Hematopathology / IMMUNOPHENOTYPE OF RICHTER SYNDROME Large Cell Lymphoma Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma A Flow Cytometric Analysis of Seven Cases

We studied 7 cases of large cell transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) immunophenotyped by multiparameter flow cytometry. The 6 women and 1 man ranged in age from 45 to 91 years. All had previous or concurrent evidence of CLL/SLL. Morphologic features and sites of involvement of the diffuse large B-cell lymphoma (DLBCL) were heterogeneous; 2 cases had paraimmunoblastic morphologic features. Six DLBCLs had an immunophenotype consistent with CLL: CD19+, CD5+, CD23+, and FMC7 negative (3 cases) or very dim (2 cases); 1 case was not studied for FMC7. CD20 was dim in 3 of these, moderate to bright in 2, and variable in 1. Surface immunoglobulin was dim in 2 cases and moderate or bright in 4. Five of 6 expressed CD38. Comparison with the immunophenotypes of the previous or coexistent CLL/SLL (4 of 6 cases) revealed minor modulations in antigen expression but no major alterations. The seventh DLBCL lacked CD5 expression, but otherwise had immunophenotypic features similar to CLL. These findings indicate that DLBCL arising in CLL/SLL tends to retain a CLL immunophenotype, in contrast with de novo CD5+ large cell lymphomas that uncommonly express such a phenotype. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common B-cell lymphoproliferative disorder with a characteristically indolent clinical course. A diffuse large B-cell lymphoma (DLBCL) occurs in a small minority of patients (approximately 2% of cases).1 This transformation is termed Richter syndrome when associated with a constellation of clinical features that includes an abrupt change in clinical status; rapidly enlarging, asymmetric lymphadenopathy; a high serum lactate dehydrogenase level; and a poor response to aggressive therapy.2-4 Roughly two thirds of DLBCLs arising in CLL/SLL seem to represent clonal evolution of the underlying low-grade tumor, whereas in the remaining cases, they seem to be clonally unrelated, de novo neoplasms.4-25 The mechanisms underlying CLL transformation are poorly understood. Among those implicated in small numbers of cases are p53 mutations, p16 inactivation, gain of an additional chromosome 12, c-myc amplification, and Epstein-Barr virus (EBV) infection.22,26-30 The immunophenotype of CLL is characteristic, permitting distinction from other small B-cell neoplasms in the large majority of cases. Specifically, nearly all cases of CLL express CD19, the T-cell–associated antigen CD5, and CD23.31-36 Most in addition lack FMC7 and show relatively dim expression of CD20 and surface immunoglobulin (SIg). Among small B-cell disorders, CD5 expression is restricted essentially to CLL and mantle cell lymphoma. However, one occasionally encounters a CD5-expressing DLBCL with no evidence of a coexisting or antecedent small B-cell neoplasm.37-40 In such cases, it is not clear whether these represent de novo processes or transformations of undetected small-cell neoplasms. While we and others have shown that de novo CD5+ DLBCL rarely has an immunophenotype resembling CLL, the literature data on the immunophenotypic Am J Clin Pathol 2001;115:385-395 385 © American Society of Clinical Pathologists Kroft et al / IMMUNOPHENOTYPE OF RICHTER SYNDROME features of DLBCL transformation of CLL/SLL are sparse. For this reason, we reviewed our institutional experience with the immunophenotypic features of such cases. Materials and Methods