Objective Perineural invasion (PNI) negatively affects disease-specific survival in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC). We aim to analyze the prognostic implications of PNI-related features. Study Design Retrospective cohort study. Setting Academic tertiary care hospital. Methods Retrospective chart review was performed on 104 patients diagnosed with HNcSCC between January 2011 and October 2019 who underwent resection, parotidectomy, and neck dissection with more than 1 year of follow-up. PNI was classified as incidental (identified on histopathology alone) or clinical (present on radiography and/or physical exam). Primary outcome measures were overall survival and disease-free survival (DFS). Kaplan-Meier analysis, logistic regression, and Cox regression were performed. Results The overall 5-year DFS was 57.9%. Sixty-one patients had PNI. On histopathology, 28 lesions showed complete nerve encirclement, 10 involved >5 nerves, and 12 involved named nerves. Patients with facial weakness ( P = .026) and positive margins ( P = .0029) had a higher likelihood of histopathologic PNI, and positive margins retained significance on multivariable analysis ( P = .0079). Worse DFS was seen in patients with PNI ( P = .004), advanced tumor stage ( P = .049), positive margins ( P = .014), and >5 nerves involved ( P = .0061). Furthermore, histopathologic PNI was a predictor of DFS (hazard ratio [HR], 3.07; 95% CI, 0.33-1.38; P = .0061) overall and in the clinical PNI cohort (HR, 3.43; 95% CI, 1.65-7.10; P = .00091). Conclusion DFS was significantly worse in patients with PNI, facial nerve weakness, advanced T stage, positive margins, and multiple nerve involvement. Further characterization of PNI features may help improve prognostic predictions and identify patients who may benefit from more aggressive treatment.

The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.