Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an adenocarcinoma arising from the bile ducts within the liver, proximal to the second order ducts. It is the second commonest primary liver cancer after hepatocellular carcinoma, with rising incidence.

It accounts for about 10% to 20% of primary liver cancers and 10% to 20% of cholangiocarcinomas, with a peak age of 60 to 70 years. Five year survival is about 10% to 25% overall and about 25% to 40% after resection.

Risk factors are primary sclerosing cholangitis, hepatolithiasis, liver fluke infection (Opisthorchis viverrini, Clonorchis sinensis) in south east Asia, cirrhosis, hepatitis B and C, biliary malformations (choledochal cysts, Caroli disease), diabetes, obesity, metabolic dysfunction associated steatotic liver disease, alcohol and toxins.

Pathophysiology.

Chronic biliary inflammation and cholestasis cause genetic and epigenetic changes. Common molecular alterations include IDH1 mutation (about 15%), FGFR2 fusions (about 10% to 15%), BRAF V600E (about 5%), HER2 amplification and microsatellite instability (under 3%).

Often silent until advanced: abdominal pain, weight loss, malaise, fever, night sweats and a palpable mass. Jaundice is less frequent than in perihilar disease. It may be found incidentally on imaging in cirrhosis or primary sclerosing cholangitis.

Red flags.

• Weight loss with a liver mass.
• Jaundice with cholangitis.
• Raised CA 19-9 with a new mass in primary sclerosing cholangitis.
• Bone pain or ascites.

Multiphase magnetic resonance imaging or CT shows a peripheral mass with rim or progressive delayed enhancement, capsular retraction, and satellite nodules. CA 19-9 (not specific), carcinoembryonic antigen and alpha fetoprotein help differentiate from hepatocellular carcinoma.

Biopsy confirms the diagnosis when treatment is not surgical. Stage with chest, abdomen and pelvis CT, and positron emission tomography for nodal and distant disease; staging laparoscopy may be used.

Molecular profiling (IDH1, FGFR2, BRAF, HER2, microsatellite instability, NTRK) guides therapy.

Differential diagnosis.

• Hepatocellular carcinoma.
• Combined hepatocellular cholangiocarcinoma.
• Liver metastases (adenocarcinoma of other origin).
• Liver abscess.
• Mucinous cystic neoplasm.
• Inflammatory pseudotumour.

Surgery is the only potentially curative treatment: resection with negative margins and regional lymph node assessment in patients with adequate liver remnant. Liver transplantation is considered in carefully selected cirrhotic patients with small tumours (2 cm or less) in specialist 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; avoid with warfarin or adjust carefully.

Unresectable or metastatic disease:

• Gemcitabine, cisplatin and durvalumab: 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 (thyroid, liver, colitis); use carboplatin when creatinine clearance is under 60 mL/min, and reduce gemcitabine in hepatic impairment (start at 800 mg/m2).
• Second line: FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 bolus then 2,400 mg/m2 over 46 hours, every 14 days; monitor counts and neuropathy; reduce for hepatic and renal impairment).
• Targeted therapy by mutation: ivosidenib 500 mg orally once daily (IDH1); pemigatinib 13.5 mg orally once daily for 14 days then 7 days off (FGFR2 fusion); dabrafenib with trametinib (BRAF V600E); monitor liver enzymes, phosphate (FGFR inhibitors), eye toxicity and QTc; reduce for hepatic impairment.

Locoregional therapy (ablation, transarterial chemoembolisation, radioembolisation, hepatic arterial infusion) is used for liver confined unresectable disease. Biliary drainage treats obstruction. Palliative care starts early.

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

Referral and escalation. Hepatobiliary multidisciplinary team, oncology and transplant centre; genetics for molecular testing.