Abstract
Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma, but histologic grading alone lacks reproducibility and prognostic power. This study evaluates whether pattern-based p53 and p16 immunohistochemistry (IHC) can serve as alternative markers to genomic loss of heterozygosity (LOH) testing in predicting OED progression. From a previously characterized LOH cohort, 64 patients were assessed with IHC for p53 and p16 using defined abnormal staining patterns (overexpression, cytoplasmic, or null). Abnormal p53 expression occurred in 19% of cases, with 93% specificity, and was significantly associated with reduced progression-free survival (PFS; 8-year PFS, 25% vs. 74%; P = 0.0011). Abnormal p16 expression was observed in 56% of cases with 95% sensitivity and was significantly associated with 8-year PFS (42% vs. 96%; P < 0.0001). Combined p53/p16-abnormal IHCs identified 95% of the progressing lesions and yielded superior risk discrimination (log-rank P < 0.0001), particularly at the 3-year follow-up mark. Concordance analysis revealed moderate agreement between p16 IHC and 9p LOH (κ = 0.39) and fair agreement between p53 IHC and 17p LOH (κ = 0.21), indicating that IHC and LOH detect related but distinct molecular disruptions. Chronologic evaluation of serial biopsies supported a sequential model in which p16 alteration precedes p53 alteration during malignant progression. Taken together, these findings highlight the potential of a pattern-based approach with combined p53/p16 IHC as a feasible, scalable, and clinically accessible tool to guide surveillance intensity and timely clinical intervention, thereby reducing progression risks. PREVENTION RELEVANCE: In this study, we demonstrate that p53/p16 pattern-based IHC provides a practical and sensitive tool for predicting progression in OED. Its clinical accessibility may facilitate early detection of high-risk lesions, optimizing triage, surveillance, and preventative treatment strategies to reduce the incidence of high-grade lesions or oral cancer.