BACKGROUND: Pleural effusions (PEs) are frequent in patients with non-small cell lung cancer (NSCLC) and have prognostic implications. Detection of malignant cells in pleural fluid defines metastatic disease. However, PE cytology has limited sensitivity, leaving a substantial number of PEs cytology negative (Cyt-). We assessed the prognostic significance of cytology positive (Cyt+) and negative effusions and compared biochemical, cellular, and cytokine profiles of NSCLC associated PEs. METHODS: In this retrospective analysis of a prospectively collected prospective multicenter cohort study, PEs were collected from patients with confirmed NSCLC between 2021 and 2025. Effusions were classified as Cyt + or Cyt - based on cytopathology. Clinical data, pleural fluid biochemistry, and differential cell counts were recorded. Cytokine concentrations were measured in PE supernatant using a multiplex ELISA panel and correlated with survival. RESULTS: 111 NSCLC patients with PEs were included in this study (51 Cyt + and 60 Cyt - cases). Cyt + effusions were characterized by significantly lower pH and higher lactate, LDH, and protein concentrations. One year survival was not different in both groups. High pleural lymphocyte counts and a lower pleural neutrophil to lymphocyte ratio were associated with mortality. Cytokine profiling revealed significantly lower IL-5 levels in Cyt + effusions, while other cytokines were comparable. Higher Th2 associated cytokine levels (IL-4 and IL-5) correlated with improved survival independent of cytology status. CONCLUSION: NSCLC-associated cytology positive PEs show distinct immunological features. Survival in patients with Cyt + PEs was similar to those with Cyt- effusions. Pleural immune composition, particularly lymphocyte related markers and Th2 cytokines, may provide additional prognostic information beyond cytology alone.
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