{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T03:45:12Z","timestamp":1770349512757,"version":"3.49.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Distinguishing grade 3 pancreatic neuroendocrine tumors (PanNETs) from neuroendocrine carcinomas (PanNECs) is sometimes challenging. Recently, a diffuse p16-positive pattern was reported in PanNECs but not in grade 3 PanNETs, suggesting that p16 could help differentiate these entities. This study aimed to investigate p16 expression in PanNETs of various grades and its association with clinicopathologic features.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A total of 114 PanNETs were selected, and their H&amp;E resection slides were reviewed for pathologic features, with a focus on morphologic variants. Tissue microarrays were constructed, and p16 immunohistochemistry was performed. The results were categorized as diffuse positive, partial positive, or negative. Patient electronic health records were reviewed for follow-up data.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among the 114 PanNETs reviewed, 13 (11.4%) exhibited diffuse p16 expression, 40 (35.1%) were negative, and 61 (53.5%) had partial expression. Diffuse p16 expression occurred in 6 of 38 (15.8%) grade 1, 6 of 60 (10.0%) grade 2, and 1 of 16 (6.3%) grade 3 tumors. Expression did not differ substantially with patient demographics, tumor size, grading, staging, or survival, but diffuse p16 expression was more frequent in body\/tail tumors (12\/65 [18.5%], P =\u2009.019) and in stromal-rich tumors (10\/23 [43.5%], P\u2009&amp;lt;\u2009.001).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Diffuse p16 expression is not uncommon in PanNETs and may be associated with stroma-rich variants.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajcp\/aqae184","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T17:35:40Z","timestamp":1737740140000},"page":"758-765","source":"Crossref","is-referenced-by-count":2,"title":["Diffuse expression of p16 in pancreatic neuroendocrine tumors (PanNETs) and the association of morphology variants"],"prefix":"10.1093","volume":"163","author":[{"given":"John","family":"Yablonski","sequence":"first","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, NC ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5962-6479","authenticated-orcid":false,"given":"Chanjuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, NC ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-5482","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, NC ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"2025052712492673900_CIT0001","first-page":"343","article-title":"Neuroendocrine neoplasms: Introduction","volume-title":"Digestive System Tumours: WHO Classification of Tumours","author":"Kloppel","year":"2019","edition":"5"},{"key":"2025052712492673900_CIT0002","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1097\/PAS.0000000000000169","article-title":"Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases","volume":"38","author":"Basturk","year":"2014","journal-title":"Am J Surg Pathol."},{"key":"2025052712492673900_CIT0003","doi-asserted-by":"publisher","first-page":"100065","DOI":"10.1016\/j.modpat.2022.100065","article-title":"Integrated genomic and clinicopathologic approach distinguishes pancreatic grade 3 neuroendocrine tumor from neuroendocrine carcinoma and identifies a subset with molecular overlap","volume":"36","author":"Umetsu","year":"2023","journal-title":"Mod Pathol."},{"key":"2025052712492673900_CIT0004","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1148\/radiol.10100046","article-title":"Pancreatic duct stenosis secondary to small endocrine neoplasms: a manifestation of serotonin production","volume":"257","author":"Shi","year":"2010","journal-title":"Radiology."},{"key":"2025052712492673900_CIT0005","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s12022-020-09628-z","article-title":"Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognostic stratification","volume":"31","author":"Xue","year":"2020","journal-title":"Endocr Pathol."},{"key":"2025052712492673900_CIT0006","doi-asserted-by":"publisher","first-page":"e31","DOI":"10.11622\/smedj.2013036","article-title":"Lipid-rich variant of pancreatic endocrine tumour with inhibin positivity and microscopic foci of microcystic adenoma-like areas: emphasis on histopathology","volume":"54","author":"Rao","year":"2013","journal-title":"Singapore Med J."},{"key":"2025052712492673900_CIT0007","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1097\/PAS.0000000000000662","article-title":"A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas","volume":"40","author":"Tang","year":"2016","journal-title":"Am J Surg Pathol."},{"key":"2025052712492673900_CIT0008","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1097\/MPA.0000000000000735","article-title":"Treatment response and outcomes of grade 3 pancreatic neuroendocrine neoplasms based on morphology: well differentiated versus poorly differentiated","volume":"46","author":"Raj","year":"2017","journal-title":". Pancreas."},{"key":"2025052712492673900_CIT0009","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s00428-021-03211-5","article-title":"Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls","volume":"480","author":"Konukiewitz","year":"2022","journal-title":"Virchows Arch."},{"key":"2025052712492673900_CIT0010","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1111\/his.12535","article-title":"Cadherin 17 is frequently expressed by \u2018sclerosing variant\u2019 pancreatic neuroendocrine tumour","volume":"66","author":"Johnson","year":"2015","journal-title":"Histopathology."},{"key":"2025052712492673900_CIT0011","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/26155","article-title":"Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a","volume":"395","author":"Russo","year":"1998","journal-title":"Nature."},{"key":"2025052712492673900_CIT0012","doi-asserted-by":"publisher","first-page":"332","DOI":"10.6092\/1590-8577\/841","article-title":"Molecular biology of pancreatic cancer: how useful is it in clinical practice","volume":"13","author":"Sakorafas","year":"2012","journal-title":"JOP."},{"key":"2025052712492673900_CIT0013","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/nature24462","article-title":"Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer","volume":"551","author":"Balachandran","year":"2017","journal-title":"Nature."},{"key":"2025052712492673900_CIT0014","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1038\/s41388-022-02184-2","article-title":"Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism","volume":"41","author":"Journo","year":"2022","journal-title":"Oncogene."},{"key":"2025052712492673900_CIT0015","doi-asserted-by":"publisher","first-page":"e02872","DOI":"10.7554\/eLife.02872","article-title":"Cyclin D activates the Rb tumor suppressor by mono-phosphorylation","volume":"3","author":"Narasimha","year":"2014","journal-title":"Elife"},{"key":"2025052712492673900_CIT0016","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1158\/1078-0432.CCR-15-0548","article-title":"Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas","volume":"22","author":"Tang","year":"2016","journal-title":"Clin Cancer Res."},{"key":"2025052712492673900_CIT0017","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1507\/endocrj.EJ22-0010","article-title":"Significance of interstitial fibrosis and p16 in papillary thyroid carcinoma","volume":"69","author":"Wang","year":"2022","journal-title":"Endocr J."},{"key":"2025052712492673900_CIT0018","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1097\/PAI.0000000000001124","article-title":"Expression of human papillomavirus and the p16 gene in oral potentially malignant disorders (OPMD): a comparative study with oral squamous cell carcinoma","volume":"31","author":"Baddevithana","year":"2023","journal-title":"Appl Immunohistochem Mol Morphol."},{"key":"2025052712492673900_CIT0019","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1111\/j.1582-4934.2002.tb00188.x","article-title":"MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis","volume":"6","author":"Demopoulos","year":"2002","journal-title":"J Cell Mol Med."},{"key":"2025052712492673900_CIT0020","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12931-022-02067-w","article-title":"Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival","volume":"23","author":"Keow","year":"2022","journal-title":"Respir Res."},{"key":"2025052712492673900_CIT0021","doi-asserted-by":"publisher","first-page":"e001010","DOI":"10.1136\/lupus-2023-001010","article-title":"p16 Ink4a, a marker of cellular senescence, is associated with renal disease in the B6. NZMSle1\/Sle2\/Sle3 mouse model of lupus","volume":"10","author":"Tilman","year":"2023","journal-title":"Lupus Sci Med."},{"key":"2025052712492673900_CIT0022","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s12884-023-05476-x","article-title":"Loss of p16 does not protect against premature ovarian insufficiency caused by alkylating agents","volume":"23","author":"Liu","year":"2023","journal-title":"BMC Pregnancy Childbirth."},{"key":"2025052712492673900_CIT0023","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1097\/HEP.0000000000000307","article-title":"p16 INK4A drives nonalcoholic fatty liver disease phenotypes in high fat diet fed mice through biliary E2F1\/FOXO1\/IGF-1 signaling","volume":"78","author":"Kundu","year":"2023","journal-title":"Hepatology."}],"container-title":["American Journal of Clinical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajcp\/article-pdf\/163\/5\/758\/61621345\/aqae184.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajcp\/article-pdf\/163\/5\/758\/61621345\/aqae184.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T16:49:47Z","timestamp":1748364587000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajcp\/article\/163\/5\/758\/7978856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,1,24]]},"published-print":{"date-parts":[[2025,5,17]]}},"URL":"https:\/\/doi.org\/10.1093\/ajcp\/aqae184","relation":{},"ISSN":["0002-9173","1943-7722"],"issn-type":[{"value":"0002-9173","type":"print"},{"value":"1943-7722","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,5]]},"published":{"date-parts":[[2025,1,24]]}}}