Mutational Status of Chronic Lymphocytic Leukemia (CLL) Determines Clonlal Evolution in Classical Hodgkin’s Lymphoma Variant of Richter’s Transformation.

Approximately 5% of CLL patients transform during their clinical course into a high grade lymphoma, referred to as Richter’s transformation, most commonly DLBCL, rarely (0.4%) classical Hodgkin’s lymphoma (cHL). Most cases of cHL transformation are Epstein-Barr virus positive and are often related to fludarabine treatment. Only a handful of cases in the literature, most of them EBV positive, have been studied for their clonal relationship with the pre-existing CLL. EBV negative cHL cases in CLL patients are rare and have not been well investigated. We have studied 2 EBV positive and 8 EBV negative cHL cases using single cell laser microdissection combined with PCR analysis for the IgH gene rearrangement. ZAP-70 immunohistochemical staining was used as a surrogate for Ig gene mutational status. Three cases of EBV negative and 1 EBV positive cHL case arose in ZAP-70 negative (mutated) CLL while 5 EBV negative and 1 EBV positve cHL cases arose in ZAP-70 positive (unmutated) CLL. Surprisingly, regardless of the EBV status, all 4 cHL cases from ZAP-70 negative (mutated) CLL shared the same clonal origin with the pre-existing CLL. In contrast, all 6 cHL cases from ZAP-70 positive (unmutated) CLL exhibited a different clonal origin. These results demonstrate that the mutational status of the CLL, and not the EBV status of the cHL, determines the nature of the evolution to cHL. Additional EBV positive cHL cases are currently under investigation. Passage through the germinal center may predict the ability of a CLL B-cell to transform to a Hodgkin’s cell.