Fluctuational Imaging for the Diagnosis of Hepatic Hemangioma: A Multicenter, Prospective Study

\[Background and Rationale\] Hepatic hemangioma is the most common benign tumor of the liver, with a reported prevalence of up to 20% in the general population. On B-mode ultrasonography, a typical hemangioma appears as a well-defined hyperechoic lesion compared with the surrounding liver parenchyma. However, hyperechogenicity is observed in only approximately 70% of cases, while the remaining lesions may appear hypoechoic or mixed echogenic. Additional sonographic features such as posterior acoustic enhancement or an echogenic rim may aid diagnosis, but none are specific to hemangioma. Consequently, contrast-enhanced CT or MRI is commonly required for definitive diagnosis, even when a hemangioma is strongly suspected on conventional ultrasound. In 2020, Kobayashi et al. (Ultrasound Med Biol 2021;47:941-946)reported a novel ultrasound finding termed the "fluttering sign," defined as continuous motion of tiny hyperechoic dots within a hemangioma during real-time scanning. Although the precise mechanism has not been experimentally validated, this phenomenon is presumed to reflect motion of acoustic scatterers, mainly red blood cells, induced by the ultrasound beam. The fluttering sign was observed in approximately 39% of hyperechoic hemangiomas and in up to 85% of hypoechoic or mixed-echoic hemangiomas, suggesting potential lesion specificity. A major limitation of the fluttering sign is its subjectivity, as visual assessment during real-time ultrasound is highly operator-dependent. To address this limitation, Imamura et al. (Sci Rep 2022;12:4701) developed a computer-based algorithm named Fluctuational Imaging (FLI), which objectively quantifies fluttering motion. FLI demonstrated almost perfect agreement with visual assessment of the fluttering sign (Cohen's kappa = 0.95). \[Study Objectives\] Although FLI is theoretically expected to be specific to hemangiomas, no study has systematically evaluated its behavior across a broad spectrum of non-hemangioma hepatic lesions. The primary objective of this study is to investigate whether the proportion of FLI-positive findings is significantly higher in hepatic hemangiomas than in non-hemangioma liver lesions. \[Risk-Benefit Assessment\] FLI is based on conventional diagnostic ultrasound physics and does not impose additional risk to patients. If FLI enables confident diagnosis of hepatic hemangioma using ultrasound alone, it may reduce unnecessary contrast-enhanced CT or MRI examinations, thereby decreasing healthcare costs, radiation exposure, and contrast-related risks. Overall, the anticipated benefits outweigh potential risks.

\[Study Population and Sample Size\] This is an exploratory, prospective, multicenter study. A predefined sample size is not required. With an estimated enrollment of approximately 100 cases per institution over one year and participation of four institutions, approximately 400 cases are expected. \[Eligibility Criteria\] Eligible participants are adults aged 19 years or older with a focal hepatic lesion ≥1 cm that has been definitively diagnosed or is expected to be diagnosed within one month after FLI examination, and who provide informed consent. Patients unable to hold their breath for at least 5 seconds, those with inadequate B-mode image quality, lesions \<1 cm on ultrasound, or without definitive diagnosis within one month are excluded. \[Reference Standard\] The reference standard for lesion diagnosis was defined as follows: hepatic hemangiomas were confirmed by histopathology or by typical imaging features with size stability for at least two years; hepatocellular carcinoma was confirmed by histopathology or by the presence of an LR-5 lesion in patients with liver cirrhosis; all other hepatic lesions (including metastasis, cholangiocarcinoma, adenoma, focal nodular hyperplasia, and angiomyolipoma) required histopathological confirmation. \[Study Design and Statistical Analysis\] After informed consent, FLI is performed on the target lesion. FLI maps are anonymized and independently reviewed by four readers, each classifying findings as positive or negative. The primary endpoint is comparison of FLI-positive proportions between hemangioma and non-hemangioma groups using chi-square or Fisher's exact tests. Interreader agreement will be evaluated using Fleiss' kappa. The secondary endpoint of this study is to explore how the diagnostic performance of FLI for hepatic hemangioma varies according to lesion echogenicity and lesion depth. Continuous variables will be analyzed using Student's t-test or Mann-Whitney U test, as appropriate. A p-value \< 0.05 will be considered statistically significant.