Growth and Clinical Outcomes of Screen-detected Pulmonary Subsolid Nodules After 5 Years of Stability

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Abstract Rationale: Increased low-dose computed tomography (LDCT) screening identifies many pulmonary subsolid nodules (SSNs), most of which are indolent adenocarcinoma spectrum lesions. However, evidence regarding their disease trajectory is primarily based on small studies with limited follow-up. This study evaluates the growth and clinical outcomes of screen-detected SSNs that remained stable for 5 years. Methods: This retrospective cohort study analyzed the trajectory of SSNs (3—30 mm) beyond 5 years of stability, detected through self-initiated LDCT screening at two tertiary hospitals in South Korea between January 2003 and December 2017. Follow-up continued until June 2024. The primary outcome was SSN growth, defined as an increase in mean diameter≥2mm, an increase in solid portion≥2mm, or the development of a new solid portion. Secondary outcomes included growth resulting in stage shift, growth patterns, lung cancer diagnosis, recurrence, and lung cancer-related mortality. Risk factors for growth were evaluated using Cox proportional hazards regression. Results: Among 66,800 screened participants, 1,360 (2.0%) had 2,178 SSNs (1,995 [91.6%] pure ground-glass nodules [pGGNs] and 183 [8.4%] part-solid nodules [PSNs]) that remained stable for 5 years. During a median 10.4-year follow-up, 74 SSNs (3.4%; 66 pGGNs; 8 PSNs) showed growth. Of these, 71 (95.9%) increased in mean diameter, 28 (37.8%) showed a solid portion increase, and 20 (27.0%) developed a new solid portion. The median time from detection to first growth was 8.0 years, with a median diameter increase of 2.0mm. 50 (67.6%) remained unchanged after the first growth. Over the entire follow-up, the median diameter increase was 3.0mm. Three SSNs (5.5%) grew by≥10mm, and two (2.7%) had a stage shift from Tis to T1mi. Among SSNs that grew, 23 (31.1%) underwent biopsies (all surgical), and 21 (28.4%) were diagnosed with primary lung cancer (1 adenocarcinoma in situ; 8 minimally invasive adenocarcinoma; 12 invasive adenocarcinoma). The stage distribution was 1 carcinoma in situ and 20 IA. No recurrences or lung cancer-related mortality occurred. Among the 2,104 SSNs that did not grow, there were no lung cancer diagnoses or related mortality. Factors associated with growth included a history of other cancers, emphysema, number of SSNs, air bronchograms, pleural attachment, pleural tagging, and irregular margins. Conclusion: After 5 years of stability, 3.4% of SSNs exceeded the 2mm growth threshold. However, lung cancer-related outcomes did not differ between SSNs that grew and those that remained stable. A more clinically relevant growth threshold or alternative metrics is needed to determine appropriate follow-up duration and intervals for SSNs.

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