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Zhang et al. Hepatoma Res 2020;6:30 I http://dx.doi.org/10.20517/2394-5079.2020.17 Page 5 of 16

histological grades of HCC, and the values of K and V have proved to be significantly related to the tumor
ep
e
microvascular density. There is no difference among these DCE-MRI deprived parameters for discriminating
low- from high-grade HCC in terms of their performance. This means that DCE-MRI using gadoxetic acid
[23]
has great potential for the qualitative assessment of tumor neoangiogenesis and aggressiveness of HCC .
RESTRICTED DIFFUSION MOVEMENT OF WATER MOLECULES WITHIN TUMOR CELLS
HCC is easier to recognize pathologically because of its distinctive cytological atypia and architectural
[24]
abnormalities compared with other cirrhotic nodules . The early HCC nodule is well differentiated with an
indistinct appearance, while HCC nodules that have progressed are mostly moderately differentiated with a
distinct pattern and often, with a more disordered cellular structure [25,26] .

DWI is a noninvasive technique for visualizing the 3D microscopic movement of water molecules within
cells to provide information regarding physiological tissue characteristics. HCC and other cancers usually
possess higher cellularity, tissue disorganization, and less extracellular space, resulting in impedance of
water diffusion; therefore, DWI shows a high-intensity signal [27,28] . In the past few years, many studies have
investigated the apparent diffusion coefficient (ADC) value of DWI in predicting the differentiation of
HCC [29-31] . The conclusions however, were not consistent. This might be due to the fact that DWI cannot
simply reflect the diffusion of water molecules in living tissues and capillary perfusion affects the stability of
DWI performance as well.

Intravoxel incoherent motion (IVIM), as a DWI-derived novel technique, enables monitoring of tissue
[32]
diffusivity and microcapillary perfusion independently . IVIM-derived parameters such as perfusion
fraction (fp) and diffusion coefficient (D) combined with ADC of DWI, are reported to correlate with
2
[33]
-3
HCC histological grade [33-35] . In the study by Granata et al. , ADC (2.11 × 10 mm /s), fp (47.33%) and D
(0.94 × 10 mm /s) values were considered as the optimal cut-off points in distinguishing high- from low-
-3
2
grade HCCs. However, the study only included Edmondson-Steiner grade 1 to 3 HCC nodules and did not
include Edmondson-Steiner grade 4 HCC, which made identification of high-grade HCCs non specific.
[34]
Woo et al. , explored the relationship of ADC and D values with the histological grade of HCC. The results
showed that there was a significant negative correlation between ADC and D values with the histologic grade
of HCC. Moreover, the D value had better diagnostic performance than the ADC value for differentiating
[35]
low- and high-grade HCC. Similar results were reported by Sokmen et al. , Therefore, both studies
improved the design of the experiments, and further confirmed the results on the basis of the findings by
[33]
Granata et al. , which indicated that the combination of DWI and IVIM could be used to determine the
degree of HCC differentiation rather than using DWI alone. However, due to defects in the study design (i.e.,
retrospective study), insufficient sample size and an unclear gold standard, further prospective studies are
needed.

Diffusion kurtosis imaging (DKI) is an attempt to provide a more accurate model of diffusion, and to reflect
[36]
tissue heterogeneity in non-Gaussian diffusion behavior . Recently, our team validated the performance of
[37]
DKI in predicting the degree of differentiation of HCC . The results showed that mean apparent kurtosis
coefficient (MK) and ADC values are significantly correlated with the grade of HCC [Figure 1]. In addition,
the MK value represents a higher specificity than the ADC in differentiating high-grade from low-grade
HCCs. We speculated that this might be due to the fact that increased tumor cellularity results in decreased
extracellular space and the restricted diffusion of water molecules, which is visually presented as decreased
ADC and MD in higher-grade HCC. Furthermore, a higher MK value may be an independent risk factor for
early tumor recurrence and poor prognosis in HCC patients, which might be related to the higher-grade of
HCC that often tend to be more proliferative, aggressive and heterogeneous, and result in a more irregular
[38]
tumor microstructure .