Morphology of Tumor-Associated Macrophages Dictates the Prognosis of Patients with Colorectal Liver Metastases

Abstract

Background: In the era of precision medicine there is a need of reliable prognostic markers to cope with the clinical heterogeneity of patients with colorectal liver metastases (CLM) and, for their predominance in metastatic tissues, tumor-associated macrophages (TAMs) emerge as promising candidates. The aim of this study was to test the presence of discrete TAMs in CLM patients, and to test their role on recurrence-free survival (RFS). Methods: NCT038888638 is a single-center study that examined a cohort of CLM patients that underwent hepatectomy between 2005 and 2017. TAMs cell density, cell area and cell perimeter were quantified in 3 non-contiguous and non-overlapping areas of by means of immuno-reactive area of CD163+ macrophages. The association of TAMs metrics and RFS was tested by using receiver operating characteristics (ROC) curves, and multivariate Cox regression analysis. Results: 101 patients resected between 2005 and 2017 were considered. Among density (AUC=0.555;95%CI=0.410-0.701;P=0.449), perimeter (AUC=0.526;95%CI=0.383-0.671;P=0.708) and area (AUC=0.791;95%CI=0.572-0.841;P=0.006) of CD163+ TAMs, only the latter was significantly associated with differences in survival time. Small and large TAMs, as defined by using the best cutoff value extrapolated from the ROC curve (area:60.39μm2;Se=0.79;Sp=0.44), were clearly associated with significantly different 5-year RFS rates of 27.8% and 0.2% respectively (P< 0.001). At the multivariate analysis, including TAMs area and several prognostic factors, only TAMs area was found to be independently statistically associated with RFS (HR=3.41;95%CI=1.13-5.43;P=0.001). Conclusions: Macrophage morphology is associated with CLM patients' prognosis. Quantitative morphometric characterization of TAMs can serve as an easily quantifiable correlate of functional diversity with prognostic significance.