What are the characteristics and treatment options of cholangiocarcinoma?

Cholangiocarcinoma Features and Treatment

Cholangiocarcinoma is a rare biliary adenocarcinoma with poor outcomes, characterized by multifocal disease (5%), high rates of lymph node involvement (50%), and peritoneal/distant metastases (10-20%) at presentation, with surgery being the only curative treatment option despite low 5-year survival rates (9-18% for proximal lesions and 20-30% for distal lesions). 1

Classification and Epidemiology

Cholangiocarcinoma is classified based on anatomical location:

• Intrahepatic cholangiocarcinoma:

  • Peripheral mass-forming tumors
  • Central periductal infiltrating tumors 2

• Extrahepatic cholangiocarcinoma:

  • Perihilar (Klatskin tumors)
  • Distal cholangiocarcinoma 1, 3

The incidence of cholangiocarcinoma has been increasing globally over recent decades, affecting predominantly elderly populations with male predominance 4.

Diagnostic Approach

Clinical Presentation

• Obstructive jaundice (persistent and progressive) is the major clinical sign 5
• Often diagnosed at advanced stages when unresectable 3

Diagnostic Workup

1. Initial imaging: Ultrasonography (detects bile duct dilation) 1, 5

2. Second-line non-invasive imaging:

   • MRI/MRCP or spiral CT 1
   • These should precede invasive cholangiography

3. Invasive procedures:

   • ERCP/PTC: Reserved for tissue diagnosis, therapeutic decompression for cholangitis, or stent insertion in unresectable tumors 1, 5
   • Laparoscopy: To detect peritoneal or superficial liver metastases in potentially resectable cases 1

4. Preoperative assessment (if resectability not excluded):

   • Hepatic arteriography
   • Portal vein evaluation 5

5. Metastatic workup:

   • Chest radiography
   • CT abdomen (unless MRI/MRCP already done)
   • Evaluation for other primary sites (pancreas, stomach, breast, lung, colon) 1

Tumor Markers

• Increased CA 19-9 or CA-125 when associated with elevated carcinoembryonic antigen (CEA) 5
• K-ras mutation and aberrant p53 expression in approximately one-third of intrahepatic cholangiocarcinomas 5

Treatment Strategies

Surgical Management

1. Resectable disease:

   • For Klatskin tumors (based on Bismuth classification):

     • Types I and II: En bloc resection of extrahepatic bile ducts and gallbladder, regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy
     • Type III: Above plus right or left hepatectomy
     • Type IV: Above plus extended right or left hepatectomy 1

   • For distal cholangiocarcinoma: Pancreatoduodenectomy 1

   • For intrahepatic cholangiocarcinoma: Resection of involved segments or lobe of the liver 1

   • Segment 1 removal should be considered with stages II-IV hilar cholangiocarcinoma 1

2. Liver transplantation:

   • Generally contraindicated due to rapid recurrence and death within three years
   • May be considered in very early intrahepatic cholangiocarcinoma at specialized centers
   • Experimental protocols with preoperative chemoirradiation have shown promising results in selected patients 1, 3

Palliative Management for Unresectable Disease

1. Biliary drainage:

   • Endoscopic stenting preferred over surgical bypass for symptom palliation 1
   • Stenting procedures with adequate biliary drainage improve survival 1

2. Systemic therapy:

   • First-line: Gemcitabine plus cisplatin 3, 4
   • Second-line: Fluoropyrimidines 4
   • Adjuvant: Capecitabine following resection 3

3. Radiation therapy:

   • Important for preoperative neoadjuvant therapy, postoperative adjuvant therapy, and palliative treatment
   • Newer modalities include stereotactic body radiotherapy (SBRT) and proton therapy 6

4. Emerging therapies:

   • Targeted therapies against molecular alterations in cholangiocarcinoma cells
   • Immune checkpoint inhibitors targeting PD-1, PD-L1, CTLA-4
   • Cancer vaccines and adoptive cell therapy 3

Prognosis

• Median survival:

  • Intrahepatic cholangiocarcinoma without hilar involvement: 18-30 months
  • Perihilar tumors: 12-24 months 1

• Five-year survival rates:

  • Intrahepatic cholangiocarcinoma: Up to 40% (best results in Japan)
  • Hilar cholangiocarcinoma: 20%
  • Distal extrahepatic cholangiocarcinoma: 20-30% 1

Clinical Pitfalls and Caveats

1. Avoid routine biliary drainage before assessing resectability or preoperatively, except in cases of acute cholangitis 1

2. Do not delay surgical exploration in patients without unequivocal signs of unresectability, as surgery offers the only chance for cure 5

3. Beware of multifocal disease (5% of cases), which affects surgical outcomes and requires adequate margin sampling 1

4. Consider referral to centers of excellence for patients with unresectable or recurrent disease for potential enrollment in clinical trials 2

5. Ensure comprehensive staging before treatment decisions, as lymph node involvement (present in 50% at diagnosis) significantly impacts surgical outcomes 1