What is Cholangiocarcinoma?

Cholangiocarcinoma: Definition, Classification, and Clinical Significance

Cholangiocarcinoma (CCA) is a rare but aggressive malignant tumor originating from bile duct epithelial cells, representing the second most common primary liver cancer after hepatocellular carcinoma, accounting for 10-15% of all primary liver cancers. 1

Anatomical Classification

Cholangiocarcinoma is classified based on anatomical location:

1. Intrahepatic CCA (iCCA) - 20-25% of cases

   • Arises from bile ductules proximal to second-order bile ducts
   • Further subclassified into small-duct-type and large-duct-type 2

2. Extrahepatic CCA

   • Perihilar CCA (pCCA) - 50-60% of cases
     • Arises in right/left hepatic ducts or at their junction
     • Also known as "Klatskin tumors"
   • Distal CCA (dCCA) - 20-25% of cases
     • Arises from epithelium distal to insertion of cystic duct 1

3. Multifocal disease - About 5% of cases 1

Epidemiology and Risk Factors

• Global incidence has been increasing over recent decades 1
• Age-standardized incidence rates vary:
  • Low in Europe, USA, and Australasia (0.3-3.5 cases per 100,000)
  • Very high in regions with liver fluke infections (up to 85 cases per 100,000 in northeastern Thailand) 1

Major Risk Factors:

• Age (65% of patients are over 65 years old)
• Primary sclerosing cholangitis (PSC) (lifetime risk 5-15%)
• Chronic intraductal gallstones
• Bile duct adenoma and biliary papillomatosis
• Caroli's disease (cystic dilatation of ducts, lifetime risk 7%)
• Choledochal cysts (about 5% transform, risk increases with age)
• Smoking (especially with PSC)
• Liver flukes (in Southeast Asia)
• Chronic typhoid carriers (sixfold increased risk) 1
• Hepatic cirrhosis from chronic viral hepatitis 3

Pathology

• Histology: 90-95% are adenocarcinomas 3
• Growth patterns: Mass-forming, periductal infiltrating, or intraductal 2
• Molecular characteristics:
  • Inactivation of tumor suppressor genes (p53, APC, Smad-4, bcl-2, p16)
  • Mutations in oncogenes (K-ras, c-myc, c-erbB-2, c-neu)
  • Chromosomal aneuploidy in up to 25% of periampullary tumors 1
  • FGFR pathway alterations are particularly relevant 4

Clinical Presentation

• Biliary obstruction symptoms: Jaundice, pale stool, dark urine, pruritus
• Pain: Right upper quadrant pain
• Infection: Fever and rigors (suggesting cholangitis, unusual without drainage attempts)
• Systemic symptoms: Malaise, fatigue, weight loss (especially with proximal tumors)
• Incidental findings: Abnormal liver function tests or imaging studies 1

Prognosis and Treatment

CCA carries a very poor prognosis due to typically late clinical presentation and poor response to current therapeutics 5. Treatment options include:

1. Surgery: Only potentially curative treatment

   • 9-18% five-year survival for proximal lesions
   • 20-30% five-year survival for distal lesions 1

2. Systemic therapy:

   • First-line: Gemcitabine and cisplatin for unresectable disease
   • Adjuvant: Capecitabine after resection 6

3. Emerging therapies:

   • Targeted therapies (especially FGFR inhibitors)
   • Immunotherapy (checkpoint inhibitors)
   • Combination approaches 5, 6, 4

Clinical Pitfalls and Challenges

• Diagnostic challenges: Often diagnosed at advanced stages when unresectable 2
• Differential diagnosis: Difficult to distinguish from metastatic adenocarcinoma to the liver 2
• Lymph node involvement: Present in 50% of patients at presentation
• Peritoneal and distant metastases: Present in 10-20% of patients at presentation 1
• No specific immunohistochemical profile: Makes definitive diagnosis challenging 2

The recent advances in molecular profiling and targeted therapies offer new hope for improved outcomes in this aggressive malignancy, with precision medicine approaches becoming increasingly important for treatment decisions.