Revisiting the Full Spectrum of Helicobacter pylori-Related Gastric Lymphoma

Abstract

Early stage gastric diffuse large B-cell lymphomas (DLBCLs) with histological features of mucosa-associated lymphoid tissue (MALT) origin (DLBCL[MALT]) are also closely related to Helicobacter pylori (Hp) infection, apart from the classical gastric MALT lymphoma, and are cured by Hp eradication therapy (HPE). Whether some gastric “pure” DLBCLs (without histological features of MALT) are also Hp-related is clinically very important, since this subtype of gastric lymphoma is relatively common in the population and is still universally treated with intensive systemic chemotherapy. A large proportion of early stage gastric “pure” DLBCL can achieve long-term complete remission after HPE. However, the precise mechanisms of Hp-dependent (with complete regression of tumors after HPE) lymphomagenesis of gastric “pure” DLBCL, DLBCL(MALT), and MALT lymphoma remain uncertain. In the classical conception, gastric MALT lymphoma is indirectly caused by Hp through T-cell stimulation, with the aid of costimulatory molecules. To explore the direct interactions between Hp and lymphoma B-cells of Hp-dependent gastric MALT lymphoma, DLBCL(MALT), and “pure” DLBCLs, we assessed the participation of Hp-encoded cytotoxin-associated gene A (CagA) in the lymphomagenesis of these tumors. We discovered that CagA oncogenic protein and its regulated signaling molecules including phospho-Src homology-2 domain-containing phosphatase (p-SHP-2) and phospho-extracellular signal-regulated kinase (p-ERK) correlated significantly with Hp-dependence of gastric MALT lymphoma. This finding supports previous observations that the CagA protein of Hp can be translocated into B-cell lymphoma cells, thereby leading to survival signals. Furthermore, we demonstrated that Hp-positive and CagA-expressing gastric “pure” DLBCLs behave in a less biologically aggressive manner, and have better clinical outcomes; this is a distinguishing entity, and its cell origin may include germinal center B cells. In addition, we found that the expression of CagA, p-SHP-2, and p-ERK correlated significantly with the Hp-dependence of gastric DLBCL(MALT) and “pure” DLBCL. These findings indicate that the spectrum of Hp-related gastric lymphomas including MALT lymphoma, DLBCL(MALT), and “pure” DLBCL, is much wider than was previously thought. Further explorations of the spectrum, lymphomagenesis, and therapeutics of Hp-related gastric lymphoma are warranted.