Prognostic factors in Epstein-Barr virus-associated stage I–III gastric carcinoma: Implications for a unique type of carcinogenesis

Abstract

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. However, the prognostic factors remain unclear, particularly in UICC/AJCC stage I-III cancer. We retrospectively enrolled 1,020 patients with stage I-III gastric cancer that received radical gastrectomy with lymphadenectomy. Formalin-fixed, paraffin‑embedded surgical specimens were retrieved to construct tissue microarrays. EBV positivity was identified by in situ hybridization with EBV-encoded small RNA, and the histological classification was reviewed. Fifty-two cases of EBVaGC were identified, exhibiting a male predominance (p=0.003), a higher prevalence in stump cancer (p<0.001), and poorly differentiated carcinoma (p=0.010) compared with the controls. The survival analysis revealed no difference in survival between the EBVaGC cases and the EBV-negative cases (p=0.977). The multivariate analysis showed that EBVaGC cases with a tumor size >5 cm, non-lymphoepithelioma-like carcinoma (LELC), or a lymph node ratio >0.15 had a worse overall survival (hazard ratio 2.884, 12.178 and 19.352; p=0.027, 0.005 and <0.0001, respectively). The depth of tumor invasion and the number of lymph node metastases did not reach statistical significance (p=0.834 and 0.833, respectively). These prognostic factors, tumor size, LELC classification and lymph node ratio, may reflect a unique type of carcinogenesis of EBVaGC and may be considered when selecting high-risk patients for adjuvant treatment.

Outlooks on Epstein-Barr virus associated gastric cancer

“…Defined by the presence of EBV in gastric cancer cells, EBVaGC has an annual incidence of 75,000–90,000 cases per year, representing the largest subpopulation among EBV-related tumors [15]. EBVaGC was first reported by Burke et al in 1990 using polymerase chain reaction (PCR) in gastric carcinoma cells resembling lymphoepithelioma [15].…”

“…EBVaGC was first reported by Burke et al in 1990 using polymerase chain reaction (PCR) in gastric carcinoma cells resembling lymphoepithelioma [15]. In 1992, in situ hybridization technique allowed Shibata et al to identify EBV in 16% of gastric adenocarcinoma samples by localizing EBV-encoded small RNA 1 (EBER1) [16].…”

“…The pooled estimate of EBVaGC frequencies in North and South America, Asia and Europe is 9.9%, 8.3% and 9.2% respectively [15]. Table 4 provides a list of different countries with their EBVaGC frequencies reported to date.…”

Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?

“…EBV-positive subtype tumors are predominantly located in the gastric fundus or body, and preferentially occur in males. ARID1A and BCOR mutations are prevalent, whereas genetic alterations of TP53 are rare (15) (37) . Notably, 80% of EBVpositive subtype tumors harbor mutations in phosphatidylinositol 3-kinase CA (PIK3CA) and amplification of JAK2, CD274, and PDCD1LG2, which encode receptor tyrosine kinase, PD-L1 and PD-L2, respectively, are also common (15) .…”

Role of Epstein Barr Virus and Gastric Carcinoma

“…El virus de Epstein-Barr (VEB) se presenta en el 10% como promedio mundial (rango del 2%-20%) en CG 18 .La proteína LMP2A activa la DNA metiltransferasa 1 por inducir la fosforilación del STAT3, causando hipermetilación de PTEN. Genes latentes y microRNAs tienen capacidad oncogénica para favorecer la proliferación, motilidad y antiapoptosis 19 .…”