{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T07:22:44Z","timestamp":1760080964261,"version":"3.37.3"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100018935","name":"Universit\u00e4tsklinikum Erlangen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100018935","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like)\u00a0small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin\u2009+\u2009chromogranin A) and myogenic (desmin\u2009+\u2009myogenin) marker expression and for <jats:italic>TERT<\/jats:italic> promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of  RMS-related other\u00a0genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. <jats:italic>TERT<\/jats:italic> promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of <jats:italic>TERT<\/jats:italic> promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of <jats:italic>TERT<\/jats:italic> promoter mutation in 2 of 3 RMS and lack of <jats:italic>FOXO1<\/jats:italic> and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.<\/jats:p>","DOI":"10.1007\/s00428-024-03835-3","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T05:01:28Z","timestamp":1717477288000},"page":"615-623","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults\u2014A comparative analysis in favor of a common histogenesis"],"prefix":"10.1007","volume":"485","author":[{"given":"Veronika","family":"Bahlinger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Stoehr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arndt","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ond\u0159ej","family":"Hes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abbas","family":"Agaimy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"issue":"2","key":"3835_CR1","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.hoc.2014.10.001","volume":"29","author":"N Malats","year":"2015","unstructured":"Malats N, Real FX (2015) Epidemiology of bladder cancer. Hematol Oncol Clin North Am 29(2):177\u201389 (vii)","journal-title":"Hematol Oncol Clin North Am"},{"issue":"11","key":"3835_CR2","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1016\/j.humpath.2006.05.009","volume":"37","author":"A Lopez-Beltran","year":"2006","unstructured":"Lopez-Beltran A, Cheng L (2006) Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 37(11):1371\u20131388","journal-title":"Hum Pathol"},{"issue":"11","key":"3835_CR3","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1001\/jamaoncol.2016.7013","volume":"3","author":"EJ Kouba","year":"2017","unstructured":"Kouba EJ, Cheng L (2017) Understanding the genetic landscape of small cell carcinoma of the urinary bladder and implications for diagnosis, prognosis, and treatment: a review. JAMA Oncol 3(11):1570\u20131578","journal-title":"JAMA Oncol"},{"issue":"12","key":"3835_CR4","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1007\/s12032-019-1321-x","volume":"36","author":"Y Wang","year":"2019","unstructured":"Wang Y et al (2019) Small cell carcinoma of the bladder: the characteristics of molecular alterations, treatment, and follow-up. Med Oncol 36(12):98","journal-title":"Med Oncol"},{"key":"3835_CR5","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/1750-1172-6-75","volume":"6","author":"N Ismaili","year":"2011","unstructured":"Ismaili N (2011) A rare bladder cancer\u2013small cell carcinoma: review and update. Orphanet J Rare Dis 6:75","journal-title":"Orphanet J Rare Dis"},{"issue":"2","key":"3835_CR6","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1097\/00000478-200002000-00008","volume":"24","author":"V Eusebi","year":"2000","unstructured":"Eusebi V et al (2000) Small cell neuroendocrine carcinoma with skeletal muscle differentiation: report of three cases. Am J Surg Pathol 24(2):223\u2013230","journal-title":"Am J Surg Pathol"},{"issue":"7","key":"3835_CR7","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1097\/PAS.0b013e3181650e4a","volume":"32","author":"GP Paner","year":"2008","unstructured":"Paner GP et al (2008) Rhabdomyosarcoma of the urinary bladder in adults: predilection for alveolar morphology with anaplasia and significant morphologic overlap with small cell carcinoma. Am J Surg Pathol 32(7):1022\u20131028","journal-title":"Am J Surg Pathol"},{"issue":"2","key":"3835_CR8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.urolonc.2015.12.012","volume":"34","author":"K Kieran","year":"2016","unstructured":"Kieran K, Shnorhavorian M (2016) Current standards of care in bladder and prostate rhabdomyosarcoma. Urol Oncol 34(2):93\u2013102","journal-title":"Urol Oncol"},{"issue":"5","key":"3835_CR9","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.eururo.2022.07.002","volume":"82","author":"GJ Netto","year":"2022","unstructured":"Netto GJ, Amin MB, Berney DM et al (2022) The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs-part B: prostate and urinary tract tumors. Eur Urol 82(5):469\u2013482. https:\/\/doi.org\/10.1016\/j.eururo.2022.07.002","journal-title":"Eur Urol"},{"issue":"2","key":"3835_CR10","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.eururo.2013.08.057","volume":"65","author":"CD Hurst","year":"2014","unstructured":"Hurst CD, Platt FM, Knowles MA (2014) Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine. Eur Urol 65(2):367\u2013369","journal-title":"Eur Urol"},{"issue":"1","key":"3835_CR11","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nbt.1754","volume":"29","author":"JT Robinson","year":"2011","unstructured":"Robinson JT et al (2011) Integrative genomics viewer. Nat Biotechnol 29(1):24\u201326","journal-title":"Nat Biotechnol"},{"issue":"7","key":"3835_CR12","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/modpathol.2008.86","volume":"21","author":"A Bahrami","year":"2008","unstructured":"Bahrami A et al (2008) Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall. Mod Pathol 21(7):795\u2013806","journal-title":"Mod Pathol"},{"issue":"4","key":"3835_CR13","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1097\/PAT.0000000000000091","volume":"46","author":"K Erlenbach-Wunsch","year":"2014","unstructured":"Erlenbach-Wunsch K et al (2014) Expression of the LIM homeobox domain transcription factor ISL1 (Islet-1) is frequent in rhabdomyosarcoma but very limited in other soft tissue sarcoma types. Pathology 46(4):289\u2013295","journal-title":"Pathology"},{"issue":"2","key":"3835_CR14","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s12105-017-0851-9","volume":"12","author":"LDR Thompson","year":"2018","unstructured":"Thompson LDR et al (2018) Sinonasal tract alveolar rhabdomyosarcoma in adults: a clinicopathologic and immunophenotypic study of fifty-two cases with emphasis on epithelial immunoreactivity. Head Neck Pathol 12(2):181\u2013192","journal-title":"Head Neck Pathol"},{"issue":"5","key":"3835_CR15","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1002\/cncr.20456","volume":"101","author":"L Cheng","year":"2004","unstructured":"Cheng L et al (2004) Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer 101(5):957\u2013962","journal-title":"Cancer"},{"issue":"1","key":"3835_CR16","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1186\/s13256-018-1870-1","volume":"12","author":"M Ahsaini","year":"2018","unstructured":"Ahsaini M et al (2018) A rare pure embryonal rhabdomyosarcoma of the urinary bladder in an adult successfully managed with neoadjuvant chemotherapy and surgery: a case report. J Med Case Rep 12(1):329","journal-title":"J Med Case Rep"},{"issue":"2","key":"3835_CR17","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.eururo.2013.08.052","volume":"65","author":"Y Allory","year":"2014","unstructured":"Allory Y et al (2014) Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur Urol 65(2):360\u2013366","journal-title":"Eur Urol"},{"key":"3835_CR18","doi-asserted-by":"crossref","unstructured":"Hoffman-Censits J et al (2021) Urothelial Cancers with small cell variant histology have confirmed high tumor mutational burden, frequent TP53 and RB mutations, and a unique gene expression profile. Eur Urol Oncol 4:297\u2013300","DOI":"10.1016\/j.euo.2019.12.002"},{"issue":"6","key":"3835_CR19","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.euf.2017.03.007","volume":"4","author":"DS Priemer","year":"2018","unstructured":"Priemer DS et al (2018) Small-cell carcinomas of the urinary bladder and prostate: TERT promoter mutation status differentiates sites of malignancy and provides evidence of common clonality between small-cell carcinoma of the urinary bladder and urothelial carcinoma. Eur Urol Focus 4(6):880\u2013888","journal-title":"Eur Urol Focus"},{"issue":"2","key":"3835_CR20","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1016\/j.ygeno.2019.09.017","volume":"112","author":"AK Siraj","year":"2020","unstructured":"Siraj AK et al (2020) Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population. Genomics 112(2):1746\u20131753","journal-title":"Genomics"},{"key":"3835_CR21","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.humpath.2019.03.007","volume":"88","author":"S Gupta","year":"2019","unstructured":"Gupta S et al (2019) A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma. Hum Pathol 88:48\u201359","journal-title":"Hum Pathol"},{"issue":"21","key":"3835_CR22","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.3390\/cancers15215269","volume":"15","author":"A Zarrabi","year":"2023","unstructured":"Zarrabi A, Perrin D, Kavoosi M et al (2023) Rhabdomyosarcoma: current therapy, challenges, and future approaches to treatment strategies. Cancers (Basel) 15(21):5269. https:\/\/doi.org\/10.3390\/cancers15215269","journal-title":"Cancers (Basel)"},{"issue":"16","key":"3835_CR23","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1200\/JCO.2008.19.0256","volume":"27","author":"AO Siefker-Radtke","year":"2009","unstructured":"Siefker-Radtke AO, Kamat AM, Grossman HB et al (2009) Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide\/doxorubicin and etoposide\/cisplatin in small-cell urothelial cancer. J Clin Oncol 27(16):2592\u20132597. https:\/\/doi.org\/10.1200\/JCO.2008.19.0256","journal-title":"J Clin Oncol"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-024-03835-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-024-03835-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-024-03835-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T12:11:09Z","timestamp":1730203869000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-024-03835-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,4]]},"references-count":23,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["3835"],"URL":"https:\/\/doi.org\/10.1007\/s00428-024-03835-3","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"type":"print","value":"0945-6317"},{"type":"electronic","value":"1432-2307"}],"subject":[],"published":{"date-parts":[[2024,6,4]]},"assertion":[{"value":"24 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki and the protocol approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-N\u00fcrnberg (No. 329_16B).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The senior author of this study (AA) is the Editor-in-Chief of Virchows Archiv.\u00a0The authors declare no other\u00a0competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}