Beyond Helicobacter pylori: Current Insights into H. pylori-Naive Gastric Cancer.

[BACKGROUND] The increasing global incidence of Helicobacter pylori-naive gastric cancer (HPnGC) has established it as a clinical entity warranting further study of its diagnosis, pathogenesis, etiologies, classifications, and management.

[SUMMARY] HPnGC Helicobacter pylori-naive gastric cancer (HPnGC) is an emerging and distinct clinical entity, with its relative burden increasing as global efforts for Helicobacter pylori (HP) eradication succeeds. The cancer is linked to specific etiologies such as Epstein-Barr virus, autoimmune gastritis, and certain hereditary cancer predisposition syndromes, and is characterized by more aggressive histological subtypes, unfavorable anatomical locations, advanced stages at diagnosis, and ultimately poorer prognosis compared to its H. pylori-positive counterpart. Diagnosis requires stringent multi-modal confirmation of absent infection. Currently, endoscopic, surgical, and systemic treatments are similar to those for Helicobacter pylori-positive gastric cancer.

[KEY MESSAGES] This review demonstrates wide knowledge gaps and areas requiring further clarification. Accurate diagnosis remains challenging due to the absence of standardized criteria, highlighting the need for a robust diagnostic framework. Furthermore, it is imperative for further research into the different molecular subtypes and carcinogenic mechanisms to identify cost-effective surveillance methods and effective treatment strategies that contribute to the development of a comprehensive and practical clinical guideline.