Cholangiocarcinoma

Synonyms: CCC, 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 occur in the perihilar region (classical Klatskin tumour) near confluence of right and left hepatic ducts.
• Tumours occurring between upper border of pancreas and Ampulla of Vater are the next most common and are classified as distal extrahepatic tumours.
• Also occurs (least commonly) as an intrahepatic tumour.

• Incidence is 1-2 per 100,000 population per year in UK and US.^1,2
• There is a high incidence of cholangiocarcinoma in south-east 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.²
• 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).¹ This may be due to better diagnosis or a true increase in the disease's incidence due to unknown mechanisms.¹

Risk factors

• Most cases occur in those aged over 60 years.
• Male:female ratio is approximately 1.5:14.
• Inflammatory bowel disease: 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. A subset of patients with Crohn's disease may also be at risk.³
• Infection with the liver flukes Clonorchis sinensis and Opisthorchis viverrini have been causally linked. Ascaris lumbricoides infection has been implicated.²
• Industrial chemical exposure: chemicals used in the aircraft, rubber and wood-finishing industries have been implicated.²
• Thorium exposure is associated with an increase in cases of cholangiocarcinoma.³
• Congenital choledochal cysts.
• Caroli disease (rare congenital disorder of intrahepatic bile ducts associated with autosomal recessive polycystic kidney disease where bile ducts become chronically dilated).
• Recently implicated potential risk factors for intrahepatic form include hepatitis C, HIV, cirrhosis and diabetes.⁴

• Jaundice is an early feature in perihilar tumours, usually with hepatomegaly.
• Pale-coloured stools, passage of dark urine, upper GI pain (dull ache upper right quadrant), weight loss, anorexia and general malaise are common features.
• Pruritus may be the presenting symptom predating jaundice on occasions.
• 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.

• Liver function tests: elevated conjugated bilirubin. Cholestatic picture with markedly elevated alkaline phosphatase, gamma-GT elevated with aminotransferases affected minimally.
• 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.
• Prothrombin time and INR may be prolonged.
• Ultrasound and CT scan: hilar tumours show dilatation of intrahepatic biliary tree.
• MRI cholangiography or ERCP may show obstruction in the hilum. ERCP may be used to obtain samples for biopsy/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.

• 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

• Early surgery offers the only hope of cure but few patients are diagnosed soon enough.⁵
• Aggressive surgical resection (including hepatic resection ± hepatic transplantation⁶) with adjuvant chemotherapy may offer a cure rate of around 30% in suitable candidates at the best centres.^7,8
• Adjuvant chemotherapy is thought to be of benefit but there is no consensus on its effect or optimal regimens.⁹ Palliative biliary drainage procedures may improve symptoms of biliary obstruction, but are associated with significant morbidity and mortality.
• 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.⁶

Non-surgical therapy

• ERCP (endoscopic retrograde cholangiopancreaticography) may be used to stent the bile duct to relieve symptoms; they are prone to occlusion and may need replacing every 3 months or so. Self-expanding metal stents seem to offer the best technical outcome.¹⁰ However there is no evidence to support the benefit of ERCP with stenting in patients with malignant pancreaticobiliary diseases while awaiting surgery.¹¹
• Photodynamic therapy is an experimental treatment which may have some benefit, in terms of prolonging survival.²
• Chemotherapy and external beam radiotherapy may be used as palliative measures to improve symptoms.¹⁰
• The reality for most patients is that their long term survival is unlikely and good palliative symptom-relieving care is the mainstay of management.

• 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 is much better for those with extrahepatic tumours who are suitable for early surgical intervention.
• Intrahepatic lesions carry the worst prognosis.
• Progressive deterioration with average survival from diagnosis of 12-18 months.
• Slow growing tumour, so if biliary drainage can be produced for hilar tumours, prognosis may be improved.