Prognostic Significance of CD68+ Macrophages and FoxP3+ Regulatory T Cells in Neuroendocrine Tumors

Abstract

Aim

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable immune microenvironment. This study aimed to analyze the infiltration of NETs by CD68⁺ tumor-associated macrophages (TAMs) and FoxP3⁺ regulatory T cells (Tregs) using Qupath software for semi-automated histopathological quantification

Methods

Thirty-two patients with resected NETs were included. CD68 and FoxP3 expression were assessed by immunohistochemistry followed by automated cell detection and spatial analysis.

Results

The mean percentage of CD68⁺ cells was 0.35%, with no significant differences between pancreatic and gastrointestinal NETs. FoxP3⁺ cells were less frequent (mean: 0.06%), with higher levels in gastrointestinal NETs compared to pancreatic NETs (p < 0.05). Kaplan-Meier analysis revealed that CD68⁺ cells showed a trend to positive correlation with progression-free survival (PFS) and overall survival (OS). Thereby, patients exceeding a 0.1% CD68⁺ cell threshold exhibited longer survival (PFS: not reached vs. 106 months). In contrast, FoxP3⁺ cells showed a trend to inverse correlation with survival; patients with >0.05% FoxP3⁺ cells had shorter PFS (36 months vs. 147 months) and OS (180 months vs. not reached). Multivariate Cox regression identified N-stage as the sole predictor of OS. CD68⁺ TAM density was not associated with other clinical parameters, while FoxP3⁺ cell infiltration correlated significantly with venous invasion and advanced N- and M-stages.

Conclusion

These findings highlight the potential prognostic relevance of immune cell infiltration in NETs and underscore the utility of Qupath for quantifying immune markers in histopathological analyses. The contrasting roles of CD68⁺ TAMs and FoxP3⁺ Tregs in the NET microenvironment warrant further exploration to inform immunotherapeutic strategies.

Keywords

Neuroendocrine Tumor - Immune System - Peptide-Receptor-Radionuclide-Therapy

Publication History

Received: 26 September 2025

Accepted: 05 November 2025

Article published online:
01 December 2025

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