Lung adenocarcinoma with malignant serous effusions: A comprehensive clinicopathologic, molecular, and outcome analysis

Abstract Background Malignant serous effusions (MSEs), including pleural, pericardial, and peritoneal effusions, are common in advanced lung adenocarcinoma (LUAD). However, integrated clinicopathologic, molecular, treatment, and outcome data across effusion sites remain incompletely defined. Methods This study retrospectively analyzed 120 cytology‐confirmed LUAD‐associated MSE cases from a single academic center by integrating gross fluid features, cytopathology, immunohistochemistry, targeted next‐generation sequencing (NGS), systemic therapy, and clinical outcomes, including survival from first malignant effusion (SME) and overall survival (OS). Results Effusions were pleural (85 of 120; 70.8%), pericardial (28 of 120; 23.3%), and peritoneal (7 of 120; 5.8%). Median SME was 3.8 months, and was shortest in the small peritoneal effusion subgroup (1.0 months). OS differed by site, with pericardial involvement showing the shortest OS (6.1 months). Thyroid transcription factor 1 (TTF‐1) was positive in 72.5% of cases. Programmed death ligand 1 (PD‐L1) testing ( n = 85) showed a tumor proportion score (TPS) of ≥1% in 80% of cases and TPS of ≥50% in 36.5% of cases. Molecular profiling was completed in 111 of 120 cases (92.5%) by identifying TP53 mutations in 47 of 111 (42.3%) and actionable driver alterations in 42.3% of cases, most commonly involving EGFR , KRAS , BRAF , ALK , and ROS1 . TTF‐1 positivity was associated with higher rates of actionable driver alterations and higher PD‐L1 expression. PD‐L1 negativity, TTF‐1 negativity, and an absence of actionable driver alterations were associated with shorter SME and OS. Dual TTF‐1/PD‐L1 negativity defined the poorest risk subgroup (median SME, 1.2 months; median OS, 1.4 months). Multivariable analysis confirmed that TTF‐1 negativity and a lack of actionable drivers remained independently adverse. Among treated patients, immunotherapy‐based regimens were associated with the longest SME (6.7 months), whereas tyrosine kinase inhibitor–based therapy was associated with the longest OS (26.0 months). Conclusions Integration of cytology, immunophenotype, genomics, and treatment delineates distinct prognostic subsets in LUAD with MSE. The absence of actionable driver alterations and TTF‐1 negativity remains an independent adverse prognostic factor, with dual TTF‐1/PD‐L1‐negative MSE showing particularly poor SME and OS.