Peritumoral stiffness as a novel noninvasive biomarker: Predicting TACE response in intermediate-stage hepatocellular carcinoma via 2D-shear wave elastography.

4143 Background: Intermediate-stage hepatocellular carcinoma (HCC) demonstrates considerable biological and clinical heterogeneity, making it challenging to predict treatment response to transcatheter arterial chemoembolization (TACE). This multicenter retrospective study evaluated the association between preoperative tissue stiffness measurements obtained by 2D-shear wave elastography (2D-SWE) and TACE outcomes in intermediate-stage HCC, aiming to identify an optimal peritumoral stiffness cutoff value for prognostic stratification and clinical decision-making. Methods: A total of 115 patients with intermediate-stage HCC were enrolled. Preoperative 2D-SWE was performed to measure stiffness of the tumor (TSWE), peritumoral tissue (PSWE), and background liver parenchyma (LSWE). Cox proportional hazards regression and Kaplan-Meier analyses were conducted to determine whether 2D-SWE-derived stiffness parameters independently predicted TACE efficacy. Immunohistochemical staining, immunofluorescence, and RNA sequencing were performed to characterize the biological features of peritumoral tissue associated with varying PSWE values. Results: Mean stiffness values demonstrated a progressive gradient from liver parenchyma (LSWE: 13.0 kPa) through peritumoral tissue (PSWE: 18.9 kPa) to tumor tissue (TSWE: 25.6 kPa). Univariate and multivariate analyses identified primary tumor size and PSWE as independent prognostic factors for both overall survival (OS) and time to progression (TTP). A PSWE cutoff of 19.04 kPa achieved the highest discriminatory performance for predicting objective response rate (ORR) and disease control rate (DCR) (AUROC = 0.691 and 0.695, respectively). Patients with low PSWE demonstrated significantly superior OS (26.0 vs 17.5 months, P = 0.008) and TTP (11.6 vs 9.5 months, P = 0.026) compared to those with high PSWE. RNA sequencing revealed 778 differentially expressed genes enriched in angiogenesis and fibrosis-related pathways. Notably, patients with elevated PSWE exhibited enhanced stromal activation and angiogenesis in peritumoral regions, including increased collagen deposition, α-SMA, COL-I, VEGF expression, and CD31+ microvessel density, correlating with inferior TACE response. Conclusions: Preoperative peritumoral stiffness measured by 2D-SWE serves as a promising noninvasive prognostic biomarker for intermediate-stage HCC patients undergoing TACE, offering valuable insights for personalized treatment stratification.