{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:39:12Z","timestamp":1777894752845,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: This study evaluated the diagnostic accuracy of cervical cytology, CINtec\u00ae (p16\/Ki-67 dual staining), and PD-L1 immunohistochemistry, individually and in combination with high-risk HPV (HR-HPV) testing, for identifying histologically confirmed cervical lesions ranging from CIN1 to invasive carcinoma. Methods: We conducted a prospective cross-sectional study including 114 patients who underwent cervical cytology, CINtec\u00ae, PD-L1 staining, HPV genotyping, and histopathologic confirmation at a tertiary clinical center between September 2024 and September 2025. Sensitivity, specificity, PPV, NPV, and ROC performance were calculated for each test across lesion categories. Multivariable logistic regression models incorporating HR-HPV status were used to assess added predictive value. Results: All tests showed poor performance for CIN1 (cytology AUC 0.488; CINtec\u00ae 0.374; PD-L1 0.366). Diagnostic accuracy improved markedly with lesion severity. For CIN3, CINtec\u00ae demonstrated the highest discriminative ability (AUC 0.826), with cytology and PD-L1 also performing well (AUC 0.820 and 0.753). Cytology achieved the strongest ROC performance for CIN2+ (AUC 0.937), CIN3+ (0.913), and invasive carcinoma (0.887). PD-L1 consistently showed lower accuracy across categories. Cytology + HR-HPV demonstrated the highest AUC across all lesion categories. Conclusions: Cytology and CINtec\u00ae exhibited strong diagnostic accuracy for high-grade lesions, while PD-L1 showed limited utility as an independent screening marker. Combining cytology with HR-HPV testing enhanced predictive performance across all lesion categories. These findings support the continued use of cytology-based triage and highlight CINtec\u00ae as a valuable adjunct for high-grade disease detection. Because this study used a high-prevalence referral cohort, specificity may be overestimated and not representative of population-based screening.<\/jats:p>","DOI":"10.3390\/jcm15031171","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T15:38:12Z","timestamp":1770046692000},"page":"1171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prospective Evaluation of Cytology, CINtec\u00ae and PD-L1 for the Detection of Cervical Intraepithelial Neoplasia: A Single-Center Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2494-1801","authenticated-orcid":false,"given":"Alexandru","family":"Hamod","sequence":"first","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihaela","family":"Grigore","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-392X","authenticated-orcid":false,"given":"Ingrid-Andrada","family":"Vasilache","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-7923","authenticated-orcid":false,"given":"Ramona-Gabriela","family":"Ursu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oancea","family":"Mihaela","sequence":"additional","affiliation":[{"name":"IInd Department of Obstetrics Gynecology, Iuliu Ha\u0163ieganu University of Medicine and Pharmacy Cluj-Napoca, 13 Emil Isac, 400023 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Razvan","family":"Popovici","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana-Maria","family":"Grigore","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3994-6579","authenticated-orcid":false,"given":"Ludmila","family":"Lozneanu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan-Constantin","family":"Andronic","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9240-2175","authenticated-orcid":false,"given":"Manuela","family":"Ciocoiu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/jnci\/djv257","article-title":"p16\/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women","volume":"107","author":"Wentzensen","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gisca, T., Munteanu, I.-V., Vasilache, I.-A., Melinte-Popescu, A.-S., Volovat, S., Scripcariu, I.-S., Balan, R.-A., Pavaleanu, I., Socolov, R., and Carauleanu, A. (2024). A prospective study on the progression, recurrence, and regression of cervical lesions: Assessing various screening approaches. J. Clin. Med., 13.","DOI":"10.20944\/preprints202402.1219.v1"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Munteanu, I.V., Socolov, D., Socolov, R., Adam, A.M., Adam, G., Vasilache, I.A., Vicoveanu, P., Harabor, V., Harabor, A., and Calin, A.M. (2025). Clinical and Virological Profiles Associated with CINTEC\u00ae PLUS Positivity: A Data-Driven Clustering and Modeling Study. Diagnostics, 15.","DOI":"10.3390\/diagnostics15172200"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.20953\/1726-1678-2025-1-97-103","article-title":"Clinical evaluation of p16\/Ki-67 dual staining in cervical cytology","volume":"24","author":"Poznyak","year":"2025","journal-title":"Vopr. Ginekol. Aku\u0161erstva I Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.7150\/jca.32743","article-title":"Application of p16\/Ki-67 dual-staining cytology in cervical cancers","volume":"10","author":"Yu","year":"2019","journal-title":"J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/ijgo.70432","article-title":"Application of P16\/Ki-67 dual-staining for the detection of high-grade cervical lesions in the triage of patients with minor abnormal cytology: A meta-analysis","volume":"172","author":"Zhang","year":"2025","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_8","first-page":"1","article-title":"p16\/Ki-67 dual staining as a predictive value for cervical cancer compared to other conventional triage tools: A descriptive literature review","volume":"45","author":"Crespo","year":"2024","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"ref_9","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":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S422","DOI":"10.1093\/advances\/nmz081","article-title":"Plant-Based Dietary Patterns, Plant Foods, and Age-Related Cognitive Decline","volume":"10","author":"Rajaram","year":"2019","journal-title":"Adv. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.21873\/anticanres.15738","article-title":"p16\/Ki-67 Dual Staining Is a Reliable Biomarker for Risk Stratification for Patients with Borderline\/Mild Cytology in Cervical Cancer Screening","volume":"42","author":"Magkana","year":"2022","journal-title":"Anticancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1038\/modpathol.2015.108","article-title":"Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers","volume":"28","author":"Mezache","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13000-017-0631-6","article-title":"Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas","volume":"12","author":"Reddy","year":"2017","journal-title":"Diagn. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.3802\/jgo.2024.35.e105","article-title":"Prevalence and prognostic value of PD-L1 expression and tumor mutational burden in persistent, recurrent, or metastatic cervical cancer","volume":"35","author":"Baek","year":"2024","journal-title":"J. Gynecol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/s41379-021-00780-3","article-title":"Clinicopathologic and genomic characterization of PD-L1-positive uterine cervical carcinoma","volume":"34","author":"Huang","year":"2021","journal-title":"Mod. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhao, D., Zhang, L., Xie, F., Peng, D., Wei, J., Jiang, L., Zhang, S., and Qi, D. (2020). Outcomes of prior cervical cytology and HR-HPV testing in women subsequently diagnosed with CIN1, CIN2\/3, and invasive cervical cancer: A 4-year routine clinical experience after implementation of systematic training and quality control programs. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07321-2"},{"key":"ref_17","first-page":"132","article-title":"Evaluation of p16INK4a\/Ki-67 Dual Immunostaining in Liquid-based Cytology for Diagnosis of Uterine Cervical Dysplasia and Cancer","volume":"47","author":"Sung","year":"2015","journal-title":"J. Clin. Lab. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/PGP.0000000000001035","article-title":"LINE-1 ORF1p is a Promising Biomarker in Cervical Intraepithelial Neoplasia Degree Assessment","volume":"44","author":"Karkas","year":"2024","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3892\/ol.2016.5441","article-title":"Cervical intraepithelial neoplasia in pregnancy: Interference of pregnancy status with p16 and Ki-67 protein expression","volume":"13","author":"Ciavattini","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_20","first-page":"516","article-title":"The Clinical Significance of HPV L1\/PD-L1 Tests Combined with Colposcopy for Cervical Precancerous Lesions and Cervical Cancer","volume":"52","author":"Luo","year":"2021","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban J. Sichuan Univ. Med. Sci. Ed."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lu, Z., Knapp, M., Downs, S., Ali, R., Morgan, T., Ruff, H., Qin, X., and Fan, G. (2025). Retrospective Analysis of Human Papillomavirus Genotyping and Cytology (Pap Smears) in Cervical Cancer Screening: An Institutional Experience in the State of Oregon, USA. Diagnostics, 15.","DOI":"10.3390\/diagnostics15040419"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"S\u00f8rbye, S.W., Suhrke, P., Rev\u00e5, B.W., Berland, J., Maurseth, R., and Al-Shibli, K. (2017). Accuracy of cervical cytology: Comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway. BMC Clin. Pathol., 17.","DOI":"10.1186\/s12907-017-0058-8"},{"key":"ref_23","first-page":"CD008587","article-title":"Cytology versus HPV testing for cervical cancer screening in the general population","volume":"8","author":"Koliopoulos","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mikalsen, M.P., Simonsen, G.S., and S\u00f8rbye, S.W. (2024). Impact of HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) in Women Aged 20\u201325 in the Northern Part of Norway: A 15-Year Study. Vaccines, 12.","DOI":"10.3390\/vaccines12040421"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S587","DOI":"10.4103\/0973-1482.183216","article-title":"Meta-analysis on the performance of p16\/Ki-67 dual immunostaining in detecting high-grade cervical intraepithelial neoplasm","volume":"14","author":"Sun","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.1158\/1078-0432.CCR-12-0270","article-title":"Performance of p16\/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population","volume":"18","author":"Wentzensen","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1002\/ijc.29290","article-title":"Triaging HPV-positive women with normal cytology by p16\/Ki-67 dual-stained cytology testing: Baseline and longitudinal data","volume":"136","author":"Uijterwaal","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"\u00d8vestad, I.T., Dalen, I., Andersland, M.S., Vintermyr, O.K., Moltu, P., Berland, J.M., Janssen, E.A.M., and Haugland, H.K. (2023). Triaging HPV-Positive Cervical Samples with p16 and Ki-67 Dual Stained Cytology within an Organized Screening Program-A Prospective Observational Study from Western Norway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087158"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e29271","DOI":"10.1002\/jmv.29271","article-title":"p16\/Ki67 dual stain triage versus cytology in primary human papillomavirus-based cervical cancer screening with limited genotyping","volume":"95","author":"Trzeszcz","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"155712","DOI":"10.1016\/j.prp.2024.155712","article-title":"The role of programmed death-ligand 1 (PDL-1) in high-grade cervical intraepithelial neoplasia (CIN2+) development and recurrence: A systematic review of literature about HPV-CIN2+-PDL-1 axis","volume":"264","author":"Dominoni","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/aogs.15019","article-title":"High rate of persistent HPV detection after diagnostic cervical excision in older screen-positive women","volume":"104","author":"Gustafson","year":"2025","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_32","first-page":"492","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":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e70405","DOI":"10.1002\/jmv.70405","article-title":"Improving Detection of CIN2+ and CIN3+ Lesions: Evaluation of E6\/E7 mRNA, P16, and Ki-67, Individually and in Combination","volume":"97","author":"Huang","year":"2025","journal-title":"J. Med. Virol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1171\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T05:12:45Z","timestamp":1770613965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["jcm15031171"],"URL":"https:\/\/doi.org\/10.3390\/jcm15031171","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]}}}