# 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

## TL;DR

This study shows that the number and arrangement of tumor-associated macrophages in bone tumors can predict patient outcomes and how well they respond to a specific drug.

## Contribution

The study introduces TAM density and spatial distribution as novel prognostic and treatment response indicators in GCTB.

## Key findings

- Higher CD68⁺ and CD163⁺ TAM densities correlate with worse progression-free survival.
- Smaller nearest neighbor distance and higher CD68⁺ effective percentage predict poorer outcomes.
- Ineffective denosumab treatment is linked to higher TAM effective percentage and density.

## 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.

From January 2015 to December 2020, 393 samples of GCTB were collected from five centers.

The density of CD68+ TAMs, CD163+ TAMs, and IRF8+ TAMs was counted by computer‐aided image analysis, and their spatial parameters including NND and EP were measured by HALO. Higher CD68+ TAMs and CD163+ TAMs densities were significantly correlated with inferior PFS. TAMs NND displayed a positive correlation with PFS. Higher CD68+ EP was linked to poorer PFS, whereas higher CD163+ EP was associated with better PFS. The ineffective denosumab‐treated group exhibited significantly higher CD68+ and IRF8+ TAMs density, as well as higher TAMs EP compared to the effective group.