Abstract / Summary
Background/Objectives: Differentiating benign, borderline, and malignant ovarian cystic lesions before surgery remains challenging, and many women undergo operations for lesions that prove benign. Most cystic lesions contain fluid that lies in direct contact with the lesion and forms part of the tumour microenvironment, potentially concentrating tumour-derived molecules diluted in the circulation. This review presents the current evidence on the value of ovarian cyst fluid analysis for the discovery of diagnostic and prognostic biomarkers across benign, borderline, and malignant lesions. Methods: We reviewed studies analysing ovarian cyst fluid using proteomic, glycoproteomic, metabolomic, inflammatory, and tumour-DNA approaches, together with conventional biomarkers and cytology, and considered pre-analytical and methodological factors affecting their interpretation. Results: Cyst fluid harbours proteins, glycoproteins, metabolites, cytokines, and DNA with tumour-specific mutations, frequently at concentrations exceeding those in matched serum. Multiple candidates discriminate malignant from benign lesions, and borderline lesions often show intermediate signatures. No single marker outperforms established CA125-based protocols, but multi-marker and multi-omics combinations have shown improved diagnostic performance within individual studies. Conclusions: Ovarian cyst fluid is a biologically enriched, underexploited substrate and a potential adjunct to existing diagnostic pathways. Realising its clinical potential will require standardised pre-analytics, validated multi-analyte panels, and prospective studies addressing clinical utility and reproducibility.