Mucosa associated lymphoid tissue (MALT) lymphoma of the stomach is associated with Helicobacter pylori infection in the large majority of patients.¹ The decisive role of H pylori in the development of gastric MALT lymphoma has resulted in attempts to treat gastric MALT lymphoma using antibiotic eradication of the bacteria. Following pioneering work published by Wotherspoon and colleagues,² a large number of studies have clearly shown the benefit of H pylori eradication as the standard treatment for patients with early stage H pylori associated gastric MALT lymphoma, resulting in response rates of 70–80%³ in selected patients. Based on current knowledge, patients treated solely with H pylori eradication have an excellent long term outcome, as evidenced by sustained complete remissions after eradication and a very low rate of relapse.⁴

In patients with H pylori associated gastric MALT lymphoma, risk factors predictive of lymphoma regression following antibiotic treatment have been published in recent years. The first investigation on this topic defined restriction of the lymphoma to the mucosa and submucosa as a positive predictive factor, as opposed to more advanced stages.⁵ In addition, the presence of an underlying autoimmune disease⁶ and probably monoclonal immunoglobulin production by lymphoma cells⁷ have been reported as adverse prognostic indicators.

The most extensively studied prognostic factor however is the presence of t(11;18)(q21;q21) in gastric MALT lymphoma. It occurs exclusively in MALT lymphoma and is found in 24% of patients with gastric MALT lymphoma.⁷ According to recent findings, it identifies patients whose lymphoma will not regress following antibiotic treatment.^8,9 In the largest series to date, Liu and colleagues⁹ investigated 111 patients and found t(11;18)(q21;q21) in 42/63 non-responders but in only 2/48 patients responding to antibiotic treatment.

In addition to the data published on t(11;18)(q21;q21), a small series by Taji et al has recently suggested that the presence of trisomy 3 may also predict non-response of the lymphoma to H pylori eradication.¹⁰ Also, nuclear expression of nuclear factor κB or BCL10 have been reported to be predictive of a H pylori independent status for gastric MALT lymphoma.¹¹

In 5–10% of patients with gastric MALT lymphoma, however, no evidence of H pylori infection can be demonstrated. As this cohort of patients is very rare, only limited clinical data have been published to date. A multicentre analysis to characterise MALT lymphoma in such patients has shown a higher rate of t(11;18)(q21;q21) than in patients with H pylori infection,¹² with 9/17 cases (53%) being positive. According to this study, H pylori eradication was performed in 5/17 cases, and none had responded to treatment. These patients, however, had either been positive for t(11;18)(q21;q21) or were followed for only a short time, suggesting that the conclusions from this series cannot be extrapolated to all patients with H pylori negative MALT lymphoma.

These facts, together with a report including three patients with H pylori negative MALT lymphomas arising in the rectum who responded to antibiotic treatment,¹³ have prompted us to treat six patients with early stage H pylori negative gastric MALT lymphoma with H pylori eradication.

PATIENTS AND METHODS

From December 2003, patients with localised gastric lymphoma who tested negative for H pylori were given antibiotic treatment. Eight cases of H pylori negative gastric MALT lymphoma were referred to our institution but two had advanced disease beyond the stomach and were given chemotherapy. Thus six consecutive patients (one female, five males) with histologically verified MALT lymphoma of the stomach were studied. Histological diagnosis of MALT lymphoma was performed according to the criteria outlined in the WHO classification,¹⁴ and histological assessment was performed by a reference haematopathologist (AC). Immunological phenotyping on paraffin sections was done for demonstration of light chain restriction and the phenotype CD20+CD5−CD10−cyclinD1− which, in the context of the microscopic appearance, is consistent with MALT lymphoma. None of the patients had evidence of H pylori infection, as judged by histology, urease breath test, serological testing, or stool antigen testing, and no evidence of Helicobacter heilmannii (HH) infection was present.

Staging consisted of endosonography, gastroscopy plus multiple biopsies, enteroclysma (computed tomography (CT)), enteroscopy, CT of the thorax and abdomen, magnetic resonance imaging of the lachrymal and salivary glands, colonoscopy with multiple biopsies, and a bone marrow biopsy. In all patients, routine assessment of MALT lymphoma associated genetic aberrations was performed on biopsy samples. The presence of t(11;18)(q21;q21) was evaluated by reverse transcriptase-polymerase chain reaction while t(14;18)(q32;q21) involving IGH/MALT1, t(1;14)(p22;q32), and trisomies 3 and 18 were assessed by FISH, as previously published.¹⁵

After obtaining informed consent, patients were given antibiotic treatment with clarithromycin 2×500 mg for seven days and metronidazole 2×500 mg for seven days, while pantoprazole was administered at a dose of 2×40 mg as continuous therapy during the observation period (that is, for a minimum of 12 months).

Patients were followed by regular endoscopies with histological assessment of biopsy samples every three months following antibiotic treatment for assessment of response, and CT of the thorax and abdomen was also performed every three months to rule out distant spread of the disease.

RESULTS

All six patients had MALT lymphoma without transformation to diffuse large B cell lymphoma, and staging showed restriction of the disease to the stomach (stage I) in all cases. In two patients, endosonography showed restriction of the lymphoma to the mucosa and submucosa while the remaining four cases had involvement of the whole gastric wall. Five patients were diagnosed with MALT lymphoma due to unspecific epigastric pain leading to gastroscopy, while in one patient anaemia due to chronic bleeding was the leading symptom. Ulcerated lesions were present in three patients. Testing for the presence of an underlying autoimmune disease was negative in all patients. In five patients, none of the genetic changes investigated was present, while one was positive for t(11;18)(q21;q21).

All patients underwent antibiotic treatment as scheduled. Regular endoscopic follow up showed response of the lymphoma in five of our patients, with four achieving complete remission (CR) between three and nine months after eradication, one patient developing partial remission (PR) after six months, while one patient had stable disease for 12 months before being referred for chemotherapy. In all patients, responses were verified by at least 2–4 additional endoscopies to rule out sampling bias. Interestingly, the patient with evidence of t(11;18)(q21;q21) developed a CR three months after eradication, which is ongoing after a follow up of 12 months. After a follow up of 12, 16, 18, 19, and 19 months, respectively, all six patients are alive, and four remain in CR. One patient relapsed in the stomach 14 months after initial CR.

DISCUSSION

These data suggest that patients with early stage gastric MALT lymphoma may still benefit from antibiotic treatment even in the absence of H pylori infection. In fact, four patients had a CR, one a PR, and one stable disease. The latter patient was referred for chemotherapy after 12 months of stable disease. In view of the interval of stable disease, however, one might speculate that a wait and see strategy for a longer time could have been applied as patients with H pylori positive gastric MALT lymphoma have been reported to achieve delayed remission following antibiotic therapy. Our data are in contrast with other series, and a definite explanation for our findings is lacking. Of interest is the fact that only one of the six patients was found to be positive for t(11;18)(q21;q21). This percentage is lower than expected compared with recent data reporting that approximately 50% of H pylori negative gastric MALT lymphomas are positive.¹² However, this patient also responded to treatment, with a CR of the lymphoma in spite of the fact that t(11;18)(q21;q21) has been demonstrated as the most significant prognostic factor for non-response.

To date, a definite explanation for our findings is still lacking but one might speculate that bacteria other than H pylori might be involved in the development of gastric MALT lymphoma. Based on current knowledge, however, only highly specialised bacteria such as H pylori or H heilmannii have been demonstrated to be able to survive in the gastric environment. Nevertheless, one cannot rule out the possibility that hitherto undetected bacterial agents capable of surviving in the stomach might play a role in the development of the rare H pylori negative gastric MALT lymphomas. If this assumption is indeed correct, one might expect response to broad spectrum antibiotic therapy, as evidenced in our patients. The rarity of H pylori negative gastric MALT lymphoma, however, would require a large scale effort to identify such bacteria. While Campylobacter jejuni has been implicated in the development of a special form of MALT lymphoma arising in the small intestine (IPSID),¹⁶ to date it has not been found in primary gastric MALT lymphomas. In addition, it is not endemic in the Austrian population, and none of the patients related episodes of severe diarrhoea or prolonged stays abroad in the last five years. That a primary gastric MALT lymphoma was indeed present in all of our patients was demonstrated by the stringent staging routine used (including enteroscopy to evaluate the small bowel), which failed to detect additional lymphoma foci outside the stomach. Therefore, the hypothesis of a non-gastric bacterial infection leading to development of gastric MALT lymphoma seems highly unlikely.

As MALT lymphoma is an immunologically driven disease to some extent, an additional hypothesis might focus on potential immunomodulatory effects of the antibiotic agents used. In fact, macrolides such as clarithromycin, which formed part of our triple therapy, have repeatedly been implicated as having immunomodulatory and anti-inflammatory properties,¹⁷ which might result in an as yet undiscovered effects against MALT lymphomas.

Our findings suggest that H pylori negative patients with stage I gastric MALT lymphoma should be given the chance of antibiotic therapy as initial treatment, provided that regular follow up is performed.