Cholangiocarcinoma

Synonym: Klatskin's tumour

What is cholangiocarcinoma?

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

• Most commonly, they occur in the perihilar region (classical hilar cholangiocarcinoma) 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.

• Can also occur (least commonly) as an intrahepatic tumour.

How common is cholangiocarcinoma? (Epidemiology)

• Incidence is around 1-2 per 100,000 population per year in the UK and the USA. ²

• Most cases occur in those aged over 60 years.

• There is a high incidence of cholangiocarcinoma in Southeast Asian countries, due to chronic endemic parasitic infection with liver flukes.²

• The incidence of intrahepatic cholangiocarcinoma is increasing in Western countries. This may reflect improved diagnostics, migration patterns, an increased burden of chronic liver disease, and changes in diagnostic classification systems.³⁴

Risk factors

Chronic inflammation of the biliary epithelium is thought to be the critical shared feature of risk factors.⁴

• 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 or Opisthorchis viverrini has been causally linked. Ascaris lumbricoides infection has also been implicated.⁵

• Industrial chemical exposure: occupationally-related cholangiocarcinoma cases have been reported in the printing industry and in people exposed to asbestos.⁶

• Thorium exposure is associated with an increase in cases of cholangiocarcinoma.⁷

• Congenital abnormalities of the bile ducts - eg, choledochal cysts. ⁸

• 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).⁹

• Other likely risk factors for the intrahepatic form include hepatitis C, HIV, cirrhosis, obesity, alcohol, smoking, and diabetes.¹⁰⁸

Symptoms of cholangiocarcinoma (presentation)¹¹

• Most patients develop symptoms only once the disease had advanced.

• Intrahepatic cholangiocarcinomas present with non-specific symptoms such as abdominal pain, night sweats, and cachexia.

• Jaundice is an early feature in perihilar tumours, sometimes with hepatomegaly.

• Fever is more common in perihilar tumours.

• 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.

• The presence of a palpable gallbladder (Courvoisier's sign) may occur with tumours distal to the cystic duct.

Investigations^{12 13}

Diagnosis should be made on the basis of radiological investigations (including CT or MRI) and pathological assessment from a biopsy, fine-needle aspiration or biliary brush cytology.⁴

• There are no blood tests that are diagnostic for cholangiocarcinoma,⁸ but testing is usually performed as part of the diagnostic process to look for other conditions, assess liver synthetic function, and aid the diagnosis.

• LFTs may show an obstructive picture. Aminotransferases are typically normal, but may be elevated in acute obstruction or cholangitis.⁸

• Prothrombin time and INR may be prolonged if there has been a prolonged period of biliary obstruction..

• Tumour markers: carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) tumour markers may be raised. These have poor sensitivity and specificity, but may be useful alongside other diagnostic tests.⁸

• Imaging tests are the main diagnostic modality for cholangiocarcinomas.

• Ultrasound and CT scan: hilar tumours show dilatation of intrahepatic biliary tree. Ultrasonography is reliable for excluding gallstones, but is operator-dependent and cannot exclude cholangiocarcinoma alone.⁸

• Contrast MRI is the optimal imaging for diagnosis of cholangiocarcinoma.⁸ However, it is inferior to CT for detecting distant metastases.

• MRI cholangiography or endoscopic retrograde cholangiopancreatography (ERCP) shows 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.

Staging⁴

Staging is based on the tumour, node and metastasis (TNM) classification with some modifications for intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and distal cholangiocarcinoma. Hilar cholangiocarcinoma is clinically staged depending on the involvement of the hepatic ducts according to the Bismuth-Corlette classification (see European Society for Medical Oncology (ESMO) guideline reference for details).⁴

The initial diagnostic tests may provide staging information. Additionally, a contrast CT of the abdomen, chest and pelvis should be performed to look for metastatic disease. Many surgical centres also offer a staging laparoscopy to exclude local metastatic disease in people with imaging suggestive of resectable disease.⁸

Management of cholangiocarcinoma

Surgery

• Complete surgical resection is the only intervention to offer a chance of cure but fewer than 33% are resectable at diagnosis.⁸

• Intrahepatic and Klatskin tumours require liver resection. ^{8 14}

• Distal cholangiocarcinomas are managed by pancreatoduodenectomy.⁸

• Aggressive surgical resection (including liver resection ± liver transplantation) with adjuvant chemotherapy has been reported to achieve a 65% recurrence-free survival at five years in carefully-selected patients.¹⁵

• Palliative surgery may be 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, such as with capecitabine.⁴

• Adjuvant radiation therapy and pre-operative radiation therapy have 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.¹⁶

Non-surgical therapy

Postoperative treatment after non-curative resection of cholangiocarcinoma remains controversial, and both supportive care and palliative chemotherapy and/or radiotherapy may be considered.⁴

• Stents:
  

  • ERCP may be used to stent the bile duct to relieve symptoms; they are prone to occlusion and may need replacing approximately every three months.

  • Self-expanding metal stents seem to offer the best technical outcome.¹⁷

  • However, there is no evidence to support the benefit of ERCP with stenting in patients with malignant pancreaticobiliary diseases while awaiting surgery.¹⁸

• For advanced cholangiocarcinoma, endoscopic biliary stenting has become an established treatment. Evidence supports the use of metal stents over plastic to improve survival and stent patency. Other treatments such as radiofrequency ablation, transarterial chemoembolisation and radiotherapy have shown promise, and cisplatin and gemcitabine are first-line chemotherapy agents in advanced cholangiocarcinoma.¹⁹⁴

Chemotherapy used without radiotherapy has not shown any significant local control or survival benefit.

• 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, given its investigational nature.⁴

• The reality for most patients is that their long-term survival is limited and good palliative symptom-relieving care is the mainstay of management.

Complications of cholangiocarcinoma

• 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.

Even in patients undergoing aggressive surgery, five-year survival rates are 10-40% for cholangiocarcinoma.

• Prognosis is much better for those with extrahepatic tumours who are suitable for early surgical intervention.

• Intrahepatic lesions carry the worst prognosis.