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Page 2 of 16 Cardinale et al. Hepatoma Res 2018;4:20 I http://dx.doi.org/10.20517/2394-5079.2018.46

Figure 1. Worldwide incidence (cases/100,000) of cholangiocarcinoma (CCA). Data refer to the period 1971-2009. Green colour
identifies areas with lower incidence (< 6/100,000 cases, rare cancer), while pink colour indicates countries where CCA is not a rare
cancer (> 6/100,000 cases). Diagnoses have been classified according to the International Classification of Diseases (ICD-O-1, ICD-O-2,
ICD-O-3, ICD-10, ICD-V9, ICD-V10, ICD-O). Where available, the more incident form [intrahepatic (IH) vs. extrahepatic (EH) CCA] and
the temporal trend of incidence (↑increasing trend; ↕stable trend; ↓decreasing trend) have been reported. This figure was modified from
[3]
Banales et al. with permission
of the pathogenesis and the pronounced heterogeneity affected in particularly iCCAs had impeded clinical
goals in iCCA . This review will focus on the advances of iCCA epidemiology, classifications and histo-
[10]
morphology, risk factors, molecular pathogenesis and clinical presentation revealing the existence of multiple
subtypes of iCCA.

THE BURDEN OF iCCA
The epidemiologic trend of CCA shows a constant and dramatic increase in incidence and mortality
worldwide , clearly depicting CCA relevance among others types of cancer. A progressive increase in
[1-3]
intrahepatic CCA incidence was reported, while the incidences of both perihilar CCA and distal CCA seem
to be stable . The incidence of CCA in European countries ranges from 1 to more than 4 cases/100,000
[1-3]
[1-3]
[Figure 1]. However, the difficulties with classification coding for CCA, and with the various terminology that
is used, determined an underestimation of CCA burden. In a recent report, the four ICD-10 (International
Classification of Diseases) sub codes were agreed on for CCA and used . This report showed that in England
[11]
alone (not the whole of the UK), in 2013, 1965 new CCAs were diagnosed with an incidence rate of 3.65 per
100,000 population, while, 2161 deaths and a mortality rate of 4.01 per 100,000 population were registered.
The number of deaths per 100,000 population for the CCA in the period from 2010 to 2013 in England
tragically surpassed the ones for the hepatocellular carcinoma (HCC), with 7743 vs. 6899 deaths in 2013 for