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Abbreviation: GI, Gastrointestinal. Source: From Ref. 7.

Abbreviation: GI, Gastrointestinal. Source: From Ref. 7.

S lom ach

MALT lymphoma DLBCL

Colon

Mamie cell lymphoma Follicular lymphoma DLBCL [uncommon]

(20). Ongoing somatic immunoglobulin gene mutations suggest that continued antigen stimulation plays a role in clonal expansion (21). As genetic events occur, MALT lymphoma can acquire autonomous growth that is H. pylori independent.

Several genetic aberrations are associated with MALT lymphomas, including the translocations t(11;18)(q21;q21), t(1;14)(p23;q32), t(14;18)(q32;q21) which occur more frequently in non-GI MALT lymphomas (22), and trisomy 3 (23), 12, and 18, respectively. This discussion will focus on the two well-described genetic abnormalities associated with GI lymphomas— t(11;18)(q21;q21) and t(1;14)(p23;q32). The translocation t(11;18)(q21;q21) fuses the N-terminus of the apoptosis inhibitor gene API2 with the C-terminus of the MALT1 gene on chromosome 18q (24), resulting in constitutive activation of nuclear factor-kappaB (NF-kB) and modulation of cellular activation, proliferation, and survival signaling. This translocation has been found in 30% to 60% of low-grade MALT lymphomas (25), but has been identified in virtually no cases of high-grade DLBCL (26). In MALT lymphoma that harbors t(11;18) (q21;q21), the translocation is usually the sole genetic abnormality; these tumors do not typically transform into DLBCL. The t(11;18)(q21;q21) translocation has been associated with infection with the more virulent CagA-positive strains of H. pylori (27). In contrast, MALT lymphoma without t(11;18)(q21;q21) has been shown to develop multiple other genetic aberrations, such as allelic imbalances and loss of heterozygosity that are similar to those found in high-grade DLBCL of the stomach, implicating the development of multiple genetic events in progression to DLBCL (28).

The t(1;14)(p23;q32) gene mutation is identified in ~5% of MALT lymphomas. This translocation deregulates BCL10 protein expression by juxtaposing the BCL10 gene under control of the immunoglobulin-heavy chain (IgH) gene promoter (29,30). Dysregulation of BCL10 by this translocation links antigen-receptor signaling to nuclear translocation and constitutive activation of NF-kB, which transactivates genes that regulate the proliferation and survival of B-lymphocytes (31-35).

Numerous therapeutic studies demonstrate that eradication of H. pylori with combination antibiotic regimens result in regression of MALT lymphoma with typical overall response rates (ORR) of ~75%, and study findings ranging between 60% and 92% (36-40). The earliest study of antibiotic intervention was reported by Wotherspoon et al. (36), who observed complete eradication ofH. pylori with antimicrobial therapy in six patients and corresponding regression of MALT lymphoma in five of these patients. This finding was subsequently confirmed in several larger series (37-40). In a prospective trial of 34 patients with stage IE or II2E gastric MALT treated with antibiotic doublets, 79% of H. pylori-positive patients achieved an objective regression to antibiotics [complete response (CR) 50%], although half of partial responders eventually failed therapy. None of the H. pylori-negative patients achieved a response to antibiotics (39). In addition to H. pylori status, other factors predictive of regression of gastric MALT lymphoma to antimicrobial therapy include the depth of mucosal involvement and regional lymph-node status evaluated by endoscopic ultrasound (9).

Between 20% and 30% of H. pylori-positive gastric MALT are refractory to antibiotic therapy. Several studies indicate that the t(11;18)(q21;q21) translocation is identified in higher frequencies (60-75%) in patients resistant to H. pylori eradication (41,42). This finding suggests that the API2-MALT1 fusion may confer a H. pylori-independent growth advantage of MALT lymphoma. In H. pylori-negative patients, t(11;18)(q21;q21) was also found in frequencies >50%, and were correlated with disease in advanced presentation (stage IIE and above) (43). Recent findings suggest that BCL-10 and NF-kB can also predict H.-pylori-independent status of gastric MALT lymphoma either with or without t(11;18)(q21;q21) (44).

Eradication of H. pylori and regression of MALT lymphoma has traditionally been evaluated by both histopathology review and polymerase chain reaction (PCR) (45). When LEL lesions are not identified on histologic examination, PCR analysis may detect monoclonal bands for the immunoglobulin heavy chain variable (IgVH) region representing the lymphoma clone (45). Thiede et al. (46) reported that 45% of patients achieving a CR to antibiotic therapy harbored monoclonal bands on PCR analysis with persistence of monoclonality often for years. These persisting monoclonal cells were identified as basal lymphoid cell clusters on microdissection studies, and speculated to be the B-cell lymphoma in a quiescent state (46). The finding of ongoing somatic mutation and clonal evolution after eradication of H. pylori supports the concept of continuing autoreactivity (47). Thus, while the clinical significance of these monoclonal PCR products remains unclear, this may be an indicator of patients predisposed to disease relapse. These findings suggest that antibiotics suppress rather than eradicate the neoplastic clone, and that long-term follow up of MALT lymphoma is required particularly in patients with PCR evidence of disease.

Small series demonstrate the favorable natural history of patients with H. pylori-associated MALT lymphoma, initially treated with antibiotics and who were then managed expectantly despite persistent clonality (48). Long-term follow up of MALT lymphomas indicate that late relapses do occur despite high CR rates requiring ongoing surveillance (49). Anecdotal cases of gastric adenocarcinoma arising in previously treated H. pylori-positive MALT lymphoma have also been described (50).

Both local and systemic treatment strategies have been employed for antibiotic-refractory MALT lymphoma. While no prospective data comparing surgery, systemic chemotherapy, or combined modality therapy is available, favorable outcomes have been reported with all types of treatment (51,52). In one retrospective series of stages IE and IIE, gastric MALT lymphoma treated with different therapies, freedom from progression (FFP) (81% chemotherapy, 86% surgery, 95% combination) and OS were similar in all treatment groups irrespective of the therapeutic approach (52).

Local therapy remains an effective option for MALT lymphoma that is refractory to antibiotics. The role of definitive radiotherapy was assessed in a prospective single institutional study from Memorial Sloan-Kettering Cancer Center (53). Seventeen patients with stage IE or II2E gastric MALT lymphoma refractory to antibiotics were treated with radiotherapy (median dose, 30 Gy) to the stomach and adjacent lymph nodes. All patients achieved a CR with 100% event-free survival (EFS) at 27 months median follow up. A correlative molecular study in this patient cohort revealed that the majority of these patients remained positive by clonotypic PCR despite sustained biopsy-proven remissions, suggesting that persisting monoclonal cells may lack additional intra- or intercellular signaling required to exert a malignant phenotype (54). The favorable outcomes with radiotherapy for localized MALT lymphoma are corroborated by a series of 103 patients from Princess Margaret Hospital (55), which included stage IE or IIE MALT of various anatomic sites with the findings of an aggregate five-year disease-free survival (DFS) of 77% and OS of 98%. All gastric MALT lymphomas achieved a CR and remained in continuous remission. Treatment was well tolerated with minimal adverse effects.

Cytotoxic chemotherapy for MALT lymphomas has not been evaluated extensively, but established active agents include alkylators as single agents (56) or in combination (57). Alkylator therapy (cyclophosphamide or chlorambucil) given as protracted oral treatment has been reported in the literature to achieve CR rates of 75% in patients with stage I and IV MALT lymphomas (56). The combination of mitoxantrone, chlorambucil, and prednisone (MCP) yielded an ORR of 93% (CR 53%) in a small series of patients with all types of MALT lymphoma of both limited and advanced stages (57). More recent data from the LY03 cooperative group study from the IELSG, Groupe d'Etude des Lymphomes de l'Adulte (GELA), and the United Kingdom Lymphoma Group assessed the benefit of chlorambucil consolidation following antibiotic therapy for H. pylori-associated MALT lymphoma. Patients with a histologic CR after antibiotic therapy were randomized to receive chlorambucil or observation. A preliminary report of the molecular results of this study shows that 74% of patients achieved a histologic CR, while 56% had a molecular CR by PCR analysis (58). The activity of cladribine, a purine analog, was reported in a prospective phase II study of 25 assessable patients with an aggregate CR rate of 84%. All patients with gastric MALT presentation achieved a CR (59). The t(11;18)(q21;q21) translocation did not adversely affect the response of gastric MALT lymphoma to cladribine (60).

Rituximab is a chimeric monoclonal antibody that recognizes the pan B-cell antigen CD20 and has significant clinical activity in MALT lymphomas (61-63). The IELSG conducted a phase II study of rituximab for four weekly doses in 34 evaluable patients with untreated or relapsed MALT lymphoma of all stages and various primary sites. Of 15 patients with gastric MALT lymphoma, 13 patients received prior treatment with antibiotics for H. pylori but subsequently relapsed. The ORR for primary gastric disease was 64% with chemotherapy-naive patients achieving more favorable responses. Results were notable for a high relapse rate (36%) in the entire study cohort (62). In 26 assessable patients with gastric MALT lymphoma, who were ineligible for or resistant to antibiotic therapy, single-agent rituximab yielded an

ORR of 77% with 46% complete responders. The t(11;18)(q21;q21) translocation was evaluated by fluorescence in situ hybridization in this study, but did not correlate with disease response (63).

Taken together, the literature supports the use of antibiotics as first-line therapy for H. pylori-positive patients through epidemiologic data and clinical treatment results from multiple single-arm studies. For relapsed patients or H. pylori-negative disease, radiotherapy represents an acceptable treatment for localized MALT lymphoma, although evidence is present only in the form of single cohort studies. Systemic therapy with either conventional cytotoxic chemotherapy and/or immunotherapy may be utilized for patients with more advanced presentation of disease, while less commonly used to treat localized disease.

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