Role of Macrophages in the Progression of Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasia. It is postulated that genetic alterations and tumor antigens can stimulate immune response, orchestrating tumor immune microenvironment. In its turn, immune microenvironment can facilitate cancer progression. It is well known that macrophages are the most important players in tumor development and progression. However, it is still unclear whether there are any relations between number and type of macrophages in progression of papillary thyroid carcinoma. The purpose of this study was to evaluate possible immune-mediated mechanisms of development and progression of papillary thyroid carcinoma, namely estimating the number and type of tumor-associated macrophages and their association with the characteristics of PTC. Material and methods. 60 patients with histopathologically confirmed PTC and 27 patients with follicular adenoma (FA) were enrolled in the study. We considered the tumor size, extra thyroidal extension (ETE), lymphovascular invasion, regional lymph nodes metastases, histological variant of PTC, as well as intensity of inflammatory infiltration and vascularization. To assess tumor associated macrophages and their role in tumor progression immunohistochemical investigation was conducted with the following markers: CD68 to assess the whole set of macrophages and CD163 to evaluate M2-type macrophages. In addition, angiogenesis was considered using VEGF and blood vessels number was evaluated using semi-quantitative score system. Results and discussion. According to the obtained data, PTC was associated with increased number of macrophages, comparing with normal thyroid and follicular adenoma (P<0.0001). Number of macrophages correlated with degree of inflammatory infiltration. These cells were located in tumor and in some cases they were in capsule and around it. In addition, the number of CD163 cells was much higher in patients with invasive growth, demonstrating the possible role of M2 macrophages in PTC progression. Tight relationship was found between the number of M2 macrophages and metastases in the lymph nodes (OR=8.56; 95% CI 2.46-28.22; P=0.0004). Macrophages count was related with high microvascular density (P=0.006), VEGF expression (P<0.0001), intrathyroid invasion (P=0.03) and lymph node dissemination (P=0.005). In addition, the strong correlation between count of CD163+ and MCT+ cells in tumor and lymph nodes was found. We suppose the inflammatory mediated signaling pathways activation in PTC metastasis development. Expression of VEGF was found in tumor cells and in stroma. VEGF expression in tumor cells varied from low to high and correlated with degree of infiltration (r=0.677; P<0.001) and number of M2 macrophages (r=0.812; P<0.0001). In addition there were numerous VEGF positive cells inside infiltrates. Their accumulation around malignant nodules was associated with features of invasion. Conclusions. Thus, increased number of PTC-associated CD163+ macrophages is associated with an increased risk of metastasis to regional lymph nodes due to overexpression of VEGF and tumor cell invasiveness.