Biliary tract cancers are rare, with an estimated 12,000 newly diagnosed cases per year, not including intrahepatic cholangiocarcinoma.1 Biliary tract cancers are divided into intrahepatic, extrahepatic cholangiocarcinoma, and gallbladder cancer. Extrahepatic cholangiocarcinoma can then be divided into perihilar cholangiocarcinoma (Klatskin tumor) and distal common bile duct cancer.2 Gallbladder cancer is the most common type of biliary tract cancers, followed by perihilar and then distal common bile duct cholangiocarcinoma. Although intrahepatic cholangiocarcinoma represents only approximately 10 percent of biliary tumors, in recent years, incidence of intrahepatic cholangiocarcinoma has increased.
The cholangiocarcinoma also can be classified by the growth pattern of the tumor: mass-forming, periductal infiltrating, and intraductal. The mass-forming type is most commonly observed for intrahepatic cholangiocarcinoma and is associated with a high rate of lymph node metastasis.2 The periductal infiltrating type is commonly seen in perihilar cholangiocarcinoma. Intraductal growth type can be seen in any part of the biliary tree and is the rarest of the three. For intrahepatic cholangiocarcinoma, mixed type of mass-forming and periductal infiltrating is associated with significantly worse prognosis with no reported five-year survival and median overall survival of 8.3 months.3
Extrahepatic cholangiocarcinoma typically presents with obstructive jaundice. On the other hand, intrahepatic cholangiocarcinoma rarely exhibits symptoms and is incidentally detected by cross-sectional imaging. Consequently, intrahepatic cholangiocarcinoma often is diagnosed in late stage. Furthermore, diagnosis of intrahepatic cholangiocarcinoma is a diagnosis of exclusion, with broad differential diagnoses of metastatic cancer, hepatocellular carcinoma, cholangiocarcinoma, or benign liver mass. Meticulous and systemic diagnostic work-ups should be employed to establish the diagnosis of intrahepatic cholangiocarcinoma. High-quality, enhanced cross-sectional imaging is a must and sometimes needs both computed tomography (CT) and magnetic resonance imaging (MRI) to characterize the mass and narrow the list of differential diagnoses. Detailed medical history, including colon cancer risk and screening, alcohol consumption, viral hepatitis risk, travel history, and exposure to hepatotoxin, should be taken. Lab tests should include viral hepatitis panel, autoimmune hepatitis serology, iron studies, copper studies, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, and alpha fetoprotein. CA19-9 could be diagnostic in cases of primary sclerosing cholangitis; however, in other cases, sensitivity is relatively low, particularly in the presence of biliary obstruction or cholangitis.4
High-quality cross-sectional imaging is the cornerstone of the diagnosis and treatment of this difficult disease. Particularly for hilar cholangiocarcinoma, liver protocoled CT or preferably enhanced MRI should be obtained before any instrumentation to the biliary tree. Once the biliary tree is decompressed, it is difficult to accurately assess the extent of the tumor in biliary tree, which creates significant difficulty in assessing whether the tumor can be resected and developing a surgical plan.
Biliary tract cancers are biologically aggressive with poor prognosis. Even for resected distal cholangiocarcinoma, which has better prognosis among cholangiocarcinoma, five-year survival has been reported as 36–42 percent.5,6 Five-year survival rates among patients with perihilar and intrahepatic cholangiocarcinoma are reported as 20–43 percent and 20–35 percent, respectively.6,7
Surgical resection is the mainstay of the curative-intent treatment; however, resection typically involves either large liver resection or pancreaticoduodenectomy with nodal dissection. Node dissection is an integral part of the surgical treatment because nodal metastasis is one of the strongest prognostic factors. Dissection of the node should include the lymph nodes along the hepatic artery to the celiac axis and lymph nodes along the common bile duct to retropancreatic area. Another important prognostic factor is margin negative resection. For the hilar cholangiocarcinoma, many experts recommend routine addition of caudate lobe resection to necessary liver resection to decrease the risk of margin positive resection because bile ducts of the caudate lobe originate from the hilar portion of the bile duct. Most cases of perihilar cholangiocarcinoma require resection of a significant amount of the liver—either lobectomy or trisectionectomy. Because of the magnitude of the operation, associated morbidities and mortalities are significant.
NCDB data analysis
The National Cancer Database (NCDB) from 2012 to 2014 captured 72.5 percent of the cancer cases in U.S.8 For the following analysis, NCDB data from 2010 to 2013 for patients 18 to 79 years old diagnosed with their first or only malignant or in situ primary were analyzed for intrahepatic, perihilar, and distal cholangiocarcinoma. The three types of cholangiocarcinoma were defined by primary site, histology/behavior, and a site-specific factor that distinguishes the subsite of the primary site C24.0.
The primary site for intrahepatic cholangiocarcinoma was C22.1, whereas distal and perihilar were C24.0. For all three cholangiocarcinoma types, the histology/behavior codes were 8160/3 and 8180/3. Only distal and perihilar cholangiocarcinoma used the site-specific factor to define cholangiocarcinoma type.
Distal cholangiocarcinoma’s site-specific factor values consisted of distal bile duct, common bile duct, common duct not otherwise specified, and subsite of extrahepatic bile ducts not stated or subsite stated as middle extrahepatic bile duct and treated with pancreaticoduodenectomy.
Although we could not narrow it down because of the limited amount of granular data available in the NCDB, considering relatively advanced primary tumor, if adequate nodal dissection is not routinely employed, then under-staging could create lower survival.
Perihilar cholangiocarcinoma site-specific factor values consisted of perihilar bile duct(s), proximal extrahepatic bile duct(s), hepatic duct(s), Klatskin tumor, and subsite of extrahepatic bile ducts not stated or subsite stated as middle extrahepatic bile duct and treated with combined hepatic and hilar resection.
Three-year survival analysis was performed using the Kaplan-Meier method and 95 percent confidence limits. The Commission on Cancer (CoC) program category—academic versus community (consisting of community and comprehensive community) cancer programs—was examined by the type of cholangiocarcinoma and the American Joint Committee on Cancer, 7th Edition pathologic stage group. This analysis was completed using Statistical Analysis System (9.4, Cary, NC) along with the significance threshold of p <0.05.
Of the three types of cholangiocarcinoma, 63.6 percent were intrahepatic, 18.7 percent were distal, and 17.7 percent were perihilar, with the majority of cholangiocarcinomas diagnosed and/or treated at academic cancer programs (see Table 1).
Table 1. Cancer type for diagnosis years 2010–2013
Survival differences existed for patients of certain pathologic stages and types of cholangiocarcinoma between academic and community cancer programs. For instance, survival data on stage I distal cholangiocarcinoma—a resectable, relatively small tumor without nodal or distant metastasis—demonstrated that patients at academic cancer programs did better than patients who were at the community cancer programs, although the difference was not statistically significant (see Figure 1).9
Figure 1. Distal cholangiocarcinoma pathologic stage I by CoC program category
There are multiple possible causes of this difference; however, considering early separation of the survival curve and complex nature of the operation (Whipple), it could be directly related to outcome of the procedure. In addition, stage III intrahepatic cholangiocarcinoma—which was defined as a tumor that is large and exposed on the surface of the liver or invading a nearby organ—had better survival in the academic cancer program patient group compared with the community cancer program patient group (see Figure 2).9 Again, there was no statistical difference in three-year overall survival; however, there was a statistical difference in survival between six and 18 months (see Figure 2).
Figure 2. Intrahepatic cholangiocarcinoma pathologic stage III by CoC program category
Although we could not narrow it down because of the limited amount of granular data available in the NCDB, considering relatively advanced primary tumor, if adequate nodal dissection is not routinely employed, then under-staging could create lower survival. Other possible causes of this result are late mortality from the operation and underutilization of the adjuvant treatment.
These types of data can be used for quality improvement at each cancer program, particularly on rare cancer types, and root-cause analysis should be conducted for significant variation from standard outcome to improve the treatment.
Statistical support for this column was provided by Amanda E. Browner, MS, Statistician, NCDB.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
- Lendvai G, Szekerczés T, Illyés I, et al. Cholangiocarcinoma: Classification, histopathology and molecular carcinogenesis. Pathol Oncol Res. November 17, 2018 [Epub ahead of print].
- Yeh CN, Yeh TS, Chen TC, Jan YY, Chen MF. Gross pathological classification of peripheral cholangiocarcinoma determines the efficacy of hepatectomy. J Gastroenterol. 2013;48(5):647-659.
- Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50(9):1734-1740.
- Ethun CG, Lopez-Aguiar AG, Pawlik TM, et al. Distal cholangiocarcinoma and pancreas adenocarcinoma: Are they really the same disease? A 13-institution study from the U.S. Extrahepatic Biliary Malignancy Consortium and the Central Pancreas Consortium. J Am Coll Surg. 2017;224(4):406-413.
- DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755-762.
- Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: Systematic review and meta-analysis. JAMA Surg. 2014;149(6):565-574.
- Mallin K, Browner A, Palis B, et al. Incident cases captured in the National Cancer Database compared with those in U.S. population based central cancer registries in 2012–2014. Ann Surg Oncol. 2019;26(6):1604-1612.
- Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. New York, NY: Springer; 2011.