Another Piece of the MALT Lymphomas Jigsaw
Authors: Emanuele Zucca, Francesco Bertoni
Journal: Journal of Clinical Oncology (2005)

In this issue, Ferreri et al add to the fascinating story of mucosa-associated lymphoid tissue (MALT) lymphomas, whose growth is stimulated by chronic inflammatory processes, showing that Chlamydia psittaci– eradicating antibiotic therapy can be followed by histologic regression of marginal-zone lymphomas of ocular adnexa. MALT lymphoma was first described in 1983 by Isaacson and Wright, who recognized a striking histologic similarity between cases of immunoproliferative small intestinal disease (IPSID) and gastric low-grade lymphoma. The histologic features were close to those of the Peyer’s patches, and it soon became evident that similar cases can be found at other mucosal sites, and the term mucosa-associated lymphoid tissue was proposed. Later, it was demonstrated that the B cells of MALT lymphoma share the cytologic features and immunophenotype of marginal-zone B-cell lymphomas; therefore, the WHO lymphoma classification of 2001 designated this lymphoma as the “extranodal marginalzone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)”; and IPSID is now considered a MALT lymphoma variant that involves mainly the proximal small intestine. Since the 1970s, it has been known that certain cases of stage A IPSID may regress after antibiotic therapies eliminating unknown organism(s). However, it was the demonstration that Helicobacter pylori infection is a risk factor for gastric MALT lymphoma and that eradication of the microorganism can result in histologic lymphoma regression in more than half of the treated patients that made this tumor a popular model of antigen-driven lymphomagenesis. Primary gastric MALT lymphoma is the most common MALT lymphoma and the most widely studied to date. In the stomach, where lymphocytes are not normally present, the onset of MALT lymphoma is preceded by the acquisition of MALT as a result of H pylori infection, and the regression of gastric MALT lymphoma can be achieved after anti-Helicobacter therapy. The association of H pylori with gastric MALT lymphoma has led to the hypothesis that the microorganism may provide the antigenic stimulus for sustaining the growth of the lymphoma in the stomach. However, the tumor-derived immunoglobulins usually do not recognize H pylori, but recognize various autoantigens. Sequence analysis of the immunoglobulin genes expressed by the gastric MALT lymphoma B cells shows a pattern of somatic hypermutation, indicating that the tumor cell has undergone antigen selection in germinal centers. Ongoing mutations of the immunoglobulin genes can also be found, suggesting that clonal expansion of tumor cells continues to be at least partially driven by a long-term antigen stimulation. It can be postulated that the interaction of host T-cell and antigen-presenting cells with bacterial antigens leads to a cascade of complex events, which finally results in autonomous clonal B-cell expansion and proliferation, bearing specific genomic aberrations. Extranodal lymphomas of the MALT are relatively rare, accounting for approximately 8% of all nonHodgkin’s lymphomas. On the contrary, H pylori can be found in the stomach of more than one half of the world population. Thus, both bacterial and host individual additional factors have to interact to cause lymphoma. Polymorphisms affecting genes, such as IL1RN and GSTT1, are involved in inflammatory responses. Therefore, antioxidative capacity may represent at least part of the genetic background for the lymphomagenesis in individual H pylori– infected persons. Free radicals are likely to play a role in development of B-cell genomic damages in the chronic gastritis, and their presence is increased in the presence of the cytotoxin-associated antigen A (CagA) –positive strains of H pylori. Until now, at least three recurrent translocations have been described in MALT lymphomas; these translocations are t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18) (q32;q21). The most common aberration is t(11;18), which results in a fusion of the apoptosis inhibitor gene API2 on chromosome 11q21 with the MALT1 gene on chromosome 18q21. t(11;18) is present in at least one third of patients with extranodal marginal-zone B-cell lymphoma of MALT type but not in patients with nodal marginal-zone JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005