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Page 2 of 12 Pedica et al. Hepatoma Res 2021;7:71 https://dx.doi.org/10.20517/2394-5079.2021.89

important targetable molecular alterations have recently been described, regarding around 15%-20% of the
intrahepatic cholangiocarcinoma, whilst the extrahepatic bile duct cancer is rarely a suitable subject for
targeted therapy. These aberrations are FGFR2 fusions, IDH1/2 mutations, more rarely BRAF V600E and
BRCA1/2 alterations, neurotrophic receptor tyrosine kinase (NTRK) fusions and microsatellite instability
(MSI). These represent an important advancement in the understanding of the disease, although further
investigation is mandatory for our patients.

HISTOPATHOLOGY OF BILIARY TRACT CANCER
Cholangiocarcinoma is a malignant epithelial neoplasm, generally an adenocarcinoma, arising from the
biliary tree and includes a wide range of malignant tumours, commonly in the context of a non-cirrhotic
liver. The term “cholangiocarcinoma” should be used for intrahepatic malignancies (iCCA), whilst the
extrahepatic ones should be called “of the extrahepatic bile ducts” (eCCA) (sec. WHO 2019 ). This
[1]
classification is supposed to follow the probable cell of origin of these neoplasms and agree with the TNM
system. In fact, the TNM staging system subdivides iCCA as located proximal to the second order bile
ducts, from the perihilar eCCA, developing in the right and left hepatic duct or at the confluence between
the two, and the distal eCCA that involves the common bile duct. The eCCA are divided from the insertion
of the cystic duct. iCCA can arise from the bile ductules until the second-order bile ducts or segmental bile
[1]
ducts, and the WHO 2019 subdivides between “small duct type” and “large duct type” iCCA . The “small
duct type” is generally peripheral, mass forming, typically made of small tubules and ductules, not
[2,3]
producing mucus [Figure 1] and can arise in the context of cirrhosis . The “large duct type” more
commonly arises in the intrahepatic perihilar region and generally presents as a highly desmoplastic lesion
with poorly defined margins, typically with periductal infiltrating pattern of growth. It generally shows all
the typical aspects of the extrahepatic bile duct adenocarcinoma in terms of aggressiveness, with large
vessels and nerves infiltration [Figure 2].

The “small duct type” iCCA can arise in the context of a ductal plate malformation or a biliary
adenofibroma, as occasionally reported in the literature . Biliary adenofibroma is a recently introduced
[4,5]
[1]
category in the WHO 2019 , representing a mass forming lesion made of glands and stroma, with cystic
dilatation, covered by biliary cuboidal epithelium without significant atypia not communicating with the
biliary tree , and in fact after extensive sampling of the tumour it is possible to appreciate aspects
[6]
resembling an underlying biliary adenofibroma [Figure 3A and B]. The “large duct type” iCCA is usually
associated with preinvasive neoplasms such as biliary intraepithelial neoplasms (BilIN) or intraductal
[1]
papillary neoplasms of the bile ducts (IPNB) . BilIN presents with flat or micropapillary proliferation of the
biliary epithelium not radiologically visible, now subdivided between low grade and high grade depending
on architecture and cytological alterations [Figure 4]. IPNB is a grossly visible lesion, radiologically
[1]
detectable and generally associated with dilatation of the bile ducts. Both the preinvasive lesions of the
biliary tree have their pancreatic counterpart in the pancreatic intraepithelial neoplasms and intraductal
mucinous papillary neoplasms (IPMN), although with some morphological and phenotypical differences ,
[7]
IPNB protrudes as a polyp in the lumen of a dilated bile duct and can also develop in the context of the
peribiliary glands .
[8]

The IPNB are subdivided between types I and II. Type I IPNB mainly arises in the intrahepatic bile ducts,
phenotypically gastric or intestinal [Figure 5A] and less aggressive than the type II IPNB, which is more
typical of the extrahepatic bile ducts, has an irregular architecture and shows intestinal or pancreaticobiliary
phenotype [Figure 5B].
[1]