cyclin-d1 and Hodgkin-Disease

Non-Hodgkin lymphoma may occasionally contain large transformed cells resembling Hodgkin and Reed-Sternberg cells (HRS cells). We report a 63-year-old man with HRS cells in a recurrent mantle cell lymphoma (MCL). The patient initially presented with orbital MCL and recurred after 8 years with widespread involvement. The HRS cells were present in the recurrent disease but not in the initial orbital lesions, suggesting a transformed event after a prolonged disease course. Morphologically, the HRS cells were single cells and small clusters among the MCL cells and were frequently accompanied by histiocytes but without eosinophils or other inflammatory cells. The HRS cells showed a phenotype of classic Hodgkin lymphoma (cHL). The HRS cells were clonally related to the MCL, which was demonstrated by the presence of identical t(11;14) that resulted in productive cyclin D1 expression in both cell types. Review of the literature identified 7 additional MCL cases that showed a spectrum of clinical and pathologic features ranging from scattered HRS cells to true composite MCL and cHL. The HRS cells were clonally related to MCL in 4 cases (including the current case) and unrelated in 2 cases. These findings suggest MCL with HRS cells is a heterogeneous group that may represent a spectrum of transformation at the various stages. Proof of clonal relationship between HRS cells and MCL is useful to distinguish these cases from true composite MCL and cHL.

Topics: Cell Transformation, Neoplastic; Clone Cells; Cyclin D1; Eye Neoplasms; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Reed-Sternberg Cells; Tumor Cells, Cultured

Classic Hodgkin lymphoma (cHL) is characterized by the presence of Hodgkin Reed-Sternberg (HRS) cells. Although HRS cells express PAX5, cHL frequently lacks other B-cell markers. There is now evidence that HRS cells are monoclonal and are derived from germinal center B-cells. In terms of genetic aberrations, cHL frequently exhibit activated NF-kB signaling pathway. In this study, we present a case of cHL harboring a t(11;14) (q13;q32)/CCND1::IGH, identified by chromosome and fluorescence in situ hybridization analysis and with CCND1 expression in HRS cells. We also analyzed recurrent cytogenetic aberrations in t(11;14) positive mantle cell lymphoma (MCL) and those found in cHL from the literature to assess genetic overlap, clonal evolution, and to identify potential signaling pathways in cHL with CCND1::IGH. This analysis suggests the development of t(11;14)+ cHL and MCL from a transformed precursor cell with t(11;14) through genetic evolution and consequent deregulated pathways, including the NF-κB and NOTCH1 signaling.

Topics: Adult; Chromosome Aberrations; Cyclin D1; Hodgkin Disease; Humans; In Situ Hybridization, Fluorescence; Lymphoma, Mantle-Cell; Translocation, Genetic

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed-Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5

Topics: Aged; Autografts; Biomarkers, Tumor; Cyclin D1; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Hodgkin Disease; Humans; In Situ Hybridization, Fluorescence; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Male; Reed-Sternberg Cells; Tumor Suppressor Protein p53

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

Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) VH gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post-)germinal center (GC) B cell. This also demonstrates the (post-)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function-impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.

Topics: Aged; B-Lymphocytes; Clone Cells; Cyclin D1; Germinal Center; Hodgkin Disease; Humans; Immunoglobulin Heavy Chains; In Situ Hybridization, Fluorescence; Laser Capture Microdissection; Lymphoma, Mantle-Cell; Male; Mutation; Polymerase Chain Reaction; Translocation, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53

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

Fucoxanthin (FX) is a natural carotenoid with reported antitumorigenic activity. This study explored the effects of FX and its deacetylated product, fucoxanthinol (FXOH), on B-cell malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma and Epstein-Barr virus-immortalized B cells. Both FX and FXOH reduced the viability of these malignant B cells in a dose-dependent manner accompanied by the induction of cell cycle arrest during G1 phase and caspase-dependent apoptosis. FXOH was approximately twice more potent than FX in these activities. In contrast, normal peripheral blood mononuclear cells were resistant to FX and FXOH. Strong and constitutive activation of nuclear factor-κB (NF-κB) is a common characteristic of many B-cell malignancies, and FXOH suppressed constitutive NF-κB activity. NF-κB inhibition was accompanied by downregulation of NF-κB-dependent anti-apoptotic and cell cycle regulator gene products, including Bcl-2, cIAP-2, XIAP, cyclin D1 and cyclin D2. The results indicated that FX and FXOH are potentially useful therapeutic agents in B-cell malignancies characterized by aberrant regulation of NF-κB.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; B-Lymphocytes; beta Carotene; Burkitt Lymphoma; Caspases; Cell Line, Transformed; Cyclin D1; Cyclin D2; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Herpesvirus 4, Human; Hodgkin Disease; Humans; NF-kappa B; X-Linked Inhibitor of Apoptosis Protein; Xanthophylls

Topics: Aged, 80 and over; Antigens, CD20; Cyclin D1; Female; Herpesvirus 4, Human; Hodgkin Disease; Humans; Ki-1 Antigen; Lymphoma, Mantle-Cell; Neoplasms, Multiple Primary; Reed-Sternberg Cells

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.

Topics: Alternative Splicing; Cell Cycle; Cell Line, Tumor; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; DNA Methylation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Lymph Nodes; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Protein Isoforms; Proto-Oncogene Proteins c-mdm2; RNA, Messenger; RNA, Neoplasm; Thymus Gland; Tumor Suppressor Protein p53

Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.

Topics: Antigens, CD; Apoptosis; Carrier Proteins; Caspase 9; Caspases; CD30 Ligand; CD40 Ligand; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Chromones; Cyclin D1; Dose-Response Relationship, Drug; Flow Cytometry; G1 Phase; Hodgkin Disease; Humans; Membrane Glycoproteins; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Tumor Necrosis Factors

Topics: Aged; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Fatal Outcome; Female; Hodgkin Disease; Humans; In Situ Hybridization, Fluorescence; Ki-1 Antigen; Lewis X Antigen; Lymphoma, Mantle-Cell; Reed-Sternberg Cells; Translocation, Genetic

The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G1-phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21CIP1 and p27KIP1. Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S- or G2-phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G1-phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carrier Proteins; Cell Cycle Proteins; Child; Cyclin A; Cyclin D1; Cyclin D3; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Female; Hodgkin Disease; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Proliferating Cell Nuclear Antigen; Reed-Sternberg Cells

Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.

Topics: Cell Transformation, Neoplastic; Clone Cells; Cyclin D1; Genes, bcl-2; Genes, Tumor Suppressor; Hodgkin Disease; Humans; Immunoglobulin Heavy Chains; Lymphoma; Lymphoma, Non-Hodgkin; Mutation; Translocation, Genetic; Tumor Suppressor Protein p53

Signal cascades of mitogen-actived protein kinase(MAPK) and signal transducer and activator of transcription 3 (Stat3) are two main signal transduction pathways which were associated with cell proliferation and malignant transformation.MAPK and Stat3 proteins are activated by phosphorylation. The biological effects which are caused by multiple cytokines produced by Hodgkin's lymphoma(HL) cells are mediated through MAPK and Stat3 signal pathways. This study was designed to investigate significance of MAPK and Stat3 phosphorylation(p-MAPK and p-Stat3) and cyclin D1 protein expression in HL.. SP immunohistochemistry was used to detect expression of p-MAPK, p-Stat3, and cyclin D1 protein in 45 cases of HL of various types.. The expression positive rates of p-MAPK, p-Stat3, and cyclin D1 proteins were 73.3%(33/45),64.4%(29/45), and 68.9%(31/45), respectively. The positive expression levels of p-MAPK and cyclin D1 protein gradually increased(P< 0.05), whereas that of p-stat3 had no significant difference(P >0.05) in four subsets(LR:lymphocyte-rich classical type; NS:nodular sclerosis type; MC:mixed cellularity type; LD:lymphocyte depletion type) of all cases. The expression of p-MAPK was positively related to that of cyclin D1 protein (r(s)=0.7254,P< 0.01), but the expression of p-Stat3 was not related to that of cyclin D1 protein (r(s)=0.2197,P >0.05).. The data suggest that activation of MAPK may play an important role in genesis and progression of HL, but Stat3 activation is not associated with the progression of HL. MAPK may induce overexpression of cyclin D1 protein and results in persistent proliferation of RS/H cells in genesis and development of HL.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclin D1; DNA-Binding Proteins; Female; Hodgkin Disease; Humans; Immunohistochemistry; Lymphoma; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinases; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Transcription, Genetic

The expressions of p42/44 mitogen-activated protein kinase(p42/p44MAPK) and cyclin D1 protein were detected by SP immunohistochemical technique in 40 cases of Hodgkin's disease(HD) and 13 cases of reactive hyperplasia(RH). The results showed that p42/p44MAPK and cyclin D1 protein were both overexpressed in RS/H cells of HD(positive rates were 72.5% and 70% respectively), and their positive rates were positively correlated(P < 0.01). The data suggest that MAPK cascades signal transduction may play an important role in genesis of HD. MAPK may induce overexpression of cyclin D1 protein and result in persistent proliferation and progression of RS/H cells.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclin D1; Female; Hodgkin Disease; Humans; Immunohistochemistry; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Pseudolymphoma; Reed-Sternberg Cells; Signal Transduction

t(11;14)(q13;q32) observed in B-cell malignancies is associated with cyclin D1 (bcl-1, PRAD1, CCND1) overexpression. We devised a simple competitive reverse transcription-polymerase chain reaction (RT-PCR) assay for rapid detection of cyclin D1 overexpression. Sharing a single upstream primer derived from a homologous sequence in cyclins D1, D2 and D3, each PCR product serves as a competitor and cyclin D1 overexpression is determined by comparing the intensities of the three amplified products. We analyzed cyclin D1 in clinical specimens from 104 patients with lymphoid malignancies. Cyclin D1 overexpression was evident in 13 of 104 (7/72 non-Hodgkin's lymphomas, 0/6 adult T-cell lymphoma/leukemias, 0/4 Hodgkin's diseases, 0/11 acute lymphoblastic leukemias, 3/4 multiple myelomas, 1/2 Waldenström's macroglobulinemias, 1/2 prolymphocytic leukemias and 1/3 chronic lymphocytic leukemias). Among 72 patients for whom cytogenetic studies had been done, all 7 patients with t(11;14) were positive. The relative expression levels of D-type cyclins altered dramatically in the presence of t(11;14). Thus, this RT-PCR assay can identify tumors with cyclin D1 overexpression. Cyclin D1 overexpression was frequent in extranodal specimens (11 out of 32 vs. 2 of 72 lymph nodes) and was restricted to specific types of lymphoid malignancies, as observed using other methods. This reliable assay should be suitable to provide clinical guidance for the diagnosis and management of lymphoid malignancies, especially in the case of extranodal involvement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Cyclin D1; Female; Hodgkin Disease; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transcription, Genetic; Waldenstrom Macroglobulinemia