Cholangiocarcinoma: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Cholangiocarcinoma (CCA) is a malignant tumor arising from bile duct epithelium (cholangiocytes). It is classified as intrahepatic (iCCA, ~20%), perihilar/Klatskin tumor (~50%), or distal extrahepatic (~30%). CCA represents approximately 3% of GI cancers globally, with incidence of intrahepatic CCA rising worldwide. Most cases are diagnosed at advanced stage due to insidious onset and lack of effective screening.

Primary sclerosing cholangitis (PSC) confers 10-15% lifetime risk in Western countries. Liver flukes (Opisthorchis viverrini, Clonorchis sinensis) are major risk factors in Southeast Asia. Cirrhosis, HBV, HCV, biliary stones, choledochal cysts, and NAFLD also increase risk. Key molecular drivers: FGFR2 fusions (approximately 15% iCCA), IDH1 mutations (approximately 15% iCCA), KRAS (approximately 25%), TP53, ARID1A, BRCA1/2, HER2 amplification, MSI.

Perihilar/distal CCA: painless obstructive jaundice (bilirubin elevation, dark urine, pale stools, pruritus), right upper quadrant pain, and weight loss. Charcot's triad (fever, jaundice, RUQ pain) when biliary infection complicates obstruction. Intrahepatic CCA: often asymptomatic until advanced, presenting as an incidental liver mass or constitutional symptoms. CA 19-9 >100 U/mL is elevated in approximately 75% but non-specific.

CT abdomen plus MRCP for anatomy and extent. Cholangioscopy (SpyGlass) with biopsies or ERCP with brush cytology for tissue sampling from perihilar/distal CCA. Percutaneous CT-guided biopsy for iCCA. Comprehensive molecular NGS panel: FGFR2 fusion, IDH1 mutation, KRAS, BRAF, NTRK, RET, HER2, MSI/MMR, TMB — all are potentially actionable. PET/CT for staging. Portal vein embolization (PVE) to augment future liver remnant before major hepatectomy.

Resectable iCCA: major hepatectomy (R0 mandatory) plus adjuvant capecitabine. Resectable perihilar CCA: ipsilateral hepatectomy with caudate lobe; distal CCA: Whipple procedure. Liver transplantation for selected unresectable perihilar CCA (strict criteria: <3 cm, no mets, neoadjuvant chemoradiation, <6 months wait). Palliative biliary stenting. First-line metastatic: gemcitabine plus cisplatin plus durvalumab. Second-line targeted: pemigatinib/futibatinib (FGFR2+), ivosidenib (IDH1+), pembrolizumab (MSI-H), larotrectinib (NTRK), neratinib/trastuzumab (HER2+).

Resected CCA: 5-year OS approximately 25-40% with R0 resection. Metastatic: historical median OS with gemcitabine-cisplatin approximately 11.7 months; with addition of durvalumab (TOPAZ-1 trial): median OS approximately 12.8 months with sustained OS benefit at 24 months (24.9% vs 10.4%). Molecular-targeted therapies improve outcomes in biomarker-selected patients; comprehensive molecular profiling is now standard of care.