Pathogenesis and treatment of extranodal lymphomas: the fascinating model of mucosa-associated lymphoid tissue lymphoma.

Extranodal lymphomas of the mucosa-associated lymphoid tissue (MALT) account for approximately 8% of all non-Hodgkin’s lymphomas and comprises up to 50% of primary gastric lymphomas, however they can arise in virtually any extranodal site.1-3 Their histologic features are similar regardless of the site of origin.4 MALT lymphoma usually arises in mucosal sites where lymphocytes are not normally present and where a MALT is acquired in response to either chronic infectious conditions or autoimmune processes (such as Helicobacter pylori gastritis, Hashimoto’s thyroiditis, Sjögren’s syndrome). Certain histological features suggest that the cells of MALT lymphoma may be participating in an immune response. These include the presence of scattered transformed blasts, the plasma cell differentiation, the presence of reactive T-cells, and the follicular colonization.1-3 In the stomach the onset of MALT lymphoma is preceded by the acquisition of MALT as a result of H. pylori infection and there is a compelling evidence for a pathogenetic role of this infection in gastric lymphoma supported by epidemiological, molecular and clinical findings.5-8 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.1-3 However, the tumor-derived immunoglobulin usually does not recognise H. pylori but recognises various autoantigens.9 Sequence analysis of the immunoglobulin genes expressed by the gastric MALT lymphoma B cells shows a pattern of somatic hypermutation that suggests that the tumor cell has undergone antigen selection in germinal centers. In addition, ongoing mutations (intraclonal variation) of the immunoglobulin genes have been found in many cases.10-12 This finding suggests that clonal expansion of tumor cells continues to be at least partially driven by a long-term antigen stimulation, which gives the B-cell clones with increased affinity a growth advantage over those that cannot respond or that respond less efficiently to the antigen.10 Because of the persistent antigenic stimulation, the clone may become more susceptible to genetic alterations that can result in neoplastic transformation and tumor progression. The most common nonrandom structural chromosomal aberration is the t(11;18)(q21;q21), which results in a fusion of the apoptosis inhibitor gene API2 on chromosome 11q21 with the MALT1, a paracaspase gene on chromosome 18q21.13-16 The t(11;18) is present in at least one third of cases and has been found in several anatomic localizations of MALT lymphomas (lung, stomach, orbit), but not in nodal marginal zone lymphoma, splenic marginal zone lymphoma or mucosal diffuse large cell lymphoma. It is often the sole cytogenetic alteration. This latter finding suggests a major pathogenetic role for this translocation.2 A second nonrandom translocation, much more rarely detected, the t(1;14)(p22;q32), has been shown to deregulate the expression of a survival-related gene, BCL10,17-18 which is highly expressed in the nucleus of the neoplastic B cells of MALT lymphomas carrying this translocation. Nuclear expression of Bcl10 is also present in the MALT lymphomas carrying the t(11;18)(q21;q21). It appears that nuclear localization of Bcl10 can occur as the result of two apparently independent cytogenetic events, while Bcl10 is expressed only in the cytoplasm in MALT lymphomas without these translocations as well as in non-neoplastic germinal center and marginal zone B cells.3,19-20 Indeed these two seemingly disparate translocations that target BCL10 and MALT1 appear to affect the same signaling pathway, the result of which is the activation of NFkB. NfkB is a transcription factor with a central role in the activation of genes involved in immunity, inflammation and apoptosis. Under physiological conditions, Bcl10 and MALT1 form a tight bond and synergize to increase activation of NFkB. Unlike wild type MALT1, which is dependent upon an interaction with Bcl10 as a mechanism for oligomerization and auto-activation, the API2-MALT1 fusion protein may possess a mechanism for self-oligomerization resulting in constitutive activation of the NFkB pathway independent of BCL10.21-25 Thus, in MALT lymphoma, the t(1;14) or t(11;18) translocations lead to a dramatic increase in NFkB activity. This constitutive activation of the NFkB pathway is likely critical to lymphoma antigen-independent growth and lymphoma progression.2-3 This may not only be important for the pathogenesis of MALT lymphomas but may also have a prognostic relevance. Indeed, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression are significantly higher in tumors that have disseminated beyond the stomach.3 Moreover, the t(11;18)(q21;q21) seems also strong-