Gastric neoplasm with foveolar-cell differentiation in Helicobacter pylori-naïve patients

The incidence of Helicobacter pylori (Hp)-naïve gastric neoplasms (HpNGNs) is increasing due to a growing Hp-naïve population and improved recognition. Among these, HpNGNs that predominantly exhibit foveolar-cell differentiation include foveolar-type gastric adenomas (FGA) and fundic gland polyps with dysplasia (FGPD). Traditionally, FGAs have been considered large, whitish, flat lesions (flat-type FGA), primarily associated with syndromic conditions, such as familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), while sporadic cases are rare. This type exhibits a gastric immunophenotype with diverse differentiation, mainly toward foveolar cells, and harbors APC and KRAS mutations in all sporadic and most syndromic cases. A distinct subset of FGAs, termed foveolar-type gastric adenoma with a raspberry-like appearance (FGA-RA), has been identified. It presents as small, reddish polyps with unique macroscopic and microscopic features and only occurs sporadically. FGA-RA often mimics gastric hyperplastic polyps macroscopically and typically exhibits low-grade dysplasia, making biopsy-based diagnosis challenging and leading to its historical underrecognition. It shows pure foveolar differentiation and consistently harbors Krüppel-like factor 4 (KLF4) mutations. FGPD primarily develops sporadically in Hp-naïve individuals with long-term proton pump inhibitor use. A syndromic form, resembling flat-type FGAs, is also associated with FAP and GAPPS. Histologically, FGPD features dysplasia confined to the superficial foveolar epithelium and mucus neck cells overlying fundic gland polyps, with APC mutations detected in approximately 50% of cases. This review explores the clinicopathological and molecular characteristics of HpNGNs with predominant foveolar cell differentiation, emphasizing the need for an updated histological diagnostic framework.