Prognostic Significance of Skp2 Expression and Therapeutic Interventions in Synovial Sarcoma

Background Synovial sarcoma (SS) is a highly aggressive soft tissue malignancy predominantly affecting young adults, characterized by poor prognosis in advanced stages. S-phase kinase-associated protein 2 (Skp2), an F-box protein implicated in tumor progression, has emerged as a significant prognostic biomarker in various cancers; however, its clinical relevance in SS remains poorly defined. This study aimed to investigate the prognostic significance of Skp2 expression in SS and explore its potential as a therapeutic target. Methods We retrospectively analyzed clinicopathological data from 49 patients with histologically confirmed SS who underwent surgical resection. Skp2 expression was evaluated by immunohistochemistry, with expression levels classified as high (>5%) or low (≤ 5). Kaplan-Meier analyses, univariate and multivariate Cox regression models, and restricted cubic spline (RCS) analysis were utilized to assess the relationship between Skp2 expression and clinical outcomes, including overall survival (OS) and progression-free survival (PFS). Results The median follow-up duration was 54 months (range, 6–123 months). Patients with high Skp2 expression exhibited significantly poorer 5-year OS and PFS compared to patients with low expression (OS: 43.2% vs 84.8%, P  = 0.003; PFS: 42.5% vs 63.9%, P  = 0.15). Multivariate analyses confirmed high Skp2 expression (OS: adjusted Hazard Ratio (HR) = 7.63, P = 0.005; PFS: adjusted HR = 9.7, P < 0.001), large tumor diameter (≥ 8.4 cm; OS: HR = 9.49, P = 0.003; PFS: HR = 6.04, P = 0.004), marginal surgical resection (HR = 0.08, P = 0.002), and distant metastasis (HR = 23.83, P < 0.001) as independent adverse prognostic factors. RCS analysis revealed a nonlinear, positive correlation between Skp2 expression levels and mortality risk, supporting the clinical relevance of the established cut-off value (5%). Conclusions Elevated Skp2 expression is an independent predictor of unfavorable prognosis in patients with SS, associated with increased tumor aggressiveness and metastatic potential. These findings highlight Skp2 as a promising prognostic biomarker and potential therapeutic target, underscoring the need for further prospective studies to validate these results and evaluate Skp2-targeted treatment strategies.