Several lymphoma-specific genetic events in parallel can be found in mature B-cell neoplasms.

The mature B-cell neoplasms frequently result from translocations involving the IGH gene localized on 14q32. In rare instances, combinations of different IGH rearrangements were described, and even coincidence of three genetic lymphoma-specific events has been rarely reported. We here present eight patients with triple hit lymphoma, and two with four different lymphoma specific events detected by chromosome banding analysis and interphase FISH (seven males, three females, 47-82 years). All showed bone marrow involvement (Burkitt's lymphoma: n = 5, diffuse large B-cell lymphoma: n = 2; features intermediate between BL/DLBCL: n = 1; secondary aggressive B-cell lymphoma: n = 1; follicular lymphoma: n = 1). Eight patients had triple hit lymphoma combining IGH-BCL2/t(14;18)(q32;q21), MYC/8q24, and BCL6/3q27 rearrangements. Two showed an additional IGH-CCND1/t(11;14)(q13;q32) as fourth genetic event (according to research of the Mitelman database, the first reports on four genetic hits in lymphomas). All cases had complex aberrant karyotypes (median, 11 cytogenetic alterations per patient). Interphase FISH revealed a high rate of CDKN2A deletions (five of nine cases investigated; 56%), being homozygous in two of these cases. At the time of study, four of nine patients with follow-up data were alive (44%), one of these in remission. The two patients with four genetic hits died 6 and 9 days from diagnosis. Additional cases of lymphomas with three or four genetic hits should be collected to evaluate whether their clinical course differs from dual hit lymphomas.