cyclin-d1 and Lymphoma--Large-Cell--Anaplastic

Malignant lymphoma is a heterogeneous category embracing three major types of lymphoid neoplasms: B cell neoplasms, T and NK cell neoplasms, and Hodgkin lymphoma. Within each type, distinct disease entities are defined based on a combination of morphology, immunophenotype, genetic features and clinical syndromes, the emphasis on which represents a new paradigm in the lymphoma classification of the World Health Organization (WHO). These lymphoma entities often have distinctive cytogenetic abnormalities, usually involving translocations that place a potential cellular oncogene under the influence of the immunoglobulin in some low-grade B-cell lymphomas. Both pathologists and oncologists are now concerned with better understanding each disease entity and its spectrum of morphology, genetic events, and clinical behaviors. Over the last decade, significant progress has been made in the molecular characterizations of mantle cell lymphoma, anaplastic large cell lymphoma, and marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), which have not only provided insights into the pathogenesis of lymphomas, but also valuable data that could lead to therapies based on their clinical behavior.

Topics: Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Chromosome Aberrations; Cyclin D1; Humans; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Mantle-Cell; Molecular Diagnostic Techniques; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases

Scattered reports in the literature have shown that Cyclin D1 mRNA and protein may be expressed in anaplastic large cell lymphoma (ALCL). ALCLs are characterized by the presence of ALK translocations. Aberrant Cyclin D1 expression seems to promote proliferation in other types of lymphoma, while a growth promoting CCND1/TACSD1(TROP2) fusion product has also been described in tumors. Herein, we investigated 44 ALCL cases for chromosome 11 and CCND1 status (by FISH), cyclin D1 mRNA expression (by in situ hybridization and RT-PCR) and Cyclin D1 protein (by immunohistochemistry with two different monoclonal antibodies), as well as for the expression of Trop-2/GA733-1 (by immunohistochemistry). Polysomy of CCND1 (11q13) and chromosome 11 was found in 15/38 evaluated cases (39.5%). This change was specific for CD30+ neoplastic cells, as shown by double fluorescent staining. Neoplastic cells in the majority of ALCL expressed cyclin D1 mRNA (29/41 [70.7%]), in association with the presence of ALK translocations (p=0.024) and systemic, rather than cutaneous disease (p=0.021). Remarkably, however, Cyclin D1 protein was not detected in neoplastic cells (0/44 cases), neither were these found positive for Trop-2. In conclusion, aberrant copies of CCND1 / chromosome 11 may be observed in ALCL, probably as a consequence of the reported ploidy changes in these tumors. ALCL may often express cyclin D1 mRNA, which, however, does not result in the production of functional Cyclin D1 protein or Trop-2, suggesting that these proteins do not play a role in the pathogenesis of ALCL.

Topics: Adolescent; Adult; Aged; Child; Chromosomes, Human, Pair 11; Cyclin D1; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Gene Dosage; Gene Expression; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Indoles; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Male; Middle Aged; Rhodamines; RNA, Messenger; Young Adult

Upregulation of cyclin D1/B-cell leukemia/lymphoma 1 (CCND1/BCL1) is present in most mantle cell lymphomas with the t(11;14)(q13;q32) translocation. However, little is known about the abnormalities of CCND1 and its regulator RB1 in primary cutaneous T-cell lymphomas (CTCL). We analyzed CCND and RB status in CTCL using fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and Affymetrix expression microarray. FISH revealed loss of CCND1/BCL1 in five of nine Sézary syndrome (SS) cases but gain in two cases, and RB1 loss in four of seven SS cases. IHC showed absent CCND1/BCL1 expression in 18 of 30 SS, 10 of 23 mycosis fungoides (MF), and three of 10 primary cutaneous CD30+ anaplastic large-cell lymphoma (C-ALCL). Increased CCND1/BCL1 expression was seen in nine MF, seven C-ALCL, and six SS cases. Absent RB1 expression was detected in 8 of 12 MF and 7 of 9 SS cases, and raised RB1 expression in 7 of 8 C-ALCL. Affymetrix revealed increased gene expression of CCND2 in four of eight CTCL cases, CCND3 in three cases, and CDKN2C in two cases with a normal expression of CCND1 and RB1. These findings suggest heterogeneous abnormalities of CCND and RB in CTCL, in which dysregulated CCND and RB1 may lead to impaired cell cycle control.

Topics: Cell Nucleus; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell, Cutaneous; Male; Mycosis Fungoides; Oligonucleotide Array Sequence Analysis; Retinoblastoma Protein; Sezary Syndrome; Skin Neoplasms; Up-Regulation