Distal Cholangiocarcinoma

Distal cholangiocarcinoma is a malignant tumour of the extrahepatic bile duct arising between the insertion of the cystic duct and the ampulla of Vater. It is a cancer of the bile duct epithelium and is treated differently from perihilar and intrahepatic disease.

It accounts for about 20% to 30% of cholangiocarcinomas, with a peak age of 65 to 75 years and a mild male predominance. Five year survival after resection is 20% to 40% with negative nodes and about 10% to 20% with positive nodes.

Risk factors are primary sclerosing cholangitis, choledochal cysts, choledocholithiasis, liver fluke infection, chronic pancreatitis and biliary papillomatosis. Many cases have no identified risk factor.

Pathophysiology.

Chronic biliary inflammation and bile acid exposure lead to dysplasia and invasive adenocarcinoma. Tumours spread along the duct wall, invade the pancreatic head and nerves, and metastasise to peripancreatic nodes.

Common molecular changes are KRAS, TP53, SMAD4 and CDKN2A alterations, with less frequent ERBB2 amplification and microsatellite instability.

Painless obstructive jaundice with dark urine, pale stools and itching, weight loss, a palpable non-tender gallbladder (Courvoisier sign), vague abdominal pain and cholangitis.

Red flags.

• Fever with jaundice (cholangitis).
• Rapid weight loss.
• Back pain (nerve invasion).
• Ascites or a palpable liver mass.

Cholestatic liver tests with raised bilirubin. CA 19-9 is raised in many but is unreliable in obstruction. Multiphase CT and magnetic resonance cholangiopancreatography show a distal stricture with upstream duct dilatation and define vessel involvement. Endoscopic ultrasound with sampling and endoscopic retrograde cholangiopancreatography with brushings or intraductal biopsy give tissue. Stage with chest CT and consider positron emission tomography.

Differential diagnosis.

• Pancreatic head adenocarcinoma.
• Ampullary or duodenal carcinoma.
• Benign biliary stricture.
• Chronic pancreatitis with stricture.
• IgG4-related sclerosing cholangitis.
• Choledocholithiasis.

Pancreatoduodenectomy with regional lymphadenectomy (at least 12 nodes) is the curative treatment, aiming for negative margins. Preoperative biliary drainage is used for cholangitis, severe jaundice with delayed surgery or neoadjuvant treatment, using a metal stent when possible.

• Capecitabine (adjuvant after resection): 1,250 mg/m2 orally twice daily on days 1 to 14 of a 21-day cycle for 8 cycles; maximum 2,500 mg/m2 daily; monitor blood counts, liver and renal function, hand foot syndrome and diarrhoea; reduce the dose by 25% for creatinine clearance 30 to 50 mL/min and avoid if under 30 mL/min; avoid with warfarin or adjust carefully.
• Gemcitabine, cisplatin and durvalumab (unresectable or metastatic): gemcitabine 1,000 mg/m2 IV and cisplatin 25 mg/m2 IV on days 1 and 8 of a 21-day cycle for up to 8 cycles, with durvalumab 1,500 mg IV on day 1 of each cycle, then durvalumab 1,500 mg every 4 weeks alone until progression; maximum cisplatin cumulative dose as limited by toxicity; monitor blood counts, renal function, hearing, electrolytes and immune adverse effects; use carboplatin when creatinine clearance is under 60 mL/min, and reduce gemcitabine in hepatic impairment.
• Piperacillin-tazobactam (cholangitis): 4.5 g IV every 6 hours for 4 to 7 days after drainage; maximum 18 g daily; monitor renal function and counts; reduce for creatinine clearance under 40 mL/min.

Palliation is by endoscopic metal stent or percutaneous drainage, and by pain control with coeliac plexus block when needed.

Monitoring. Imaging and CA 19-9 every 3 months for 2 years after resection, then every 6 months.

Referral and escalation. Hepatobiliary and pancreatic surgery, oncology and therapeutic endoscopy.