<italic>Helicobacter pylori</italic>-Naïve Gastric Neoplasms: Clinicopathological and Molecular Features and Diagnostic Challenges.

backgroundWith the increasing proportion of the Helicobacter pylori (Hp)-naïve population in Japan, conventional Hp-infected gastric neoplasms (HpIGNs) have decreased, whereas Hp-naïve gastric neoplasms (HpNGNs) are being detected more frequently. SUMMARY: Hp infection remodels the gastric mucosa and promotes tumorigenesis through a high mutational burden and epigenetic dysregulation, contributing to the histologically diverse and aggressive nature of HpIGNs. In contrast, HpNGNs arise with few genetic and epigenetic alterations, resulting in limited morphological diversity determined by the type of their background mucosa. Most HpNGNs arise in the fundic gland mucosa and exhibit a gastric phenotype, whereas those arising from the pyloric gland mucosa or gastric cardia show a variable phenotype. Regardless of histologic subtype, HpNGNs are generally biologically indolent, except for a subset arising in the gastric cardia. The histological classification of HpNGNs does not always fit conventional diagnostic frameworks for gastric neoplasms. In particular, foveolar-type adenomas (FGAs) need to be subclassified into flat and raspberry types, which represent distinct molecular entities. Furthermore, HpNGNs with a MUC6-dominant gastric phenotype, including gastric adenocarcinomas of fundic gland or fundic gland mucosa type and some flat-type FGAs with partial MUC6-dominant components, and pyloric gland adenomas form a morphological and molecular continuum, occasionally making histological distinction difficult. A comprehensive disease concept integrating these lesions may help resolve this diagnostic issue. KEY MESSAGES: As the prevalence of Hp infection continues to decline worldwide, HpNGNs are expected to emerge as a distinct disease entity, highlighting the need for refined diagnostic frameworks and risk-based surveillance strategies in the post-Hp era.