Gastric Mucosa-Associated Lymphoid Tissue Lymphomas: More Than a Fascinating Model
Authors: E. Roggero, E. Zucca, F. Cavalli
Journal: JNCI Journal of the National Cancer Institute (1997)

Information about mucosa-associated lymphoid tissue (MALT) has accumulated progressively over the past decade. MALT lymphoma is usually associated with a pre-existing disorder in sites where lymphocytes are not normally present and where an acquired MALT develops in response to either infectious conditions (i.e., in the stomach) or to autoimmune processes (i.e., in salivary glands or the thyroids). In the context of these prolonged, lymphoid-reactive proliferations, the outgrowth of a pathologic clone can progressively replace the normal lymphocytes (1,2). MALT lymphoma has been included in the Revised European–American Classification of Lymphoid neoplasms (R.E.A.L. classification) as a specific subtype, i.e., the extranodal marginal-zone B-cell lymphomas (3). Marginal-zone B-cell MALT lymphomas comprised 7.6% of more than 1400 non-Hodgkin’s lymphomas in a recent international evaluation of the clinical significance of the REAL classification (4). Several lines of evidence, including sequence analysis of the immunoglobulin variable-region heavy-chain genes, strongly suggest that Helicobacter pylori provides the antigenic stimulus for sustaining the growth of MALT lymphomas in the stomach (5–7). This antigen-driven clonal expansion, which is mediated by mucosal T cells, may explain the tendency of low-grade MALT lymphomas to remain localized in the mucosal sites and to regress after H. pylori eradication (8,9). During this clonal expansion, genetic alterations continue to occur until a point is reached when autonomous (i.e., H. pylori-independent) growth is possible, while additional alterations can then result in highgrade transformation. The principal histologic feature of low-grade MALT lymphomas is the presence of a variable number of lymphoepithelial lesions, resulting from the partial destruction of gastric glands by aggregates of smallto medium-sized neoplastic lymphocytes (10). Since early or borderline cases can be confused with H. pylori-related follicular gastritis, a scoring system has been devised to enhance diagnostic confidence (11). Low-grade MALT lymphoma is usually a very indolent disease, often remaining localized for a prolonged period, with some cases showing no progression for several years even without treatment. There is increasing evidence that eradication of H. pylori can be the sole initial treatment when the disease is limited to the stomach, as is the case in at least 80% of the patients (11–14). However, it is still unknown whether treatment for H. pylori will avert relapse and, thereby, definitely cure at least some of the patients. Hence, long-term results of the initial studies are eagerly awaited. A first update of the German multicenter trial (13) is published in this issue of the Journal (15). However, this report is only a modest addition to our knowledge about the duration of remission, since the median follow-up (2 years) is not much longer than that of other reports and in view of the very indolent course of this disease. Furthermore, it is unfortunate that the authors used neither the recently recommended staging criteria (16) nor the histologic score proposed by Wotherspoon et al. (11), an omission that can impede comparison with other series. However, in many respects, the report is a valuable contribution. First, it confirms the efficacy of antibiotics in inducing apparently durable lymphoma remission. Analogous data have been reported by our group and other groups, although, according to our experience, expecting a remission rate of greater than 80% in an unselected patient population appears overly optimistic. The efficacy of antibiotics, in fact, may be reduced in instances of locally advanced disease with bulky masses or deep infiltration of the gastric wall and in cases with increased numbers of scattered blast cells in the biopsy. Second, Neubauer et al. (15) relate their observation that patients not responding to the eradication of H. pylori may harbor high-grade lesions, which initially were not or could not have been seen. Finally, this report of a larger and thoroughly studied series supports the findings of Savio et al. (17) that polymerase chain reaction (PCR)-detectable B-cell monoclonality may often persist after the disappearance of histologically detectable MALT lymphoma. This result confirms not only that histologic examination remains the cornerstone of the management of this disease (17) but also that the significance of PCR-detectable monoclonality is questionable, since (at least as of now) the relapse rate does not seem to be influenced by this finding. Where do we go from here? First, only a much longer follow-up can clarify the possible merits of H. pylori eradication. Nevertheless, we believe that this conservative approach as the sole initial treatment for localized disease should not be regarded as ‘‘still investigational,’’ as