p53 and Ki-67 as Biomarkers of Tumour Behaviour in Oral Squamous Cell Carcinoma
DOI:
https://doi.org/10.36283/ziun-pjmd15-2/029Keywords:
Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Protein p53, Ki-67 Antigen, Biomarkers, Lymphatic Metastasis, Tumor Suppressor ProteinsAbstract
Background: Oral squamous cell carcinoma (OSCC) is observed to account for most of the malignancies in the oral cavity. This systematic review and meta-analysis aimed to assess whether p53 and Ki-67 expression form a prognostic marker in oral squamous cell carcinoma (OSCC), and its relationships to the lymph node metastasis (LNM) and tumor aggressiveness.
Methodology: PubMed, Scopus, Web of Science, and Google Scholar were searched up to the month November 2025. The studies that were included were observational cohort and cross-sectional studies that assessed p53 or Ki-67 expression in immunohistochemistry (IHC) and provided extractable counts of high/low expression and LNM. Titles, abstracts, and full texts were screened by two reviewers, and disagreements were settled by a third reviewer. The risk of bias was also determined based on the Newcastle–Ottawa Scale (NOS) and the certainty of evidence was determined based on a GRADE methodology.
Results: There was no statistically significant correlation between the p53 expression and LNM (OR = 6.56; 95% CI: 0.28-155.9; I2 = 89%), indicating that the heterogeneity was high. On the contrary, Ki-67 overexpression was much related to LNM (OR = 5.67; 95% CI: 2.22-14.51; I2 = 35%), and this effect was reported in all studies. The stability of the Ki-67 pooled estimate was validated by the sensitivity analysis, but the results of p53 were sensitive to the elimination of specific studies.
Conclusion: Ki-67 overexpression can serve as a predictable prognostic biomarker of metastasis to the lymph node, and p53 outcomes are inconclusive due to the heterogeneity of the methodology.
References
1.Imbesi Bellantoni M, Picciolo G, Pirrotta I, Irrera N, Vaccaro M, Vaccaro F, et al. Oral cavity squamous cell carcinoma: an update of the pharmacological treatment. Biomedicines 2023;11:1112. doi:10.3390/biomedicines11041112
2.Zhou Y, Wang L, Liu M, Jiang H, Wu Y. Oral squamous cell carcinoma: insights into cellular heterogeneity, drug resistance, and evolutionary trajectories. Cell Biol Toxicol 2025;41:101. doi:10.1007/s10565-025-10048-0
3.Jangir NK, Singh A, Jain P, Khemka S. The predictive value of depth of invasion and tumor size on risk of neck node metastasis in squamous cell carcinoma of the oral cavity: a prospective study. J Cancer Res Ther 2022;18:977–83. doi:10.4103/jcrt.JCRT_783_20
4.Zhang X, Xie J, Yang Z, Yu CKW, Hu Y, Qin J. Tumour heterogeneity and personalized treatment screening based on single-cell transcriptomics. Comput Struct Biotechnol J 2025;27:307–20. doi:10.1016/j.csbj.2024.12.020
5.Liu R, Sun K, Wang Y, Jiang Y, Kang J, Ma H. The effects of proliferating cell nuclear antigen and p53 in patients with oral squamous cell carcinoma: a systematic review and meta-analysis. Ann Transl Med 2021;9:1739. doi:10.21037/atm-21-6133
6.Davey MG, Hynes SO, Kerin MJ, Miller N, Lowery AJ, Davey MG, et al. Ki-67 as a prognostic biomarker in invasive breast cancer. Cancers 2021;13:4455. doi:10.3390/cancers13174455
7.Sun X, Kaufman PD. Ki-67: more than a proliferation marker. Chromosoma 2018;127:175–86. doi:10.1007/s00412-018-0659-8
8.Dinu A, Aşchie M, Deacu M, Chisoi A, Enciu M, Cojocaru O, et al. Clinico-morphological correlations with Ki-67 and p53 immunohistochemical expression in high-grade gastrointestinal neuroendocrine neoplasms. Gastrointest Disord 2025;7. doi:10.3390/gidisord7030051
9.Schaafsma E, Takacs EM, Kaur S, Cheng C, Kurokawa M. Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature. Sci Rep 2022;12:1317. doi:10.1038/s41598-022-05243-6
10.Erdian DN, Ham MF, Khoirunnisa D, Harahap AS. High Ki-67 labelling index correlates with aggressive clinicopathological features in papillary thyroid carcinoma: a retrospective study. Thyroid Res 2025;18:54. doi:10.1186/s13044-025-00265-4
11.Đokić S, Gazić B, Kuzmanov BG, Blazina J, Miceska S, Čugura T, et al. Clinical and analytical validation of two methods for Ki-67 scoring in formalin-fixed paraffin-embedded tissue sections of early breast cancer. Cancers 2024;16. doi:10.3390/cancers16071405
12.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi:10.1136/bmj.n71
13.Fekete JT, Gyorffy B. MetaAnalysisOnline.com: an online tool for the rapid meta-analysis of clinical and epidemiological studies. J Med Internet Res 2025.
14.Da Ros Motta R, Zettler CG, Cambruzzi E, Jotz GP, Berni RB. Ki-67 and p53 correlation prognostic value in squamous cell carcinomas of the oral cavity and tongue. Braz J Otorhinolaryngol 2015;75:544–9. doi:10.1016/S1808-8694(15)30494-8
15.Deshmukh AV, Gupta A, Chaudhari AG, Gangane NM. Correlation of p53 expression with clinical presentation and prognosis of oral squamous cell carcinoma patients: a pilot study. Indian J Otolaryngol Head Neck Surg 2022;74:1836–40. doi:10.1007/s12070-020-01859-0
16.Suresh TN, Hemalatha A, Harendra Kumar ML, Azeem Mohiyuddin SM. Evaluation of histomorphological and immunohistochemical parameters as biomarkers of cervical lymph node metastasis in squamous cell carcinoma of oral cavity: a retrospective study. J Oral Maxillofac Pathol 2015;19:18. doi:10.4103/0973-029X.157195
17.Coutinho-Camillo CM, Lourenço SV, Nishimoto IN, Kowalski LP, Soares FA. Nucleophosmin, p53 and Ki-67 expression patterns on an oral squamous cell carcinoma tissue microarray. Hum Pathol 2010;41:1079–86. doi:10.1016/j.humpath.2009.12.010
18.Bhuyan L, Sarangi S, Das BK, Das SN, Nayak S. Proliferative index in invasive tumor front of oral squamous cell carcinoma: a potential prognostic indicator. J Contemp Dent Pract 2018;19:170–6. doi:10.5005/jp-journals-10024-2232
19.Gawande M, Chaudhary M, Sharma P, Hande A, Patil S, Sonone A. Expression of p53 at invasive front of oral squamous cell carcinoma and negative histopathological surgical margins to establish correlation at 3-year survival. J Oral Maxillofac Pathol 2020;24:582. doi:10.4103/jomfp.JOMFP_106_20
20.Cortegoso AVB, Laureano NK, Silva AD da, Danilevicz CK, Magnusson AS, Visioli F, et al. Cell proliferation markers at the invasive tumor front of oral squamous cell carcinoma: comparative analysis in relation to clinicopathological parameters of patients. J Appl Oral Sci 2017;25:318–23. doi:10.1590/1678-7757-2016-0238
21.Babu B, Hallikeri K, Kumar K. Immunoexpression of p53 and Ki-67 correlated with clinicopathological parameters in predicting recurrence of oral squamous cell carcinoma. Asian J Med Sci 2020;11:1–8. doi:10.3126/ajms.v11i2.27022
22.Dash KC, Mahapatra N, Bhuyan L, Panda A, Behura SS, Mishra P. An immunohistochemical study showing Ki-67 as an analytical marker in oral malignant and premalignant lesions. J Pharm Bioallied Sci 2020;12:S274–8. doi:10.4103/jpbs.JPBS_83_20
23.Chaudhari M, Shukla S, Tamhane A, Acharya S, Bhake A. Histopathological grading of oral squamous cell carcinoma and its correlation with Ki-67 – a proliferative marker. J Evid Based Med Healthc 2018;5:1690–5. doi:10.18410/jebmh/2018/355
24.Sharma SC, Maheshwari V, Narula V, Verma S, Jain A, Alam K. Prognostic and predictive impact of Ki-67 in premalignant and malignant squamous cell lesions of oral cavity. Int J Head Neck Surg 2014;4:61–5. doi:10.5005/jp-journals-10001-1141
25.Jing Y, Zhou Q, Zhu H, Zhang Y, Song Y, Zhang X, et al. Ki-67 is an independent prognostic marker for the recurrence and relapse of oral squamous cell carcinoma. Oncol Lett 2019;17:974–80. doi:10.3892/ol.2018.9647
26.Sahoo A, Nazir A, Chandrashekhar SP, Vyas T, Sikdar SD, Paul M, et al. Evaluating the diagnosis of cervical lymph node metastasis in oral squamous cell carcinoma by clinicopathologic investigation. J Pharm Bioallied Sci 2025;17:S2764–6. doi:10.4103/jpbs.jpbs_1158_25
27.Kamala KA, Sankethguddad S. P53 and Ki-67 biomarkers are predictors for malignant transformation in oral submucous fibrosis: a prospective study. Asian Pac J Cancer Prev 2024;25:4129–36. doi:10.31557/APJCP.2024.25.12.4129
28.Davey MG, Hynes SO, Kerin MJ, Miller N, Lowery AJ. Ki-67 as a prognostic biomarker in invasive breast cancer. Cancers 2021;13:4455. doi:10.3390/cancers13174455
29.Chen Y, Zhong N-N, Cao L-M, Liu B, Bu L-L. Surgical margins in head and neck squamous cell carcinoma: a narrative review. Int J Surg 2024;110:3680–700. doi:10.1097/JS9.0000000000001306
30.Savas IN, Coskun A. The future of tumor markers: advancing early malignancy detection through omics technologies, continuous monitoring, and personalized reference intervals. Biomolecules 2025;15:1011. doi:10.3390/biom15071011
31.Cabral LG de S, Martins IM, Paulo EP de A, Pomini KT, Poyet J-L, Maria DA, et al. Molecular mechanisms in the carcinogenesis of oral squamous cell carcinoma: a literature review. Biomolecules 2025;15. doi:10.3390/biom15050621
32.Liu Y, Su Z, Tavana O, Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell 2024;42:946–67. doi:10.1016/j.ccell.2024.04.009
33.Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, et al. p53 signalling in cancer progression and therapy. Cancer Cell Int 2021;21:703. doi:10.1186/s12935-021-02396-8
34.Al-Rawi NH, Kawas SA, Ani MA, Alnuaimi AS, El-Sayed W, Alrashdan MS. Prediction of lymphovascular and perineural invasion of oral squamous cell carcinoma by combined expression of p63 and cyclin D1. Eur J Dent 2023;17:1170–8. doi:10.1055/s-0042-1760301
35.Morand GB, Diaconescu A, Ibrahim I, Lamarche G, Ruas JS, Dalfen J, et al. Molecular prognostic indicators in HPV-positive oropharyngeal cancer: an updated review. Clin Exp Metastasis 2022;39:407–16. doi:10.1007/s10585-022-10148-9
36.García-Chávez JN, Contreras-Paredes A, González-Espinosa C, Martínez-Ramírez I, Langley E, Lizano M, et al. Association of gene expression profiles in HPV-positive head and neck squamous cell carcinoma with patient outcome: in search of prognostic biomarkers. Int J Mol Sci 2025;26. doi:10.3390/ijms26125894
37.Mo C-K, Liu J, Chen S, Storrs E, Targino da Costa ALN, Houston A, et al. Tumour evolution and microenvironment interactions in 2D and 3D space. Nature 2024;634:1178–86. doi:10.1038/s41586-024-08087-4
38.Minaei E, Mueller SA, Ashford B, Thind AS, Mitchell J, Perry JR, et al. Cancer progression gene expression profiling identifies the urokinase plasminogen activator receptor as a biomarker of metastasis in cutaneous squamous cell carcinoma. Front Oncol 2022;12. doi:10.3389/fonc.2022.835929
39.Rais G, Mokfi R, Boutaggount F, Maskrout M, Bennour S, Senoussi C, et al. Assessment of the predictive role of Ki-67 in breast cancer patients’ responses to neoadjuvant chemotherapy. Eur J Breast Health 2024. doi:10.4274/ejbh.galenos.2024.2024-3-8
40.Li K, Wang S, Li Z, Yu Q, Liu L, Li F, et al. Prognostic value of Ki-67 in the invasive zone of oral squamous cell carcinoma. J Oral Pathol Med 2025;54:173–81. doi:10.1111/jop.13608
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