Radiographic ground-glass nodules predict less aggressive features and favorable immune landscapes in early lung adenocarcinoma and its precursors.

Background: Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related deaths globally, often due to late-stage diagnosis. Advancements in computed tomography (CT) have revolutionized the detection of indeterminate pulmonary nodules (IPNs), spanning benign lesions to early-stage LUAD. We aimed to understand early lung carcinogenesis and identify clinicopathological and immune features that may influence patient prognosis.

Methods: This study retrospectively integrates clinical, radiographic, pathological, and immune data from 174 patients with resected pulmonary nodules, including atypical adenomatous hyperplasia (AAH, n=19), adenocarcinoma in situ (AIS, n=50), minimally invasive adenocarcinoma (MIA, n=40), and stage I invasive adenocarcinoma (ADC, n=65).

Results: Among 174 resected nodules, ground-glass nodules (GGNs) were observed in 54.6% of all cases. Early-stage ADCs exhibited the lowest proportion of GGNs compared to AAH, AIS, and MIA, respectively (AAH: 52.6%; AIS: 86.0%; MIA: 72.5%; ADC: 20.0%; P<0.001). Well differentiated ADCs were significantly associated with lower rates of pleural traction (6.7%) and lymphovascular invasion (0%) compared to poorly differentiated ADCs (pleural traction: 36.4%, lymphovascular invasion: 18.2%). Immune profiling showed a progressive decline in CD8⁺ T cells and an increased CD4/CD8 ratio from AAH to ADC. GGNs exhibited lower intratumoral CD4⁺ and CD8⁺ T cell densities than non-GGNs, consistent with their indolent histology and less invasive behavior. Radiographic appearance was strongly correlated with tumor differentiation and aggressiveness.

Conclusions: These insights deepen our understanding of early lung carcinogenesis and offer potential pathways for prognostic stratification and personalized care for patients presenting with IPNs during CT screening.