Polarization and Distribution of Tumor-Associated Macrophages and COX-2 Expression in Basal Cell Carcinoma of the Ocular Adnexae

<i>Purpose</i>: Basal cell carcinoma (BCC) is a locally invasive skin tumor which can be subdivided into a circumscribed nodular and an invasive fibrosing subtype. There is increasing evidence that macrophages play an important role in interacting between tumor cells and their microenvironment, thereby affecting not only the invasive potential but also the patients’ prognosis. Thus, we wanted to compare these two BCC variants with regard to tumor-related inflammation, COX-2 expression, distribution, and polarization of tumor-associated macrophages. <i>Material and Methods</i>: 30 BCCs (nodular: <i>n</i> = 15; fibrosing: <i>n</i> = 15) of the ocular adnexae were investigated by histopathology and immunohistochemistry. The grade of inflammation was evaluated on hematoxylin and eosin stains (score: 0–3). Immunohistochemical stains for CD68 (macrophages), Ki67 (proliferative activity), and COX-2 as well as immunofluorescence stains for CD68 and CD163 (to distinguish M1 and M2 macrophage subtypes) were performed. SPSS was used for statistical analysis. <i>Results</i>: Fibrosing BCCs were predominantly located on the lower lid, while nodular BCCs showed a broader distribution (<i>p</i> = 0.013). The fibrosing BCC subtype was associated with a higher degree of inflammation (<i>p</i> p = 0.012). COX-2-positive cells were predominantly located on the infiltrating edge of the tumor. Macrophage polarization was balanced regarding M1 and M2 macrophage subtypes. There was no difference in macrophage number (<i>p</i> = 0.389) or polarization (<i>p</i> = 0.161) between nodular and fibrosing BCC. <i>Conclusions</i>: The findings indicate that COX-2 represents a factor for invasion of BCC. Macrophage polarization did not play a major role for aggressive behavior. However, other inflammatory components than tumor-associated macrophages seem to be involved in tissue destruction and thereby an invading growth pattern since fibrosing BCC revealed a significantly more intense inflammatory reaction in the surrounding tissue.

【研究目的】基底细胞癌（Basal cell carcinoma, BCC）是一类局部侵袭性皮肤肿瘤，可分为局限性结节型与侵袭性纤维化亚型。现有越来越多的证据表明，巨噬细胞在肿瘤细胞与其微环境的相互作用中扮演重要角色，不仅可影响肿瘤的侵袭潜能，还会对患者的预后产生作用。因此，本研究拟从肿瘤相关炎症、COX-2表达、肿瘤相关巨噬细胞的分布及极化状态等维度，对这两种BCC亚型开展对比分析。【材料与方法】本研究对30例眼附属器部位的BCC样本（结节型15例，纤维化型15例）进行组织病理学与免疫组织化学检测。以苏木精-伊红染色法评估炎症程度，评分范围为0~3分。此外，还完成了针对CD68（巨噬细胞标志物）、Ki67（增殖活性标志物）及COX-2的免疫组化染色，以及针对CD68与CD163的免疫荧光染色，以区分M1型与M2型巨噬细胞亚型。统计学分析采用SPSS软件进行。【结果】纤维化型BCC主要分布于下眼睑，而结节型BCC的分布范围更广（p=0.013）。纤维化型BCC亚型伴随更高程度的炎症反应（p=0.012）。COX-2阳性细胞主要定位于肿瘤的浸润边缘。巨噬细胞极化在M1与M2亚型间呈平衡状态。结节型与纤维化型BCC在巨噬细胞数量（p=0.389）或极化状态（p=0.161）上均无显著差异。【结论】本研究结果提示，COX-2可作为BCC侵袭性的相关影响因子。巨噬细胞极化并未在肿瘤的侵袭性行为中发挥主要作用。然而，除肿瘤相关巨噬细胞外的其他炎症成分，似乎参与了组织破坏过程并进而促成侵袭性生长模式，这是因为纤维化型BCC的周围组织呈现出显著更强烈的炎症反应。