Mucosa-associated lymphoid tissue (MALT) lymphomas represent ∼7% of all non-Hodgkin's lymphomas and can arise at any extranodal site; however, at least one-third of them present as a primary gastric lymphoma.
The most common presenting symptoms of gastric MALT lymphoma are non-specific upper gastrointestinal complaints that often lead to an endoscopy usually revealing non-specific gastritis or peptic ulcer with mass lesions being unusual.
Diagnosis is based on the histopathologic evaluation of the gastric biopsies [III, A]. If the presence of active Helicobacter pylori infection is not demonstrated by histochemistry, it must be ruled out by urea breath test and/or faecal antigen test.
In addition to routine histology and immunohistochemistry, FISH analysis (or PCR) for detection of t(11;18) may be useful for identifying patients that are unlikely to respond to antibiotic therapy [III, B].
staging and risk assessment
The initial staging procedures should include a gastroduodenal endoscopy with multiple biopsies taken from each region of the stomach, duodenum, gastro-esophageal junction and from any abnormal-appearing site. Endoscopic ultrasound is recommended to evaluate the regional lymph nodes and gastric wall infiltration [III, A]. Work-up studies should include complete blood counts, basic biochemical studies, including lactate dehydrogenase (LDH) and β2-microglobulin, CT of the chest, abdomen and pelvis, and a bone marrow aspirate and biopsy [IV, C]. The value of positron emission tomography (PET) scan is controversial and has little clinical utility [IV, D].
Eradication of H. pylori with antibiotics should be employed as the sole initial treatment of localized (i.e. confined to the stomach) H. pylori-positive gastric MALT lymphoma [II, A]. Any of the highly effective anti-helicobacter antibiotic regimens proposed can be used. In case of unsuccessful H. pylori eradication, a second-line therapy should be attempted with alternative triple- or quadruple-therapy regimens of proton-pump inhibitor plus antibiotics. Helicobacter pylori eradication can induce lymphoma regression and long-term clinical disease control in most patients. The length of time necessary to obtain a remission can span from very few months to >12 months. It is reasonable to attend for at least 12 months before starting another treatment in patients who achieve a clinical and endoscopic remission together with eradication of H. pylori, albeit having persistent (residual) lymphoma at the histological level [III, B]. Several studies of post-antibiotic molecular follow-up have shown the persistence of monoclonal B cells after histological regression of the lymphoma. In these cases, watchful waiting is recommended, while active anticancer treatment (see below) should be reserved for persistently symptomatic or progressive disease.
In H. pylori-negative cases or patients who fail antibiotic therapy, irradiation and systemic therapies should be applied depending on the stage of disease; surgery has been not shown to achieve superior results in comparison with more conservative approaches in various trials.
Excellent disease control using radiation therapy alone has been reported by several institutions supporting the use of modest-dose involved-field radiotherapy (30–40 Gy radiation to the stomach and perigastric nodes given in 4 weeks) for patients with stage I–II MALT lymphoma of the stomach without evidence of H. pylori infection or persistent lymphoma after antibiotic eradication [III, B].
Patients with systemic disease should be considered for systemic chemotherapy [III] and/or immunotherapy with anti-CD20 monoclonal antibodies [III]. Only a few compounds and regimens have been tested specifically in MALT lymphomas. Oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogues (fludarabine, cladribine) can result in a high rate of disease control. The activity of the anti-CD20 monoclonal antibody rituximab has also been shown in phase II studies and its efficacy in combination with chlorambucil is being investigated in a randomized study. There is no clear evidence in the published literature to recommend any specific drug or regimen; it should, however, be mentioned that treatment with purine analogues might be associated with an increased risk of secondary myelodisplasia. Aggressive anthracycline-containing regimens are not usually necessary and should be reserved for the few patients with high tumour burden.
Lymphoma with diffuse large cell infiltration should be treated according to the recommendations for diffuse large cell lymphoma.
response evaluation and follow-up
Histological evaluation of repeat biopsies remains an essential follow-up procedure. Unfortunately, the interpretation of lymphoid infiltrate in post-treatment gastric biopsies can be very difficult and there are no uniform criteria for the definition of histological remission. A preliminary breath test or stool antigen test should be performed at least 4 weeks after the antibiotic treatment to document H. pylori eradication. Then, a strict endoscopic follow-up is recommended, with multiple biopsies taken 2–3 months after treatment, and subsequently, at least twice per year for 2 years, to monitor the histological regression of the lymphoma. Gastric MALT lymphomas have limited tendency to distant spreading and to histological transformation. Transient histological local relapses are possible but tend to be self-limiting especially in the absence of H. pylori reinfection. In the case of persistent but stable residual disease or histological relapse (without distant dissemination and/or gross endoscopic tumour) a watch-and-wait policy appears to be safe [IV, C]. Nevertheless, long-term careful endoscopic and systemic (blood counts and minimal adequate radiological or ultrasound examinations) follow-up once per year is recommended for all patients. Indeed, the risk of gastric adenocarcinoma among patients diagnosed with gastric MALT lymphoma has been reported to be sixfold higher than in the general population.
Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading are considered justified standard clinical practice by the expert authors and the ESMO faculty.