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Page 2 of 5 Zhang et al. Hepatoma Res 2023;9:5 https://dx.doi.org/10.20517/2394-5079.2023.11

The nationwide screening of primary liver cancer shows that hepatocellular carcinoma (HCC), ICC, and
combined hepatocellular-cholangiocarcinoma account for 93.0%, 4.3%, and 1.6% of primary liver cancer,
[3]
[4]
respectively, in China . The incidence of ICC is on the rise, especially in people over 65 years old . HBV
infection is probably one of the most important factors in China among the risk factors for ICC
development . The application of multiple therapies, including antiviral treatment and targeted therapies,
[5,6]
[7,8]
can prolong long-term survival in ICC .
There are three main macroscope patterns of ICC, including mass forming pattern, periductal infiltrating
pattern, and mixed pattern (mass forming pattern + periductal infiltrating pattern). Different sampling
methods are recommended according to the macroscope patterns. For mass forming and mixed pattern
ICCs, the seven-point baseline sampling method is recommended. For the periductal infiltrating pattern
ICC, the specimen is mainly collected from the junction between the invaded bile duct wall and liver
parenchyma as well as the surgical margin, so as to check the extent of ICC invasion and the presence of
precancerous lesions.

Intrahepatic biliary ducts can be divided into three bile duct groups, the large bile duct group (area bile
ducts-segmental bile ducts, 300-800 μm), the small bile duct group (interlobular bile ducts-septal bile ducts,
15-300 μm), and the terminal bile duct group (canals of Hering, < 15 μm). Based on the histological and
anatomical characteristics of bile duct groups, ICC is histologically classified into four subtypes, namely
large bile duct, small bile duct, cholangiolocarcinoma, and ICC with ductal plate malformation pattern .
[5,9]
ICC with different histological subtypes is highly heterogeneous in cell origin, tissue structure,
immunophenotype, and molecular alteration.

The morphological characteristic of large bile duct subtype, which originates from the intrahepatic large bile
ducts group, shows columnar tumor cells and mucus-secreting cells arranged in irregular ductal patterns,
with a desmoplastic response. This subtype usually shows an aggressive growth pattern with portal triads,
vascular, lymphatic, and perineural invasion, as well as lymph node metastasis. Immunohistochemical
(IHC) markers, such as S100 calcium-binding protein P (S100P), mucin 5AC, and trefoil factor 1 are
positive. The representative molecular alteration is KRAS mutation. Large bile duct subtype has the worst
postoperative prognosis among the ICC subtypes.

Small bile duct subtype arises from the interlobular bile duct or septal bile ducts, showing cuboidal or low-
columnar cells arranged in a regular ductal pattern. Small bile duct subtype is less aggressive than large bile
duct subtype, rarely invading the portal areas, blood vessels, lymphatic vessels, and nerves, and rarely
involving lymph node metastasis. C-reactive protein (CRP), N-cadherin, and CD56 are useful biomarkers
for confirming small bile duct subtype. It is noteworthy that S100P may also be positive in small bile duct
subtype, depending on the selected clones of antibodies. Isocitrate dehydrogenase1/2 mutations and FGFR2
fusion/rearrangement are presentative targeted therapeutic markers, which are recommended to be detected
in small bile duct subtype. The postoperative prognosis of small bile duct subtype is much better than that
of the large bile duct subtype. The 5-year recurrence-free survival rate of small bile duct and large bile duct
subtypes is 10% and 38%, respectively, and the 5-year overall survival rate is 20% and 60%, respectively .
[10]

Cholangiolocarcinoma originates from the smallest branches of the intrahepatic biliary tree (canals of
Hering and bile ductules) and is considered a unique small bile duct subtype. Cholangiolocarcinoma is
morphologically characterized by well-differentiated angular small ductular loosely arranged in hyalinized
collagen fiber stroma. This subtype is less invasive. The IHC markers and molecular variations are similar to
those of small bile duct subtype. It is important to note that HCC-like ICC often appears in