especially in advanced disease.
• Weight loss is variable.
• Pale-coloured stools, passage of dark urine, upper gastrointestinal pain (dull ache in the upper right quadrant), weight loss, anorexia and general malaise are common features.
• Pruritus may be the presenting symptom predating jaundice on occasions.
• Hepatomegaly.
• Splenomegaly is present if prolonged biliary obstruction has caused secondary biliary cirrhosis.
• The presence of a palpable gallbladder (Courvoisier's sign) may occur with tumours distal to the cystic duct.

Investigations¹

• Liver function tests: elevated conjugated bilirubin. Cholestatic picture with markedly elevated alkaline phosphatase, gamma-GT elevated with aminotransferases affected minimally.
• Prothrombin time and INR may be prolonged.
• Tumour markers: carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) tumour markers may be raised (also found in other causes of obstructive jaundice).
• Alphafetoprotein is not produced by cholangiocarcinoma.
• Ultrasound and CT scan: hilar tumours show dilatation of intrahepatic biliary tree.
• MRI cholangiography or endoscopic retrograde cholangiopancreatography (ERCP) show the site of obstruction. ERCP may be used to obtain samples for biopsy or cytological analysis.
• Angiography may be conducted as a prelude to surgical intervention, as encasement of the hepatic arteries or portal vein precludes successful surgical therapy.

Differential diagnosis

• Acute cholecystitis
• Bile duct strictures
• Extrabiliary tumour compressing biliary system
• Biliary adenoma
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Ascending cholangitis
• Obstructive choledocholithiasis
• Pancreatic tumours
• Choledochal cysts
• Acute hepatitis

Staging¹

• T: primary tumour:
  • TX: primary tumour cannot be assessed
  • T0: no evidence of primary tumour
  • TIS: carcinoma in situ
  • T1a: tumour invades mucosa
  • T1b: tumour invades muscularis
  • T2: tumour invades perimuscular connective tissue
  • T3: tumour invades liver, gallbladder, duodenum, stomach, pancreas or colon
• N: regional lymph nodes:
  • NX: regional lymph nodes cannot be assessed
  • N0: no metastases in regional lymph nodes
  • N1: metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal ligament
  • N2: metastases in peripancreatic (head only), periduodenal, posterior pancreatoduodenal, periportal, celiac, or superior mesenteric regional lymph nodes
• M: metastasis:
  • MX: presence of metastases cannot be assessed
  • M0: no distant metastases
  • M1: distant metastases (includes lymph node metastases beyond N2)

TNM groupings by stage

• Stage 0: TIS N0 M0
• Stage I: T1 N0 M0
• Stage II: T2 N0 M0
• Stage III: T1-2 N1-2 M0
• Stage IVa: T3 N0-2 M0
• Stage IVb: T1-3 N0-2 M1

Management

Surgery

• Complete surgical resection is the only intervention to offer a chance of cure but only about 10% of patients present with early stage disease and are considered for curative resection.⁶
• Intrahepatic and Klatskin tumours require liver resection.¹
• Aggressive surgical resection (including hepatic resection ± hepatic transplantation⁷) with adjuvant chemotherapy may offer a cure rate of around 30% in suitable candidates at the best centres.^8,9
• Palliative surgery is required if stenting cannot be achieved. Surgical bypass procedures may be required for biliary obstruction, especially for tumours in the common bile duct.
• Adjuvant chemotherapy is thought to be of benefit but there is no consensus on its effect or optimal regimens.¹⁰
• Adjuvant and preoperative radiation therapy has been used to reduce tumours in an effort to make them resectable. Radiotherapy without surgery, with or without chemotherapy, has been shown to improve survival in patients with inoperable or unresectable tumours.⁷

Nonsurgical therapy

• Stents:
  • Endoscopic retrograde cholangiopancreatography (ERCP) may be used to stent the bile duct to relieve symptoms; they are prone to occlusion and may need replacing approximately every 3 months.
  • Self-expanding metal stents seem to offer the best technical outcome.¹¹
  • However, there is no evidence to support the benefit of ERCP with stenting in patients with malignant pancreaticobiliary diseases while awaiting surgery.¹²
• Photodynamic therapy is an experimental treatment which may have some benefit, in terms of prolonging survival but is not currently recommended as part of routine management.¹³
• The reality for most patients is that their long-term survival is unlikely and good palliative symptom-relieving care is the mainstay of management.

Complications

• The risk of biliary tract sepsis is increased and may cause a deterioration which is amenable to antibiotic therapy.
• Secondary biliary cirrhosis occurs in 10-20% of patients.

Prognosis

• Progressive deterioration with average survival of 12-18 months from diagnosis. The overall survival rates are low because many patients present with unresectable or metastatic disease.
• Prognosis is much better for those with extrahepatic tumours who are suitable for early surgical intervention.
• Intrahepatic lesions carry the worst prognosis.

Document references

1. Darwin PE; Cholangiocarcinoma; eMedicine, January 2009.
2. Taylor-Robinson SD, Toledano MB, Arora S, et al; Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut. 2001 Jun;48(6):816-20. [abstract]
3. Zhu AX, Lauwers GY, Tanabe KK; Cholangiocarcinoma in association with Thorotrast exposure. J Hepatobiliary Pancreat Surg. 2004;11(6):430-3. [abstract]
4. Friedman JR; Caroli Disease; eMedicine, September 2009.
5. Shaib YH, El-Serag HB, Davila JA, et al; Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology. 2005 Mar;128(3):620-6. [abstract]
6. Han SL, Zhu GB, Yao JG, et al; Diagnosis and surgical treatment of primary hepatic cholangiocarcinoma. Hepatogastroenterology. 2005 Mar-Apr;52(62):348-51. [abstract]
7. Pandey D, Lee KH, Tan KC; The role of liver transplantation for hilar cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2007 Jun;6(3):248-53. [abstract]
8. Zervos EE, Osborne D, Goldin SB, et al; Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach. Am J Surg. 2005 Nov;190(5):810-5. [abstract]
9. Ghali P, Marotta PJ, Yoshida EM, et al; Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl. 2005 Nov;11(11):1412-6. [abstract]
10. Puhalla H, Schuell B, Pokorny H, et al; Treatment and outcome of intrahepatic cholangiocellular carcinoma. Am J Surg. 2005 Feb;189(2):173-7. [abstract]
11. Singhal D, van Gulik TM, Gouma DJ; Palliative management of hilar cholangiocarcinoma. Surg Oncol. 2005 Aug;14(2):59-74. [abstract]
12. Mumtaz K, Hamid S, Jafri W; Endoscopic retrograde cholangiopancreaticography with or without stenting in patients with pancreaticobiliary malignancy, prior to surgery. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006001. [abstract]
13. Photodynamic therapy for bile duct cancer, NICE (2005)

Internet and further reading

• Macmillan Cancer Suppport, Bile duct cancer (cholangiocarcinoma)
• US National Cancer Institute; Information on extrahepatic bile duct cancer
• Online Mendelian Inheritance in Man; Caroli disease

Acknowledgements