Extranodal Marginal Zone Lymphoma
By William B. Ershler, MD
The term marginal-zone lymphoma (MZL) refers to three distinct but closely related lymphoprolferative disorders: mucosa-associated lymphoid tissue (MALT) lymphoma (extranodal MZL), splenic MZL, and nodal MZL. Although all three are derived from a common cell of origin (marginal zone B cell), they are likely to display different clinical manifestations. The common cell of origin is derived from the periphery of the lymphoid B-follicle. A feature of this micro-anatomic location is the exposure to an influx of antigens (e.g., in the gastric mucosa, spleen, or lymph nodes) and there has been an increased understanding of the role of inflammation and infection in the pathogenesis of these disorders, most notably for gastric MALT, for which the association with Helicobacter pylori is now irrefutable.1-3
In fact, H. pylori eradication therapy leads to complete lymphoma regression in about 80% of cases with early-stage disease.4 However, the link between infection and MZL is less clear for non-gastric variants. Nonetheless, when extranodal MZL occurs at other sites (e.g., skin, lacrimal gland, ocular adnexa, small intestine) consideration of other chronic infections, such as Borrelia burgdorferi (skin),5 Chlamydophila psittaci (ocular),6 or Campylobacter jejuni (small intestine),7 should be pursued. There is also an association between MALT lymphoma and certain autoimmune disorders such as Sjogren syndrome and systemic lupus erythematosus.8 The strength of these associations is variable. Nonetheless, a common thread in the pathogenesis of extranodal MZL is chronic antigenic stimulation and inflammation. Laboratory investigations have revealed a central role for aberrant NFkB activation in the pathogenesis of MALT lymphoma in certain cases.9
Although a number of chromosomal abnormalities have been associated with MALT lymphoma, the most common is t(11;18)(q21;q21),10 which occurs in up to 50% of patients with gastric MALT lymphoma, less frequently in pulmonary MALT lymphoma, but only rarely in other extranodal MZL.11 Among those with gastric MALT lymphoma, the presence or absence of t(11;18)(q21;q21) does not relate to morphology or immunophenotype. However, there has been some suggestion that those who are t(11;18)(q21;q21)+ are more resistant to complete regression after H. pylori eradication.12
Additional cytogenetic changes have been described for extranodal, splenic, and nodal MZL, and these include trisomies 3 and 18, occurring in anywhere from 15% to 60% of cases. Other cytogenetic findings have been quite heterogeneous and there are no unique abnormalities currently documented.
Patients with gastric MALT lymphoma most commonly present with non-specific gastrointestinal complaints, and upper endoscopy often reveals gastritis or ulcer or less commonly a gastric mass. The diagnosis hinges on gastric biopsy and the demonstration by histochemistry of H. pylori. The fluorescence in situ hybridization demonstration of t(11;18)(q21;q21) may be useful for identifying those who might not respond to antibiotic therapy alone. For most patients, H. pylori eradication results in complete regression of the MALT lymphoma and most of these regressions are durable. Standard anti-helicobacter treatment, including proton pump inhibitor plus antibiotics (e.g., clarithromycin plus amoxicillin or tetracycline, metrinidizole with bismuth subcitrate) is sufficient. However, close follow-up is recommended with repeat endoscopy and biopsies at 2 or 3 months. For some with minimal residual disease (if H. pylori is confirmed to be eradicated), observation alone is reasonable as long as patients can be followed closely. The long-term risk for transformation to more malignant lymphoma is less common for gastric MALT lymphoma than for other indolent histologies.13
For patients with persistent disease after H. pylori treatment, excellent disease control (for those with Stage I or II disease) has been achieved by radiation therapy, particularly with modern treatment plans that include three-dimensional conformal and intensity-modulated radiotherapy. For those with systemic disease, immunotherapy with rituximab with or without chemotherapy has been effective.
For patients with non-gastric MZL, particularly for those in whom chronic infection is not defined, treatment recommendations follow those established for indolent B-cell lymphoma. Radiation therapy is recommended for those with localized disease. However, systemic therapy with rituximab with or without chemotherapy should be considered for those with more widespread involvement. Clinical trials have demonstrated that response rates as high as 70% can be achieved with rituximab alone.14
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5. Roggero E, et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Human Pathol 2000;31:263-268.
6. Ferreri AJ, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004;96:586-594.
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8. Ekstrom Smedby K, et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: A pooled analysis within the InterLymph Consortium. Blood 2008;111:4029-4038.
9. Ho L, et al. MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 2005;105:2891-2899.
10. Sagaert X, et al. MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells. Modern Pathol 2006;19:225-232.
11. Streubel B, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004;18:1722-1726.
12. Liu H, et al. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 2001;357:39-40.
13. Stathis A, et al. Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann Oncol 2009;20:1086-1093.
14. Conconi A, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003;102:2741-2745.
Financial Disclosure: Clinical Oncology Alert's Editor, William Ershler, MD, and peer reviewer, V.R. Veerapalli, MD, report no financial relationships to this field of study.