Independent Validation of a Machine Learning Classifier for Predicting Mediastinal Lymph Node Metastases in Non-Small Cell Lung Cancer Using Routinely Obtainable [18F]FDG-PET/CT Parameters

In non-small cell lung cancer (NSCLC), [¹⁸F]FDG-PET/CT is limited in pretherapeutic lymph node (LN) staging by false-positives. We previously demonstrated that a machine learning (ML) classifier using routine [¹⁸F]FDG-PET/CT and clinical variables can improve diagnostic accuracy compared to visual assessment. The present study aimed at independent validation. Cohort 1 (Charité) included 87 NSCLC patients (surgical and non-surgical), prospectively enrolled at our institution. Cohort 2 (TCIA) comprised 124 patients with primary surgery from the multi-institution NSCLC Radiogenomics dataset. Our ML classifier for differentiating N0/1 vs. N2/3 status was applied without modification. As comparator, the combined standard PET/CT criterion of "mediastinal LN uptake > mediastinum and/or short-axis > 10 mm" was used. Histology of N2/3 LNs served as reference standard. Prevalence of pN2/3 differed significantly between cohorts (Charité: 40%, TCIA: 12%; <i>p</i> < 0.001). Specificity was similar between ML and the standard PET/CT criterion in the Charité cohort (65% vs. 60%; <i>p</i> = 0.5) but significantly higher with ML in TCIA (90% vs. 70%; <i>p</i> < 0.001). Sensitivity for pN2/3 was comparable between the two comparators in both the Charité cohort (97% each; <i>p</i> = 1.0) and TCIA (27% vs. 33%; <i>p</i> = 1.0). Lower sensitivity in TCIA patients reflects the preselection of surgical patients who had already been clinically staged and deemed suitable for surgery. The diagnostic performance of the ML classifier and its (potentially) superior specificity were thus successfully validated in two independent cohorts.