Clinicopathologic and Genomic Characteristics of Cyclin D1-Negative Pleomorphic/Blastoid Mantle Cell Lymphoma

Most cases of mantle cell lymphoma (MCL) overexpress cyclin D1 due to an IGH-CCND1 translocation. Rarely, MCL may lack the cyclin D1 positivity and the IGH-CCND1 translocation, but it still shares similar clinical features and gene expression profiles with the cyclin D1-positive MCL. The pleomorphic/blastoid variant of MCL (PMCL) is associated with aggressive biological behavior and poor prognosis. The diagnosis of cyclin D1-negative PMCL is difficult due to its morphologic similarity to diffuse large B-cell lymphoma (DLBCL) and its lack of diagnostic cyclin D1 expression. To date, only rare cases of cyclin D1-negative PMCL have been reported, and the clinicopathologic, immunophenotypic and genomic features of such tumors are largely unknown. Recently, we established an immunohistochemical algorithm to identify cyclin D1-negative PMCL. Out of 500 B-cell lymphomas morphologically compatible with DLBCL, we identified 10 cases of PMCL, including 4 cyclin D1-negative cases. Their genome-wide copy number profiles were similar to those of previously reported MCLs, confirming the diagnosis. Compared to previously reported classical MCL, we found more common copy number gains or losses involved in the oncogenesis of MCL in our PMCL cases. Interestingly, copy number gains of PIK3CA and CCDC50 were detected in all four cyclin D1-negative PMCLs but only in 40% of cyclin D1-positive PMCLs. We speculated that more common secondary genetic alterations could result in stronger oncogenic signals and less dependence on the driving CCND1 translocation, but further study on more tumors, including detection of genetic mutations, is needed. In this project, more cases of PMCL will be identified out of other 1000 cases of B-cell lymphomas morphologically compatible with DLBCL. We will study the clinical, morphologic, immunophenotypic and genomic features of cyclin D1-negative PMCL. Cases of cyclin D1-positive PMCL, cyclin D1-positive DLBCL and SOX11-positive DLBCL will also be studied for comparison. The genomic study will include fluorescence in situ hybridization for CCND1, CCND2 and CCND3 translocations, quantitative polymerase chain reaction to detect mRNA of CCND2 and CCND3, genome-wide copy number analysis, and whole exome sequencing. Our results will characterize this rare subset of MCL and provide invaluable information for future diagnosis and treatment.

Project ID:PC10607-0353
External Project ID:MOST106-2320-B182-018