Meta‐Analysis of Non‐Blood Liquid Biopsy Specimens: Diagnostic Performance in Cancer Detection

ABSTRACT Background Non‐blood liquid biopsy specimens represent an emerging frontier in cancer diagnostics, offering anatomically relevant alternatives to traditional blood‐based analyses. These specimens provide unique advantages including proximity to tumor sites and potentially higher concentrations of tumor‐derived biomarkers. Objective To systematically evaluate the diagnostic performance of various non‐blood liquid biopsy specimens across multiple cancer types through comprehensive meta‐analysis. Methods A systematic literature search was conducted across PubMed databases for studies published between 2013 and 2024. Studies evaluating non‐blood liquid biopsy for cancer detection were included. Data extraction focused on diagnostic accuracy metrics including sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios. Random‐effects meta‐analysis was performed using hierarchical modeling to account for heterogeneity. Results Twenty studies encompassing 13,486 participants were analyzed across nine specimen types. Overall pooled diagnostic performance demonstrated sensitivity of 76.2% (95% CI: 71.2%–81.2%) and specificity of 77.8% (95% CI: 72.8%–82.8%), with a diagnostic odds ratio of 11.2. Aqueous humor achieved the highest individual performance with 96% sensitivity and 100% specificity for retinoblastoma detection. Cerebrospinal fluid (CSF) demonstrated excellent performance across brain tumor types with 88.9% sensitivity and 76.1% specificity. Heterogeneity was observed across specimen types and cancer contexts. The significant variability observed among different specimen types, especially in saliva where the I 2 value for specificity is 78.9%. Conclusions Non‐blood liquid biopsy specimens demonstrate clinically meaningful diagnostic performance across diverse cancer types, with specimen‐specific advantages for anatomically relevant malignancies. The identification of optimal specimen‐cancer pairings provides immediate clinical utility for precision cancer diagnostics. Future research should focus on standardization of collection protocols and larger validation studies.