Cyclin D1-negative mantle cell lymphoma with cryptic t(12;14)(p13;q32) and cyclin D2 overexpression

To the editor:

Virtually all cases of mantle cell lymphoma (MCL) carry the t(11;14)(q13;q32) translocation, leading to the juxtaposition of the CCND1/CYCLIND1 gene to the immunoglobulin heavy chain (IGH) joining region, resulting in cyclin D1 mRNA and protein overexpression.^1-3  The existence of “true” MCL negative for cyclin D1 has been controversial but was recently substantiated by gene expression profiling.⁴  Fu et al reported 6 cases of cyclin D1-negative lymphomas with pathologic and clinical features otherwise typical of MCL, and a molecular signature similar to that of cyclin D1-positive MCL. In these cyclin D1-negative MCL, the tumor cells overexpressed instead either cyclin D2 or cyclin D3, but had no evidence of chromosomal aberration involving the corresponding CCND2 and CCND3 genetic loci. Subsequently, 2 additional cases of cyclin D1-negative/cyclin D2-positive MCL were reported to harbor a t(2;12)(p11;p13) fusing the CCND2 gene to the IGK locus.⁵ 

Here, we report a case of cyclin D1-negative MCL with strong nuclear expression of cyclin D2 and a cryptic t(12;14)(p13;q32), juxtaposing the CCND2 gene next to the IGH locus. This lymphoma occurred in a 52-year-old man with stage IV disease involving the bone marrow and gastrointestinal tract. The diagnostic lymph node biopsy showed morphologic and immunopheno-typic features typical of MCL (CD20⁺, CD5⁺, CD10⁻, CD23⁻, CD43⁺, BCL-2⁺, BCL-6⁻), except for lack of cyclin D1 expression (Figure 1A-E). Conversely, most nuclei were positive for cyclin D2 (Figure 1F) and by competitive real-time–polymerase chain reaction (RT-PCR) cyclin D2 mRNA was overexpressed. Conventional cytogenetic analysis yielded 4 mitoses with a normal karyotype. Interphase FISH performed with LSI IGH/CCND1 Dual Color, Dual Fusion Translocation Probes (Vysis, Downer's Grove, IL) was negative for the t(11;14)(q13;q32), but demonstrated rearrangement of the IGH locus. Q-banded karyotype established from a bone marrow sample was 43,XY,−1,der(8)t(8;8)(p23;q13),−11,−13,add(15)(p11),der(17)tdic(1;17)p22;p12),add(21)(q22),-22, +mar[cp2]/46,XY[17]. FISH performed on bone marrow cells with the LSI IGH Dual Color, Break Apart Rearrangement Probe (Vysis), showed a rearrangement of the 14q32 region (Figure 1G). Because of apparent cyclin D2 overexpression, the tumor cells were investigated for a CCND2 rearrangement, using a break apart FISH assay as previously described.⁴  A break in the CCND2 locus was clearly demonstrated, with the telomeric probe mapping to 14q32 (Figure 1H). The short arms of both chromosomes 12 were normal, demonstrating a derivative 14 through a cryptic t(12;14)(p13;q32) translocation. Interphase FISH confirmed a CCND2 rearrangement in the lymph node (Figure 1I).

This is the first description of a cyclin D1-negative MCL with a t(12;14)(p13;q32) and cyclin D2 overexpression. Of the 4 cyclin D1-negative/cyclin D2-positive MCL previously reported, 2 were found to harbor a genetic alteration of the CCND2 gene, due to a translocation to the IGK locus.^4,5  Our findings in the current case confirm that CCND2 is recurrently targeted by chromosomal rearrangements in cyclin D1-negative MCL, and identify IGH as a previously undescribed translocation partner. By analogy to other translocations involved in B-cell lymphomas, one would have expected to find this translocation more often. Interestingly, the t(12;14)(p13;q32) translocation has, to date, not been described. This is likely due to the rarity of true cyclin D1-negative MCL with CCND2 alterations but also to the cryptic nature of this rearrangement. Systematic FISH investigation of suspected cyclin D1-negative MCL overexpressing cyclin D2 without obvious 12p13 and/or 14q32 rearrangements might lead to the identification of additional cases harboring this hitherto unrecognized translocation.