January 16, 2007


Synonyms and related keywords: cholangiocarcinoma, CCC, biliary duct system, perihilar tumors, Klatskin tumors, adenocarcinoma, primary sclerosing cholangitis, PSC


Background: Cholangiocarcinomas (CCCs) are malignancies of the biliary duct system that may originate in the liver and extrahepatic bile ducts, which terminate at the ampulla of Vater. CCCs are encountered in 3 geographic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. Perihilar tumors are the most common, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after Klatskin's description of them in 1965), occur at the bifurcation of right and left hepatic ducts. Distal extrahepatic tumors are located from the upper border of the pancreas to the ampulla. More than 95% of these tumors are ductal adenocarcinomas; many patients present with unresectable or metastatic disease.

Pathophysiology: Cholangiocarcinoma is a tumor that arises from the intrahepatic or extrahepatic biliary epithelium. More than 90% are adenocarcinomas, and the remainder are squamous cell tumors. The etiology of most bile duct cancers remains undetermined. Long-standing inflammation, as with primary sclerosing cholangitis (PSC) or chronic parasitic infection, has been suggested to play a role by inducing hyperplasia, cellular proliferation, and, ultimately, malignant transformation.

Cholangiocarcinomas tend to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes. Local extension occurs into the liver, porta hepatis, and regional lymph nodes of the celiac and pancreaticoduodenal chains. Life-threatening infection (cholangitis) may occur that requires immediate antibiotic intervention and aggressive biliary drainage.


  • In the US: Each year, approximately 2500 cases occur, compared to 5000 cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. Average incidence is 1 case per 100,000 persons per year.
  • Internationally: Incidence in most Western countries ranges from 2-6 cases per 100,000 people per year. The highest incidences are in Japan at 5.5 cases per 100,000 people and in Israel at 7.3 cases per 100,000 people.

Mortality/Morbidity: Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary drainage), median survival rate is low since most patients (90%) are not eligible for curative resection.

Race: Native Americans have the highest occurrence rate in North America at 6.5 cases per 100,000 people. The high prevalence of cholangiocarcinoma among people of Asian decent is attributable to endemic chronic parasitic infestation.

Sex: The male-to-female ratio is 1.5:1.

Age: Highest prevalence rate occurs in patients aged approximately 60 years.


History: Symptoms may include jaundice, clay-colored stools, bilirubinuria (dark urine), pruritus, weight loss, and abdominal pain.


Causes: The etiology of most bile duct cancers remains undetermined. Currently, gallstones are not believed to increase the risk of CCC. Chronic viral hepatitis and cirrhosis also do not appear to be risk factors.


Bile Duct Strictures
Bile Duct Tumors
Biliary Disease
Biliary Obstruction
Choledochal Cysts

Other Problems to be Considered:



Lab Studies:

Imaging Studies:

  • Ultrasound may demonstrate biliary ductal dilatation and larger hilar lesions.
    • Small lesions and distal CCCs are difficult to visualize.
    • Patients with underlying PSC may have limited ductal dilatation secondary to ductal fibrosis.
    • Doppler ultrasound may show vascular encasement or thrombosis.
  • CT scan resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions.
    • CT scan also has the capability to evaluate for pathologic intraabdominal lymphadenopathy.
    • Helical CT scans are accurate in diagnosing the level of biliary obstruction. 3D and multiphase CT images may improve CT yield.
  • MRI demonstrates hepatic parenchyma.
    • MR cholangiography enables imaging bile ducts and, in combination with MR angiography, permits staging (excluding vascular involvement).
    • This technique likely will replace angiography for vascular evaluation.
  • New techniques
    • Preliminary evaluation with positron emission tomography (PET) has shown promise in diagnosing underlying PSC. Small lesions (ie, less than 1 cm) have been demonstrated. PET is accurate for detecting nodular carcinomas, but the sensitivity diminishes for infiltrating lesions. PET should be interpreted with caution in patients with PSC and stents in place. PET/CT has been shown to be valuable in detecting unsuspected distant metastasis (Petrowsky, 2006)
    • Endoscopic ultrasonography (EUS) enables both bile duct visualization and nodal evaluation. This technique also has the capability to aspirate for cytologic studies. EUS-guided fine-needle aspiration results may be positive when other diagnostic tests are inconclusive.
    • Intraductal EUS allows direct ultrasonographic evaluation of the lesion.
  • Cholangiography includes MR cholangiography (as noted above), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTC).

Other Tests:

  • Angiography: Evaluation of vascular involvement is important if considering surgical treatment. Arteriography demonstrating extensive encasement of the hepatic arteries or portal vein precludes curative resection. Combining the findings on cholangiography with those on arteriography has been found to have a greater accuracy in predicting unresectability. However, an occasional patient has compression of vascular structures rather than true malignant invasion.


  • ERCP demonstrates the site of obstruction by direct retrograde dye injection and excludes ampullary pathology by endoscopic evaluation.
    • Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material for histologic studies.
    • Palliative stenting to relieve biliary obstruction can be performed at the time of evaluation.
  • PTC may allow access to proximal lesions with obstruction of both right and left hepatic ducts. Material for cytologic studies may be obtained and drainage performed.
  • Other methods to obtain tissue include CT- or ultrasound-guided needle aspiration if mass lesion is present and EUS fine-needle aspiration.
Histologic Findings: Classic cholangiocarcinomas are well to moderately differentiated adenocarcinomas that exhibit glandular or acinar structures; intracytoplasmic mucin is almost always observed. Characteristically, cells are cuboidal or low columnar and resemble biliary epithelium. In more poorly differentiated tumors, solid cords of cells without lumens may be present. Mitotic figures are rare. A dense fibrous stroma is characteristic and may dominate the histologic architecture. It tends to invade lymphatics, blood vessels, perineural and periductal spaces, and portal tracts. Spread along the lumen of large bile ducts can be seen, especially with hilar tumors.

Tumor cells provoke variable desmoplastic reactions. Cytologic studies on material obtained by any method often yield nondiagnostic results secondary to desmoplastic reaction. For this reason, sensitivity and positive predictive value of brush cytologic studies for dominant strictures in PSC are rather poor.

Staging: The American Joint Committee on Cancer guidelines in the AJCC Cancer Staging Manual, Fifth Edition, following the tumor, node, and metastasis (TNM) classification system, with depth of tumor penetration and regional spread defined pathologically, should be followed.

  • T - Primary tumor
    • TX - Primary tumor cannot be assessed
    • T0 - No evidence of primary tumor
    • TIS - Carcinoma in situ
    • T1a - Tumor invades mucosa
    • T1b - Tumor invades muscularis
    • T2 - Tumor invades perimuscular connective tissue
    • T3 - Tumor invades liver, gallbladder, duodenum, stomach, pancreas, or colon
  • N - Regional lymph nodes
    • NX - Regional lymph nodes cannot be assessed
    • N0 - No metastases in regional lymph nodes
    • N1 - Metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal ligament
    • N2 - Metastases in peripancreatic (head only), periduodenal, posterior pancreatoduodenal, periportal, celiac, or superior mesenteric regional lymph nodes
  • M - Metastasis
    • MX - Presence of metastases cannot be assessed
    • M0 - No distant metastases
    • M1 - Distant metastases (includes lymph node metastases beyond N2)
  • TNM groupings by stage
    • Stage 0 - TIS N0 M0
    • Stage I - T1 N0 M0
    • Stage II - T2 N0 M0
    • Stage III - T1-2 N1-2 M0
    • Stage IVa - T3 N0-2 M0
    • Stage IVb - T1-3 N0-2 M1


Medical Care:

  • Primary radiotherapy without surgery, with or without chemotherapy, has provided a survival advantage and significant palliation over stent placement or bypass surgery alone in patients with medially inoperable or unresectable tumors.
  • Chemotherapy agents used without radiotherapy or surgery do not appear to provide any local control or meaningful survival benefit.
  • The most used agent is 5-fluorouracil, but many agents have been tested in phase I/II trials. Partial responses, lasting from weeks to months, have been observed in 10-35% of trials (Thongprasert, 2005).
  • For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent can relieve pain in the mid back associated with retroperitoneal tumor growth.

Surgical Care: Complete surgical resection is the only therapy to afford a chance of cure. Unfortunately, only 10% of patients present with early stage disease and are considered for curative resection. Intrahepatic and Klatskin tumors require liver resection, which may not be an option for older patients with comorbid conditions. In a recent series report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid ductal (33%) or distal tumors (56%). Survival rate for patients with proximal tumors can be 40% if negative margins are obtained.

  • Orthotopic liver transplantation is considered for some patients with proximal tumors who are not candidates for resection because of the extent of tumor spread in the liver. The largest series reports a 53% 5-year survival rate and a 38% complete pathologic response rate with preoperative radiation therapy and chemotherapy. Liver transplantation may have a survival benefit over palliative treatments, especially for patients with tumors in the initial stages. A more recent study has demonstrated a 5-year survival rate greater than 80% in select patients.
  • Distal tumors are resected via Whipple procedure; periampullary region tumors have a uniformly better prognosis, with a long-term survival rate of 30-40%.
  • Patterns of treatment failure after curative surgery show disappointingly high rates of tumor bed and regional nodal recurrence. This finding may be due in part to the narrow pathologic margins; however, regional node failure rate is approximately 50% and distal metastases rate 30-40%. Failures are correlated with TNM stage.
  • Palliative procedures are required if internal stenting cannot be accomplished and/or external stenting is not desirable or cannot be obtained; surgical bypass, particularly for tumors in common bile duct, should be performed.

Consultations: Gastroenterologists, interventional radiologists, and transplant/biliary surgeons play a key role in diagnosis and management. Radiation oncology and medical oncology specialists are part of the multidisciplinary team taking part in the treatment of both patients with curatively resected tumors and those with unresectable tumors. Radiation oncologists have taken a more significant role in therapy for CCC since the early 1980s.


Further Outpatient Care:




Medical/Legal Pitfalls:

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