cyclin-d1 and Lymphoma--Large-B-Cell--Diffuse

Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases. Here, we describe the first reported case of concurrent chronic myeloid leukemia and diffuse large B-cell lymphoma in a background of chronic lymphocytic leukemia.. A 60-year-old Saudi man known to have diabetes, hypertension, and chronic active hepatitis B was diagnosed as having Rai stage II chronic lymphocytic leukemia, with trisomy 12 and rearrangement of the CCND1 gene in December 2012. He required no therapy until January 2016 when he developed significant anemia, thrombocytopenia, and constitutional symptoms. He received six cycles of fludarabine, cyclophosphamide, and rituximab, after which he achieved complete remission. One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. Fluorescence in situ hybridization from bone marrow aspirate was positive for translocation (9;22) and reverse transcription polymerase chain reaction detected BCR-ABL fusion gene consistent with chronic myeloid leukemia. He had no morphologic or immunophenotypic evidence of chronic lymphocytic leukemia at the time. Imatinib, a first-line tyrosine kinase inhibitor, was started. Eight months later, a screening imaging revealed new liver lesions, which were confirmed to be diffuse large B-cell lymphoma.. In chronic lymphocytic leukemia, progressive leukocytosis and splenomegaly caused by emerging chronic myeloid leukemia can be easily overlooked. It is unlikely that chronic myeloid leukemia arose as a result of clonal evolution secondary to fludarabine treatment given the very short interval after receiving fludarabine. It is also unlikely that imatinib contributed to the development of diffuse large B-cell lymphoma; rather, diffuse large B-cell lymphoma arose as a result of Richter's transformation. Fludarabine, trisomy 12, and CCND1 gene rearrangement might have increased the risk of Richter's transformation in this patient.

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 12; Cyclin D1; Cyclophosphamide; Disease Progression; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Rituximab; Treatment Outcome; Trisomy; Vidarabine

De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a subtype of DLBCL found predominantly in older individuals. This particular subtype has been associated with a female predominance and a more aggressive clinical course. Conversely, this entity has not been described in the pediatric population. We report a case of a 12 year-old boy who presented with an ileocecal intussusception. Radiologic, morphologic, and immunophenotypic analysis revealed an isolated extranodal mass consistent with a CD5+ DLBCL, germinal center cell phenotype. Fluorescent in situ hybridization analysis was negative for cMYC, BCL6, BCL2, MLL, and IGH/CCND1 rearrangement and showed loss of one copy of MLL in 32% cells. The patient was treated with four cycles of cyclophosphamide, vincristine, prednisolone, methotrexate, and doxorubicin and achieved complete remission. To the best of our knowledge, this is the first detailed report of a de novo CD5+ DLBCL occurring in a child.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; Child; Child, Preschool; Cyclin D1; Gene Rearrangement; Histone-Lysine N-Methyltransferase; Humans; Ileum; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Male; Myeloid-Lymphoid Leukemia Protein; Young Adult

Topics: Cyclin D1; Gene Rearrangement; Humans; Lymphoma, Large B-Cell, Diffuse

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) occasionally undergoes Richter transformation, mostly to diffuse large B-cell lymphoma, but its evolution to other types of B-cell lymphoma is rare. We report a CLL evolved to mantle cell lymphoma by acquiring t(11;14)(q13;q32); CCND1-IGH.. A Retrospective review of clinical and laboratory data.. A 39-year-old male patient was diagnosed with CLL/SLL, and was initially followed without specific treatment, but subsequently received chlorambucil/fludarabine/rituximab due to exacerbated lymphocytosis. While his CLL/SLL waned and waxed, the immunophenotype and genotype of neoplastic B-cells remained unchanged, without cyclin D1 expression and CCND1-IGH fusion. Eleven years after the diagnosis, the patient's disease showed evidence of progression. Bone marrow examination demonstrated "CLL" with the morphology and immunophenotype similar to those seen in the previous biopsies. Unexpectedly, the neoplastic B-cells demonstrated cyclin D1 expression and harbored t(11;14)(q13;q32); CCND1-IGH, suggesting a clonal evolution to mantle cell lymphoma. He subsequently received cytoreductive chemotherapy followed by allogenic bone marrow transplant and remained in remission since then.. The retention of immunophenotype suggests a clonal relationship between CLL/SLL and mantle cell lymphoma. While the acquisition of t(11;14)(q13;q32); CCND1-IGH likely alters the disease course, the pathogenesis of this illegitimate translocation in CLL remains to be studied.

Topics: Adult; Cyclin D1; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Oncogene Proteins, Fusion; Translocation, Genetic

Topics: Cyclin D1; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Receptor Protein-Tyrosine Kinases; Retrospective Studies

Follicular lymphoma (FL) is a mature B-cell lymphoma that can transform into a more aggressive disease such as diffuse large B-cell lymphoma, Burkitt lymphoma, or precursor B-lymphoblastic leukaemia/lymphoma. The process of transformation of FL occurs by the acquisition of additional genetic alterations, e.g. c-MYC rearrangement, TP53, and cyclin D1 inactivation. Herein, we describe four such cases of FL that transformed into more aggressive B-cell non-Hodgkin lymphomas within six months of their initial diagnosis. Subsequent testing of c-myc, P53 and cyclin D1 by immunohistochemistry and fluorescence in situ hybridization was done to further analyse their role in the process of transformation.

Topics: Cyclin D1; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse

Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cyclin D1; DEAD-box RNA Helicases; Disease Progression; Drug Resistance, Neoplasm; Exome Sequencing; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mitogen-Activated Protein Kinases; Mutation; Prognosis; STAT3 Transcription Factor

Pleomorphic mantle cell lymphoma (PMCL) can closely mimic diffuse large B-cell lymphoma (DLBCL) morphologically, and expression of CD5 and cyclin D1 is helpful for differential diagnosis. To date, no cases of CD5/cyclin D1 double-negative PMCL have been reported. Four cases of B-cell lymphoma with an immunophenotype of CD5(-) cyclin D1(-) SOX11(+) and morphologic features compatible with DLBCL were included. Two were previously identified, and the other 2 were screened from 500 cases of B-cell lymphoma. We analyzed their clinicopathologic, immunophenotypic, genetic, and gene expression features. Cases of cyclin D1-positive PMCL, cyclin D1-negative PMCL, germinal center B-cell (GCB) DLBCL, and activated B cell (ABC) DLBCL were also studied for comparison. Similar to other PMCL cases, these 4 patients were mainly elderly male individuals with an aggressive clinical course. None of these tumors had detectable translocations involving CCND1, CCND2, CCND3, CCNE1, CCNE2, MYC, BCL2, or BCL6. The genome-wide copy number profile of these 4 cases was similar to that of cyclin D1-negative PMCL. None of these tumors had high expression of cyclin D1, cyclin D2, or cyclin D3. Similar to cyclin D1-negative PMCL, these cases had higher expression of cyclin E1 and cyclin E2 compared with cyclin D1-positive PMCL. The gene expression pattern of these tumors was also similar to that of cyclin D1-negative PMCL. Here we report for the first time 4 cases of CD5/cyclin D1 double-negative PMCL. SOX11 positivity is useful to identify these rare tumors, and further genetic and gene expression analysis can be used to confirm the diagnosis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; CD5 Antigens; Cyclin D1; Diagnosis, Differential; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Phenotype; SOXC Transcription Factors

Mantle cell lymphomas (MCLs) are the prototypic B-cell non-Hodgkin lymphomas defined by cyclin D1 gene (CCND1; or other cyclin D family gene) rearrangements. However, extremely rare cases of diffuse large B-cell lymphomas (DLBCLs) harboring CCND1 rearrangements, resulting in cyclin D1 protein expression, have also been reported. In this report, we describe an unusual primary large B-cell lymphoma of non-germinal center immunophenotype of the central nervous system (CNS) in an elderly male patient, which was negative for CD5 and SOX11, and exhibited cyclin D1 expression. Fluorescence in situ hybridization analysis detected IGH-CCND1 and BCL6 rearrangements. This case may represent the first report of a primary CNS DLBCL with IGH-CCND1 rearrangement. The clinico-pathologic features that can help differentiate primary CNS MCL from primary DLBCL of the CNS with IGH-CCND1 rearrangement are discussed.

Topics: Aged, 80 and over; Biomarkers, Tumor; Biopsy; Central Nervous System Neoplasms; Cyclin D1; Gene Expression; Gene Rearrangement; Humans; Immunohistochemistry; Immunophenotyping; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Oncogene Proteins, Fusion

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.

Topics: Aged; Aged, 80 and over; Cyclin D1; Diagnosis, Differential; DNA Copy Number Variations; Female; Humans; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged

Despite improved survival for the patients with diffuse large B cell lymphoma (DLBCL), the prognosis after relapse is poor. LincRNA-p21 is a long intergenic noncoding RNA, which is located on chromosome 17, approximately 15 kb upstream from the Cdkn1a (p21) gene. However, its clinical importance and biological role in DLBCL prognosis are unknown. In this study, we conducted quantitative reverse-transcription polymerase chain reaction to investigate the lincRNA-p21 expression in DLBCL. We found that lincRNA-p21 levels were markedly decreased in DLBCL tissues compared with normal. Its expression level was significantly correlated with Ann Arbor stages, B symptoms, performance status, IPI score and serum LDH. Moreover, patients with high levels of LincRNA-p21 expression had a favorable overall survival and progression-free survival. Furthermore, ectopic expression of lincRNA-p21 inhibited cell proliferation, arrested cycle progression and modulated cyclin D1, CDK4 and p21 expression in DLBCL cell lines. These results demonstrated lincRNA-p21 can be identified as a potential novel prognostic biomarker for prognosis in DLBCL and regulate cell proliferation and cycle in vitro. Our findings highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.

Topics: Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclophosphamide; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; L-Lactate Dehydrogenase; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prednisone; Prognosis; Recurrence; Rituximab; RNA, Long Noncoding; Signal Transduction; Survival Analysis; Vincristine

To characterize the clinicopathological and genetic features of pleomorphic mantle cell lymphoma (PMCL), which morphologically mimics diffuse large B cell lymphoma (DLBCL).. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Biomarkers, Tumor; Class I Phosphatidylinositol 3-Kinases; Cyclin D1; Diagnosis, Differential; Female; Gene Dosage; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Intracellular Signaling Peptides and Proteins; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Polymerase Chain Reaction; Young Adult

Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Cyclin D1; Female; Hodgkin Disease; Humans; Immunohistochemistry; Immunophenotyping; In Situ Hybridization, Fluorescence; Lymphocytes; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Young Adult

Cyclin D1-positive tumor cells are commonly found in mantle cell lymphoma but they are very rare in diffuse large B-cell lymphoma.. Here we present a rare case of cyclin D1-positive diffuse large B-cell lymphoma in the right tonsil of a 50-year-old man. Computed tomographic imaging detected a mass, about 2.5 cm × 1.8 cm in size, in the left side of the oropharynx.. Microscopically, the tumor cells were located under the pharyngeal mucosa and diffusely arranged. The tumor cells were large, with marked nuclear atypia. On performing immunohistochemistry, the tumor cells showed diffuse positive staining for CD10, CD20, cyclin D1, and Pax-5, and negative staining for CD3, CD15, CD30, CD56, and CK. Bcl-6 and Mum-1 expression were observed in 60% and 80% of tumor cells, respectively. The tumor Ki67 index was about 60%. Based on these findings, The tumor was diagnosed as a rare cyclin D1-positive diffuse large B-cell lymphoma rather than a mantle cell lymphoma.. Cyclin D1-positive large B-cell lymphoma is rare, but as large B-cell lymphoma is a common type of lymphoma, cyclin D1-positive large B-cell lymphoma should be considered a major possibility during differential diagnosis, including in the tonsils.

Topics: Chemoradiotherapy; Cyclin D1; Germinal Center; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Palatine Tonsil; PAX5 Transcription Factor; Tomography, X-Ray Computed

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. Exploring a novel and important biomarker is indispensable for understanding the mechanism and clinical course of DLBCL. Emerging studies have shown that aberrant expression of long noncoding RNA (lncRNAs) is strongly associated with carcinogenesis. The aim of this study was to investigate the value of lncRNA LUNAR1 in DLBCL. Quantitative real-time PCR was performed to illustrate the patterns of LUNAR1 expression in tumor tissues and cell lines. The higher expression of LUNAR1 was significantly correlated with stage, rituximab and IPI. Univariate and multivariate analyses showed that LUNAR1 expression served as an independent predictor for overall survival and progression-free survival. Receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic values and the area under the ROC curve of LUNAR1 was up to 0.9420. Further experiments revealed that LUNAR1 knockdown significantly repressed cell proliferation of DLBCL by regulating E2F1, cyclin D1 and p21. In conclusion, our results indicate that LUNAR1 may serve as a candidate prognostic biomarker through growth regulation in DLBCL.

Topics: Age Factors; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease-Free Survival; Down-Regulation; E2F1 Transcription Factor; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Staging; Prognosis; Real-Time Polymerase Chain Reaction; RNA, Long Noncoding; RNA, Small Interfering; ROC Curve; Sex Factors; Transfection

To demonstrate and confirm the existence of cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) with IGH-CCND1 rearrangement and discuss the rationale of differentiating this entity from blastoid and pleomorphic variants of mantle cell lymphoma (MCL).. Two cyclin D1-positive lymphomas with morphologic features of DLBCL and IGH-CCND1 translocations were characterized with respect to clinical features, as well as morphologic, immunophenotypic, cytogenetic, and molecular findings.. The large tumor cells were CD20+, CD5-, CD10-, BCL6+, MUM1+, and cyclin D1+ in both cases. SOX11 was negative. Epstein-Barr virus-encoded RNA in situ hybridization demonstrated diffuse positivity in case 1. BCL6 and IGH-CCND1 rearrangements were identified by fluorescence in situ hybridization in both cases. Specifically, the diagnosis of a relapsed DLBCL with acquisition of IGH-CCND1 was rendered for case 1, molecularly confirmed by the detection of identical monoclonal IGH rearrangements between the initial diagnostic DLBCL and relapse lymphoma.. Our study demonstrates convincingly that IGH-CCND1 rearrangement leading to cyclin D1 overexpression can occur in DLBCL and pose a potential diagnostic pitfall, requiring thorough knowledge of the clinicopathologic findings to allow accurate discrimination from a blastoid or pleomorphic MCL. The coexistence of IGH-CCND1 and IGH-BCL6 rearrangements suggest that BCL6 and cyclin D1 may cooperate in the pathogenesis of DLBCL.

Topics: Biomarkers, Tumor; Cyclin D1; DNA-Binding Proteins; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-6; Tissue Array Analysis; Translocation, Genetic

Mantle cell lymphoma (MCL) is a B-cell neoplasm with a variable and generally aggressive clinical course. So far our knowledge of skin involvement of MCL is limited. To understand the clinical and histopathologic features of MCL with skin involvement, the files of the Lymph Node Registry Kiel were screened for MCL diagnosed in the skin. Over a period of 13 years, 1321 biopsy specimens were diagnosed as MCL; among them, 14 patients (1%) showed skin involvement. Of these, skin was the initial site of manifestation in 6/11 (55%) cases. One patient presented with a skin-limited lymphoma. Furthermore, 7/12 (58%) patients presented with lesions on the leg. The lymphomas were highly proliferative with blastoid cytology in 12/14 (86%) cases. Moreover, the immunophenotype with expression of BCL2 (100%), MUM-1/IRF4 (83%), and IgM (82%) and lack of CD10 (25%) and BCL6 (0%) closely resembled the features of primary cutaneous diffuse large B-cell lymphoma, leg type. Solely the expression of cyclin D1 (100%) and the presence of t(11;14) (100%) allowed a distinction from cases of primary cutaneous diffuse large B-cell lymphoma, leg type. Only 2 MCL cases with skin involvement presented with classical cytology. Interestingly, in these 2 cases skin involvement occurred simultaneously in a lesion of coexisting primary cutaneous marginal zone lymphoma. Our data suggest that clinical presentation on the leg and blastoid cytology along with high proliferation and expression of Bcl2, Mum-1/IRF4, and IgM are typical for MCL involving the skin. Lymphomas with these features might be erroneously diagnosed as diffuse large B-cell lymphoma, leg type, if cyclin D1 staining is not performed.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy; Cell Proliferation; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Diagnosis, Differential; Female; Germany; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Leg; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Predictive Value of Tests; Registries; Retrospective Studies; Skin Neoplasms; Time Factors; Translocation, Genetic

To study expression of CD68, cyclin D1 protein and rearrangement of bcl-6 gene impact on the prognosis of diffuse large B-cell lymphoma (DLBCL).. Gets paraffin samples of the 105 cases DLBCL with the detailed follow-up information, and were studied by using immunohistochemical EnVision method for CD3, CD10, CD20, CD68, cyclin D1, bcl-6, MUM 1, SOX-11 immunolabeling. The DLBCL were classified into germinal center B cell-like (GCB) subtypes and non-germinal center B cell-like (non-GCB) subtypes according to Hans'algorithm. Application of fluorescence in situ hybridization (FISH) technique to detect the bcl-6 gene rearrangement. The relationship between CD68, cyclin D1 protein, the bcl-6 gene and the curative effect of chemotherapy and survival was analyzed using statistical software. Respectively by GCB type, non-GCB type immune phenotype and CHOP, R-CHOP chemotherapy group, compare the curative effects.. 105 patients had GCB 19 cases (18.1%), non-GCB 86 cases (81.9%), CD68 expression was 18 cases (17.1%), cyclin D1 high expression 36 cases (34.3%), bcl-6 gene rearrangement in 21 cases (21.9%), there is no correlation among the three (P > 0.05). One-way analysis of variance showed that age ≤ 60 years, clinical stage I-II, IPI score 0 to 2 points, LDH (U/L) < 245 IU/L,GCB subtypes, R-CHOP therapy, the prognosis of patients with better (P < 0.05), But gender, primary site no correlation with prognosis (P > 0.05). CD68, cyclin D1 high expression, bcl-6 rearrangement had poor prognosis (P < 0.05). Stratification analysis results show GCB-type or non-GCB type with high expression of CD68 contrast alloimmune phenotype groups had a poor prognosis, non-GCB type with high expression of cyclin D1 and rearrangement of bcl-6 gene had a poor prognosis (P < 0.001, P = 0.02). Treatment scheme of layered display, the CHOP treatment, significantly correlated with overall survival with high expression of CD68, cyclin D1 (P < 0.05), the R-CHOP treatment, there was no statistically significant difference between CD68, cyclin D1 high expression and overall survival (P = 0.428 and 0.168). Multivariate COX model analysis showed that high expression of CD68 (P = 0.026), high expression of cyclin D1 (P = 0.003) and high levels of LDH (P = 0.005) were adverse prognostic factors independent.. high expression of CD68, cyclin D1 and rearrangement of bcl-6 gene suggests poor prognosis, CD68, cyclin D1 protein and bcl-6 gene can be used as a prognostic indicator in patients with DLBCL.

Topics: Antibodies, Monoclonal, Murine-Derived; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Cyclin D1; Cyclophosphamide; DNA-Binding Proteins; Doxorubicin; Gene Rearrangement; Germinal Center; Humans; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Prednisone; Prognosis; Proto-Oncogene Proteins c-bcl-6; Rituximab; Vincristine

Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression.. The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene (CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression.. In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 (BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog (MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase (MDM2), MDM4, and tumor protein 53 (TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL.. Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal, Murine-Derived; Cyclin D1; Cyclophosphamide; Daunorubicin; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Mice; Middle Aged; Prednisone; Prevalence; Prognosis; Rituximab; Vincristine; Young Adult

Overexpression of cyclin D1 in diffuse large B-cell lymphomas (DLBCLs) is observable in about 5% of cases and is linked to gains of additional CYCLIN D1 gene copies or deregulation at the mRNA level. All cyclin D1-positive DLBCL cases reported so far lack the canonical t(11;14)(q13;q32) translocation that is a genetic hallmark and the primary cause of cyclin D1 overexpression in mantle cell lymphoma (MCL). Using standard histologic and genetic techniques, complemented with genome-wide aberration analysis by array comparative genomic hybridization, we characterized 2 exceptional cases of blastoid B-cell lymphomas with cyclin D1 overexpression, both bearing genetic rearrangements in the CYCLIN D1 gene locus. One of them had a t(11;14)(q13;q32) translocation and featured morphology, immunophenotype, and genetic copy number aberrations typical of DLBCL. The second case had a complex t(4;11;14) translocation, but the other features were intermediate between DLBCL and MCL and did not allow unambiguous classification in any of the current diagnostic lymphoma categories. On the basis of these findings, we conclude that detection of t(11;14) should not preclude a diagnosis of cyclin D1-positive DLBCL when all other parameters are in agreement with such a diagnosis. Moreover, a yet unacknowledged diagnostic "gray zone" may exist between DLBCL and MCL.

Topics: Aged; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Comparative Genomic Hybridization; Cyclin D1; Female; Genes, bcl-1; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Translocation, Genetic

Current immunohistochemical methods to study the expression of multiple proteins in a single tissue section suffer from several limitations. In this article, we report on sequential immunohistochemistry (S-IHC), a novel, easy method that allows the study of numerous proteins in a single tissue section, while requiring very limited optimization.. In S-IHC, a tissue section is stained for multiple antibodies, with intermediate scanning of the section and elution of chromogen and antibodies. Overlays are made of the digital images, allowing assessment of multiple proteins in the same tissue section. We used S-IHC to study nine nodular lymphocyte-predominant Hodgkin lymphomas (NLPHLs) and 10 T-cell-rich and histiocyte-rich diffuse large B-cell lymphomas (T/HRBCLs) for expression of cyclin D1, CD20, and CD68. We observed cyclin D1 expression in single tumour cells in 44% of NLPHLs and 60% of T/HRBCLs. Comparison of S-IHC with classic single immunohistochemical staining revealed discrepancies in eight cases (42%), demonstrating the difficulty of differentiating tumour cells from histiocytes on morphological grounds, and stressing the additional value of S-IHC.. For research and diagnostic purposes, S-IHC is a promising technique that assesses the expression of numerous proteins in single tissue sections with complete architectural information, allowing phenotypic characterization of single cells.

Topics: Antigens, CD; Antigens, CD20; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Cyclin D1; Female; Histiocytes; Hodgkin Disease; Humans; Immunohistochemistry; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; T-Lymphocytes

Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.. We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.. pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.. The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cyclin D1; Cyclophosphamide; Doxorubicin; Female; Gene Expression; Genes, bcl-2; Genes, myc; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; NF-kappa B; Phosphorylation; Prednisone; Prognosis; Proto-Oncogene Proteins c-akt; Rituximab; Signal Transduction; STAT3 Transcription Factor; Tumor Burden; Tumor Suppressor Protein p53; Vincristine

Topics: Antigens, CD20; Antirheumatic Agents; CD5 Antigens; Cyclin D1; Eyelid Neoplasms; Eyelids; Herpesvirus 4, Human; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Neoplasm Regression, Spontaneous

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclin D1; Dexamethasone; Diagnosis, Differential; Follow-Up Studies; Histiocytic Necrotizing Lymphadenitis; Humans; Infectious Mononucleosis; Ki-67 Antigen; Lymph Nodes; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Neck; Pyrazines; SOXC Transcription Factors

SOX11 is mainly correlated with embryo neurogenesis and remodeling of tissues. D cyclins (cyclin D1, cyclin D2, and cyclin D3) work in cell transformation. We assessed the expression of SOX11, cyclin D1, cyclin D2, and cyclin D3 mRNA in 152 patients with B-cell lymphocytic proliferative diseases (B-LPD) using qRT-PCR and we detected SOX11 protein using immunohistochemistry in 15 B-LPD patients, to clarify the clinical significance of the four genes in B-LPD. Data showed the transcriptional levels of SOX11 and cyclin D1 were higher for the mantle cell lymphoma (MCL) samples compared with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), and healthy collators. The expression levels of cyclin D1 and cyclin D2 were both higher in DLBCL than in SMZL. The expression levels of the four genes were highly related to each other. Three of 4 MCL patients showed nuclear staining for SOX11, while other 11 B-LPD examples were negative. Furthermore, we also found the ZAP70-positive CLL patients had higher SOX11 expression levels than ZAP70-negative CLL patients. It was revealed that MCL patients have higher expression levels of SOX11 and cyclin D1 mRNA, specially expressed nuclear SOX11 protein.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cyclin D1; Cyclin D2; Cyclin D3; Female; Humans; Immunoenzyme Techniques; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; SOXC Transcription Factors

Topics: CD5 Antigens; Cyclin D1; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Translocation, Genetic

To characterize the frequency and clinicopathological features of cyclin D1-positive diffuse large B-cell lymphoma (DLBCL) and the usefulness of SOX11 in the differential diagnosis from mantle cell lymphoma (MCL).. We retrospectively stained 206 consecutive DLBCLs for cyclin D1, and identified three (1.5%) positive cases, comprising two in the elderly with necrosis, and a third with a starry-sky pattern. All three cases shared the same non-germinal centre B-cell (non-GCB) phenotype [CD5-/CD10-/bcl-6+/MUM1+/SOX11-], Epstein-Barr virus (EBV) negativity, and absence of CCND1 aberrations by fluorescence in-situ hybridization. The third case showed both BCL6 and MYC rearrangements: a double-hit lymphoma. In the same period there were 22 MCLs, all expressing cyclin D1, with 89% cases expressing SOX11, a frequency that is statistically different from cyclin D1-positive DLBCL. Notably, we identified a pleomorphic MCL initially misdiagnosed as DLBCL. A separate cohort of 98 DLBCL cases was negative for SOX11, with only one case expressing cyclin D1 with a GCB phenotype (CD10+/bcl-6+/MUM1-). The two patients with tumour necrosis rapidly died of disease. The other two were in complete remission after immunochemotherapy.. Cyclin D1-positive DLBCLs are rare, and they are negative for SOX11 or CCND1 aberration. SOX11 is useful in differentiating cyclin D1-positive DLBCL from MCL.

Topics: Adult; Aged; Biomarkers, Tumor; Cyclin D1; Diagnosis, Differential; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Retrospective Studies; SOXC Transcription Factors; Tissue Array Analysis

To evaluate the value of cytomorphologic and immunocytochemical approaches in the diagnosis of hematologic neoplasms in serous effusion.. The cytospin and Thinprep smears of effusion specimens were prepared from 23 cases of lymphoid malignancies with histological confirmation and 30 cases of benign effusions used as control. Morphological assessment of the cellular components was conducted, including the ratio of mesothelium to lymphocyte, karyomorphism of lymphoid cell and the presence of apoptosis and mitosis. Immunocytochemical study was performed in all the cases, with flow cytometry in one case.. Among the 23 tumor cases, 14 represented disease relapse, and in the remaining nine cases, the serous effusion was the primary manifestation. The proportion of mesothelium was low in the tumor group, being less than 10% in 20 cases (87.0%, 20/23). It was more than 10% in most of benign cases (20/30, 66.7%). Lymphoid cells were prominent (> 80% cells) in 69.6% of the tumor cases, and the cellular component in some control cases (63.3%, 19/30) showed fewer lymphocytes. Nipple-like projection of lymphocytic nuclei could be detected in almost all the tumor cases (91.3%, 21/23), but was occasionally found in the control group (26.7%, 8/30). Apoptosis and mitosis were obvious in lymphomatous effusion, but observed in only 6.7% of the control cases. Significant difference of the previously mentioned cytomorphologic features existed between the tumor and control groups (P < 0.01). The results of immunocytochemical staining in cell block were identical to the corresponding immunohistochemistry, and one case of mantle cell lymphoma was confirmed by flow cytometry. The cytologic findings seen in all the 23 studied cases were in agreement with the corresponding histologic diagnosis.. Some cytomorphologic features, including decreased number of mesothelium, increased number of lymphoid cells, nuclear nipple-like projection, and the presence of apoptosis and mitosis, are very useful for diagnosing lymphoid malignancy in serous effusion. Immunocytochemistry is an important approach to the cytodiagnosis and classification of lymphoma.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Ascitic Fluid; Cyclin D1; Cytodiagnosis; Female; Humans; Immunohistochemistry; Interferon Regulatory Factors; Lymphocytes; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mitosis; Pleural Effusion, Malignant; Young Adult

The aims of this study were to analyze the incidence and morphology of cyclin D1+ DLBCL and cases of Richter transformation (RT), and to elucidate possible molecular mechanisms of cyclin D1 overexpression. Seventy-two cases of de novo DLBCL and 12 cases of RT were included in this study. Cyclin D1 positivity was found in 10/66 (15%) cases of unselected de novo DLBCL and in 2/11 (18%) cases of RT. Seven independently identified cases of cyclin D1+ DLBCL, including one RT, were added to the study. Centroblastic morphology was found in 17/19 (89%) cases of cyclin D1+, most with a post-germinal center phenotype (CD10-, BCL6+, MUM1+). No alterations in the CCND1 gene indicative for a translocation t(11;14) were identified by FISH. Analysis of the MYC locus yielded gene copy alterations in five cases and no disruption of the gene locus in any case, suggesting an alternative mechanism of cyclin D1 deregulation.

Topics: Cell Transformation, Neoplastic; Chromosome Aberrations; Chromosomes, Human, Pair 11; Cyclin D1; Cytogenetic Analysis; Gene Dosage; Gene Expression Regulation, Neoplastic; Genes, myc; Genetic Loci; Germinal Center; Humans; Immunophenotyping; In Situ Hybridization, Fluorescence; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Translocation, Genetic

Increased expression of cyclin D1 is notoriously associated with mantle cell lymphoma because of translocation t(11;14)(q13;q32) or variants involving the cyclin D1 gene. We present an unusual case of CD5-negative diffuse large B-cell lymphoma expressing cyclin D1 in the absence of translocation by fluorescence in situ hybridization analysis. Using array-comparative genomic hybridization, we found a complex karyotype without the characteristic chromosomal aberrations accompanying cyclin D1 translocation in mantle cell lymphoma; instead, there was monoallelic deletion of AKT interacting protein and glycogen synthase kinase-3 β genes, both involved in the AKT/glycogen synthase kinase-3 β cascade-controlling nuclear levels of cyclin D1. These findings suggest that posttranslational events regulating cyclin D1 activity may take place also in a subset of diffuse large B-cell lymphomas and contribute to lymphomagenesis. As a consequence, the sole cyclin D1 positivity by immunohistochemistry may not be enough to distinguish pleomorphic/blastoid mantle cell lymphoma from diffuse large B-cell lymphoma. Search for t(11;14) with fluorescence in situ hybridization probes should always be performed in doubtful cases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; Comparative Genomic Hybridization; Cyclin D1; Humans; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Male; Microarray Analysis; Neoplasm Staging; Translocation, Genetic; Treatment Outcome

D-cyclin proteins play a central role in cell-cycle regulation and are involved in the pathogenesis of lymphomas. In mantle-cell lymphoma, the t(11;14) translocation leads to overexpression of cyclin-D1, in addition to which cyclin-D1-negative mantle-cell lymphoma that overexpress cyclin-D2 or D3 have also been described. Although cyclin-D2 and D3 have been implicated in the prognosis of specific lymphoma subtypes, a thorough characterization of D-cyclin protein expression in human hematolymphoid neoplasia has not been reported. To evaluate the tissue expression patterns of D-cyclins, particularly D2 and D3, in normal and neoplastic hematolymphoid tissues, we optimized the commercially available antibodies for D-cyclins for use on paraffin-embedded tissue and stained tissue microarrays of over 700 patient samples. Our results show that cyclin-D2 and D3 proteins are expressed in many more lymphoma subtypes than cyclin-D1. Cyclin-D1, D2 and D3 were expressed in 100, 22 and 6% of mantle-cell lymphomas and 2, 49 and 20% of diffuse large B-cell lymphomas. Fluorescence in situ hybridization studies confirmed the presence of the CCND1/IGH translocation in the majority of mantle-cell lymphoma, but not in diffuse large B-cell lymphoma that expressed cyclin-D1 protein. In addition, a subset of follicular, marginal zone, lymphoplasmacytic, lymphoblastic, classical Hodgkin, mature T-cell and natural killer cell lymphomas and acute myeloid leukemias also expressed cyclin-D2 and D3. These data support the hypothesis that dysregulation of cell-cycle control by D-cyclins contribute to the pathogenesis of hematolymphoid neoplasia, and suggest a potential role for these proteins in the prognostic and therapeutic aspects of these diseases. For diagnostic purposes, however, the expression of D-cyclin proteins should be interpreted with caution in the subclassification of lymphoma types.

Topics: Biomarkers, Tumor; Cyclin D1; Cyclin D2; Cyclin D3; Female; Humans; Immunoglobulin Heavy Chains; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Tissue Array Analysis; Translocation, Genetic

Cyclin D1, an important component of cell cycle machinery and a protein with known oncogenic potential, is downregulated in normal mature B lymphocytes. Its expression detected in a number of malignancies, including B-cell lymphomas, may be important for oncogenesis.. In our work, we determined the level of cyclin D1 expression in various B-cell lymphomas (i.e., mantle cell lymphoma, B-cell chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and compared it with normal B cells. For cyclin D1 level evaluation, the real-time quantitative polymerase chain reaction data was normalized. We tested five reference genes for stability on our sample set and using the three most stable ones (YWHAZ, ubiquitin c, and HPRT) obtained rather small intra-group variance for cyclin D1 expression in most lymphomas. This allowed their statistically significant ranking according to cyclin D1 expression level.. Median values of normalized cyclin D1 expression determined by real-time quantitative polymerase chain reaction were 1.32 for mantle cell lymphoma, 0.02 for B-cell chronic lymphocytic leukemia, 0.009 for diffuse large B-cell lymphoma, 0.004 for marginal zone lymphoma, 0.002 for follicular lymphoma compared with 0.0003 for reactive lymphoid tissue, and 0.00004 for sorted B cells of healthy donors.. Our data demonstrate that mantle cell lymphoma, a lymphoma with t(11;14)(q13;q32) translocation, has the level of cyclin D1 increased by four orders of magnitude, while other B-cell lymphomas without t(11;14)(q13;q32) translocation still have the level of cyclin D1 significantly elevated above that of normal lymphocytes (2 orders for B-cell chronic lymphocytic leukemia and an order for other lymphomas) and suggests more than one method of its upregulation in malignant B cells.

Topics: Aged; B-Lymphocytes; Cyclin D1; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Immunohistochemistry; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Spleen

We present a case of diffuse large B-cell lymphoma CD5 negative, Cyclin D1 positive presenting as ruptured spleen in a 63-year-old man requiring emergent splenectomy. Tumor cells showed marked pleomorphism, anaplasia, and increased mitotic figures with positive Cyclin D1, BCL6, MUM1, P53, and a high MIB1 proliferative fraction. The patient received multiple therapies and ultimately died. This case raises the differential diagnoses of pleomorphic mantle cell lymphoma and other aggressive lymphomas with pleomorphic, anaplastic, and Reed-Sternberg-like cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; Cyclin D1; Diagnosis, Differential; Fatal Outcome; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Rupture, Spontaneous; Splenic Rupture; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (OR(AG), 1.41; 95% CI, 1.10-1.81; OR(GG), 1.65; 95% CI, 1.25-2.19; P(trend) = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (OR(AG), 1.34; 95% CI, 1.08-1.68; OR(AA), 1.60; 95% CI, 1.22-2.08; P(trend) = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Biomarkers, Tumor; Case-Control Studies; Cell Cycle; Cyclin D1; DNA-Binding Proteins; DNA, Neoplasm; Female; Genotype; Haplotypes; Humans; Lymphocytes; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Membrane Proteins; Microfilament Proteins; Middle Aged; Oncogene Proteins; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; Young Adult

This report describes an unusual case of cyclin D1 expression by an otherwise typical follicular lymphoma, of low histological grade. BCL2-IGH and CCND1-IGH fusions were identified by interphase fluorescence in situ hybridisation.

Topics: Biomarkers, Tumor; Cyclin D1; Female; Humans; In Situ Hybridization, Fluorescence; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Mixed Tumor, Malignant; Recurrence

Topics: Chromosomes, Human, Pair 3; Cyclin D1; DNA-Binding Proteins; Female; Gene Rearrangement, B-Lymphocyte; Humans; Immunoglobulins; In Situ Hybridization, Fluorescence; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Proto-Oncogene Proteins c-bcl-6

To explore the prognostic factors of primary nodal diffuse large B-cell lymphomas (N-DLBCL).. According to the 2001 WHO classification of tumors of hematopoietic and lymphoid tissue, 51 cases of primary N-DLBCL were collected for clinical data analysis and immunohistochemical assay. Antibodies used for study were anti-CD20, CD79alpha, CD45RO, CD3, Bcl-2, Ki-67, CD30, CD15, kappa, lambda, Cyclin D1, TdT, GFAP, CK, MPO. The survival data was analyzed.. Of the 51 cases of N-DLBCLs, 40 were reclassified as centroblastic, 3 B-immunoblastic, 1 T-cell/histiocytes rich, 2 B-cell anaplastic large cell, 1 plasmablastic, and 4 unclassified. Expression of Bcl-2 oncoprotein was observed in 24 cases (47.1%). The median Ki-67 index was 50.0% and the index more than 40% was found in 35 cases (68.6%). Survival analysis of 35 cases had follow up data showed that the 2 year and 5-year overall survival (OS) rates were 48.54% and 35.30%, respectively. The 5-year OS rates patients with International Prognosis Index (IPI) >/= 3 was lower than that with IPI < 3 (P < 0.01). The 5-year OS rates for patients with B symptoms was lower than that without B symptoms (P < 0.05). The 5-year OS rates for patients with Ki-67 index more than 40% was lower than that with less than 40% (P < 0.05). The expression of Bcl-2 oncoprotein was uncorrelated to prognosis (P > 0.05).. IPI, B symptoms and Ki-67 index are the prognostic factors for patients with N-DLBCL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD20; Child; Child, Preschool; Cyclin D1; Female; Follow-Up Studies; Humans; Immunohistochemistry; Ki-1 Antigen; Ki-67 Antigen; Leukocyte Common Antigens; Lewis X Antigen; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prognosis; Survival Analysis; Young Adult

In the Western world the second most common type of non-Hodgkin's lymphomas is follicular lymphoma (FL) comprising 30-35% of all cases. According to the data of the National Cancer Registry and our institute, this ratio is lower in Hungary and is about 15-20%, but the occurrence shows an increasing tendency.. Our aim was to survey and revise FLs that had been diagnosed at the National Institute of Oncology between 1990-1995. We studied the diagnostic relevance of histology, immunohistochemistry and the detection of immunoglobulin heavy chain (IgH) and bcl-2 gene rearrangements.. We surveyed 53 cases that were previously diagnosed as follicular or centrocytic, centroblastic lymphoma. Following histological re-examination, immunohistochemistry (CD20, CD3, bcl-2, CD10, bcl-6, CD5, p53, cyclin D1 and Ki-67) was performed on each case. We also studied the IgH and bcl-2 (major breakpoint region=MBR) gene rearrangement on paraffin embedded samples with conventional PCR methods. The classification was made according to the new WHO classification.. After the revision of the 53 cases we found 37 follicular, 11 diffuse large B-cell, 1 mantle cell and 1 marginal zone lymphomas, 1 nodular lymphocyte predominant Hodgkin's lymphoma and 2 follicular hyperplasias. The grade of the FLs correlated with the expression of different antigens. CD10, bcl-2 expression and the proliferation index with Ki-67 showed good correlation with the grade of FLs. We could detect bcl-2 gene rearrangement in 55% of the FLs.. Considering the diagnostic relevance of the different methods we can conclude that histology alone is not sufficient to make a correct diagnosis. Ninety percent of our cases were solvable with the help of immunohistochemistry and in 10% of the cases the diagnosis was partly based on the molecular pathological results.

Topics: Antigens, CD; Biomarkers, Tumor; Cyclin D1; Diagnosis, Differential; Gene Rearrangement; Humans; Immunohistochemistry; Ki-67 Antigen; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Retrospective Studies; Tumor Suppressor Protein p53

Prognosis of mantle cell lymphoma (MCL) remains poor. Patients who achieve a response to first line therapy usually relapse, and the probability of cure remains low. Glutathione-S-transferase pi (GST-pi) overexpression has been associated with alkylating agents and anthracycline resistance. GST-pi gene is located in 11q13 and is coamplified along with CCND1 gene in some human solid tumors.. We performed immunohistochemical analysis of GST-pi expression in 24 consecutive MCLs, 12 follicular lymphomas (FLs), and 69 diffuse large B-cell lymphomas (DLBCLs). Cases were classified in three groups: high GST-pi expression (> 50% of cells were stained), moderate (5 to 50% cells were stained), or absent (< 5% cells were stained). GST-pi and CCND1 mRNA levels were also assessed by real-time reverse transcription-PCR analysis.. All MCLs exhibit high GST-pi protein expression, compared with 29% of the DLBCLs and none of the FLs. MCLs expressed high levels of GST-pi and CCND1 mRNAs compared with DLBCLs and FLs. There was a strong relation between GST-pi and CCND1 mRNAs transcript levels in MCLs but not in DLBCLs. In conclusion, protein and mRNA GST-pi expression is high in MCL compared with FL and DLBCL.. Overexpression of CCND1 in MCL is associated with a transcriptional up-regulation of the GST-pi gene. Our results suggest that the glutathione system could play a role in drug resistance in MCL.

Topics: Adult; Aged; Aged, 80 and over; Cyclin D1; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Immunohistochemistry; Isoenzymes; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.

Topics: Apoptosis Regulatory Proteins; Bayes Theorem; Carrier Proteins; Chromosomes, Human, Pair 14; Cyclin D1; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Genes, bcl-2; Germinal Center; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neprilysin; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Survival Analysis; Survival Rate; Translocation, Genetic

Cyclin D1 overexpression is a valuable marker for the diagnosis of mantle cell lymphoma (MCL). We used a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method to quantify levels of cyclin D1, CD20, and cyclophilin A mRNA in manually microdissected, paraffin-embedded tissue sections using an ABI 7700 qRT-PCR system. The study group included 21 cases of MCL and 37 cases of other types of B-cell non-Hodgkin's lymphoma. Cyclin D1 mRNA copy number was normalized to CD20 and cyclophilin A mRNA and evaluated statistically by analysis of variance. The relative cyclin D1 levels were similar whether normalized to CD20 or cyclophilin A, indicating that CD20 levels are stable and can be used as a B-cell-specific normalizer. Statistically significant differences were found in the median levels of cyclin D1 mRNA (expressed as % CD20 mRNA) among cases of MCL (87.6), small lymphocytic lymphoma (9.9), follicular lymphoma (2.4), diffuse large B-cell lymphoma (5.9), marginal zone B-cell lymphoma (39.8), and Burkitt lymphoma (7.1) (P < 0.05). We conclude that qRT-PCR can be used to quantify cyclin D1 mRNA levels in archival tissue sections. Normalization of cyclin D1 to a B-cell-specific marker more accurately reflects overexpression by MCL than other methods that normalize using constitutively expressed mRNA species.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD20; Archives; Biomarkers, Tumor; Burkitt Lymphoma; Cyclin D1; Cyclophilin A; DNA Primers; Female; Humans; Immunoenzyme Techniques; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Paraffin Embedding; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm

De novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5- DLBCL and mantle cell lymphoma (MCL). To further characterize CD5+ DLBCL, 109 patients with CD5+ DLBCL were reviewed, and the results were compared with those of 384 CD5- DLBCL and 128 cyclin D1+ MCL patients. Patients with CD5+ DLBCL showed a higher age distribution (median, 66 years; P =.0083) and a female predominance (male-female ratio, 49:60, P =.011) compared with those with CD5- DLBCL. CD5+ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5- DLBCL: 69% older than 60 years (P =.039), 34% with performance status greater than 1 (P =.0016), 69% with serum lactate dehydrogenase level higher than normal (P <.0001), 62% with stage III/IV disease at diagnosis (P =.0023), 35% with more than one extranodal site (P =.023), and 40% with B symptoms (P =.0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5+ DLBCL than for those with CD5- DLBCL (P =.00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5- DLBCL (P <.0001) but lower than that for cyclin D1+ MCL (P =.0015). Histopathologically, CD5+ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5+ DLBCL was characterized by a CD5+CD10-CD19+CD20+CD21-CD23- cyclin D1- phenotype and a predominance of surface IgMkappa. Of particular interest is that CD5+ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5- DLBCL (P =.0026). These findings suggest that CD5+ DLBCL may constitute a unique subgroup of DLBCL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; CD5 Antigens; Cyclin D1; Female; Humans; Immunohistochemistry; Immunophenotyping; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Phenotype; Prognosis; Treatment Outcome

The clinicopathological features of histiocyte-rich, T-cell-rich B-cell lymphoma (HRTR-BCL) were first recognized in 1992. In this study, 60 cases of HRTR-BCL were analysed in order to provide a detailed morphological and immunophenotypical profile of the disorder.. HRTR-BCL is easily distinguished from other B-cell lymphomas rich in stromal T-cells by (i) a diffuse or vaguely nodular growth pattern, (ii) the presence of a minority population of CD15-, CD20+ large neoplastic B-cells, (iii) a prominent stromal component composed of both T-cells and non-epithelioid histiocytes, and (iv) the scarcity of small reactive B-cells. These criteria also enable a reliable distinction from lymphocyte-rich classical Hodgkin's lymphoma (CHL), from lymphocyte-predominant Hodgkin's lymphoma (LPHL), paragranuloma type and from peripheral T-cell lymphoma. Based on the morphology of the neoplastic cells and on their frequent bcl-6 immunoreactivity, we speculate that HRTR-BCL may be derived from a progenitor cell of germinal centre origin.. HRTR-BCL presents characteristic clinical features, affecting predominantly middle-aged men who present with advanced stage disease and are at high risk of treatment failure. Considering these distinctive clinicopathological features, recognizing HRTR-BCL as a lymphoma entity may be justified.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD20; Biomarkers, Tumor; Cyclin D1; Diagnosis, Differential; Female; Histiocytes; Humans; Immunoenzyme Techniques; Immunophenotyping; Lewis X Antigen; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Spleen; T-Lymphocytes

This study analysed the morphologic differences between leukaemic mantle cell lymphoma, follicular lymphoma, nodal marginal zone lymphoma, and diffuse large B-cell lymphoma in peripheral blood. Additionally, we investigated the role of cyclin D1 expression in B-lymphoproliferative disorders.. The morphologic analysis of the leukaemic cells was performed on cytocentrifuge preparations after separation of mononuclear cells from peripheral blood using a Ficoll-Hypaque density gradient. Cyclin D1 protein expression was studied with the catalyzed signal amplification system. The expression of other markers (CD5, CD23, light chain immunoglobulins) was analysed by the APAAP method.. We describe in detail the morphology of the lymphoma cells in eight patients with mantle cell lymphoma, six patients with follicular lymphoma, 11 patients with nodal marginal zone lymphoma, and seven patients with diffuse large B-cell lymphoma. The morphological distinction between these lymphoma cells is a challenge for the haematologist. The investigation of cytocentrifuge preparations of mononuclear cells allows the detection of lymphoma cells also in cases with nondiagnostic white cell differential. Additionally, the immunotype (light chain restriction, CD5, CD23, and cyclin D1) of 108 patients with leukaemic B-lymphoproliferative disorders was studied. Diffuse nuclear expression of cyclin D1 protein (>20%) was specific for mantle cell lymphoma. However, only 6/8 patients showed cyclin-D1 positivity.. The morphologic analysis of lymphoma cells in cytocentrifuge preparations of mononuclear leukocytes in combination with immunocytochemical investigation allows the detection of mantle cells, centrocytes of follicular lymphoma, marginal zone cells, and cells of the diffuse large B-cell lymphoma in peripheral blood. The positivity of cyclin D1 protein improves the differentiation of mantle cells from other lymphoma cells.

Topics: Biomarkers, Tumor; Cyclin D1; Diagnosis, Differential; Humans; Immunohistochemistry; Leukocytes, Mononuclear; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Sensitivity and Specificity

To investigate the role of the cell cycle regulators p21(Waf1), p27(Kip1), retinoblastoma (Rb), and cyclin D1 in Richter's transformation of chronic lymphocytic leukemia (CLL), we analyzed 19 CLL and eight Richter's syndrome (RS) tumors, previously characterized for p53 and ARF/INK4a abnormalities. p21(Waf1)immunohistochemical expression was negative in 12 of 15 CLL (80%), whereas it was moderate or strong in three of seven RS (43%). p21(Waf1) gene was in germline configuration in all the tumors analyzed. Four immunohistochemical patterns of p53 and p21(Waf1) expression were observed: (1) p53-/p21- in 10 of 15 CLL (67%), but only in two of six RS (33%); (2) p53+/p21+ in three CLL (20%) and two RS (33%); (3) p53-/p21+ in one RS; and (4) p53++/p21- in two CLL and one RS. Two p53+/p21+ CLL evolved into RS. p53 mutations clustered around the p53++/p21- (two CLL and one RS) and p53-/p21- (one CLL and one RS) tumors. While the majority of CLL displayed strong p27 immunoreactivity, RS tumors were constantly p27-negative. p27(Kip1) gene was in germline configuration in all the tumors analyzed. Most CLL cases were negative for Rb expression. In contrast, all RS exhibited strong Rb expression. Cyclin D1 overexpression was only detected in one CLL evolving into RS and one RS. In conclusion, a p53+/p21- immunohistochemical pattern is shown exclusively by p53-mutated CLL/RS. Additionally, our results suggest a possible implication of moderate/strong p21(Waf1) expression, loss of p27 expression, and cyclin D1 overexpression in the Richter's transformation of CLL.

Topics: Adult; Aged; Cell Cycle; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Female; Genes, p53; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mutation; Retinoblastoma Protein; Tumor Suppressor Proteins

Knowledge of the role of cell-cycle regulators in the pathogenesis of acquired immune deficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHLs) is scarce. Here we analyzed 86 systemic AIDS-NHLs and 20 AIDS-primary central nervous system lymphomas for expression of p27(Kip1), a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27(Kip1), the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage. We report that AIDS-immunoblastic lymphomas (AIDS-IBLs), either systemic or primarily localized to the central nervous system, consistently express p27(Kip1) protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27(Kip1) to inhibit the cell cycle in AIDS-IBL. Conversely, the remaining systemic AIDS-NHLs and AIDS-primary central nervous system lymphomas preferentially fail to express p27(Kip1). Expression of p27(Kip1) in Epstein-Barr virus-positive AIDS-NHLs generally associates with latent membrane protein 1 (LMP1) expression and is related to a late stage of B-cell differentiation, characterized by the BCL-6-/MUM1+/syn-1+/- phenotypic profile, whereas it seems to be unrelated to the expression of cellular cyclins. In B cells in vitro, induction of LMP-1 expression under the control of inducible promoters up-regulates expression of p27(Kip1), thus providing a putative mechanistic explanation for the association between LMP1 and p27(Kip1) observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27(Kip1) positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.

Topics: Arabidopsis Proteins; B-Lymphocytes; Cell Cycle Proteins; Cell Differentiation; Cyclin D1; Cyclin D3; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; DNA-Binding Proteins; Humans; Interferon Regulatory Factors; Ki-67 Antigen; Lymphoid Tissue; Lymphoma, AIDS-Related; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasm Staging; Phenotype; Plant Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-6; Transcription Factors; Tumor Suppressor Proteins; Viral Matrix Proteins

Mantle cell lymphoma (MCL), and its leukemic phase, constitute a well-studied hematologic malignancy with known overall survival, prognostic indicators, morphologic findings at diagnosis and in bone marrow, and known incidence of the bcl-1 immunoglobulin gene rearrangement. Large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype (CD5+, CD23-), including but not limited to blastic MCL, prolymphocytoid MCL, blastic mantle cell leukemia, and prolymphocytic mantle cell leukemia, are not as well characterized. Although blastic MCL is known to be associated with a shorter overall survival than conventional MCL, the large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype have not been described as fully as conventional MCL.. The purpose of the present study was to describe the large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype.. Nineteen cases of large cell variants of CD5+, CD23- B-cell lymphoma/leukemia are reviewed and described in regard to morphology, bone marrow morphological findings, Cyclin D1 immunostaining, and bcl-1 analysis. Clinical data were not available owing to the varied clinical sources of the specimens.. Tertiary-care academic institution.. Lymph node involvement in blastic CD5+, CD23- B-cell lymphoma was diffuse (100%) with a nodular component (33%) or focal mantle zone pattern (10%). Bone marrow involvement in blastic CD5+, CD23- B-cell lymphoma was seen in only 27% of cases and was composed predominantly of small, slightly irregular lymphocytes. Cyclin D1 was demonstrated in 60% of the 15 cases analyzed and more sensitive in B5-fixed tissue. Bcl-1 (performed in 5 cases) was not detected in the 4 cases of blastic CD5+, CD23- B-cell lymphoma analyzed and was detected in the case of the prolymphocytoid MCL. Cyclin D1 was demonstrated in all 4 bcl-1 negative cases and was negative in the bcl-1 positive prolymphocytoid MCL.. Careful analysis of clinical data, morphology, immunophenotype, Cyclin D1 expression, and molecular analysis are required to differentiate the unusual large cell variants of MCL from other processes.

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow; CD5 Antigens; Cyclin D1; DNA, Neoplasm; Female; Flow Cytometry; Gene Rearrangement; Genes, bcl-1; Humans; Immunoenzyme Techniques; Immunophenotyping; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Polymerase Chain Reaction; Receptors, IgE; Retrospective Studies

An inverse correlation between p27(Kip1) expression and proliferation has been recently established in tissues derived from human lymphomas. The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)/phospholipase C-gamma (PLCgamma) complex also appears to play an important role in cell proliferation and malignant transformation of anaplastic large cell lymphoma (ALCL). In this study, we report that SUDHL-1 and KARPAS 299 ALCL-derived cell lines present different sensitivity to the antiproliferative effect of recombinant adenovirus-mediated p27(Kip1) expression or to serum-starvation in culture media. The results indicate that exogenous p27(Kip1) may interact with the NPM-ALK/PLCgamma pathway in SUDHL-1 but not in KARPAS 299 cells. This interaction correlates with changes in cell cycle and cell morphology observed mainly in SUDHL-1 cells. The percentage of SUDHL-1 cells in S phase declines, whereas it is almost unchanged in KARPAS 299 cells as compared to the controls after 96 h of infection with the recombinant adenovirus. Furthermore KARPAS 299 cells are resistant to serum-starvation due to deficient p27(Kip1)-upregulation and G1 arrest, whereas SUDHL-1 cells respond with increased G1 phase and p27(Kip1)-upregulation after 48 h of serum-starvation. Both cell lines express appropriate variation of levels of cyclins E and A, and Rb-phosphorylation as expected by growing them in culture media with different FBS content. Although both cell lines express cyclin D2, SUDHL-1 cells only present high level of cyclin D3. Moreover SUDHL-1 cells express high level of PTEN and the PKB/Akt pathway is constitutively activated in both cell lines. Lastly SUDHL-1 cells show higher levels of phosphotyrosine-containing proteins that is correlated with a higher NPM-ALK-associated autophosphorylation activity compared to KARPAS 299 cells. Our study clearly identifies some of the biochemical differences that may explain the difference in sensitivity to antiproliferative stimuli shown by two cell lines derived from the same type of lymphoma.

Topics: Adenoviridae; Apoptosis; Cell Cycle; Cell Cycle Proteins; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 5; Culture Media, Serum-Free; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Genetic Vectors; Humans; Isoenzymes; Lymphoma, Large B-Cell, Diffuse; Neoplasm Proteins; Phospholipase C gamma; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotyrosine; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Recombinant Fusion Proteins; S Phase; Transfection; Translocation, Genetic; Tumor Cells, Cultured; Tumor Suppressor Proteins; Type C Phospholipases

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.

Topics: Antigens, Nuclear; Carrier Proteins; Cell Cycle Proteins; Chromosome Aberrations; Cyclin D1; Cyclin D3; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; Cyclins; Databases as Topic; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; Female; Genes, p53; Genes, Retinoblastoma; Humans; Loss of Heterozygosity; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Staging; Nuclear Proteins; Polymorphism, Single-Stranded Conformational; Predictive Value of Tests; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Proto-Oncogenes; Retinoblastoma-Binding Protein 1; Survival Analysis; Transcription Factor DP1; Transcription Factors

We reviewed our institutional experience with de novo CD5+, large B-cell lymphomas to determine whether they represent a distinct entity and are related to CD5+ small B-cell disorders. We identified 13 cases with multiparameter flow cytometry over a period of 58 months (5% of large B-cell lymphomas) in 7 females and 6 males. Three groups were identified. Group 1 (2 cases) had diffuse splenic red pulp involvement with a distinctive cordal pattern of infiltration, no other clinical evidence of mass disease, microscopic disseminated disease on further workup, and an identical immunoglobulin-negative immunophenotype. Group 2 cases (7 cases) were clinically and morphologically heterogeneous and had an immunophenotype resembling mantle cell lymphoma (FMC7-positive, CD23-). Group 3 (4 cases) had miscellaneous immunophenotypes, including one closely resembling chronic lymphocytic leukemia. Cyclin D1 was positive in only 1 of 10 evaluable cases (group 2). We conclude that CD5+ diffuse large B-cell lymphomas are heterogeneous; most cases do not seem to be related to chronic lymphocytic leukemia or mantle cell lymphoma. However, we identified a subgroup of primary splenic CD5+ large B-cell lymphoma with diffuse red pulp involvement and believe this may represent a distinct clinicopathologic entity.

Topics: Adolescent; Adult; Aged; Antigens, CD; Antigens, Neoplasm; Cyclin D1; Female; Genes, p53; Humans; Immunoenzyme Techniques; Immunophenotyping; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Staging; Point Mutation; Splenic Neoplasms

Cyclin D1 participates in cell-cycle control, in the progression through the G(1) phase and in the transition from the G(1) to the S phase. The CCND1 locus, located in 11q13, is amplified and cyclin-D1 protein is over-expressed in a wide range of human solid tumors. In some B-lymphoid malignancies, the t(11;14)(q13;q32) translocation joins the Ig heavy-chain locus to the CCND1 locus and leads to cyclin-D1 over-expression. In this study, a series of 127 patients presenting a B-chronic lymphoproliferative disorder (B-CLPD) was analyzed using a competitive RT-PCR designed to detect cyclin-D1-mRNA over-expression. Cyclin-D1 mRNA was expressed in patients with mantle-cell lymphoma (MCL; 10/10), hairy-cell leukemia (HCL; 3/5), B-chronic lymphoid leukemia (B-CLL; 4/111) and B large-cell lymphoma (BLCL; 1/1). Densitometric analysis of RT-PCR products and Western-blot autoradiograms, in addition to cytogenetic data, indicated that activation of the cyclin-D1 gene occurred independently of the t(11;14)(q13;q32) translocation in patients with HCL. Indeed, a normal-sized protein of 36 kDa exhibiting a level incompatible with gene activation by a translocation mechanism was detected in lymphoid cells with a normal karyotype. Moreover, we found a discrepancy between cyclin-D1 mRNA and protein levels in MCL and B-CLL, which suggested that some regulatory mechanisms acting at a post-transcriptional level persist in tumor cells.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Humans; Karyotyping; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Protein Processing, Post-Translational; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Transcriptional Activation

Immunohistochemical expression of PRAD1/cyclin D1 protein has been investigated in 106 tissue specimens of 104 cases of lymphoma, non-neoplastic lymphoid disorders and other hematologic malignancies by employing the monoclonal antibody 5D4 with formalin-fixed paraffin-embedded sections, using the microwave oven heating method. Positive neoplastic cells were found in 60 (74%) of 81 cases of non-Hodgkin's lymphoma. The positivity pattern was nuclear in 17 (85%) of 20 cases of mantle cell lymphoma in which cytoplasmic staining was also seen. This pattern of cyclin D1 positivity was in contrast to the negative staining of normal reactive mantle zones. In the other cases, positivity appeared to lie within the cell cytoplasm without nuclear staining, and most of the nodal follicular and diffuse B-cell lymphomas variously expressed PRAD1/cyclin D1. In contrast, the reaction was absent in a significant number of T-cell and extranodal B-cell lymphomas. Immunolocalization of PRAD1/cyclin D1 expression appears to be a useful diagnostic adjunct to discriminate mantle cell lymphoma from other non-Hodgkin's lymphomas.

Topics: Antigens, CD; Biomarkers, Tumor; CD5 Antigens; Cyclin D1; Cyclins; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Lymphoid Tissue; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Oncogene Proteins; Proto-Oncogene Proteins