**1. Introduction**

Gastric lymphoma, the most common non-Hodgkin lymphoma, has become an interesting research topic because of its unique clinicopathological features, wide spectrum of histological subtypes, and specific treatment strategies [1–4]. Histologically, gastric lymphomas are the most common B-cell neoplasms; mucosaassociated lymphoid tissue (MALT) lymphoma (renamed as marginal zone B-cell lymphoma with MALT type) and diffuse large B-cell lymphoma (DLBCL) with and without histological evidence of MALT origin are the most common subtypes according to the World Health Organization (WHO), in addition to rare mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma [3–6]. MALT lymphoma, which histologically consists primarily of diffuse small- and medium-sized lymphocytes, resembling centrocytes (centrocyte-like cells, CCLs) and lymphoepithelial lesions (LELs), was first described by Isaacson and Wright et al. in 1983 [1, 2, 7, 8]. At the same time, Marshall and Warren described the direct link between *Helicobacter pylori* (*Hp*) (a gram-negative, spiral rod-shaped bacterium) infection, and gastritis and peptic ulcer disease [9]. After one decade, Wotherspoon and Isaacson et al. found that 31% of patients with *Hp*-positive gastritis had lymphoid follicles, and 92% of patients with gastric MALT lymphoma had *Hp* infections, indicating a close association between *Hp* infection and the development of MALT and MALT lymphoma of the stomach [10]. Subsequently, they demonstrated that approximately 60% of patients with gastric MALT lymphoma achieved complete remission (CR) after being treated with antibiotics that eradicate *Hp* infection [11]. Subsequently, most investigators started administrating first-line *Hp* eradication therapy (HPE) by combining proton pump inhibitors (PPIs), amoxicillin, clarithromycin, bismuth, metronidazole, or tetracycline in the treatment of localized *Hp*-positive gastric MALT lymphoma [12–14]. By reviewing 32 clinical studies of first-line HPE for gastric MALT lymphoma patients (most prospective studies), Zullo et al. demonstrated that 1091 (77.5%) of 1408 patients achieved CR after successful first-line HPE; among these patients, patients with stage I disease had a higher CR rate than those with stage II disease (78.4% vs. 55.6%, P = 0.0003) [15]. Although some patients with gastric MALT lymphoma may take more than 12 months to achieve CR after completing HPE, most patients achieved CR within 12 months after completing HPE [15–17]. Therefore, eradication of *Hp* infection by antibiotics in addition to a PPI has been well conceded as the first-line treatment for early-stage *Hp*-positive gastric MALT lymphoma.

In contrast to gastric MALT lymphoma, high-grade transformed MALT lymphoma, relabeled as DLBCL with histological evidence of MALT origin DLBCL(MALT), is conventionally considered as *Hp*-independent (the lack of CR of lymphoma after HPE) according to the WHO [4–6]; as per WHO, patients with DLBCL(MALT) should be treated with systemic chemotherapy [18–20]. However, in the past decade, our group and other investigators have found that early-stage gastric DLBCL(MALT) is as responsive to first-line antibiotics as its low-grade counterpart, MALT lymphoma [21–25]. These observations have led to a drastic change in the standard therapy for patients with gastric DLBCL(MALT); many of these patents are now spared from experiencing the severe toxicity of intensive systemic chemotherapy.

Gastric "pure" DLBCL (DLBCL without histological evidence of MALT origin) is generally assumed as originating de novo instead of originating from high-grade transformed MALT lymphoma, and is thus regarded as having a rare association with *Hp* infection [3–6]. Considering that gastric "pure" DLBCLs comprise approximately half of gastric lymphomas, and this subgroup of patients are conventionally treated with systemic chemotherapy [4, 6, 8], it is worthwhile to explore whether some *Hp*-positive gastric "pure" DLBCL remain *Hp*-dependent. Our explorative study showed that antibiotics alone resulted in CR in 69% of patients with early

#### *Revisiting the Full Spectrum of* Helicobacter pylori*-Related Gastric Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.97424*

stage gastric "pure" DLBCL, and these *Hp*-dependent (the presence of CR of lymphoma after HPE) patients remained in CR after a 4-year rigorous endoscopic follow-up, whereas patients without CR after antibiotic treatment were still responsive to subsequent salvage chemotherapy [26]. Two other studies also demonstrated that some patients with *Hp*-positive early stage gastric "pure" DLBCL achieved CR through antibiotic eradication of *Hp*, and most *Hp*-dependent patients remained lymphoma-free after long-term follow up [27, 28]. In addition, among patients with gastric "pure" DLBCL receiving systemic chemotherapy, the *Hp*-positive group had less aggressive behaviors and better clinical outcomes than the *Hp*-negative group [29–31]. These findings suggest that for patients with *Hp*-positive localized gastric "pure" DLBCL, the administration of first-line antibiotic treatment, followed by careful monitoring of tumor response before and after antibiotic treatment using meticulous endoscopic examination, may allow certain patients to avoid the adverse effects of chemotherapy. Importantly, the explanation as to why some "pure" DLBCLs are still *Hp*-dependent can allow us to explore the precise molecular mechanisms of *Hp*-dependent lymphomagenesis of gastric DLBCL.

Regarding the lymphomagenesis of gastric MALT lymphoma, the classical concept is that *Hp* can only stimulate T cells, and then *Hp*-specific T cells transform the marginal-zone B cells into lymphoma [32–35]. Direct interaction between *Hp* and B cells was not considered to exist. However, several studies have observed that *Hp*-encoding cytotoxin-associated gene A (CagA) can be translocated into B cells, thereby activating survival signals of B-lymphoma cells, including tyrosine phosphorylation-dependent and -independent signaling [35–37]. Our group further observed that the CagA molecule and its triggering signaling molecules such as phospho–Src homology-2 domain-containing phosphatase (p-SHP-2), phospho– extracellular signal-regulated kinase (p-ERK), phospho-*p38* mitogen-activated protein kinases (p-p38 MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL are expressed in tumor cells of gastric MALT lymphoma patients [38–40]. Furthermore, CagA and its controlled signaling molecules significantly correlated with the *Hp*-dependence of these tumors [40]. In addition, our group showed that CagA, p-SHP-2, and p-ERK were closely associated with the *Hp*-dependence of gastric DLBCL(MALT) and "pure" DLBCL [41]. These observations pose a strong challenge to the classical concept of indirect *Hp*-specific T-cell stimulation, and suggest the possibility that a direct interaction between *Hp* and B cells exists in a wide spectrum of gastric lymphoma including MALT lymphoma, DLBCL(MALT), and "pure" DLBCL.

In this chapter, we will describe the association between *Hp* infection and MALT lymphoma, the novel use of first-line HPE in curing gastric DLBCL with and without histological evidence of MALT, and a wide spectrum of *Hp*-related gastric lymphomas; in addition, we present the possible molecular mechanisms and cellular origins of *Hp*-related gastric lymphoma.
