Abstract / Summary
Background/Objectives: Chronic inflammation is increasingly recognized as a driver of head and neck squamous cell carcinoma (HNSCC) progression, but the interplay between local immune surveillance and angiolymphatic remodeling remains incompletely characterized. We hypothesized that advanced HNSCC stage would be associated with lower epithelial CD1a+ Langerhans cell density alongside higher proliferation, reduced E-cadherin-mediated adhesion, and higher angiogenic/lymphangiogenic activity, and aimed to relate this marker pattern to tumor stage defined by combined histopathological and radiological criteria. Methods: Fifty HNSCC specimens were included (mean age, 63.9 ± 8.7 years; 86% male; 88% current or former smokers). Specimens were evaluated immunohistochemically for CD1a (primary Langerhans cell metric) and S100 (supportive marker), Ki-67, E-cadherin, VEGF, and Ki-67/D2-40 double staining (proliferating lymphatic vessel density (pLVD), reported descriptively only), alongside hematoxylin and eosin (H&E)-based histological grading and combined histopathological/radiological (CT/MRI) staging. Associations were assessed using Spearman correlation, Mann–Whitney U/chi-square tests, and multivariable logistic regression. Results: CD1a+ epithelial density, the primary Langerhans-cell metric, was significantly lower in advanced-stage and node-positive tumors (median 22.30 vs. 32.75 cells/mm2, p = 0.0008; and 19.05 vs. 31.15 cells/mm2, p < 0.0001, respectively), while the Ki-67 index and VEGF immunoreactive score were correspondingly higher (all p ≤ 0.001), with a parallel decrease in E-cadherin H-score. CD1a+ density showed moderate inverse or direct correlations with the other evaluated markers (|ρ| = 0.56–0.64; all p < 0.001). On multivariable analysis, lower CD1a+ epithelial density remained associated with nodal disease (pathological or clinical/radiological nodal status) after adjustment for T category (OR = 5.98 per 10-cell/mm2 decrease; 95% CI, 1.75–20.35; p = 0.004), together with T category (OR = 12.07; 95% CI, 1.99–73.06; p = 0.007), a finding robust to marker specification in a sensitivity analysis using the S100/CD1a composite metric (OR = 5.55; 95% CI, 1.61–19.18; p = 0.007). Conclusions: In this cross-sectional cohort, lower epithelial CD1a+ Langerhans cell density was associated with advanced stage and nodal positivity and occurred alongside higher proliferative activity, higher VEGF expression, and lower E-cadherin expression. These routinely assessable tissue biomarkers may provide a feasible framework for future biomarker-based risk stratification and warrant investigation for potential diagnostic adjunctive value. However, prospective validation in independent cohorts, including formal assessment of diagnostic performance, is required before any diagnostic, prognostic, predictive, or treatment-selection role can be proposed.