Abstract
Background: Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and lymphoepithelioma-like GC. Methods: A total of 460 GC patients receiving curative surgery were enrolled. The clinicopathological features, genetic alterations and prognoses were compared between patients with and without EBV infection. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. For lymphoepithelioma-like GC, EBV-positive tumors had more PI3K/AKT pathway mutations than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more PI3K/AKT pathway mutations. Immunotherapy and targeted therapy may be beneficial for these groups of patients. Routine EBV survey is recommended in GC.
Highlights
Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of the four major types of GC [1].Compared with EBV-negative GC, EBV-positive GC is associated with lymphocyte infiltration, genetic mutations in PIK3CA and ARID1A and the hypermethylation of CpG islands [1,2].EBV-encoded small RNAs (EBERs) are abundantly expressed in most the neoplastic cells of the tumor tissue, and the EBER-in situ hybridization (ISH) technique is served as a gold standard to define EBV-associated GC [3]
Patients with EBV-positive GC were associated with having more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like GC, more lymphoid stroma, fewer Helicobacter pylori (HP) infections, higher
GC patients, EBV-positive tumors were associated with greater programmed death-ligand 1 (PD-L1) expression and more liver metastases than EBV-negative tumors; for lymphoepithelioma-like GC patients, EBV-positive tumors were associated with more PI3K/AKT pathway mutations than EBV-negative tumors
Summary
Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of the four major types of GC [1].Compared with EBV-negative GC, EBV-positive GC is associated with lymphocyte infiltration, genetic mutations in PIK3CA and ARID1A and the hypermethylation of CpG islands [1,2].EBV-encoded small RNAs (EBERs) are abundantly expressed in most the neoplastic cells of the tumor tissue, and the EBER-in situ hybridization (ISH) technique is served as a gold standard to define EBV-associated GC [3]. EBV-positive GC which is known to have high programmed death-ligand 1 (PD-L1) expression mainly has morphologic features of GC with lymphoid stroma, that is, so-called lymphoepithelioma-like GC, with similarities to nasopharyngeal carcinoma and different from the typical intestinal-type or diffuse-type GC [4]. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more
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