RESUMO
Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.
Assuntos
Genômica , Neoplasias Renais/genética , Pesquisa Biomédica , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/patologiaRESUMO
Current models of Wilms tumour development propose that histological features of the tumours are programmed by the underlying molecular aberrations. For example, tumours associated with WT1 mutations arise from intralobar nephrogenic rests (ILNR), concur with CTNNB1 mutations and have distinct histology, whereas tumours with IGF2 loss of imprinting (LOI) often arise from perilobar nephrogenic rests (PLNR). Intriguingly, ILNR and PLNR are found simultaneously in Wilms tumours in children with overgrowth who have constitutional IGF2 LOI. We therefore examined whether the precursor lesions or early epigenetic changes are the primary determinant of Wilms tumour histology. We examined the histological features and gene expression profiles of IGF2 LOI tumours and WT1-mutant tumours which are associated with PLNR and/or ILNR. Two distinct types of IGF2 LOI tumours were identified: the first type had a blastemal-predominant histology associated with PLNR, while the second subtype had a myogenic histology, increased expression of mesenchymal lineage genes and an association with ILNR, similar to WT1-mutant tumours. These ILNR-associated IGF2 LOI tumours also showed signatures of activation of the WNT signalling pathway: differential expression of beta-catenin targets (MMP2, RARG, DKK1) and WNT antagonist genes (DKK1, WIF1, SFRP4). Unexpectedly, the majority of these tumours had CTNNB1 mutations, which are normally only seen in WT1-mutant tumours. The absence of WT1 mutations in tumours with IGF2 LOI indicated that CTNNB1 mutations occur predominantly in tumours arising from ILNR independent of the presence or absence of WT1 mutations. Thus, even though these two classes of tumours with IGF2 LOI have the same underlying predisposing epigenetic error, the tumour histology and the gene expression profiles are determined by the nature of the precursor cells within the nephrogenic rests and subsequent CTNNB1 mutations.
Assuntos
Neoplasias Renais/patologia , Tumor de Wilms/patologia , Sequência de Bases , Criança , Epigênese Genética , Perfilação da Expressão Gênica , Genes do Tumor de Wilms , Impressão Genômica , Humanos , Fator de Crescimento Insulin-Like II/genética , Neoplasias Renais/genética , Perda de Heterozigosidade , Dados de Sequência Molecular , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante , RNA não Traduzido , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas WT1/genética , Tumor de Wilms/genética , beta Catenina/genéticaRESUMO
Karyotype analysis can provide clues to significant genes involved in the genesis and growth of pancreas cancer. The genome of pancreas cancer is complex, and G-band analysis cannot resolve many of the karyotypic abnormalities seen. We studied the karyotypes of 15 recently established cell lines using molecular cytogenetic tools. Comparative genomic hybridization (CGH) analysis of all 15 lines identified genomic gains of 3q, 8q, 11q, 17q, and chromosome 20 in nine or more cell lines. CGH confirmed frequent loss of chromosome 18, 17p, 6q, and 8p. 14/15 cell lines demonstrated loss of chromosome 18q, either by loss of a copy of chromosome 18 (n = 5), all of 18q (n = 7) or portions of 18q (n = 2). Multicolor FISH (Spectral Karyotyping, or SKY) of 11 lines identified many complex structural chromosomal aberrations. 93 structurally abnormal chromosomes were evaluated, for which SKY added new information to 67. Several potentially site-specific recurrent rearrangements were observed. Chromosome region 18q11.2 was recurrently involved in nine cell lines, including formation of derivative chromosomes 18 from a t(18;22) (three cell lines), t(17;18) (two cell lines), and t(12;18), t(15;18), t(18;20), and ins(6;18) (one cell line each). To further define the breakpoints involved on chromosome 18, YACs from the 18q11.2 region, spanning approximately 8 Mb, were used to perform targeted FISH analyses of these lines. We found significant heterogeneity in the breakpoints despite their G-band similarity, including multiple independent regions of loss proximal to the already identified loss of DPC4 at 18q21.
Assuntos
Adenocarcinoma/genética , Aberrações Cromossômicas , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Bandeamento Cromossômico , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 8 , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Metáfase , Hibridização de Ácido Nucleico , Neoplasias Pancreáticas/patologiaRESUMO
Despite aggressive salvage regimens, approximately half of all children who suffer a Wilms' tumour recurrence will die of their disease. Although there are increasing data on molecular genetic prognostic factors present in the tumour at diagnosis, there is little information regarding the molecular events that occur with Wilms' tumour progression and relapse. In the present study, microarray-based comparative genomic hybridization (aCGH) analysis has been carried out on 58 Wilms' tumour samples, which included 38 untreated primary and 20 recurrent tumours. A higher degree of copy number changes was observed in the recurrent tumours (33.0% genomic clones) than in the primary tumour (21.2%). Paired analysis highlighted the acquisition of 15q gain with high levels of IGF1R expression in the tumour recurrence in two cases. The most statistically significant abnormality acquired between diagnosis and relapse was loss of 17p. One case that experienced 17p loss was classified as favourable histology at diagnosis, but exhibited diffuse anaplasia at recurrence and had a homozygous TP53 deletion. Another instructive case with a constitutional 11p13 deletion presented with bilateral tumours and suffered two subsequent recurrences in the left kidney. A somatic WT1 mutation was found only in the right kidney tumour, while the constitutional 11p13 deletion was the only abnormality detected in the initial left kidney tumour by aCGH. The two subsequent relapses in the left kidney contained an accumulation of additional genetic alterations, including an independent WT1 mutation.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Perfilação da Expressão Gênica , Recidiva Local de Neoplasia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Tumor de Wilms/genética , Aniridia/complicações , Aniridia/genética , Análise Mutacional de DNA , Progressão da Doença , Feminino , Deleção de Genes , Genes do Tumor de Wilms , Genes p53 , Homozigoto , Humanos , Interpretação de Imagem Assistida por Computador , Lactente , Masculino , Recidiva Local de Neoplasia/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tumor de Wilms/complicações , Tumor de Wilms/patologiaRESUMO
Studies examining altered imprinted gene expression in cancer compare the observed expression pattern to the normal expression pattern for a given tissue of origin, usually the somatic expression pattern for the imprinted gene. Germ cell tumors (GCTs), however, require a developmental stage-dependent comparison. To explore using methylation as an indicator of germ cell development, we determined the pattern of methylation at the 5' untranslated region of SNRPN in 89 GCTs from both children and adults. Fifty-one of 84 tumors (60.7%) (12/30 (40%) of cultured pediatric GCTs, 23/36 (63.9%) of frozen adult GCTs, and 16/23 (69.5%) of frozen pediatric GCTs, with five samples having results from both cultured and uncultured material) demonstrated a nonsomatic methylation pattern after dual digestion with XbaI, NotI, and Southern blot analysis. In contrast, only 2 of 18 (11%) control samples (16 non-GCTs and 2 normal ovaries) exhibited a nonsomatic pattern. In both cases, the result was shown to be due to copy number differences between maternal and paternal homologs, unlike the GCTs in which there was no evidence of an uneven homolog number. A comparison of the data for only the gonadal GCTs and the control data showed a highly significant difference in the proportion of tumors with methylation alterations at this locus (P = 0.0000539). Since there is no published evidence of the involvement of SNRPN methylation changes in the development of malignancy, the data suggest that the methylation pattern of SNRPN in GCTs reflects that of the primordial germ cell giving rise to the tumor.
Assuntos
Autoantígenos/genética , Metilação de DNA , Células Germinativas/crescimento & desenvolvimento , Germinoma/genética , Germinoma/patologia , Adolescente , Adulto , Criança , Pré-Escolar , DNA de Neoplasias/metabolismo , Feminino , Impressão Genômica/genética , Células Germinativas/patologia , Germinoma/metabolismo , Germinoma/secundário , Humanos , Lactente , Recém-Nascido , Masculino , Ribonucleoproteínas Nucleares Pequenas/genética , Células Tumorais Cultivadas , Proteínas Centrais de snRNPRESUMO
The most common malignant germ cell tumor of early childhood is the endodermal sinus tumor (CEST), also known as yolk sac tumor. Previous cytogenetic studies of CEST have demonstrated recurrent deletion of distal regions of chromosomes 1p and 6q. Studies utilizing comparative genomic hybridization have likewise demonstrated loss of distal 6q, however these studies show discrepant data concerning chromosome 1 abnormalities. This study analyses 18 CESTs for loss of heterozygosity (LOH) of distal chromosome 6q utilizing 17 microsatellite markers and 13 tumors were analysed for LOH of distal 1p using two microsatellite markers. LOH of 6q was found in 13/18 tumors (72 %). This data confirms that loss of genetic material on 6q is one of the most common abnormalities in CESTs and narrows the region of loss, enabling candidate tumor suppressor genes to be identified and analysed. In addition, LOH of 1p36 was identified in five of 11 informative tumors, clarifying prior conflicting data and confirming that 1p deletion is a common event in CESTs.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 6/genética , Tumor do Seio Endodérmico/genética , Frequência do Gene/genética , Perda de Heterozigosidade/genética , Repetições de Microssatélites/genética , Pré-Escolar , Humanos , Lactente , Masculino , Neoplasias Testiculares/genéticaRESUMO
BACKGROUND: Loss of imprinting (LOI) of the insulin-like growth factor-II (IGF2) gene, an epigenetic alteration associated with expression of the normally silent maternal allele, was observed first in Wilms tumor. Although LOI has subsequently been detected in most adult tumors, the biologic role of LOI in cancer remains obscure. We analyzed the imprinting status of Wilms tumors with respect to pathologic subtype, stage, and patient's age at diagnosis and examined the expression of genes potentially affected by LOI. METHODS: Of 60 Wilms tumors examined, 25 were informative for an ApaI polymorphism in the IGF2 gene, allowing analysis of allele-specific gene expression, and could be classified by pathologic subtype. Gene expression was measured quantitatively by real-time polymerase chain reaction, and pathologic analysis was blinded for genetic status. All statistical tests were two-sided. RESULTS: We observed LOI of IGF2 in nine (90%) of 10 Wilms tumors classified as having a pathologic subtype associated with a later stage of renal development and in only one (6.7%) of 15 Wilms tumors with a pathologic subtype associated with an earlier stage of renal development (P< .001). LOI was associated with a 2.2-fold increase (95% confidence interval [CI] = 1.6-fold to 3.1-fold) in IGF2 expression (P< .001). Children whose Wilms tumors displayed LOI of IGF2 were statistically significantly older at diagnosis (median = 65 months; interquartile range [IQR] = 47-83 months) than children whose tumors displayed normal imprinting (median = 24 months; IQR = 13-35 months; P< .001). CONCLUSIONS: These data demonstrate a clear relationship between LOI and altered expression of IGF2 in Wilms tumors and provide a molecular basis for understanding the divergent pathogenesis of this cancer. Analysis of LOI could provide a valuable molecular tool for the classification of Wilms tumor.
Assuntos
Regulação Neoplásica da Expressão Gênica , Impressão Genômica/genética , Fator de Crescimento Insulin-Like II/genética , Tumor de Wilms/classificação , Tumor de Wilms/genética , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Genes do Tumor de Wilms , Humanos , Lactente , Rim/citologia , Rim/metabolismo , Perda de Heterozigosidade/genética , Modelos Biológicos , Reação em Cadeia da Polimerase , Tumor de Wilms/patologiaRESUMO
Pediatric germ cell tumors (GCTs) commonly arise at extragonadal sites. It has been proposed that nongonadal GCTs arise from ectopic primordial germ cells that have aberrantly migrated during embryogenesis. During a time between their migration and development to mature gametes, primordial germ cells are characterized by their lack of imprinting, which can be assessed by the evaluation of allelic gene expression and DNA methylation in differentially methylated control regions. To elucidate the cellular origin of nongonadal GCTs, we evaluated the imprinting status of 21 gonadal and 21 nongonadal pediatric GCTs. Allele-specific H19 and IGF-2 expression was assessed with reverse transcription-PCR followed by digestion at polymorphic restriction sites. DNA methylation was evaluated after bisulfite modification, PCR amplification, and restriction digestion at a consistently methylated CpG dinucleotide within the 5' flanking region of the SNRPN gene. These results were compared with genetic gains and losses determined by comparative genomic hybridization. Seven of 15 informative tumors showed biallelic H19 expression, and 8 of 17 informative tumors showed biallelic IGF-2 expression. The frequency of biallelic gene expression was comparable in gonadal and nongonadal GCTs. Sixteen of 19 gonadal GCTs and 17 of 21 nongonadal GCTs showed absence of methylation of SNRPN consistent with loss of imprinting. One testicular GCT and three nongonadal GCTs showed a somatic methylation pattern. Two ovarian teratomas and one mediastinal teratoma showed only methylated SNRPN, consistent with entry into meiosis. Twenty-one of 22 non-GCT control samples showed a somatic methylation pattern. Gonadal and nongonadal germ cell tumors are derived from primordial germ cells that have consistently lost the imprinting of SNRPN and partly lost imprinting of H19 and IGF-2. Because the imprinting pattern of the latter genes differs from that found in testicular GCTs of adult patients, our data suggest that pediatric GCTs arise from a different stage of germ cell development.
Assuntos
Impressão Genômica , Germinoma/genética , Germinoma/patologia , Ribonucleoproteínas Nucleares Pequenas , Adolescente , Adulto , Alelos , Autoantígenos/genética , Criança , Pré-Escolar , Metilação de DNA , Feminino , Expressão Gênica , Humanos , Lactente , Fator de Crescimento Insulin-Like II/genética , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Hibridização de Ácido Nucleico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Longo não Codificante , RNA não Traduzido/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Proteínas Centrais de snRNPAssuntos
Fusão Gênica Artificial , Proteínas de Ligação a DNA/genética , Fibrossarcoma/genética , Receptor trkC/genética , Proteínas Repressoras/genética , Neoplasias de Tecidos Moles/genética , Proteínas de Ligação a DNA/análise , Fibrossarcoma/química , Fibrossarcoma/congênito , Fibrossarcoma/diagnóstico , Humanos , Lactente , Recém-Nascido , Proteínas Proto-Oncogênicas c-ets , RNA Neoplásico/análise , Receptor trkC/análise , Proteínas Repressoras/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/congênito , Neoplasias de Tecidos Moles/diagnóstico , Fatores de Transcrição , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Ewing sarcoma-primitive neuroectodermal tumor (EWS/PNET) belongs to the group of pediatric small round blue cell tumors; although EWS/PNET is classically a tumor of the soft tissue or bone in children and young adults, individual cases have been described in patients of all ages. A group of chromosomal translocations involving the EWS gene and a member of the Ets transcription factor family of genes has been detected in EWS/PNET, and heterogeneity in the precise breakpoint of the translocation has been shown to generate a group of related fusion transcripts that may have prognostic significance. Within the last decade, the clinicopathologic spectrum of EWS/PNET has been markedly expanded by recognition that the tumor may also have a visceral origin. To determine whether visceral EWS/PNET has the same pattern of genetic alterations and range of fusion transcripts as EWS/PNET of bone and soft tissue, we performed reverse-transcription polymerase chain reaction-based testing of formalin-fixed, paraffin-embedded tissue from a series of visceral tumors for which the diagnosis of EWS/PNET was well established. Together with additional cases compiled from the literature, EWS-Fli1 (or a related fusion transcript) was present in 18 of 19 visceral EWS/PNET, with a distribution of transcript types not statistically different from EWS/PNET of soft tissue and bone (P >.05, chi(2) test). These results firmly establish the genetic relationship between EWS/PNET of visceral sites, soft tissue, and bone.
Assuntos
Neoplasias Abdominais/patologia , Tumores Neuroectodérmicos Primitivos Periféricos/patologia , Sarcoma de Ewing/patologia , Neoplasias de Tecidos Moles/patologia , Vísceras/patologia , Neoplasias Abdominais/química , Neoplasias Abdominais/genética , Adolescente , Adulto , Biomarcadores Tumorais/análise , Primers do DNA/química , DNA de Neoplasias/análise , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Tumores Neuroectodérmicos Primitivos Periféricos/química , Tumores Neuroectodérmicos Primitivos Periféricos/genética , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1 , RNA Mensageiro/metabolismo , RNA Neoplásico/análise , Proteína EWS de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Ewing/química , Sarcoma de Ewing/genética , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Tomografia Computadorizada por Raios X , Fatores de Transcrição/análise , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Germ Cell Tumors (GCTs) in children and adolescents constitute a clinically and histologically heterogeneous group of tumors. Compared to GCTs in adults, the numbers of GCTs in children analyzed with cytogenetic and molecular genetic techniques is limited. However, the data available to date reveal a pattern of cytogenetic aberrations different from that in adults. Comparative genomic hybridization (CGH) is a valuable technique for the genetic profiling of tumors that allows screening for chromosomal imbalances consistent with amplification of oncogenes and loss of putative tumor suppressor genes. As CGH does not require tissue culture, it also allows analysing archival tissue samples. PATIENTS: This study focuses exclusively on GCTs in children younger than ten years of age and summarizes the genetic data of 51 tumors. Eighteen teratomas and 33 malignant GCTs were included. Primary sites were the testis (n=10), coccyx (n=13), mediastinum (n=20), ovary (n=5), CNS (n=2), and the face (n=1). METHODS: The experimental procedure includes differential enzymatic fluorescence labeling of tumor and control DNA followed by comparative hybridization to normal male chromosomes, karyotyping and computerized analysis of the fluorescence profiles. RESULTS: With the exception of one testicular and two ovarian tumors, malignant GCTs in children do not show chromosomal gain of 12p, which is characteristic of GCTs in adult patients. Irrespective of the primary site, childhood GCTs show chromosomal imbalances of chromosome 1 (loss of distal 1p, gain of 1q), deletion of 4q and 6q as well as gain of 20q at a high frequency. CONCLUSIONS: These studies will help guiding further investigations elucidating the role of putative tumor suppressor genes at e.g. 1p36 and 6q. In addition, further studies incorporated in prospective therapeutic protocols are necessary to evaluate the prognostic relevance of specific genetic aberrations.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , DNA de Neoplasias/análise , Germinoma/genética , Hibridização de Ácido Nucleico , Adolescente , Adulto , Fatores Etários , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Análise Citogenética , Tumor do Seio Endodérmico/genética , Neoplasias Faciais/genética , Feminino , Germinoma/classificação , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias do Mediastino/genética , Hibridização de Ácido Nucleico/métodos , Neoplasias Ovarianas/genética , Estudos Retrospectivos , Região Sacrococcígea , Teratoma/genética , Neoplasias Testiculares/genética , Células Tumorais CultivadasRESUMO
We report two cases of a hitherto undescribed pediatric renal neoplasm that is distinctive at the morphological, immunohistochemical, ultrastructural, and cytogenetic levels. On light microscopy, the tumors are composed of nests of polygonal, clear to eosinophilic cells associated with a subpopulation of smaller cells that surround hyaline material. Despite their epithelioid morphology, these tumors do not label immunohistochemically for epithelial markers but instead label focally for melanocytic markers HMB45 and Melan A. The hyaline material is positive with periodic acid-Schiff and methenamine-silver histochemical stains, and labels immunohistochemically for type 4 collagen. Ultrastructural examination confirms that it represents basement membrane material. Cytogenetic analysis reveals the identical t(6;11)(p21.1;q12) chromosome translocation as the sole abnormality in these two tumors, confirming their identity and distinctive nature.
Assuntos
Membrana Basal/ultraestrutura , Biomarcadores Tumorais/análise , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteínas de Neoplasias/análise , Translocação Genética , Adolescente , Antígenos de Neoplasias , Biomarcadores Tumorais/imunologia , Criança , Humanos , Imuno-Histoquímica , Cariotipagem , Neoplasias Renais/química , Masculino , Antígenos Específicos de Melanoma , Microscopia Eletrônica , Proteínas de Neoplasias/imunologiaRESUMO
This article is the offshoot of a Pediatric Oncology Group (POG) seminar presented at the Adams Mark Hotel, Denver, Colorado, Friday, May 21, 1999, titled "The Frozen Section in Pediatric Solid Tumors--Crucial Issues." There were eight presenters who spoke on a wide range of topics that included historical perspectives of the frozen section and discussion of the following systems: brain, renal, germ cell, bone, soft tissue, and lymph nodes. To complement these presentations, a pediatric surgeon explained his concern and philosophy regarding the use of frozen sections, and a lawyer tackled the issues and risks in rendering a frozen section diagnosis. We think that this review covers all the important aspects of the frozen section in our current practice of pediatric pathology.
Assuntos
Secções Congeladas/história , Neoplasias/história , Pediatria/história , Pré-Escolar , Secções Congeladas/tendências , História do Século XIX , História do Século XX , Humanos , Lactente , Neoplasias/patologiaRESUMO
The authors report nine new metanephric adenofibroma (MAFs; previously termed nephrogenic adenofibroma) and 16 related tumors from the files of the National Wilms Tumor Study Group Pathology Center (NWTSGPC). All tumors contained a variable amount of a bland spindle cell stroma, which is essentially identical to the recently described metanephric stromal tumor (MST). Features that distinguish this stroma from congenital mesoblastic nephroma (CMN) include intratumoral angiodysplasia, concentric cuffing of entrapped tubules ("onion skinning"), and heterologous differentiation. The epithelial components of these lesions spanned a wide range of appearances. All tumors contained at least focally an inactive embryonal epithelium identical morphologically to metanephric adenoma (MA), and hence each case could be classified as containing MAF. The epithelium of nine tumors had this appearance throughout, and hence these were considered usual MAFs. The epithelium of four tumors demonstrated increased mitotic activity but was otherwise similar to MA. The epithelial component of seven tumors spanned a morphologic spectrum from inactive MA to malignant epithelial predominant Wilms tumor (WT), with gradual transitions noted in several cases. Five other tumors contained a carcinomatous component distinct from these lesions but identical morphologically to papillary renal cell carcinoma (PRCC). In one of these cases, this component had metastasized to the regional lymph nodes at the time of diagnosis. No tumor recurred during follow-up, although almost all patients received adjuvant therapy for WT regardless of their tumor's histology and NWTSGPC diagnosis. In conclusion, MAF is a biphasic tumor that spans the morphologic spectrum between benign pure stromal (MST) and pure epithelial (MA) lesions, and can merge with the morphology of WT, supporting the concept that these are all related lesions. A relationship to PRCC is also evident.
Assuntos
Adenofibroma/patologia , Neoplasias Renais/patologia , Tumor de Wilms/patologia , Adenofibroma/química , Adenofibroma/classificação , Adenoma/química , Adenoma/classificação , Adenoma/patologia , Adolescente , Adulto , Biomarcadores Tumorais/análise , Carcinoma Papilar/química , Carcinoma Papilar/classificação , Carcinoma Papilar/patologia , Carcinoma de Células Renais/química , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/patologia , Criança , Pré-Escolar , Células Epiteliais/química , Células Epiteliais/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Lactente , Neoplasias Renais/química , Neoplasias Renais/classificação , Masculino , Proteínas de Neoplasias/análise , Células Estromais/patologia , Tumor de Wilms/química , Tumor de Wilms/classificaçãoRESUMO
The pathogenesis of lower urinary tract obstruction is disputed, particularly its relation to both abnormal prostatic development and the prune belly syndrome (PBS). In an attempt to clarify this issue we examined 11 males (17-38 weeks gestation) with PBS who were autopsied at our institution. The lower urinary tract was embedded intact and prepared as serial histologic sections. Of the 11 cases, 8 demonstrated mechanical obstruction of the lower urinary tract. In five of these eight cases, a "flap-valve" structure was formed by an abnormal angulation between the prostatic and penile portions of the urethra. These had dilated, thin-walled bladders and prostates and moderate to severe renal dysplasia. One of the eight cases had a valve-like obstruction at the level of the mid-prostatic urethra associated with a complex cloacal malformation and a thin-walled bladder, another case had an epithelial plug at the penile meatus, and the last of the eight cases had a posterior urethral valve. The three remaining cases showed no mechanical obstruction. However, each had megacystis with marked thickening, interstitial fibrosis, and disarray of smooth muscle bundles in the bladder wall. In 10 cases, the prostate had no or only sparse, flattened glands. These results suggest that the abnormal development of the prostate in PBS may be explained as a pressure-induced dysplasia rather than a primary maldevelopment. The findings further suggest that abnormal prostatic development and the prune belly syndrome may arise from either anatomic obstruction of various types or functional obstruction from megacystis.
Assuntos
Próstata/anormalidades , Síndrome do Abdome em Ameixa Seca/etiologia , Uretra/anormalidades , Obstrução Uretral/congênito , Obstrução Uretral/etiologia , Bexiga Urinária/anormalidades , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Síndrome do Abdome em Ameixa Seca/patologia , Estudos Retrospectivos , Uretra/diagnóstico por imagem , Obstrução Uretral/patologia , UrografiaRESUMO
495 medulloblastomas (MBs) from 6 Pediatric Oncology Group (POG) protocols were reviewed to assess the incidence and prognostic significance of "large cell" and "anaplastic" variants. "Large cell" medulloblastomas (LC MBs) were those with focal or diffuse, large, round neoplastic cells with prominent nucleoli. "Anaplastic" MBs (A MBs) were those with nuclei that were also large but markedly atypical with coarse chromatin and irregular shapes. Twenty-one cases were identified in the combined LC/A MB group, comprising about 4% of all MBs. Survival curves and Kaplan-Meier estimates of survival probabilities were examined separately for the LC/A MB and control groups. The logrank test for detecting poorer survival in the 21 cases was significant (p < 0.0001). Fluorescence in situ hybridization for c-myc showed amplification in 4 of 11 cases of the LC/A phenotype and 1 additional case of high level gain at 8q24 was disclosed by comparative genomic hybridization. Comparative genomic hybridization confirmed c-myc amplification and found evidence for isochromosome 17q in 3 of 4 LC/A cases studied successfully. One additional tumor showed high level gain restricted to 2p13 consistent with n-myc amplification. Monosomy 22, common in atypical teratoid/rhabdoid tumors, was not found. These results suggest that LC/A MB phenotype could be, at least in part, a correlate of c-myc, and possibly n-myc, amplification. The study thus confirms original observations about the LC MB in regard to histological features, immunohistochemical findings, c-myc amplification, cytogenetic findings, and poor prognosis.
Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Anaplasia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/mortalidade , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Incidência , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidade , Prognatismo , Proteínas Proto-Oncogênicas c-myc/genética , Distribuição por Sexo , Análise de Sobrevida , Sinaptofisina/análiseRESUMO
Partial hydatidiform moles (PHM) have defined villous abnormalities and are usually triploid. Their diagnosis often can be made by morphology alone, without confirmation of ploidy, but considerable interobserver variability exists. Other genetic abnormalities such as trisomy can result in placentas with abnormal villous morphology (AVM) similar to that seen in PHMs, leading to diagnostic confusion. Twenty-three cases originally diagnosed as either PHM or AVM were independently reviewed by 3 pathologists. The consensus diagnosis was PHM in 14 cases and AVM in 9. Cases with AVM showed insufficient features for an unequivocal diagnosis of PHM. DNA content was determined on paraffin-embedded tissue by fluorescence in situ hybridization (fsSH) using a chromosome 1 centromeric probe and by image cytometry (IC). Thirteen of 14 cases (93%) classified as PHM were triploid by both FISH and IC. Seven cases of AVM were diploid by FISH and IC, and 1 was triploid by FISH and IC. One of the 9 cases of AVM was determined to be trisomy 18 by karyotyping. This good correlation of consensus diagnosis with ploidy data was much greater than that obtained based on original diagnoses. Comparative genomic hybridization performed on 6 cases of AVM showed gain of chromosome 21 in 1 case and loss of X in another. PHMs displayed at least 3 of the following histologic features: 2 discrete populations of villi, circumferential mild trophoblastic hyperplasia, trophoblastic inclusions, prominent scalloping of villi, cistern formation. Nontriploid AVMs displayed at most 2 of the diagnostic features of PHM. Placentas with genetic abnormalities other than triploidy can display morphologic changes suggestive of PHM and can be misinterpreted as such by routine light microscopy. Stringent application of morphologic criteria improves the correlation of the diagnosis of PHM with triploidy.
Assuntos
DNA de Neoplasias/metabolismo , Mola Hidatiforme/patologia , Placenta/patologia , Neoplasias Uterinas/patologia , Vilosidades Coriônicas/anormalidades , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Mola Hidatiforme/genética , Hibridização in Situ Fluorescente , Hibridização de Ácido Nucleico , Placenta/metabolismo , Poliploidia , Gravidez , Complicações Neoplásicas na Gravidez/metabolismo , Complicações Neoplásicas na Gravidez/patologia , Primeiro Trimestre da Gravidez , Neoplasias Uterinas/genéticaRESUMO
We report 15 primary renal neoplasms with morphologic, immunohistochemical, and molecular features identical to those of synovial sarcoma. These tumors form a distinct subset of the entity previously designated as embryonal sarcoma of the kidney. Most were diagnosed between the ages of 20 and 50 years. On gross examination, tumors are large, partially necrotic, and usually contain smooth-walled cysts. Microscopically, tumors are characterized by mitotically active, monomorphic plump spindle cells with indistinct cell borders growing in short, intersecting fascicles. Grossly identified cysts are lined by mitotically inactive polygonal eosinophilic cells with apically oriented nuclei ("hobnailed epithelium"). The spindle cells are immunoreactive for vimentin, often immunoreactive for EMA, but typically non-immunoreactive for desmin, actin, S100, or cytokeratins, whereas the cyst epithelium is cytokeratin-positive. These findings are consistent with monophasic, spindled synovial sarcoma encircling dilated native renal collecting ducts. The presence of an SYT-SSX gene fusion resulting from the t(X;18) characteristic of synovial sarcoma was demonstrated by reverse transcriptase polymerase chain reaction in three of three tumors in which adequate RNA could be obtained from paraffin blocks. An additional case demonstrated the characteristic t(X; 18) translocation on cytogenetic analysis, but adequate material to perform molecular studies was not available in this case or the remaining 11 cases. Primary renal synovial sarcoma is a distinctive clinicopathologic entity confirmed by molecular detection of SYT-SSX fusion transcripts.
Assuntos
Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Adulto , Fusão Gênica Artificial , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 18 , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microscopia , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Cromossomo XRESUMO
Childhood endodermal sinus tumors (CEST) are a distinct category of germ cell tumors that involve the testis and extragonadal sites of young children. Recurrent deletions of 1p and 6q have been reported by classic cytogenetic analysis of a small number of cases. Comparative genomic hybridization, a technique that screens the entire genome for genetic abnormalities, is applied to additionally define the genetic changes present in CESTs. Sixteen frozen CESTs (10 testicular, 6 extragonadal) obtained from Pediatric Oncology Group-affiliated institutions or from the Cooperative Human Tissue Network were analyzed. The most common changes were gain of 20q (10 tumors), 1q (6 tumors), 11q and 22 (4 tumors each), and loss of 6q (8 tumors with common deleted region of 6q24-qter), 16q (4 tumors), and 1p (4 tumors). Localized regions of gain were identified at 8q24 (2 tumors both showing c-myc amplification by fluorescence in situ hybridization). Gain of 12p, characteristic of adolescent germ cell tumor, was present in one testicular tumor. Comparative genomic hybridization was useful in defining genetic differences between adult and childhood tumors, in determining the common regions deleted on chromosome 6, and in identifying other involved loci to be correlated with clinical parameters in future studies.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 6 , Tumor do Seio Endodérmico/genética , Germinoma/genética , Neoplasias Testiculares/genética , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , MasculinoRESUMO
We report the second molecularly-confirmed primary prostatic synovial sarcoma. The diagnosis was particularly elusive at the light microscopic level in that the tumor failed to show epithelial differentiation, but it did show combined spindle-cell and poorly differentiated (round-cell) morphologies. The immunohistochemical staining profile was nonspecific and potentially misleading. Only by demonstration of the characteristic SYT-SSX gene fusion of synovial sarcoma by reverse transcriptase polymerase chain reaction (RT-PCR) analysis of RNA extracted from archival material could the diagnosis be confirmed. This case further illustrates the use of this technique in diagnostic pathology.