{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:39:40Z","timestamp":1781671180328,"version":"3.54.5"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009553","name":"Agentura Pro Zdravotnick\u00fd V\u00fdzkum \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["NU22-03-00130"],"award-info":[{"award-number":["NU22-03-00130"]}],"id":[{"id":"10.13039\/501100009553","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cooperatio Medical Diagnostics and Basic Medical Sciences","award":["(BBMRI_CZ LM2023033"],"award-info":[{"award-number":["(BBMRI_CZ LM2023033"]}]},{"name":"Cooperatio Medical Diagnostics and Basic Medical Sciences","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}]},{"DOI":"10.13039\/501100016366","name":"V\u0161eobecn\u00e1 Fakultn\u00ed Nemocnice v Praze","doi-asserted-by":"publisher","award":["00064165"],"award-info":[{"award-number":["00064165"]}],"id":[{"id":"10.13039\/501100016366","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022761","name":"Fakultn\u00ed Thomayerova nemocnice","doi-asserted-by":"publisher","award":["00064190"],"award-info":[{"award-number":["00064190"]}],"id":[{"id":"10.13039\/100022761","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal\/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular <jats:italic>TP53<\/jats:italic> alteration was detected in 92 out of 125 tumors (73.6%). The <jats:italic>TP53<\/jats:italic> mutation was shown to be prognostic and\u00a0associated with shorter overall survival (<jats:italic>p<\/jats:italic>\u2009=\u20090.041). The multivariate analysis of p53 and <jats:italic>TP53<\/jats:italic> mutational status found that it impacted overall survival relative to distinct sites of tumor locations (<jats:italic>p<\/jats:italic>\u2009=\u20090.004 and <jats:italic>p<\/jats:italic>\u2009=\u20090.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and <jats:italic>TP53<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20090.002; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001\u00a0resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a <jats:italic>TP53<\/jats:italic> mutation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, <jats:italic>TP53<\/jats:italic> genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression \/ <jats:italic>TP53<\/jats:italic> molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.<\/jats:p>","DOI":"10.1007\/s00428-025-04024-6","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T19:28:53Z","timestamp":1737574133000},"page":"557-564","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Correlation between p53 immunoexpression and TP53 mutation status in extrapulmonary small cell neuroendocrine carcinomas and its association with patient survival"],"prefix":"10.1007","volume":"487","author":[{"given":"Kl\u00e1ra","family":"Pavl\u00ed\u010dkov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hojn\u00fd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Waldauf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Dundr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"H\u00e1jkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00e1n","family":"\u0160vajdler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Fabian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva Staniczkov\u00e1","family":"Zambo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslava","family":"Fl\u00eddrov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Laco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Hornychov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricie","family":"Delongov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"\u0160karda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hrudka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radoslav","family":"Mat\u011bj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"issue":"10","key":"4024_CR1","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/nrc2723","volume":"9","author":"AJ Levine","year":"2009","unstructured":"Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9(10):749\u2013758","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"4024_CR2","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/(SICI)1096-9896(199901)187:1<112::AID-PATH250>3.0.CO;2-3","volume":"187","author":"C Prives","year":"1999","unstructured":"Prives C, Hall PA (1999) The p53 pathway. J Pathol 187(1):112\u2013126","journal-title":"J Pathol"},{"issue":"5","key":"4024_CR3","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1177\/1066896913502529","volume":"21","author":"JK Chan","year":"2013","unstructured":"Chan JK, Ip YT, Cheuk W (2013) The utility of immunohistochemistry for providing genetic information on tumors. Int J Surg Pathol 21(5):455\u2013475","journal-title":"Int J Surg Pathol"},{"issue":"1","key":"4024_CR4","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s13000-022-01273-w","volume":"17","author":"YN Sung","year":"2022","unstructured":"Sung YN, Kim D, Kim J (2022) p53 immunostaining pattern is a useful surrogate marker for TP53 gene mutations. Diagn Pathol 17(1):92","journal-title":"Diagn Pathol"},{"key":"4024_CR5","doi-asserted-by":"crossref","unstructured":"Jimbo N, Ohbayashi C, Fujii T, Takeda M, Mitsui S, Tsukamoto R, Tanaka Y, Itoh T, Maniwa Y (2023) Implication of cytoplasmic p53 expression in pulmonary neuroendocrine carcinoma using next-generation sequencing analysis. Histopathology; 84(2):336\u2013342","DOI":"10.1111\/his.15059"},{"issue":"1","key":"4024_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188556","volume":"1876","author":"LJ Hernandez Borrero","year":"2021","unstructured":"Hernandez Borrero LJ, El-Deiry WS (2021) Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 1876(1):188556","journal-title":"Biochim Biophys Acta Rev Cancer"},{"issue":"1","key":"4024_CR7","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1053\/j.seminoncol.2006.11.017","volume":"34","author":"SR Frazier","year":"2007","unstructured":"Frazier SR, Kaplan PA, Loy TS (2007) The pathology of extrapulmonary small cell carcinoma. Semin Oncol 34(1):30\u201338","journal-title":"Semin Oncol"},{"issue":"5","key":"4024_CR8","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1001\/jamaoncol.2020.8072","volume":"7","author":"J Stelwagen","year":"2021","unstructured":"Stelwagen J, de Vries EGE, Walenkamp AME (2021) Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review. JAMA Oncol 7(5):759\u2013770","journal-title":"JAMA Oncol"},{"issue":"6","key":"4024_CR9","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.ccr.2011.04.019","volume":"19","author":"KD Sutherland","year":"2011","unstructured":"Sutherland KD, Proost N, Brouns I, Adriaensen D, Song JY, Berns A (2011) Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell 19(6):754\u2013764","journal-title":"Cancer Cell"},{"key":"4024_CR10","doi-asserted-by":"crossref","unstructured":"Struzinska I, Hajkova N, Hojny J, Krkavcova E, Michalkova R, Bui QH, Matej R, Laco J, Drozenova J, Fabian P et al (2024) Somatic Genomic and Transcriptomic Characterization of Primary Ovarian Serous Borderline Tumors and Low-Grade Serous Carcinomas. J Mol Diagn; 26(4):257\u2013266","DOI":"10.1016\/j.jmoldx.2023.12.004"},{"key":"4024_CR11","unstructured":"OncoKB. In., https:\/\/www.oncokb.org\/. Accessed 24 Nov 2023"},{"key":"4024_CR12","unstructured":"ClinVar. In., database 20230819. https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/. Accessed 24 Nov 2023"},{"key":"4024_CR13","unstructured":"Team RC (2024) A Language and Environment for Statistical Computing_. R Foundation for Statistical https:\/\/www.r-project.org\/"},{"key":"4024_CR14","unstructured":"M TT (2024) A Package for Survival Analysis in R. R package version 3.7\u20130 https:\/\/cran.r-project.org\/web\/packages\/survival\/vignettes\/survival.pdf"},{"key":"4024_CR15","doi-asserted-by":"publisher","unstructured":"Pavl\u00ed\u010dkov\u00e1 K, Hojny J, Waldauf P, Svajdler M, Dudr P, Fabian P et al Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases.\u00a0 Lab Invest in press.\u00a0https:\/\/doi.org\/10.1016\/j.labinv.2025.104093","DOI":"10.1016\/j.labinv.2025.104093"},{"issue":"7563","key":"4024_CR16","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nature14664","volume":"524","author":"J George","year":"2015","unstructured":"George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524(7563):47\u201353","journal-title":"Nature"},{"issue":"4","key":"4024_CR17","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1097\/PAS.0000000000000169","volume":"38","author":"O Basturk","year":"2014","unstructured":"Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM, Vakiani E, La Rosa S, Jang KT, Frankel WL et al (2014) Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 38(4):437\u2013447","journal-title":"Am J Surg Pathol"},{"issue":"4","key":"4024_CR18","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/modpathol.2016.217","volume":"30","author":"B Konukiewitz","year":"2017","unstructured":"Konukiewitz B, Schlitter AM, Jesinghaus M, Pfister D, Steiger K, Segler A, Agaimy A, Sipos B, Zamboni G, Weichert W et al (2017) Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. Mod Pathol 30(4):587\u2013598","journal-title":"Mod Pathol"},{"issue":"3","key":"4024_CR19","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/(SICI)1096-9896(199911)189:3<358::AID-PATH452>3.0.CO;2-1","volume":"189","author":"J Yuan","year":"1999","unstructured":"Yuan J, Knorr J, Altmannsberger M, Goeckenjan G, Ahr A, Scharl A, Strebhardt K (1999) Expression of p16 and lack of pRB in primary small cell lung cancer. J Pathol 189(3):358\u2013362","journal-title":"J Pathol"},{"issue":"5","key":"4024_CR20","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1001\/jamaoncol.2020.8072","volume":"7","author":"J Stelwagen","year":"2021","unstructured":"Stelwagen J, de Vries EGE, Walenkamp AME (2021) Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review. JAMA Oncol 7(5):759\u2013770. https:\/\/doi.org\/10.1001\/jamaoncol.2020.8072","journal-title":"JAMA Oncol"},{"key":"4024_CR21","doi-asserted-by":"publisher","first-page":"175883592091529","DOI":"10.1177\/1758835920915299","volume":"12","author":"MG McNamara","year":"2020","unstructured":"McNamara MG, Frizziero M, Jacobs T et al (2020) Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: a systematic review and meta-analysis. Ther Adv Med Oncol 12:1758835920915299. https:\/\/doi.org\/10.1177\/1758835920915299","journal-title":"Ther Adv Med Oncol"},{"issue":"5035","key":"4024_CR22","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1126\/science.1659741","volume":"254","author":"RA Weinberg","year":"1991","unstructured":"Weinberg RA (1991) Tumor suppressor genes. Science 254(5035):1138\u20131146","journal-title":"Science"},{"key":"4024_CR23","doi-asserted-by":"crossref","unstructured":"Huang SC, Chang IY, Chen TC, Lin HC, Tsai CY, Hsu JT, Yeh CN, Chang SC, Yeh TS: Redefining aberrant P53 expression of gastric cancer and its distinct clinical significance among molecular-histologic subtypes. Asian J Surg 2024.","DOI":"10.1016\/j.asjsur.2024.05.121"},{"key":"4024_CR24","doi-asserted-by":"crossref","unstructured":"Boldrin E, Piano MA, Bernaudo F, Alfieri R, Biasin MR, Montagner IM, Volpato A, Mattara G, Lamacchia F, Magni G et al: p53\/TP53 Status Assessment in Gastroesophageal Adenocarcinoma. Cancers (Basel) 2023, 15(10).","DOI":"10.3390\/cancers15102783"},{"key":"4024_CR25","doi-asserted-by":"publisher","first-page":"6096350","DOI":"10.1155\/2019\/6096350","volume":"2019","author":"S Su","year":"2019","unstructured":"Su S, Zou JJ, Zeng YY, Cen WC, Zhou W, Liu Y, Su DH, Zhang XL, Huang HY, Lei A et al (2019) Tumor Mutational Burden and Genomic Alterations in Chinese Small Cell Lung Cancer Measured by Whole-Exome Sequencing. Biomed Res Int 2019:6096350","journal-title":"Biomed Res Int"},{"issue":"10","key":"4024_CR26","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/nrg2841","volume":"11","author":"M Meyerson","year":"2010","unstructured":"Meyerson M, Gabriel S, Getz G (2010) Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 11(10):685\u2013696","journal-title":"Nat Rev Genet"},{"issue":"2","key":"4024_CR27","first-page":"155","volume":"4","author":"M Daniels","year":"2012","unstructured":"Daniels M, Goh F, Wright CM, Sriram KB, Relan V, Clarke BE, Duhig EE, Bowman RV, Yang IA, Fong KM (2012) Whole genome sequencing for lung cancer. J Thorac Dis 4(2):155\u2013163","journal-title":"J Thorac Dis"},{"issue":"2","key":"4024_CR28","first-page":"275","volume":"1865","author":"A Kazanets","year":"2016","unstructured":"Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M (2016) Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. Biochim Biophys Acta 1865(2):275\u2013288","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"4024_CR29","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/cdd.2009.68","volume":"17","author":"JC Marine","year":"2010","unstructured":"Marine JC, Lozano G (2010) Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 17(1):93\u2013102","journal-title":"Cell Death Differ"},{"issue":"4529","key":"4024_CR30","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1126\/science.6274023","volume":"215","author":"J Whang-Peng","year":"1982","unstructured":"Whang-Peng J, Kao-Shan CS, Lee EC, Bunn PA, Carney DN, Gazdar AF, Minna JD (1982) Specific chromosome defect associated with human small-cell lung cancer; deletion 3p(14\u201323). Science 215(4529):181\u2013182","journal-title":"Science"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04024-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-025-04024-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04024-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:30:54Z","timestamp":1759296654000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-025-04024-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["4024"],"URL":"https:\/\/doi.org\/10.1007\/s00428-025-04024-6","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]},"assertion":[{"value":"25 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 January 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}