{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:03:23Z","timestamp":1793117003501,"version":"4.5.0"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The implementation of high-risk human papillomavirus testing (hrHPV testing) as a screening method in substitute for cytology has evoked the need for more sensitive and less objective tests for the triage of HPV-positive women. In a cohort of 1763 HPV-positive women, the potential of immunocytochemical p16 and Ki-67 dual staining as compared to cytology, alone or in combination with HPV partial genotyping, was tested for triage of women attending a cervical cancer screening program. Performance was measured using sensitivity, specificity, and positive and negative predictive values. Comparisons were assessed using logistic regression models and the McNemar test. Dual staining was evaluated in a prospectively collected study cohort of 1763 HPV-screened women. For triage of CIN2+ and CIN3+, NPV and sensitivity, 91.8% and 94.2% versus 87.9% and 89.7%, respectively, were significantly higher using dual staining together with HPV 16\/18 positive, as compared to cytology (p &lt; 0.001). The specificities, however, were lower for dual staining as compared to cytology. Conclusions: Dual staining is safer for decision-making regarding HPV-positive women\u2019s need for follow-up with colposcopy and biopsy, as compared to cytology.<\/jats:p>","DOI":"10.3390\/ijms24087158","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T02:29:15Z","timestamp":1681352955000},"page":"7158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Triaging HPV-Positive Cervical Samples with p16 and Ki-67 Dual Stained Cytology within an Organized Screening Program\u2014A Prospective Observational Study from Western Norway"],"prefix":"10.3390","volume":"24","author":[{"given":"Irene Tveiter\u00e5s","family":"\u00d8vestad","sequence":"first","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8160-3211","authenticated-orcid":false,"given":"Ingvild","family":"Dalen","sequence":"additional","affiliation":[{"name":"Department of Research, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie S.","family":"Andersland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Haukeland University Hospital, 5053 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav K.","family":"Vintermyr","sequence":"additional","affiliation":[{"name":"Department of Pathology, Haukeland University Hospital, 5053 Bergen, Norway"},{"name":"Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Moltu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannicke M.","family":"Berland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-5396","authenticated-orcid":false,"given":"Emilius A. M.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"},{"name":"Department of Chemistry, Bioscience and Environmental Technology, University of Stavanger, 4021 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Kristian","family":"Haugland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Haukeland University Hospital, 5053 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F","article-title":"Human papillomavirus is a necessary cause of invasive cervical cancer worldwide","volume":"189","author":"Walboomers","year":"1999","journal-title":"J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"F24","DOI":"10.1016\/j.vaccine.2012.05.089","article-title":"Updating the Natural History of Human Papillomavirus and Anogenital Cancers","volume":"30","author":"Moscicki","year":"2012","journal-title":"Vaccine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/ijc.27828","article-title":"Patterns of persistent genital human papillomavirus infection among women worldwide: A literature review and meta-analysis","volume":"133","author":"Rositch","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1158\/1055-9965.EPI-06-0846","article-title":"Incidence and Duration of Cervical Human Papillomavirus 6, 11, 16, and 18 Infections in Young Women: An Evaluation from Multiple Analytic Perspectives","volume":"16","author":"Insinga","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1002\/ijc.32195","article-title":"Recent increase in incidence of cervical precancerous lesions in Norway: Nationwide study from 1992 to 2016","volume":"145","author":"Orumaa","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a1754","DOI":"10.1136\/bmj.a1754","article-title":"Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: Joint European cohort study","volume":"337","author":"Dillner","year":"2008","journal-title":"BMJ"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1001\/jama.2018.7464","article-title":"Effect of Screening with Primary Cervical HPV Testing vs. Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months","volume":"320","author":"Ogilvie","year":"2018","journal-title":"JAMA"},{"key":"ref_8","first-page":"46","article-title":"Baseline Cytology, Human Papillomavirus Testing, and Risk for Cervical Neoplasia: A 10-Year Cohort Analysis","volume":"95","author":"Sherman","year":"2003","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1002\/ijc.29374","article-title":"Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology","volume":"137","author":"Thomsen","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S0140-6736(13)62218-7","article-title":"Efficacy of HPV-based screening for prevention of invasive cervical cancer: Follow-up of four European randomised controlled trials","volume":"383","author":"Ronco","year":"2014","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"g130","DOI":"10.1136\/bmj.g130","article-title":"Long term duration of protective effect for HPV negative women: Follow-up of primary HPV screening randomised controlled trial","volume":"348","author":"Smelov","year":"2014","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1038\/s41416-020-0790-1","article-title":"Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening","volume":"122","author":"Hashim","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1158\/1055-9965.EPI-22-0340","article-title":"Randomized Implementation of a Primary Human Papillomavirus Testing\u2013based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway","volume":"31","author":"Castle","year":"2022","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1038\/s41416-020-0787-9","article-title":"Triage of HPV-positive women in Norway using cytology, HPV16\/18 genotyping and HPV persistence","volume":"122","author":"Arbyn","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1002\/ijc.30926","article-title":"How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination","volume":"141","author":"Velentzis","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s10552-016-0732-7","article-title":"The potential harms of primary human papillomavirus screening in over-screened women: A microsimulation study","volume":"27","author":"Naber","year":"2016","journal-title":"Cancer Causes Control"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.1016\/j.jcv.2015.11.015","article-title":"Triage of HPV positive women in cervical cancer screening","volume":"76","author":"Wentzensen","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/path.4424","article-title":"Are 20 human papillomavirus types causing cervical cancer?","volume":"234","author":"Arbyn","year":"2014","journal-title":"J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/JOC.JOC_173_20","article-title":"Validation of CINtec\u00ae PLUS cytology kit in the diagnosis of persistent HPV infections\u2014Cohort study in the Portuguese population","volume":"38","author":"Fernandes","year":"2021","journal-title":"J. Cytol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/ijc.33250","article-title":"Dual staining for p16\/Ki-67 to detect high-grade cervical lesions: Results from the Screening Triage Ascertaining Intraepithelial Neoplasia by Immunostain Testing study","volume":"148","author":"Gotlieb","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100206","DOI":"10.1016\/j.pvr.2020.100206","article-title":"CINtec PLUS and cobas HPV testing for triaging Canadian women referred to colposcopy with a history of low-grade squamous intraepithelial lesion: Baseline findings","volume":"10","author":"Ratnam","year":"2020","journal-title":"Papillomavirus Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/ijc.33812","article-title":"Clinical validation of p16\/Ki-67 dual-stained cytology triage of HPV -positive women: Results from the IMPACT trial","volume":"150","author":"Wright","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ctrv.2008.10.005","article-title":"p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: A systematic review and meta-analysis","volume":"35","author":"Tsoumpou","year":"2009","journal-title":"Cancer Treat. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1136\/jclinpath-2018-205271","article-title":"Three-tiered score for Ki-67 and p16(ink4a) improves accuracy and reproducibility of grading CIN lesions","volume":"71","author":"Leeman","year":"2018","journal-title":"J. Clin. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1136\/amiajnl-2011-000536","article-title":"Use of electronic health record data to evaluate overuse of cervical cancer screening","volume":"19","author":"Mathias","year":"2012","journal-title":"J. Am. Med. Inform. Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1086\/425907","article-title":"Incidence, Duration, and Determinants of Cervical Human Papillomavirus Infection in a Cohort of Colombian Women with Normal Cytological Results","volume":"190","author":"Posso","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1001\/jamainternmed.2019.0306","article-title":"Clinical Evaluation of Human Papillomavirus Screening With p16\/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program","volume":"179","author":"Wentzensen","year":"2019","journal-title":"JAMA Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ajcp\/aqy073","article-title":"Clinical Utility of CINtec PLUS Triage in Equivocal Cervical Cytology and Human Papillomavirus Primary Screening","volume":"150","author":"McMenamin","year":"2018","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"k499","DOI":"10.1136\/bmj.k499","article-title":"Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: Systematic review and meta-analysis","volume":"360","author":"Tainio","year":"2018","journal-title":"BMJ"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/cyt.12426","article-title":"Intra- and inter-observer reproducibility of CINtec\u00aePLUSin ThinPrep\u00aecytology preparations","volume":"28","author":"McMenamin","year":"2017","journal-title":"Cytopathology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1001\/jama.287.16.2114","article-title":"The 2001 Bethesda SystemTerminology for Reporting Results of Cervical Cytology","volume":"287","author":"Solomon","year":"2002","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.0006-341X.2000.00345.x","article-title":"Comparisons of Predictive Values of Binary Medical Diagnostic Tests for Paired Designs","volume":"56","author":"Leisenring","year":"2000","journal-title":"Biometrics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:14:52Z","timestamp":1760123692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,12]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087158"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087158","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,12]]}}}