{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:44:53Z","timestamp":1790286293839,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be difficult to diagnose due to histological overlap with small cell lung carcinoma (SCLC). SCLC comprises multiple transcription factor\u2010based subtypes. We aimed to evaluate the clinicopathological significance of transcription factor\u2010based subtyping in pulmonary LCNEC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      We identified a consecutive series of 117 patients in 2010\u20132024 with samples diagnosed as pulmonary LCNEC (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200970) or high\u2010grade neuroendocrine carcinoma with combined or intermediate morphology (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200947). Cytomorphological score was assessed as a weighted average from two areas. Immunohistochemistry (IHC) for ASCL1, NeuroD1, POU2F3, YAP1, and HNF4A was evaluated using\n                      <jats:italic>H<\/jats:italic>\n                      \u2010scores, with subtype assignment based on the highest\n                      <jats:italic>H<\/jats:italic>\n                      \u2010score. Next\u2010generation sequencing (NGS) was performed in selected cases. IHC subtyping identified 73 (62%) ASCL1\u2010dominant, 20 (17%) YAP1\u2010dominant, 9 (8%) NeuroD1\u2010dominant, 7 (6%) POU2F3\u2010dominant, 2 (2%) HNF4A\u2010dominant, and 6\u00a0(5%) quintuple\u2010negative samples. While YAP1 was often co\u2010expressed with other subtypes and HNF4A was frequently co\u2010expressed with ASCL1, POU2F3 was mutually exclusive from ASCL1\/NeuroD1\/HNF4A. Unlike ASCL1\/NeuroD1\/POU2F3, YAP1 and HNF4A\n                      <jats:italic>H<\/jats:italic>\n                      \u2010scores each correlated with large\u2010cell morphology\u2014both across the entire cohort and in the lung resection subgroup. NeuroD1 dominance was more common in tumours with combined\/intermediate morphology than LCNEC. Some of the tumours with intermediate morphology straddling between prototypical LCNEC and SCLC harboured POU2F3 dominance, or\n                      <jats:italic>EGFR<\/jats:italic>\n                      or other non\u2010\n                      <jats:italic>KRAS<\/jats:italic>\n                      driver mutations. In 19 patients with multiple samples (including nine with paired pre\u2010 and post\u2010treatment samples), all showed concordant subtypes after accounting for codominance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>YAP1 and HNF4A expression correlated significantly with large\u2010cell morphology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.70055","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:28:57Z","timestamp":1764152937000},"page":"810-830","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcription factor\u2010based subtype assignment in pulmonary large cell neuroendocrine carcinoma"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8568-1591","authenticated-orcid":false,"given":"Yin P","family":"Hung","sequence":"first","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komson","family":"Wannasai","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Pathology Faculty of Medicine, Chiang Mai University  Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5006-3569","authenticated-orcid":false,"given":"Catherine B","family":"Meador","sequence":"additional","affiliation":[{"name":"Department of Medicine Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L","family":"Ganci","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B","family":"Rider","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte I","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-2265","authenticated-orcid":false,"given":"Mari","family":"Mino\u2010Kenudson","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-199106000-00003"},{"key":"e_1_2_11_3_1","first-page":"144","volume-title":"WHO classification of tumors series, thoracic tumors","author":"Rekhtman N","year":"2021"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000589"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19821001)50:7<1380::AID-CNCR2820500725>3.0.CO;2-K"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1309\/H40B-8W14-4Q47-03EP"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-200209000-00009"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000002145"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2010.03486.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2016.01.003"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00374-7"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2946"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0355"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2023.107454"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03099-x"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr.2020.02.13"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.05.020"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0133-9"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.01.016"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.12.014"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.09.009"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2022.06.004"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.08.763"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5922"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100184"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14872"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.15034"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2023.100561"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.05.002"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0361"},{"key":"e_1_2_11_31_1","first-page":"139","volume-title":"WHO classification of tumors series, thoracic tumors","author":"Beasley MB","year":"2021"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0248-2"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncy.22170"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.10.023"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.01.002"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000070"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14306"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-1115"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.15059"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.path.2019.08.012"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2017.110"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2360"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2024.100677"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1102873"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1921"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.labinv.2025.104192"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14679"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14664"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0620"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0286"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.314815.118"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2025.03.009"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.911294"},{"key":"e_1_2_11_54_1","article-title":"Histologic characterization of small cell transformation from EGFR\u2010mutant non\u2010small cell lung carcinoma after EGFR\u2010targeted therapy","volume":"33","author":"Lepus C","year":"2020","journal-title":"Mod. Pathol."},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66524"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj1415"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-24-292"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.labinv.2025.104210"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800038"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.11.018"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2024.100627"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000002081"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/2056-4538.70001"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31826be303"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70055","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.70055","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70055","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T07:06:57Z","timestamp":1770793617000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.70055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":63,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/his.70055"],"URL":"https:\/\/doi.org\/10.1111\/his.70055","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]},"assertion":[{"value":"2025-07-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}