When it comes to cholangiocarcinoma, some risk factors matter more than others. The following epidemiological overview of cholangiocarcinoma can help us understand why.

Cholangiocarcinoma represents around 3% of all gastrointestinal malignancies and is the second most common primary liver cancer (after hepatocellular carcinoma). It affects both men and women in roughly the same proportions, with a slight male preponderance. 

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Cholangiocarcinoma in the West is largely a disease of old age: most patients are diagnosed in their seventh decade of life. It is worth noting that the incidence of cholangiocarcinoma varies greatly between Western and Eastern countries. Compared to the West, the incidence in Asian nations, such as China, Thailand, South Korea, and Japan, is significantly higher. 

Curiously, the incidence of cholangiocarcinoma also can vary greatly between different regions of the same nation. Take Thailand, for example. The age-standardized incidence rate of cholangiocarcinoma in Northeast Thailand is 85 per 100,000 population; in South Thailand, that figure is a mere 5.7 per 100,000 population. Khan et al wrote, “Presumably, these variations in incidence reflect, at least partly, differences in geographical risk factors as well as genetic determinants.”

Another interesting point about the epidemiology of cholangiocarcinoma is the issue of misclassification. Most diseases are designated specific classification codes, and cholangiocarcinoma is no different. However, the World Health Organization International Classification of Diseases (ICD) coding system for cholangiocarcinoma has been inconsistent.

Three Distinct Subtypes

The main issue here is that most hepatic oncology specialists believe there to be three distinct subtypes of cholangiocarcinoma: intrahepatic (iCCA), perihilar (pCCA), and distal/extrahepatic (dCCA). This way of classifying cholangiocarcinoma is based on its anatomical site of origin. 

Szymańska wrote, “The boundary between the intra- and extrahepatic biliary tree has been somewhat confused in the literature . . . The nomenclature of the subtypes have been extensively discussed and revised in the past decade, and different terms referring to the same entities can be encountered in both clinical guidelines and in scientific literature.”

For example, some scientists make a distinction between pCCA and dCCA, while others do not. This is a legacy problem because in the past, pCCA was referred to as “Klatskin tumors”, and many researchers still do.

In medical literature today, the misclassification of pCCA as iCCA still occurs, which is especially problematic because pCCA is the most common subtype of cholangiocarcinoma, while iCCA is the least. Therefore, reported changes in incidence rates of cholangiocarcinoma subtypes should be interpreted with caution. By extension, risk factors determined via incidence rates should likewise be interpreted cautiously. 

Varying Degrees of Risk

With that in mind, let’s look at the risk factors associated with cholangiocarcinoma. Rodrigues and colleagues listed a number of common ones:

  • Toxins
  • Liver fluke
  • Autoimmune/inflammatory conditions, such as Crohn’s disease and ulcerative colitis
  • Bile duct-related conditions
  • Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
  • Type 2 diabetes
  • Choledochal cysts
  • Choledochal stones
  • Cirrhosis
  • Viral hepatitis
  • Alcohol. 

It is important to note that varying degrees of risk are attached to various factors in different subtypes of cholangiocarcinoma.

“Compelling evidence supports the notion that cholangiocarcinoma heterogeneity is the result of a complex interaction between the host‐specific genetic background and a different geographical distribution of the risk factors associated with this disease,” Khan et al wrote in a review article.

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Khan and colleagues listed a number of risk factors that have different strengths of association in iCCA compared to the 2 forms of extrahepatic cholangiocarcinoma (eCCA). Most risk factors are applicable to both subtypes of cholangiocarcinomas, but here are a few that are not: 

  • Hepatolithiasis is very strongly associated with iCCA but has no association with eCCA. 
  • Alcohol is moderately associated with iCCA but has no association with eCCA. 
  • Asbestos is strongly associated with iCCA but has no association with eCCA. 
  • Hepatitis B and C are strongly associated with iCCA but have a weak/modest association with eCCA. 
  • Chronic pancreatitis is moderately associated with iCCA but has a strong association with eCCA. 
  • Cirrhosis has a strong to very strong association with iCCA but a moderate to strong association with eCCA.  

And this brings us back to how the confusing classification of cholangiocarcinoma has impacted risk factor studies. Because risk factor studies rely heavily on the incidence of a disease in any particular location, the misclassification/changing classification of a disease has a disorienting impact. In Western nations, about half of cholangiocarcinoma cases are still diagnosed without identifiable risk factors. 

“As cholangiocarcinoma still remains a relatively rare cancer, misclassification can introduce significant biases in the identification of risk factors associated with this disease,” Khan and colleagues wrote. “A more refined cholangiocarcinoma classification, along with an accurate diagnosis and patient anamnesis, is therefore required to better clarify the underlying etiology of this disease.” 


Rodrigues PM, Olaizola P, Paiva NA, et al. Pathogenesis of cholangiocarcinoma. Annu Rev Pathol. 2021;16:433-463. doi:10.1146/annurev-pathol-030220-020455

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

Szymańska K. Cholangiocarcinoma: diagnosis and treatment. Encyclopedia of Cancer. Elsevier; 2019, pages 367-371. Accessed February 6, 2022.