{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T09:30:50Z","timestamp":1782207050917,"version":"3.54.5"},"reference-count":37,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015459","name":"Danish Cancer Society Research Center","doi-asserted-by":"publisher","award":["R248\u2010A14476"],"award-info":[{"award-number":["R248\u2010A14476"]}],"id":[{"id":"10.13039\/100015459","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008262","name":"Harboefonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008262","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010983","name":"Health Research Fund of Central Denmark Region","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010983","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cervical intraepithelial neoplasia grade 2 (CIN2) is a heterogeneous diagnosis with a high likelihood of spontaneous regression. Therefore, active surveillance for CIN2 has been implemented as an option in younger women in many countries. Yet, little is known about markers that may accurately predict the likelihood of regression to support active surveillance. Here, we aimed to assess whether p16<jats:sup>INK4a<\/jats:sup> and HPV E4 status are associated with the likelihood of CIN2 regression. We conducted a historical cohort study on women aged 23\u201340 diagnosed with untreated CIN2 following cytology\u2010based screening. Women were diagnosed at Aarhus University Hospital, Denmark from January 2000 to December 2010. Archived tissue samples were sectioned for p16<jats:sup>INK4a<\/jats:sup> and HPV E4 immunohistochemistry and HPV genotyping. We used a modified Poisson model to estimate the relative risk of regression, adjusting for age and cytology (aRR). A total of 443 women with CIN2 were included. Most women (73.8%) were aged \u226430, and half had a high\u2010grade cytology (48.8%). Overall, 47.6% regressed, and regression was less likely in p16<jats:sup>INK4a<\/jats:sup>\u2010positive compared to p16<jats:sup>INK4a<\/jats:sup>\u2010negative women (aRR 0.77; 95% CI 0.64\u20130.94). Among p16<jats:sup>INK4a<\/jats:sup>\u2010positive women, the risk of regression varied by HPV type and HPVE4 status, with lower risk in HPV16\u2010positive women compared to those without (aRR 0.54; 95% CI 0.40\u20130.75) and in HPVE4\u2010negative compared to HPVE4 positive women (aRR 0.73; 95% CI 0.54\u20130.98). When we restricted to expert\u2010confirmed CIN2, the risk of regression did not vary by p16<jats:sup>INK4a<\/jats:sup> or HPVE4 status, while HPV16 positive remained at a lower risk of regression compared to women without HPV16.<\/jats:p>","DOI":"10.1002\/ijc.35469","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T09:49:22Z","timestamp":1746438562000},"page":"1294-1303","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>p16<sup>INK4a<\/sup><\/scp> and <scp>HPV E4<\/scp> immunohistochemistry for the prediction of regression of cervical intraepithelial neoplasia grade 2\u2014A historical cohort study"],"prefix":"10.1002","volume":"157","author":[{"given":"Rikke","family":"Damgaard","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, NIDO \u2010 Centre for Research and Education G\u00f8dstrup Hospital  Herning Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Cerba Research  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark H.","family":"Stoler","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Virginia Health  Charlottesville VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miekel","family":"van de Sandt","sequence":"additional","affiliation":[{"name":"Cerba Research  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurits N. C.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Cerba Research  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G. V.","family":"Quint","sequence":"additional","affiliation":[{"name":"Cerba Research  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, NIDO \u2010 Centre for Research and Education G\u00f8dstrup Hospital  Herning Denmark"},{"name":"Department of Clinical Epidemiology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patti E.","family":"Gravitt","sequence":"additional","affiliation":[{"name":"Division of Global Health National Cancer Institute  Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Steiniche","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, NIDO \u2010 Centre for Research and Education G\u00f8dstrup Hospital  Herning Denmark"},{"name":"Department of Pathology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lone K.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Medicine University of Southern Denmark  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4616-9827","authenticated-orcid":false,"given":"Anne","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, NIDO \u2010 Centre for Research and Education G\u00f8dstrup Hospital  Herning Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k499"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2023.08.008"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000004705"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2024.01.029"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2022.06.051"},{"key":"e_1_2_12_7_1","first-page":"705","article-title":"Expression of E6\/E7 mRNA from \u2018high risk\u2019 human papillomavirus in relation to CIN grade, viral load and p16INK4a","volume":"29","author":"Andersson S","year":"2006","journal-title":"Int J Oncol"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cyt.12299"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-200309000-00013"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2019-000343"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2010.06.011"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000498"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000984"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2018.08.011"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2013.07.008"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33566"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2855"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.18342"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/0284186X.2017.1355110"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1258\/096914106776179773"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1926"},{"key":"e_1_2_12_22_1","unstructured":"Danish National Guidelines for examination treatment and control of cervical dysplasia 2012 p. 1\u201326.2012."},{"key":"e_1_2_12_23_1","unstructured":"Health DNBo.Danish National Guidelines. 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