Consensus in Oral Epithelial Dysplasia Classification: A Comparative Analysis of H&E-stained Sections With and Without p53/p16 Immunohistochemistry

Abstract

Diagnosis and classification of oral epithelial dysplasia (OED) is critical to identifying and prognosticating patients at risk of squamous cell carcinoma (SCC). However, conventional 3-tiered and 2-tiered grading systems suffer from poor inter-pathologist agreement, and SCC may arise from all grades of OED. This study evaluated pathologist agreement in OED classification as p53 wildtype, p53 abnormal, and HPV-associated based on recent evidence demonstrating the utility of p53/p16 immunohistochemistry (IHC) in this setting and increased risk of p53 abnormal OED progression to SCC, regardless of histologic grade. Fifty digital biopsy specimens were evaluated for diagnosis by 18 subspecialty-trained pathologists, with OED graded utilizing 3-tiered, 2-tiered, and p53 wildtype/p53 abnormal/HPV-associated schemata. Cases were reviewed first without and subsequently with p53/p16 IHC. The cohort consisted of 8 cases of p53 wildtype, 24 cases of p53 abnormal, and 18 cases of HPV-associated OED. Inter-pathologist agreement in OED grading according to 3-tiered (κ=0.32) and 2-tiered (κ=0.39) systems by H&E was poor, but fair-to-good (κ=0.59) in classification as p53 wildtype/p53 abnormal/HPV-associated by H&E and IHC. Classification of OED as p53 wildtype, p53 abnormal, or HPV-associated using p53/p16 IHC outperformed conventional grading in this cohort enriched for p53 abnormal OED, which required correct interpretation of p53 IHC, historically deemed challenging. Routine use of IHC also identifies a wider histologic spectrum of HPV-associated OED than is currently appreciated. More work is needed to determine the efficacy of this classification system in predicting patient outcomes and in guiding management decisions in real-world cohorts.

Keywords: leukoplakia; oral epithelial dysplasia; oral potentially malignant disorder; p16; p53; squamous cell carcinoma.