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.
Highlights
Gastric “pure” diffuse large B-cell lymphoma (DLBCL) (DLBCL without histological evidence of mucosa-associated lymphoid tissue (MALT) origin) is generally assumed as originating de novo instead of originating from high-grade transformed MALT lymphoma, and is regarded as having a rare association with Helicobacter pylori (Hp) infection [3–6]
These findings show that the tumor remission rates after Hp eradication therapy (HPE) are identical between MALT lymphoma and DLBCL(MALT) of the stomach (Table 1), which overthrows the classical concept that the transformation of MALT lymphoma into high-grade DLBCL(MALT) is associated with the acquisition of Hp-independence and DLBCL(MALT) is unlikely to respond to HPE
In addition to the classical MALT lymphoma, we demonstrated that DLBCL with (DLBCL[MALT]) and without (“pure” DLBCL) histological evidence of MALT lymphoma are all closely related to Hp
Summary
A gram-negative and spiral rod-shaped bacterium that has evolved to grow in the environment of the stomach, infects approximately 50% of the population worldwide [42, 43]. Tsai et al and Kuo et al showed that ulcerative lesions, proximal locations of tumors, and tumors invading the muscularis propria or serosa correlated significantly with the Hp-independence of gastric MALT lymphoma [25, 39] In another large cohort study of a Korean population, Gong et al reported that Hp infection was detected in 317 (91.9%) of 345 patients with gastric MALT lymphoma using histology, a urea breath test, a rapid urease test, or a serologic test [50]. A “watch and wait” treatment strategy may be advisable for patients with gastric MALT lymphoma who achieved probable minimal residual disease or tumor PR (according to GELA criteria) after successful HPE
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