Cholangiocarcinoma (CCA)

Cholangiocarcinoma (CCA) comprises a group of malignant tumors that form in the biliary tree. CCA is the second most common cancer affecting the liver.1

Classification of CCA is made according to the site of origin of the tumor within the biliary tree. Tumors can be named as intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). pCCA and dCCA are also known as extrahepatic, however, the use of this term is not recommended since it is referring to tumors that are clinically different in their characteristics and for which different treatment options are available.1 CCA can be classified as mass-forming, periductal infiltrating and intraductal papillary, according to the macroscopic growth pattern presented. iCCA type are usually mass-forming whereas pCCA are periductal-infiltrating.2 

The distinction of these different types of tumors has relevance since they are correlated with epidemiological differences.3

CCA Epidemiology

CCA are responsible for 15% to 20% of the primary malignancies that affect the liver and the biliary system.1,3 These tumors present an incidence of 0.3-6 per 100,000 inhabitants per year and a global mortality estimated is 1-6 per 100,000 inhabitants per year, which reveals the poor prognosis associated with the disease.4,5 The rates of incidence for this disease are different across the continents but also within the same continent. Even though CCA are rare in the Western countries, they are common in Asia.3 The higher incidences are observed in Southeast Asia, with a rate of 0.1-71.3 per 100,000 inhabitants.1,2 

The diagnosis of CCA is commonly achieved when the disease is already in an advanced stage, and the average age of diagnosis is situated above 50 years old.2 Estimated male to female ratio is 1.2-1.5:1, with males presenting higher incidence of these neoplasms.3

CCA Risk Factors

Although the etiology of the malignancies of the biliary tree is unknown, there are several established CCA causes. Many of these causes are shared between the different subtypes of CCA but others appear to be linked more specifically to one form rather than other forms.1 These causes include pre-existing conditions, such as primary sclerosing cholangitis (PSC). Patients with PSC present a 5% to 20% risk of developing a tumor and the disease may be identified in these individuals before age 40.2 Other diseases and medical conditions, such as Caroli’s and type I and IV biliary cysts, may increase the risk of CCA formation by 30-fold. The consequent reflux of pancreatic enzymes observed in these patients contributes to the development of tumoral cells.6

Parasitic infections are also a recognized CCA risk factor.3 Ingestion of raw or undercooked food containing the parasites Opisthorchis viverrini (O. viverrini) and Clonorchis sinensis (C. sinensis) opens the way to chronic irritation that consequently fragilize cholangiocytes, which increases susceptibility to carcinogens.7 Other medical conditions can induce inflammation and irritation of the biliary cells, and through this mechanism increase the risk of malignancy. This is observed in patients with hepatolithiasis, a disease particularly significant in Asian countries where up to 10% of these patients develop iCCA.8 Inflammatory bowel disease (IBD) also has been suggested as a possible risk factor for developing CCA and has been studied primarily associated with PSC patients, but also as an independent potential risk of tumorigenesis.3

Exposition to chemicals may also be a cause for formation of tumors in the biliary duct. An important example of this exposition is the administration of thorium dioxide (Thorotrast), which was used as a radiologic contrast medium until the 1960s. Studies relate the use of this chemical with CCA. As the half-life of thorium dioxide is 400 years, there is a long latency period from administration of the contrast until the CCA diagnosis.9,10

Infection by hepatitis virus (B and C), cirrhosis, diabetes mellitus, high alcohol consumption and smoking are additional factors that have been studied in CCA development.2,3 Obesity and metabolic syndrome have also been noted for their interference in CCA formation.11

Genetic polymorphisms involving genes that encode enzymes with roles in DNA repair, in carcinogens metabolism or in the immune response are correlated with tumorigenesis.12 Mutations in oncogenes, such as KRAS, and in tumor suppressor genes such as TP53, have been identified.13

CCA Pathophysiology

CCA typically present features of adenocarcinomas, however, studies point to hepatic progenitor cells as the cells of origin for the tumors.14 Cholangiocarcinogenesis results from the malignant transformation of cholangiocytes and is influenced by inflammation and cholestasis.14 Tumor development occurs in different phases that include hyperplastic and metaplastic changes.15 Several proinflammatory cytokines are activated leading to the enhanced expression of cyclooxygenase 2 (COX-2). COX-2 is then able to interfere with CCA growth, with upregulation of pro-oncogenic pathways such as the hepatocyte growth factor (HGF).2 


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  11. Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol. 2020 Jan;72(1):95-103. doi: 10.1016/j.jhep.2019.09.007
  12. 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
  13. Jiao Y, Pawlik TM, Anders RA,  et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013 Dec;45(12):1470-1473. doi:10.1038/ng.2813
  14. Raggi C, Invernizzi P, Andersen JB. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol. 2015 Jan;62(1):198-207. doi:10.1016/j.jhep.2014.09.007
  15. Sirica AE. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology. 2005 Jan;41(1):5-15. doi: 10.1002/hep.20537

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