Safety Profile and Adverse Event Management in Flexible Endoscopic Treatment of Zenker’s Diverticulum: A Systematic Review

Background and Objectives: Flexible endoscopic septal division (FESD) and third-space techniques represent first-line treatments for symptomatic Zenker’s diverticulum (ZD). While technical and clinical success rates are well established, data regarding adverse events (AEs) and their clinical management remain fragmented in recent literature. This systematic review aimed to evaluate the incidence, typology, and therapeutic strategies for AEs associated with flexible endoscopic ZD treatments. Materials and Methods: A systematic search of PubMed/MEDLINE, Embase, and Scopus was conducted up to July 2026 according to PRISMA guidelines. Studies reporting adult patients undergoing flexible endoscopic interventions for ZD reporting data on complication rates and management were included. Methodological quality was evaluated using the MINORS index. Results: Sixty studies were evaluated, comprising 53 cohort series (64 cohorts, 3172 patients, 3266 procedures: 2119 FESD and 1147 third-space procedures) for pooled quantitative incidence estimation, and 7 single-case reports retained for qualitative complication mapping. Bleeding occurred in 4.2% of cases (5.9% in FESD vs. 1.1% in third-space techniques), with most events occurring intraoperatively and resolving entirely through endoscopic hemostasis. Perforation occurred in 3.2% of procedures (3.9% in FESD vs. 1.8% in third-space series), while mucosal leaks were reported in 0.6% (0.2% in FESD vs. 1.5% in third-space). Severe infectious sequelae, such as abscesses (0.2%) and acute mediastinitis (0.1%), were rare. Conservative measures and endoscopic salvage modalities successfully treated transmural defects, with surgical conversion required in only three perforation cases (<0.1%). Isolated subcutaneous emphysema or pneumomediastinum occurred in 1.3% of cases and resolved uneventfully under conservative observation. Direct procedure-related mortality was 0.03% (1/3266). Conclusions: Flexible endoscopic management of ZD demonstrates a high safety profile with minimal procedural mortality. Complication management has shifted from surgical rescue to conservative protocols and versatile endoscopic salvage. Standardized AE grading and ongoing randomized trials are required to refine procedural selection.