{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:26:16Z","timestamp":1792679176785,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Clear Cell Sarcoma (CCS) of soft tissue is a rare and highly malignant neoplasm primarily affecting young adults, often presenting in the deep soft tissues of the extremities. Despite morphological and immunophenotypic similarities to melanoma, CCS arises from connective tissues and is characterized by a distinct genetic hallmark: the EWSR1-ATF1 fusion resulting from t(12;22)(q13;q12) translocation. This genetic signature is absent in melanoma, making molecular diagnosis essential for accurate differentiation. Additionally, recent evidence highlights the utility of PRAME as an immunohistochemical marker to distinguish CCS from melanoma and other neoplasms. Clinically, CCS commonly involves tendons and aponeuroses, with metastatic potential leading to poor prognoses despite optimal local disease management. Histologically, CCS features lobular growth, spindle-to-epithelioid cells with clear cytoplasm, and low mitotic activity, often necessitating a multimodal diagnostic approach incorporating histopathology, immunohistochemistry, and molecular testing. Therapeutically, wide surgical excision remains the cornerstone for localized disease, with sentinel lymph node biopsy aiding in staging. Adjuvant radiotherapy is considered in select cases, while chemotherapy has limited efficacy in metastatic settings. Emerging treatments, including targeted therapies focusing on EWSR1-ATF1-driven pathways and immune checkpoint inhibitors, offer hope for improved outcomes. This review synthesizes current knowledge on CCS, emphasizing diagnostic challenges, the role of PRAME, and advancements in therapeutic strategies to enhance patient care.<\/jats:p>","DOI":"10.3390\/jcm14041233","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T05:10:22Z","timestamp":1739423422000},"page":"1233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Clear Cell Sarcoma (CCS) of the Soft Tissue: An Update Narrative Review with Emphasis on the Utility of PRAME in Differential Diagnosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0325-4316","authenticated-orcid":false,"given":"Gerardo","family":"Cazzato","sequence":"first","affiliation":[{"name":"Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-6350","authenticated-orcid":false,"given":"Francesco","family":"Piscazzi","sequence":"additional","affiliation":[{"name":"Dermatology Unit, IRCSS Humanitas Research Hospital, 20089 Rozzano, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4071-4898","authenticated-orcid":false,"given":"Alessandra","family":"Filosa","sequence":"additional","affiliation":[{"name":"Pathology Department, \u201cA. Murri\u201d Hospital-ASUR Marche, Aree Vaste n. 4 and 5, 63900 Fermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4676-0761","authenticated-orcid":false,"given":"Anna","family":"Colagrande","sequence":"additional","affiliation":[{"name":"Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-8014","authenticated-orcid":false,"given":"Paolo","family":"Del Fiore","sequence":"additional","affiliation":[{"name":"Soft Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5718-7003","authenticated-orcid":false,"given":"Francesca","family":"Ambrogio","sequence":"additional","affiliation":[{"name":"Section of Dermatology and Venereology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1773-3370","authenticated-orcid":false,"given":"Chiara","family":"Battilotti","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8656-2927","authenticated-orcid":false,"given":"Andrea","family":"Danese","sequence":"additional","affiliation":[{"name":"Section of Dermatology and Venerology, Department of Medicine, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Federico","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Department of Health Sciences, Magna Grecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5014-1122","authenticated-orcid":false,"given":"Fortunato","family":"Cassalia","sequence":"additional","affiliation":[{"name":"Dermatology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/PAT.0000000000000050","article-title":"WHO classification of soft tissue tumours: An update based on the 2013 (4th) edition","volume":"46","author":"Jo","year":"2014","journal-title":"Pathology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1002\/1097-0142(196509)18:9<1163::AID-CNCR2820180916>3.0.CO;2-0","article-title":"Clear-cell sarcoma of tendons and aponeuroses. 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