Clinical and prognostic significance of spatial distribution of CD163-positive tumor-associated macrophages in pleural mesothelioma

Objectives: Pleural mesothelioma (PM) remains a fatal malignancy despite multimodal therapy. Macrophages activated by asbestos and tumor-derived factors may develop into tumor-associated macrophages (TAMs) with tumor-promoting properties. However, the spatial distribution and clinical impact of these TAMs in PM remain poorly defined. Methods: We retrospectively analyzed 101 consecutive patients with PM treated at Kyoto University Hospital and Hyogo Prefectural Amagasaki General Medical Center between 1998 and 2010. CD163 immunohistochemistry was performed to quantify pro-tumoral TAMs in intratumoral and peritumoral regions, while Ki-67 staining assessed tumor proliferation. The intratumoral region was defined as an area within the tumor or, if not feasible, as a field containing ≥70% tumor tissue. The peritumoral region was defined as an adjacent stromal area containing >70% stroma. Optimal cutoffs for TAM densities were determined using the minimum p-value method with pretreatment C-reactive protein (CRP). Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox regression model was employed for univariable and multivariable analyses to examine factors influencing survival. Results: Intratumoral and peritumoral CD163-positive TAM densities were 660.8 ± 565.9 and 223.1 ± 195.6 cells/mm², respectively, and were moderately correlated (r = 0.505, p < 0.001). Both intratumoral and peritumoral TAM densities correlated with CRP (r = 0.283 and 0.255, p < 0.05) and Ki-67 (r = 0.498 and 0.435, p < 0.001). Intratumoral TAMs were more abundant in sarcomatoid histology (p < 0.001) and in advanced stage (p = 0.043), whereas peritumoral TAMs showed no significant associations with clinicopathologic factors. High CD163-positive TAM density predicted poorer OS in both regions: intratumoral high versus low groups showed 5-year OS rates of 13.3% and 23.2% (p = 0.044), and peritumoral high versus low groups showed 5-year OS rates of 13.2% and 24.1% (p = 0.046). In multivariable analysis, peritumoral CD163-positive TAM-high status (HR = 1.700, 95% CI 1.034-2.796, p = 0.037) remained an independent prognostic factor along with stage and histology. Conclusions: In PM, high densities of CD163-positive TAMs were associated with systemic inflammation and tumor proliferation. The spatial distribution of these TAMs may indicate a prognostically relevant tumor immune microenvironment, and peritumoral TAMs in particular showed independent prognostic significance. These findings suggest that TAM spatial profiling may serve as a practical biomarker for risk stratification.