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Zhang et al. Hepatoma Res 2020;6:30 I http://dx.doi.org/10.20517/2394-5079.2020.17 Page 7 of 16

(Gd-EOB-DTPA) have been produced and used in HCC diagnosis and characterization. However, SPION-
enhanced MRI has lower sensitivity than Gd-EOB-DTPA-enhanced MRI, especially for early HCCs without
early enhancement; thus, SPION-enhanced MRI is rarely used as the contrast agent of choice in Western
countries. However, SPION-enhanced MRI is still used in the East as a means of evaluating treatment
[44]
response in HCC .

Decreased expression levels of OATP during multi-step hepatocarcinogenesis are inversely correlated with
HCC tumor grade and aggressiveness [45,46] . However, some well-differentiated HCCs and approximately
5%-12% of moderately differentiated HCCs overexpress OATP8, which is thought to be associated with a
[45]
genetic alteration or of a different cellular origin . A consensus report has been reached on the application
and prospects of developing Gd-EOB-DTPA enhanced MRI for the early diagnosis, follow-up and outcome
[47]
monitoring of HCC patients . The report indicated that hypervascularity on the arterial phase and the low
signal on HBP images of Gd-EOB-DTPA-enhanced MRI is more sensitive to the diagnosis of HCC when
compared with CT. Moreover, HBP imaging provides critical information during the follow-up of cirrhosis-
related nodules, especially for those with a diameter less than 2 cm, for predicting the histological grade of
the tumor [46,48] . The above research suggests that functional MRI technologies, especially the HBP scan of
Gd-EOB-DTPA-enhanced-MRI, will gradually become an essential means for predicting the differentiation
of tumors and precise characterization of HCC.

FDG CONCENTRATION
The upregulation of glycogen metabolism is a prominent feature of tumor cells and it promotes survival,
[49]
proliferation, and resistance to antitumor therapy . Previous studies have identified that aberrant tumor cell
metabolism was associated with the expression of genes encoding enzymes leading to glycogen metabolic
[50]
reprogramming and promoting HCC progression .
18
Uptake of fluorine-18 FDG ( F-FDG) based on increased glucose metabolism in tumor cells is considered
[51]
as a sensitive indicator of tumor viability . PET imaging provides the metabolic status of tumor tissues
18
with high sensitivity and specificity. Therefore, F-FDG/PET, as a product of the combination of the above
two mechanisms, is often used as an effective means for tumor characterization and evaluation of tumor

response. Standardized uptake value, a semi-quantitative index of FDG/PET, is reported to be related to
HCC-histological grade and poor prognosis of patients, with poorly differentiated or high-grade tumors
[52]
showing higher intensities on FDG-PET . Moreover, the advent of novel radiopharmaceuticals recently
11
such as C-choline has improved the diagnostic performance of HCC characterization and tumor grade
[53]
assessment .
In comparison with PET/CT, PET/MRI shows a higher sensitivity for displaying composition and structure
of tissues. PET/MRI in combination with DWI has an advantage in the differentiation of tumor tissue from
[54]
non-tumor liver parenchyma, and is also helpful for understanding tumor characteristics . However,
FDG-PET/MRI is mostly limited to the diagnosis of HCC and research on the value of FDG-PET MRI in
predicting poor differentiation and prognosis of HCC is still lacking.

MVI
MVI is typically correlated with aggressive biological behaviors of HCC, and is generally considered as a
[55]
risk factor for early recurrence of HCC in patients . Tumor characteristics, such as a larger diameter and
tumor size, multiple lesions, incomplete capsule, and an irregular tumor margin, can be used as biomarkers
in predicting the presence of MVI [56,57] . Moreover, significantly increased serum levels of parameters such as
α-fetoprotein, PIVKA-II, and cytokines (e.g., interleukin-35, phospho-beta1 integrin, transforming growth
factor-beta1, p-Smad-2, and E-cadherin) suggest the possibility of MVI [58-61] .