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AIMS: Differentiated or HPV-independent vulvar intraepithelial neoplasia (dVIN) can progress rapidly to invasive cancer and accurate pathological diagnosis is essential to facilitate appropriate interventions. Histological similarities of dVIN with non-neoplastic lesions, however, often make the diagnosis less reproducible. We investigated among a diverse group of pathologists whether the diagnostic agreement improves with the use of p53 immunohistochemistry (IHC) interpreted using the pattern-based schema.METHODS AND RESULTS: Fifty haematoxylin-eosin (HE) stained archival slides (30 dVIN and 20 non-dysplastic vulvar lesions) were selected and p53-IHC was performed. Twenty-four board-certified pathologists from eight countries first assessed the HE slides alone, and after a washout period, re-evaluated them alongside the p53-IHC slides. During both rounds, slides were diagnosed as dVIN, favour dVIN, favour no-VIN or no-VIN. p53-IHC was scored as wild-type or mutant (diffuse, basal, cytoplasmic or null). Kappa (κ) statistics and McNemar's test were used for statistical analyses. Overall diagnostic agreement for dVIN saw a significant increase in the Kappa value (κ = 0.6 vs. κ = 0.4, P = 0.002) when HE and p53-IHC slides were assessed together compared with histology assessment alone, although the level of agreement remained moderate. For p53-IHC assessment, overall agreement was substantial (κ = 0.7). Diagnoses changing from no-VIN/favour no-VIN to dVIN correlated significantly with the identification of a p53-mutant pattern (P < 0.001).CONCLUSIONS: Our findings indicate that p53-IHC is a robust ancillary tool that can be reproducibly interpreted by pathologists with varying experience levels and supports the routine use of p53-IHC in cases where dVIN is considered in the differential diagnosis.