Molecular diagnostics and targeted therapeutic strategies in epithelioid sarcoma: A scoping review

Background Epithelioid sarcoma (ES) is a malignant soft-tissue neoplasm with a low incidence, aggressive behaviour, epithelioid morphology, and a high risk of local recurrence and metastasis. Recognition of SMARCB1/INI1 deletion and resultant SWI/SNF complex dysfunction has reshaped its diagnosis and enabled targeted therapy. Objectives This scoping review aimed to map the literature on molecular diagnostic approaches and systemic therapeutic strategies in epithelioid sarcoma, with emphasis on translational relevance, clinical outcomes, and evidence gaps. Methods A scoping review was conducted in accordance with PRISMA-ScR guidelines. PubMed/MEDLINE, Web of Science, and Embase were searched for studies published between January 2010 and June 2026. After de-duplication, two reviewers screened titles and abstracts, and full texts were assessed against predefined eligibility criteria (≥3 ES patients). Data were synthesized narratively. Results Twenty-three studies (published 2011–2026; 8 to 1,123 ES patients each) met the inclusion criteria. Loss of SMARCB1/INI1 expression was the consistent diagnostic finding, reported by immunohistochemistry in the large majority of classic and proximal ES (e.g., 19/21 [90%] and 47/54 [87%] in the largest series) and confirmed genetically by homozygous SMARCB1 deletion (36/40 by FISH). Multi-omics analyses established that classic and proximal ES are distinct molecular and immunologic entities. Conventional chemotherapy produced low objective response rates (first-line real-world rwORR 15%; median OS 15.2 months). The EZH2 inhibitor tazemetostat achieved an objective response in 15% (9/62) of patients with a median OS of 19 months. Conclusions Molecular diagnostics, centred on SMARCB1/INI1 loss, have reshaped the classification of epithelioid sarcoma, and EZH2 inhibition provides the first biologically targeted option for SMARCB1-deficient disease; however, response rates remain modest and the overall evidence base is limited and heterogeneous. Future advances will require biomarker development, innovative trial designs, and international collaboration to improve outcomes in this ultra-rare malignancy.