{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:41:16Z","timestamp":1787510476135,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Very limited information exists about the role of p16\/Ki67 dual staining on glandular cells in detecting glandular precancerous lesions and cervical adenocarcinoma. In this study, we investigated the diagnostic accuracy of p16\/Ki67 dual staining for the detection of glandular and squamous lesions on the uterine cervix and for cancer of the upper reproductive tract. We performed a retrospective analysis of prospectively collected data on 96 patients with glandular cell abnormalities. We analyzed the diagnostic accuracy of p16\/Ki67 dual staining for atypical glandular cells, not otherwise specified (AGC-NOS); atypical glandular cells, favor neoplastic (AGC-FN); adenocarcinoma in situ (AIS); and A-CA (cervical adenocarcinoma). A separate analysis for the detection of squamous precancerous lesions and squamous-cell carcinoma (CIN3+) and for cancer of the upper reproductive tract (EC\/OC) was performed. Among patients who had normal histology or a low-grade lesion on final analysis, only 8.5% had positive dual staining. On the other hand, 85.7% of patients with AIS+ on final histology had positive dual staining. The respective specificities of p16\/Ki67 dual staining on AGC-NOS for the detection of AIS+ (adenocarcinoma in situ or cervical adenocarcinoma), CIN3+ and EC\/OC were 91.5%, 88.7% and 86.4%. High specificity values of p16\/Ki67 dual staining on cervical smears labelled as AGC-NOS for the detection of CIN3+ and AIS+ suggest that this method might be a useful addition in cervical cancer screening.<\/jats:p>","DOI":"10.3390\/cancers16091621","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T08:08:27Z","timestamp":1713859707000},"page":"1621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["P16\/Ki67 Dual Staining in Glandular Cell Abnormalities of the Uterine Cervix"],"prefix":"10.3390","volume":"16","author":[{"given":"Sa\u0161a","family":"Jeromel","sequence":"first","affiliation":[{"name":"Medical Faculty, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alenka","family":"Rep\u0161e Fokter","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cytology, General Hospital Celje, Oblakova 5, 3000 Celje, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andra\u017e","family":"Dovnik","sequence":"additional","affiliation":[{"name":"Medical Faculty, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia"},{"name":"University Clinic for Gynaecology and Obstetrics, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","unstructured":"Ayhan, A., Reed, N., Gultekin, M., and Dursun, P. (2016). Textbook of Gynaecological Oncology, European Society of Gynaecological Oncology. [2nd ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1097\/AOG.0b013e3181e4629f","article-title":"From human papillomavirus to cervical cancer","volume":"116","author":"Schiffman","year":"2010","journal-title":"Obstet. Gynecol."},{"key":"ref_3","first-page":"11","article-title":"Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer","volume":"15","author":"Sen","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.cmi.2019.09.006","article-title":"Primary HPV-based cervical cancer screening in Europe: Implementation status, challenges, and future plans","volume":"26","author":"Maver","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1158\/1055-9965.EPI-13-0173","article-title":"Primary hrHPV DNA testing in cervical cancer screening: How to manage screen-positive women? A POBASCAM trial substudy","volume":"23","author":"Dijkstra","year":"2014","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/ijc.26056","article-title":"Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening","volume":"130","author":"Rijkaart","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8476","DOI":"10.3390\/cimb45100534","article-title":"The Role of p16\/Ki67 Dual Staining in Cervical Cancer Screening","volume":"45","author":"Dovnik","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1093\/jnci\/djt235","article-title":"Screening for cervical cancer precursors with p16\/Ki-67 dual-stained cytology: Results of the PALMS study","volume":"105","author":"Ikenberg","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/LGT.0b013e31828aeb39","article-title":"Improved abnormal Pap smear triage using cervical cancer biomarkers","volume":"18","author":"Killeen","year":"2014","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/cncy.21542","article-title":"Prospective evaluation of p16\/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results","volume":"123","author":"Bergeron","year":"2015","journal-title":"Cancer Cytopathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"djv257","DOI":"10.1093\/jnci\/djv257","article-title":"p16\/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-PositiveWomen","volume":"107","author":"Wentzensen","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_12","unstructured":"Ayhan, A., Reed, N., Gultekin, M., and Dursun, P. (2016). Textbook of Gynaecological Oncology, European Society of Gynaecological Oncology. [2nd ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.semradonc.2021.02.006","article-title":"Biology of HPV Mediated Carcinogenesis and Tumor Progression","volume":"31","author":"Cosper","year":"2021","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000528931","article-title":"Overview of Ancillary Techniques in Cervical Cytology","volume":"67","author":"Olivas","year":"2023","journal-title":"Acta Cytol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/cncy.20140","article-title":"p16\/ki-67 dual-stain cytology in the triage of ASCUS and LSIL papanicolaou cytology: Results from the European equivocal or mildly abnormal Papanicolaou cytology study","volume":"119","author":"Schmidt","year":"2011","journal-title":"Cancer Cytopathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/cncy.21233","article-title":"Evaluation of p16(INK4a)\/Ki-67 dual stain in comparison with an mRNA humanpapillomavirus test on liquid-based cytology samples with low-grade squamous intraepithelial lesion","volume":"121","author":"Christensen","year":"2013","journal-title":"Cancer Cytopathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1002\/cncy.22631","article-title":"Utility of p16\/Ki67 double immunocytochemistry for detection of cervical adenocarcinoma","volume":"130","author":"Ryu","year":"2022","journal-title":"Cancer Cytopathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1158\/0008-5472.CAN-18-3109","article-title":"Epidemiologic and clinical analysis of cervical cancer using data from the population-based Osaka cancer registry","volume":"79","author":"Yagi","year":"2019","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/cam4.971","article-title":"Increasing incidence of invasive and in situ cervical adenocarcinoma in the Netherlands during 2004\u20132013","volume":"6","author":"Siebers","year":"2017","journal-title":"Cancer Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/gyno.2000.5826","article-title":"The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States\u2014A 24-year population-based study","volume":"78","author":"Smith","year":"2000","journal-title":"Gynecol. Oncol."},{"key":"ref_21","first-page":"1151","article-title":"Cervical cancer: The increasing incidence of adenocarcinoma and adenosquamous carcinoma in younger women","volume":"164","author":"Liu","year":"2001","journal-title":"CMAJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejogrb.2019.06.006","article-title":"Glandular cell abnormalities in cervical cytology: What has changed in this decade and what has not?","volume":"240","author":"Kumar","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1158\/1055-9965.EPI-05-0231","article-title":"Incidence trends of adenocarcinoma of the cervix in 13 European countries","volume":"14","author":"Bray","year":"2005","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giannella, L., Di Giuseppe, J., Delli Carpini, G., Grelloni, C., Fichera, M., Sartini, G., Caimmi, S., Natalini, L., and Ciavattini, A. (2022). HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315022"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/cncy.21724","article-title":"Clinical significance of atypical glandular cells in Pap tests: An analysis of more than 3000 cases at a large academic women\u2019s center","volume":"124","author":"Pradhan","year":"2016","journal-title":"Cancer Cytopathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"203","DOI":"10.4103\/JOC.JOC_209_16","article-title":"Histological Follow-Up in Patients with Atypical Glandular Cells on Pap Smears","volume":"34","author":"Boyraz","year":"2017","journal-title":"J. Cytol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.5468\/OGS.2013.56.2.76","article-title":"Clinicopathological significance of atypical glandular cells on Pap smear","volume":"56","author":"Kim","year":"2013","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1525-1438.2006.00346.x","article-title":"A cytohistologic study of atypical glandular cells detected in cervical smears during cervical screening tests in Iran","volume":"16","author":"Mood","year":"2006","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21181","DOI":"10.18632\/oncotarget.8307","article-title":"Evaluation of p16\/Ki-67 dual staining in detection of cervical precancer and cancers: A multicenter study in China","volume":"7","author":"Yu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1309\/AJCP00INMGIFYFNQ","article-title":"CINtec PLUS immunocytochemistry as a tool for the cytologic diagnosis of glandular lesions of the cervix uteri","volume":"138","author":"Ravarino","year":"2012","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/cncy.20188","article-title":"Immunocytochemical colocalization of P16(INK4a) and Ki-67 predicts CIN2\/3 and AIS\/adenocarcinoma","volume":"120","author":"Singh","year":"2012","journal-title":"Cancer Cytopathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/1097-0142(20010225)93:1<8::AID-CNCR9001>3.0.CO;2-K","article-title":"Papanicolaou smear sensitivity for the detection of adenocarcinoma of the cervix: A study of 49 cases","volume":"93","author":"Krane","year":"2001","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/01.PGP.0000055172.04957.2F","article-title":"p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma","volume":"22","author":"McCluggage","year":"2003","journal-title":"Int. J. Gynecol. Pathol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/9\/1621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:32:35Z","timestamp":1760106755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/9\/1621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,23]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["cancers16091621"],"URL":"https:\/\/doi.org\/10.3390\/cancers16091621","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,23]]}}}