Background: Little is known about the difference in enhancement patterns of hepatocellular carcinoma (HCC) during multistep hepatocarcinogenesis between the post-vascular phase of Sonazoid-enhanced ultrasonography (SEUS) and hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine (Gd-EOB-DTPA)-enhanced MRI, as well as uptakes of Sonazoid and Gd-EOB-DTPA by HCC. Methods: Seventy patients with 73 histologically proven HCCs (33 hypovascular well-differentiated HCCs and 40 progressed HCCs) and 9 dysplastic nodules (DNs) were enrolled. Enhancement patterns of the lesions on the post-vascular phase of SEUS and hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI were evaluated. Uptakes of Sonazoid and Gd-EOB-DTPA were assessed by Sonazoid enhancement index and EOB enhancement ratio in relation to immunohistochemistry of CD68 and organic anion transporting polypeptide 8 (OATP8), respectively. Results: On the post-vascular phase of SEUS, none of the 9 DNs and 3 of 33 hypovascular well-differentiated HCCs (9 %) were hypoechoic, whereas 3 of 9 DNs (33 %) and 31 of 33 hypovascular well-differentiated HCCs (94 %) showed hypointensity on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. Of 31 progressed HCCs, 95 and 93 % were hypoechoic and hypointense on the post-vascular phase of SEUS and hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI, respectively. Sonazoid enhancement indexes decreased in progressed HCCs, correlating with lower Kupffer cell numbers (P < 0.001). EOB enhancement ratios decreased in hypovascular well-differentiated and progressed HCCs, as OATP8 expression declined (P < 0.001). Conclusions: In stepwise hepatocarcinogenesis, uptake of Sonazoid starts decreasing later than that of Gd-EOB-DTPA. Although signal reductions on the post-vascular phase of SEUS or hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI suggest HCC, hypoechoic appearance on the post-vascular phase of SEUS might be HCC-specific, particularly progressed HCC.
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