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

## TL;DR

This study finds that combining FoxP3+ cell and PNAd+ vessel markers improves predicting survival in oral tongue cancer patients.

## Contribution

The study introduces a combined biomarker model that improves risk stratification beyond standard pTNM staging in OTSCC.

## Key findings

- High FoxP3+ cell density independently predicts increased disease-specific death in OTSCC patients.
- Combining FoxP3 and PNAd markers improves prognostic accuracy beyond traditional pTNM staging.
- High PNAd/low FoxP3 tumors show excellent prognosis, while low PNAd/high FoxP3 tumors confer the highest risk.

## Abstract

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).

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.

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).

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.

The online version contains supplementary material available at 10.1007/s12105-026-01904-4.