Prognostic Significance of the Density and Spatial Distribution of Tumor‐Associated Macrophages in Giant Cell Tumor of Bone and Their Association With Denosumab Treatment Responsiveness

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Abstract
Given the lack of reliable indicators for predicting prognosis and treatment response in giant cell tumor of bone (GCTB) patients, this study aimed to identify new prognostic factors by analyzing the effect of tumor‐associated macrophages (TAMs) on prognosis and denosumab treatment responsiveness. The expression of CD68⁺TAMs, CD163⁺TAMs, and IRF8⁺TAMs was detected using polychromatic fluorescence immunohistochemistry in 162 GCTB samples. TAM density was quantified through computer‐aided image analysis, and spatial parameters, including nearest neighbor distance (NND) and effective percentage (EP), were measured using HALO software. Results showed that higher densities of CD68⁺ and CD163⁺ TAMs were significantly associated with inferior progression‐free survival (PFS). A smaller NND was linked to shorter PFS. Additionally, higher CD68⁺ EP was associated with poorer PFS, whereas higher CD163⁺ EP correlated with better PFS. Receiver operating characteristic curve analysis demonstrated that TAM parameters' predictive performance was comparable to Campanacci and surgical approach in three subgroups. The ineffective denosumab‐treated group had significantly higher TAMs EP compared to the effective group. In conclusion, TAMs significantly influence the prognosis of GCTB patients and are correlated with certain invasive tumor phenotypes. Elevated TAMs levels may be associated with reduced efficacy of denosumab treatment.

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