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Cholangiocarcinoma (C22.1)

Cholangiocarcinoma is a malignant tumor arising from the epithelial cells of the bile ducts, known as cholangiocytes. It is an aggressive and often difficult-to-diagnose cancer that can occur anywhere along the biliary tree and is broadly classified into intrahepatic, perihilar, and distal extrahepatic subtypes based on anatomic location. Cholangiocarcinoma is relatively uncommon but carries a poor prognosis because many patients present with advanced or unresectable disease. Major risk factors include chronic biliary inflammation and injury, primary sclerosing cholangitis, biliary tract cysts, hepatolithiasis, chronic viral hepatitis, cirrhosis, liver fluke infections in endemic regions, and certain toxic or environmental exposures. Pathophysiologically, chronic inflammation and cholestatic injury promote progressive genetic and epigenetic alterations within cholangiocytes, leading to dysregulated proliferation, resistance to apoptosis, angiogenesis, and invasive tumor growth. Common molecular abnormalities include FGFR2 fusions, IDH1 mutations, KRAS mutations, HER2 amplification, BRAF alterations, and abnormalities in DNA repair and immune checkpoint signaling pathways. Clinically, patients may present with jaundice, pruritus, abdominal pain, weight loss, cholangitis, or abnormal liver function tests depending on tumor location and biliary obstruction. Diagnosis typically involves imaging studies such as MRI/MRCP or CT scanning, serum tumor markers such as CA 19-9, and tissue confirmation through biopsy or biliary brushings. Advances in molecular profiling have increasingly transformed cholangiocarcinoma into a biomarker-driven disease, enabling the use of targeted therapies and immunotherapies in selected patients with actionable genomic alterations.

Causes

The etiology of cholangiocarcinoma is strongly linked to chronic inflammation, injury, and prolonged cholestatic stress affecting the biliary epithelium. Persistent inflammatory signaling within the bile ducts promotes repeated cycles of cellular injury and regeneration that increase the likelihood of genetic and epigenetic alterations in cholangiocytes. Major risk factors include Primary Sclerosing Cholangitis, biliary tract cysts, hepatolithiasis, chronic viral hepatitis, cirrhosis, and parasitic liver fluke infections such as Opisthorchis viverrini and Clonorchis sinensis in endemic regions. Additional contributors include metabolic liver disease, diabetes, obesity, smoking, and environmental or occupational toxin exposure. Over time, these inflammatory and carcinogenic insults drive mutations and molecular alterations involving pathways such as KRAS, IDH1, FGFR2, TP53, HER2, and DNA repair mechanisms, ultimately leading to malignant transformation and invasive growth of bile duct epithelial cells

Pathophysiology

The pathophysiology of cholangiocarcinoma involves chronic inflammatory and cholestatic injury to cholangiocytes that drives progressive genetic instability, dysregulated cellular signaling, and malignant transformation of the biliary epithelium. Persistent bile duct inflammation activates cytokine-mediated pathways such as IL-6, STAT3, NF-κB, and TGF-β signaling, promoting cellular proliferation, resistance to apoptosis, oxidative stress, and fibrotic remodeling. Repeated injury and regeneration increase the accumulation of oncogenic mutations and chromosomal abnormalities involving pathways such as KRAS, TP53, IDH1/2, FGFR2, HER2, BRAF, and DNA repair mechanisms. As malignant cholangiocytes proliferate, they stimulate angiogenesis, remodel the extracellular matrix, and invade surrounding hepatic tissue, vascular structures, and lymphatics. The dense desmoplastic tumor microenvironment characteristic of cholangiocarcinoma further contributes to immune evasion, therapeutic resistance, and aggressive local invasion. Tumor growth progressively obstructs bile flow, producing cholestasis, jaundice, hepatocellular injury, and recurrent biliary inflammation, while advanced disease may metastasize to regional lymph nodes, liver, lungs, peritoneum, or distant organs.

Clinical features

The clinical features of cholangiocarcinoma vary depending on the location and extent of the tumor but commonly result from progressive biliary obstruction and hepatic dysfunction. Patients with extrahepatic or perihilar tumors frequently present with painless jaundice, dark urine, pale stools, pruritus, and cholestatic liver enzyme abnormalities due to impaired bile flow. Additional symptoms may include right upper quadrant or epigastric abdominal pain, fatigue, anorexia, unintentional weight loss, nausea, and fever, particularly when recurrent cholangitis develops. Intrahepatic cholangiocarcinoma may remain clinically silent for longer periods and often presents later with abdominal discomfort, hepatomegaly, or constitutional symptoms rather than overt jaundice. Advanced disease can lead to ascites, cachexia, portal hypertension, liver failure, or metastatic symptoms involving the lungs, bones, or peritoneum. Because early symptoms are often nonspecific and biliary obstruction may develop gradually, many patients are diagnosed at an advanced or unresectable stage.

Diagnosis

The diagnosis of cholangiocarcinoma involves a combination of laboratory evaluation, imaging studies, endoscopic procedures, and histopathologic confirmation. Patients commonly demonstrate a cholestatic pattern of liver injury with elevated bilirubin, alkaline phosphatase, and gamma-glutamyl transferase levels, while serum tumor markers such as CA 19-9 and CEA may provide supportive but nonspecific evidence. Imaging with contrast-enhanced CT scanning, MRI, and magnetic resonance cholangiopancreatography (MRCP) is central for identifying biliary strictures, mass lesions, vascular involvement, and metastatic spread. Endoscopic techniques such as ERCP or endoscopic ultrasound may allow biliary brushings, biopsies, stent placement, and tissue acquisition for cytologic or histologic evaluation. Definitive diagnosis is established through pathologic confirmation of malignant biliary epithelial cells. Molecular profiling is increasingly important because actionable alterations such as FGFR2 fusions, IDH1 mutations, HER2 amplification, BRAF mutations, microsatellite instability, or NRG1 fusions may guide targeted therapy and immunotherapy selection in advanced disease.

Mechanism of action videos

Biological pathways

  • Downstream signal transduction
  • Signaling by FGFR2 fusions
  • Defective Base Excision Repair Associated with NEIL1
  • Signaling by Receptor Tyrosine Kinases
  • Signaling by FGFR in disease
  • RAF/MAP kinase cascade
  • PI3K/AKT Signaling in Cancer
  • MAPK1/MAPK3 signaling
  • MAPK family signaling cascades
  • Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
  • Intracellular signaling by second messengers
  • IRS-related events triggered by IGF1R
  • IRS-mediated signalling
  • Diseases of signal transduction by growth factor receptors and second messengers
  • Constitutive Signaling by Aberrant PI3K in Cancer
  • Insulin receptor signalling cascade
  • IGF1R signaling cascade
  • Cellular Senescence
  • PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
  • Signal Transduction
  • Negative regulation of the PI3K/AKT network
  • Signaling by Insulin receptor
  • PI3K Cascade
  • Signaling by FGFR
  • PIP3 activates AKT signaling
  • Generic Transcription Pathway
  • RNA Polymerase II Transcription
  • VEGF ligand-receptor interactions
  • VEGF binds to VEGFR leading to receptor dimerization
  • Cellular responses to stimuli
  • Oncogene Induced Senescence
  • Downstream signaling of activated FGFR2
  • Transcriptional Regulation by VENTX
  • Gene expression (Transcription)
  • SHC-mediated cascade:FGFR2
  • FRS-mediated FGFR2 signaling
  • VEGFA-VEGFR2 Pathway
  • FGFR2 mutant receptor activation
  • Signaling by FGFR2 IIIa TM
  • Regulation of MITF-M-dependent genes involved in cell cycle and proliferation

Clinical trials

  • Phase 1b/2a Study of GNS561 in Combination With Trametinib in Advanced KRAS Mutated Cholangiocarcinoma
  • A Phase 3, Multicenter, Randomized, Open-label, Study Evaluating the Efficacy and Safety of Nanvuranlat in Patients With Previously Treated Advanced Biliary Tract Cancer
  • A Dose Escalation and Dose Optimization Phase 1a/1b Study to Evaluate Safety, Tolerability and Dosimetry of Radioligand Therapy With LY4337713 in Adults With FAP-Positive Solid Tumors (FiREBOLT)
  • An Open-label, Phase 1a/1b, Dose Escalation and Dose Expansion Study Investigating the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PHST001 in Adult Patients With Advanced Relapsed and/or Refractory Solid Tumors
  • A Single-Arm, Exploratory Clinical Study of Adebrelimab Combined With S-1 in Patients With Resected Cholangiocarcinoma
  • DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
  • First-in-human, Open-label, Multi-site, Phase I/IIa, Dose Escalation Trial With Expansion Cohorts to Evaluate Safety and Preliminary Efficacy of BNT329 in Participants With Advanced Solid Tumors Known to Express CA19-9
  • A Phase I/II Study of M3814 and Avelumab in Combination With Hypofractionated Radiation in Patients With Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies
  • Phase 1 Trial of Safety and Preliminary Efficacy of Segmental Ablative Radioembolization in Combination With Tremelimumab Plus Durvalumab (MEDI4736) in Patients With Unresectable, or Oligo-Metastatic Cholangiocarcinoma Who Are Not Candidates for Curative Therapy (RAIDEN Trial)
  • A Phase 1, Open-Label, First-in-Human, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of MT-304 in Adults With Advanced HER2-Expressing Solid Tumors
  • FOLFOX in Combination With Binimetinib as 2nd Line Therapy for Patients With Advanced Biliary Tract Cancers With MAPK Pathway Alterations: A ComboMATCH Treatment Trial
  • A Phase II Trial of Durvalumab With Gemcitabine and Cisplatin as Neoadjuvant Therapy for High-Risk Resectable Intrahepatic Cholangiocarcinoma
  • A Randomized Phase II Trial Evaluating Chemotherapy Plus Atezolizumab vs Chemotherapy Plus Bevacizumab and Atezolizumab in Advanced Combined Hepatocellular Carcinoma-Cholangiocarcinoma
  • A First-in-human Phase 1 Dose-escalation Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of KST-6051 in Patients With Advanced or Metastatic Solid Tumors With a KRAS Mutation
  • A Phase 1 Study of SynKIR-110, Autologous T Cells Transduced With Mesothelin KIR-CAR, in Subjects With Mesothelin-Expressing Advanced Ovarian Cancer, Cholangiocarcinoma, or Mesothelioma
  • An Open-label Randomized Trial of the Efficacy and Safety of Zanidatamab With Standard-of-care Therapy Against Standard-of-care Therapy Alone for Advanced HER2-positive Biliary Tract Cancer
  • Diagnostic Value of 68Ga-FAPI-46 PET/CT in the Initial Work-up of Pancreatic and Biliary Cancers Eligible to a Curative Treatment
  • A Phase 1b/2, Safety Lead-in and Dose-Expansion, Open Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Activity of Ivosidenib in Combination With Durvalumab and Gemcitabine/Cisplatin as First-line Therapy in Participants With Locally Advanced, Unresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
  • A Phase II Study of Pemigatinib Plus Durvalumab (MEDI4736) in Previously Treated Advanced Intrahepatic Cholangiocarcinoma Patients With FGFR-2 Fusion or Rearrangement
  • Phase II Study Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers
  • A Phase 2/3 Randomized, Controlled Study of CTX-009 in Combination With Paclitaxel Versus Paclitaxel Alone in Adult Patients With Unresectable Advanced, Metastatic or Recurrent Biliary Tract Cancers Who Have Received One Prior Systemic Chemotherapy Regimen
  • Open-label, Phase II Clinical Study of Chidamide Combined With Chemotherapy and Immunotherapy as First-line Treatment for Advanced Intrahepatic Cholangiocarcinoma
  • Phase II Study of the Combination of Durvalumab (MEDI4736) (PDL1 Inhibitor) and Olaparib (PARP Inhibitor) in Advanced Cholangiocarcinoma After Initial Chemotherapy and Durvalumab (BIL-PPP)
  • A Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Anti-tumor Activity of TNG462 as a Single Agent and in Combination in Patients With MTAP-deleted Advanced or Metastatic Solid Tumors
  • 18F-Fibroblast Activation Protein Inhibitor ([18F]FAPI-74) PET Imaging for Cancer Detection
  • Phase II Study Evaluating the Efficacy of PDS01ADC in Combination With Hepatic Artery Infusion Pump (HAIP) and Systemic Therapy for Subjects With Metastatic Colorectal Cancer, Intrahepatic Cholangiocarcinoma, or Metastatic Adrenocortical Carcinoma
  • A Phase 1b/2a Dose Escalation Study of BOLD-100 in Combination With FOLFOX Chemotherapy in Patients With Advanced Solid Tumours
  • A Phase II, Single-arm, Prospective Clinical Study of Neoadjuvant Therapy With Tislelizumab Combined With Radiotherapy and Gemcitabine-Platinum Chemotherapy for Borderline Resectable or Unresectable Hilar Cholangiocarcinoma
  • A Phase 2, Open-Label, Single-Arm Study of Lirafugratinib in Patients With Previously Treated, Unresectable, Locally Advanced or Metastatic Solid Tumors (Excluding Cholangiocarcinoma) With FGFR2 Fusion or Rearrangement
  • A Pilot Multi-arm Study of sEphB4-HSA in Combination With Different Chemotherapy Regimens in Patients With Specific Advanced or Metastatic Solid Tumors
  • A Phase II Study of Olaparib and AZD6738 in Isocitrate Dehydrogenase (IDH) Mutant Solid Tumors
  • A Phase 1, First-in-Human, Open Label, Dose Escalation and Cohort Expansion Study of MGC028 in Participants With Advanced Solid Tumors
  • A Phase 1a/1b Study of the Pan-KRAS Inhibitor LY4066434 in Participants With KRAS Mutant Solid Tumors
  • A Phase 1 Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations
  • A Single Arm Phase 2 Study of Y-90 SIRT in Combination With Durvalumab (MEDI 4736) and Gemcitabine/Cisplatin in Locally Advanced, Unresectable or Metastatic Intrahepatic Cholangiocarcinoma
  • A Randomized Phase II Study of Systemic Chemotherapy With or Without HAI FUDR/Dexamethasone in Patients With Unresectable Intrahepatic Cholangiocarcinoma
  • MC1641 Phase II Study Of Intratumoral Injection Of Autologous Dendritic Cells Combined With Immune Checkpoint Inhibition After High-Dose Conformal External Beam Radiotherapy In Patients With Unresectable Primary Liver Cancer
  • A Phase 1a/1b Multicenter, Open-label Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Evidence of Antitumor Activity of PLN-101095 as Monotherapy and in Combination With Pembrolizumab in Adult Participants With Advanced or Metastatic Solid Tumors Who Have Disease Progression While on an Immune Checkpoint Inhibitor (FORTIFY)
  • A Phase 1/2 Study of a Selective FGFR2/3 Inhibitor, CGT4859, in Patients With Cholangiocarcinoma and Other Advanced Solid Tumors Harboring FGFR2 and/or FGFR3 Genetic Alterations
  • A Phase II Study of Single Tremelimumab With Regular Interval Durvalumab (STRIDE) Plus Gemcitabine and Cisplatin (GEMCIS) in Locally Advanced Unresectable/Metastatic Combined Hepatocellular-cholangiocarcinoma (cHCC-CCA)

Therapeutic area: Oncology

Cholangiocarcinoma (C22.1)