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Zhang et al. Hepatoma Res 2020;6:30 I http://dx.doi.org/10.20517/2394-5079.2020.17 Page 11 of 16

OATP expression [99,101] . The results showed that a high enhancement ratio on HBP images of Gadoxetic acid-
enhanced-MRI indicate the mutation of CTNBB1, and is closely associated with a higher differentiation
grade of HCC. Moreover, a high value of ADC on DWI images could also be used as an indicator of HCC
with the CTNBB1 mutation [101] .

Ki-67
Ki-67 is highly correlated with the staging, grading and recurrence of HCCs. The overexpression of Ki-
[102]
67 indicates a high possibility of adverse pathological features and invasive behaviors of the tumor . The
trans
parameter K of free-breathing DCE-MRI using gadoxetic acid is reported to be highly associated with
Ki67 proliferation status, and the lower value of K trans indicate higher Ki-67 indices and histological grades of
HCC [103] . In addition, the T1 rt-20 min, tumor-to-muscle signal intensity ratio, ADC value and the arterial
inhomogeneous enhancement pattern on gadoxetic acid-enhanced-MRI are also correlated with high-Ki-67
expression [104-106] . Furthermore, texture analysis, on the basis of gadoxetic acid-enhanced-MRI, can be applied
as a tentative approach to preoperatively predict the Ki-67 status of HCC after curative resection [107] .

Cytokeratin-19
Cytokeratin-19 (CK-19) are important keratin proteins expressed in liver tissue and show differential
expression at different stages of physiological development of the liver. The expression of CK-19 is correlated
with some clinicopathological features of tumor such as poor differentiation, metastasis, and early recurrence
after tumor resection or radiofrequency ablation [108] . The arterial rim enhancement, targetoid appearance,
non-peripheral “washout”, and irregular tumor margins on gadoxetic acid-enhanced MRI are reported to
be effective imaging markers for evaluating the CK-19 status of HCC [109-112] . Moreover, lower tumor-to-liver
ADC and signal intensity ratios in HBP images may be helpful for predicting CK19-positive HCC with early
recurrence [112] .

Epithelial cell adhesion molecule
Epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein expressed in most normal epithelial
cells, and has been proven to be involved in a series of biological processes such as cell proliferation [113] . It
has been reported that the overexpression of EpCAM is closely correlated with the angiogenesis and poor
outcomes in HCC [114] . In addition, EpCAM-positive HCC is also considered to be a subtype of human HCC
with a poor prognosis [115] . However, the imaging biomarkers that can be used to reflect EpCAM-positive
[63]
status in HCC have not been described. Recently, Rhee et al. , used the imaging feature of irregular rim-
like hyperenhancement as the poor prognostic index to explore the value of gadoxetic acid-enhanced MRI
in predicting the overexpression of immunomarkers including EpCAM. However, results showed there is
no statistically significant association between irregular rim-like hyperenhancement and EpCAM status in
HCC. Therefore, whether imaging markers can be used to indicate EpCAM positive HCC is still unclear.

CONCLUSION
Hepatocarcinogenesis is a progressive and multi-stage process of molecular heterogeneity and histological
dedifferentiation. The poor prognosis of HCC is strongly associated with the presence of aggressive biological
behaviors in tumors. Modern noninvasive imaging technologies such as CEUS, DEC-CT/MRI and PET
imaging improve the efficiency of early identification, characterization and assessment of HCC, and have
been widely used for screening, diagnosis, and improving the survival of HCC patients. The increasing use
of multiparametric functional methods, including DWI and its derived-technologies (IVIM, DKI), contrast
enhanced-MRI with SPION or Gd-EOB-DTPA, MRE, chemical-shift MRI, radiomics and AI, for assessing
tumor morphology, vascularity, cellularity, metabolic capability, texture, radiomics features, OATP function,
and Kupffer cell function, thereby providing early, accurate and reliable evidence of the aggressive biological
behaviors of HCC is most encouraging for clinicians and radiologists. Although liver imaging has obvious
advantages in identifying the poor prognosis of HCC, currently, there is no doubt that multidisciplinary