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Cholangiocarcinoma: Practice Essentials, Pathophysiology, Epidemiology

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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:

  • Jaundice (most common manifestation)

  • Clay-colored stools

  • Bilirubinuria (dark urine)

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 2024 is estimated to be 28,000 for men and 13,630 for women, with deaths estimated at 19,120 and 10,720, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 5900 for men and 6450 for women, with estimated deaths of 1950 and 2580, respectively. [13]  

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Author

Peter E Darwin, MD Professor of Medicine, Director of GI Endoscopy, Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine

Peter E Darwin, MD is a member of the following medical societies: American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Andrew S Kennedy, MD, FACRO Physician-in-Chief, Radiation Oncology, Sarah Cannon; Director, Radiation Oncology Research, Sarah Cannon Research Institute

Andrew S Kennedy, MD, FACRO is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Society for Radiation Oncology, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Radiological Society of North America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, The Scientific Research Honor Society, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

Additional Contributors

Elwyn C Cabebe, MD Associate Medical Director, Stanford Cancer Networks; Medical Director, Stanford Cancer Center South Bay (CCSB); Medical Director of Oncology Quality, Stanford Medical Partners

Elwyn C Cabebe, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Association of Northern California Oncologists, Philippine Medical Society of Northern California, Santa Clara County Medical Association, Monterey County Medical Society

Disclosure: Nothing to disclose.