• From the Department of Radiology, Cardiothoracic Imaging, Duke University Medical Center, Durham, NC (H.C., H.P.M., P.K., E.F.P.); Department of Radiology, Hanyang University College of Medicine, Hanyang University Guri Hospital, 153 Gyeongchun-ro, Guri-si, Gyeonggi-do, South Korea (Y.L.); and Department of Biostatistics and Center for Statistical Sciences, Brown University School of Public Health, Providence, RI (F.D., Y.W.).

Background There are currently no evidence-based guidelines for the management of enlarged mediastinal lymph nodes found on lung cancer screening (LCS) CT scans. Purpose To assess the frequency and clinical significance of enlarged mediastinal lymph nodes on the initial LCS CT scans in National Lung Screening Trial (NLST) participants. Materials and Methods A retrospective review of the NLST database identified all CT trial participants with at least one enlarged (≥1.0 cm) mediastinal lymph node identified by site readers on initial CT scans. Each study was reviewed independently by two thoracic radiologists to measure the two largest nodes and to record morphologic characteristics. Scans with extensively calcified mediastinal lymph nodes or nodes measuring less than 1 cm were excluded. Frequency and time to lung cancer diagnosis, lung cancer stage, and histologic findings were compared between NLST participants with and without lymphadenopathy. Results Of the 26 722 NLST participants, 422 (1.6%) had enlarged noncalcified mediastinal lymph nodes on the initial LCS CT scan. Mediastinal lymphadenopathy was associated with an increase in lung cancer cases (72 of 422 participants [17.1%; 95% CI: 13.6, 21.0] vs 1017 of 26 300 [3.9%; 95% CI: 3.6, 4.1]; P < .001), earlier diagnosis (restricted mean survival time ± standard error, 2285 days ± 44 vs 2611 days ± 2; P < .001), the presence of lung nodules (P < .001), advanced stage at presentation (22 of 72 participants [31%] with cancer at stage IIIA vs 410 of 1017 [40.3%] at stage IA; P < .001), and increased mortality (P < .001). The majority of participants with lung cancers in the LCS group with mediastinal lymphadenopathy were detected at initial LCS CT (50 of 422 participants [11.8%; 95% CI: 8.9, 15.3] vs T1-T7, 22 of 422 [5.3%; 95% CI: 3.3, 7.8]; P < .001). There was no association between mediastinal lymphadenopathy and lung cancer histologic findings, CT appearance, or location of lung nodules (P > .05 based on unadjusted pairwise association analyses). Conclusion Noncalcified mediastinal lymphadenopathy in the low-dose lung cancer screening study sample was associated with an increase in lung cancer, an earlier diagnosis, more advanced-stage disease, and increased mortality. More aggressive treatment of these patients appears warranted. © RSNA, 2021 Online supplemental material is available for this article. See also the editorials by McLoud and by Mascalchi and Zompatori in this issue.