API2-MALT1 Fusion Gene: Its Relationship With MALT Lymphoma And Its Progression

[Background and Objective] The chromosomal translocationt(11;18) (q21;q21) is the commonest chromosomal aberration associated with mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). This translocation creates a new fusion gene API2-MALT1, resulting in the production of API2-MALT1 fusion transcripts. Some diffuse large B-cell lymphomas (DLBCL) are known to be associated with MALT lymphoma. Whether this translocation is present or not in diffuse large B-cell lymphomas of the gastrointestinal tract and thyroid gland is interesting. In this study a group cases of MALT lymphoma, extranodal DLBCL and Hashimoto's thyroiditis was analyzed by using RT-PCR and nested PCR in order to find the t(ll;18) translocation and its variants in formalin-fixed, paraffin-embedded tissues. The cases with API2-MALT1 fusion transcripts and without API2-MALT1 fusion transcripts were compared with clinical data, morphological features, immunophenotyping, expression of apoptosis assiocated with proteins AP12 and caspase 3, and the infection by Helicobacter pylori. This study attempts to confirm whether lymphoma with AP12-MALTI fusion transcripts is a true clinicopathological entity and therole of API2-MALT1 fusion transcripts in the pathogenesis of MALT lymphoma and its progression.[Materials and Methods] In present study we selected 62 cases ofMALT lymphoma, 32 cases of extranodal DLBCL (16 in stomach, 13 inbowel and 3 in thyroid gland) and 8 cases of Hashimoto's thyroiditis. Allcases were retrieved from the files of the Department of Pathology, WestChina Hospital, Sichuan University between 1990 and 2003. Hematoxylinand eosin-stained sections were re-evaluated according to the. WHOclassification of hematopoietic and lymphoid tissue (2001). Formalin fixedand paraffin embedded tissue specimens were cut to immunohistochemicalstaining (LCA, CD20, CD45RO, CD5, cyclin Dl, kappa, lambda light chain,Ki-67, API2 protein and caspase 3) and extraction of total RNA. RT-PCRwas used to detect the transcripts of API2-MALT1 fusion gene, API2 geneand caspase 3 gene. Otherwise the apoptosic index was measured by TUNELand the infection of Helicobacter pylori was detected by blue and PCRmethods. All patients were followed and divided into two groups accordingto the expression of API2-MALT1 fusion gene or not for the statistic analysis.Results In Hashimoto's thyroiditis (n=8) there was no transcript ofAPI2-MALT1 fusion gene, whereas the transcripts of API2-MALT1 fusiongene were found in 28 of 62 cases (45.16%) of MALT lymphoma and 11 of32 casese (34.34%) of extranodal DLBCL (p=0.32). The frequency of thetranscripts of API2-MALT1 fusion gene was lower in thyroid gland (1/12),higher in the lung (5/10), stomach (16/31) and bowel (6/9) in MALTlymphoma (p=0.001), whereas similar distribution in thyroid gland (1/3),stomach (4/16) and bowel (6/13) in extranodal DLBCL. The variant oftranscripts of AP12-MALT 1 fusion gene, A1446-M1123, was detected more frequently than another variant, A1446-M814 (28/39 vs 11/39, 71.79% vs 28.21%, p=0.003). Clinically, the patients with transcripts of API2-MALT1 fusion gene (API2-MALT1+) appeared earlier staging than those without transcripts of API2-MALT1 fusion gene (API2-MALTl')(p=0.001) and lower relapse rate (4/33 vs 18/45, 12.12% vs 40.00%, p=0.01). The 5 year survival rate in API2-MALT1+ patients was 79.18%, whereas 53.62% in API2-MALTV patients (p=0.001). Infectious rates by Helicobacter pylori in the gastric lymphomas between the two groups were 5/20 and 7/27, respectively (p=0.60). There were no significant statistic differences in the expression of API2 mRNA and API2 protein, caspase 3 mRNA and protein, apoptotic index and proliferative index between these two groups.Conclusions In the stomach, bowel, lung and thyroid gland, the lymphoma patients with transcripts of API2-MALT1 fusion gene, whether MALT lymphoma or DLBCL, show a more indolent clinical behavior than those without transcripts of API2-MALT1 fusion gene. Some diffuse large B cell lymphomas in extranodal regions are derived from MALT lymphoma. So it is reasonable that lymphoma with transcripts of API2-MALT1 fusion gene seems a distinct clinicopathological entity. The morphological transformation from MALT lymphoma to DLBCL could imply the progression of this spectrum.