{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:22:04Z","timestamp":1790792524357,"version":"4.1.0"},"reference-count":73,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Cervical intraepithelial neoplasia grade 2 (CIN2) represents a controversial lesion in cervical cancer prevention. Traditionally included in the aggregate CIN2+ endpoint for reasons of diagnostic stability and statistical power, isolated CIN2 has unique biological characteristics: greater interobserver variability, a high probability of spontaneous regression and a lower risk of progression compared to CIN3. Objectives: To critically describe the epidemiology, natural history and management strategies of CIN2, integrating data from clinical and population-based studies and comparing the recommendations of the main international guidelines. Methods: A narrative review was conducted using a search of PubMed and Scopus (1990\u2013January 2025). Prospective and retrospective studies on isolated CIN2, screening and vaccination trials with CIN2+ endpoints, biomarker research, and consensus documents (ASCCP, ESGO, GISCi, Ministry of Health, WHO) were included. Results: Clinical studies have shown a high probability of CIN2 regression (50\u201370% within two years, &gt;70% in those &lt;25 years), compared to a 10\u201315% risk of progression, especially in the presence of persistent HPV16. Screening trials and vaccine evaluations with CIN2+ endpoints have documented the efficacy of the HPV test and a dramatic reduction in lesions in vaccinated cohorts, which was also confirmed for isolated CIN2. The most recent guidelines have progressively adopted a risk-based approach, which allows for active surveillance in young women or those seeking to conceive, while the WHO maintains a screen-and-treat model in resource-limited countries. Conclusions: CIN2 is not a lesion to be treated automatically, but rather a paradigmatic model for personalized management. Integrating epidemiological and clinical data, supported by biomarkers, allows for reducing overtreatment without compromising oncological safety.<\/jats:p>","DOI":"10.3390\/diagnostics15192512","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T15:07:48Z","timestamp":1759417668000},"page":"2512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CIN2 in the Era of Risk-Based Management and HPV Vaccination: Epidemiology, Natural History and Guidelines"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1557-1538","authenticated-orcid":false,"given":"Maria Teresa","family":"Bruno","sequence":"first","affiliation":[{"name":"Department of General Surgery and Medical Surgery Specialties, Gynecological Clinic, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9690-8198","authenticated-orcid":false,"given":"Alessia","family":"Pagana","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Medical Surgery Specialties, Gynecological Clinic, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Lo Giudice","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Medical Surgery Specialties, Gynecological Clinic, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Marzio","family":"Panella","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Medical Surgery Specialties, Gynecological Clinic, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7481-623X","authenticated-orcid":false,"given":"Giuseppe","family":"Mascellino","sequence":"additional","affiliation":[{"name":"Unit of Obstetrics and Gynecology, \u201cPaolo Giaccone\u201d Hospital, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1543-2802","authenticated-orcid":false,"given":"Antonio Simone","family":"Lagan\u00e0","sequence":"additional","affiliation":[{"name":"Unit of Obstetrics and Gynecology, \u201cPaolo Giaccone\u201d Hospital, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1136\/jcp.55.4.244","article-title":"The causal relation between human papillomavirus and cervical cancer","volume":"55","author":"Bosch","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S0140-6736(13)62218-7","article-title":"International HPV screening working group. 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_3","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S1473-3099(14)71073-4","article-title":"Population-level impact and herd effects following human papillomavirus vaccination programmes: A systematic review and meta-analysis","volume":"15","author":"Drolet","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1097\/00004347-199304000-00018","article-title":"Natural history of cervical intraepithelial neoplasia: A critical review","volume":"12","year":"1993","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1001\/jama.285.11.1500","article-title":"Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: Realistic estimates from the ASCUS-LSIL Triage Study","volume":"285","author":"Stoler","year":"2001","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/PGP.0b013e31826916c7","article-title":"The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology","volume":"32","author":"Darragh","year":"2013","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Cassaro, N., Mazza, G., Guaita, A., and Boemi, S. (2022). Spontaneous regression of cervical intraepithelial neoplasia 3 in women with a biopsy-cone interval of greater than 11 weeks. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10179-1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ygyno.2014.11.076","article-title":"Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test","volume":"136","author":"Wright","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1470-2045(09)70360-2","article-title":"Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: A randomised controlled trial","volume":"11","author":"Ronco","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1097\/AOG.0b013e3181fe777f","article-title":"Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women","volume":"116","author":"Moscicki","year":"2010","journal-title":"Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1097\/LGT.0000000000000215","article-title":"Regression and Progression Predictors of CIN2 in Women Younger Than 25 Years","volume":"20","author":"Loopik","year":"2016","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00404-022-06680-4","article-title":"Regression rate of high-grade cervical intraepithelial lesions in women younger than 25 years","volume":"307","author":"Ehret","year":"2023","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/1471-0528.16081","article-title":"Conservative management of women with cervical intraepithelial neoplasia grade 2 in Denmark: A cohort study","volume":"127","author":"Skorstengaard","year":"2020","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/S1473-3099(20)30860-4","article-title":"Optimal human papillomavirus vaccination strategies to prevent cervical cancer in low-income and middle-income countries in the context of limited resources: A mathematical modelling analysis","volume":"21","author":"Drolet","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(21)02178-4","article-title":"The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: A register-based observational study","volume":"398","author":"Falcaro","year":"2021","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e140","DOI":"10.1016\/S1470-2045(24)00524-2","article-title":"Active surveillance of cervical intraepithelial neoplasia grade 2: 2025 British Society of Colposcopy and Cervical Pathology and European Society of Gynaecologic Oncology consensus statement","volume":"26","author":"Kyrgiou","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Scalia, G., Cassaro, N., Costanzo, M., and Boemi, S. (2020). Conservative management of CIN2 p16 positive lesions in women with multiple HPV infection. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05530-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1089\/jwh.2020.8918","article-title":"Summary of Current Guidelines for Cervical Cancer Screening and Management of Abnormal Test Results: 2016\u20132020","volume":"30","author":"Perkins","year":"2021","journal-title":"J. Women\u2019s Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1136\/ijgc-2019-000343","article-title":"Prognostic factors for spontaneous regression of high-risk human papillomavirus-positive cervical intra-epithelial neoplasia grade 2","volume":"29","author":"Koeneman","year":"2019","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1158\/1940-6207.CAPR-17-0293","article-title":"Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21\u201339 Years","volume":"11","author":"Silver","year":"2018","journal-title":"Cancer Prev. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2023.08.008","article-title":"Clinical course of cervical intraepithelial neoplasia grade 2: A population-based cohort study","volume":"229","author":"Lycke","year":"2023","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"96","DOI":"10.15585\/mmwr.mm7406a4","article-title":"Trends in Cervical Precancers Identified Through Population-Based Surveillance\u2014Human Papillomavirus Vaccine Impact Monitoring Project, Five Sites, United States, 2008\u20132022. MMWR","volume":"74","author":"Gargano","year":"2025","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1016\/S0140-6736(11)60551-5","article-title":"Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: An ecological study","volume":"377","author":"Brotherton","year":"2011","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gertig, D.M., Brotherton, J.M., Budd, A.C., Drennan, K., Chappell, G., and Saville, A.M. (2013). Impact of a population-based HPV vaccination program on cervical abnormalities: A data linkage study. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-227"},{"key":"ref_26","first-page":"915","article-title":"Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program","volume":"25","author":"Dehlendorff","year":"2014","journal-title":"Cancer Causes Control"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1002\/ijc.32752","article-title":"Risk of cervical intraepithelial neoplasia grade 2 or worse after conization in relation to HPV vaccination status","volume":"147","author":"Sand","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Panella, M.M., Valenti, G., Ruggeri, Z., Sgalambro, F., Reina, S., and Mereu, L. (2024). Cervical Intraepithelial Neoplasia Grade 3 (CIN3) in Women Younger than 30 Years Was Significantly Associated with HPV16\/18 Genotypes. Cancers, 16.","DOI":"10.3390\/cancers16112043"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1007\/s00404-022-06548-7","article-title":"Burden of CIN2+\u2009diagnoses and conizations in women aged 18\u201345 years-a retrospective secondary data analysis of German statutory health insurance claims data","volume":"306","author":"Reuschenbach","year":"2022","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1097\/AOG.0b013e3182883a34","article-title":"2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors","volume":"121","author":"Massad","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"ref_32","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-Positive Women","volume":"107","author":"Wentzensen","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s12985-022-01822-1","article-title":"Possible role of negative human papillomavirus E6\/E7 mRNA as a predictor of regression of cervical intraepithelial neoplasia 2 lesions in hr-HPV positive women","volume":"19","author":"Bruno","year":"2022","journal-title":"Virol. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1097\/PAS.0b013e3181e8b2c4","article-title":"Using biomarkers as objective standards in the diagnosis of cervical biopsies","volume":"34","author":"Galgano","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/S1470-2045(17)30700-3","article-title":"Incomplete excision of cervical precancer as a predictor of treatment failure: A systematic review and meta-analysis","volume":"18","author":"Arbyn","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ygyno.2016.10.031","article-title":"Triaging HPV-positive women with p16\/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial","volume":"144","author":"Wright","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1097\/LGT.0000000000000802","article-title":"Recommendations for Use of p16\/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus","volume":"28","author":"Clarke","year":"2024","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Valenti, G., Ruggeri, Z., Incognito, G.G., Coretti, P., Montana, G.D., Panella, M.M., and Mereu, L. (2024). Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicenter Retrospective Study. Diagnostics, 14.","DOI":"10.3390\/diagnostics14050509"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Prete, R.D., Ronga, L., Addati, G., Magrone, R., Abbasciano, A., Carlo, D.D., and Santacroce, L. (2019). A Retrospective Study about the Impact of Switching from Nested PCR to Multiplex Real-Time PCR on the Distribution of the Human Papillomavirus (HPV) Genotypes. Medicina, 55.","DOI":"10.3390\/medicina55080418"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1750-9378-4-8","article-title":"Classification of weakly carcinogenic human papillomavirus types: Addressing the limits of epidemiology at the borderline","volume":"4","author":"Schiffman","year":"2009","journal-title":"Infect. Agents Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1097\/LGT.0b013e3182854253","article-title":"Five-year risks of CIN 3+ and cervical cancer among women with HPV testing of ASC-US Pap results","volume":"17","author":"Katki","year":"2013","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/jnci\/djq562","article-title":"Human papillomavirus testing in the prevention of cervical cancer","volume":"103","author":"Schiffman","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/jnci\/dji073","article-title":"Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women","volume":"97","author":"Strickler","year":"2005","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/0956462413491735","article-title":"Incidence and progression of cervical lesions in women with HIV: A systematic global review","volume":"25","author":"Denslow","year":"2014","journal-title":"Int. J. STD AIDS"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1097\/01.aids.0000253361.63578.14","article-title":"Human papillomavirus types among women infected with HIV: A meta-analysis","volume":"20","author":"Clifford","year":"2006","journal-title":"Aids"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1097\/QAI.0b013e31828177d7","article-title":"Invasive cervical cancer risk among HIV-infected women: A North American multicohort collaboration prospective study","volume":"62","author":"Abraham","year":"2013","journal-title":"AIDS J. Acquir. Immune Defic. Syndr."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Del Pino, M., Mart\u00ed, C., Torras, I., Henere, C., Munmany, M., Marimon, L., Saco, A., Torn\u00e9, A., and Ordi, J. (2020). HPV Vaccination as Adjuvant to Conization in Women with Cervical Intraepithelial Neoplasia: A Study under Real-Life Conditions. Vaccines, 8.","DOI":"10.3390\/vaccines8020245"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1002\/ijc.30391","article-title":"Prior human papillomavirus-16\/18 AS04-adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post-hoc analysis from a randomized controlled trial","volume":"139","author":"Garland","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e070135","DOI":"10.1136\/bmj-2022-070135","article-title":"Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: Systematic review and meta-analysis","volume":"378","author":"Kechagias","year":"2022","journal-title":"BMJ"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1093\/infdis\/jiy075","article-title":"Very Low Prevalence of Vaccine Human Papillomavirus Types Among 18- to 35-Year Old Australian Women 9 Years Following Implementation of Vaccination","volume":"217","author":"Machalek","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(19)30298-3","article-title":"Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: Updated systematic review and meta-analysis","volume":"394","author":"Drolet","year":"2019","journal-title":"Lancet"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1016\/S2468-2667(18)30183-X","article-title":"The projected timeframe until cervical cancer elimination in Australia: A modelling study","volume":"4","author":"Hall","year":"2019","journal-title":"Lancet Public Health"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1056\/NEJMoa1917338","article-title":"HPV Vaccination and the Risk of Invasive Cervical Cancer","volume":"383","author":"Lei","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1093\/cid\/ciw354","article-title":"Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience","volume":"63","author":"Garland","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Guaita, A., Boemi, S., Mazza, G., Sudano, M.C., and Palumbo, M. (2023). Performance of p16\/Ki67 Immunostaining for Triage of Elderly Women with Atypical Squamous Cells of Undetermined Significance. J. Clin. Med., 12.","DOI":"10.3390\/jcm12103400"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.ygyno.2016.02.012","article-title":"Validation of the FAM19A4\/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women","volume":"141","author":"Verhoef","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S1470-2045(14)70019-1","article-title":"Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): A randomised controlled non-inferiority trial","volume":"15","author":"Verhoef","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/ijc.29824","article-title":"Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16\/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study)","volume":"138","author":"Luttmer","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/LGT.0000000000000525","article-title":"2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors","volume":"24","author":"Perkins","year":"2020","journal-title":"J. Low. Genit. Tract Dis."},{"key":"ref_61","unstructured":"American College of Obstetricians and Gynecologists (2020). Practice Advisory: Updated Guidelines for Management of Cervical Cancer Screening Abnormalities, ACOG."},{"key":"ref_62","unstructured":"American College of Obstetricians and Gynecologists (2021). Practice Bulletin No. 229: Cervical Cancer Screening. Obstet. Gynecol., 138, e55\u2013e75."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/s41416-020-0920-9","article-title":"Cervical screening: ESGO-EFC position paper of the European Society of Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy (EFC)","volume":"123","author":"Kyrgiou","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_64","unstructured":"National Institute for Health and Care Excellence (NICE) (2024). Cervical Screening\u2014Clinical Knowledge Summaries (CKS), NICE. Available online: https:\/\/cks.nice.org.uk\/topics\/cervical-screening\/."},{"key":"ref_65","unstructured":"NHS England (2025, August 29). Cervical Screening Programme and Colposcopy Management: NHS CSP, Available online: https:\/\/www.gov.uk\/government\/publications\/cervical-screening-programme-and-colposcopy-management."},{"key":"ref_66","unstructured":"NHS England (2025). NHS Rolls Out More Personalised Cervical Screening for Millions, NHS. Available online: https:\/\/www.england.nhs.uk\/2025\/06\/nhs-rolls-out-more-personalised-cervical-screening-for-millions\/."},{"key":"ref_67","unstructured":"Italian Cervical Screening Group (GISCi) (2021). Recommendations for the Management of CIN2, GISCi. Available online: https:\/\/gisci.it\/documenti\/lg-condivise\/LLGG-197-GISCi-cervice-utero_14ott_Racc2.pdf."},{"key":"ref_68","unstructured":"Ministry of Health (2025, August 26). National Guidelines for the Prevention and Management of Precancerous Cervical Lesions, Available online: https:\/\/gisci.it\/documenti\/linee-guida\/LG_197_GISCi_Biomarcatori-screening-cervicale_29ago24.pdf."},{"key":"ref_69","unstructured":"World Health Organization (2021). WHO Guideline for Screening and Treatment of Cervical Pre-Cancer Lesions for Cervical Cancer Prevention, WHO. [2nd ed.]."},{"key":"ref_70","unstructured":"World Health Organization (2024). Guidance on p16\/Ki-67 Dual-Stain Cytology for Triage of HPV-Positive Women, WHO."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0140-6736(06)68181-6","article-title":"Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: Systematic review and meta-analysis","volume":"367","author":"Kyrgiou","year":"2006","journal-title":"Lancet"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"a1284","DOI":"10.1136\/bmj.a1284","article-title":"Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: Meta-analysis","volume":"337","author":"Arbyn","year":"2008","journal-title":"BMJ"},{"key":"ref_73","first-page":"CD012847","article-title":"Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease","volume":"11","author":"Kyrgiou","year":"2017","journal-title":"Cochrane Database Syst. Rev."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/19\/2512\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T15:21:03Z","timestamp":1759418463000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/19\/2512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,2]]},"references-count":73,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["diagnostics15192512"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15192512","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,2]]}}}