Prevalence of Invasive Lung Cancer in Pure Ground Glass Nodules less than 30 mm: A Systematic Review

Background: The IASLC TNM proposal suggests that pure ground glass nodules less than 30 mm should be classified as cTis corresponding to pathologic adenocarcinoma in situ implying no invasive malignancy potential. We sought to ascertain the proportion of pure ground glass nodules that harbour tissue confirmed minimally invasive or invasive adenocarcinoma.

Methods: We analyzed data from 3,874 individuals with pure ground glass nodules less than 30 mm, reported in 28 observational studies identified through a systematic search of electronic databases. The primary outcome was the prevalence of invasive malignancy by random effects meta-analysis, and we used meta-regression to determine the impact of baseline risk, size, and country of investigation on overall effect size. The study was registered with PROSPERO (CRD42021286261).

Results: All published studies were retrospective (n = 28) and the majority conducted in Asia (n = 25). Baseline patient cohorts were mainly from published surgical series (n = 22) or lung cancer screening programs (n = 6). The proportion of minimally invasive and invasive cancer ranged from 0.9 % to 100 % with a pooled prevalence of 42.4 % [95 % CI: 0.28, 0.57].

Considerable heterogeneity was observed (I₂ =99 %) and patient selection was the most significant contribution, accounting for 73 % of the observed heterogeneity (p < 0.0001). Meta-regression based on size selection and country of investigation revealed no significant contribution to effect size effect or heterogeneity.

Conclusions: Pure ground glass nodules less than 30 mm harbour a high proportion of invasive malignancy, contrary to the IASLC staging proposals and opinions from numerous guidelines across the world.