Cancer Bioinformatics, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
J Pathol. 2023 Aug;260(4):376-389. doi: 10.1002/path.6088. Epub 2023 May 25.
The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated in large cohorts. We used a deep learning (DL) framework to quantify morphological features in haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 breast cancer patients, 5,228 axillary LNs, cancer-free and involved, were assessed. Generalisable multiscale DL frameworks were developed to capture and quantify germinal centres (GCs) and sinuses. Cox regression proportional hazard models tested the association between smuLymphNet-captured GC and sinus quantifications and distant metastasis-free survival (DMFS). smuLymphNet achieved a Dice coefficient of 0.86 and 0.74 for capturing GCs and sinuses, respectively, and was comparable to an interpathologist Dice coefficient of 0.66 (GC) and 0.60 (sinus). smuLymphNet-captured sinuses were increased in LNs harbouring GCs (p < 0.001). smuLymphNet-captured GCs retained clinical relevance in LN-positive TNBC patients whose cancer-free LNs had on average ≥2 GCs, had longer DMFS (hazard ratio [HR] = 0.28, p = 0.02) and extended GCs' prognostic value to LN-negative TNBC patients (HR = 0.14, p = 0.002). Enlarged smuLymphNet-captured sinuses in involved LNs were associated with superior DMFS in LN-positive TNBC patients in a cohort from Guy's Hospital (multivariate HR = 0.39, p = 0.039) and with distant recurrence-free survival in 95 LN-positive TNBC patients of the Dutch-N4plus trial (HR = 0.44, p = 0.024). Heuristic scoring of subcapsular sinuses in LNs of LN-positive Tianjin TNBC patients (n = 85) cross-validated the association of enlarged sinuses with shorter DMFS (involved LNs: HR = 0.33, p = 0.029 and cancer-free LNs: HR = 0.21 p = 0.01). Morphological LN features reflective of cancer-associated responses are robustly quantifiable by smuLymphNet. Our findings further strengthen the value of assessment of LN properties beyond the detection of metastatic deposits for prognostication of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
淋巴结（LNs）中系统免疫反应对三阴性乳腺癌（TNBC）患者具有预后价值的观点，此前尚未在大型队列中进行研究。我们使用深度学习（DL）框架来量化数字化全切片图像中苏木精和伊红染色的 LNs 的形态特征。从 345 名乳腺癌患者中，评估了 5228 个腋窝 LNs，包括癌旁和受累的 LNs。开发了通用多尺度 DL 框架来捕获和量化生发中心（GCs）和窦。Cox 回归比例风险模型测试了 smuLymphNet 捕获的 GC 和窦定量与远处无转移生存（DMFS）之间的关联。smuLymphNet 分别捕获 GC 和窦的 Dice 系数为 0.86 和 0.74，与病理学家之间的 Dice 系数 0.66（GC）和 0.60（窦）相当。在含有 GCs 的 LNs 中，smuLymphNet 捕获的窦增多（p<0.001）。在 LN 阳性的 TNBC 患者中，smuLymphNet 捕获的 GC 保留了临床相关性，这些患者的无癌 LNs 平均有≥2 个 GC，DMFS 更长（危险比[HR]＝0.28，p＝0.02），并将 GC 的预后价值扩展到 LN 阴性的 TNBC 患者（HR＝0.14，p＝0.002）。在 Guy's 医院的队列中，受累 LNs 中 smuLymphNet 捕获的扩大窦与 LN 阳性的 TNBC 患者的 DMFS 更好相关（多变量 HR＝0.39，p＝0.039），在 95 例 LN 阳性的荷兰 N4plus 试验中的 TNBC 患者中与远处无复发生存相关（HR＝0.44，p＝0.024）。对 LN 阳性天津 TNBC 患者（n＝85）的 LNs 中包膜下窦的启发式评分交叉验证了扩大的窦与较短的 DMFS 之间的关联（受累 LNs：HR＝0.33，p＝0.029 和无癌 LNs：HR＝0.21，p＝0.01）。smuLymphNet 可以可靠地定量反映与癌症相关反应的 LN 形态特征。我们的发现进一步加强了评估 LN 特性对 TNBC 患者预后的价值，超出了对转移灶检测的评估。
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