Retrospective Lung-RADS v2022 Characterization of Fatal Lung Cancer Cases in the National Lung Screening Trial

RATIONALE AND OBJECTIVES: Persistent lung cancer mortality despite screening is multifactorial. Characterizing computed tomography (CT) findings preceding fatal lung cancer may identify imaging features and screening challenges that warrant further study. MATERIALS AND METHODS: We conducted a retrospective, outcome-enriched case series nested within the 26,722-participant low-dose computed tomography arm of the National Lung Screening Trial. Among 359 participants who died of lung cancer within the prespecified interval, exclusions for positive baseline screening (n = 186), incomplete screening (n = 28), withdrawal/declined screening (n = 19), unavailable CTs (n = 6), or three negative screens followed by death 2+ years after the final screen (n = 29) yielded 91 participants. Screening CTs were retrospectively assessed using the Lung Imaging Reporting and Data System (Lung-RADS) v2022. Four thoracic radiologists independently reviewed visible-in-retrospect nodules and adjudicated whether they met criteria for suspicion. RESULTS: Of 91 participants, 22 (24%; 95% confidence interval (CI), 17%-34%) had visible-in-retrospect nodules considered suspicious under Lung-RADS v2022 ("missed"), 16 (18%; 95% CI, 11%-27%) had visible nodules not meeting suspicion criteria ("not callable"), 50 (55%; 95% CI, 45%-65%) had no visible-in-retrospect nodule, and 3 (3.3%) were inconclusive. Missed nodules were frequently juxtapleural (41%), obscured (50%), or irregularly bordered (68%); not-callable nodules were frequently <6 mm (75%), juxtapleural (56%), or irregularly bordered (56%). CONCLUSION: In this selected fatal-case series, small and juxtapleural nodules were common among visible nodules not meeting Lung-RADS v2022 suspicion criteria. These findings warrant evaluation in representative screening populations and should not be interpreted as estimates of population-level Lung-RADS performance.