Not all type of lepidic pattern is useful for distinguishing whether metachronous multiple lung adenocarcinomas are separate primary lung cancers.

Our research aims to ascertain the value of precursor and outgrowth lepidic in aiding the confirmation of multiple lung adenocarcinomas as separate primary lung cancers (SPLC). A total of 151 patients with metachronous multiple invasive adenocarcinomas were included in this study. Driver mutation tests（at least five genes: EGFR, ALK, KRAS, BRAF, and ROS1） were conducted on 302 tumors collected from 151 patients. And the cases were grouped based on the lepidic pattern status in the second tumor of the paired tumors. When comparing the driver mutation results of paired tumors, precursor lepidic group had a higher rate of mutation inconsistency(56.8 %, 54/95) than outgrowth(23.8 %, 5/21) and no-lepidic groups(34.3 %, 12/35)(p = 0.014). The precursor lepidic group demonstrated significantly better relapse-free survival (RFS: p < 0.001) and overall survival (OS: p < 0.001) than the outgrowth and no-lepidic groups. Although multivariate analysis revealed that the presence of precursor lepidic was not an independent risk factor for RFS (p = 0.489) or OS (p = 0.086), upon eliminating the confounding effects of lepidic content and tumor grade, the precursor lepidic group continued to exhibit a favorable prognostic advantage. In addition, patients with inconsistent mutations have a superior prognosis compared with those with identical or no mutations. However, this effect was more pronounced in tumors lacking the precursor lepidic components. Our findings suggest that precursor lepidic aids in diagnosing multiple lung adenocarcinomas as SPLC, while outgrowth lepidic does not. Additional molecular testing may be helpful in cases without precursor lepidic.