Atypical Translocations in Mantle Cell Lymphoma: A Cytogenetic Diagnostic Dilemma
Joshua R Menke, Dragan Jevremovic, Rhett P Ketterling, William R Sukov. UCSF, San Francisco, CA; Mayo Clinic, Rochester, MN
Background: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma whose primary genetic event has classically been the translocation (11;14)(q13;q32) that juxtaposes the Ig JH region to CCND1 on chromosome 11q13 and results in overexpression of cyclin D1. Typically detection of CCND1/IGH fusion by FISH is considered diagnostic of MCL. Several variant translocations pairing CCND1 with other partners have rarely been described in MCL.
Design: Five MCL cases with rearrangements of 11q13 not involving 14q32 were identified based on results of CpG stimulated conventional chromosome studies performed on peripheral blood or bone marrow. Morphologic, flow cytometric and immunophenotypic (IHC) features were reviewed. FISH studies were performed on fixed cell pellets obtained from the original culture material using commercially available CCND1/IGH fusion and CCND1 break apart probes (Abbott Molecular) and laboratory developed dual color, double fusion probes for detection of fusion of CCND1 with the Ig kappa light chain region (IGKC) and Ig lambda light chain region (IGLC).
Results: IHC showed most cases expressed CD5 and CD20 without co-expression of CD23 and all expressed cyclin D1. Chromosome analysis showed one case each with t(2;11)(p11.2;q13), t(11;12)(q13;p11.2), t(11;22)(q13;q11.2) and 2 cases with t(11;22)(q13;q13). FISH with a CCND1/IGH fusion probe was negative for fusion but showed an extra CCND1 signal. FISH using CCND1 break-apart probe confirmed CCND1 rearrangement in all cases and dual-color, double fusion probes confirmed a CCND1/IGKC fusion in the case with t(2;11)(p11.2;q13) and CCND1/IGLC fusion in the cases with t(11;22)(q13;q11.2) and t(11;22)(q13;q13). By FISH the case with t(11;12)(q13;p11.2) was negative for all CCND1 fusions but showed CCND1 rearrangement. Follow up ranged from 9 mos to 2 yrs with four patients in clinical remission at last follow-up but one who died 9 months after diagnosis.
Conclusions: These cases indicate that the standard FISH CCND1/IGH fusion probe used in most cytogenetics laboratories will be negative for the typical fusion in rare cases of MCL. Unless a CCND1 rearrangement is suspected based on CpG stimulated chromosome studies, an atypical CCND1 signal pattern is recognized using the CCND1/IGH probe or a break apart CCND1 FISH probe is utilized, these MCL cases will likely be misdiagnosed. We have also identified a novel translocation between CCND1 and an unknown gene on chromosome 12p11.2 resulting in MCL and suggest that this unknown fusion partner participates in cyclin D1 overexpression.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 261, Tuesday Afternoon