Csf-derived Extracellular Vesicle Biomarkers for Non-invasive Diagnosis and Prognosis of Leptomeningeal Metastasis: A Systematic Review

Introduction: Leptomeningeal metastasis (LM) represents a devastating complication in patients with advanced cancers, yet it is challenging to diagnose and monitor with traditional methods. Extracellular vesicles (EVs) and exosomes in Cerebrospinal Fluid (CSF) are gaining attention as a potential liquid biopsy biomarker for LM, offering potential for early detection, prognosis, and treatment response evaluation. We conduct a systematic review evaluating the current potential of CSF-derived EVs and exosomal biomarkers in LM.

Methods: Following PRISMA guidelines, we conducted a comprehensive search across Web of Science and Scopus databases to identify all relevant studies published to date. Studies included in the review focused on CSF-derived EVs or exosomal markers in LM populations, specifically targeting protein, miRNA, and mRNA biomarkers. We selected studies assessing the role of EV-derived biomarkers in LM diagnosis, monitoring disease progression, and evaluating treatment response. Comparators included LM-negative groups to ensure robust specificity and diagnostic accuracy.

Results: A total of 11 studies were included, from 2013 to 2024, each exploring distinct EV-derived biomarkers across non-small cell lung cancer, glioma, and medulloblastoma populations with LM. miR-21, miR-374a-5p, and an eight-miRNA signature were identified as significant diagnostic indicators, with miR-21 also linked to methotrexate resistance. Proteomic analyses identified FN1 and transketolase (TKT) as reliable indicators of LM severity and tumor progression, especially in medulloblastoma. Comparative studies demonstrated high diagnostic sensitivity and specificity for certain markers, such as miR-483-5p and miR-342-5p, supporting CSF over serum for biomarker detection due to enhanced sensitivity.

Conclusion : The findings highlight the potential of CSF-derived EVs in LM diagnosis and management. Biomarkers like miR-21, FN1, and TKT offer promising avenues for non-invasive detection and prognostic assessment, while miRNA signatures may aid in early diagnosis and therapeutic decision-making. Further validation studies are needed to standardize EV profiling for clinical application in LM and related CNS malignancies.