Molecular heterogeneity of splenic marginal zone lymphomas: analysis of mutations in the 5 ' non-coding region of the bcl-6 gene

Splenic marginal zone lymphoma (SMZL) has been recognized as a distinctive type of small B cell lymphoma, and defined on the basis of its morphologica l, phenotypic, clinical and molecular characteristics. In spite of this, th e borders of the entity, the homogeneity of the cases and the presumably ce ll origin of SMZL remain controversial issues. The frequency of mutation in the 5' non-coding region of the bcl-6 gene has been used as a marker of ge rminal center derivation, which may be used to establish the molecular hete rogeneity of different non-Hodgkin lymphoma (NHL) types. This roughly paral lels the characteristics and frequency of the somatic hypermutations found in the immunoglobulin heavy chain variable region (IgV(H)) genes. This stud y analyzed mutations of bcl-6 in the 5' non-coding region in 22 SMZL cases and, for the purpose of comparison with different B cell subsets, in microd issected germinal centers, mantle zones and marginal zone subpopulations fr om reactive splenic lymphoid follicles. A majority of the SMZL cases studie d, 19/22 (87%), bear unmutated bcl-6 gene, while mutation was only observed in 3/22 (13%) cases. Analysis of normal B cell subpopulations showed bcl-6 hypermutation in 3/10 (30%) germinal center clones, 5/14 (35%) marginal zo ne clones; and unmutated sequences in all clones derived from mantle cells. The frequency of these mutations in normal spleen confirms previous findin gs on the hypermutation IgV(H) process in normal B cell populations. The da ta presented here support the existence of molecular heterogeneity in this entity, and give additional results in favor of the hypothesis that, in spi te of initial morphological observations, a significant proportion of SMZL cases could derive from an unmutated naive precursor, different from the ma rginal zone, and possibly located in the mantle zone of splenic lymphoid fo llicles. Thus the marginal zone differentiation of these tumors could be re lated more with the splenic microenvironment than it is to the histogenetic characteristics of the tumor.