{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T07:37:19Z","timestamp":1792222639134,"version":"4.4.0"},"reference-count":37,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"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>The risk of overtreatment or not treating an occult carcinoma exists in women at risk of residual disease after a LEEP excision for CIN3. Our goal was to discover an efficient method to select patients requiring a second LEEP from those requiring a FU only through an mRNA-detection test. In a population of 686 women undergoing a LEEP excision for CIN 3, we selected 285 women at risk of residual disease and subjected them to a search for E6\/E7 mRNA HPV. The women with negative mRNA were subjected to a follow up, while the women with positive mRNA were subjected to a second LEEP. The histological examination of the second cone revealed 120 (85.7%) cases of residual disease in the mRNA-positive women: 40 cases of CIN2, 51 cases of CIN3, 11 cases of squamous microinvasive carcinoma, 7 cases of squamous carcinoma, 9 cases of AIS (adenocarcinoma in situ) and 2 cases of adenocarcinoma. Among the mRNA-negative women undergoing a follow up, there were only five cases of residual disease. During the follow-up period of about 6 years, we witnessed the regression of the residual disease and the elimination of the virus, just as predicted by the negative result of the mRNA test. Testing patients for E6\/E7 mRNA allowed us to identify women with residual disease (CIN2+) and treat them appropriately.<\/jats:p>","DOI":"10.3390\/cancers15174203","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T09:10:56Z","timestamp":1692695456000},"page":"4203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Overexpression of E6\/E7 mRNA HPV Is a Prognostic Biomarker for Residual Disease Progression in Women Undergoing LEEP for Cervical Intraepithelial Neoplasia 3"],"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 Surgical and Medical-Surgery Specialities, University of Catania, 95124 Catania, Italy"},{"name":"Multidisciplinary Research Center in Papillomavirus Pathology, University of Catania, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Bonanno","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Azienda di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi Nesima, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Sgalambro","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, University Hospital \u201cG. Rodolico\u201d, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Cavallaro","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, University Hospital \u201cG. Rodolico\u201d, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Boemi","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Center in Papillomavirus Pathology, University of Catania, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2022, May 15). How Many Cancers Are Linked with HPV Each Year?, Available online: http:\/\/www.cdc.gov\/cancer\/hpv\/statistics\/cases.htm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s12985-018-0957-z","article-title":"HPV genotype determination and E6\/E7 mRNA detection for management of HPV positive women","volume":"15","author":"Bruno","year":"2018","journal-title":"Virol. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.vaccine.2005.09.054","article-title":"The epidemiology of genital human papillomavirus infection","volume":"24","author":"Trottier","year":"2006","journal-title":"Vaccine"},{"key":"ref_4","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, World Health Organization, and International Agency for Research on Cancer Human Papillomaviruses (2007). Human Papillomaviruses."},{"key":"ref_5","first-page":"376","article-title":"Prevalence genotypes and distribution of human papillomavirus infection in women with abnormal cervical cytology in Catania, Italy","volume":"38","author":"Bruno","year":"2016","journal-title":"G. Ital. Di Ostet. E Ginecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejogrb.2016.03.021","article-title":"Risk Factors for Residual Disease after Cervical Conization in Patients with Cervical Intraepithelial Neoplasia Grades 2 and 3 and Positive Surgical Margins","volume":"201","author":"Ayhan","year":"2016","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.5468\/ogs.20049","article-title":"Risk Factors Type-Specific Persistence of High-Risk Human Papillomavirus and Residual\/Recurrent Cervical Intraepithelial Neoplasia after Surgical Treatment","volume":"63","author":"Ouh","year":"2020","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/LGT.0000000000000525","article-title":"The 2019 ASCCP Risk-Based Management Consensus Guidelines Committee 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_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s11684-017-0517-8","article-title":"Triage for management of cervical high-grade squamous intraepithelial lesion patients with positive margin by conization: A retrospective analysis","volume":"11","author":"Dou","year":"2017","journal-title":"Front. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ajog.2011.01.003","article-title":"Cervical conization and the risk of preterm delivery","volume":"2005","author":"Bevis","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/0092623X.2019.1586019","article-title":"Sexual behavior of women with diagnosed HPV","volume":"45","author":"Caruso","year":"2019","journal-title":"J. Sex Marital Ther."},{"key":"ref_13","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: Systematic Review and Meta-Analysis","volume":"18","author":"Arbyn","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_14","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":"2020","journal-title":"Virol. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1093\/jnci\/djaa105","article-title":"The New Technology for Cervical Cancer 2 Working Group. p16\/ki67 and E6\/E7 mRNA Accuracy and Prognostic Value in Triaging HPV DNA-Positive Women","volume":"113","author":"Carozzi","year":"2021","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Caruso, S., Bica, F., Arcidiacono, G., and Boemi, S. (2021). Evidence for HPV DNA in the placenta of women who resorted to elective abortion. BMC Pregnancy Childbirth, 21.","DOI":"10.1186\/s12884-021-03937-9"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12985-019-1145-5","article-title":"Management of ASC-US\/HPV positive post-menopausal woman","volume":"16","author":"Bruno","year":"2019","journal-title":"Virol. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jviromet.2007.01.036","article-title":"PreTect HPV-Proofer: Real-time detection and typing of E6\/E7 mRNA from carcinogenic human papillomaviruses","volume":"142","author":"Molden","year":"2007","journal-title":"J. Virol. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0002-9378(95)90253-8","article-title":"Predictive factors from cold knife conization for residual cervical intraepithelial neoplasia in subsequent hysterectomy","volume":"173","author":"Moore","year":"1995","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ijgo.2009.05.027","article-title":"Factors associated with positive margins in patients with cervical intraepithelial neoplasia grade 3 and postconization management","volume":"107","author":"Lu","year":"2009","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_21","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\u2014Cone interval of greater than 11 weeks. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10179-1"},{"key":"ref_22","first-page":"663","article-title":"Loop Electrosurgical Excision Procedure vs. Cold Knife Cone in Treatment of Cervical Intraepithelial Neoplasia: Review of 447 Cases","volume":"47","author":"Wang","year":"2017","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1067\/mob.2003.633","article-title":"2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia","volume":"189","author":"Wright","year":"2003","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/00128360-200301000-00008","article-title":"Hysterectomy for treatment of CIN","volume":"7","author":"Kesic","year":"2003","journal-title":"J. Low Genit. Tract. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1111\/j.1447-0756.2007.00628.x","article-title":"Cervical intraepithelial neoplasia II-III with endocervical cone margin involvement after cervical loop conization: Is there any predictor for residual disease?","volume":"33","author":"Kietpeerakool","year":"2007","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_26","first-page":"17","article-title":"Prognostic Value of Human Papillomavirus Genotyping before and after Cervical Conization for Squamous Intraepithelial Lesion","volume":"67","author":"Lida","year":"2022","journal-title":"Acta Cytol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/1471-0528.15932","article-title":"Evaluation of the intraoperative human papillomavirus test as a marker of early cure at 12 months after electrosurgical excision procedure in women with cervical high-grade squamous intraepithelial lesion: A prospective cohort study","volume":"127","author":"Rabasa","year":"2020","journal-title":"BJOG"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1111\/j.1471-0528.2011.03068.x","article-title":"Treatment of cervical cancer precursors: Influence of age, completeness of excision and cone depth on therapeutic failure, and on adverse obstetric outcomes","volume":"118","author":"Arbyn","year":"2011","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/1471-0528.15996","article-title":"Long-term predictors of recurrent cervical intraepithelial neoplasia 2-3 after treatment with a large loop excision of the transformation zone: A retrospective study","volume":"127","author":"Tous","year":"2020","journal-title":"BJOG"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1093\/jnci\/djn065","article-title":"New Technologies for Cervical Cancer Screening Working Group. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test","volume":"100","author":"Ronco","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/ijc.20839","article-title":"Predicting CIN2+ when detecting HPV mRNA and DNA by PreTect HPV-proofer and consensus PCR: A 2-year follow-up of women with ASCUS or LSIL Pap smear","volume":"114","author":"Molden","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.ygyno.2010.11.013","article-title":"HPV mRNA tests for the detection of cervical intraepithelial neoplasia: A systematic review","volume":"120","author":"Burger","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1128\/JCM.02147-10","article-title":"Aptima HPV E6\/E7 mRNA Test Is as sensitive as hybrid capture 2 assay but more specific at detecting cervical Precancer and Cancer","volume":"49","author":"Ratnam","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"S\u00f8rbye, S.W., Fismen, S., Gutteberg, T.J., Mortensen, E.S., and Skjeldestad, F.E. (2014). HPV mRNA is more specific than HPV DNA in triage of women with minor cervical lesions. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112934"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"613","DOI":"10.4103\/jcrt.JCRT_56_17","article-title":"The clinical application of HPV E6\/E7 mRNA testing in triaging women with atypical squamous cells of undetermined significance or low-grade squamous intra-epithelial lesion pap smear: A meta-analysis","volume":"13","author":"Yang","year":"2017","journal-title":"J. Cancer Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1056\/NEJMoa021641","article-title":"Epidemiological classification of human papillomavirus types associated with cervical cancer","volume":"348","author":"Munoz","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/ijc.22527","article-title":"Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update","volume":"121","author":"Smith","year":"2007","journal-title":"Int. J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:39:16Z","timestamp":1760128756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,22]]},"references-count":37,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cancers15174203"],"URL":"https:\/\/doi.org\/10.3390\/cancers15174203","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,22]]}}}