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Clin. Med.","JCM"],"abstract":"<jats:p>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\u2013Armitage 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\u20134.41, p = 0.017) and Lesion 2 size (adjusted OR = 0.79\/mm, p &lt; 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\u2014PD-L1 TPS \u2265 1%, Ki-67 \u2265 10%, Ki-67 \u2265 20%, STAS, and pleural invasion\u2014showed significant increasing trends (all p \u2264 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\u201351.84, 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\u2014particularly the distinction between IAC + IAC and IAC + AIS\/MIA pairs\u2014may complement single-lesion staging, pending prospective validation.<\/jats:p>","DOI":"10.3390\/jcm15187317","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:09:35Z","timestamp":1790075375000},"page":"7317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paired Inter-Lesion Invasiveness and Recurrence Risk in Synchronous Multiple Primary Lung Adenocarcinoma: Focus on the IAC-Dominant Subgroup"],"prefix":"10.3390","volume":"15","author":[{"given":"Xueyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Tong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Dong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yajie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Hecheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S523","DOI":"10.21037\/jtd.2019.01.56","article-title":"Multiple primary lung cancer: A rising challenge","volume":"11","author":"Chen","year":"2019","journal-title":"J. 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