Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study
Keywords:
Uterine cervical dysplasia, Cyclin-dependent kinase inhibitor p21, Ki-67 antigen, Cervical intraepithelial neoplasia, Cervical intraepithelial neoplasia grade 2, CIN2, p16INK4a, Ki-67Abstract
BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression.
OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma).
DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions.
METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms.
RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively.
CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.
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Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population- based case-control study of prospectively recorded data. BMJ. 2009;339:b2968. PMID: 19638651; http://doi.org/10.1136/bmj.b2968.
Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Divisão de Detecção Precoce e Apoio à Organização de Rede. Brazilian Cervical Cancer Screening Guidelines. Rio de Janeiro: INCA; 2016. Available from: https:// www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/ diretrizesparaorastreamentodocancerdocolodoutero_2016_corrigido. pdf. Accessed in 2023 (Jan 30).
Loopik DL, Bekkers RLM, Massuger LFAG, et al. Justifying conservative management of CIN2 in women younger than 25 years - A populationbased study. Gynecol Oncol. 2019;152(1):82-6. PMID: 30413339; https:// doi.org/10.1016/j.ygyno.2018.10.038.
Munro A, Powell RG, Cohen PA, et al. Spontaneous regression of CIN2 in women aged 18-24 years: a retrospective study of a statewide population in Western Australia. Acta Obstet Gynecol Scand. 2016;95(3):291-8. PMID: 26660398; https://doi.org/10.1111/aogs.12835.
Godfrey MAL, Nikolopoulos M, Garner JE, et al. Conservative management of cervical intraepithelial neoplasia grade 2 (CIN2) in women under 30 years of age: A cohort study. Eur J Obstet Gynecol Reprod Biol. 2018;228:267-73. PMID: 30048921; https://doi.org/10.1016/j.ejogrb.2018.07.018.
Bruno MT, Scalia G, Cassaro N, Costanzo M, Boemi S. Conservative management of CIN2 p16 positive lesions in women with multiple HPV infection. BMC Infect Dis. 2020;20(1):801. PMID: 33121447; https:// doi.org/10.1186/s12879-020-05530-5.
Tainio K, Athanasiou A, Tikkinen KAO, et al. Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. BMJ. 2018;360:k499. PMID: 29487049; https://doi.org/10.1136/bmj.k499.
Salvadó A, Miralpeix E, Solé-Sedeno JM, et al. Predictor factors for conservative management of cervical intraepithelial neoplasia grade 2: Cytology and HPV genotyping. Gynecol Oncol. 2021;162(3):569-574. PMID: 34226019; https://doi.org/10.1016/j.ygyno.2021.06.019.
Bjørge T, Skare GB, Bjørge L, Tropé A, Lönnberg S. Adverse pregnancy outcomes after treatment for cervical intraepithelial neoplasia. Obstet Gynecol. 2016;128(6):1265-73. PMID: 27824756; https://doi.org/10.1097/ aog.0000000000001777.
Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016;354:i3633. PMID: 27469988; https://doi.org/10.1136/bmj.i3633.
Mark K, Frost A, Hussey H, et al. Rates of regression of cervical dysplasia between initial biopsy and excisional procedure in routine clinical practice. Arch Gynecol Obstet. 2019;299(3):841-6. PMID: 30607589; https://doi.org/10.1007/s00404-018-5026-8.
Underwood M, Arbyn M, Parry-Smith W, et al. Accuracy of colposcopy-directed punch biopsies: a systematic review and meta-analysis. BJOG. 2012;119(11):1293301. PMID: 22882742; https://doi.org/10.1111/j.1471-0528.2012.03444.x.
Kim SI, Kim SJ, Suh DH, et al. Pathologic discrepancies between colposcopy-directed biopsy and loop electrosurgical excision procedure of the uterine cervix in women with cytologic high-grade squamous intraepithelial lesions. J Gynecol Oncol. 2020;31(2):e13. PMID: 31912671; https://doi.org/10.3802/jgo.2020.31.e13.
Collaço LM, Wendling LU, Noronha L, et al. Análise do controle de qualidade das biópsias e produtos de cirurgia de alta frequência no Programa de Prevenção do Câncer do Colo do Útero do estado do Paraná, Brasil. Rev Bras Cancerol. 2012;58:489-96. https://doi. org/10.32635/2176-9745.RBC.2012v58n3.607.
Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report.
Am J Clin Pathol. 2007;127(5):805-15. PMID: 17439841; https://doi. org/10.1309/pt3pnc1ql2f4d2vl.
Darragh TM, Colgan TJ, Cox JT, et al. 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. Arch Pathol Lab Med. 2012;136(10):1266-97. PMID: 22742517; https://doi.org/10.5858/arpa.lgt200570.
Reuschenbach M, Wentzensen N, Dijkstra MG, Doeberitz MK, Arbyn M. p16INK4a immunohistochemistry in cervical biopsy specimens: A systematic review and meta-analysis of the interobserver agreement.
Am J Clin Pathol. 2014;142:767-772. PMID: 25389329; https://doi.
org/10.1309/ajcp3tphv4trizek.
Kanthiya K, Khunnarong J, Tangjitgamol S, Puripat N, Tanvanich S. Expression of the p16 and Ki67 in cervical squamous intraepithelial lesions and cancer. Asian Pac J Cancer Prev. 2016;17:3201-3206. PMID: 27509952.
El-Zein M, Gotlieb W, Gilbert L, et al. Dual staining for p16/Ki-67 to detect high-grade cervical lesions: Results from the Screening Triage Ascertaining Intraepithelial Neoplasia by Immunostain Testing study. Int J Cancer. 2021;148(2):492-501. PMID: 32781481; http://doi.org/10.1002/ ijc.33250.
Miyamoto S, Hasegawa J, Morioka M, et al. The association between p16 and Ki-67 immunohistostaining and the progression of cervical intraepithelial neoplasia grade 2. Int J Gynaecol Obstet. 2016;134(1):458. PMID: 27233813; http://doi.org/10.1016/j.ijgo.2015.12.005.
Miralpeix E, Solé-Sedeño JM, Mancebo G, et al. Value of p16INK4a and Ki67 immunohistochemical staining in cervical intraepithelial neoplasia grade 2 biopsies as biomarkers for cervical intraepithelial neoplasia grade 3 in cone results. Anal Quant Cytopathol Histpathol. 2016;38(1):1-
PMID: 27363060.
Pires ARC, Andreiuolo FM, Souza SR. TMA for all: a new method for the construction of tissue microarrays without recipient paraffin block using custom-built needles. Diagn Pathol. 2006;1:14. PMID: 16869973; https://doi.org/10.1186/1746-1596-1-14.
Miralpeix E, Genovés J, Solé-Sedeño JM, et al. Usefulness of p16INK4a staining for managing histological high-grade squamous intraepithelial cervical lesions. Mod Pathol. 2017;30(2):304-10. PMID: 27739439; http://doi.org/10.1038/modpathol.2016.168.
Koeneman MM, Hendriks N, Kooreman LF, et al. Prognostic factors for spontaneous regression of high-risk human papillomavirus-positive cervical intra-epithelial neoplasia grade 2. Int J Gynecol Cancer. 2019;29(6):1003-9. PMID: 31079058; http://doi.org/10.1136/ijgc-2019000343.
Romagosa C, Simonetti S, López-Vicente L, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087-97. PMID: 21297668; http://doi.org/10.1038/onc.2010.614.
Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130(8):1715-25. PMID: 22025288; http://doi.org/10.1002/ijc.27316.
Zhang X, Xu Y, Meng T, Shen D. Analysis of factors affecting the prognosis of patients with cervical intraepithelial neoplasia 2. Oncol Lett. 2020;20(2):1810-
PMID: 32724424; http://doi.org/10.3892/ol.2020.11711.
Castle PE, Adcock R, Cuzick J, et al. New Mexico HPV Pap Registry Steering Committee; p16 IHC Study Panel. Relationships of p16
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