Skip to main content
SpringerLink
Log in

Prevalence of P16 Immunohistochemistry Positive Staining and Its Correlation to Clinical and Radiological Staging of Squamous Cell Carcinoma of the Cervix

  • Original Article
  • Published:
The Journal of Obstetrics and Gynecology of India Aims and scope Submit manuscript

Abstract

Background

Cervical cancer is the fourth most common genital tract cancer and fourth common cause of death among the causes of neoplasm-related mortality in women worldwide. Squamous cell carcinoma is the most common type and constitutes about 90% of all pathological types of cervical cancer. Cyclin-dependent kinase inhibitor 2A (CDKN2A; p16) is a gene that is located on chromosome 9 that encodes a protein (P16) that inhibits cyclin-dependent kinases 4 and 6 which are inhibitors of retinoblastoma protein; the net result is reactivation of retinoblastoma protein and arrest of cell cycle in G1 phase. So, expression of p16 protein within cancer cell may denote good prognosis. The presence of a soft marker that can detect hidden advanced stages in apparently clinically and radiologically early resectable stages of cervical cancer and can replace life-threatening preoperative lymphadenectomy is of great importance. Is P16 protein which when expressed is associated with good prognosis in other cancer can be this soft marker?

Aim of the study

The aim of this study is to estimate the prevalence of cyclin-dependent kinase inhibitor 2A (CDKN2A; p16) immunohistochemistry positive staining in squamous cell carcinoma of the cervix and to correlate its positivity  to clinical and radiological disease stage.

Patients and Methods

An analytical cross-sectional observational prospective and retrospective study was conducted on 60 invasive squamous cell cervical cancer patients from gyne-oncology unit at Al Shatby university hospital after taking a written consent and following approval by Alexandria medical school institutional ethics committee. Inclusion criteria included all patients with invasive squamous cell carcinoma of the cervix prospective and retrospective from January 2019 till June 2022 diagnosed by taking wedge, punch and cone biopsy followed by histopathological examination that confirmed the diagnosis and showed grading and types of squamous cell carcinoma. Clinical examination, vaginal ultrasonographic scanning, computerized axial tomography and magnetic resonance imaging were carried out to all cases, and data were recorded for clinical and radiological staging purposes. All data were collected, coded, tabulated and statistically analyzed to estimate the prevalence of p16 positivity in the study cases and to correlate its positivity with clinical and radiological disease stage.

Result

In relation to prevalence of p16 immunostaining, 34 cases (56.7%) were positive in comparison with 26 cases (43.3%) being negative. Considering correlation between early resectable stage and late nonresectable stage with P16 positive and negative staining, the result showed the following: 32 cases (53.3%) were resectable, 30 cases (88.2%) of them were P16 positive immunostaining compared to 2 cases (7.7%) being P16 negative immunostaining while nonresectable cases were 28 cases (46.7%), 4 cases (11.8%) only were P16 positive compared to 24 cases (92.3%) being P16 immunostaining negative, so most of early resectable stage cases were P16 positive immunostaining and most of late nonresectable stage cases were P16 negative immunostaining. There is a positive significant correlation between early resectable stage in relation to positive P16 immunostaining, and the same was present between late nonresectable stage and negative P16 immunostaining (p = 0.000).

Conclusion

The present study concluded that P16 positive immunostaining prevalence in cervical squamous cell carcinoma was 56.7% and its positive staining is highly correlated with early resectable clinically and radiologically disease stage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF. Global burden of disease cancer collaboration. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27.

    Article  PubMed  Google Scholar 

  3. Simms KT, Hanley SJB, Smith MA, Keane A, Canfell K. Impact of HPV vaccine hesitancy on cervical cancer in Japan: a modelling study. Lancet Public Health. 2020;5:e223–34.

    Article  PubMed  Google Scholar 

  4. Gadkari R, Ravi R, Bhatia JK. Cervical cancers: varieties and the lower anogenital squamous terminology. Cytojournal. 2022;14(19):39. https://doi.org/10.25259/CMAS_03_14_2021.

    Article  Google Scholar 

  5. Tjalma WA, Van Waes TR, Van den Eeden M, Bogers M. Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix. Best practice and research. Clin Obstet Gynaecol. 2005;19:469–83.

    CAS  Google Scholar 

  6. Songock WK, Kim SM, Bodily JM. The human papillomavirus E7 oncoprotein as a regulator of transcription. Virus Res. 2017;231:56–75. https://doi.org/10.1016/j.virusres.2016.10.017.

    Article  CAS  PubMed  Google Scholar 

  7. Yim EK, Park JS. The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat. 2005;37(6):319–24.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tyagi S, Chabes L, Wysocka J, Herr W. E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol Cell. 2007;27(1):107–19.

    Article  CAS  PubMed  Google Scholar 

  9. Komata T, Kanzawa T, Takeuchi H, Germano M, Schreiber M, Kondo Y, Kondo S. Antitumour effect of cyclin-dependent kinase inhibitors (p16INK4A, p18INK4C, p19INK4D, p21WAF1/CIP1 and p27KIP1) on malignant glioma cells. Br J Cancer. 2003;88(8):1277–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Klussmann P, Gültekin E, Weissenborn J, Wieland U, Dries V, Dienes P, Fuchs G. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol. 2003;162(3):747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Díaz-Feijoo B, Torné A, Tejerizo Á, Benito V, Hernández A, Ruiz R, Gil-Moreno A. Prognostic value and therapeutic implication of laparoscopic extraperitoneal paraaortic staging in locally advanced cervical cancer: a Spanish multicenter study. Ann Surg Oncol. 2020;27(8):2829–39.

    Article  PubMed  Google Scholar 

  12. Park J, Kim J, Song K, Nam H, Park Y, Kim S, Kim Y. Definitive chemoradiotherapy versus radical hysterectomy followed by tailored adjuvant therapy in women with early-stage cervical cancer presenting with pelvic lymph node metastasis on pretreatment evaluation: a propensity score matching analysis. Cancers. 2021;13(15):3703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Harter P, Sehouli J, Lorusso D, Reuss A, Vergote I, Marth C, Du Bois A. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N Engl J Med. 2019;380(9):822–32.

    Article  PubMed  Google Scholar 

  14. Grønhøj Larsen C, Gyldenløve M, Jensen DH, Therkildsen MH, Kiss K, Norrild B, Konge L, von Buchwald C. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review. Br J Cancer. 2014;110(6):1587–94. https://doi.org/10.1038/bjc.2014.42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Buskwofie A, David-West G, Clare CA. A review of cervical cancer: incidence and disparities. J Natl Med Assoc. 2020;112(2):229–32.

    PubMed  Google Scholar 

  16. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) study group. J Natl Cancer Inst. 1995;87(11):796–802.

    Article  CAS  PubMed  Google Scholar 

  17. Fernandes A, Viveros-Carreño D, Hoegl J, Ávila M, Pareja R. Human papillomavirus-independent cervical cancer. Int J Gynecol Cancer. 2022;32(1):1–7.

    Article  PubMed  Google Scholar 

  18. Jiao Y, Feng Y, Wang X. Regulation of tumor suppressor gene CDKN2A and encoded p16-INK4a protein by covalent modifications. Biochemistry (Mosc). 2018;83(11):1289–98. https://doi.org/10.1134/S0006297918110019.

    Article  CAS  PubMed  Google Scholar 

  19. Langendijk JA, Psyrri A. The prognostic significance of p16 overexpression in oropharyngeal squamous cell carcinoma: implications for treatment strategies and future clinical studies. Ann Oncol. 2010;21(10):1931–4.

    Article  CAS  PubMed  Google Scholar 

  20. Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T. Immunohistochemical overexpression of p16 protein associated with intact retinoblastoma protein expression in cervical cancer and cervical intraepithelial neoplasia. Pathol Int. 1998;48(8):580–5.

    Article  CAS  PubMed  Google Scholar 

  21. De Wispelaere N, Rico SD, Bauer M, Luebke AM, Kluth M, Büscheck F, Hube-Magg C, Höflmayer D, Gorbokon N, Weidemann S, Möller K, Fraune C, Bernreuther C, Simon R, Kähler C, Menz A, Hinsch A, Jacobsen F, Lebok P, Clauditz T, Sauter G, Uhlig R, Wilczak W, Steurer S, Burandt E, Krech R, Dum D, Krech T, Marx A, Minner S. High prevalence of p16 staining in malignant tumors. PLoS ONE. 2022;17(7):e0262877. https://doi.org/10.1371/journal.pone.0262877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lin J, Albers E, Qin J, Kaufmann M. Prognostic significance of overexpressed p16INK4a in patients with cervical cancer: a meta-analysis. PLoS ONE. 2014;9(9):e106384.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Arians N, Prigge ES, Nachtigall T, Reuschenbach M, Koerber SA, Debus J, von Knebel DM, Lindel K. Overexpression of p16INK4a Serves as prognostic marker in squamous cell vulvar cancer patients treated With radiotherapy irrespective of HPV-status. Front Oncol. 2019;9:891–901.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ishikawa M, Nakayama K, Nakamura K, Yamashita H, Ishibashi T, Minamoto T, Sawada K, Yoshimura Y, Iida K, Razia S, Ishikawa N, Nakayama S, Otsuki Y, Kyo S. P16INK4A expression might be associated with a favorable prognosis for cervical adenocarcinoma via dysregulation of the RB pathway. Sci Rep. 2021;11(1):18236. https://doi.org/10.1038/s41598-021-97703-8.PMID:34521948;PMCID:PMC8440605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi Q, Xu L, Yang R, Meng Y, Qiu L. Ki-67 and P16 proteins in cervical cancer and precancerous lesions of young women and the diagnostic value for cervical cancer and precancerous lesions. Oncol Lett. 2019;18(2):1351–5.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Obstetrics and Gynecology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Hossam H. El Sokkary

  2. Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Eman Sheta

Authors
  1. Hossam H. El Sokkary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eman Sheta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hossam H. El Sokkary.

Ethics declarations

Conflict of interest

All the authors declare that they have no conflict of interest.

Consent for publication

Written consent was obtained from each participant.

Ethical Approval

This was an analytical cross-sectional observational Prospective and retrospective study involving collection of patient data who were undergoing standard management protocols and hence there was no direct risk to the participants. This study was approved by Ethics Committee of faculty of medicine, Alexandria university, Egypt, member of ICLAS (International Council for Laboratory Animal Science), (reference number: 0305452).

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Research involving human participants

This study was performed in line with the principles of the Declaration of Helsinki. Ethical approval was provided by Ethics Committee of faculty of medicine, Alexandria university, Egypt, member of ICLAS (International Council for Laboratory Animal Science), (reference number: 0305452).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dr. Hossam H. El Sokkary is an associate professor, Department of Obstetrics and Gynaecology, Faculty of medicine, Alexandria university, Alexandria, Egypt. Dr. Eman Sheta is an Lecturer, Department of Pathology, Faculty of medicine, Alexandria university, Alexandria, Egypt.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El Sokkary, H.H., Sheta, E. Prevalence of P16 Immunohistochemistry Positive Staining and Its Correlation to Clinical and Radiological Staging of Squamous Cell Carcinoma of the Cervix. J Obstet Gynecol India 73 (Suppl 1), 142–149 (2023). https://doi.org/10.1007/s13224-023-01772-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13224-023-01772-w

Keywords

Search

Navigation