{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:10:10Z","timestamp":1788527410846,"version":"build-2803163510"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Soft tissue sarcomas account for approximately 10% of all cancers in the pediatric population, with undifferentiated round cell sarcomas-historically referred to as Ewing-like sarcomas-forming a notable subset. Recent molecular profiling has reclassified these tumors into distinct subtypes, including CIC::DUX4-rearranged sarcomas. While CIC::DUX4 sarcomas are more commonly found in adults, they are rarer in children and are typically located in deep soft tissues. The current study focuses on pediatric cases of superficially located CIC::DUX4 sarcomas, aiming to describe their clinical, morphological, and molecular features. This retrospective study includes pediatric patients diagnosed with superficial CIC::DUX4-rearranged sarcoma from January 2018 to December 2024. Relevant clinical data, including patient demographics, tumor location, and follow-up outcomes, were extracted from medical records. Tumor samples were examined histologically, and RNA sequencing was performed to confirm the presence of the CIC::DUX4 fusion. For survival analysis, we compared our series with 27 pediatric deep-seated CIC::DUX4 sarcomas. Five cases of superficial CIC::DUX4 sarcoma were identified. The patients ranged from 4 to 18\u00a0years old, with a mean age of 10.6\u00a0years. Only one patient presented with pulmonary metastases at diagnosis. All patients underwent excisional biopsies. Follow-up revealed complete remission in all cases and a statistically significant difference in OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.00256) and DFS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0239) compared to deep-seated CIC::DUX4 sarcoma. This study presents the first pediatric case series of superficial CIC::DUX4 sarcomas. While CIC::DUX4 sarcomas in adults are known for their aggressive behavior, our findings suggest that superficial tumors with well-defined margins in children may have a more favorable prognosis. These results highlight the need for further research into the biological behavior and long-term outcomes of these rare pediatric tumors.\n                  <\/jats:p>","DOI":"10.1007\/s00428-025-04231-1","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T01:57:31Z","timestamp":1759802251000},"page":"887-896","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Superficially located CIC::DUX4-rearranged sarcomas in children: insights from a long-term survival case series"],"prefix":"10.1007","volume":"488","author":[{"given":"Gina","family":"Del Vecchio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Alaggio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Stracuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Gaggero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Giovannoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Barresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Arienzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Maria","family":"Milano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Di Prete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Cota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Cesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Orbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Arciuolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"issue":"4","key":"4231_CR1","doi-asserted-by":"publisher","first-page":"e945","DOI":"10.1542\/peds.2013-3926","volume":"134","author":"DA Siegel","year":"2014","unstructured":"Siegel DA, King J, Tai E, Buchanan N, Ajani UA, Li J (2014) Cancer incidence rates and trends among children and adolescents in the United States, 2001\u20132009. Pediatrics 134(4):e945\u2013e955. https:\/\/doi.org\/10.1542\/peds.2013-3926","journal-title":"Pediatrics"},{"key":"4231_CR2","unstructured":"WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours (2020) Lyon (France): International Agency for Research on Cancer; (WHO classification of tumours series, 5th ed.; vol. 3). https:\/\/publications.iarc.fr\/588"},{"issue":"13","key":"4231_CR3","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1093\/hmg\/ddl136","volume":"15","author":"M Kawamura-Saito","year":"2006","unstructured":"Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, Gotoh T, Motoi T, Fukayama M, Aburatani H, Takizawa T, Nakamura T (2006) Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 15(13):2125\u20132137. https:\/\/doi.org\/10.1093\/hmg\/ddl136","journal-title":"Hum Mol Genet"},{"issue":"13","key":"4231_CR4","doi-asserted-by":"publisher","first-page":"14346","DOI":"10.1002\/cam4.6113","volume":"12","author":"M Sparber-Sauer","year":"2023","unstructured":"Sparber-Sauer M, Corradini N, Affinita MC, Milano GM, Pierron G, Carton M, Tirode F, Pissaloux D, Alaggio R, Vokuhl C, Bisogno G, Berlanga P, Ferrari A, Orbach D (2023) Clinical characteristics and outcomes for children, adolescents and young adults with \u201cCIC-fused\u201d or \u201cBCOR-rearranged\u201d soft tissue sarcomas: a multi-institutional European retrospective analysis. Cancer Med 12(13):14346\u201314359. https:\/\/doi.org\/10.1002\/cam4.6113","journal-title":"Cancer Med"},{"key":"4231_CR5","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ejca.2023.01.003","volume":"183","author":"E Palmerini","year":"2023","unstructured":"Palmerini E, Gambarotti M, Italiano A, Nathenson MJ, Ratan R, Dileo P, Provenzano S, Jones RL, DuBois SG, Martin-Broto J, de Alava E, Baldi GG, Grignani G, Ferraresi V, Brunello A, Paoluzzi L, Bertulli R, Hindi N, Montemurro M, Rothermundt C, Cocchi S, Salguero-Aranda C, Donati D, Martin JD, Abdelhamid Ahmed AH, Mazzocca A, Carretta E, Cesari M, Pierini M, Righi A, Sbaraglia M, Laginestra MA, Scotlandi K, Dei Tos AP, Ibrahim T, Stacchiotti S, Vincenzi B (2023) A global collaborative study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl). Eur J Cancer 183:11\u201323. https:\/\/doi.org\/10.1016\/j.ejca.2023.01.003","journal-title":"Eur J Cancer"},{"issue":"2","key":"4231_CR6","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/cup.14748","volume":"52","author":"DF Faden","year":"2025","unstructured":"Faden DF, Rodriguez O, Abdelmalek M, Kovarik C (2025) CIC-DUX4 sarcoma of the skin: a rare case report and literature review. J Cutan Pathol 52(2):92\u201398. https:\/\/doi.org\/10.1111\/cup.14748","journal-title":"J Cutan Pathol"},{"issue":"6","key":"4231_CR7","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1111\/cup.13639","volume":"47","author":"N Maloney","year":"2020","unstructured":"Maloney N, Smith SM, Peters SB, Batistatou A, Evangelou Z, Harms PW, Chan MP, Antonescu CR, Linos K (2020) Expanding the differential of superficial tumors with round-cell morphology: report of three cases of CIC-rearranged sarcoma, a potentially under-recognized entity. J Cutan Pathol 47(6):535\u2013540. https:\/\/doi.org\/10.1111\/cup.13639","journal-title":"J Cutan Pathol"},{"issue":"2","key":"4231_CR8","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.pathol.2019.09.015","volume":"52","author":"I Br\u010di\u0107","year":"2020","unstructured":"Br\u010di\u0107 I, Brodowicz T, Cerroni L, Kashofer K, Serbanescu GL, Kasseroler MT, Amann G, Scheipl S, Szkandera J, Leithner A, Liegl-Atzwanger B (2020) Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. Pathology 52(2):236\u2013242. https:\/\/doi.org\/10.1016\/j.pathol.2019.09.015","journal-title":"Pathology"},{"issue":"6","key":"4231_CR9","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1111\/cup.13656","volume":"47","author":"JS Ko","year":"2020","unstructured":"Ko JS, Marusic Z, Azzato EM, Farkas DH, Van Arnam J, Seiwerth S, Fritchie K, Patel RM, Rubin BP, Billings SD (2020) Superficial sarcomas with CIC rearrangement are aggressive neoplasms: a series of eight cases. J Cutan Pathol 47(6):509\u2013516. https:\/\/doi.org\/10.1111\/cup.13656","journal-title":"J Cutan Pathol"},{"issue":"12","key":"4231_CR10","doi-asserted-by":"publisher","first-page":"e594","DOI":"10.1111\/1346-8138.16157","volume":"48","author":"E Maejima","year":"2021","unstructured":"Maejima E, Mitsui H, Ohnuma T, Oishi N, Odate T, Deguchi N, Inozume T, Ogawa Y, Shimada S, Kondo T, Kawamura T (2021) Case of CIC-DUX4 sarcoma of the skin: histological simulant of epithelioid angiosarcoma. J Dermatol 48(12):e594\u2013e595. https:\/\/doi.org\/10.1111\/1346-8138.16157","journal-title":"J Dermatol"},{"issue":"1","key":"4231_CR11","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/modpathol.2008.156","volume":"22","author":"MJ Terrier-Lacombe","year":"2009","unstructured":"Terrier-Lacombe MJ, Guillou L, Chibon F, Gallagher G, Benhattar J, Terrier P, Ranch\u00e8re D, Coindre JM (2009) Superficial primitive Ewing\u2019s sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22(1):87\u201394. https:\/\/doi.org\/10.1038\/modpathol.2008.156","journal-title":"Mod Pathol"},{"issue":"3","key":"4231_CR12","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1101\/gr.257246.119","volume":"31","author":"S Uhrig","year":"2021","unstructured":"Uhrig S, Ellermann J, Walther T, Burkhardt P, Fr\u00f6hlich M, Hutter B, Toprak UH, Neumann O, Stenzinger A, Scholl C, Fr\u00f6hling S, Brors B (2021) Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res 31(3):448\u2013460. https:\/\/doi.org\/10.1101\/gr.257246.119","journal-title":"Genome Res"},{"issue":"1","key":"4231_CR13","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.path.2023.06.003","volume":"17","author":"N Makise","year":"2024","unstructured":"Makise N, Yoshida A (2024) CIC-Rearranged sarcoma. Surg Pathol Clin 17(1):141\u2013151. https:\/\/doi.org\/10.1016\/j.path.2023.06.003","journal-title":"Surg Pathol Clin"},{"issue":"1","key":"4231_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cancergencyto.2009.06.015","volume":"195","author":"M Yoshimoto","year":"2009","unstructured":"Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR (2009) Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC-DUX4 fusion gene event. Cancer Genet Cytogenet 195(1):1\u201311. https:\/\/doi.org\/10.1016\/j.cancergencyto.2009.06.015","journal-title":"Cancer Genet Cytogenet"},{"issue":"7","key":"4231_CR15","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1097\/PAS.0000000000000846","volume":"41","author":"CR Antonescu","year":"2017","unstructured":"Antonescu CR, Owosho AA, Zhang L, Chen S, Deniz K, Huryn JM, Kao YC, Huang SC, Singer S, Tap W, Schaefer IM, Fletcher CD (2017) Sarcomas with CIC-rearrangements are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am J Surg Pathol 41(7):941\u2013949. https:\/\/doi.org\/10.1097\/PAS.0000000000000846","journal-title":"Am J Surg Pathol"},{"issue":"9","key":"4231_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113114","volume":"42","author":"AA Smith","year":"2023","unstructured":"Smith AA, Nip Y, Bennett SR, Hamm DC, Lemmers RJLF, van der Vliet PJ, Setty M, van der Maarel SM, Tapscott SJ (2023) DUX4 expression in cancer induces a metastable early embryonic totipotent program. Cell Rep 42(9):113114. https:\/\/doi.org\/10.1016\/j.celrep.2023.113114","journal-title":"Cell Rep"},{"issue":"5","key":"4231_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100103","volume":"36","author":"K Linos","year":"2023","unstructured":"Linos K, Dermawan JK, Bale T, Rosenblum MK, Singer S, Tap W, Dickson MA, Hornick JL, Antonescu CR (2023) Expanding the molecular diversity of CIC-rearranged sarcomas with novel and very rare partners. Mod Pathol 36(5):100103. https:\/\/doi.org\/10.1016\/j.modpat.2023.100103","journal-title":"Mod Pathol"},{"issue":"7","key":"4231_CR18","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1002\/gcc.22172","volume":"53","author":"K Specht","year":"2014","unstructured":"Specht K, Sung YS, Zhang L, Richter GH, Fletcher CD, Antonescu CR (2014) Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53(7):622\u2013633. https:\/\/doi.org\/10.1002\/gcc.22172","journal-title":"Genes Chromosomes Cancer"},{"issue":"5","key":"4231_CR19","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1097\/PAS.0000000000000582","volume":"40","author":"SC Huang","year":"2016","unstructured":"Huang SC, Zhang L, Sung YS, Chen CL, Kao YC, Agaram NP, Singer S, Tap WD, D\u2019Angelo S, Antonescu CR (2016) Recurrent CIC gene abnormalities in angiosarcomas: a molecular study of 120 cases with concurrent investigation of PLCG1, KDR, MYC, and FLT4 gene alterations. Am J Surg Pathol 40(5):645\u2013655. https:\/\/doi.org\/10.1097\/PAS.0000000000000582","journal-title":"Am J Surg Pathol"},{"key":"4231_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2022.153779","volume":"231","author":"MJ Song","year":"2022","unstructured":"Song MJ, Cho KJ, Kim TI, Kim W, Song JS (2022) Distinct histologic and genetic characteristics of round cell sarcoma with CIC-DUX4 fusion and comparison with ewing sarcoma. Pathology 231:153779. https:\/\/doi.org\/10.1016\/j.prp.2022.153779","journal-title":"Pathology"},{"issue":"3","key":"4231_CR21","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1097\/PAS.0000000000000570","volume":"40","author":"A Yoshida","year":"2016","unstructured":"Yoshida A, Goto K, Kodaira M, Kobayashi E, Kawamoto H, Mori T, Yoshimoto S, Endo O, Kodama N, Kushima R, Hiraoka N, Motoi T, Kawai A (2016) CIC-rearranged sarcomas: a study of 20 cases and comparisons with Ewing sarcomas. Am J Surg Pathol 40(3):313\u2013323. https:\/\/doi.org\/10.1097\/PAS.0000000000000570","journal-title":"Am J Surg Pathol"},{"key":"4231_CR22","doi-asserted-by":"publisher","unstructured":"Murphy J, Resch EE, Leland C et al (2024) Clinical outcomes of patients with CIC-rearranged sarcoma: a single institution retrospective analysis. J Cancer Res Clin Oncol 150(3):112. Published 2024 Mar 4. https:\/\/doi.org\/10.1007\/s00432-024-05631-7","DOI":"10.1007\/s00432-024-05631-7"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04231-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-025-04231-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04231-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T15:49:56Z","timestamp":1775490596000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-025-04231-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":22,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["4231"],"URL":"https:\/\/doi.org\/10.1007\/s00428-025-04231-1","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"assertion":[{"value":"14 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in adherence to the Good Clinical Practice guidelines and the Declaration of Helsinki (1975, as revised in 2013). All samples were fully anonymized. The study was approved by the Ethics Committee under the following protocol number: 5\u2009\u00d7\u20091000_202405_INNOVALAGGIO.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}