Clinicopathological and molecular correlates of micropapillary/solid and lepidic patterns in lung adenocarcinoma

Invasive non-mucinous lung adenocarcinoma (INMA) is biologically heterogeneous, with histological patterns defining distinct subtypes; however, the significance of non-predominant components is not fully characterized. We investigated the associations of micropapillary/solid (MP/S) and lepidic (Lep) components with clinicopathological features, molecular profiles, and perioperative circulating tumor DNA (ctDNA) dynamics in a Chinese cohort. We retrospectively analyzed 73 INMA patients with definitive histological subtyping and next-generation sequencing data. Tumors were assessed for MP/S and Lep components irrespective of predominance. Histologic patterns were correlated with clinicopathological variables, genomic alterations, and individualized tumor-informed ctDNA detection. The cohort was predominantly early-stage, with 71.2% (52/73) having stage I disease (IA: 37; IB: 15) and 28.8% (21/73) with stage II–IV disease. MP/S+ tumors correlated with male sex (55.2% vs. 22.7%, P = 0.006) and smoking history (44.8% vs. 20.5%, P = 0.037), whereas lepidic components were associated with a lower Ki-67 proliferation index (8% vs. 20%, P = 0.020). The MP/S + Lep− subgroup exhibited the highest Ki-67 expression (30%, P = 0.037 vs. MP/S − Lep+). Exploratory genomic analyses revealed numeric differences in the MP/S + Lep− subgroup, including enrichment of KRAS , MET , STK11 , and CDKN2A alterations and a lower EGFR alteration rate (all not significant). Detectable perioperative ctDNA (7/31 preoperative, 5/28 postoperative) occurred exclusively in lepidic-negative tumors, a non-significant association. The presence of MP/S and lepidic components, irrespective of predominance, is associated with distinct biological features in INMA. The MP/S + Lep- phenotype may represent a subgroup characterized by high proliferation activity and suggestive molecular features. The detection of ctDNA was observed exclusively in lepidic-negative tumors, representing an exploratory observation that warrants further investigation.