Prognostic Factors in Primary Head and Neck Cutaneous Squamous Cell Carcinoma: A Large-Scale, Multi-Institutional...

Current staging systems for head and neck cutaneous squamous cell carcinoma (HNCSCC), such as AJCC8 and BWH, often fail to adequately stratify high-risk patients, particularly due to the exclusion of important biological and host factors. This study aimed to identify independent prognostic factors for HNCSCC outcomes in the largest multi-institutional retrospective series to date.

De-identified data from 8,610 primary HNCSCC tumors, treated with curative intent surgery across multiple international centers, were analyzed. Outcomes included local recurrence (LR), locoregional metastasis (LM), distant metastasis (DM), and disease-specific death (DSD). Multivariable Fine-Gray subdistribution hazard regression models with robust standard errors clustered at the patient level were fitted to generate exploratory hypotheses regarding independent hazard determinants.

During a median follow-up of 31.4 months (IQR 14.2-52.8), the cumulative incidence was 3.3% for LR, 2.7% for LM, 0.5% for DM, and 1.2% for DSD. Multivariable analysis confirmed that tumor diameter, poor differentiation, deep invasion, and large-caliber perineural invasion (LCPNI) were the strongest predictors, being significantly associated with at least three of the four outcomes. Notably, factors currently excluded from or weighted differently in staging systems also proved critical: Immunosuppression was significantly associated with LR (SHR 2.03) and DSD (SHR 1.70); and lymphovascular invasion (LVI) was independently associated with LM (SHR 3.00). Poor differentiation demonstrated high prognostic impact, being a significant predictor for all four endpoints.

Tumor diameter, poor differentiation, deep invasion, LCPNI, immunosuppression status, and LVI are the most critical independent factors for HNCSCC prognosis. Our multi-institutional data provide a robust framework for hypothesis generation, highlighting that incorporating host biological features and non-anatomic variables could significantly refine future staging system discussions.