Perihilar Cholangiocarcinoma

Perihilar cholangiocarcinoma (Klatskin tumour) is a malignant tumour of the bile duct arising between the second order intrahepatic ducts and the insertion of the cystic duct. It accounts for about 50% to 60% of cholangiocarcinoma.

The mean age is 60 to 70 years, with a slight male predominance. Five year survival is about 10% without surgery and 20% to 40% after complete resection.

The Bismuth-Corlette classification describes ductal involvement: type I under the confluence, type II at the confluence, type IIIa and IIIb involving the right or left hepatic duct, and type IV involving both.

Risk factors are primary sclerosing cholangitis, hepatolithiasis, liver flukes, choledochal cysts and chronic biliary inflammation. Spread is by longitudinal growth along the duct, perineural invasion, and to lymph nodes.

Pathophysiology.

Chronic inflammation and bile stasis drive dysplasia and invasive carcinoma. Obstruction of the biliary confluence causes jaundice, cholangitis and secondary liver atrophy of the involved lobe, with hypertrophy of the other.

Painless jaundice (the commonest presentation), pruritus, dark urine, pale stool, weight loss, malaise and cholangitis. Abdominal pain is a late feature.

Red flags.

• Jaundice with fever and rigors (cholangitis).
• Rapid weight loss.
• Ascites or distant metastases.
• Hepatic lobar atrophy with portal vein involvement.

Liver tests show a cholestatic pattern. CA 19-9 is raised but not specific in obstruction. Magnetic resonance cholangiopancreatography and multiphase CT show the stricture and extent, vascular involvement and liver volumes. Endoscopic brush cytology, intraductal biopsy and fluorescence in situ hybridisation or endoscopic ultrasound sampling give tissue; avoid percutaneous biopsy in potentially resectable disease because of tumour seeding. Stage with chest CT and positron emission tomography when indicated, and laparoscopy where appropriate.

Differential diagnosis.

• Benign biliary stricture.
• Primary sclerosing cholangitis.
• IgG4-related sclerosing cholangitis.
• Gallbladder cancer with extension.
• Mirizzi syndrome.
• Lymph node compression.

Surgery is the only cure: major hepatectomy with extrahepatic bile duct resection, caudate lobectomy and regional lymphadenectomy, with biliary enteric reconstruction. The future liver remnant should be over 30% in a normal liver and over 40% with cholestasis or after chemotherapy; portal vein embolisation increases a small remnant.

Preoperative biliary drainage is used only for cholangitis, when jaundice is severe with planned major hepatectomy, or when surgery is delayed; drain the future liver remnant.

Liver transplantation after neoadjuvant chemoradiotherapy is an option in selected patients with unresectable early disease (tumour 3 cm or less radially, no intra- or extrahepatic metastases, no lymph node disease) or primary sclerosing cholangitis, in expert centres.

• 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.
• 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 by endoscopic or percutaneous stenting should drain over 50% of the liver volume (usually one lobe when it is free of atrophy); photodynamic therapy or radiofrequency ablation within the duct are alternatives in selected cases.

Monitoring. Imaging every 3 months for 2 years after resection, then every 6 months; CA 19-9 and liver tests at each visit; stent patency and cholangitis episodes.

Referral and escalation. Hepatobiliary multidisciplinary team, interventional endoscopy, oncology and transplant centre.