To determine the diagnostic accuracy of combining CEUS and CT/MRI LI-RADS major imaging features for the improved categorization of liver observations indeterminate on both CT/MRI and CEUS. A retrospective analysis using a database from a prospective study conducted at 11 centers in North America and Europe from 2018 to 2022 included a total of 109 participants at risk for HCC who had liver observations with indeterminate characterization (LR3, LR-4, and LR-M) on both CEUS and CT/MRI. The individual CEUS and CT/MRI LI-RADS major features were extracted from the original study and analyzed in various combinations. Reference standards included biopsy, explant histology, and follow-up CT/MRI. The diagnostic performance of the combinations of LI-RADS major features for definitive diagnosis of HCC was calculated. A reverse, stepwise logistical regression sub-analysis was also performed. This study included 114 observations indeterminate on both CT/MRI and CEUS. These observations were categorized as LR-3 (n = 37), LR-4 (n = 41), and LR-M (n = 36) on CT/MRI and LR-3 (n = 48), LR-4 (n = 36), LR-M (n = 29), and LR-TIV (n = 1) on CEUS. Of them, 43.0% (49/114) were confirmed as HCC, 37.3% (43/114) non-malignant, and 19.3% (22/114) non-hepatocellular malignancies. The highest diagnostic accuracy among the combinations of imaging features was achieved in CT/MRI LR-3 observations, where the combination of CEUS arterial phase hyper-enhancement (APHE) + CT/MRI APHE had 96.7% specificity, 75.0% positive predictive value (PPV), and 86.5% accuracy for HCC. The combination of LI-RADS major features on CT/MRI and CEUS showed higher specificity, PPV, and accuracy compared to individual modalities' assessments, particularly for CT/MRI LR-3 observations.
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