Abstract
Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.
Highlights
Gastric cancer (GC) is the second cause of cancer related mortality worldwide [1]
In the gastritis samples the morphology of the epithelial glands was not atypical and superficial degenerative changes were observed in only a few samples; all gastritis were classified as non-atrophic (NAG)
It has been documented that H. pylori tends to be absent in tumor microenvironments [11]; in agreement, less than 20% of the tumor samples showed bacterial colonization, whereas H. pylori was observed in 64% of the non-atrophic gastritis (NAG) biopsies. 19 biopsies from gastric bypasses were included as a reference of patients with obesity-related inflammation, but without gastric symptoms
Summary
There are two main histological types of gastric adenocarcinoma based on Lauren’s classification: intestinal and diffuse [2]. Intestinal GC is a malignancy preceded by inflammatory lesions of increased severity: the earliest gastric lesion is a non-atrophic gastritis (NAG), which evolves to an atrophic gastritis (AG), intestinal metaplasia, dysplasia and GC; this sequential progression is recognized as the Correa sequence [3]. The diffuse type of GC does not follow the Correa sequence; it is accepted that a chronic NAG is a major risk for this type of GC [4]. Infection of the gastric mucosa by Helicobacter pylori (H. pylori) is considered the main risk factor for intestinal and diffuse GC, and for chronic inflammatory responses triggering tissue damage [5]. More than 80% of lymphoepithelioma-like (LEL) GCs, a rare
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