**5. A proportion of gastric "pure" DLBCL patients can be cured by first-line HPE**

Although the origin of gastric "pure" DLBCL is usually considered as de novo and not from high-grade transformed MALT lymphoma, there are several evidences demonstrating the epidemiological link between *Hp* infection and gastric "pure" DLBCL [44, 69–71]. In a case–control study in a Japanese population, Ishikura et al. disclosed a close association between *Hp* infection and risk of development of gastric lymphoma, in which the odds ratios for MALT lymphoma and DLBCL were 1.96 (95% confidence interval [CI], 1.00–3.86), and 1.92 (95% CI, 0.74–4.95), respectively [72].

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

Because the differentiation between "pure" DLBCL and DLBCL(MALT) is not clearly defined as per histopathological manifestations [57, 58], exploration of the therapeutic efficacy of first-line HPE in gastric "pure" DLBCL has rarely been studied as these patients should be treated with aggressive chemotherapy according to recommendations from the WHO advisory committee [5, 57]. However, a proportion of gastric "pure" DLBCL patients are elderly and have a relatively large number of comorbidities; such patients cannot tolerate the adverse effects of systemic chemotherapy. For these elderly gastric "pure" DLBCL patients with comorbidities, several anecdotal case reports showed that the administration of first-line HPE can cause complete regression of tumors [73–75], suggesting that a certain proportion of gastric "pure" DLBCLs are *Hp*-related, and the growth of these lymphoma cells is *Hp*-dependent.

Since 2001, our group and other investigators have shown that early stage gastric DLBCL(MALT) is *Hp*-dependent and is cured by first-line HPE [21–24]. Consequently, HPE has become the first-line treatment for patients with localized gastric DLBCL(MALT) at our institution. Kuo et al. further designed a pilot study to investigate the therapeutic efficacies of first-line HPE in stage IE/IIE1 gastric "pure" DLBCL patients who are monitored by the following approaches: (1) intensive endoscopic regular follow-up, and (2) immediate administration of systemic rituximab-based chemotherapy (immunochemotherapy) if tumors are stable or progressive [26]. This pilot study revealed that first-line HPE resulted in CR in 11 (68.8%) of 16 *Hp*-positive gastric "pure" DLBCL patients, with a median interval to CR of 2.1 months (**Figure 3**) [26]. Although there were a limited number of gastric "pure" DLBCL patients, the CR rate showed a trend of being higher in tumors involving the mucosa/submucosa than in tumors spread into the muscularis propria or beyond (100% [5/5] vs. 54.5% [6/11], P = 0.119) [26]. After a median follow-up of 3.9 years (95% CI, 3.7 to 4.1), 10 *Hp*-dependent patients were alive and free of lymphoma, but one patient died of lung cancer [26]. Considering that the tumors may rapidly progress and cause morbidity or mortality if tumors are unresponsive to antibiotic treatment, *Hp*-independent gastric "pure" DLBCL patients were immediately treated with immunochemotherapy, and the 5-year overall survival (OS) rate was compatible with patients receiving first-line conventional immunochemotherapy (88.9% vs. 78.3%, P = 0.551) [26].

In another retrospective study conducted in a Japanese population, Tari et al. revealed that among 15 patients with stage IE gastric "pure" DLBCL, four (26.7%) patients achieved CR after successful HPE with a HPE regimen consisting of rabeprazole, amoxicillin, and metronidazole [27]. In their studies, all four patients with CR presented with superficial endoscopic findings and remained lymphoma-free for 7–100 months, whereas 11 *Hp*-independent patients responded completely to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) for three courses, followed by radiotherapy [27]. Endoscopic ultrasound staging also showed the CR rate for tumors limited to the mucosa and the shallow portion of the submucosa was 80% (4/5 cases), whereas that for tumors extending to the deep portion of the submucosa or beyond, it was 0% (0/10 cases) [27]. The HG-L1 trial was a multicenter phase II study which explored first-line HPE consisting of clarithromycin, tinidazole or metronidazole, and omeprazole in 16 patients with stage I *Hp*-positive gastric DLBCL ("pure" DLBCL, n = 11; DLBCL(MALT), n = 5) [28]. Reporting on this trial, Ferrei et al. revealed that eight (50%) patients achieved CR and three patients achieved PR at two months after HPE, and the remaining two patients with PR achieved CR after receiving single rituximab treatment [28]. In addition, the remaining patients with stable or progressive diseases were all converted to CR after receiving salvaged management with R-CHOP [28]. This prospective trial demonstrated that the therapeutic efficacies of HPE in Western populations with gastric DLBCL are the same as those in Asian populations.

#### **Figure 3.**

*Changes of endoscopic features and images in an example of* Helicobacter pylori *(*Hp*)-dependent stage IIE1 gastric "pure" diffuse large B-cell lymphoma (DLBCL) before and after completion of Hp eradication therapy (HPE) (A) Endoscopy shows multiple ulcerative tumors at the anterior and posterior walls of the greater curvature of the gastric body in an 89-year-old woman before HPE (Histopathology disclosed "pure" DLBCL without histological evidence of mucosa-associated lymphoid tissue). (B) Endoscopic ultrasound examination shows increased thickness of 2nd/3rd layers (submucosal involvement) with maximal thickness (0.7 cm) (white arrow) and multiple perigastric lymphadenopathies in the body of the stomach. (C) Positron emission tomography and computed tomography (CT) reveal intense hot areas (white arrow) at the upper to middle gastric wall of the stomach (standard uptake value max early/delay = 21.5/37.6) (demonstrated at axial, coronal, and sagittal views). (D) One month after completion of HPE, endoscopy shows regressed ulcerative masses at the gastric body in the same case A. (E) Eight months after completion of HPE, complete remission was achieved except for ulcerative scarring (Histopathology disclosed chronic gastritis without intestinal metaplasia) in the same case A. (F) At the same time, CT shows no gastric wall thickening (white arrow) in the gastric body in the same case A.* Hp*,* Helicobacter pylori*; HPE, Hp eradication therapy; DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue; CT, computer tomography; SUV, standard uptake value; CR, complete remission.*

Taken together, these findings indicate that approximately 50% of gastric "pure" DLBCL patients whose tumors are still *Hp*-dependent, are highly responsive to first-line HPE (**Table 1**). Importantly, HPE treatment may result in a quick response of tumors to CR and to long-lasting CR in these *Hp*-dependent gastric "pure" DLBCL patients. Even if the tumors invade the deep layer or the perigastric lymph nodes, some patients with gastric "pure" DLBCL are still cured by first-line HPE (**Figure 3**). Furthermore, gastric "pure" DLBCL patients who do not respond to first-line HPE are successfully salvaged with rituximab-based chemotherapy. Therefore, the use of first-line HPE as an exclusive treatment to avoid potential adverse effects of chemotherapy or radiotherapy for localized *Hp*-positive for gastric "pure" DLBCL patients is suggested, because this subgroup of patients is frequently older than 70 years.
