Evaluation of p16 expression in carcinomas of the uterine cervix diagnosed only on cervical biopsies

  • Received 28.07.2025
  • Revised 20.11.2025
  • Accepted 30.12.2025
  • Published 06.01.2026
  • 299 Views
  • Retrieved from Vol. 11, No. 2, 2025
  • Pages 57-64

The use of differing diagnostic terms by pathologists in their histopathological reports relating to tumours of the uterine cervix can affect the clinical decision-making of treating physicians or surgeons. A retrospective cross-sectional study was conducted with the aim of evaluating p16 expression in all cervical carcinomas diagnosed solely through cervical biopsies, following a review of their previous diagnoses. Any association between p16 expression and the age of the patient or previous diagnosis was also examined. The mean, median and mode ages in the study were 53±12.4, 60, and 65 years, respectively. In 70 out of 393 cervical biopsies (17.8%) were diagnosed cervical carcinomas. A significant inconsistency in the use of diagnostic terminology by pathologists was observed. Of the 53 cases submitted for p16 immunostaining, 50 cases (94.3%) were p16 positive, and 3 (5.7%) were negative. Moreover, 88.7% of cases were reclassified as squamous cell carcinoma, human papillomavirus-associated, 5.7% as squamous cell carcinoma, human papillomavirus-independent, and 5.7% as Adenocarcinoma, human papillomavirus-associated of the uterine cervix. A mean age at diagnosis of 65 years was not significantly associated; however, the previous categories of large cell non-keratinising and keratinising squamous cell carcinoma showed the highest p16 positivity (p < 0.001). The inclusion of p16 status in pathological reports would not only promote uniformity in histopathological reporting but also assist physicians and surgeons in determining the appropriate treatment approach, predictive value, and prognosis

human papillomavirus; immunohistochemistry; squamous cell; haematoxylin; eosin

https://doi.org/10.63341/ijmmr/2.2025.57
  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. DOI: 10.3322/caac.21834
  2. Neumeyer S, Tanaka LF, Liang LA, Klug SJ. Epidemiology of cervical cancer in elderly women: Analysis of incidence, treatment, and survival using German registry data. Cancer Med. 2023;12(16):17284–95. DOI: 10.1002/cam4.6318
  3. World Health Organization. The WHO classification of tumours. Female genital tumours. 5th ed. Lyon: IARC Publications; 2020. 335–78 P.
  4. Höhn AK, Brambs CE, Hiller GGR, May D, Schmoeckel E, Horn LC. 2020 WHO classification of female genital tumors. Geburtshilfe Frauenheilkd. 2021;81(10):1145–53. DOI: 10.1055/a-1545-4279
  5. Chaganti PD, Konkay K, Varghese AM. A comparative analysis of clinicopathological features of HPV-associated and HPV-independent cervical carcinomas based on P16 INK4a immunohistochemistry: A one-year retrospective study. Indian J Pathol Microbiol. 2024;67(1):74–9. DOI: 10.4103/ijpm.ijpm_700_22
  6. Cho WK, Kim HS, Park W, Kim YS, Kang J, Kim YB, et al. The updated World Health Organization classification better predicts survival in patients with endocervical adenocarcinoma (KROG 20-07). Int J Radiat Oncol Biol Phys. 2023;117(1):154–63. DOI: 10.1016/j.ijrobp.2023.03.048
  7. Medeiros FS, dos Santos Gomes FO, Paiva LA, da Silva NCH, da Silva MC, Rygaard MCV, et al. Hierarchical evaluation of histology and p16-labeling can improve the risk assessment on cervical intraepithelial neoplasia progression. Exp Mol Pathol. 2022;124:104734. DOI: 10.1016/j.yexmp.2021.104734
  8. Zuberi Z, Mremi A, Chilongola JO, Semango G, Sauli E. Expression analysis of p16 and TOP2A protein biomarkers in cervical cancer lesions and their correlation with clinico-histopathological characteristics in a referral hospital, Tanzania. PLoS ONE. 2021;16(10):e0259096. DOI: 10.1371/journal.pone.0259096
  9. Ebisch RMF, Rijstenberg LL, Soltani GG, van der Horst J, Vedder JEM, Hermsen M, et al. Adjunctive use of p16 immunohistochemistry for optimizing management of CIN lesions in a high-risk human papillomavirus-positive population. Acta Obstet Gynecol Scand. 2022;101(11):1328–36. DOI: 10.1111/aogs.14459
  10. The World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects [Internet]. [cited 2024 October 8]. Available from: https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/
  11. World Health Organization. The WHO classification of tumours. Female genital tumours. 4th ed. Lyon: IARC Publications; 2014. 170–89 P.
  12. Mlynarczyk-Bonikowska B, Rudnicka L. HPV infections – classification, pathogenesis, and potential new therapies. Int J Mol Sci. 2024;25(14):7616. DOI: 10.3390/ijms25147616
  13. Del Moral-Hernández O, Hernández-Sotelo D, Alarcón-Romero LDC, Mendoza-Catalán MA, Flores-Alfaro E, Castro-Coronel Y, et al. TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: A biomarkers panel for progression risk of cervical premalignant lesions. BMC Cancer. 2021;21(1):39. DOI: 10.1186/s12885-020-07740-1
  14. Liu Y, Ai H. Comprehensive insights into human papillomavirus and cervical cancer: Pathophysiology, screening, and vaccination strategies. Biochim Biophys Acta Rev Cancer. 2024;1879(6):189192. DOI: 10.1016/j.bbcan.2024.189192
  15. Gnade CM, Hill EK, Botkin HE, Hefel AR, Hansen HE, Sheets KA, et al. Is the age of cervical cancer diagnosis changing over time? J Gynecol Obstet Hum Reprod. 2021;50(7):102040. DOI: 10.1016/j.jogoh.2020.102040
  16. Nicolás I, Saco A, Barnadas E, Marimon L, Rakislova N, Fusté P, et al. Prognostic implications of genotyping and p16 immunostaining in HPV-positive tumors of the uterine cervix. Mod Pathol. 2020;33(1):128–37. DOI: 10.1038/s41379-019-0360-3
  17. Gravdal BH, Lönnberg S, Skare GB, Sulo G, Bjørge T. Cervical cancer in women under 30 years of age in Norway: A population-based cohort study. BMC Women's Health. 2021;21:110. DOI: 10.1186/s12905-021-01242-3
  18. Ismail RM, Gaballah A, Salama AH, Shakweer MM, Meckawy GR, Faisal MM. Prognostic impact of human papilloma virus infection on cervical cancer patients reflected by p16ink4a expression: Single institution experience. Asian Pac J Cancer Biol. 2023;8(2):119–25. DOI: 10.31557/apjcb.2023.8.2.119-125
  19. Vedula B, Rama Reddy BV, Rajani M, Naidu SRR, Srikanth Reddy K. Expression of p16 in cervical premalignant and malignant lesions-IHC study. Indian J Pathol Oncol. 2020;7(3):404–7. DOI: 10.18231/j.ijpo.2020.080
  20. Burmeister CA, Khan SF, Schäfer G, Mbatani N, Adams T, Moodley J, et al. Cervical cancer therapies: Current challenges and future perspectives. Tumour Virus Res. 2022;13:200238. DOI: 10.1016/j.tvr.2022.200238
  21. Da Mata S, Ferreira J, Nicolás I, Esteves S, Esteves G, Lérias S, et al. P16 and HPV genotype significance in HPV-associated cervical cancer – a large cohort of two tertiary referral centers. Int J Mol Sci. 2021;22(5):2294. DOI: 10.3390/ijms22052294
  22. Ishikawa M, Nakayama K, Nakamura K, Yamashita H, Ishibashi T, Minamoto T, et al. P16INK4A expression might be associated with a favorable prognosis for cervical adenocarcinoma via dysregulation of the RB pathway. Sci Rep. 2021;11:18236. DOI: 10.1038/s41598-021-97703-8
  23. Xing B, Guo J, Sheng Y, Wu G, Zhao Y. Human papillomavirus-negative cervical cancer: A comprehensive review. Front Oncol. 2021;10:606335. DOI: 10.3389/fonc.2020.606335
  24. Lee JE, Chung Y, Rhee S, Kim TH. Untold story of human cervical cancers: HPV-negative cervical cancer. BMB Rep. 2022;55(9):429–38. DOI: 10.5483/BMBRep.2022.55.9.042