**4. High-grade transformation does not confer** *Hp***-independence of gastric lymphoma**

It was previously believed that the transformation of MALT lymphoma into high-grade MALT lymphoma, is associated with the acquisition of *Hp*independence (lack of CR of tumors after HPE); high-grade MALT lymphoma is thus considered as a *Hp*-independent tumor that is non-responsive to antibiotics (**Figure 1**) [18–20, 56]. Clinicians who administer first-line HPE to treat patients with high-grade gastric MALT lymphoma do so as they may regard MALT lymphoma as similar to low-grade MALT lymphoma that is highly responsive to HPE. Thus, to avoid such a confusion, Harris et al. in a 1999 WHO classification advised that high-grade MALT lymphoma should be renamed as DLBCL with histologic evidence of MALT (DLBCL[MALT]), and not as transformed high-grade MALT lymphoma [57]. In 2008, the WHO lymphoma classification advocated that histological manifestations of gastric lymphoma that display large-cell B-cell transformation in the MALT lymphoma background should be classified as DLBCLs rather than as high-grade transformed MALT lymphomas [5]. In this milieu, the presence of large B cells comprising LELs does not alter the pathological diagnosis of DLBCL [5, 6]. Regardless of this, the existence of complementary MALT lymphoma components in DLBCL should be appraised consistently [4, 5, 58].

However, two independent prospective studies and one retrospective study have revealed that a certain proportion of early-stage *Hp*-positive gastric DLBCL(MALT) patients were still responsive to first-line HPE, and thus achieved CR and subsequent long-term remission [21–24]. In the first prospective study, Chen et al. (Taiwan study group) demonstrated that 10 (62.5%) of 15 patients with early-stage gastric DLBCL(MALT) achieved CR after receiving first-line HPE, and remained lymphoma-free during a long-term follow-up [21]. In another prospective study assessing the association between clinicopathological features and tumor response

#### **Figure 1.**

*Gastric diffuse large B-cell lymphoma as well as gastric mucosa-associated lymphoid tissue (MALT) lymphoma are* Helicobacter pylori*-dependent, and are cured by first-line Hp eradication therapy (HPE). In contrast to the classic concept that gastric diffuse large B-cell lymphomas (DLBCLs) with and without histological evidence of MALT lymphoma are not responsive to HPE, several evidences demonstrated that*  Hp*-related gastric lymphoma does not involve loss of* Hp*-dependence and is responsive to HPE, indicating that the spectrum of* Hp*-related gastric lymphoma is much wider than was originally thought.*

to HPE in gastric MALT lymphoma and DLBCL(MALT), Nakamura et al. reported that five (50%) of 10 gastric DLBCL(MLAT) patients had CR, whereas 4/6 with mucosa and submucosa involvement and 1/4 patients with tumor involvement in the muscularis propria were *Hp*-dependent [22]. Of these, five *Hp*-dependent patients were still free of lymphoma after a median follow-up of five years [22]. Mongnar et al. retrospectively analyzed eight patients with gastric DLBCL(MALT) who initially received HPE, of whom seven patients had CR [23]. Among these *Hp*-dependent patients, four patients did not receive further treatment, whereas one patient developed recurrence at six months after completing HPE, and another two patients underwent surgery later (one patient received chemotherapy because of residual MALT lymphoma in the surgical specimen) [23].

In 2005, Chen et al. reported the clinical outcome of a prospective study using first-line HPE for treating 24 patients with gastric DLBCL(MALT) and 36 patients with gastric MALT lymphoma, and demonstrated that 24 (80%) of 30 patients with MALT lymphoma and 14 (63.6%) of 22 patients with DLBCL(MALT) achieved CR after successful HPE [24]. The median time to CR after the completion of HPE for *Hp*-dependent patients was six months for DLBCL(MALT), and 10 months for MALT lymphoma [24]. Interestingly, after a median long-term follow-up (MALT lymphoma, 70 months; DLBCL[MALT], 56 months) for these *Hp*-dependent patients, the tumor did not recur in the DLBCL(MALT) case, but recurred in three cases of MALT lymphoma [24]. Regarding the depth of tumor infiltration associated with tumors responsive to HPE, the CR rate was 80% (8/10) for tumors limited to the mucosa or submucosa, and 29.4% (5/17) for tumors invading the muscularis propria or beyond (P = 0.018) [24].

In 2008, Cavanna et al. [59] reviewed the anecdotal cases series reporting the CR after antibiotic treatment for gastric DLBCL(MALT) and the results of HPE for patients with gastric DLBCL(MALT) obtained from Chen et al. [21, 24], Nakamura et al. [22], Morgan et al. [23], Hiyama et al. [60], and Alpen et al. [61]. Cavanna et al. showed that 42 (68.9%) of 61 cases of gastric DLBCL(MALT) responded completely to antibiotics eradicating *Hp*; most patients in this study presented with stage IE (30 cases), with tumor invasion to the mucosa or submucosa (21 of 33 cases were evaluable) [59]. However, age, sex, and tumor location (proximal or distal components) did not predict the response of tumors to HPE [59]. Although depth of invasion and stage of gastric DLBCL(MALT) were closely associated with

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

*Hp*-independence, there were a few cases of stage IIE1 (perigastric lymph node involvement) tumors that were dependent on *Hp* and achieved CR after HPE [59]. Zullo et al. analyzed the pooled data obtained from 1271 patients with gastric MALT lymphoma or DLBCL(MALT) through 34 studies exploring the treatment efficacy of first-line HPE, and revealed that a *Hp* eradication rate of 91% can be achieved using dual therapy for 14 days or triple therapy for seven to 14 days [62]. In their analyses, the CR rate was 78.5% for MALT lymphoma patients (n = 1215), and 62% for DLBCL(MALT) patients (n = 52) [62]. In the report of therapeutic efficacies of first-line HPE in gastric DLBCL(MALT) patients by Kuo et al. [26], the CR rate was 56.3% (18/32) with a median interval to CR of 5.0 months; the CR rate was significantly associated with the tumor extent (mucosa/submucosa vs. beyond: 80% [8/10] vs. 29.4% [5/17], P = 0.018) [26].

It should be noted that if patients with gastric DLBCL(MALT) do not respond well to antibiotic treatment, the tumor may rapidly progress and cause potential morbidities in these patients. However, for *Hp*-independent gastric DLBCL(MALT) patients, subsequent systemic chemotherapy could result in CR and let patients remain disease-free during long-term follow-up [21–25, 63]; this implies that a delay in the administration of systemic chemotherapy to 6–8 weeks after HPE with antibiotics is unlikely to influence the response of these tumors to conventional immunochemotherapy. These findings may support the contention that

#### **Figure 2.**

*Changes of endoscopic features in an example of stage IE* Helicobacter pylori *(*Hp*)-dependent localized gastric diffuse large B-cell lymphoma (DLBCL) with mucosa-associated lymphoid tissue (MALT) (DLBCL[MALT]) before and after completion of Hp eradication therapy (HPE) (A) Endoscopy shows several ulcerative mass lesions with nodular and irregular margins at the antrum of a 74-year-old man before HPE (Histopathology disclosed DLBCL[MALT], DLBCL-predominant). (B) Computed tomography (CT) shows moderate wall thickening (white arrow) in the gastric antrum but no enlargement of perigastric lymph nodes in the same case A. (C) One month after the completion of HPE, endoscopy shows two partially regressed ulcerative masses at the gastric angle in the same case A (D) Four months after completion of HPE, complete remission was achieved in the same case A. Right bottom, CT shows no gastric wall thickening (white arrow).*  Hp*,* Helicobacter pylori*; HPE, Hp eradication therapy; DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue; CT, computed tomography; CR, complete remission.*



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

first-line HPE should be administered to additional populations of stage IIE1 gastric DLBCL(MALT) patients. This concept is further supported by a prospective clinical trial (T3206) designed by the TCOG in evaluating the treatment efficacy of first-line HPE consisting of omeprazole, amoxicillin, and clarithromycin for 14 days in patients with *Hp*-positive stage IE or stage IIE1 MALT lymphoma, and DLBCL(MALT) of the stomach [25]. This trial revealed that 8 (80%) of 10 patients with DLBCL(MALT) and 26 (76.5%) of 36 patients with MALT lymphoma achieved CR (**Figure 2**); the CR rate was not different between stage IE (75%) and stage IIE1 (66.7%) [25]. After a median follow-up of 59 months, all eight *Hp*-dependent DLBCL(MALT) patients remained lymphoma-free, whereas three (7.7%) of the 26 *Hp*-dependent MALT lymphoma patients relapsed after a median follow-up of 82 months [25]. Notably, tumor invasions to the perigastric lymph nodes are not exclusive to *Hp*-dependent cases, suggesting that pivotal mechanisms exist in these tumors; this is because lymphoma cells of the perigastric lymph nodes communicate indirectly with the *Hp* bacteria.

Taken together, these findings show that the tumor remission rates after 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 thus DLBCL(MALT) is unlikely to respond to HPE. These clinical discoveries are in line with previous molecular studies showing the difference in clonalities between MALT lymphoma components and DLBCL components of the same stomach [64–66]. Kuo et al. compared the patterns of *IgH* rearrangement between DLBCL and MALT lymphoma components of the same gastric DLBCL(MALT) patients receiving HPE, and revealed that different clonal origins of the two co-existing components contributed to the differential response to HPE [67]. In the long-term follow-up of gastric MALT lymphoma without remission, Liu et al. showed that the frequency of development of DLBCL from MALT lymphoma was less than 2%, suggesting rare high-grade transformation in gastric MALT lymphoma [68]. These results indicate that some DLBCL components may evolve independently from their co-existing MALT lymphoma counterparts in gastric DLBCL(MALT). Overall, with reference to clinical impact, first-line HPE resulting in a durable CR rate of approximately 60% has revolutionized the treatment of gastric DLBCL(MALT), and has helped 60% of DLBCL(MALT) patients to avoid the risks of systemic chemotherapy (**Table 1**). With reference to molecular impact, the high-grade transformation of gastric MALT lymphoma does not confer *Hp*-independence to the tumor cells (**Figure 1**); this finding will eventually lead to the revision of the current lymphoma classification, such as the Revised European American Lymphoma Classification (REAL)/WHO. In the REAL/WHO, high-grade gastric MALT lymphoma is classified as DLBCL with histological evidence of MALT (DLBCL[MALT]), and is recommended to be treated as common DLBCL [3, 5, 57].
