Potential utility of BALF biomarkers in differentiating lung cancer from benign and inflammatory pulmonary diseases: a systematic review and meta-analysis

Abstract

Distinguishing lung cancer from benign and inflammatory pulmonary disease can remain difficult even after radiological assessment. Bronchoalveolar lavage fluid (BALF) samples the local pulmonary environment and may add to the diagnostic work-up. We systematically reviewed BALF vascular endothelial growth factor (VEGF) and interleukin-12 (IL-12) concentrations for differentiating lung cancer from these conditions. PubMed, Scopus, EBSCO, Cochrane CENTRAL, and ProQuest were searched through June 20, 2026. Eligible studies quantitatively measured VEGF and/or IL-12 in patients with lung cancer and included a relevant comparison group. Study quality was assessed with the Newcastle-Ottawa Scale. Pooled effect sizes (mean differences [MDs], or standardized mean differences [SMDs] when heterogeneity exceeded 50%) were estimated using random-effects models, with VEGF analyses stratified by comparator type. Nine studies (644 participants; 379 disease samples, 265 controls) were included. Overall VEGF differences were not significant (SMD 0.73; 95% CI, − 0.13 to 1.59; I²=93%; p = 0.09), nor for contralateral-lung comparisons (SMD − 0.43; 95% CI, − 2.27 to 1.42; I²=92%; p = 0.65). VEGF was significantly higher in lung cancer than in benign masses (SMD 2.08; 95% CI, 1.24 to 2.93; I²=74%; p < 0.00001) and other non-malignant pulmonary diseases (SMD 0.51; 95% CI, 0.20 to 0.82; I²=0%; p = 0.001), though each subgroup comprised only two studies (hypothesis-generating). IL-12 was higher in disease groups (MD 12.77; 95% CI, 3.08 to 22.45; I²=55%; p = 0.010), but from only two studies from the same group, precluding independent replication. VEGF showed its most consistent signal versus benign masses and other non-malignant pulmonary diseases, though these findings remain hypothesis-generating. Evidence for IL-12 was more limited and lacked independent replication. BALF-based VEGF and IL-12 currently have limited standalone clinical use, tissue-based diagnosis remains recommended when invasive work-up is undertaken. Prospective studies with standardized BALF sampling, assay methods, and diagnostic-accuracy reporting are still needed.