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Tamai. Hepatoma Res 2018;4:75 I http://dx.doi.org/10.20517/2394-5079.2018.98 Page 3 of 11

made by the accumulation for each MFI sequence using CEUS with perflubutane microbubbles (Sonazoid®;
Daiichi-Sankyo, Tokyo, Japan). They classified HCCs into four grades: grade 1 (iso-fine/vascular), grade 2
(hypo-fine), grade 3 (hypovascular), and grade 4 (hypo-irregular). When HCC was assessed as grade 4, sen-
sitivity, specificity, positive PPV, NPV, and accuracy of the diagnosis for poorly differentiated HCC are 100%,
91%, 50%, 100%, and 92% respectively, and those of the diagnosis for MVI are 40%, 92%, 67%, 80%, and 78%
respectively.

The correlation between histologic grading and tumor enhancement washout time on CEUS has also been
[14]
reported [13-17] . For example, Xu et al. analyzed the enhancement pattern of HCC using time-intensity
curve. They observed that the time to peak, contrast-enhanced time, and wash-out time of well differentiated
HCCs were longer than those of the moderately to poorly differentiated HCCs, whereas the enhancement
slope and clearance slope of the well differentiated lesions were lower than those of the moderately to poorly
[15]
differentiated lesions. However, Pei et al. reported that washout time is the only significant factor (among
all the time-intensity curve parameters) correlated to histologic grading. Washout time in the well-, moderately-, and
[17]
poorly differentiated HCCs was 36.66 ± 9.61, 19.37 ± 2.83, and 11.61 ± 2.78 s, respectively. Feng et al. re-
ported using the washout rate to predict HCC differentiation. They demonstrated that when the cutoff point
was set at washout before 40 s from contrast injection, the ability to distinguish poorly differentiated from
moderately- and well differentiated HCCs could be performed with a sensitivity, specificity, and area under
the curve (AUC) of 24%, 97%, and 0.68, respectively.

Additionally, several reports have demonstrated the correlation between macroscopic HCC type and Kupffer
[18]
imaging (post vascular phase) using Sonazoid CEUS. Hatanaka et al. reported that the sensitivity, specificity,
PPV, NPV, and accuracy of CEUS for predicting for the non-SN type were 80%, 96%, 92%, 89% and 90%, respec-
[19]
tively. Tada et al. also reported that those in small HCCs (3 cm or less) were 87%, 93%, 91%, 84% and 94%, re-
[20]
spectively. Furthermore, Hatanaka et al. demonstrated that CEUS was more accurate at distinguishing mac-
roscopic type than contrast CT. This could be explained by the difficulty in evaluating the shapes of nodules
[21]
on contrast CT because of the partial volume effect. Nuta et al. also indicated that HCCs with an irregular
defect visualized during Kupffer-phase of CEUS were characterized by more frequent MVI and intrahepatic
metastasis. They demonstrated that Kupffer-phase images were more accurate at predicting the macroscopic
pathologic type with high grade malignancy (SNEG or CMN type) than conventional B mode (CEUS AUC
0.89 vs. B-mode US AUC 0.78), and diagnostic accuracy was also significantly higher with Kupffer-phase imag-
ing (92%) than with conventional B-mode imaging (74%). The sensitivity, specificity, PPV, NPV, and accuracy of
US studies cited in this review were summarized in Table 1 except for not available reports.

PREDICTION OF MVI USING CONTRAST CT
Contrast multi-detector low CT is commonly used for the definite diagnostic imaging of HCC. The diagnos-
tic information obtained by contrast CT is tumor vascularity and morphology. There are some reports about the
[22]
correlation between histologic differentiation and tumor vascularity. For example, Asayama et al. indicated
that the arterial blood supply decreases significantly in poorly differentiated HCCs compared to moderately
[23]
differentiated HCCs. Sanada et al. demonstrated that small HCCs intermingled with hypovascular areas
and hypervascular areas in the arterial phase of contrast CT included poorly differentiated HCC compo-
[24]
nents. Kawamura et al. also reported that heterogeneous enhancement with irregular ring-like structures
in the arterial phase was a significant independent predictor of poorly differentiated HCC. On the other
[25]
hand, fast tumor enhancement washout is also associated with poorly differentiated HCC. Nishie et al.
indicated that poorly differentiated HCCs show faster tumor enhancement washout on contrast CT than
[26]
non-poorly differentiated HCCs. However, Nakachi et al. demonstrated that the diagnostic accuracy for
poorly differentiated HCC using tumor enhancement washout in the venous phase was low compared with
heterogenous tumor enhancement in the arterial phase. They showed that sensitivity, specificity, PPV, NPV,
and accuracy for predicting poor differentiation in small HCCs (up to 3 cm in diameter) by heterogenous