Cholangiocarcinoma

Updated: Jan 12, 2022
  • Author: Peter E Darwin, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Overview

Practice Essentials

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, 5] CCCs are encountered in three anatomic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. See the image below.

Bismuth classification for perihilar cholangiocarc Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.

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 1965 [6] ), occur at the bifurcation of right and left hepatic ducts. [7] 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.

Signs and symptoms

Signs and symptoms of cholangiocarcinoma include the following:

Diagnosis

Lab studies:

  • Extrahepatic cholestasis is reflected in elevated levels of conjugated (ie, direct) bilirubin, alkaline phosphatase, and gamma-glutamyltransferase (GGT).
  • Levels of aminotransferases (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may be normal or minimally elevated.
  • Biochemical tests of liver function (ie, albumin, prothrombin time [PT]) are normal in early disease; with prolonged obstruction, the PT can become elevated because of vitamin K malabsorption.
  • Hypercalcemia may occur occasionally in the absence of osteolytic metastasis.

Imaging studies:

  • In general, ultrasonography or computed tomography (CT) is performed initially, followed by some form of cholangiography.
  • Ultrasound may demonstrate biliary duct dilatation and larger hilar lesions.
  • Endoscopic ultrasonography (EUS) enables both bile duct visualization and nodal evaluation

Procedures:

  • Endoscopic retrograde cholangiopancreatography (ERCP) demonstrates the site of obstruction, excludes ampullary pathology, and allows collection of specimens for histologic studies. Palliative stenting to relieve biliary obstruction can be performed at the time of evaluation.
  • Percutaneous transhepatic cholangiography (PTC) may allow access to proximal lesions with obstruction of both right and left hepatic ducts, permitting collection of material for cytologic studies and performance of drainage.
  • CT- or ultrasound-guided needle aspiration, if a mass lesion is present
  • EUS-guided fine-needle aspiration has a greater sensitivity for detecting malignancy than ERCP with brush cytology but has the potential for tumor seeding.

Management

Complete surgical resection is the only therapy to afford a chance of cure for cholangiocarcinoma. Unfortunately, many patients present with unresectable disease. Additional treatment measures in cholangiocarcinoma may include the following [8] :

  • Stenting
  • Photodynamic therapy (PDT)
  • Radiation therapy
  • Chemotherapy
  • Targeted agents, in cases with actionable driver mutations

See Treatment and Medication.

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Pathophysiology

Cholangiocarcinomas arise 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.

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Epidemiology

Frequency

United States

Each year, approximately 2500 cases of cholangiocarcinoma occur, compared with 5000 cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. The average incidence is one case per 100,000 population per year.

A study by Singal et al found that the frequency of intrahepatic cholangiocarcinoma has increased over time and is most commonly noted in women older than 60 years. [9]

International

Worldwide, cholangiocarcinoma is the second most common primary hepatic malignancy, after hepatocellular carcinoma, comprising about 15% of all primary liver tumors. The incidence and mortality rates of cholangiocarcinoma have increased steadily over the past decades. Currently, cholangiocarcinoma has an incidence rate of 0.3-6/100,000 inhabitants per year, with a mortality rate of 1-6/100,000 inhabitants per year. Incidence rates are particularly elevated in certain regions, such as South Korea, China, and Thailand. [10] 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.

Occupational cholangiocarcinoma has been documented in workers at printing companies in Japan who had been exposed to high concentrations of chemical compounds, including 1,2-dichloropropane (1,2-DCP) and/or dichloromethane. [11] Heavy infestation by the liver flukes Clonorchis sinensis (endemic predominantly in Asian countries, including Korea, China, Taiwan, Vietnam, and far eastern Russia) and Opisthorchis viverrini (the Southeast Asian liver fluke) has been linked to the development of cholangiocarcinoma. [12]

Mortality/Morbidity

Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary drainage), the median survival rate is low, since most patients (90%) are not eligible for curative resection. The overall survival is approximately 6 months.

Race-, sex-, and age-related demographics

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.

In both males and females, cholangiocarcinoma is most common in persons in their 60s and 70s. 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 2022 is estimated to be 28,600 for men and 12,660 for women, with deaths estimated at 20,420 and 10,100, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 5710 for men and 6420 for women, with estimated deaths of 1830 and 2570, respectively. [13]  

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