Rethinking the Prognostic Role of Necrosis in Soft-Tissue Sarcoma: Multidisciplinary Insights from the Sarcoma Academy

<b>Background:</b> Soft-tissue sarcomas (STSs) represent a heterogeneous group of malignancies with widely varying treatment responses and biological behaviors. While spontaneous necrosis (present at diagnosis) is recognized in established sarcoma grading systems, the prognostic significance of therapy-induced necrosis remains uncertain. Inconsistent definitions, methodological variability, and clinical confounders further complicate the interpretation of necrosis as an independent prognostic marker. <b>Methods:</b> This communication synthesizes findings from an international, multidisciplinary webinar hosted by the Sarcoma Academy, critically assessing the utility of therapy-induced necrosis in STS management. Discussions encompassed surgical, pathological, oncological, and radiological perspectives, emphasizing how necrosis is defined, measured, and contextualized in patient care. <b>Results:</b> Heterogeneity in STS subtypes, varied treatment protocols, and sampling inconsistencies challenge the prognostic value of post-treatment necrosis. While substantial necrosis may sometimes signal effective therapy, it can also reflect the tumor's aggressive nature. The panel underscored the utility of measuring the percentage of viable tumor cells, rather than necrosis alone, to obtain a more standardized and reproducible measure of therapy response. Emerging approaches-such as radiomics, molecular profiling, immune-based analyses, and real-world evidence (RWE) protocols-offer promising avenues for refining prognostication and guiding personalized therapy in STS. <b>Conclusions:</b> A focus solely on therapy-induced necrosis is insufficient to predict outcomes in STS. Instead, a multidisciplinary framework-combining standardized pathology protocols, quantification of viable tumor cells, advanced imaging, and innovative clinical trial designs-can better capture both treatment effects and underlying tumor biology. Future collaborative studies and hybrid trial methodologies are needed to determine which STS subgroups gain the most from intensified treatments aimed at maximizing necrosis, and how to balance such interventions with surgical considerations, toxicity, and overall patient well-being.