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Zhang et al. Hepatoma Res 2023;9:5 https://dx.doi.org/10.20517/2394-5079.2023.11 Page 3 of 5

cholangiolocarcinoma [11-13] . HCC-like ICC is composed of polygonal eosinophilic tumoral cells arranged in a
trabecular pattern, morphologically resembling HCC, and prone to be misdiagnosed. It is recommended to
use IHC staining to distinguish HCC-like ICC from HCC. The former expresses cholangiocyte-lineage
markers, such as CK7 and CK19, but not hepatocyte-lineage markers, such as Arginase-1 (ARG1) and
Hepatocyte Paraffin 1 (Hepar-1). The surgical prognosis of cholangiolocarcinoma is better than that of
small bile duct and large bile duct subtypes [14,15] .

Ductal plate malformation subtype is another special and rare small bile duct subtype, characterized by
irregular dilated cystic lumens with polypoid protrusions in the lumen [5,12,16] . This subtype is less aggressive
and its postoperative prognosis is generally well. The IHC markers and molecular alterations of ductal plate
malformation subtype are similar to those of small bile duct subtype.

The mixed type (hybrid pattern) of ICC, which contains multiple ICC components, may reflect different
biological behaviors and clinical prognoses. It is recommended to describe the proportion of each
histological component in the pathological report. The combination of large bile duct subtype markers
(S100p + mucin 5AC) with small bile duct subtype markers (CRP + N-cadherin) is suggested as the first-line
IHC panel for ICC subclassification. The recommended second-line panel includes MUC6, trefoil factor 1,
and CD56.

At present, the diagnostic terminology of “ICC” is not fully consistent. WHO classification recommends
using the term “intrahepatic cholangiocarcinoma” rather than “cholangiocellularcarcinoma” and
[5]
“cholangiolocellularcarcinoma” , whereas the 8th UICC-TNM staging system prefers to use
“cholangiocellular carcinoma” to refer to cholangiolocarcinoma and ICC [17,18] . The consensus supports the
opinion of WHO and recommends using “intrahepatic cholangiocarcinoma” as the standard term for
pathological diagnosis.

In the era of targeted therapy and the recent shift towards immunotherapy for ICC, specific biomarkers
have been proposed by both the National Comprehensive Cancer Network (NCCN) and the Chinese
Society of Clinical Oncology (CSCO) guidelines for biliary tract cancers, which put forward higher
requirements for the detection of biomarkers. The consensus classified and summarized all the molecular
targets of ICC based on the molecular characteristics of different ICC subtypes, and listed the corresponding
[2]
targeted drugs and detection methods , establishing a molecular-pathological foundation for the precise
and individualized treatment of ICC.

Accurate pathological classification is the basis for personalized treatment and prognosis prediction of ICC.
The present consensus emphasized the establishment of a diagnostic model for the ICC pathological
classification . In this model, clinical characteristics, macroscopic patterns, cell morphology, histological
[2]
structure, immunophenotype, and biomarkers for targeted therapy and immunotherapy should be
comprehensively considered for subtype diagnosis. This consensus, together with the previously established
guidelines for the pathological diagnosis of HCC [19,20] , may improve the overall homogeneity of pathological
diagnosis of primary liver cancer in China.

DECLARATIONS
Authors’ contributions
Conception and design: Cong W, Yuan J
Manuscript writing: Zhang X, Wang H, Chen J, Sheng X, Zhang H, Zhang L