{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T08:31:50Z","timestamp":1775032310903,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"\n Background<\/jats:title>\n While human papillomavirus testing has become the primary screening modality for cervical cancer prevention, its implementation necessitates supplementary triage strategies. The viral oncoproteins E6 and E7, serving as primary mediators of high-risk HPV (hrHPV)-induced carcinogenesis, emerge as viable candidates for this risk stratification. We aimed to examine the clinical diagnostic performance of HPV E6\/E7 immunocytochemical (ICC) assay in exfoliated cervical cells samples, to investigate the feasibility of using it as a potential biomarker in clinical triage algorithms for hrHPV-positive populations.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We prospectively collected and analyzed 1,005 hrHPV-positive cases from Beijing Obstetrics and Gynecology Hospital, Capital Medical University during September 2023 and March 2025. The diagnostic and triaging performance of HPV E6\/E7 ICC assay were evaluated by sensitivity, specificity, positive predictive values, negative predictive values and operating characteristic curve.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n When used to detect CIN2+, the sensitivity of HPV E6\/E7 ICC detection is (0.88, 95% CI: 0.82\u20130.92), which is better than that of cytological detection (0.609, 95% CI: 0.53\u20130.67),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f26.23,\n p &lt;<\/jats:italic>\n 0.05; the NPV of. HPV E6\/E7 ICC detection is (0.95, 95% CI: 0.92\u20130.97), which is better than that of cytological detection (0.85, 95% CI: 0.82\u20130.88),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f38.14,\n p\u202f&lt;<\/jats:italic>\n \u202f0.05. When the HPV typing test result is 16\/18+,the sensitivity of HPV E6\/E7 ICC detection is (0.93, 95% CI:0.86\u20130.96), which is better than that of cytological detection (0.61, 95% CI:0.52\u20130.70),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f33.47,\n p\u202f&lt;<\/jats:italic>\n \u202f0.05; the NPV of HPV E6\/E7 ICC detection is (0.940, 95% CI:0.89\u20130.97), which is better than that of cytological detection (0.81, 95% CI:0.75\u20130.85),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f13.84,\n p\u202f&lt;<\/jats:italic>\n \u202f0.05. When the HPV typing test result is other hrHPV type, the sensitivity of HPV E6\/E7 ICC detection is (0.81, 95% CI:0.71\u20130.89), which is better than that of cytological detection (0.75, 95% CI:0.64\u20130.84),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f0.914,\n p<\/jats:italic>\n \u202f=\u202f0.339; the NPV of HPV E6\/E7 ICC detection is (0.95, 95% CI:0.92\u20130.97), which is better than that of cytological detection (0.91, 95% CI:0.86\u20130.94),\n \u03c7<\/jats:italic>\n 2<\/jats:sup>\n \u202f=\u202f4.29,\n p<\/jats:italic>\n \u202f=\u202f0.038.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n HPV E6\/E7 ICC assay with high-sensitivity feature may be potential new biomarkers for hrHPV positive women. In addition, its triaging performance is better than that of cytology.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmed.2026.1745006","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T05:40:34Z","timestamp":1775022034000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A prospective observational study on the value of HPV E6\/E7 oncoprotein immunocytochemistry for triaging HPV-positive women"],"prefix":"10.3389","volume":"13","author":[{"given":"Zangyu","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiamin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taihe Hospital","place":["Shiyan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinwei","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"ref2","first-page":"322","article-title":"Global burden of cervical cancer: current estimates, temporal trend and future projections based on the GLOBOCAN 2022","volume":"5","author":"Wu","year":"2025","journal-title":"J Natl Cancer Cent"},{"key":"ref3","doi-asserted-by":"publisher","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":"ref4","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1158\/1055-9965.EPI-20-0846","article-title":"Assessing impact of HPV vaccination on cervical cancer incidence among women aged 15-29 years in the United States, 1999-2017: an ecologic study","volume":"30","author":"Mix","year":"2021","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1093\/jnci\/djn444","article-title":"Efficacy of HPV DNA testing with cytology triage and\/or repeat HPV DNA testing in primary cervical cancer screening","volume":"101","author":"Naucler","year":"2009","journal-title":"J Natl Cancer Inst"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.tim.2017.07.007","article-title":"The HPV E6\/E7 oncogenes: key factors for viral carcinogenesis and therapeutic targets","volume":"26","author":"Hoppe-Seyler","year":"2018","journal-title":"Trends Microbiol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1002\/ijc.28640","article-title":"Is HPV DNA testing specificity comparable to that of cytological testing in primary cervical cancer screening? Results of a meta-analysis of randomized controlled trials","volume":"135","author":"Pileggi","year":"2014","journal-title":"Int J Cancer"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3322\/caac.21139","article-title":"American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer","volume":"62","author":"Saslow","year":"2012","journal-title":"CA Cancer J Clin"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1093\/jnci\/djn044","article-title":"Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections","volume":"100","author":"Rodr\u00edguez","year":"2008","journal-title":"JNCI J Natl Cancer Inst"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1002\/ijc.33414","article-title":"Adjunctive testing by cytology, p16\/Ki-67 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Notes","author":"Nayar","year":"2015"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.jncc.2022.06.003","article-title":"Head-to-head comparison of 7 high-sensitive human papillomavirus nucleic acid detection technologies with the SPF10 LiPA-25 system","volume":"2","author":"Yin","year":"2022","journal-title":"J Natl Cancer Cent"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.gocm.2023.10.005","article-title":"Guidelines for cervical cancer screening in China I","volume":"3","author":"Li","year":"2023","journal-title":"Gynecol Obstetr Clin Med"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1097\/AOG.0b013e3182883a34","article-title":"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 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Genet"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"6358","DOI":"10.1128\/JVI.07069-11","article-title":"Reconstruction of human papillomavirus type 16-mediated early-stage neoplasia implicates E6\/E7 deregulation and the loss of contact inhibition in neoplastic progression","volume":"86","author":"Isaacson Wechsler","year":"2012","journal-title":"J Virol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"6251","DOI":"10.3892\/ol.2017.6932","article-title":"E6\/E7 proteins are potential markers for the screening and diagnosis of cervical pre-cancerous lesions and cervical cancer in a Chinese population","volume":"14","author":"Shi","year":"2017","journal-title":"Oncol Lett"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1007\/s10552-011-9757-0","article-title":"Diagnostic and prognostic validity of the human papillomavirus E6\/E7 mRNA test in cervical cytological samples of HC2-positive patients","volume":"22","author":"Benevolo","year":"2011","journal-title":"Cancer Causes Control"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1158\/1055-9965.EPI-04-0410","article-title":"Comparison of human papillomavirus messenger RNA and DNA detection: a cross-sectional study of 4,136 women >30 years of age with a 2-year follow-up of high-grade squamous intraepithelial lesion","volume":"14","author":"Molden","year":"2005","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/jmv.20153","article-title":"Detection of high-risk human papillomavirus E6 and E7 oncogene transcripts in cervical scrapes by nested RT-polymerase chain reaction","volume":"74","author":"Sotlar","year":"2004","journal-title":"J Med Virol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"S29","DOI":"10.1016\/S1386-6532(09)70006-X","article-title":"NucliSENS EasyQ HPV v1 test - testing for 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Positive for human papillomavirus","volume":"28","author":"Clarke","year":"2024","journal-title":"J Low Genit Tract Dis"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1001\/jamaoncol.2018.4270","article-title":"Five-year risk of cervical precancer following p16\/Ki-67 dual-stain triage of HPV-positive women","volume":"5","author":"Clarke","year":"2019","journal-title":"JAMA Oncol"},{"key":"ref39","doi-asserted-by":"publisher","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":"ref40","doi-asserted-by":"publisher","first-page":"2343192","DOI":"10.1080\/21645515.2024.2343192","article-title":"Distribution of HPV types among women with HPV-related diseases and exploration of lineages and variants of HPV 52 and 58 among HPV-infected patients in China: a 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