eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Cholangiocarcinoma

Author: Peter E Darwin, MD, Associate Professor, Director of GI Endoscopy, Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine
Coauthor(s): Andrew Scott Kennedy, MD, Co-Medical Director, Wake Radiology Oncology; Jennifer Lynn Bonheur, MD, Attending Physician, Division of Gastroenterology, Lenox Hill Hospital
Contributor Information and Disclosures

Updated: Jan 8, 2009

Introduction

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.^1,2,3,4 CCCs are encountered in 3 geographic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. Perihilar tumors are the most common CCCs, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after Klatskin's description of them in 1965⁵ ), occur at the bifurcation of right and left hepatic ducts (see Image 1).⁶ 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. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative colitis and chronic cholecystitis. 

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.

Frequency

United States

Each year, approximately 2500 cases of CCC 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.

International

Incidence in most Western countries ranges from 2 to 6 cases per 100,000 people per year. The highest annual 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. The overall survival is approximately 6 months.

Race

Native Americans have the highest annual incidence in North America, at 6.5 cases per 100,000 people. This rate is about 6 times higher than that in non – Native American populations. The high prevalence of cholangiocarcinoma in people of Asian descent is attributable to endemic chronic parasitic infestation.

Sex

The male-to-female ratio for cholangiocarcinoma is 1:2.5 in patients in their 60s and 70s and 1:15 in patients younger than 40 years. According to the American Cancer Society, the number of new cases of liver and intrahepatic bile duct cancer in 2007 is estimated to be 13,650 for men and 5,510 for women, with estimated mortality of 11,280 and 5,500, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 4,380 for men and 4,870 for women, with estimated mortality rates of 1,260 and 1,990, respectively.⁷

Age

Highest prevalence rate occurs in males and females in their 60s and 70s.

Clinical

History

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

• Jaundice is the most common manifestation of bile duct cancer and, in general, is best detected in direct sunlight. The obstruction and subsequent cholestasis tend to occur early if the tumor is located in the common bile duct or common hepatic duct. Jaundice often occurs later in perihilar or intrahepatic tumors and is often a marker of advanced disease. The excess of conjugated bilirubin is associated with bilirubinuria and acholic stools.
• Pruritus usually is preceded by jaundice, but itching may be the initial symptom of cholangiocarcinoma. Pruritus may be related to circulating bile acids.
• Weight loss is a variable finding and may be present in one third of patients at the time of diagnosis.
• Abdominal pain is relatively common in advanced disease and often is described as a dull ache in the right upper quadrant.

Physical

• If the cholangiocarcinoma is located distal to the cystic duct takeoff, the patient may have a palpable gallbladder, which commonly is known as Courvoisier sign.
• An abdominal mass or palpable lymphadenopathy is uncommon, but hepatomegaly may be noted in as many as 25% of patients.

Causes

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

• Infections
  • In Southeast Asia, chronic infections with liver flukes, Clonorchis sinensis, and Opisthorchis viverrini have been causally related to cholangiocarcinoma.
  • Other parasites, such as Ascaris lumbricoides, have been implicated in the pathogenesis of cholangiocarcinoma.
  • Observations have raised the possibility that bacterial infections with Helicobacter species may play an etiologic role in biliary cancer.⁸
• Inflammatory bowel disease
  • A strong relationship exists between cholangiocarcinoma and primary sclerosing cholangitis. Cholangiocarcinoma generally develops in patients with long-standing ulcerative colitis and primary sclerosing cholangitis.⁹
  • The lifetime risk of developing this cancer in the setting of primary sclerosing cholangitis is 10-20%. At increased risk are patients with ulcerative colitis without symptomatic primary sclerosing cholangitis and a small subset of patients with Crohn disease.
• Chemical exposures
  • Certain chemical exposures have been implicated in the development of bile duct cancers, primarily in workers in the aircraft, rubber, and wood-finishing industries.
  • Cholangiocarcinoma occasionally has developed years after administration of the radiopaque medium thorium dioxide (ie, thorotrast).
• Congenital diseases of the biliary tree, including choledochal cysts and Caroli disease, have been associated with cholangiocarcinoma.
• Other conditions rarely associated with cholangiocarcinoma include bile duct adenomas, biliary papillomatosis, and alpha ₁ -antitrypsin deficiency.

• Search for CME/CE on This Topic »

• Cholangiocarcinoma (Radiology)
• Gallbladder Cancer (Oncology)
• Bile Duct Tumors (General Surgery)
• Inflammatory Bowel Disease (Gastroenterology)

• High-Dose Ursodeoxycholic Acid May Worsen Outcome of Cholangitis

• Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression
• Endoscopic Tissue Diagnosis of Cholangiocarcinoma
• Digestive Cancer in the Elderly