Significant Incidental Findings in the National Lung Screening Trial and Diagnosis of Extrapulmonary Cancer

Importance: Significant incidental findings (SIFs) not related to lung cancer have been widely reported in patients undergoing lung cancer screening with low-dose computed tomography (LDCT). It is unclear whether SIFs are associated with extrapulmonary cancer diagnoses. Objective: To examine the association between an SIF considered to be potentially indicative of extrapulmonary cancer (cancer SIF) detected at LDCT lung cancer screening and diagnosis of an extrapulmonary cancer within 1 year of the screen. Design, Setting, and Participants: This retrospective cohort study analyzed data from National Lung Screening Trial (NLST) participants. The NLST participants were randomly assigned to either LDCT or chest radiography to determine whether LDCT was associated with a reduction in lung cancer mortality compared with chest radiography alone. Participants aged 55 to 74 years were recruited between August 2002 and April 2004. They received up to 3 rounds of screening and were followed up for 5 to 7 years. The study concluded December 31, 2009. This analysis was restricted to participants in the LDCT arm and was conducted between June and December 2025. Exposure: Detection of a cancer SIF (ie, SIF potentially indicative of a cancer) at any lung cancer screening round in the NLST. Main Outcomes and Measures: The primary outcome was diagnosis of an extrapulmonary cancer within 1 year of a screening round. Extrapulmonary cancers were classified using Surveillance, Epidemiology, and End Results (SEER) Program organ system categories. Cancer SIFs were mapped to specific SEER cancer categories. Multilevel logistic regression was used to assess the association between detection of a cancer SIF and diagnosis of an extrapulmonary cancer. Results: The study included 75 104 LDCT screening rounds performed in 26 445 participants (mean [SD] age, 61.4 [5.0] years; 59.0% male). Cancer SIFs were reported for 2265 screening rounds (3.0%) in 1807 participants (6.8%) across the 3 screening rounds. An extrapulmonary cancer was diagnosed following a screening round with a cancer SIF (n = 2265) for 67 participants (3.0%). The marginal risk difference, after covariates and participant-specific adjustments, was 13.89 (95% confidence limit [CL], 7.03-20.75) per 1000 participants. The marginal risk differences were significantly higher for urinary cancers (17.03 [95% CL, 8.55-25.50] per 1000 participants) and other SEER cancer categories, including lymphoma and leukemia (13.83 [95% CL, 3.46-24.21] per 1000 participants). Conclusions and Relevance: This cohort study found that cancer SIFs were associated with an increased risk of an extrapulmonary cancer diagnosis in the year following an LDCT lung cancer screening examination. These findings suggest that certain SIFs should be evaluated as potential indicators of undiagnosed cancers.