cyclin-d1 and Lymphoma--T-Cell--Cutaneous

We describe the histopathological and clinical characteristics of 177 PCSM-LPD diagnosed at our consultation centre. We performed immunohistochemical multistaining in a subset of cases (n = 46) including PD1, Cyclin D1, and multiple markers of proliferation. We evaluated clonal T-cell-receptor-(TCR) rearrangements and used tissue microdissection to analyse TCR-clonality of PD1(+) cells.. The cohort of n = 177 PCSM-LPD included 84 males and 93 females (median age 57, range 13-85). Clinical presentation was as a solitary nodule or plaque (head and neck > trunk > extremities). Most patients were treated by local excision or steroids (96%, 69/72); relapses occurred in 12/65 (18%) of patients with follow up. Histopathology revealed the predominance of a nodular pattern (75%, 134/177) and frequent clustering of PD1(+) large cells (70%, 103/147). We detected Cyclin D1 and PD1 coexpression (>10% of PD1(+)-cells) in 26/46 (57%), which was not associated with CCND1 breaks or amplifications. PD1(+)-cells in PCSM-LPDs showed a significantly higher expression of proliferation-associated proteins compared to PD1(-)-cells. A clonal TCR-rearrangement was present in 176/177 (99%), with a clonal persistence in 7/8 patients at relapse including distant sites. Tissue-microdissection revealed PD1(+)-cells as the source of clonality, whilst PD1(-)-cells remained polyclonal.. PCSM-LPD is a clinically indolent, albeit neoplastic, disease driven by clonal expansion of PD1(+)-cells. We demonstrate Cyclin D1-expression associated with accelerated proliferation as a surprising new biological feature of the disease.

Topics: CD4-Positive T-Lymphocytes; Cell Proliferation; Cyclin D1; Female; Humans; Lymphoma, T-Cell, Cutaneous; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms

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

In the present study we investigated the pathogenetic role of c-myc, bcl-2, and lyt-10 oncogenes, bcl-1 locus, and p53 suppressor gene in a representative panel of cutaneous lymphomas, including 25 cases of cutaneous B cell lymphoma (CBCL) and 29 cases of cutaneous T cell lymphoma (CTCL). In our analysis four cases of CBCL were found rearranged for bcl-2 and two for the bcl-1 locus. Two cases of CTCL and one case of CBCL were found rearranged for lyt-10. No rearrangements of c-myc oncogene were found in CBCL. Analysis of p53 gene showed mutation only in one case of mycosis fungoides in tumoral stage, at codon 163 of p53 gene (TAC-->CAC; Tyr--> Asp). Our data suggest that in primary CBCL bcl-2 oncogenes and bcl-1 locus are rarely involved. Furthermore, in primary CTCL p53 gene is not affected at significant frequency. The occurrence of p53 mutation in a patient affected by mycosis fungoides in tumoral stage may represent an involvement of p53 gene in tumor progression of CTCL, a finding observed in several types of human cancer.

Topics: Base Sequence; Chromosome Aberrations; Cyclin D1; DNA Mutational Analysis; DNA, Neoplasm; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Gene Rearrangement, T-Lymphocyte; Genes, Immunoglobulin; Genes, myc; Genes, p53; Humans; Lymphoma, B-Cell; Lymphoma, T-Cell, Cutaneous; Molecular Sequence Data; Mycosis Fungoides; NF-kappa B; NF-kappa B p52 Subunit; Oncogenes; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Skin Neoplasms