Newly formed adrenergic nerve fibers and perineural invasion in head and neck squamous cell carcinoma: a multicohort study

Abstract Objective This study investigated the role of newly formed adrenergic nerve fibers in the tumor microenvironment in promoting tumor growth, focusing on the relationship between perineural invasion and adrenergic axonogenesis in oral cavity cancer. Methods We analyzed 70 and 14 patients with oral tongue squamous cell carcinoma and oral cavity squamous cell carcinoma, respectively, from our institution and 465 patients with head and neck cancer from The Cancer Genome Atlas (TCGA). In the oral tongue squamous cell carcinoma cohort, the extent of tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) immunostaining in peritumoral nerves were evaluated and compared with perineural invasion. In the oral cavity squamous cell carcinoma and TCGA cohorts, TH and GAP43 expressions were compared with perineural invasion. Survival was analyzed based on gene expression levels in TCGA cohort. Results In the oral tongue squamous cell carcinoma cohort, TH positivity was associated with perineural invasion (P = .01). A positive correlation was observed between wild-type p53 immunostaining and TH negativity (P = .03). Double immunostaining for TH and GAP43 showed a 76% concordance rate. In the oral cavity squamous cell carcinoma cohort, a positive association between GAP43 expression and perineural invasion was suggested. TCGA cohort showed a positive association between TH expression and perineural invasion (P < .001). High GAP43 expression was associated with poor prognosis (P = .04). Conclusions TH expression may play a role in adrenergic axonogenesis in the tumor microenvironment and may participate in the pathogenesis of perineural invasion in oral cavity squamous cell carcinoma.