Genetic abnormalities

Sequence analysis of the immunoglobulin genes expressed by the splenic marginal zone B cells shows that approximately half of the cases bear unmutated and half have mutated immunoglobulin heavy-chain genes,89 90 suggesting the possibility that this lymphoma subtype derives from different B-cell subsets than those normally present in the marginal zone. Cases with unmutated IgH genes may have a poorer prognosis and are more commonly associated with the presence of chromosome 7q loss,89 but it has to be underscored that the 7q deletions are relatively common in hematologic malignancies and not specific for splenic MZL. Gain of chromosome 3 appears to be another common abnormality.9192 The t(9;14)(p13;q32) translocation which juxtaposes the IgH locus to the PAX5 gene93'94 has also been reported; however, its frequency is controversial.95 Using cDNA microarray, Thieblemont et al. have compared the gene expression profile of splenic MZL, mantle cell lymphoma, and small lymphocytic lymphoma.96 The gene coding for the serine threonine kinase AKT1 was the most representative among the gene clusters specific for splenic MZL; its possible role in the pathogenesis of splenic MZL needs to be further clarified.

Association with infectious agents Despite relevant geographic variations, hepatitis C virus (HCV) seems to be involved in splenic MZL and nodal MZL

lymphomagenesis.97-101 Of great interest, some patients with splenic lymphoma with villous lym-phocyes and HCV infection achieved a lymphoma remission after treatment with interferon alfa with or without concomitant ribavirin.101102 This suggests a strict relationship between HCV and splenic MZL, indicating the necessity to search for HCV infection in patients affected by this lymphoma subtype. Analogous to the H. Pylori infection in the gastric MZL, it appears that HCV may be responsible for an antigen-driven stimulation of the lymphoma clone. Prospective studies are warranted to confirm this interesting finding.

An association with malaria and with Epstein-Barr virus infection, both acting as strong polyclonal B-cell activators, has been shown in tropical Africa.103-105 Tropical splenic lymphoma appears as a form of splenic MZL, characterized by a high percentage of circulating villous lymphocytes, unmutated immunoglobulin genes, and a predilection for middle-age women.

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