Association between vitamin D deficiency and longitudinal risk of head and neck cancer: a multi-institutional retrospective study.

Background: Vitamin D is implicated in cancer biology through its regulation of cellular proliferation, apoptosis, and immune surveillance; however, evidence linking vitamin D deficiency (VDD) to head and neck cancer (HNC) risk remains limited by small sample sizes and inadequate control for confounders. Methods: Using the TriNetX Global Collaborative Network, we conducted a retrospective cohort study comparing adults with laboratory-confirmed VDD (25-hydroxyvitamin D < 20 ng/mL) against controls (≥30 ng/mL). After applying the exclusion criteria and 1:1 propensity score matching, 108,010 patients per group were retained. In a separate exploratory dose-response analysis, patients with vitamin D insufficiency (20.0-29.9 ng/mL) were compared with the same sufficiency threshold (≥30 ng/mL). A 180-day landmark period was applied to mitigate reverse causation, with follow-up extending to 10 years. The primary outcome was incident HNC; the secondary outcomes included laryngeal, oral, and other HNC subtypes. Positive (osteoporotic fracture) and negative (appendicitis) control outcomes were assessed to evaluate internal validity. Results: VDD was associated with a significantly higher risk of incident HNC (HR 1.56, 95% CI 1.43-1.70, Conclusion: In this observational study, VDD was significantly associated with an increased risk of HNC, with consistency across subtypes and a dose-response gradient. However, the observational design precludes causal inference, and residual confounding cannot be fully excluded. Prospective studies with detailed lifestyle data are needed to confirm these findings.