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Cardinale et al. Hepatoma Res 2018;4:20 I http://dx.doi.org/10.20517/2394-5079.2018.46 Page 3 of 16

CCA and HCC respectively . The trend in iCCA incidence is paralleled also by the fact that mortality for
[11]
primary liver cancer has become more uniform across Europe over recent years with an evident decline of
HCC mortality, but, in contrast, intrahepatic CCA mortality has substantially increased for the most part of
Europe [12,13] . Over recent years intrahepatic CCA accounted for over a fourth of all liver cancer deaths in men
and 50% in women . Liver cancer mortality rates are expected to rise by 58% in the UK between 2014 and
[12]
2035, i.e., to 16 deaths per 100,000 people by 2035 . Considering epidemiology trend in primary liver cancer,
[14]
half of deaths for primary liver cancer will be determined by intrahepatic CCA [12-14] . Furthermore, when the
mortality rates for all malignancies are considered, the untargeted problem of CCA emerged clearly. Indeed,
while a reduction of the mortality rate from 19 malignancies (comprising breast, lung, colon, etc.) was shown
from 1990 to 2009 (US data), the mortality rate for malignancies of liver and bile ducts increased by more
than 40% and 60% in females and males, respectively . Finally, it is noteworthy to mention that CCA is the
[15]
most frequent cause of metastasis of unknown origin, and thus further highlights how we still do not know
the real burden of CCA .
[16]

NEW INSIGHTS INTO iCCA CLASSIFICATIONS
A huge number of different classifications have been proposed for CCA [1-10,17] . The most updated one, but
still discussed, identify on the basis of the anatomical localization the iCCA, the pCCA and the dCCA .
[1-3]
However, being a topographic classification it suffers several pitfalls, and, of course, it does not reflect
different biological features. Firstly, it should be noted that, the diagnosis of CCA frequently occurs at an
advanced stage, where, the differentiation between the intra-hepatic or extra-hepatic location results is very
difficult, and sometimes impossible . Since, small bile ducts and ductules are also present in the perihilar
[1-3]
liver parenchyma, then, pCCA as iCCA, may originate either from these smaller ducts and this cannot be
discriminated based on gross morphology. Similarly, the iCCA may originate from larger or smaller portion
of intrahepatic biliary tree. Third, recent studies demonstrated how, from a pathological and molecular
point of view, differences between pCCA and the iCCA originated from larger bile ducts ceased to exist and,
therefore, the distinction between these two forms of CCA is losing relevance . Taking into consideration
[4,9]
the macroscopic pattern of growth, iCCA has been classified in mass-forming (MF), periductal infiltrating
(PI), and intraductal growing (IG) . As far as pCCA and dCCA are concerned, either a PI or IG pattern has
[2,3]
been recognized. For pCCA a nodular + PI growth pattern predominates (> 80%) [2,5,17,18] .

On the histological level, while, the vast majority of pCCA and dCCA are mucinous adenocarcinomas,
iCCAs are highly heterogeneous tumors and several classifications have been proposed [4,5,9,19] . The small
bile duct type (mixed) iCCAs display an almost exclusively MF growth pattern [4,5,9,19] , and are frequently
associated with chronic liver diseases (viral hepatitis or cirrhosis) [4,5,9,19,20] . Notably, this subtype shares clinic-
pathological similarities with cytokeratin (CK) 19-positive hepatocarcinoma (HCC) [4,21] . On the other hand,
large bile duct type (mucinous) iCCAs may grossly appear as MF, PI or IG types; they are more frequently
associated with PSC and can be preceded by pre-neoplastic lesions such as biliary intraepithelial neoplasm
(BiIN) or intraductal papillary neoplasm (IPNB) [4,5,9,19] . Interestingly, the large bile duct type (mucinous)
iCCAs share phenotypic traits with pCCA and pancreatic cancers .
[4]
In our opinion, this histological subtyping should be taken into serious consideration because it underlines
different risk factors, molecular profile, and clinical management [3,4,9,14,22-28] .

MULTIPLE RISK FACTORS REVEAL iCCA SUBTYPE-SPECIFIC PATHOGENESIS
Although CCA is a rare cancer (incidence < 6/100,000) in most countries, its incidence may reach an extremely
high in some populations of Chile, Bolivia, South Korea and North Thailand [Figure 1]. The different
[29]
prevalence of risk factor in geographic areas may explain the variation in incidence rates of CCA. For example,
in Thailand regions, the very high incidence of CCA is closely related to the incidence of liver flukes [30-32] .