Date of Award

5-30-2026

Thesis Type

PhD

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Divisions

Faculty of Dentistry

Department

Department of Oro-maxillofacial Surgical & Medical Sciences

Institution

Universiti Malaya

Abstract

Introduction: Oral squamous cell carcinoma (OSCC) is the most common oral malignancy with a rising incidence in younger adults. Human Papillomavirus (HPV) infection has emerged as a notable risk factor, with p16 being a surrogate marker. Tumour-infiltrating lymphocytes (TILs), including regulatory T cells (Tregs) identified by Forkhead box P3 (FOXP3), contribute to immune modulation within the OSCC tumour microenvironment (TME). Objectives: The study aims to identify potential agespecific patterns in p16 expression, TILs, and FOXP3 cells in OSCC, and to examine their associations with clinicopathological and sociodemographic factors across different age groups. Methodology: 78 OSCC cases diagnosed at Universiti Malaya and the Institute for Medical Research were included (40 aged ≤45 years; 38 aged >45 years). Clinicopathological and sociodemographic data were retrieved. p16 expression was assessed using immunohistochemistry. Stromal (sTILs), intratumoral (iTILs), and total TILs and FOXP3 expression were quantified using digital image analysis. Results: p16 positivity was identified in only one patient aged ≤45 years (p = 1.000). In patients ≤45 years, moderately differentiated tumours were associated with higher sTILs (p = 0.004), while carcinoma and dysplasia at the margin showed inverse (p = 0.014) and positive (p = 0.024) association, respectively; female sex was associated with lower iTILs (p = 0.029). In patients >45 years, depth of invasion (DOI) >10 mm was associated with lower sTILs and iTILs (p = 0.006; p = 0.010), advanced stage with lower total TILs (p = 0.012), and betel nut chewing with higher iTILs (p = 0.041). Stromal and total FOXP3 cell densities differed between age groups (p = 0.036; p = 0.029), with higher levels in older patients. In patients ≤45 years, stromal FOXP3 was higher in females (p = 0.006) and lower in those with a family history of cancer (p = 0.012); erythroleukoplakic lesions showed higher stromal and total FOXP3 (p < 0.001), while buccal sulcus tumours and carcinoma near margin were associated with higher intratumoral FOXP3 (p = 0.001; p = 0.005). In patients >45 years, stromal FOXP3 was increased in alveolar process tumours and carcinoma near margin (p = 0.001; p < 0.001) whereas reduced FOXP3 was observed in moderately differentiated tumours, DOI >10 mm, and lymphovascular invasion (all p < 0.05); intratumoral FOXP3 was higher in females and lower in T4 tumours (p = 0.031; p = 0.024). Total FOXP3 was lower in tumours located at the gingiva, moderately differentiated, pN0 disease, and DOI >10 mm and higher in carcinoma near the margin (all p < 0.05). Total TILs showed a consistent positive correlation with intratumoral FOXP3 across all patients and age groups (all p < 0.001). Conclusion: p16 positive OSCC was uncommon, suggesting a limited role of p16 as a surrogate marker for HPVrelated OSCC across age groups. Tumour immune profiles demonstrated clear age- and compartment-specific differences, with tumour aggressiveness more strongly associated with reduced immune infiltration in older patients. These findings underscore the importance of age stratification and spatial immune assessment in understanding OSCC TME heterogeneity.

Initial

khm

Additional Information

Thesis (PhD) – Faculty of Dentistry, Universiti Malaya, 2026.

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