Cholangiocarcinoma

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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 1965[5] ), occur at the bifurcation of right and left hepatic ducts.[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.


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

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.

Epidemiology

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.

A study by Singal et al found that the frequency of intrahepatic cholangiocarcinoma has increased over time and is most commonly noted in females older than 60 years.[7]

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.[8]

Age

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

History

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

Physical

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.

Laboratory Studies

Imaging Studies

Other Tests

Procedures

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 lumina 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 are rather poor for dominant strictures in primary sclerosing cholangitis.

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.

Medical Care

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[6] require liver resection, which may not be an option for older patients with comorbid conditions. In one report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid-ductal tumors (33%) or distal tumors (56%). The survival rate for patients with proximal tumors can be 40% if negative margins are obtained. The National Comprehensive Cancer Network suggests reresection, ablation, or chemotherapy for intrahepatic cholangiocarcinomas that are resected with microscopic margins or residual local disease.[20] Those with no residual local disease after resection can be followed with imaging periodically.

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 cholangiocarcinomas since the early 1980s.

Further Outpatient Care

Complications

Prognosis

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Andrew Scott Kennedy, MD, Co-Medical Director, Wake Radiology Oncology

Disclosure: Nothing to disclose.

Jennifer Lynn Bonheur, MD, Attending Physician, Division of Gastroenterology, Lenox Hill Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Director, Division of Hematology and Medical Oncology, Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Disclosure: GlobeImmune Salary Consulting

References

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

Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.

Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.

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

Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.

Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.