Department of Biomedical Science, Humanitas University, Pieve Emanuele, Milan.
Department of Hepatobiliary and General Surgery.
Int J Surg. 2023 May 1;109(5):1311-1317. doi: 10.1097/JS9.0000000000000374.
Tumor-associated macrophages (TAMs) are key components of a tumoral microenvironment and have been shown to impact prognosis in different cancers. Previously reported data showed that TAM morphology correlates with prognosis in colorectal liver metastases (CLMs) after hepatectomy, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger ones (L-TAMs). This study aims to externally validate this finding.
The external cohort consisted of 84 formalin-fixed and paraffin-embedded surgical samples of CLMs and peritumoral tissue. Two-micrometer-section slides were obtained; the area and perimeter of 21 macrophages in each slide were recorded. The endpoints were TAMs morphometrics and their prognostic significance in relation to disease-free survival (DFS).
The average macrophage perimeter was 71.5±14.1 μm whilst the average area was 217.7±67.8 μm 2 . At univariate analysis, the TAM area demonstrated a statistically significant association with DFS ( P =0.0006). Optimal area cutoff value was obtained, showing a sensitivity and specificity of 92 and 56%, respectively. S-TAMs and L-TAMs were associated with 3-year DFS rates of 60 and 8.5%, respectively ( P <0.001). Multivariate analysis confirmed the predictive role of TAM area for DFS [hazard ratio (HR)=5.03; 95% CI=1.70-14.94; P =0.003]. Moreover, in a subset of patients ( n =12) characterized by unfavorable ( n =6, recurrence within 3 months) or favorable ( n =6, no recurrence after 48 months) prognosis, TAMs showed a different distribution: L-TAMs were more abundant and closer to the tumor invasive margin in patients that encountered early recurrence and tended to cluster in foci significantly larger ( P =0.02).
This external validation confirms that morphometric characterization of TAMs can serve as a simple readout of their diversity and allows to reliably stratify patient outcomes and predict disease recurrence after hepatectomy for CLMs.
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的关键组成部分，已被证明会影响不同癌症的预后。先前的报告数据表明，TAM 形态与肝切除术后结直肠癌肝转移（CLM）的预后相关，较小的 TAMs（S-TAMs）比较大的 TAMs（L-TAMs）预后更好。本研究旨在对此进行外部验证。
外部队列包括 84 例结直肠癌肝转移和肿瘤周围组织的福尔马林固定和石蜡包埋手术样本。获取 2 微米切片；记录每张幻灯片中 21 个巨噬细胞的面积和周长。终点是 TAMs 形态计量学及其与无病生存期（DFS）的相关性。
巨噬细胞平均周长为 71.5±14.1 μm，平均面积为 217.7±67.8 μm 2 。单因素分析显示，TAM 面积与 DFS 具有统计学显著相关性（ P =0.0006）。获得最佳面积截断值，敏感性和特异性分别为 92%和 56%。S-TAMs 和 L-TAMs 的 3 年 DFS 率分别为 60%和 8.5%（ P <0.001）。多因素分析证实 TAM 面积对 DFS 具有预测作用[风险比（HR）=5.03；95%CI=1.70-14.94； P =0.003]。此外，在一组具有不利（ n =6，3 个月内复发）或有利（ n =6，48 个月后无复发）预后的患者（ n =12）中，TAMs 表现出不同的分布：在早期复发的患者中，L-TAMs 更为丰富且更接近肿瘤侵袭边缘，并倾向于聚集在显著更大的病灶中（ P =0.02）。
本研究的外部验证证实，TAMs 的形态计量学特征可以作为其多样性的简单指标，并可可靠地分层患者的预后结果，预测结直肠癌肝转移患者肝切除术后的疾病复发。
