Risk of metachronous esophageal squamous cell carcinoma after endoscopic submucosal dissection in patients with multiple Lugol-voiding lesions: a long-term study

Abstract

Abstract Multiple Lugol-voiding lesions (LVLs) confer a high risk of metachronous multiple esophageal squamous cell carcinomas (ESCCs) after endoscopic submucosal dissection (ESD); however, risk heterogeneity within this high-risk group remains unclear. Precise stratification could help optimize the surveillance intensity and reduce the burden of Lugol chromoendoscopy. We aimed to identify risk factors for metachronous multiple ESCCs among patients with multiple LVLs and to explore practical risk stratification. This single-center retrospective exploratory cohort study included patients who underwent initial ESD for superficial ESCC between 2014 and 2022 and had grade C LVLs, defined as ≥10 LVLs per endoscopic field of view. Grade C LVLs were subclassified by LVL counts as subgrade α (10–20), β (21–30), and γ (≥31). Among 331 patients (median follow-up 57 months), 163 (49.2%) developed metachronous multiple ESCCs; the 5-year cumulative incidence was 55.2% (95%CI 48.8–61.7). In multivariable analysis, positive flushing response (hazard ratio [HR] 1.59, 95%CI 1.10–2.31) and subgrade γ (HR 5.34 vs. α, 95%CI 2.36–12.1) were independently associated with increased risk. Subgrade γ showed higher 5-year incidence than subgrade α/β among both flushing-positive (71.4% vs. 27.2%; P < 0.001) and flushing-negative (57.5% vs. 16.9%; P = 0.004) patients. No confirmed ESCC-related deaths occurred during follow-up. Within grade C LVLs, subgrade γ and flushing positivity were associated with an increased risk of metachronous multiple ESCCs. Combining LVL subclassification and flushing status may provide clinically relevant risk stratification and may help inform risk-adapted surveillance after ESD.