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Turati et al. Hepatoma Res 2022;8:19 https://dx.doi.org/10.20517/2394-5079.2021.130 Page 13 of 15

ICC mortality rates somewhat reflect the trends observed for hepatocellular carcinoma, with steady
[43]
increases in the USA, the UK, Australia, and Germany . However, hepatocellular carcinoma mortality
[43]
rates have been declining in France, Italy, and Spain over the last two decades , but these are not reflected
in ICC death rates. This may reflect the quantitatively different role of major risk factors, in particular HBV
and HCV, on hepatocellular carcinoma versus ICC, or improved diagnosis of ICC over recent years.

The favorable trends observed for ECC mortality in several countries worldwide are likely the result of
increasing rates of cholecystectomy, with the use of safer procedures such as laparoscopic cholecystectomy
for gallstone disease, a major risk factor for biliary tract cancers including ECC and gallbladder cancers [44,45] .
Advances in the management of PSC, strongly related to cholangiocarcinoma, especially ECC, in the West
may also account for some of the favorable mortality trends.

Among the limitations of the present analysis, misclassification with hepatocellular carcinomas, other liver
cancers, gallbladder cancers, and between ICC and ECC may affect the validity of death certification.
Notably, hilar tumors (“Klatskin” tumors) tend to invade the liver and are possibly misclassified as ICC,
even though they account for a small proportion of ECC . In our analysis, however, we only considered
[46]
countries with reasonably valid data in terms of coverage of deaths and population size. However, in
cirrhotic patients without biopsy, ICC and hepatocellular carcinoma can be misclassified. In addition,
problems in tumor registry reporting still make it difficult to accurately estimate the true incidence and
mortality of these tumors.

In conclusion, the present analysis confirmed a global increase in ICC mortality and showed more favorable
trends for ECC, with, however, some differences across countries. How much of the observed increased
mortality from ICC is attributable to a real increase in incidence, rather than improved cancer recognition,
and better classification by recent coding systems needs clarification. The widespread fall in ECC mortality
largely reflects the wider adoption of (laparoscopic) cholecystectomy for the treatment of gallstones and
related bile duct conditions.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and interpretation: La Vecchia C,
Negri E
Performed data analysis and made contributions to interpretation: Bertuccio P
Drafted the manuscript and made contributions to interpretation: Turati F

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was conducted with the contribution of the Fondazione AIRC per la Ricerca sul Cancro (project
No. 22987).

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.