Abstract
Background
Studies on the clinical performance of p16/Ki-67 dual-staining in detecting cervical lesions by menopausal status were limited.
Methods
4364 eligible women were enrolled with valid p16/Ki-67, HR-HPV, and LBC test results, including 542 cancer and 217 CIN2/3 cases. The positivity rates of p16 and Ki-67 single staining and p16/ Ki-67 dual-staining were analyzed by different pathological grades and age groups. The sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) of each test in different subgroups were calculated and compared.
Results
P16/Ki-67 dual-staining positivity increased with histopathological severity in premenopausal and postmenopausal women (P < 0.05), while no increasing trends of individual expression of p16 single staining and Ki-67 single staining were observed in postmenopausal women. P16/Ki-67 showed higher SPE (88.09% vs. 81.91%, P < 0.001) and PPV (33.8% vs. 13.18%, P < 0.001) in detecting CIN2/3, and higher SEN (89.97% vs. 82.61%, P = 0.012) and SPE (83.22% vs. 79.89%, P = 0.011) in detecting cancer in premenopausal women than postmenopausal women. For triaging the HR-HPV+ population to identify CIN2/3, p16/Ki-67 performed comparably to LBC in the premenopausal women, and showed higher PPV (51.14% vs. 23.08%, P < 0.001) in premenopausal than postmenopausal women. For triaging ASC-US/LSIL population, p16/Ki-67 demonstrated higher SPE and lower colposcopy referral rate than HR-HPV in both premenopausal and postmenopausal women.
Conclusions
Expressions of p16/Ki-67 dual-staining between premenopausal and postmenopausal women are varied. P16/Ki-67 performs better in detecting cervical lesions in premenopausal women. For triaging, p16/Ki-67 is suitable for HR-HPV+ women, especially premenopausal women, to identify CIN2/3 and women with ASC-US/LSIL.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data that support the findings of this study are available in the article.
Abbreviations
- HR-HPV:
-
High-risk human papillomavirus
- LBC:
-
Liquid-based cytology
- NILM:
-
Negative for intraepithelial lesion or malignancy
- ASC-US:
-
Atypical squamous cells of undetermined significance
- AGC:
-
Atypical glandular cells
- LSIL:
-
Low-grade squamous intraepithelial lesion
- HSIL:
-
High-grade squamous intraepithelial lesion
- ASC-H:
-
Atypical squamous cells-cannot exclude HSIL
- SCC:
-
Squamous cell carcinoma
- AIS:
-
Adenocarcinoma in situ
- ADC:
-
Adenocarcinoma
- CIN:
-
Cervical intraepithelial neoplasia
- SEN:
-
Sensitivity
- SPE:
-
Specificity
- PPV:
-
Positive predictive value
- NPV:
-
Negative predictive value
- CI:
-
Confidence interval
References
Ansari M, Mehdi G, Arif SH et al (2012) Smear patterns and spectrum of premalignant and malignant cervical epithelial lesions in postmenopausal Indian women: a hospital-based study. Diagn Cytopathol 40(11):976–983. https://doi.org/10.1002/dc.21708
Arbyn M, Simon M, Peeters E et al (2021) 2020 list of human papillomavirus assays suitable for primary cervical cancer screening. Clin Microbiol Infect 27(8):1083–1095. https://doi.org/10.1016/j.cmi.2021.04.031
Benevolo M, Allia E, Gustinucci D et al (2017) Interobserver reproducibility of cytologic p16(INK4a) /Ki-67 dual immunostaining in human papillomavirus-positive women. Cancer Cytopathol 125(3):212–220. https://doi.org/10.1002/cncy.21800
Bergeron C, Ikenberg H, Sideri M et al (2015) Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study result. Cancer Cytopathol 123(6):373–381. https://doi.org/10.1002/cncy.21542
Brown DC, Gatter KC (2002) Ki67 protein: the immaculate deception? Histopathology 40(1):2–11. https://doi.org/10.1046/j.1365-2559.2002.01343.x
Bulten J, De Wilde PC, Boonstra H et al (2000a) Proliferation in “atypical” atrophic pap smears. Gynecol Oncol 79(2):225–229. https://doi.org/10.1006/gyno.2000.5943
Bulten J, De Wilde PC, Schijf C et al (2000b) Decreased expression of Ki-67 in atrophic cervical epithelium of post-menopausal women. J Pathol 190(5):545–553. https://doi.org/10.1002/(sici)1096-9896(200004)190:5%3c545::Aid-path549%3e3.0.Co;2-s
Chen X, Xu H, Xu W et al (2017) Prevalence and genotype distribution of human papillomavirus in 961,029 screening tests in southeastern China (Zhejiang Province) between 2011 and 2015. Sci Rep 7(1):14813. https://doi.org/10.1038/s41598-017-13299-y
Chen X, Chen C, Liu L et al (2022) Evaluation of p16/Ki-67 dual-stain as triage test for high-risk HPV-positive women: a hospital-based cross-sectional study. Cancer Cytopathol. https://doi.org/10.1002/cncy.22628
Cremer ML, Alonzo TA, Alspach AE et al (2010) Diagnostic reproducibility of cervical intraepithelial neoplasia 3 and atrophy in menopausal women on hematoxylin and eosin, Ki-67, and p16 stained slides. J Low Genit Tract Dis 14(2):108–112. https://doi.org/10.1097/LGT.0b013e3181bcdc35
Cuschieri K, Wentzensen N (2008) Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomark Prev 17(10):2536–2545. https://doi.org/10.1158/1055-9965.Epi-08-0306
Kisser A, Zechmeister-Koss I (2015) A systematic review of p16/Ki-67 immuno-testing for triage of low grade cervical cytology. BJOG INt J Obst Gynaecol 122(1):64–70
Kurman RJ, Carcangiu ML, Young RH et al (2014) WHO classification of tumours of female reproductive organs. International Agency for Research on Cancer, 2014
Li J, Poi MJ, Tsai MD (2011) Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry 50(25):5566–5582. https://doi.org/10.1021/bi200642e
Li Z, Liu F, Cheng S et al (2016) Prevalence of HPV infection among 28,457 Chinese women in Yunnan Province, southwest China. Sci Rep 6:21039. https://doi.org/10.1038/srep21039
Li Y, Ma L, Yang C et al (2019) A study on service capacity of primary medical and health institutions for cervical cancer screening in urban and rural areas in China. Chin J Cancer Res 31(5):838–848. https://doi.org/10.21147/j.issn.1000-9604.2019.05.13
Li YC, Zhao YQ, Li TY et al (2020) The performance of immunocytochemistry staining as triaging tests for high-risk hpv-positive women: a 24-month prospective study. J Oncol 2020:6878761. https://doi.org/10.1155/2020/6878761
Liao GD, Sellors JW, Sun HK et al (2014) p16INK4A immunohistochemical staining and predictive value for progression of cervical intraepithelial neoplasia grade 1: a prospective study in China. Int J Cancer 134(7):1715–1724. https://doi.org/10.1002/ijc.28485
Nayar R, Wilbur DC (2015) The Bethesda system for reporting cervical cytology: definitions, criteria, and explanatory notes, 3rd edn. Springer International Publishing, Cham
Pretorius RG, Zhang WH, Belinson JL et al (2004) Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol 191(2):430–434. https://doi.org/10.1016/j.ajog.2004.02.065
Qiao YL, Jeronimo J, Zhao FH et al (2014) Lower cost strategies for triage of human papillomavirus DNA-positive women. Int J Cancer 134(12):2891–2901. https://doi.org/10.1002/ijc.28616
Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130(8):1715–1725. https://doi.org/10.1002/ijc.27316
Safaeian M, Wright TC Jr, Stoler MH et al (2021) The IMproving Primary Screening And Colposcopy Triage trial: human papillomavirus, cervical cytology, and histopathologic results from the baseline and 1-year follow-up phase. Am J Obstet Gynecol 225(3):278.e1-278.e16. https://doi.org/10.1016/j.ajog.2021.03.047
Schmidt D, Bergeron C, Denton KJ et al (2011) p16/ki-67 dual-stain cytology in the triage of ASCUS and LSIL papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study. Cancer Cytopathol 119(3):158–166. https://doi.org/10.1002/cncy.20140
Smith RA, Brooks D, Cokkinides V et al (2013) Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J Clin 63(2):88–105. https://doi.org/10.3322/caac.21174
Sun M, Shen Y, Ren ML et al (2018) Meta-analysis on the performance of p16/Ki-67 dual immunostaining in detecting high-grade cervical intraepithelial neoplasm. J Cancer Res Ther 14(10 Supplement Issue 3):S587–S593
Tjalma WAA (2017) Diagnostic performance of dual-staining cytology for cervical cancer screening: a systematic literature review. Eur J Obstet Gynecol Reprod Biol 210:275–280
Von Knebel Doeberitz M (2002) New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Cancer 38(17):2229–2242. https://doi.org/10.1016/s0959-8049(02)00462-8
Walboomers JM, Jacobs MV, Manos MM et al (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189(1):12–19. https://doi.org/10.1002/(sici)1096-9896(199909)189:1%3c12::Aid-path431%3e3.0.Co;2-f
Wang HR, Liao GD, Chen W et al (2017) Clinical value of p16/Ki-67 immunocytochemical dual staining in cervical cancer screening. Zhonghua Zhong Liu Za Zhi 39(8):636–640. https://doi.org/10.3760/cma.j.issn.0253-3766.2017.08.015
Wentzensen N, Von Knebel Doeberitz M (2007) Biomarkers in cervical cancer screening. Dis Mark 23(4):315–330. https://doi.org/10.1155/2007/678793
Wentzensen N, Schwartz L, Zuna RE et al (2012) Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res 18(15):4154–4162. https://doi.org/10.1158/1078-0432.Ccr-12-0270
Wentzensen N, Fetterman B, Tokugawa D et al (2014) Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening. Cancer Cytopathol 122(12):914–920. https://doi.org/10.1002/cncy.21473
WHO (2021) WHO Guidelines Approved by the Guidelines Review Committee [M]. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention, second edition. Geneva; World Health Organization. © World Health Organization 2021
Wright TC Jr, Stoler MH, Behrens CM et al (2012) The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol 206(1):46.e1-46.e11. https://doi.org/10.1016/j.ajog.2011.07.024
Wright TC Jr, Stoler MH, Ranger-Moore J et al (2022) Clinical validation of p16/Ki-67 dual-stained cytology triage of HPV-positive women: results from the IMPACT trial. Int J Cancer 150(3):461–471. https://doi.org/10.1002/ijc.33812
Xia C, Dong X, Li H et al (2022) Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (engl) 135(5):584–590. https://doi.org/10.1097/cm9.0000000000002108
Yu LL, Chen W, Lei XQ et al (2016) Evaluation of p16/Ki-67 dual staining in detection of cervical precancer and cancers: a multicenter study in China. Oncotarget 7(16):21181–21189. https://doi.org/10.18632/oncotarget.8307
Zhang J, Zhao Y, Dai Y et al (2021) Effectiveness of high-risk human papillomavirus testing for cervical cancer screening in China: a multicenter, open-label, randomized clinical trial. JAMA Oncol 7(2):263–270. https://doi.org/10.1001/jamaoncol.2020.6575
Ziemke P, Marquardt K, Griesser H (2014) Predictive value of the combined p16 and Ki-67 immunocytochemistry in low-grade squamous intraepithelial lesions. Acta Cytol 58(5):489–494. https://doi.org/10.1159/000367838
Zur Hausen H (1989) Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res 49(17):4677–4681
Acknowledgements
We thank all the patients who generously accepted to participate in this study. COBAS and COBAS E are trademarks of Roche.
Funding
This work was funded by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-004), National Natural Science Foundation of China (81973136), Sichuan Provincial Science and Technology Program Applied Basic Research Program (2021YJ0227), and Roche Diagnostics (Shanghai) Limited.
Author information
Authors and Affiliations
Contributions
Study concepts and Study design: YD, WC, and JY; data collection: YD, WC, TC, TL, YZ, YW, and SC; quality control of data and algorithms: TL, XL, CZ, and WC; data analysis, interpretation and statistical analysis: YD; investigation, TL, ZW, LY, and MJ; Manuscript preparation: YD; manuscript editing: YD and WC; manuscript review: WC; all authors reviewed and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dai, Y., Chen, T., Li, X. et al. Evaluation of the clinical performance of p16/Ki-67 dual-staining cytology for cervical lesion detection in premenopausal and postmenopausal Chinese women. J Cancer Res Clin Oncol 149, 10645–10658 (2023). https://doi.org/10.1007/s00432-023-04938-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-04938-1