**6.** *Hp***-positive gastric DLBCL may be part of** *Hp***-related gastric malignancies**

In addition to gastric DLBCL(MALT), gastric "pure" DLBCL is epidemiologically linked with *Hp* infection, and most gastric "pure" DLBCLs are diagnosed with limited-stage disease [42–44, 76]. Conventionally, patients with gastric "pure" DLBCLs are treated with immunochemotherapy, whereas immunochemotherapy

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

with or without subsequent radiotherapy is considered as the standard therapy for patients with localized disease [77, 78]. Considering that first-line surgical resection cannot improve the survival outcome for gastric "pure" DLBCL patients, a surgical approach is recommended for patients with severe bleeding or perforation [79–81]. Studies in Taiwanese, Japanese, and Western populations clearly demonstrated that certain patients with localized *Hp*-positive gastric "pure" DLBCL are highly responsive to first-line antibiotics eradicating *Hp*, and these patients have persistent CR for a long time after HPE [26–28]. These discoveries imply that gastric "pure" DLBCLs can be biologically classified into two types, *Hp*-related lymphoma, and *Hp*-unrelated lymphoma, each with different cellular origins, paths of tumorigenesis, and clinicopathological manifestations (**Figure 1**).

Hsu et al. retrospectively analyzed the clinicopathological features and clinical outcomes of patients with gastric DLBCL who received systemic chemotherapy, including DLBCL(MALT) (n = 17) and "pure" DLBCL (n = 26), and showed that patients with DLBCL had higher levels of serum lactate dehydrogenase (LDH 50% vs. 12%, P = 0.01) and a lower chemotherapy response rate (57.7% vs. 88.2%, P = 0.03) than those with DLBCL(MALT) [82]. Multivariate analysis identified that the presence of MALT lymphoma components, stage I and IIE1, and response to chemotherapy were independent and good prognostic factors [82]. This finding provides evidence that *Hp* infection may be associated with a better chemotherapy response and good prognosis; this is because gastric DLBCL(MALT) is generally transformed from its MALT lymphoma components in which gastric MALT lymphoma is always linked with *Hp* infection, although *Hp* examinations were not assessed in the study by Hsu et al. [82].

This hypothesis is further supported by a report from Kuo et al. who assessed the correlation between clinicopathological features and clinical outcomes, and *Hp* infection in patients (n = 95) with primary gastric "pure" DLBCLs who received conventional chemotherapy (anthracycline-based-regimens, such as CHOP or CEpirubicinOP) or immunochemotherapy (rituximab/anthracycline or rituximab-COP) as first-line therapy [29]. Kuo et al. found that the presence of *Hp* infection confirmed by histological examination, urease test, or bacterial culture, was associated with a lower International Prognostic Index score (0–1; *Hp*(+) [n = 46] vs. *Hp* (−) [n = 49]) = 65% vs. 43%, P = 0.029), a lower clinical stage (I-IIE1, 70% vs. 39%, P = 0.003), and a better CR rate (76% vs. 64%, P = 0.004) [29]. In addition, patients with *Hp* infection had a significantly better 5-year event-free survival (EFS) (71.7% vs. 31.8%, P < 0.001) and OS (76.1% vs. 39.8%, P < 0.001) than those without *Hp* infection [29]. Even among stage I-IIE1 patients, the *Hp*-positive group had a better trend for CR (88% vs. 68%, P = 0.097) and a better 5-year EFS (80.6% vs. 46.8%, P = 0.003) and OS (90.6% vs. 68.0%, P = 0.023) than the *Hp*-negative group [29]. Using multivariate analysis, Kuo et al. identified the absence of *Hp* infection as an independent predictor of worse EFS (hazard ratio [HR] = 2.509; P = 0.007) and OS (HR = 2.666; P = 0.009) [29].

The findings of Kuo et al. were endorsed by the Cheng et al. who conducted a retrospective analysis of 129 patients with primary gastric "pure" DLBCLs, in which the presence of *Hp* infection was based on a positive test for histological examination and urease breath tests [30]. In their study, the presence of *Hp* infection was significantly associated with limited stage (Stage I-II: *Hp*(+) vs. *Hp* (−), 78.6% vs. 60.3%, P = 0.027) and lower IPI score (0–1: *Hp*(+) vs. *Hp* (−), 92.2% vs. 78.2%, P = 0.022); all *Hp*-positive patients received HPE using PPI, bismuth compounds, and antibiotics, including clarithromycin, amoxicillin, tetracycline, or metronidazole, for eradicating *Hp* [30]. In addition, patients with *Hp* infections had a significantly better 5-year progression-free survival (PFS) rate (89.3% vs. 74.1%, P = 0.040) and 5-year OS (89.7% vs. 71.8%, P = 0.033) than those without *Hp* infection [30]. However,

58.9% of *Hp*-positive patients and 78.6% of *Hp*-negative patients underwent surgery as the initial treatment. Furthermore, multivariate analyses showed that in addition to ECOG performance status 0–1, the presence of *Hp* infection was a better independent predictor for PFS (HR = 0.379; P = 0.045) and OS (HR = 0.292; P = 0.021) [30].

Traditionally, MALT lymphoma is believed to be of marginal zone B-cell origin [3, 8]. Unlike MALT lymphoma, DLBCL is generally thought to originate de novo from germinal center B cells (GCB) or activated B cells [83, 84]. Previous studies showed that patients with GCB-subtype DLCBLs had better EFS and OS than those without GCB-subtype DLBCLs [85, 86]. However, in the reports of clinical outcomes of first-line chemotherapy for gastric "pure' DLBCL, Kuo et al. showed that the EFS and OS were not significantly different between GCB subtype and *non-GCB* subtype tumors according to Han's subclassification [29, 87]. Further analysis showed that the GCB subgroup lost its prognostic value in *Hp-*positive gastric DLBCL patients, but showed better survival in *Hp*-negative gastric DLBCL [29]. These results suggest that *Hp*-negative gastric DLBCL may originate de novo, and its biological significance and histologic subclassification may be more similar to that of nodal DLBCL. Similar to Kuo et al. [29], Chang et al. reported that the non-GCB subtype was not associated with the poor PFS and OS in gastric DLBCLs patients [30]. In addition, Kuo et al. showed that a proportion of *Hp*-dependent gastric DLBCLs, including DLBCL(MALT) and "pure" DLBCL, are classified as the GCB-subtype based on Han's subclassification (preliminary data) [88]. Ferreri et al. also showed that among patients with gastric "pure" DLBCL who received first-line HPE, the CR rate was comparable between GCB and non-GCB subgroups [89]. These results indicate that *Hp* may transform not only marginal zone B cells, but also GCB cells into high-grade large lymphoma cells in *Hp*-related gastric lymphoma. However,

#### **Figure 4.**

*Schema illustrating a hypothesis of heterogeneous cell origin of* Helicobacter pylori *(*Hp*)-dependent gastric diffuse large B-cell lymphoma (DLBCL). (A) Large lymphoma B cells of* Hp*-dependent gastric DLBCL of non-GCB origin may be differentiated from* Hp*-dependent MALT lymphoma components, in which lymphoma cells often lack t(11;18)(q21;q21) [134, 135, 137]. (B) Large lymphoma B cells of* Hp*-dependent gastric DLBCL in which the non-GCBs may originate de novo. The* Hp *CagA and its CagA signaling molecules may directly affect non-GCB cells, which also contribute to the development of* Hp*-dependent large B-cell lymphoma components of gastric DLBCL. (C) Large lymphoma B cells of* Hp*-dependent gastric DLBCL in which the GCBs may originate de novo. The* Hp *CagA and its CagA signaling molecules may directly affect GCB cells, which also contribute to the development of* Hp*-dependent large B-cell lymphoma components of gastric DLBCL.*

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

further explorations of the cellular origins of these *Hp*-related gastric DLBCLs are warranted. Although the immunophenotypic phenomenon of the GCB subtype cannot explain the better prognosis of *Hp*-related gastric DLBCLs, the higher level of mi-R200 in *Hp*-positive tumors functionally hampering zinc-finger E-box-binding homeobox 1 (ZEB1) may thus contribute to the less aggressive behaviors of these tumors [31], since ZEB1 overexpression was reported to significantly correlate with lymph node metastases of DLCBL, and T-cell leukemia progression [90, 91].

These findings reveal that *Hp*-related gastric "pure" DLBCLs share similar clinicopathological features with gastric MALT lymphoma, such as less aggressive behavior, more limited stages, and better prognosis; this suggests an overlapping etiology between these two gastric lymphoma groups. However, the molecular mechanisms of *Hp* infection contributing to the less aggressive nature and better prognosis of gastric "pure" DLBCL remains unclear. The possible mechanisms are as follows: (1) *Hp* CagA may directly participate in the lymphomagenesis of certain portions of gastric "pure" DLBCL, (2) *Hp* may trigger antigen presentation and regulate the triggering immune communications responsible for gastric MALT lymphoma, which may also lead to *Hp*-related gastric "pure" DLBCL, and (3) *Hp* may transform not only the marginal zone B cells, but also GCB-DLBCL cells, and the mechanisms may include a direct CagA interaction with B cells (**Figure 4**). The following is a brief summary of the possible mechanisms of *Hp*-related gastric lymphoma including MALT lymphoma, DLBCL(MALT), and "pure" DLBCL.
