Aberrant Cytoplasmic p53 Staining in Oral Squamous Cell Carcinoma and Dysplasia

p53 cytoplasmic sequestration has been shown to be a mechanism of carcinogenesis. However, until recently, an aberrant p53 cytoplasmic staining pattern by immunohistochemistry (IHC) was under-reported in oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED). Following the identification of a pilot case, the authors studied the clinicopathologic features of 4 OSCCs and 10 OEDs with p53 cytoplasmic staining pattern, 4 of which exhibited co-occurrence of nuclear null/overexpression patterns. Using next-generation sequencing (NGS), we demonstrate that this cytoplasmic staining pattern correlates with TP53 mutations that disrupt or truncate the C-terminal nuclear localization sequence (NLS) or nuclear exclusion sequence (NES). High-impact NLS-altering mutations in the same region are identified in 8.7% to 11.0% of TP53-mutant samples in the TCGA-HNSC cohort. Our study provides a practical definition for aberrant p53 cytoplasmic staining in HNSCC and OED, a diagnostic pitfall with potential biological implication. This study proposes an updated p53 IHC interpretation algorithm to facilitate further data accrual.