Confocal Laser Endomicroscopy in Brain Metastasis Surgery: A Systematic Review of the Evidence at the Tumor-Brain...

Background: Brain metastases are the most common intracranial tumors in adults and are traditionally considered well-demarcated lesions amenable to complete surgical resection. Nonetheless, increasing histopathological evidence demonstrates that metastatic cells may infiltrate beyond the contrast-enhancing margin into surrounding brain parenchyma, challenging the reliability of conventional imaging for defining true tumor boundaries. Confocal laser endomicroscopy (CLE) using Sodium Fluorescein (SF) has emerged as a novel intraoperative imaging modality capable of providing real-time, high-resolution optical biopsies, potentially improving margin assessment during metastasis surgery. Methods: A systematic literature search was performed according to PRISMA guidelines across PubMed, Embase, Scopus, Cochrane Library, and Google Scholar up to 3 March 2026. Studies evaluating intraoperative CLE with SF in adult patients with brain metastases were included. Data regarding study design, patient population, CLE system, imaging characteristics, and diagnostic performance were extracted. Risk of bias was assessed using the QUADAS-2 tool. Results: Ten studies met the inclusion criteria for qualitative synthesis, comprising over 650 patients; however, most studies included heterogeneous intracranial tumor populations, with only a subset specifically involving brain metastases. CLE enabled real-time visualization of tumor microarchitecture and demonstrated high sensitivity for tumor detection, frequently exceeding 90% in prospective studies. Specificity varied across studies, reflecting challenges in distinguishing tumor infiltration from reactive tissue at the tumor-brain interface. The MetInfilt trial highlighted that infiltrative growth patterns are common in brain metastases and can be visualized intraoperatively using CLE. Additional studies demonstrated that fluorescein-based CLE allows differentiation of tumor zones and may facilitate targeted margin assessment; however, evidence demonstrating improvement in clinically meaningful outcomes such as extent of resection, local recurrence, progression-free survival, or overall survival remains limited. Conclusions: Confocal laser endomicroscopy using SF represents a promising intraoperative adjunct for assessing tumor margins in brain metastasis surgery. By enabling real-time microscopic visualization of the metastasis-brain interface, CLE may support a more biologically informed surgical strategy.