Beyond Surgical Margins: Fully Mature Tertiary Lymphoid Structures (fmTLSs) Are Predictive Biomarkers for Local Recurrence in Primary Soft-Tissue Sarcomas

Background: Soft-tissue sarcomas (STSs) are rare and heterogeneous malignancies with generally poor and unpredictable prognosis. Tertiary lymphoid structures (TLSs) have been identified as favorable prognostic indicators in several cancer types, yet their role in STS remains poorly defined. This study investigates the prognostic relevance of TLS presence, maturity, location and density in resected STSs. Methods: We retrospectively analyzed 219 cases of primary STS surgically resected at the Bergonié Institute (France) between 1990 and 2020. TLSs were assessed for presence, spatial distribution, semi-quantitative density and degree of maturity using CD20 and CD23 immunohistochemistry, categorizing tumors as fully mature TLS-positive (fmTLS+) or -negative (fmTLS−). RNA sequencing was performed on 126 formalin-fixed paraffin-embedded samples to characterize immune microenvironment profiles. Survival outcomes—including overall survival (OS), time to locoregional progression (TTLRP), and time to distant progression (TTDP)—were analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Results: The presence of fmTLS was significantly associated with improved 5-year OS (p = 0.012) and cause-specific survival (p = 0.006). Unexpectedly, fmTLS+ tumors showed a higher rate of local recurrence (22.9% vs. 8.1%, p = 0.002). On multivariate analysis, high-density fmTLS+ tumors conferred a 2.68-fold increased risk of locoregional progression (95% CI: 1.28–5.59, p = 0.009). Transcriptomic profiling confirmed a significant correlation between fmTLS+ status and a high-immune phenotype (Φ = 0.30, p < 0.001). Conclusions: STSs with fmTLS are associated with improved OS but increased risk of local recurrence. These findings support fmTLS as a dual prognostic biomarker and highlight the need for tailored surveillance and adjuvant strategies in fmTLS+ patients.