DUAL STAINING CYTOLOGY WITH P16/KI67 FOR CERVICAL CANCER SCREENING
Abstract
Currently, cytology, HPV testing, and combined cytology with HPV testing are the methods used for cervical cancer screening in patients. The p16/Ki67 dual staining is a biomarker with high sensitivity and specificity for CIN2+ lesions. The introduction of such a biomarker for triage and identification of high-grade cervical lesions in patients, based on preliminary results from cytology and HPV screening, is necessary to prevent an excessive number of referrals for colposcopy and biopsy. The study was designed as a cross-sectional cohort study conducted at the University Clinic of Gynaecology and Obstetrics, Skopje, over a two-year period, involving a group of 81 patients aged 21 to 65 years. All patients underwent HPV DNA testing with typing, cytological testing (LB), and p16/Ki67 dual staining. The correlation of p16/Ki67 immunocytochemical status in patients with cytological verified squamous intraepithelial lesions and the presence of high-risk HPV was analysed.
The analyses revealed a significant association between high-grade cervical lesions and p16/Ki67 staining status. A positive result from p16/Ki67 dual staining was significantly associated with an HSIL finding on the Pap test (p=0.01). HSIL cytological findings were significantly more common in patients with positive immunocytochemistry (36.36% vs 5.71%). Patients positive for p16/Ki67 dual staining had more frequent positive HPV typing compared to patients with negative p16/Ki67 staining.
Keywords: p16/Ki67, immunocytochemistry, cervical cancer screening, HPV
References
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25. Rijkaart DC, Berkhof J, van Kemenade FJ, Coupe VM, Hesselink AT, Rozendaal L, Heideman DA, Verheijen RH, Bulk S, Verweij WM, Snijders PJ, Meijer CJ. Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening. Int J Cancer. 2012 Feb 1;130(3):602-10. doi: 10.1002/ijc.26056. Epub 2011 May 5. PMID: 21400507.
26. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK. Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S28-35. doi: 10.1097/LGT.0b013e318285423c. PMID: 23519302; PMCID: PMC3616419.
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28. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015 Feb;136(2):189-97. doi: 10.1016/j.ygyno.2014.11.076. Epub 2015 Jan 8. PMID: 25579108.
29. Wentzensen N, Schwartz L, Zuna RE, Smith K, Mathews C, Gold MA, Allen RA, Zhang R, Dunn ST, Walker JL, Schiffman M. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res. 2012 Aug 1;18(15):4154-62. doi: 10.1158/1078-0432.CCR-12-0270. Epub 2012 Jun 6. PMID: 22675168; PMCID: PMC4237612.
30. Liu, J., Su, S. & Liu, Y. The value of Ki67 for the diagnosis of LSIL and the problems of p16 in the diagnosis of HSIL. Sci Rep 12, 7613 (2022). https://doi.org/10.1038/s41598-022-11584-z
31. Petry KU, Schmidt D, Scherbring S, Luyten A, Reinecke-Lüthge A, Bergeron C, Kommoss F, Löning T, Ordi J, Regauer S, Ridder R. Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology. Gynecol Oncol. 2011 Jun 1;121(3):505-9. doi: 10.1016/j.ygyno.2011.02.033. Epub 2011 Mar 21. PMID: 21420158.
32. Ikenberg H, Bergeron C, Schmidt D, Griesser H, Alameda F, Angeloni C, Bogers J, Dachez R, Denton K, Hariri J, Keller T, von Knebel Doeberitz M, Neumann HH, Puig-Tintore LM, Sideri M, Rehm S, Ridder R; PALMS Study Group. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study. J Natl Cancer Inst. 2013 Oct 16;105(20):1550-7. doi: 10.1093/jnci/djt235. Epub 2013 Oct 4. PMID: 24096620; PMCID: PMC3814411.
33. Yu LL, Chen W, Lei XQ, Qin Y, Wu ZN, Pan QJ, Zhang X, Chang BF, Zhang SK, Guo HQ, Qiao YL. Evaluation of p16/Ki-67 dual staining in detection of cervical precancer and cancers: a multicenter study in China. Oncotarget. 2016 Apr 19;7(16):21181-9. doi: 10.18632/oncotarget.8307. PMID: 27029033; PMCID: PMC5008277.
34. Tay TKY, Lim KL, Hilmy MH, Thike AA, Goh ST, Song LH, Hwang JSG, Mantoo S. Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above (CIN 2+). Malays J Pathol. 2017 Dec;39(3):257-265. PMID: 29279588.
35. Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, Tokugawa D, Bodelon C, Poitras N, Lorey T, Kinney W. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. PMID: 26376685; PMCID: PMC4675094.
2. Ginsburg O Bray, F Coleman MP et al. The global burden of women's cancers: a grand challenge in global health. Lancet. 2017; 389: 847-860
3. https://www.cancer.org/cancer/acs-medical-content-and-news-staff.html
4. WHO. Global strategy to accelerate the elimination of cervical cancer as a public health problem. Geneva: World Health Organization, 2020
5. Cibula D, Raspollini MR, Planchamp F, Centeno C, Chargari C, Felix A, Fischerová D, Jahnn-Kuch D, Joly F, Kohler C, Lax S, Lorusso D, Mahantshetty U, Mathevet P, Naik R, Nout RA, Oaknin A, Peccatori F, Persson J, Querleu D, Bernabé SR, Schmid MP, Stepanyan A, Svintsitskyi V, Tamussino K, Zapardiel I, Lindegaard J. ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer - Update 2023. Int J Gynecol Cancer. 2023 May 1;33(5):649-666. doi: 10.1136/ijgc-2023-004429. PMID: 37127326; PMCID: PMC10176411.
6. Key Statistics for Cervical Cancer https://www.cancer.gov/types/cervical/causes-risk-prevention
7. Cervical cancer https://www.who.int/news-room/fact-sheets/detail/cervical-cancer
8. Pathak P, Pajai S, Kesharwani H. A Review on the Use of the HPV Vaccine in the Prevention of Cervical Cancer. Cureus. 2022 Sep 2;14(9):e28710. doi: 10.7759/cureus.28710. PMID: 36211088; PMCID: PMC9529156.
9. https://gco.iarc.who.int/media/globocan/factsheets/cancers/23-cervix-uteri-fact-sheet.pdf
10. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition (https://iris.who.int/bitstream/handle/10665/342365/9789240030824-eng.pdf?sequence=1)
11. 11.https://gco.iarc.who.int/today/en/dataviz/bars?mode=cancer&key=asr&group_populations=1&types=0&sort_by=value0&populations=807&multiple_populations=0&values_position=out&cancers_h=23&sexes=2
12. Dovnik, A.; Repše Fokter, A. The Role of p16/Ki67 Dual Staining in Cervical Cancer Screening. Curr. Issues Mol. Biol. 2023, 45, 8476–8491. https://doi.org/10.3390/ cimb45100534
13. Castle, P.E.; Stoler, M.H.; Wright, T.C., Jr.; Sharma, A.; Wright, T.L.; Behrens, C.M. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: A subanalysis of the ATHENA study. Lancet Oncol. 2011, 12, 880–890
14. Dijkstra, M.G.; van Niekerk, D.; Rijkaart, D.C.; van Kemenade, F.J.; Heideman, D.A.; Snijders, P.J.; Meijer, C.J.; Berkhof, J. Primary hrHPV DNA testing in cervical cancer screening: How to manage screen-positive women? A POBASCAM trial substudy. Cancer Epidemiol. Biomark. Prev. 2014, 23, 55–63
15. Yu L, Fei L, Liu X, Pi X, Wang L, Chen S. Application of p16/Ki-67 dual-staining cytology in cervical cancers. J Cancer 2019; 10(12):2654-2660. doi:10.7150/jca.32743. https://www.jcancer.org/v10p2654.htm.
16. Klaes R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A. et al. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res. 1999;59:6132–6.
17. McLean HQ, VanWormer JJ, Chow BDW, Birchmeier B, Vickers E, DeVries E, Meyer J, Moore J, McNeil MM, Stokley S, Gee J, Belongia EA. Improving Human Papillomavirus Vaccine Use in an Integrated Health System: Impact of a Provider and Staff Intervention. J Adolesc Health. 2017 Aug;61(2):252-258. doi: 10.1016/j.jadohealth.2017.02.019. Epub 2017 Apr 24. PMID: 28462786; PMCID: PMC6749828.
18. Petrosky E, Bocchini JA Jr, Hariri S, Chesson H, Curtis CR, Saraiya M, Unger ER, Markowitz LE; Centers for Disease Control and Prevention (CDC). Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2015 Mar 27;64(11):300-4. PMID: 25811679; PMCID: PMC4584883.
19. Maver PJ, Poljak M. Primary HPV-based cervical cancer screening in Europe: implementation status, challenges, and future plans. Clin Microbiol Infect. 2020 May;26(5):579-583. doi: 10.1016/j.cmi.2019.09.006. Epub 2019 Sep 17. PMID: 31539637.
20. Rijkaart DC, Berkhof J, van Kemenade FJ, Coupe VM, Hesselink AT, Rozendaal L, Heideman DA, Verheijen RH, Bulk S, Verweij WM, Snijders PJ, Meijer CJ. Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening. Int J Cancer. 2012 Feb 1;130(3):602-10. doi: 10.1002/ijc.26056. Epub 2011 May 5. PMID: 21400507.
21. Feldstein O, Gali-Zamir H, Schejter E, Feinberg T, Yehuda-Shnaidman E, Bornstein J, Levy T. High-risk HPV testing vs liquid-based cytology for cervical cancer screening among 25- to 30-year-old women: A historical cohort study. Acta Obstet Gynecol Scand. 2023 Feb;102(2):226-233. doi: 10.1111/aogs.14482. Epub 2022 Dec 7. PMID: 36478537; PMCID: PMC9889323.
22. Kituncharoen S, Tantbirojn P, Niruthisard S. Comparison of Unsatisfactory Rates and Detection of Abnormal Cervical Cytology Between Conventional Papanicolaou Smear and Liquid-Based Cytology (Sure Path®). Asian Pac J Cancer Prev. 2015;16(18):8491-4. doi: 10.7314/apjcp.2015.16.18.8491. PMID: 26745107.
23. Jeong H, Hong SR, Chae SW, Jin SY, Yoon HK, Lee J, Kim EK, Ha ST, Kim SN, Park EJ, Jung JJ, Sung SH, Lim SC. Comparison of Unsatisfactory Samples from Conventional Smear versus Liquid-Based Cytology in Uterine Cervical Cancer Screening Test. J Pathol Transl Med. 2017 May;51(3):314-319. doi: 10.4132/jptm.2017.03.17. Epub 2017 Apr 17. PMID: 28415159; PMCID: PMC5445207.
24. Nayar R, Wilbur DC. The Pap Test and Bethesda 2014: "The reports of my demise have been greatly exaggerated. (after a quotation from Mark Twain)". J Low Genit Tract Dis. 2015 Jul;19(3):175-84. doi: 10.1097/LGT.0000000000000115. PMID: 25943863.
25. Rijkaart DC, Berkhof J, van Kemenade FJ, Coupe VM, Hesselink AT, Rozendaal L, Heideman DA, Verheijen RH, Bulk S, Verweij WM, Snijders PJ, Meijer CJ. Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening. Int J Cancer. 2012 Feb 1;130(3):602-10. doi: 10.1002/ijc.26056. Epub 2011 May 5. PMID: 21400507.
26. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK. Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S28-35. doi: 10.1097/LGT.0b013e318285423c. PMID: 23519302; PMCID: PMC3616419.
27. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013 Apr;121(4):829-846. doi: 10.1097/AOG.0b013e3182883a34. PMID: 23635684.
28. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015 Feb;136(2):189-97. doi: 10.1016/j.ygyno.2014.11.076. Epub 2015 Jan 8. PMID: 25579108.
29. Wentzensen N, Schwartz L, Zuna RE, Smith K, Mathews C, Gold MA, Allen RA, Zhang R, Dunn ST, Walker JL, Schiffman M. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res. 2012 Aug 1;18(15):4154-62. doi: 10.1158/1078-0432.CCR-12-0270. Epub 2012 Jun 6. PMID: 22675168; PMCID: PMC4237612.
30. Liu, J., Su, S. & Liu, Y. The value of Ki67 for the diagnosis of LSIL and the problems of p16 in the diagnosis of HSIL. Sci Rep 12, 7613 (2022). https://doi.org/10.1038/s41598-022-11584-z
31. Petry KU, Schmidt D, Scherbring S, Luyten A, Reinecke-Lüthge A, Bergeron C, Kommoss F, Löning T, Ordi J, Regauer S, Ridder R. Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology. Gynecol Oncol. 2011 Jun 1;121(3):505-9. doi: 10.1016/j.ygyno.2011.02.033. Epub 2011 Mar 21. PMID: 21420158.
32. Ikenberg H, Bergeron C, Schmidt D, Griesser H, Alameda F, Angeloni C, Bogers J, Dachez R, Denton K, Hariri J, Keller T, von Knebel Doeberitz M, Neumann HH, Puig-Tintore LM, Sideri M, Rehm S, Ridder R; PALMS Study Group. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study. J Natl Cancer Inst. 2013 Oct 16;105(20):1550-7. doi: 10.1093/jnci/djt235. Epub 2013 Oct 4. PMID: 24096620; PMCID: PMC3814411.
33. Yu LL, Chen W, Lei XQ, Qin Y, Wu ZN, Pan QJ, Zhang X, Chang BF, Zhang SK, Guo HQ, Qiao YL. Evaluation of p16/Ki-67 dual staining in detection of cervical precancer and cancers: a multicenter study in China. Oncotarget. 2016 Apr 19;7(16):21181-9. doi: 10.18632/oncotarget.8307. PMID: 27029033; PMCID: PMC5008277.
34. Tay TKY, Lim KL, Hilmy MH, Thike AA, Goh ST, Song LH, Hwang JSG, Mantoo S. Comparison of the sensitivity and specificity of p16/Ki-67 dual staining and HPV DNA testing of abnormal cervical cytology in the detection of histology proven cervical intraepithelial neoplasia grade 2 and above (CIN 2+). Malays J Pathol. 2017 Dec;39(3):257-265. PMID: 29279588.
35. Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, Tokugawa D, Bodelon C, Poitras N, Lorey T, Kinney W. p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. PMID: 26376685; PMCID: PMC4675094.
Published
2024-12-29
How to Cite
MILKOVSKI, Daniel et al.
DUAL STAINING CYTOLOGY WITH P16/KI67 FOR CERVICAL CANCER SCREENING.
Journal of Morphological Sciences, [S.l.], v. 7, n. 3, p. 80-86, dec. 2024.
ISSN 2545-4706.
Available at: <http://jms.mk/jms/article/view/vol7no3-10>. Date accessed: 26 mar. 2025.
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