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机器视觉检测到的甲状腺乳头状癌患者瘤周淋巴细胞聚集与无病生存期相关。

Machine Vision-Detected Peritumoral Lymphocytic Aggregates Are Associated With Disease-Free Survival in Patients With Papillary Thyroid Carcinoma.

作者信息

Monabbati Shayan, Fu Pingfu, Asa Sylvia L, Pathak Tilak, Willis Joseph E, Shi Qiuying, Madabhushi Anant

机构信息

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio.

出版信息

Lab Invest. 2024 Dec;104(12):102168. doi: 10.1016/j.labinv.2024.102168. Epub 2024 Nov 4.

Abstract

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, with a disease recurrence rate of around 20%. Lymphoid formations, which occur in nonlymphoid tissues during chronic inflammatory, infectious, and immune responses, have been linked with tumor suppression. Lymphoid aggregates potentially enhance the body's antitumor response, offering an avenue for attracting tumor-infiltrating lymphocytes and fostering their coordination. Increasing evidence highlights the role of lymphoid aggregate density in managing tumor invasion and metastasis, with a favorable impact noted on overall and disease-free survival (DFS) across various cancer types. In this study, we present a machine vision model to predict recurrence in different histologic subtypes of PTC using measurements related to peritumoral lymphoid aggregate density. We demonstrated that quantifying peritumoral lymphocytic presence not only is associated with better prognosis but also, along with tumor-infiltrating lymphocytes within the tumor, adds additional prognostic value in the absence of well-known second mutations including TERT. Annotations of peritumoral lymphoid aggregates on 171 well-differentiated PTCs in the Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) data set were used to train a deep-learning model to predict regions of lymphoid aggregates across the entire tissue. The fractional area of the tissue regions covered by these lymphocytes was dichotomized to determine the following 2 risk groups: a significant and low density of peritumoral lymphocytes. DFS prognosticated using these risk groups via the Kaplan-Meier analysis revealed a hazard ratio (HR) of 2.51 (95% CI: 2.36, 2.66), tested on 170 new patients also from the TCGA-THCA data set. The prognostic performance of peritumoral lymphocyte aggregate density was compared against the univariate Kaplan-Meier analysis of DFS using the fractional area of intratumoral lymphocytes within the primary tumor with an HR of 2.04 (95% CI: 1.89, 2.19). Combining the lymphocyte features in and around the tumor yielded a statistically significant improvement in prognostic performance (HR, 3.17 [95% CI: 3.02, 3.32]) on training and were independently evaluated against 62 patients outside TCGA-THCA with an HR of 2.44 (95% CI: 2.19, 2.69). Multivariable Cox regression analysis on the validation set revealed that the density of peritumoral and intratumoral lymphocytes was prognostic independent of histologic subtype with a concordance index of 0.815.

摘要

乳头状甲状腺癌(PTC)是最常见的甲状腺癌形式,疾病复发率约为20%。在慢性炎症、感染和免疫反应期间,非淋巴组织中出现的淋巴样结构与肿瘤抑制有关。淋巴样聚集物可能增强机体的抗肿瘤反应,为吸引肿瘤浸润淋巴细胞并促进其协同作用提供了一条途径。越来越多的证据凸显了淋巴样聚集物密度在控制肿瘤侵袭和转移中的作用,对各种癌症类型的总生存期和无病生存期(DFS)都有积极影响。在本研究中,我们提出了一种机器视觉模型,使用与肿瘤周围淋巴样聚集物密度相关的测量值来预测PTC不同组织学亚型的复发情况。我们证明,量化肿瘤周围淋巴细胞的存在不仅与更好的预后相关,而且与肿瘤内的肿瘤浸润淋巴细胞一起,在不存在包括TERT在内的已知二次突变的情况下增加了额外的预后价值。利用癌症基因组图谱甲状腺癌(TCGA-THCA)数据集中171例高分化PTC的肿瘤周围淋巴样聚集物注释来训练一个深度学习模型,以预测整个组织中的淋巴样聚集物区域。将这些淋巴细胞覆盖的组织区域的分数面积进行二分法划分,以确定以下两个风险组:肿瘤周围淋巴细胞的高密度和低密度。通过Kaplan-Meier分析使用这些风险组预测的DFS显示风险比(HR)为2.51(95%CI:2.36,2.66),在同样来自TCGA-THCA数据集的170例新患者中进行了测试。将肿瘤周围淋巴细胞聚集物密度的预后性能与使用原发肿瘤内肿瘤内淋巴细胞分数面积对DFS进行的单变量Kaplan-Meier分析进行比较,HR为2.04(95%CI:1.89,2.19)。结合肿瘤内和肿瘤周围的淋巴细胞特征,在训练时预后性能有统计学上的显著改善(HR,3.17[95%CI:3.02,3.32]),并在TCGA-THCA之外的62例患者中进行独立评估,HR为2.44(95%CI:2.19,2.69)。对验证集进行多变量Cox回归分析显示,肿瘤周围和肿瘤内淋巴细胞的密度是独立于组织学亚型的预后因素,一致性指数为0.815。

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