Immunotherapy for Head and Neck Cutaneous Squamous Cell Carcinoma with Perineural Spread: A Systematic Review

BACKGROUND: Immunotherapy is increasingly used for head and neck cutaneous squamous cell carcinoma (cSCC) with perineural spread (PNS), though outcomes remain poorly defined. METHODS: A systematic review was conducted according to PRISMA and MOOSE guidelines. Studies reporting immunotherapy in cSCC with clinical or radiologic cranial nerve PNS were included. Data on demographics, nerve involvement, treatment, response, and outcomes were extracted. RESULTS: Twenty-three studies (150 patients) were included. Median age was 72.5 years; 78.5% were male. PNS most commonly involved CNV (83.3%) and CNVII (31.7%). Immunotherapy was primarily cemiplimab (75.2%) and pembrolizumab (19.7%). Disease control was achieved in 87.3% (complete response: 38.7%, partial response: 42.0%). Functional nerve recovery was reported in 26/64 patients with evaluable outcomes (40.6%), equivalent to 17.3% of the total cohort. Median follow-up was 16 months, with 82.3% alive. Adverse events occurred in 28%, with serious toxicity rare. CONCLUSIONS: The available evidence demonstrates that immunotherapy can achieve disease control in cSCC with PNS and that established cranial nerve dysfunction may recover in some patients. Prospective studies with standardized oncological and functional outcomes are needed to better define treatment efficacy and establish the role of immunotherapy within current treatment paradigms.