Cholangiocarcinoma (CCA)

Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tract and is classified according to tumor anatomical presentation in 3 subtypes: intrahepatic (iCCA), perihilar (pCCA; also called Klatskin tumor) and distal (dCCA).1 These two last subtypes are also considered as extrahepatic tumors.1 pCCA represents between 50% to 60% of CCA cases and dCCA 20% to 30%.2 iCCA represents about 10% of all primary liver cancers, and after hepatocellular carcinoma (HCC), is the second most common primary hepatic cancer.2 Each CCA subtype have different risk factors associated, different pathological mechanisms, clinical features, treatment, prognosis, and epidemiological variations.3

CCA Incidence

CCA develops in both genders but it is 1.2 to 1.5 times more common in males as compared to females.4 Patients have an average age higher than 50 years old with a median age for presentation of the disease at 65 years in Western countries.1 In patients with primary sclerosing cholangitis (PSC), CCA can develop earlier.5

Incidence rates of CCA show geographical variations that have been related not only to genetic backgrounds but also to the variation in geographical risk factors and to their worldwide increase.2,3,6 Epidemiological findings show that even though few risk factors may be less frequent, they can be correlated with higher CCA risk. The opposite is also identified, with more frequent risk factors having lower impact on CCA risk, so other factors are expected to be contributing to the epidemiological differences observed.6

Other reasons can support incidence trends variations, such as an increased diagnostic capability. Imaging, endoscopic and histologic procedures have been improved, which allow a more efficient diagnosis.7 Misclassification of CCA can also contribute to the incidence rates.6,7 As all versions of the main International Classification of Diseases (ICD) have not included a specific code for pCCA, a wrong classification of iCCA cases as extrahepatic tumors can be expected, affecting incidence observations.6,7 ICD editions change regularly, however, as countries adopt classification codes in different times, different classifications might be attributed to the diagnosed tumors and, as a result,  add to the differences observed between countries.6

Studies have shown that during the last 30 years iCCA incidence has increased in Western Europe, while extrahepatic cancer incidence has decreased.8 In Europe, the incidence rates vary between 0.4/100,000 and 1.8/100,000, and in the US between 0.6/100,000 and 1.0/100,000.9,10

Other studies reporting to early 2000s reveal similar findings with extrahepatic cancer decreasing in incidence in Europe, US, Australia and Japan for both genders, but with iCCA increasing.11,12 A more recent study shows that the annual percentage change (APC) in iCCA incidence in the US increased to 4.36%.13 

The higher incidence rates of CCA are observed in Southeast Asia while the lowest were in Australia.1 The annual incidence in Southeast Asia is 0.1/100,000 to 71.3/100,0001 while in Thailand an incidence rate of 85/100,000 has been observed.7 There are recognized etiological factors driving the high incidence rates found in the Asian countries. Two species of liver fluke are associated with CCA A similar correlation has been made between a different liver fluke, Opisthorchis viverrine, and incidence rates in Thailand14 Eating habits involving consumption of raw, pickled or undercooked fish are contributing for the parasitic infections.6 

CCA Mortality 

Tumors of the hepatobiliary system are responsible for 13% of cancer mortality worldwide.1 The 5-year survival percentage after diagnosis has been stable at 10%, while the 1-year mortality has improved.14 CCA is typically asymptomatic in early stages, so when a diagnosed is made it is common to find the tumor in advanced stages and with limited options for treatment. Surgery remains the curative treatment for CCA, but the percentage of successful curative interventions are as low as 50%.1 In patients with iCCA resectable tumors, the median time of disease-free survival can reach 26 months but is associated with recurrence as high as 65%.2 

Mortality for CCA has increased around the world within different time-periods: 2000-2004, 2005-1009 and 2010-2014 and overall mortality per year is 1-6 per 100,000 inhabitants (excluding the regions where incidence is higher, such as Thailand, Korea and China).7 A high mortality rate is observed in Asian patients, with 2.81 per 100,000 individuals in Japan.7 

CCA accounts for 3% of all  gastrointestinal cancers and the worst survival rates are found in between African Americans, American Indians, and Alaska Native groups.7 In between 2004 and 2014, a study shows that mortality was higher for African American (45%), following Asian (22%) and white (20%) individuals.15 During the last decade, annual mortality rates in US have decreased in 2.5%, while increasing in 9% in Europe.1


1. Blechacz B. Cholangiocarcinoma: Current Knowledge and New Developments. Gut Liver. 2017 Jan 15;11(1):13-26. doi:10.5009/gnl15568

2. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi:10.1053/j.gastro.2013.10.013

3. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016 May;13(5):261-80. doi:10.1038/nrgastro.2016.51

4. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011 Jul;54(1):173-84. doi:10.1002/hep.24351

5. Sirpal S, Chandok N. Primary sclerosing cholangitis: diagnostic and management challenges. Clin Exp Gastroenterol. 2017 Nov;10:265-273. doi:10.2147/CEG.S105872

6. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int. 2019 May;39 Suppl 1:19-31. doi:10.1111/liv.14095

7. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi:10.1038/s41575-020-0310-z

8. von Hahn T, Ciesek S, Wegener G, Plentz RR, Weismüller TJ, Wedemeyer H et al. Epidemiological trends in incidence and mortality of hepatobiliary cancers in Germany. Scand J Gastroenterol. 2011 Sep;46(9):1092-8. doi: 10.3109/00365521.2011.589472.

9. Tyson GL, Ilyas JA, Duan Z, Green LK, Younes M, El-Serag HB et al. Secular trends in the incidence of cholangiocarcinoma in the USA and the impact of misclassification. Dig Dis Sci. 2014 Dec;59(12):3103-10. doi: 10.1007/s10620-014-3276-2

10. Witjes CD, Karim-Kos HE, Visser O, de Vries E, IJzermans JN, de Man RA et al. Intrahepatic cholangiocarcinoma in a low endemic area: rising incidence and improved survival. HPB (Oxford). 2012 Nov;14(11):777-81. doi:10.1111/j.1477-2574.2012.00536.x

11. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002 Dec;37(6):806-13. doi:10.1016/s0168-8278(02)00297-0

12. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002 May ;2:10. doi:10.1186/1471-2407-2-10. PMID: 11991810

13. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist. 2016 May;21(5):594-9. doi:10.1634/theoncologist.2015-0446

14. Kirstein MM, Vogel A. Epidemiology and Risk Factors of Cholangiocarcinoma. Visc Med. 2016 Dec;32(6):395-400. Erratum in: Visc Med. 2017 Jun;33(3):226. doi:10.1159/000453013 

15. Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol. 2016 Sep;16(1):117. doi:10.1186/s12876-016-0527-z

Reviewed by Harshi Dhingra, MD, on 7/1/2021.