Primary site specific distribution and prognostic significance of p53 immunohistochemistry patterns in 1,515 patients with head and neck squamous cell carcinoma

Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a high prevalence of TP53 mutations, reported in approximately 70% of cases in The Cancer Genome Atlas (TCGA). Although primary site-specific variation in TP53 mutation prevalence and related clinical behavior has been suggested, the TCGA cohort is biased toward certain primary sites-particularly the oral cavity and larynx-with limited representation of oropharyngeal and hypopharyngeal tumors. To address this sampling bias, we aimed to clarify the prevalence and anatomical distribution of HNSCC, as well as its prognostic implications, using comprehensive p53 immunohistochemistry (IHC) in a large institutional cohort. Methods: We retrospectively analyzed 1,515 patients with HNSCC who underwent biopsy or surgery at the National Cancer Center Hospital between 2013 and 2023. TP53 status was inferred from p53-IHC patterns (wild-type, lost-type, or accumulation-type), and p16-IHC was performed to assess HPV association. Primary site-specific and subsite-specific prevalence patterns were evaluated using Fisher's exact test and odds ratios (ORs). Overall survival (OS) and disease-specific survival (DSS) were assessed in 1,364 patients after excluding carcinoma in situ, best supportive care, and outside-treated cases. Results: Among 1,515 HNSCC cases, 409 (27.0%) were classified as p53 wild-type, 736 (48.6%) as accumulation-type, and 370 (24.4%) as lost-type. The prevalence of p53 mutated-type tumors varied markedly across anatomical sites. Mutation-enriched primary sites included the hypopharynx/cervical esophagus (OR = 5.10, 95% CI: 3.49-7.46, p < 0.01), larynx (OR = 1.88, 95% CI: 1.22-2.88, p < 0.01), and oral cavity (OR = 1.54, 95% CI: 1.19-2.00, p < 0.01). In contrast, p53 wild-type tumors were significantly frequent in the oropharynx (OR = 0.25, 95% CI: 0.19-0.33, p < 0.01) and nasopharynx (OR = 0.24, 95% CI: 0.13-0.47, p < 0.01). Survival analysis revealed significantly improved outcomes in the p53 IHC wild-type group compared with the mutated-type group (median OS: not reached vs. 110 months; HR = 0.59, 95% CI: 0.46-0.76, p < 0.01; median DSS: both not reached; HR = 0.65, 95% CI: 0.47-0.89, p = 0.01). Conclusion: This large cohort study demonstrates substantial primary site-specific variation in p53 alteration patterns across HNSCC, with notable enrichment of IHC p53-mutated tumors in the hypopharynx and larynx, and enrichment of p53 IHC wild-type tumors in oropharyngeal, nasopharyngeal, and gingival cancers. The p53 IHC wild-type pattern was consistently associated with significantly better survival. These findings highlight the importance of anatomical subsite context when interpreting TP53 status and suggest that p53 IHC serves as a robust, clinically relevant biomarker in HNSCC.