Opening the black box: defining true-negative outcomes in esophageal cancer screening - a population-based study

Current negativity definition in esophageal cancer screening overlooks the risk heterogeneity between individuals with non-dysplastic Lugol's unstained lesions (ND-LULs) and normal-stained epithelium. We aimed to define the screening negativity by the incidence risk of severe dysplasia and above lesions (SDAs) after chromoendoscopy and ascertain their re-screening interval.

We enrolled 815 participants with ND-LULs and 14,123 with normal-stained epithelium from the screening arm of a community-based randomized controlled trial (RCT). The control groups included the RCT's unscreened arm (n = 16,473), and population controls matched 1:5 by birth year, sex, and village (4075 controls for ND-LULs group, 70,615 controls for normal-stained group). All participants were followed up for up to 10 years. Poisson regression and the cumulative incidence function compared the cumulative incidence of SDA between groups.

Compared with the RCT control, the cumulative incidence of SDAs was significantly higher in the ND-LULs group over 10 years (adjusted IRR = 3.16, 95% CI: 2.02-4.76) but lower in the normal-stained group (adjusted IRR = 0.52, 95% CI: 0.37-0.72). Similar results were achieved using the general population control. The cumulative incidence of SDAs in the ND-LULs group significantly exceeded controls after 2-3 years while remaining consistently lower in the normal-stained group over 10 years.

Individuals with normal Lugol staining should be considered the genuinely screening-negative population for esophageal cancer. A 10-year screening interval is recommended for normal-stained individuals, while 2-3 years are necessary for ND-LULs.