Helicobacter pylori and MALT lymphoma

Gastric MALT lymphoma offers a paradigm of infection-associated malignant disease. Moreover, successful treatment of localized MALT lymphoma patients with antibiotics alone represented a novel observation in oncology. In recent years, progress has been made in understanding the molecular basis of MALT lymphoma. H pylori infection through its diverse virulence factors triggers inflammatory responses by attracting and activating neutrophils, which release ROS. The organism also modulates immunologic responses that not only perpetuate the infection, but also stimulate the growth of malignant B cells. The oxygen radicals and other inflammatory products may cause a wide range of genetic damage, and therefore might have a role in the acquisition of genetic abnormalities in gastric MALT lymphoma. A direct correlation between the level of ROS and the level of DNA damage to the gastric mucosa has been reported, creating a link between H pylori and gastric carcinoma. The severity of DNA damage occurring in an infected individual will depend on a number of factors, including the strain and virulence of H pylori, the severity of the inflammatory response, and the individual's ability to detoxify ROS. Initially, B-cell proliferation at these sites seems to occur in an antigen-dependent manner, and additional events are required for progression to antigen-independent growth and tumor formation. Early stage gastric MALT lymphomas can be cured in about two thirds of cases by antibiotic eradication of H pylori, whereas specific genetic alterations have been detected in those that resist H pylori therapy and that are likely to have more advanced or more aggressive forms of disease. In approximately 5%-10% of gastric lymphomas there is no evidence of H pylori infection, and the pathogenesis in these cases is understood poorly. Four disparate chromosomal translocations are associated with extranodal MALT lymphoma, including t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14;q32). They most frequently affect the MALT1 gene, including both the t(11;18)(q21;q21) and t(14;18)(q32;q21), and interestingly are mutually exclusive cytogenetic events. Either 1 of these 2 translocations is present in 40%-50% of MALT lymphomas. Both have been reported in the stomach, although the t(11;18)(q21;q21) is present in 30% of cases and only a single case of gastric t(14;18)(q32;q21) has been described. The t(1;14)(p22;q32) is very rare and the t(3;14)(p14;q32) only recently was described in a small series of thyroid, skin, and orbital MALT lymphomas. However, 3 of the translocations appear to involve a common pathogenetic mechanism, leading to constitutive activation of NF-κB signaling, whereas the mechanisms underlying the new translocation involving FOXP1 is unknown. Finally, murine models using infection with several gastric Helicobacter species provided a unique experimental system to study the progression of the disease from early immune responses to fully developed malignant MALT lymphomas. These systems nicely show that Helicobacter-induced lymphoma develops through a series of molecularly distinct stages. Analysis of these stages using gene expression profiling has begun to shed light on the mechanisms involved and this approach should prove very useful in future studies. © 2005 by the American Gastroenterological Association.