title: Pleomorphic mantle cell lymphoma morphologically mimicking diffuse large B cell lymphoma: common cyclin D1 negativity and a simple immunohistochemical algorithm to avoid the diagnostic pitfall.
abstract: OBJECTIVE
  To characterize the clinicopathological and genetic features of pleomorphic mantle cell lymphoma (PMCL), which morphologically mimics diffuse large B cell lymphoma (DLBCL).
  
  
  RESULTS
  We screened systematically 500 B cell lymphomas morphologically compatible with DLBCL using an immunohistochemical algorithm of three markers (CD5, cyclin D1 and SOX11). Ten cases of PMCL were identified for further study and, surprisingly, four (40%) of them were cyclin D1-negative. These 10 patients were mainly elderly males with advanced disease, and their median survival was only 11 months. All cyclin D1-positive PMCLs tested showed an IGH-CCND1 translocation, whereas one of the four cyclin D1-negative PMCLs had a translocation involving CCND2 and a high CCND2 mRNA level (P < 0.000001). The genomewide copy number profiles of both cyclin D1-positive and cyclin D1-negative PMCLs were similar to those of classical mantle cell lymphoma (MCL) reported previously, confirming the diagnosis. Secondary genetic alterations involved in oncogenic pathways of MCL were observed more frequently in these PMCLs, possibly decreasing the dependence on the driving CCND1 translocation and accounting for the common cyclin D1 negativity. Copy number gains of PIK3CA and CCDC50 were detected in all cyclin D1-negative PMCLs but in only 40% of the cyclin D1-positive PMCLs. These additional oncogenic signals may compensate for the common absence of CCND2 translocation in cyclin D1-negative PMCL.
  
  
  CONCLUSIONS
  We demonstrate for the first time that cyclin D1 negativity is surprisingly common in PMCL morphologically mimicking DLBCL, and the use of a simple immunohistochemical algorithm can prevent misclassification and inappropriate treatment.
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chuang
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Hung
authors.initials: H
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Chang Gung Molecular Medicine Research Center and Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tong-Hong
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chi-Ju
authors.initials: CJ
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shir-Hwa
authors.initials: SH
authors.lastname: Ueng
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Chien
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chiu-Yueh
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Yung-Liang
authors.initials: YL
authors.lastname: Wan
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.|Chang Gung Molecular Medicine Research Center and Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chuen
authors.identifier: http://orcid.org/0000-0003-4770-5721
authors.initials: C
authors.lastname: Hsueh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis*; D058534:Class I Phosphatidylinositol 3-Kinases; D019938:Cyclin D1 / Q000096:biosynthesis; D003937:Diagnosis, Differential; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C478972:CCDC50 protein, human; C530104:CCND1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Mantle cell lymphoma; copy number analysis; cyclin D1; diffuse large B cell lymphoma; pleomorphic variant