Identical Clonal Origin in Three Cases of Hodgkin’s Lymphoma Variant of Richter’s Syndrome Associated with EBV Infection.

Occurrence of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL), clinically referred to as Richter’s syndrome, occasionally manifests as a lymphoproliferation resembling Hodgkin’s lymphoma (HL) and often containing the Epstein-Barr virus (EBV). Only a limited number of HL variants have been subject to informative analysis regarding EBV status and their clonal relation-ship to the CLL, with evidence of an identical clonal origin in some cases and of clonally unrelated neoplasms in most cases. We reported a clinical, pathological and molecular analysis of three new cases of Richter’s syndrome with HL features. The three patients (two males, one female), aged of 67, 70 and 74, have 4, 8 and 15-year history of CLL, respectively. At HL, clinical stages (CS) were IIIAa, IIBb and IIIBb, at HL diagnosis. All the three patients responded to HL specific chemotherapy but two of them died from infectious and cardiac complications and the last one died from HL relapse. Histologically the lesions were composite comprising areas of CLL, areas of CLL with Hodgkin Reed-Sternberg (HRS) cells and areas of HL. The HRS cells were CD45RC−/CD20−/CD79a−/CD30+/CD15+/J-chain-(all cases), Oct-2+ (case 2) and Pax-5+ (cases1 and 3). In all cases, HRS cells were positive for EBV with a latence 2 profile. Using single cell laser microdissection and PEP-PCR amplification of the immunoglobulin heavy chain gene (IgH) FR3A region of each cell type, we demonstrated a same clonal origin for the CLL cells and the HRS cells in all cases. These data were confirmed in two cases by Genescan reamplification with fluorescent FR3A primer and sequenced with BigDye Terminator chemistry. Clinicopathological presentation was similar to classical HL but persistent EBV infection is probably related to an underlined immunosuppression due to CLL and chemotherapy. Seven other cases have been reported in the literature using similar single cell techniques, four of them, EBV +, were clonally unrelated while the three other one, EBV−, were of same clonal origin. At the opposite and although our three cases are EBV+, we show that the HRS cells and CLL cells belong to the same clonal population. Our data do not support the hypothesis that EBV+ HL in CLL patients occurs as unrelated secondary neoplasm in immunocompromised patients.