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the two tumors actually share most of the risk factors, differences in the magnitude of associations have
been observed. Although the evidence is not fully consistent, and only a few investigations directly
compared the risk factors of the two tumors within the same study [7,26-28] , cirrhosis, chronic hepatitis B and
C, heavy alcohol use, diabetes, obesity, and NAFLD and its aggressive phenotype nonalcoholic
steatohepatitis (NASH) are more strongly associated with ICC, suggestive of common pathogenesis of ICC
and hepatocellular carcinoma; bile duct conditions, including gallstones, tend to be more strongly related to
ECC [6,7,29-35] . In particular, in an American study based on 2000-2011 data from the Surveillance,
Epidemiology and End Results -Medicare databases, similar risk factors for ICC and ECC were identified,
but cirrhosis, HCV infection, alcohol-related disorders, and obesity were more strongly associated with ICC
[27]
than ECC, while bile duct conditions, chronic pancreatitis, and smoking were more associated with ECC .
As for HBV infection, the association was stronger for ICC than ECC. In a meta-analysis published in 2020
and based on case-control studies, biliary duct cysts were the strongest risk factors for both ICC and ECC,
[35]
increasing the risks, respectively, by 27- and 35-fold . The pooled odds ratios (OR) for the other biliary
tract conditions considered were higher for ECC than ICC, being, respectively, 18.6 and 10.1 for
choledocholithiasis, 5.9 and 3.4 for cholelithiasis, and 2.9 and 1.8 for cholecystolithiasis. As for the other
factors analyzed, the pooled OR were 15.3 for ICC and 3.8 for ECC for cirrhosis, 4.6 for ICC and 2.1 for
ECC for HBV infection, 4.3 for ICC and 2.0 for ECC for HCV infection, 3.2 for ICC and 1.8 for ECC for
alcohol, and 1.7 for ICC and 1.5 for ECC for diabetes.

The increase in mortality from ICC observed in some Western countries may be, at least in part, the result
of a true increase in the incidence of the tumor, in turn explained by the rising prevalence of HCV in
selected generations, alcohol drinking, and NAFLD. Indeed, in the USA-as well as in most European and
[36]
American countries-the prevalence of obesity , alcohol use, diabetes, the metabolic syndrome and its
hepatic manifestation NAFLD/NASH are all rising. In addition, acute and chronic infections with HCV
[37]
have dramatically increased over recent calendar periods in the USA [38,39] , consistently with the nation’s
opioid crisis.

Conversely, the decrease in heavy alcohol use documented in the last decades in France and Italy, with the
consequent decreasing rates of cirrhosis and alcohol-related chronic liver diseases , may explain the
[40]
leveling off ICC trends observed over the most recent years.

The increase in mortality from ICC could also be due, at least in part, to a diagnostic drift favored by the
increased recognition of cholangiocarcinoma subtypes and an enhanced ability to recognize the tumor from
liver cancer due to improved diagnostic techniques. In addition, in the past, ICC was frequently
misdiagnosed as a metastatic disease from another primary site including breast, lung, pancreas, and
[15]
gastrointestinal tract . More recently, new tests and criteria have been developed to differentiate ICC from
hepatocellular or other metastatic carcinomas . In any case, differentiating intrahepatic and extrahepatic
[41]
locations may be challenging when the cancer is diagnosed at advanced stages.

In addition, hilar tumors were classified as ICC instead of ECC under prior versions of the ICD-O coding
systems. This caused an overestimation of ICC and an underestimation of ECC. However, the ICD-O-3
version, published in 2000 but adopted by different countries at different times, partially rectified the coding
allowing the classification of Klatskin tumors as both ICC and ECC. Klatskin tumors are relatively rare and
such misclassification should not have a major impact on our findings, especially in consideration that our
analysis focused on more recent data. Some studies reported increasing mortality from ICC in recent
calendar periods after correctly classifying hilar cholangiocarcinomas as ECC [13,42] . In any case, a certain role
of coding misclassification in the observed rates cannot be ruled out.