Clinical and Molecular Follow-Up
A number of molecular follow-up studies have shown that post-antibiotic histological and endoscopic remission does not necessarily translate to a cure. Long-term persistence of monoclonal B cells after histological regression of the lymphoma has been reported in about half of cases, suggesting that H pylori eradication suppresses but does not eradicate the lymphoma clones. Transient histological and molecular relapses have been reported during long-term follow-up of antibiotic-treated patients; however, without the stimulus from H pylori such a relapse usually remains a self-limiting event and does not imply frank clinical progression. The clinical relevance of the detection of monoclonal B cells by molecular methods remains unclear. In the long-term follow-up of some cases with minimal residual disease, neither clinical growth of the lymphoma nor histological transformation was documented despite persistent clonality, suggesting that a watch-and-wait policy could be feasible and safe, at least for patients who are amenable to frequent endoscopies and who do not necessarily require additional treatment.[59,61,62,79,80]
Several cases of synchronous or metachronous gastric adenocarcinomas in patients with gastric MALT lymphomas have been documented. Indeed, a tumor-registry study has shown an increased risk (six times higher) for gastric adenocarcinoma in patients with gastric MALT lymphomas compared with the general population. This supports a policy of strict follow-up even in patients with lymphoma regression after H pylori eradication. Histological evaluation of repeated biopsies is the basic follow-up procedure.
Management of Gastric H pylori–Negative or Antibiotic-Resistant Cases and of Non-Gastric Localizations
No definite guidelines exist for the management of H pylori–negative or antibiotic-resistant cases or for patients with non-gastric lymphoma. In retrospective series, no significant difference in survival was apparent between patients who received different initial treatments (including chemotherapy alone, surgery alone, surgery with additional chemotherapy or radiation therapy, or antibiotics against H pylori).[52,54,57,82]
A modest dose of involved-field radiotherapy (25 to 35 Gy) gives excellent disease control; this may be the treatment of choice for patients with stage I–II MALT lymphoma of the stomach without evidence of H pylori infection, or for those with persistent lymphoma after antibiotics, as well as for most non-gastric localized presentations. Effective radiotherapy is frequently possible for both common and rare presentations of the disease. Side effects of radiotherapy are mild and reversible. For patients with localized non-gastric MALT lymphoma, given its unique biologic behavior (a tendency to relapse in MALT tissues and an indolent course), radiotherapy is often the first-line treatment of choice. The emerging literature on localized MALT lymphomas confirms a high rate of local control, with a high proportion of patients likely to be cured of the disease. The moderate doses of radiation required for cure are generally associated with a low risk of long-term toxicity, although special considerations are needed for particular sites of localization, such as the eye or the lung.[55,56,83,84] In spite of the excellent results of radiotherapy, there is no clear consensus as to whether radiation or systemic therapy is more effective in MALT lymphomas at different locations; thus, the choice is often based on the experience of the treating center and the patient’s preferences with respect to adverse effects.
Radiotherapy can also be an effective therapy that can provide local disease control for some patients with stage III or IV disease; however, its use for the optimal management of disseminated MALT lymphomas is less clearly defined.
Because no curative treatment exists, expectant observation can be an adequate initial policy in most patients. In general, the treatment should be ‘‘patient-tailored,’’ taking into account the site and the stage of the disease, and the clinical characteristics of the individual patient. When systemic treatment is needed, enrollment in controlled clinical trials is advisable. Indeed, in the presence of disseminated or advanced disease, chemotherapy (and/or immunotherapy with anti-CD20 monoclonal antibodies) is an obvious choice, but only a few compounds and regimens have been tested specifically in MALT lymphomas.
Oral alkylating agents (either cyclophosphamide(Drug information on cyclophosphamide) or chlorambucil(Drug information on chlorambucil), with median treatment duration of 1 year) can result in a high rate of disease control. Phase II studies have demonstrated some anti-tumor activity for the purine analogs fludarabine (Fludara) and cladribine(Drug information on cladribine), although these may be associated with an increased risk of a secondary myelodysplastic syndrome. A polychemotherapy regimen (chlorambucil/mitoxantrone/prednisone) has also shown anti-tumor activity. Aggressive anthracycline-containing chemotherapy should be reserved for patients with high tumor burden (bulky masses, unfavorable international prognostic index). The activity of the anti-CD20 monoclonal antibody rituximab(Drug information on rituximab) (Rituxan) has also been demonstrated in a phase II study (with a response rate of about 70%), and this may represent an additional option for the treatment of systemic disease. The efficacy of the combination of rituximab with chlorambucil has been explored in a randomized study by the IELSG in gastric MALT lymphomas that had failed antibiotics and in non-gastric MALT lymphomas (IELSG19, NCT00210353). In a preliminary report of this trial, at a median follow-up time of 62 months, the 5-year event-free survival was significantly better for the patients treated with chlorambucil plus rituximab (68% vs 50%), who also achieved a higher complete remission rate than did those treated with chlorambucil alone (78% vs 65%, P = .025); however, 5-year overall survival was identical (88%) in both groups.
Antibiotic Treatment in Localized Non-Gastric MALT Lymphomas
In principle, antibiotic treatment in non-gastric lymphomas should be regarded as investigational. The finding that C psittaci (the etiologic agent of psittacosis) has a potential pathogenic role in the development of MALT lymphoma of the ocular adnexa and has been detected in about 80% of Italian patients may provide the rationale for antibiotic treatment of localized lesions. However, the treatment of ocular adnexal MALT lymphoma remains a controversial issue.
The prevalence of C psittaci infection in ocular adnexal lymphoma varies among countries and among different regions within the same country, being higher in Italy, Austria, Korea, and Germany, and virtually absent in Japan, France, and China. With respect to the United States, one study reported the presence of C psittaci in 6 of 17 cases (35%) from various East Coast regions, but the micro-organism was not detected in any of 112 cases included in four other North American series (incorporating patients from Miami, Chicago, Rochester, NY, and Cleveland).[89,90] Following the initial demonstration that doxycycline(Drug information on doxycycline) treatment may cause tumor regression in patients with C psittaci –associated lesions, subsequent reports on the efficacy of antibiotic therapy in ocular adnexa lymphoma produced conflicting data and apparent geographic variations. A prospective phase II study was then launched by the IELSG (IELSG 27, NCT01010295), and this has recently provided preliminary but encouraging results, showing lymphoma regression in more than 60% of patients after front-line treatment with doxycycline. Of interest, lymphoma regression after doxycycline treatment has been observed in some lymphomas with no evidence of C psittaci as well as in cases in which this treatment failed to eradicate the C psittaci infection. These results contrast with results in the better studied gastric MALT lymphoma (where H pylori–negative patients are generally unresponsive to the antibiotic treatment) and might suggest that other doxycycline-sensitive microorganisms are linked with the lymphoma. Therefore, further investigations are warranted to identify other potential infective agents and to improve antibiotic efficacy.
Extraordinary progress has been made in the past two decades in understanding the etiology and the critical cellular and molecular pathological events in MALT lymphomas—as well as in identifying easily treatable causative bacterial agents. H pylori–associated gastric MALT lymphoma has become a model of antigen-driven lymphomagenesis and is currently treated with antibiotics aimed at eradicating H pylori. However, no consensus has yet been reached regarding the initial management of non-gastric tumors. Modern radiotherapy techniques have been shown to be effective in eradicating MALT lymphoma in sites that are unlikely to respond, or that have failed to respond, to antibiotics, allowing organ preservation and the forgoing of surgery. Moreover, the availability of effective chemotherapy agents and anti-CD20 monoclonal antibodies has expanded our treatment options in these settings. In the absence of randomized trials, either immunochemotherapy or radiotherapy is currently used. The establishment of national and international groups has advanced our clinical understanding; however, there is a continued need for such groups in order to better define our treatment strategy and expand our therapeutic options in the years to come.
Financial Disclosure: The authors have no conflicts of interest that are relevant to the subject matter under consideration in this article. In particular, they have no significant financial interests to be disclosed or other relationships with the manufacturers of any products or providers of any service mentioned in the article.