{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T00:39:08Z","timestamp":1793407148380,"version":"4.5.0"},"reference-count":44,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":430,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ichiro Kanahara Foundation; Okinaka Memorial Institute for Medical Research; Foundation for Promotion of Cancer Research"},{"name":"Research fund from the Japanese Foundation for Cancer Research"}],"content-domain":{"domain":["mp.uscap.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Modern Pathology"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1038\/s41379-021-00869-9","type":"journal-article","created":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T11:02:28Z","timestamp":1625914948000},"page":"1979-1989","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":44,"title":["Clinicopathological and genomic features in patients with head and neck neuroendocrine carcinoma"],"prefix":"10.1016","volume":"34","author":[{"given":"Akihiro","family":"Ohmoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4277-0161","authenticated-orcid":false,"given":"Yukiko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reimi","family":"Asaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Urasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Yunokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Tomomatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Toshiyasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Mitani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-5800","authenticated-orcid":false,"given":"Kengo","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichi","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1038\/s41379-021-00869-9_bib1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.humpath.2013.03.016","article-title":"Extrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues","volume":"45","author":"Volante","year":"2014","journal-title":"Hum Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.oraloncology.2017.04.009","article-title":"Small cell carcinoma of the head and neck: an analysis of the National Cancer Database","volume":"69","author":"Pointer","year":"2017","journal-title":"Oral Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib3","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/cncr.31124","article-title":"Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases","volume":"124","author":"Dasari","year":"2018","journal-title":"Cancer"},{"key":"10.1038\/s41379-021-00869-9_bib4","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1177\/0003489419853601","article-title":"Small cell carcinoma in the head and neck","volume":"128","author":"Wakasaki","year":"2019","journal-title":"Ann Otol Rhinol Laryngol"},{"key":"10.1038\/s41379-021-00869-9_bib5","unstructured":"El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO classification of head and neck tumours. 4th edition, vol. 9. Lyon: International Agency for Research on Cancer (IARC); 2017."},{"key":"10.1038\/s41379-021-00869-9_bib6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/PAS.0b013e318236d822","article-title":"Head and neck large cell neuroendocrine carcinoma should be separated from atypical carcinoid on the basis of different clinical features, overall survival, and pathogenesis","volume":"36","author":"Kao","year":"2012","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib7","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12022-020-09660-z","article-title":"Genomics of high-grade neuroendocrine neoplasms: Well-differentiated neuroendocrine tumor with high-grade features (G3 NET) and neuroendocrine carcinomas (NEC) of various anatomic sites","volume":"32","author":"Uccella","year":"2021","journal-title":"Endocr Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib8","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1038\/s41379-019-0285-x","article-title":"DNA methylation-based classification of sinonasal undifferentiated carcinoma","volume":"32","author":"Dogan","year":"2019","journal-title":"Mod Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib9","unstructured":"Travis WD, Brambilla E, Burke A, Marx A, Nicholson AG. WHO classification of thumours of the lung, pleura, thymus and heart. Lyon: IARC; 2015."},{"key":"10.1038\/s41379-021-00869-9_bib10","doi-asserted-by":"crossref","unstructured":"Kosco K, Sickler B, Chan S, Alnaeeli M, Beruti S. Analytical validation of TruSight Oncology 500, a comprehensive genomic profiling LDT for use in routine patient care. Cancer Res. 2020;80:Abstract nr 4262.","DOI":"10.1158\/1538-7445.AM2020-4262"},{"key":"10.1038\/s41379-021-00869-9_bib11","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1158\/0008-5472.CAN-17-0337","article-title":"Variant review with the Integrative Genomics Viewer","volume":"77","author":"Robinson","year":"2017","journal-title":"Cancer Res"},{"key":"10.1038\/s41379-021-00869-9_bib12","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transpl"},{"key":"10.1038\/s41379-021-00869-9_bib13","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1097\/PAS.0000000000001444","article-title":"Insulinoma-associated protein 1 (INSM1) is a better marker for the diagnosis and prognosis estimation of small cell lung carcinoma than neuroendocrine phenotype markers such as chromogranin A, synaptophysin, and CD56","volume":"44","author":"Sakakibara","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib14","doi-asserted-by":"crossref","first-page":"102851","DOI":"10.1016\/j.amjoto.2020.102851","article-title":"Survival outcomes in sinonasal carcinoma with neuroendocrine differentiation: a NCDB analysis","volume":"42","author":"Issa","year":"2020","journal-title":"Am J Otolaryngol"},{"key":"10.1038\/s41379-021-00869-9_bib15","doi-asserted-by":"crossref","first-page":"R219","DOI":"10.1530\/ERC-19-0483","article-title":"Extrapulmonary poorly differentiated NECs, including molecular and immune aspects","volume":"27","author":"McNamara","year":"2020","journal-title":"Endocr Relat Cancer"},{"key":"10.1038\/s41379-021-00869-9_bib16","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ejca.2017.04.009","article-title":"Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: are they really heterogeneous? Insights from the FFCD-GTE national cohort","volume":"79","author":"Walter","year":"2017","journal-title":"Eur J Cancer"},{"key":"10.1038\/s41379-021-00869-9_bib17","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00428-016-1982-1","article-title":"p16 overexpression in high-grade neuroendocrine carcinomas of the head and neck: potential diagnostic pitfall with HPV-related carcinomas","volume":"469","author":"Alos","year":"2016","journal-title":"Virchows Arch"},{"key":"10.1038\/s41379-021-00869-9_bib18","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1097\/PAS.0000000000000580","article-title":"Large cell neuroendocrine carcinoma of the head and neck: a clinicopathologic series of 10 cases with an emphasis on HPV status","volume":"40","author":"Thompson","year":"2016","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature14664","article-title":"Comprehensive genomic profiles of small cell lung cancer","volume":"524","author":"George","year":"2015","journal-title":"Nature"},{"key":"10.1038\/s41379-021-00869-9_bib20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/PAS.0b013e3182417d36","article-title":"Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well- differentiated pancreatic neuroendocrine tumors","volume":"36","author":"Yachida","year":"2012","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib21","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1634\/theoncologist.12-5-535","article-title":"Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors","volume":"12","author":"Kunnimalaiyaan","year":"2007","journal-title":"Oncologist"},{"key":"10.1038\/s41379-021-00869-9_bib22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13577-016-0149-3","article-title":"Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1","volume":"30","author":"Ito","year":"2017","journal-title":"Hum Cell"},{"key":"10.1038\/s41379-021-00869-9_bib23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3390\/ijms18010143","article-title":"Pancreatic neuroendocrine neoplasms: basic biology, current treatment strategies and prospects for the future","volume":"18","author":"Ohmoto","year":"2017","journal-title":"Int J Mol Sci"},{"key":"10.1038\/s41379-021-00869-9_bib24","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1126\/science.1200609","article-title":"DAXX\/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors","volume":"331","author":"Jiao","year":"2011","journal-title":"Science"},{"key":"10.1038\/s41379-021-00869-9_bib25","doi-asserted-by":"crossref","unstructured":"Raj N, Soumerai T, Valentino E, Hechtman JF, Berger MF, Reidy DL. Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): a study using MSK-IMPACT. J Clin Oncol. 2016;34:abstr 246.","DOI":"10.1200\/jco.2016.34.4_suppl.246"},{"key":"10.1038\/s41379-021-00869-9_bib26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nature21063","article-title":"Whole-genome landscape of pancreatic neuroendocrine tumours","volume":"543","author":"Scarpa","year":"2017","journal-title":"Nature"},{"key":"10.1038\/s41379-021-00869-9_bib27","doi-asserted-by":"crossref","first-page":"e94132","DOI":"10.1371\/journal.pone.0094132","article-title":"Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma","volume":"9","author":"H\u00f6land","year":"2014","journal-title":"PLoS ONE"},{"key":"10.1038\/s41379-021-00869-9_bib28","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1200\/JCO.2008.20.0766","article-title":"Targeting the mTOR signaling network for cancer therapy","volume":"27","author":"Meric-Bernstam","year":"2009","journal-title":"J Clin Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/CCO.0000000000000390","article-title":"Targeting EZH2 in cancer therapy","volume":"29","author":"amagishi","year":"2017","journal-title":"Curr Opin Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib30","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/nm.3968","article-title":"SWI\/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2","volume":"21","author":"Kim","year":"2015","journal-title":"Nat Med"},{"key":"10.1038\/s41379-021-00869-9_bib31","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1097\/PAS.0000000000001428","article-title":"SMARCA4-deficient sinonasal carcinoma: a series of 10 cases expanding the genetic spectrum of SWI\/SNF-driven sinonasal malignancies","volume":"44","author":"Agaimy","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib32","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1097\/PAS.0000000000001508","article-title":"Recurrent loss of SMARCA4 in sinonasal teratocarcinosarcoma","volume":"44","author":"Rooper","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"10.1038\/s41379-021-00869-9_bib33","doi-asserted-by":"crossref","unstructured":"Bergsland EK, Roy R, Stephens P, Ross JS, Bailey M, Olshen A. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites. J Clin Oncol. 2016;34:abstr 4020.","DOI":"10.1200\/JCO.2016.34.15_suppl.4020"},{"key":"10.1038\/s41379-021-00869-9_bib34","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1126\/science.1220834","article-title":"Transforming fusions of FGFR and TACC genes in human glioblastoma","volume":"337","author":"Singh","year":"2012","journal-title":"Science"},{"key":"10.1038\/s41379-021-00869-9_bib35","doi-asserted-by":"crossref","first-page":"6551","DOI":"10.1158\/1078-0432.CCR-14-1337","article-title":"Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma","volume":"20","author":"Capelletti","year":"2014","journal-title":"Clin Cancer Res"},{"key":"10.1038\/s41379-021-00869-9_bib36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1158\/1078-0432.CCR-14-3212","article-title":"The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing","volume":"22","author":"Helsten","year":"2016","journal-title":"Clin Cancer Res"},{"key":"10.1038\/s41379-021-00869-9_bib37","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1056\/NEJMoa1817323","article-title":"Erdafitinib in locally advanced or metastatic urothelial carcinoma","volume":"381","author":"Loriot","year":"2019","journal-title":"N. Engl J Med"},{"key":"10.1038\/s41379-021-00869-9_bib38","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S1470-2045(20)30109-1","article-title":"Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study","volume":"21","author":"Abou-Alfa","year":"2020","journal-title":"Lancet Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib39","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.annonc.2020.07.002","article-title":"The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) \u226510: a decision centered on empowering patients and their physicians","volume":"31","author":"Subbiah","year":"2020","journal-title":"Ann Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib40","unstructured":"TrusightTM Oncology 500 data sheet (Illumina)."},{"key":"10.1038\/s41379-021-00869-9_bib41","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/cam4.1372","article-title":"Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients","volume":"7","author":"Vanderwalde","year":"2018","journal-title":"Cancer Med"},{"key":"10.1038\/s41379-021-00869-9_bib42","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.ygyno.2020.05.682","article-title":"Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract","volume":"158","author":"Frumovitz","year":"2020","journal-title":"Gynecol Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib43","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1200\/JCO.2019.37.15_suppl.4103","article-title":"A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC)","volume":"37","author":"Fottner","year":"2019","journal-title":"J Clin Oncol"},{"key":"10.1038\/s41379-021-00869-9_bib44","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1038\/s41416-020-0775-0","article-title":"Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials","volume":"122","author":"Vijayvergia","year":"2020","journal-title":"Br J Cancer"}],"container-title":["Modern Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41379-021-00869-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41379-021-00869-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0893395222005051?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0893395222005051?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41379-021-00869-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:32:54Z","timestamp":1760229174000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0893395222005051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":44,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["S0893395222005051"],"URL":"https:\/\/doi.org\/10.1038\/s41379-021-00869-9","relation":{},"ISSN":["0893-3952"],"issn-type":[{"value":"0893-3952","type":"print"}],"subject":[],"published":{"date-parts":[[2021,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Clinicopathological and genomic features in patients with head and neck neuroendocrine carcinoma","name":"articletitle","label":"Article Title"},{"value":"Modern Pathology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1038\/s41379-021-00869-9","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Authors.","name":"copyright","label":"Copyright"}]}}