Paired Inter-Lesion Invasiveness and Recurrence Risk in Synchronous Multiple Primary Lung Adenocarcinoma: Focus on...

Background: Whether paired invasiveness patterns, particularly when both lesions are invasive adenocarcinoma (IAC + IAC), carry prognostic value beyond single-lesion staging in synchronous multiple primary lung adenocarcinoma (SMPLA) remains unclear. We assessed preoperative predictors of concordance, its underlying clinicopathological aggressiveness gradient, and its impact on disease-free survival (DFS). Methods: We retrospectively analyzed 198 patients with two SMPLA lesions, classified as concordant (match, n = 104) or discordant (mismatch, n = 94) based on identical versus differing AIS/MIA/IAC invasiveness grade. Preoperative predictors of mismatch were assessed by multivariable logistic regression. A pre-specified WHO-based paired invasiveness score was used to test trends in six aggressiveness markers via Cochran-Armitage tests. Within an IAC-dominant subset (Lesion 1 = IAC, n = 91), Firth-penalized Cox regression assessed the effect of Lesion 2 subtype (IAC vs. AIS/MIA) on DFS. Results: Same-lobe location was more frequent in the mismatch group (75.5% vs. 58.7%, p = 0.016), and Lesion 1 PD-L1 TPS was lower (0.8% vs. 1.0%, p = 0.005). On multivariable analysis, same-lobe location (adjusted OR = 2.26, 95% CI 1.16-4.41, p = 0.017) and Lesion 2 size (adjusted OR = 0.79/mm, p < 0.001) independently predicted mismatch (AUC = 0.671); adding PD-L1 status gave no incremental discrimination (p = 0.119). Across the paired invasiveness score, five of six markers-PD-L1 TPS ≥ 1%, Ki-67 ≥ 10%, Ki-67 ≥ 20%, STAS, and pleural invasion-showed significant increasing trends (all p ≤ 0.020), while vascular invasion did not (p = 0.113). Within the IAC-dominant subset, the adverse recurrence signal was observed specifically in the IAC + IAC group (5/34 [14.7%] vs. 1/57 [1.8%] events; HR = 5.28, 95% CI 1.04-51.84, p = 0.044). This finding should be interpreted as hypothesis-generating rather than confirmatory, given only six total events and a wide confidence interval. Conclusions: In high-risk SMPLA, paired-lesion risk assessment-particularly the distinction between IAC + IAC and IAC + AIS/MIA pairs-may complement single-lesion staging, pending prospective validation.