Treatment Of Malt Lymphoma

H. pylori eradication in gastric MALT lymphoma

The regression of gastric MALT lymphoma after antibiotic eradication of H. pylori was first reported in 1993 by Wotherspoon and colleagues, who described the efficacy of antibiotic therapy in six patients with superficially invasive gastric MALT lymphoma.55 Several groups thereafter confirmed the efficacy of antibiotics in inducing apparently durable lymphoma remissions in 60-100% of patients with localized H. Pylori-positive gastric MALT lymphoma.42'49'50'52'56-58 The histologic remission can usually be documented within 6 months from the H. pylori eradication but sometimes the period required is more prolonged and the therapeutic response may be delayed up to more than 1 year.41

It is now generally accepted that eradication of H. pylori with antibiotics should be employed as the sole initial treatment of localized (i.e., confined to the gastric wall) MALT lymphoma. Actually, this is at present the best studied therapeutic approach with more than 20 reported studies.59 60 Any of the highly effective antibiotic regimens proposed61,62 can be used. Several effective anti-H. pylori programs are available and any of them can be used.61-63 It is expected that following 10-14 days of antibiotic treatment, H. pylori will be eradicated in 85-90% of the patients.63 Our regimen of choice is a 10-day triple therapy with a proton-pump inhibitor (e.g., omeprazole 20 mg b.i.d., pantoprazole 40 mg once daily, esomeprazole 40 mg once daily, or others), amoxicillin (1 g b.i.d.), and clarithromycin (500 mg b.i.d.). Metronidazole (500 mg b.i.d.) can replace amoxicillin in penicillin-allergic individuals, but metronidazole resistance is common and can reduce the treatment efficacy. After treatment, strict endoscopic follow-up is recommended, with multiple biopsies taken at 2-3 months to document H. pylori eradication and, subsequently, at least twice per year for 2 years to monitor the histologic regression of the lymphoma. In cases of unsuccessful H. pylori eradication, a second-line anti-Helicobacter therapy should be attempted with alternative triple- or quadruple-therapy regimens of proton-pump inhibitors plus antibiotics. However, it is still unknown whether H. pylori eradication will definitely cure the lymphoma; therefore, long-term follow-up of antibiotic-treated patients is mandatory. Some cases of documented tumor recurrence following H. pylori reinfection have been reported, suggesting that residual dormant tumor cells can be present despite clinical and histo-logic remission. Relapses have also been documented without H. pylori reinfection, indicating the emergence of B-cell lymphoma clones that are no longer antigen dependent.56'58

Several studies of postantibiotic molecular follow-up demonstrated a long-term persistence of monoclonal B cells after histologic regression of the lymphoma in about half of the cases, suggesting that H. pylori eradication does not eradicate the lymphoma clone.5864 Therefore, histologic evaluation of post-treatment gastric biopsies remains to be a fundamental follow-up procedure. Unfortunately, the interpretation of residual lymphoid infiltrate can be very difficult, and there are no uniform criteria for the definition of histologic remission. Wotherspoon in 1993 proposed a simple score to express the degree of confidence in the diagnosis of MALT lymphoma on small gastric biopsies.55 This scoring system has been used to evaluate the response to therapy in some trials, but many investigators found it difficult to apply in this setting and other criteria have been proposed.56 The lack of standardized and reproducible criteria can affect the comparison of the results from different clinical trials. A novel histologic grading system has been proposed by Copie-Bergman and colleagues.65 This system classifies the histologic features in posttreatment gastric biopsies as "complete histologic remission," "probable minimal residual disease," "responding residual disease," and "no change." It may become a useful tool but its reproducibility still needs to be confirmed on larger series.

The efficacy of antibiotic therapy is reduced in locally advanced disease, and as mentioned before, endoscopic ultrasound can be useful to predict the lymphoma response to H. pylori eradication. The response rate is 70-90% for the mucosa-confined lymphomas, but then decreases markedly and progressively for the tumors infiltrating the submucosa, the muscularis propria, and the serosa. In cases with documented nodal involvement, a response is unlikely.50 52 The t(11;18) translocation is absent in gastric MALT lymphomas showing complete regression,66 but present in 77% of nonresponsive tumors, including 68% of those with the disease confined to the gastric wall.67 Therefore, this translocation can be a valuable molecular marker to predict the therapeutic response of gastric MALT lymphoma to H. pylori eradication30 67 68 and in addition to routine histology and immunohistochemistry, fluorescence in situ hybridization analysis for detection of t(11;18) may be useful for identifying disease that is unlikely to respond to antibiotic therapy.

Management of H. Pylori-negative or antibiotic-resistant patients

No definite guidelines exist for the management of the subset of H. pylori-negative cases or for the patients who fail antibiotic therapy. A choice can be made among conventional oncologic modalities but there are no published randomized studies to help with the decision. In two retrospective series of patients with gastric low-grade MALT lymphoma, no statistically significant difference was apparent in survival between patients who received different initial treatments, including antibiotics against H. pylori, chemotherapy, surgery with or without additional chemotherapy, or radiation therapy.4269

Excellent disease control using radiation therapy alone has been reported by several institutions supporting the approach that modest-dose involved-field radiotherapy (30 Gy given in 4 weeks radiation to the stomach and perigastric nodes) is the treatment of choice for patients with stage I—II MALT lymphoma of the stomach without evidence of H. pylori infection or with persistent lymphoma after antibiotics.70 71 Surgery has been widely and successfully used in the past, but the precise role for surgical resection should now be redefined in view of the promising results of a more conservative approach.41

Patients with systemic disease should be considered for systemic chemotherapy and/or immunotherapy with anti-CD-20 monoclonal antibodies. Only a few compounds and regimens have been tested specifically in MALT lymphomas. Oral alkylating agents (either cyclophosphamide or chlorambucil, with median treatment duration of 1 year) can result in a high rate of disease control.72 73 More recent phase II studies demonstrated some antitumor activity of the purine analogs fludarabine74 and cladribine (2-CdA),75 possibly associated with an increased risk of secondary myelodysplastic syndrome,76 and of a combination regimen of chlorambucil/mitoxantrone/pred-nisone.77 The activity of the anti-CD20 monoclonal antibody rituximab has also been shown in a phase II study to have a response rate of about 70%,78 and it may represent an additional option for the treatment of systemic disease. Rituximab is active in gastric MALT lymphomas resistant or refractory to antibiotics, or not associated with H. pylori infection. Different from the setting of antibiotic therapy, the t(11;18)(q21;q21) translocation seems not to be a predictive marker of response to rituximab.79

Management of non-gastric localizations

The stomach is the most common and best studied site of involvement, but MALT lymphomas have also been described in various non-GI sites, such as salivary gland, thyroid, skin, conjunctiva, orbit, larynx, lung, breast, kidney, liver, prostate, and even in the intracranial dura.53 5480 One-fourth of non-GI MALT lymphomas have been reported to present with involvement of multiple mucosal sites or nonmucosal sites such as bone marrow.53 54 Nevertheless, despite presenting so often with stage IV disease, they usually have a quite indolent course regardless of treatment type (5-year survival of 90%). The rate of histologic transformation seems much lower than that in follicular lymphomas. Patients at high risk according to the IPI, and those with lymph node involvement at presentation, but not those with involvement of multiple MALT sites, have a worse outcome. Localization may have prognostic relevance. In a radiotherapy study from Toronto,70 gastric and thyroid MALT lymphomas had better outcome, whereas distant failures were common for other sites, however, despite relapse, the disease most often maintained an indolent course.

In a multicentric retrospective survey of 180 non-gastric cases observed over a long period of time, patients were treated according to the current policy of each institution at the time of diagnosis, and the presence of organ-specific problems presumably had a role in the choice of treatment. This study showed no evidence of a clear advantage for any type of therapy.53

In general, the considerations regarding the treatment of H. pylori-negative cases can be applied. Radiation therapy is the best studied approach81 and is the treatment of choice for localized lesions. The optimal management of disseminated MALT lymphomas is less clearly defined. The treatment choice should be "patient tailored," taking into account the site, the stage, and the clinical characteristics of the individual patient. The anti-CD20 antibody rituximab has shown clinical activity,78 and the efficacy of its combination with chemotherapy is being explored in a randomized study of the International Extranodal Study Group. The finding that C. psittaci is associated with MALT lymphoma of the ocular adnexa may provide the rationale for the antibiotic treatment of localized lesions and preliminary encouraging results have been reported, but this approach remains investigational and will need to be confirmed by larger clinical studies.

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