RESUMO
Carcinosarcomas of the urinary bladder are malignant biphasic tumors with an epithelial and a spindle cell component. For the histogenesis of the two components, a biclonal and a monoclonal origin are discussed. We present the immunomorphology and molecular cytogenetics of such a case. The immunohistology of biopsies of the urinary bladder revealed a poorly differentiated urothelial carcinoma (GIII) and a co-existing pleomorphic, spindle cell leiomyosarcoma (GIII). The two components were microdissected and further analyzed for gains and losses of chromosomal material using comparative genomic hybridization. In addition, loss of heterozygosity analyses were included. The tumor components revealed as overlapping core aberrations losses on the short arm of chromosome 9 and on the long arm of chromosome 11. However, both components showed additional aberrations exclusively detected in one of the components. The occurrence of overlapping aberrations strongly argues for a monoclonal origin of this tumor with a common ancestor. The additional aberrations of the components point to an independent and divergent course of tumor progression in both components.
Assuntos
Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Carcinossarcoma/genética , Carcinossarcoma/patologia , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Idoso , Carcinoma de Células de Transição/química , Carcinossarcoma/química , Aberrações Cromossômicas , Mapeamento Cromossômico , Células Clonais/química , Células Clonais/patologia , Dissecação , Evolução Fatal , Feminino , Humanos , Cariotipagem , Leiomiossarcoma/química , Micromanipulação , Hibridização de Ácido Nucleico/métodos , Neoplasias da Bexiga Urinária/químicaRESUMO
Hodgkin- and Reed-Sternberg (HRS) cells microdissected from 41 classical Hodgkin lymphomas (cHL) of 40 patients comprising 8 lymphocyte-rich (cHL-LR), 16 nodular sclerosis (cHL-NS), 15 mixed-cellularity (cHL-MC), and 2 lymphocyte-depletion (cHL-LD) subtypes were analyzed by comparative genomic hybridization for recurrently imbalanced chromosomal subregions. Chromosomal gains most frequently involved chromosome 2p (54%), 12q (37%), 17p (27%), 9p and 16p (24% each), and 17q and 20q (20% each), whereas losses primarily affected chromosome 13q (22%). Using fluorescence in situ hybridization, amplification of the REL oncogene was demonstrated within a distinct 2p15-p16 amplicon. The high frequency of 2p overrepresentations including REL, particularly in cHL-NS (88%), suggests that an alternative mechanism of constitutive activation of nuclear factor NF-kappaB is a hallmark of HRS cells. Hierarchical cluster analysis of chromosomal imbalances revealed a closer relationship among cHL-NS than other subtypes. Furthermore, there is a tendency for different subtypes of cHL-MC tumors characterized by different ages at the time of tumor onset and gain of chromosome 17p. The imbalance pattern of cHL subtypes suggests that different molecular pathways are activated, with REL or other genes on chromosomal band 2p15-p16 playing a fundamental role in the pathogenesis of classical Hodgkin lymphoma.
Assuntos
Cromossomos Humanos Par 2/genética , Dosagem de Genes , Doença de Hodgkin/genética , Adolescente , Adulto , Idoso , Criança , Análise por Conglomerados , Feminino , Genes rel/genética , Doença de Hodgkin/etiologia , Doença de Hodgkin/patologia , Humanos , Cariotipagem , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico/métodos , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Células de Reed-Sternberg/patologiaRESUMO
Structural aberrations of the short arm of chromosome 2, mostly resulting in gains of 2p13 approximately 16, have recently been described as being highly recurrent in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). As these gains consistently lead to increased copy numbers of the REL oncogene locus, we investigated the expression of the c-Rel protein in a series of 30 cHL cases with known genomic REL status as determined by comparative genomic hybridization and interphase cytogenetics. Expression of the c-Rel protein was investigated in 26 biopsies by immunohistochemistry. Distinct patterns were observed in HRS cells with no staining, cytoplasmic, and/or nuclear staining for c-Rel. All 13 samples with additional copies of the REL locus displayed nuclear staining for c-Rel, while 13 cHL samples lacking chromosome 2 (2p) gains displayed a significantly lower proportion or complete absence of HRS cells with nuclear c-Rel expression. Detailed analysis using combined immunophenotyping and interphase cytogenetics of individual HRS cells demonstrated that REL gains correlated with the presence of nuclear c-Rel staining. Additionally, in 2 cHL samples with translocation breakpoints in 2p13 approximately 16, nuclear staining of c-Rel was observed; in one of them the staining pattern was indicative of a truncated c-Rel protein. The correlation between structural aberrations involving the REL locus and nuclear c-Rel accumulation in HRS cells qualifies REL as a target gene of the frequent gains in 2p in cHL. The data suggest that REL aberrations are a genetic mechanism contributing to constitutive nuclear factor (NF)-kappa B/Rel activation in cHL.