Kupffer phase echo level ratio in contrast-enhanced ultrasound for differentiating malignant liver tumors

Kupffer phase contrast-enhanced ultrasound (CEUS) using Sonazoid allows real-time assessment of Kupffer cell function, which is often disrupted in malignant liver tumors. While qualitative assessment is established, quantitative studies remain limited. This study aimed to evaluate the diagnostic value of the echo level ratio (ELR) derived from the Kupffer phase for differentiating hepatocellular carcinoma (HCC) from non-HCC liver malignancies.

This retrospective study included 221 patients with pathologically confirmed malignant liver tumors who underwent CEUS between September 2023 and January 2025. CEUS was performed using Sonazoid with both vascular and Kupffer phase imaging. Time-intensity curve (TIC) analysis was used to derive vascular phase parameters [peak intensity (PI), time to peak (TTP), wash-in area under the curve (WiAUC), wash-out area under the curve (WoAUC), and wash-in and wash-out area under the curve (WiWoAUC)], and ELR was calculated as the mean intensity of the lesion divided by that of the adjacent liver parenchyma during the Kupffer phase. Diagnostic performance was assessed using receiver operating characteristic analysis. Inter- and intra-observer agreement was evaluated using intraclass correlation coefficients (ICCs).

Of the 221 included patients, 97 had HCC and 124 had non-HCC tumors (49 intrahepatic cholangiocarcinoma, 75 metastases). ELR was significantly lower in the HCC group than in the non-HCC group [1.20 (1.12, 1.26) vs. 1.31 (1.21, 1.41), P<0.001]. Among vascular phase parameters, PI, WoAUC, and WiWoAUC were higher in HCCs (P<0.001). The ELR achieved the highest diagnostic performance among individual parameters [area under the curve (AUC) =0.741], and combined analysis of ELR with vascular-phase parameters further improved diagnostic accuracy (AUC =0.849). All quantitative parameters showed excellent intra- and inter-observer reproducibility (ICC =0.868-0.984).

Kupffer phase quantification using the ELR provides a reproducible parameter for distinguishing HCC from other malignant liver tumors. Although sensitivity is modest, ELR offers high specificity, and its combination with vascular phase CEUS parameters significantly improves overall diagnostic accuracy. This supports the integration of ELR into CEUS workflows for more confident noninvasive liver tumor characterization.