Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling

Abstract

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.

Figure 1.

Expression profiles of mantle cell lymphoma (MCL) signature genes in 6 cases of cyclin D1-negative MCL using Affymetrix U133 A/B arrays. These expression profiles are compared with 22 cases of cyclin D1-positive MCL, 78 cases of activated B-cell-like (ABC), 85 cases of germinal center B-cell-like (GCB), and 33 cases of primary mediastinal (PMBL) variants of diffuse large B-cell lymphoma, 193 cases of follicular lymphoma (FL), 14 cases of extranodal marginal zone lymphoma, MALT type (MALT), 6 cases of splenic marginal zone lymphoma (SMZL), and 14 cases of small lymphocytic lymphoma (SLL) (median expression levels of the MCL signature genes in these entities are shown). In the 6 cases of cyclin D1-negative MCL, each column represents a single lymphoma specimen and each row represents the level of expression of a single gene in the MCL signature. Red squares indicate increased expression and green squares indicate decreased expression relative to the median expression level, according to the color scale shown over a 4-fold range. In the bottom panel, the gene expression levels of the D-type cyclins in the various entities and the 6 cases of cyclin D1-negative MCL are shown according to the color scale over a 16-fold range. For microarray data of all cases, refer to Table S1.

Figure 2.

Cytologic features and expression of D-type cyclins in cyclin D1-negative MCL. (A) Typical MCL cytology (case 1) (hematoxylin and eosin stain; original magnification, × 500); (B) cyclin D1 protein, showing only a rare nontumor cell with nuclear staining (case 1); (C) cyclin D2 protein, showing strong nuclear staining of the tumor cells (case 2); (D) cyclin D3 protein, showing strong nuclear staining of the tumor cells (case 4). Panels B-D are immunoperoxidase stains; original magnification, × 400. Figure S1 provides high-power photos of cytomorphology of other 5 cases.