FoxP3+ Cells and PNAd+ Tumour-Associated High Endothelial Venules: Synergistic Prognostic Markers in Oral Tongue Squamous Cell Carcinoma.

PURPOSE: Oral tongue squamous cell carcinoma (OTSCC) features significant immune cell infiltration. In head and neck SCC, peripheral node addressin (PNAd) + tumour-associated high endothelial venules (TA-HEVs) and CD163+ tumour-associated macrophages (TAMs) are associated with favourable and unfavourable prognoses, respectively, whereas the prognostic value of FoxP3+ cells is controversial. This national, multi-centre retrospective study evaluates the prognostic roles of these biomarkers individually and in combination in a homogeneous cohort of 126 treatment-naïve OTSCC patients diagnosed in Norway (2005–2009). METHODOLOGY: Immunohistochemistry on formalin-fixed, paraffin-embedded tissue assessed PNAd+ TA-HEVs, CD163+ TAMs, and FoxP3+ cell densities. Associations between scores and clinical/pathological variables were analysed using chi-square tests. Five-year disease-specific death (DSD) prediction was evaluated using cumulative incidence function estimation and Fine-Gray subdistribution hazard modelling to account for competing mortality. RESULTS: In multivariable competing-risk analyses, high FoxP3⁺ cell density independently predicted increased five-year DSD (sHR = 5.40, 95% CI 1.92–15.17). PNAd demonstrated context-dependent prognostic effects when analysed with FoxP3: high PNAd/low FoxP3 tumours showed excellent prognosis, whereas low PNAd/high FoxP3 conferred highest risk (combined model: PNAd sHR 2.58, 95% CI 1.25–5.34; FoxP3 sHR 8.78, 95% CI 3.53–21.87). CD163⁺ TAM density was not associated with DSD. Combined biomarker assessment added incremental prognostic value beyond pTNM staging, with higher discrimination (C-index 0.727 → 0.784) and improved model fit (ΔAICc =  − 8.93; p < 0.0001). CONCLUSIONS: Higher FoxP3+ cell density independently predicted increased DSD, while PNAd showed context-dependent prognostic value. Combined biomarker assessment improved risk stratification beyond pTNM staging, supporting investigation of integrated immune profiling for risk stratification, pending external validation. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12105-026-01904-4.