Clinical Relevance of Helicobacter pylori Coinfection in Ebstein-Barr Virus-Associated Gastric Carcinoma

Epstein-Barr virus (EBV), a ubiquitous human herpes virus with oncogenic activity, is a well-known risk factor for developing gastric carcinoma (GC). EBV infects over 90% of the adult population, mostly with a lifelong asymptomatic carrier state. Although how EBV infects gastric epithelial cells still remained unclear, cell-to-cell contactmediated EBV transmission from virus-infected mucosal B lymphocytes with EBV reactivation is a convincing hypothesis. EBV-associated GC (EBVaGC) is characterized by monoclonal proliferation of EBV-infected cells, indicating that EBV infection occurs in an early stage of carcinogenesis. In 2014, The Cancer Genome Atlas Network defined EBVaGC as one of the four subtypes of GC, based on its quite different molecular profiles from those of conventional GC. EBVaGCs exhibit a high frequency of DNA hypermethylation, and 80% have PIK3CA mutations, as well as amplifications of the JAK2, programmed death ligands 1 and 2 genes, while TP53 defects and microsatellite instability are unusual. EBVaGCs thus show distinct clinical features with a male predominance, younger age, a high frequency in postsurgical gastric stump, proximal location, and a better prognosis. Histologically, EBVaGC is particularly associated with GC with lymphoid stroma (GCLS), a rare histological variant, accounting for 1% to 4% of all GCs, and over 80% of GCLSs are associated with EBV infection as compared to 8.7% (range, 1.3% to 20.1%) of all GCs. GCLS is characterized by poorly developed tubular structures associated with prominent lymphoid infiltrate in a non-desmoplastic stroma. Increased tumorinfiltrating lymphocytes, which reflects a host immune response to tumor cells, is thought to be associated with a better prognosis in GCLS. Chronic inflammation is known for a risk factor for EBVaGC as it sets the optimal conditions necessary for gastric carcinogenesis. Helicobacter pylori (HP) is the greatest risk factor for GC, and HP-associated atrophic gastritis could serve as a lesion which enables cell-to-cell contact between infiltrated EBV-carrying lymphocytes and gastric epithelial cells. A previous study demonstrated that EBV and HP coinfection synergistically induced severe inflammation in gastric tissue and this might increase the risk of developing GC. However, it is unclear whether the carcinogenesis results from an additional inflammatory response with increased tissue damage by EBV and HP coinfection or is based on gene products interaction between EBV and HP. Since there have been also some studies which do not show any association between the two pathogens, further research is necessary to determine the clinical importance of EBV and HP coinfection in GC. In this issue of Gut and Liver, Noh et al. retrospectively enrolled 956 patients who had undergone surgery for GC between September 2014 and August 2015, and they aimed to investigate the effect of EBV and HP coinfection on the clinicopathologic features and prognosis in GC, as well as to evaluate the role of EBV infection in non-GCLS. In results, EBV and HP coinfection was significantly associated with male sex, proximal location, GCLS morphology, and equivocal p53 expression, although it did not show differences in overall survival (OS). In multivariate analysis, EBV infection alone (hazard ratio, 0.362; 95% confidence