AIM: To investigate treatment outcome of Helicobacter pylori (H. pylori)-negative low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

METHODS: In this study, we retrospectively reviewed the clinical outcome and clinicopathologic factors of stage IE H. pylori-negative low-grade gastric MALT lymphoma cases from August 1998 to June 2009.

RESULTS: A total of eleven patients with H. pylori-negative low-grade gastric MALT lymphoma were enrolled in the study and received anti-H. pylori eradication treatment and/or radiotherapy or excisional therapy. Complete remission (CR) of gastric MALT lymphoma was achieved in all patients. The time to CR was 1-66 mo (median, 1 mo).

CONCLUSION: Eradication therapy may be offered as an initial treatment option even in cases of localized H. pylori-negative gastric MALT lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma, first described in 1983 by Isaacson and Wright[1], has been recently re-classified as extranodal marginal zone lymphoma of MALT-type, in the Revised European-American Classification of Lymphoid Neoplasms (REAL)/World Health Organization (WHO) Classification of Lymphoid Neoplasms. An important feature of MALT lymphoma is the presence of lymphoepithelial lesions formed by the invasion of individual glands by aggregates of lymphoma cells[2].

In previous studies, Helicobacter pylori (H. pylori) infection was suggested to be causally associated with primary gastric MALT lymphoma[3,4]. Indeed, H. pylori provides the antigenic stimulus, which is mediated by mucosal T cells, for sustaining the growth of gastric MALT lymphoma[5]. The regression of gastric MALT lymphoma after the eradication of H. pylori was first reported in 1993 by Wotherspoon et al[3]. H. pylori eradication led to complete remission in 80% of stage IE, low-grade gastric MALT lymphoma patients, with a yearly recurrence rate of approximately 5%[6]. Currently, eradication of H. pylori is considered the accepted initial therapy in cases of localized, stage IE low-grade gastric MALT lymphoma[7].

However, there are no treatment guidelines for the management of patients who are unresponsive to antibiotic treatment or for the subset of patients who present with stage IE low-grade gastric MALT lymphoma but are H. pylori-negative and understandably do not respond to antibiotic treatment[8]. In these cases, treatment choices include the known, conventional therapeutic approaches such as surgery, chemotherapy or radiotherapy[9]. Because of the ambiguity of treatment in H. pylori-negative patients, further studies are required to clarify a treatment strategy for H. pylori-negative MALT lymphoma. In this study, we evaluated the treatment outcome of eleven H. pylori-negative low-grade gastric MALT lymphoma patients to offer therapeutic guidelines for treating H. pylori-negative low-grade gastric MALT lymphoma.

The prevalence of H. pylori in patients with low-grade gastric MALT lymphoma is variable[10]. It is possible that a reduced number of H. pylori organisms present in the infection may account for the negative H. pylori diagnostic test result in some cases, and false-negative results may also be obtained when only one diagnostic method is employed[11]. The European Guidelines generally take the gold standard to be represented by at least two tests[12]. When appropriate diagnostic methods are used, the prevalence of H. pylori infection in low-grade MALT lymphoma is high, at nearly 90%[10]. In our study, four diagnostic tests were performed and showed that true H. pylori-negative patients were included. However, additional tests, such as culture with polymerase chain reaction, would allow the detection and identification of other infective organism[13].

Due to the excellent clinical outcome of H. pylori eradication treatment, the eradication of H. pylori with antibiotics should be employed as the sole initial treatment in the localized form (confined to the stomach) of gastric MALT lymphoma[14]. However, in advanced stages with H. pylori-positive gastric MALT lymphoma and in H. pylori-negative lymphoma, definitive treatment guidelines are not yet available despite the numerous published clinical research papers[8,14,15].

Antibiotic treatment for H. pylori-negative gastric MALT lymphoma has been described in a limited number of patients. We collectively reviewed a series of four published studies including patients treated solely with the anti-H. pylori antibiotic regimen as the initial treatment for H. pylori-negative stage IE gastric MALT lymphoma (Table 3). A total of 31 patients were included in these studies, and ten patients (32%) were shown to respond to this treatment alone. Raderer et al[16] reported that five of six patients with H. pylori-negative gastric MALT lymphoma responded to antibiotic treatment (one partial remission and four complete remissions). However, Steinbach et al[17] and Ye et al[18] experienced a 0% response rate. In other words, marked variation in treatment response rate was noted. Nevertheless, instituting anti-H. pylori treatment showed satisfactory clinical outcomes and allowed for gastric preservation in a significant number of cases with H. pylori-negative gastric MALT lymphoma. Although seemingly contradictory, anti-H. pylori treatment may be advised as the first-line therapy in H. pylori-negative localized gastric MALT lymphoma. Unfortunately, the effectiveness of anti-H. pylori treatment could not be confirmed in this study, as only four out of the six patients who received the anti-H. pylori eradication regimen waited long enough to receive the follow-up endoscopic examination which was used to confirm the complete remission status of MALT lymphoma. The other two patients proceeded to radiation therapy due to various clinical and psychosocial issues. In addition, previous studies also included patients with advanced stages of disease, including IIE₁ (Table 3). However, it was not possible from the available data to categorize lymphoma regression according to tumor stage (IE vs IIE₁). Therefore, additional studies are needed to define the role of anti-H. pylori eradication therapy in advanced stages of gastric MALT lymphoma such as stages IIE, IIIE or IV.

There is still no explanation for the effectiveness of anti-H. pylori treatment in H. pylori-negative gastric MALT lymphoma[16]. However, it has been speculated that another infective organism, Helicobacter heilmannii[19], might be involved in the development of gastric MALT lymphoma. Also, one cannot rule out the possibility that unknown bacterial agents capable of surviving in the stomach might play a role in the development of rare H. pylori-negative gastric MALT lymphomas[16]. Another possibility is that low bacterial counts[20] and urease-negative H. pylori mutant strains may escape detection by the diagnostic tests that are currently available. If this assumption is correct, one might expect the noted H. pylori-negative gastric MALT lymphoma patient response to broad-spectrum antibiotic therapy. Also, MALT lymphoma is to some extent an immunologically driven disease, therefore an additional hypothesis may involve the potential immunomodulatory effects of the antibiotic agents used[16].

Disease control using radiotherapy alone has been previously reported in the literature, which supports the use of a modest dose of involved-field radiotherapy for patients with stages IE-IIE MALT lymphoma of the stomach without evidence of H. pylori infection[14]. Table 4 summarizes these previously reported cases. Including our cases, 35 of 35 cases responded to radiotherapy. One of the 35 patients reported by Akamatsu et al[21] had a partial remission, while the others all had a complete remission. Based on these results, it is prudent to say that radiotherapy is suitable in early stage (IE or IIE) H. pylori-negative gastric MALT lymphoma. In addition, excisional treatments such as endoscopic mucosal resection or laparoscopic gastric resection may represent another therapeutic option in the case of localized forms of gastric MALT lymphoma in individuals who are not suitable for, or who refuse, standard therapeutic approaches[15,20,22]. In the past, surgical treatment has often been advocated to establish accurate diagnosis, staging, and management of early-stage gastric lymphoma, which has about a 90% 5-year survival rate, but leads to significant morbidity[22]. In our study, two patients received endoscopic mucosal resection and subtotal gastrectomy, respectively. There has been no local or distant recurrence during the follow-up period of 54 to 69 mo.

In our series, therapeutic measures such as anti-H. pylori eradication, radiotherapy and excisional therapy achieved complete remission in all cases. Nevertheless, antibiotic treatment is simple, inexpensive, less harmful and H. pylori negative low grade MALT lymphoma shows a favorable long-term outcome[22]. Therefore we suggest that H. pylori eradication therapy may be an initial treatment option for localized H. pylori-negative gastric MALT lymphoma. In addition, further studies on eradication therapy are required to help in the establishment of strategies for patients with localized H. pylori-negative gastric MALT lymphoma.