Beyond vascular endothelial growth factor: synergistic diagnostic value of multiple biomarkers in malignant pleural effusion. A cross-sectional analytical study.

Malignant pleural effusion (MPE) remains a challenging diagnostic entity within the vast spectrum of pleural effusions. While vascular endothelial growth factor (VEGF) is a widely studied MPE biomarker, its diagnostic performance as a standalone marker is limited. There is growing interest in evaluating whether combined biomarker panels may provide incremental diagnostic information and reduce diagnostic uncertainty. This study aims to explore whether integrating matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and monocyte chemoattractant protein-1 (MCP-1) into VEGF provides incremental diagnostic value in distinguishing malignant from benign pleural effusions. A total of 88 pleural fluid samples were analyzed (33 malignant, 55 benign). Biomarker levels were measured using enzyme-linked immunosorbent assay. Diagnostic performance was assessed via receiver operating characteristic analysis, with optimal cut-off values identified using the Youden Index. Logistic regression models were developed for combined biomarker panels and internally validated using 5-fold cross-validation. VEGF demonstrated moderate individual diagnostic value (area under the curve 0.640; sensitivity 72.7%; specificity 58.2%; and diagnostic odds ratio of 3.71). Other individual markers showed limited accuracy. The four-marker panel (VEGF + MMP-9 + TIMP-1 + MCP-1) showed a modest increase in sensitivity, negative predictive value, and diagnostic odd ratio, although specificity remains limited. These findings suggest that combined pleural fluid biomarkers may provide incremental diagnostic information, but their performance remains modest and requires external validation before clinical application.