In recent years, as the prevalence of Helicobacter pylori (H. pylori) infection has declined, the incidence of H. pylori–uninfected gastric epithelial neoplasms (HpUGENs) has been gradually increasing in East Asia, now accounting for approximately 0.4–5.4% of all gastric dysplasia and carcinoma cases in Japan. The previous reports indicate that HpUGENs are often detected as low-grade dysplasia; however, some lesions exhibit lymphovascular invasion, or advanced stage gastric cancer. Since HpUGENs differ biologically and endoscopically from conventional H. pylori–associated gastric cancer, standardized diagnostic criteria have not yet been established, and endoscopic diagnosis remains challenging. Therefore, we aim to establish a new endoscopic diagnostic system for HpUGENs and to elucidate their clinicopathological and endoscopic characteristics.

A total of 308 lesions with HpUGENs treated by endoscopic treatment (ESD / EMR / polypectomy) at our hospital between August 2009 and October 2025 were enrolled and classified histologically, and their endoscopic and clinicopathological features were analyzed retrospectively.

All HpUGENs were histologically classified into seven types. 1. gastric adenocarcinoma of fundic-gland type (GA-FG: n = 90, U/M/L = 67/20/3, whitish, subepithelial tumor–like appearance, intramucosal lesion(M)/submucosal invasion(SM) = 39/21), 2. gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM: n = 16, U/M/L = 10/6/0, reddish elevated lesion or subepithelial tumor–like appearance, M/SM = 3/13), 3. raspberry-type gastric epithelial neoplasm (GEN) (foveolar-type adenoma: n = 155, U/M/L = 83/67/5, reddish protruded lesion, M/SM = 155/0), 4. whitish flat elevated–type GEN (n = 4, U/M/L = 4/0/0, whitish flatly elevated lesion, M/SM = 4/0), 5. other GEN with a gastric phenotype (complex type of GEN with gastric phenotype: n = 12, U/M/L = 4/4/4, M/SM = 12/0), 6. GEN with an intestinal or gastrointestinal mixed phenotype arising in the pyloric gland region (n = 7, U/M/L = 0/0/7, reddish depressed lesion, M/SM = 7/0), 7. signet-ring cell carcinoma (SRCC: n= 24, U/M/L = 0/10/14, whitish or faded color and flat or depressed lesion, M/SM = 22/2). Magnifying endoscopy with narrow band imaging (M-NBI) was performed in 219 lesions (71%). In 219 lesions, 130 lesions (59%) were diagnosed as non-cancer by M-NBI. Especially, GAFG (90/90, 100%), GAFGM (12/16, 75%), and SRCC (16/24, 67%) were difficult to diagnose as cancer by M-NBI because of the coverage and/or mixture with a non-neoplastic mucosa or gastric epithelial neoplasia with low-grade atypia.

This study demonstrated that HpUGENs can be classified into seven histological types, and further characterized by specific lesion location, color, and macroscopic appearance. For accurate diagnosis of HpUGENs, it may be necessary to fully understand histological classification and endoscopic features of these lesions using white light imaging and M-NBI based on these histological characteristics and to take a precise biopsy.