Cytogenetic Aberrations and Ig VH Gene Mutations of Clinically Benign CD5-Monoclonal B-Cell Lymphocytosis (MLUS).

Abstract

Clonal expansion of lymphocytes is a hallmark of lymphoproliferative disorders. However, the finding of clonal lymphocytes may not be diagnostic of a defined lymphoid malignancy. In this study, we had an opportunity to identify and characterize a series of 7 patients with clinically benign clonal B-cell lymphocytosis. The clonal lymphocytes were clearly of CD5− and non-CLL phenotype. All patients were elderly and identified with a mild to moderate absolute lymphocytosis (lymphocytes range 3.6–9.4 ×109/L). The clonal population accounted for 95–99% of total B cells. For a follow-up period of 4–16 years, clonal lymphocytosis was persistent but virtually not progressing. All patients remained clinically stable and totally asymptomatic. The clonal CD5− B cells were shown to have somatic hypermutations of VH gene in 6 of the 7 patients, indicating a cell origin of germinal center B lymphocytes. Karyotypic aberrations were found in 5 of 6 patients examined. Two clones were found to have an isochromosome 17q, one as the sole abnormality and one as part of a complex karyotype. The loss of the short arm of chromosome 17 resulted in loss of p53, which was confirmed by the FISH analysis in both cases. The finding of p53 loss is unusual in such a benign condition. Two other clones were shown to have 7q abnormalities; one 7q31–34 deletion and one t(2;7)(p11;q22), the latter is impliated in dysregulation of the CDK6 gene. Even though deletion of 7q is strongly associated with, and t(2;7) is confined to splenic marginal zone lymphoma (SMZL), neither patients were hematologically or clinically diagnostic for SMZL. It remains to be determined whether additional cytogenetic and molecular changes may occur to lead to progression to a clinical malignancy. The patients in this study differ from those clonal CD5− monoclonal B-cell populations identified by sensitive flow cytometry in the normal population, by the presence of absolute lymphocytosis. In addition, the phenotypic profile is distinct from that of benign variant CLL. These clinically benign lymphocytoses may represent an intermediate between covert clonal expansion and overt malignancy.