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Table 3. Genetics, molecular pathology and histopathology markers related to poor prognosis in HCC
Biomarkers Role in occurrence, development and prognosis of HCC Imaging biomarkers
CTNNB1 Its mutation accounts for 20%-40% of HCC; play pivotal role in A high enhancement ratio on HBP images of Gadoxetic acid-
the poor prognosis of HCC; HCCs with CTNNB1 mutations show enhanced-MRI; a high value of ADC on DWI images
a higher grade of differentiation with frequent pseudoglandular
patterns and bile production. The subgroup of hepatocellular
adenomas with an active β-catenin gene show high probability of
malignant transformation
Ki-67 Highly correlated with staging, grading and recurrence rate The parameter K trans of free-breathing DCE-MRI using gadoxetic
of HCC; high possibility of adverse pathological features and acid; T1 rt-20 min, tumor-to-muscle SI ratio, ADC value, and
invasive behaviors arterial inhomogeneous enhancement on gadoxetic acid-
enhanced MRI; texture analysis on gadoxetic acid-enhanced-MRI
CK-19 Correlated with some clinicopathological features of tumors such The arterial rim enhancement, targetoid appearance, non-
as poor differentiation, metastasis, and early recurrence after peripheral “washout”, and irregular tumor margin on gadoxetic
resection and radiofrequency ablation acid-enhanced MRI; lower tumor-to-liver ADC ratio, and lower
tumor-to-liver SI ratio at HBP images
EpCAM Involved in a series of biological processes such as cell No significant correlation between irregular rim-like
proliferation; the overexpression of EpCAM is correlated with the hyperenhancement on gadoxetic acid-enhanced-MRI and
angiogenesis and poor outcome of HCC; in addition, EpCAM- EpCAM status in HCC. Whether imaging markers can be used to
positive HCC is considered to be a subtype of human HCC with a indicate the EpCAM positive HCC is still unclear
poor prognosis
HCC: hepatocellular carcinoma; CTNNB1: β-catenin; HBP: hepatobiliary phase; Gd-EOB-DTPA: gadolinium-ethoxy benzyl-
diethylenetriamine penta-acetic acid; MRI: magnetic resonance imaging; ADC: apparent diffusion coefficient; DWI: diffusion-weighted
imaging; SI: signal intensity; CK-19: cytokeratin-19 (CK-19); EpCAM: epithelial cell adhesion molecule

regulatory role in embryogenesis.

Treatment approaches for cancer are largely depended on both the stage of disease at diagnosis, and
[94]
the patient’s performance status . Therefore, early detection of tumor spread or metastasis allows for
the most appropriate treatment plans and to strive for more survival opportunities for HCC patients.
Contrast-enhanced CT or MRI ensure implementation of one-step inspection and display the distinct
[12]
enhancement features of metastasis better compared to ultrasound . MRI with liver-specific contrast
agents improves diagnostic efficiency in the early identifification of intrahepatic micrometastasis, as well as
[95]
follow-up surveillance of disease development and outcomes . PET/CT has emerged as a useful modality
in diagnosing extrahepatic lesions in patients with advanced HCC and assessing tumor grading [96,97] .
Furthermore, newly developed dual-tracer PET/CT improve and complement the advantages compared to
single-tracer imaging in the evaluation of HCC metastasis, and has gradually become an alternative modality
[98]
to PET/CT for detecting extrahepatic metastasis in HCC patients .

FACTORS RELATED TO GENETICS, MOLECULAR PATHOLOGY AND
IMMUNOHISTOCHEMISTRY
HCC is the result of a multifactorial, synergistic damage from various biological factors related to genetics,
molecular pathology, and immunohistochemistry that impact upon HCC differentiation and prognosis. With
the development of liver imaging technologies, some have been detected by imaging methods and proved to
be associated with imaging biomarkers [Table 3].

β-catenin mutation
β-catenin (CTNNB1) has been recognized as the most frequently mutated oncogene during liver cancer.
Its mutation accounts for around 20%-40% of all HCC cases, and is strongly associated with larger tumors,
invasive growth, and vascular invasion. In addition, HCCs with the CTNNB1 mutation show a higher
[99]
grade of differentiation with frequent pseudoglandular patterns and bile production . Moreover, the
subgroup of hepatocellular adenomas with an active β-catenin gene shows a high probability of malignant
transformation [100] . Recently, several studies reported that gadoxetic acid-enhanced-MRI could be used
to detect the presence of CTNBB1 mutations in HCC, because the mutation of CTNNB1 would promote