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Purpose <p>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).</p> Methodology <p>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.</p> Results <p>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; <i>p</i> &lt; 0.0001).</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

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  • 发表日期：

    2026年3月26日

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  • Ibrahim Afolabi Abdulsalam,
  • Kjersti Sellæg,
  • Faith O. Benebo,
  • Nancy C. Ojei,
  • Sonja E. Steigen,
  • Lars Uhlin-Hansen,
  • Inger-Heidi Bjerkli,
  • Anna M. Wirsing,
  • Synnøve Norvoll Magnussen,
  • Elin Hadler-Olsen

摘要

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