Early-onset adenocarcinomas of the distal esophagus, gastroesophageal junction, and stomach: a systematic review and meta-analysis of 45 studies.

BACKGROUND: The incidence of adenocarcinomas of the distal esophagus, gastroesophageal junction (GEJ), and stomach diagnosed before age 50 years is increasing and early-onset disease may have a distinct phenotype. A comprehensive synthesis of clinicopathological and molecular differences between early-onset and average-onset disease remains lacking. MATERIALS AND METHODS: We carried out a Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-compliant systematic review and DerSimonian-Laird random-effects meta-analysis of observational studies comparing early-onset (<50 years) and average-onset adenocarcinomas of the distal esophagus, GEJ/cardia, and stomach. Forty-five studies (35 clinicopathological or epidemiological cohorts comprising >650 000 patients and 10 molecular cohorts) were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were computed in molecularly characterized cohorts. RESULTS: Early-onset disease was associated with advanced stage (OR 1.39, 95% CI 1.26-1.54), signet-ring histology (OR 2.52, 95% CI 1.84-3.47), synchronous distant metastasis (OR 1.20, 95% CI 1.04-1.38), high tumor grade (OR 1.61, 95% CI 1.23-2.11), and female sex (OR 1.29, 95% CI 1.14-1.44, P = 0.001). Diffuse-type histology was enriched in molecularly characterized early-onset tumors (OR 2.26), as were cadherin 1 (E-cadherin gene) alterations (OR 2.92) and germline pathogenic variants (OR 2.00), whereas microsatellite instability-high (OR 0.17) and tumor mutational burden-high (OR 0.37) were depleted. The subgroup restricted to GEJ tumors confirmed signet-ring enrichment (OR 1.87, I 2 = 2%). CONCLUSIONS: Early-onset adenocarcinomas of the distal esophagus, GEJ, and stomach appear to represent a distinct clinicopathological and molecular phenotype characterized by aggressive histopathology, enrichment of a genomically stable/cadherin 1 (E-cadherin gene)-associated profile, and a potentially more frequent inherited predisposition. These findings may inform age-aware diagnostic pathways, germline evaluation, and future therapeutic research.