Correlation between the expression of p16/INK4a and Ki-67 proteins and the histopathological diagnostic in women infected by Human papillomavirus in the Agreste region of Pernambuco State, Brazil

Correlação entre a expressão das proteínas p16/INK4a e Ki-67 e o diagnóstico histopatológico em mulheres infectadas pelo papilomavírus humano na região do Agreste de Pernambuco, Brasil

Autores

  • Paulo José Cunha Miranda Miranda Department of Pathology, Center for Health Sciences, Federal University of Pernambuco – Brazil https://orcid.org/0000-0001-9508-6289
  • Ismael Gomes da Rocha Universidade Federal de Pernambuco
  • Jacinto da Costa Silva Neto Silva Neto Department of Histology, Center for Biosciences, Federal University of Pernambuco – Brazil https://orcid.org/0000-0003-4418-801X
  • Maria Rosângela Cunha Duarte Coêlho Duarte Coêlho Department of Physiology and Pharmacology, Center for Biosciences, Federal University of Pernambuco – Brazil https://orcid.org/0000-0002-5671-5756

Palavras-chave:

Human papillomavirus, cervical câncer, Ki-67, p16/INK4a;

Resumo

Epidemiological studies have stated that cervical infection with high-risk human papillomavirus (HR-HPV) is a necessary but not sufficient cause in the development of cervical cancer. Cervical cancer is preceded by precursor lesions called cervical intraepithelial neoplasia (CIN), which are classified as CIN 1 (cervical intraepithelial neoplasia grade 1), CIN 2 (cervical intraepithelial neoplasia grade 2) and CIN 3 (cervical intraepithelial neoplasia grade 3). Markers such as p16/INK4a and Ki-67 have been studied with the aim of identifying lesions with a high risk of evolution. The objective of this study was to correlate the expression of the biomarkers p16INK4A and Ki-67 with histological diagnosis CIN 1, CIN 2, CIN 3 and cancer in HPV-infected cervical samples.The study involved conducting an analysis of 211 cases of women with histological confirmation to CIN 1, CIN 2, CIN 3 and cervical cancer. The immunohistochemical staining for the p16/INK4a and Ki-67 proteins was carried out through samples taken from the biopsies and waterproof containers that had representative tissues of the tumor. The expression of p16/INK4A was observed in 100% of the cases of cancer, 97.6% of the cases of NIC 3, 83.3% of the cases of NIC 2, as well as in 55.4% of the cases of NIC 1. In addition, the expression of Ki-67 was observed in 100% of the cases of cancer, 98.8% of the cases of NIC 3, 83.3% of the cases of NIC 2, as well as in 69.6% of the cases of NIC 1. The results obtained in this study make it possible to relate the expression of p16/INK4A and Ki-67 to the atypical histological findings found in the samples of patients infected with HPV.

Downloads

Não há dados estatísticos.

Referências

Agoff SN, Lin P, Morihara J, Mao C, Kiviat NB, Koutsky LA. p16 (INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. Mod. Pathol. v. 16, n. 7, p. 665-673, 2003.

Balasubramaniam SD, Balakrishnan V, Oon CE, Kaur G. Key molecular events in cervical cancer development. Medicina. v. 55, p. 384, 2019.

Benevolo M, Mottolese M, Marandino F, Vocaturo G, Sindico R, Piperno G, Mariani L, Sperduti I, Canalini P, Donnorso RP, Vocaturo A. Immunohistochemical expression of p16 (INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod. Pathol. v. 19, n. 3, p. 384-91, 2006.

Branca M, Ciotti M, Santini D, Di Bonito L, Giorgi C, Benedetto A, Paba P, Favalli C, Costa S, Agarossi A, Alderisio M, Syrjänen K. p16 (INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome. Int. J. Gynecol. Pathol. v. 23, n. 4, p. 354-365, 2004.

Brown DC, Gatter KC. Ki67 protein: the immaculate deception? Histopathology. v. 40, n. 1, p. 2-11, 2002.

Bubán T, Tóth L, Tanyi M, Kappelmayer J, Antal-Szalmás P. Ki-67 - new faces of an old player. Orv Hetil. v. 150, n. 23, p.1059-1070, 2009.

Costa LBE, Triglia RM, França Junior MC, Andrade LALA. P16(INK) (4a) expression. As a potential marker of low-grade cervical intraepithelial neoplasia progression. APMIS. v. 123, p. 185-189.

D’Arcangelo D, Tinaburri L, Dellambra E. The role of p16INK4a pathway in human epidermal stem cell self-renewal, aging and cancer. Int J Mol Sci. 2017;18(7):1591.

Frazer IH, Leggatt GR, Mattarollo SR. Prevention and treatment of papillomavirus-related cancers through immunization. Annu Ver Immunol. v. 29, p. 111-138, 2011.

Gargiulo F, de Francesco MA, Schreiber C, Ciravolo G, Salinaro F, Valloncini B, MancaN. Prevalence and distribution of single and multiple HPV infections in citologically abnormal cervical samples from Italian women. Virus Res. Amsterdam. v. 125, n. 2, p. 176-182, 2007.

Giarre M, Caldiera S, Malanchi I, et al. Induction of pRb degradation by the Human papillomavirus type 16 E7 protein is essential to efficiently overcome p16INK4a - imposed G1 cell cycle arrest. J. Virol. v. 75, p. 4705-4712, 2001.

Guimarães MC, Gonçalves MA, Soares CP, Bettini JS, Duarte RA, Soares EG. Immunohistochemical expression of p16INK4a and bcl-2 according to HPV type and to the progression of cervical squamous intraepithelial lesions. J. Histochem. Cytochem. v. 53, n. 4, p. 509-516, 2005.

Hebbar A, Murthy VS. Role of p16/INK4 and Ki-67 as specific biomarkers for cervical intraepithelial neoplasia: An institutional study. J Lab Prysicians. v. 9, p. 104-110.

Kalof AN, Evans MF, Simmons-Arnold L, Beatty BG, Cooper K. p16INK4A immunoexpression and HPV in situ hybridization signal patterns: potential markers of high-grade cervical intraepithelial neoplasia. Am. J. Surg. Pathol. v. 29, n. 5, p. 674-679. 2005.

Kalof AN, Cooper K. p16INK4a immunoexpression: surrogate marker of high-risk HPV and high-grade cervical intraepithelial neoplasia. Adv. Anat. Pathol. v. 13, n. 4, p. 190-194, 2006.

Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, et al. Ki67, Cyclin E and p16INK4a are complementary biomarkers for human papilloma virus – related cervical neoplasia. Am. J. Pathol, v. 25, p. 884-891, 2001.

Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, Von Knebel Doeberitz M. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int. J. Cancer. Bathesda. v. 92, n. 1, p. 276-284, 2001.

Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, Kurman RJ, Schmidt D, Stoler M, von KnebelDoeberitz M. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J SurgPathol. v. 26, n. 11, p. 1389-99, 2002.

Kruse AJ, Baak JP, de Bruin PC, Jiwa M, Snijders WP, Boodt PJ, Fons G, Houben PW, The HS. Ki-67 immunoquantitation in cervical intraepithelial neoplasia (CIN): a sensitive marker for grading. J. Pathol. v. 193, n. 1, p. 48-54, 2001.

Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A, Birembaut P, Clavel C. Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions? Hum. Pathol. v. 36, n. 10, p. 1101-1107, 2005.

Melo FLP, Lancellotti CLP, Silva MALG. Expression of the immunohistochemical markers p16 and Ki-67 and their usefulness in the diagnosis of cervical intraepithelial neoplasms. Rev Bras Ginec Obst. v. 38, p. 82-87, 2016.

Middleton K, Peh W, Southern S, Griffin H, Sotlar K, Nakahara T, El-Sherif A, Morris L, Seth R, Hibma M, Jenkins D, Lambert P, Coleman N, Doorbar J. Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J. Virol. v. 77, n. 19, p. 10186-10201, 2003.

Miralpeix E, Genovés J, Solé-Sedeño JM, Mancebo G, Lloveras B, Bellosillo B, Alameda F, Carreras R. Usefulness of p16INK4a staining for managing histological high-grade squamous intraepithelial cervical lesions. Mod Pathol. v. 30, p. 304-310, 2017.

Ozaki S, Zen Y, Inoue M. Biomarker expression in cervical intraepithelial neoplasia: potential progression predictive factors for low-grade lesions. Hum. Pathol. v. 42, n. 7, p. 1007-1012, 2011.

Pandey A, Chandra S, Nautiyal R, Shrivastav V. Expression of p16INK4a and human papillomavirus 16 with associated risk factors in cervical premalignant and malignant lesions. South Asian J Cancer. v. 7, p. 236-239, 2018.

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. v. 121, n. 3, p. 505-509, 2011.

Sano T, Oyama T, Kashiwabara K et al. Expression status of p16 protein is associated with Human papillomavirus oncogenic potencial in cervical and genital lesions. Am. J. Pathol. v. 153, p. 1741-1747, 1998.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2016. CA Cancer J Clin. v. 16, n.66, p. 7-30, 2016.

Silva-Filho AL, Bruno BN, Silva LB,Traiman P, Silva JGC,Triginelli S A. Associação entre a expressão das proteínas p53 e Ki-67 e os achados clínicos-patológicos em pacientes com carcinoma invasor de colo uterino. Revista Brasileira de Ginecologia e Obstetrícia. v. 27, n. 5, p. 243-247, 2005.

Song SH, Park HM, Eom DW, Lee JK, Lee NW, Kim AR, Hur JY, Lee KW, Park YK, Saw HS. The expression of p16 (INK4a) and Ki-67 in relation to high-risk human papilloma viral load and residual disease after conization with positive margins. Int. J. Gynecol. Cancer. v. 17, n. 4, p. 858-867, 2007.

Steenbergen RDM, Wilde J, Wilting SM, Brink AATP, Snijders PJF and Meijer CJLM HPV-mediated transformation of the anogenital tract. J. Clin. Virol. v. 32, p. 25-33, 2005.

Stephen JK, Divine G, Chen KM, Chitale D, Havard S, Worsham MJ. Significance of p16 in Site-specific HPV Positive and HPV Negative Head and Neck Squamous Cell Carcinoma. Cancer Clin. Oncol. v. 2, n. 1, p. 51-61, 2013.

Tsoumpou I, Arbyn M, Kyrgiou M, et al. p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and metaanalysis. Cancer Treatment. Rev. v. 35, p. 210-220, 2009.

Vats A, Trejo-Cerro O, Massimi P, Banks L. Regulation of HPV E7 stability by E6-associated protein (E6AP). J Virol. 2022;96(16):e0066322.

Walts AE, Bose S. p16, Ki-67, and BD ProExCimmunostaining: a practical approach for diagnosis of cervical intraepithelial neoplasia. Hum. Pathol. v. 40, n. 7, p. 957-964, 2009.

Wang JL, Zheng BY, Li XD, Angström T, Lindström MS, Wallin KL. Predictive significance of the alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression of cervical cancer. Clin. Cancer Res. v. 10, n. 7, p. 2407-2414, 2004.

Wentzensen N, von Knebel Doeberitz M. Biomarkers in cervical cancer screening. Dis. Markers. v. 23, p. 315-330, 2007.

Zhang S, Xu H, Zhang L, Qiao Y. Cervical cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. v. 32, p. 720-728, 2020.

Zur Hausen H. Papillomaviruses in the causation of human cancers - a brief historical account. Virology. v. 384, p. 260-265, 2009.

Downloads

Publicado

2023-11-14

Edição

2023: Collaborative Practices

Seção

Articles