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
The major goals of Kawasaki disease (KD) therapy are to reduce inflammation and prevent thrombosis in the coronary arteries (CA), but some children do not respond to currently available non-specific therapies. New treatments have been difficult to develop because the molecular pathogenesis is unknown. In order to identify dysregulated gene expression in KD CA, we performed high-throughput RNA sequencing on KD and control CA, validated potentially dysregulated genes by real-time reverse transcription-polymerase chain reaction (RT-PCR) and localized protein expression by immunohistochemistry. Signalling lymphocyte activation molecule CD84 was up-regulated 16-fold (P < 0·01) in acute KD CA (within 2 months of onset) and 32-fold (P < 0·01) in chronic CA (5 months to years after onset). CD84 was localized to inflammatory cells in KD tissues. Genes associated with cellular proliferation, motility and survival were also up-regulated in KD CA, and immune activation molecules MX2 and SP140 were up-regulated in chronic KD. CD84, which facilitates immune responses and stabilizes platelet aggregates, is markedly up-regulated in KD CA in patients with acute and chronic arterial disease. We provide the first molecular evidence of dysregulated inflammatory responses persisting for months to years in CA significantly damaged by KD.
Assuntos
Antígenos CD/metabolismo , Antígenos Nucleares/metabolismo , Plaquetas/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Proteínas de Resistência a Myxovirus/metabolismo , Fatores de Transcrição/metabolismo , Calcificação Vascular/imunologia , Doença Aguda , Antígenos CD/genética , Antígenos Nucleares/genética , Processos de Crescimento Celular/genética , Movimento Celular/genética , Sobrevivência Celular/genética , Doença Crônica , Vasos Coronários/patologia , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/genética , Proteínas de Resistência a Myxovirus/genética , Agregação Plaquetária/genética , RNA Mensageiro/análise , Família de Moléculas de Sinalização da Ativação Linfocitária , Fatores de Transcrição/genética , Regulação para Cima , Calcificação Vascular/sangue , Calcificação Vascular/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
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
Ovarian germ cell tumors (OGCTs) show a heterogeneity that is not seen in their testicular counterparts and include benign mature cystic teratomas, intermediate immature teratomas, malignant germ cell tumors [GCTs (dysgerminomas, endodermal sinus tumors, and mixed GCTs)], and GCTs arising in dysgenetic gonads of 46,XY individuals. Comparative genomic hybridization was used to analyze 27 OGCTs for regions of relative gain or loss. The analysis of 21 malignant OGCTs (12 dysgerminomas, 6 endodermal sinus tumors, and 3 mixed GCTs) demonstrated genetic alterations similar to those reported in adult testicular GCTs. The most common regions gained include chromosomes 12p (16 of 21 tumors), 21 (10 of 21 tumors), 8 (8 of 21 tumors), and 1q (6 of 21 tumors). The most common region lost was chromosome 13. Regions of high-level gain were identified at 12p11-12 and 4q11. The profile of gains and losses was similar in the different histological subtypes within this category. One tumor presented in a 46,XY patient; this tumor was diploid and showed a gain of 12p. Immature teratomas (six cases) showed only one case with an abnormality, which was a gain of chromosome 14. We conclude that malignant OGCTs are genetically similar to those found in the adult testis; however, immature teratomas show no consistent gains or losses and are therefore different from those presenting in the adult testis. A review of the literature suggests that genetic abnormalities in this group may herald a worse prognosis. Lastly, OGCTs in dysgenetic gonads arise in a diploid rather than a tetraploid cell line, yet they also show a gain of 12p.
Assuntos
Aberrações Cromossômicas/genética , Neoplasias Ovarianas/genética , Teratoma/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Hibridização de Ácido NucleicoRESUMO
Inflammatory myofibroblastic tumor (IMT) is a relatively rare soft tissue tumor. The reactive versus neoplastic pathogenesis of this tumor is unresolved. We found clonal chromosome aberrations involving 2p23 upon metaphase analysis of two IMTs. Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated rearrangement of the probe in both of these cases and in a third case, and immunohistochemistry revealed ALK expression in all three cases. 2p22-24 involvement has been reported previously in four additional cases of IMT. We suggest that chromosomal rearrangements involving 2p23 near or within ALK are recurrent alterations in IMT and that ALK may have a novel role outside its previously recognized realm of lymphoid neoplasms.
Assuntos
Cromossomos Humanos Par 2 , Neoplasias de Tecido Muscular/genética , Quinase do Linfoma Anaplásico , Criança , Sondas de DNA , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Neoplasias de Tecido Muscular/metabolismo , Proteínas Tirosina Quinases/biossíntese , Receptores Proteína Tirosina QuinasesRESUMO
We have previously shown that the p57KIP2 gene, which encodes a cyclin-dependent kinase inhibitor, undergoes genomic imprinting and lies within a 700-kb domain of imprinted genes on 11p15, including IGF2 and H19. Loss of heterozygosity and loss of imprinting (LOI) of this region are frequently observed in Wilms' tumor (WT) and other embryonal malignancies. Although LOI of p57KIP2 was observed in some WTs (approximately 10%), allele-specific expression was preserved in most tumors examined. Because our initial studies were inconclusive concerning the absolute expression level of p57KIP2 in WT, we developed a sensitive and quantitative RNase protection assay to determine if changes in p57KIP2 expression play a role in WT. Expression of p57KIP2 was found to be virtually absent in 21 of 21 WTs compared to matched normal kidney from the same patients, as well as compared to fetal kidney. We also examined p57KIP2 expression in the normal kidney and tongue of patients with Beckwith-Wiedemann syndrome (BWS), which predisposes to WT and also involves LOI of IGF2 and H19. Although p57KIP2 was undetectable in BWS tongue, similar results were also observed in postnatal non-BWS tongue samples. Most primary skin fibroblast cultures of BWS cell lines exhibited normal imprinting of p57KIP2. However, one BWS patient did show LOI of p57KIP2 in skin fibroblasts. Thus, p57KIP2 is part of a domain of genes on 11p15 that show altered expression and, in some cases, altered imprinting in WT and BWS.
Assuntos
Síndrome de Beckwith-Wiedemann/genética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Deleção de Genes , Neoplasias Renais/genética , Proteínas Nucleares/metabolismo , Tumor de Wilms/genética , Síndrome de Beckwith-Wiedemann/enzimologia , Inibidor de Quinase Dependente de Ciclina p57 , Humanos , Neoplasias Renais/enzimologia , Proteínas Nucleares/genética , Tumor de Wilms/enzimologiaRESUMO
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 snRNPRESUMO
Telomerase is a reverse transcriptase that maintains chromosome ends, compensating for the progressive loss of DNA that occurs during replication. High telomerase enzyme activity is an unfavorable prognostic feature for several types of cancers. We investigated whether telomerase level predicts outcome for patients with the pediatric renal malignancy Wilms' tumor. In a case-cohort study of 78 patients with favorable histology Wilms' tumor, we compared tumor telomerase levels in patients with and without eventual recurrence. Three measures of telomerase were used: (a) telomerase enzyme activity; (b) expression of hTR, the RNA component of telomerase; and (c) mRNA expression of hTERT, the gene that encodes the catalytic component of the enzyme. Of the evaluable samples, 81% had detectable telomerase activity, 97% had detectable hTERT transcript, and 100% had detectable hTR. Weak correlations were observed between telomerase activity and hTR level (r = 0.34, P = 0.02) and between telomerase activity and hTERT mRNA level (r = 0.32, P = 0.04). Of the variables assessed, only hTERT mRNA expression correlated with outcome. The median hTERT mRNA level in tumors with recurrence was higher than that in tumors without recurrence (1.42 versus 0.97 units, P = 0.023, Wilcoxon). Univariate analysis of hTERT mRNA level as a continuous variable suggested that each unit increase in hTERT mRNA level increased the risk of recurrence (RR) by a factor of 1.66 [95% confidence interval (CI), 1.2-2.3; P < 0.005]. Compared with tumors with hTERT mRNA levels of 0-1 units, tumors with hTERT mRNA levels of 1-2 units had a RR of 2.72 (95% CI, 0.91-8.13; P = 0.074), and tumors with hTERT mRNA levels >2 units had a RR of 6.40 (95% CI, 1.49-27.67, P = 0.013). Multivariate analysis of hTERT mRNA level as a predictor of recurrence, adjusted for tumor stage and age at diagnosis, revealed a RR of 1.48 (95% CI, 0.9-2.6; P = 0.16). Measurement of hTERT mRNA level may, therefore, enable clinicians to identify a population of patients at high risk for recurrence and to adjust their therapy accordingly. A larger study will be necessary to determine whether hTERT expression is an independent prognostic indicator. Further biological investigation is warranted to discern whether the link between high hTERT expression and unfavorable prognosis is causative or correlative.
Assuntos
Neoplasias Renais/genética , Recidiva Local de Neoplasia , RNA Mensageiro/análise , RNA , Telomerase/genética , Pré-Escolar , DNA/análise , Proteínas de Ligação a DNA , Feminino , Humanos , Lactente , Recém-Nascido , Neoplasias Renais/patologia , Masculino , PrognósticoRESUMO
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
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
The condition termed "46,XY gonadal dysgenesis" is characterized by a 46,XY karyotype and incomplete testicular determination. It is likely the result of a mutation in the gene for the testicular determination factor or in another gene involved in the early stages of testicular differentiation. In view of the present interest in the identification of gene(s) initiating the differentiation of the embryonic gonads into testes, we have reviewed the phenotype of 15 patients with 46,XY gonadal dysgenesis to use this information for future molecular studies. Seven patients presented a complete form, 46,XY pure gonadal dysgenesis, including streak gonads, normal Müllerian structures, and normal female external genitalia. The structure of the streak gonads in these patients presented some variation. Eight patients presented an incomplete form, 46,XY partial gonadal dysgenesis, with ambiguous external genitalia and partial development of Müllerian and Wolffian structures. Among them, 3 had bilateral dysgenetic testes, and 4 had a streak gonad on one side with a contralateral dysgenetic testis. The streak gonads showed ovarian stroma with occasional primitive sex cords devoid of germ cells. However, a primordial follicle was observed in 1 streak gonad. The dysgenetic testes showed disorganized seminiferous tubules and ovarian stroma. In some patients, the ovarian stroma was intermixed with testicular tissue, while in others, distinct ovarian and testicular portions were present. In 1 patient, the dysgenetic testis contained a focus of well-differentiated ovarian tissue with primordial follicles. Our observations support the hypothesis that streak gonads in 46,XY pure gonadal dysgenesis arise from fetal ovaries and that dysgenetic testes in the partial form in 46,XY partial gonadal dysgenesis develop from ovotestis.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Disgenesia Gonadal 46 XY/fisiopatologia , Diferenciação Sexual , Adolescente , Criança , Pré-Escolar , Feminino , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/patologia , Gônadas/patologia , Humanos , Lactente , Cariotipagem , MasculinoRESUMO
Blood group antigens have been implicated as markers in oncogenesis; however, studies of blood group antigen expression in the prostate have yielded conflicting data. This study examined the expression of A, B, H, X, and Lewis antigens in 30 prostates removed for adenocarcinoma, by utilizing monoclonal antibodies, Ulex europaeus agglutinin I (for H type-2 chains), and the secretor status. A, B, and Ulex staining of the normal prostate most commonly demonstrated strong straining of 5-15% of cells. Staining of central and peripheral zones was similar, and nodules of hyperplasia showed no difference in staining. Antibodies to Le(a), Le(b), and X showed no staining or only pale staining of less than 10% of the normal prostatic epithelial cells. Ulex staining of intermediate and high-grade areas of tumor showed a diffuse staining pattern that was consistently greater than that of the normal glands. In contrast, low-grade tumors stained similarly to normal glands with Ulex. In 15 of 16 cases of dysplasia, Ulex staining was increased over normal and was similar to the adjacent carcinoma. A, B, Le(a), Le(b), and X antigens were negative in adenocarcinoma and dysplasia. This study supports the hypothesis that dysplasia represents a premalignant lesion; it further suggests that concomitant with malignant transformation, a disturbance occurs in enzyme activity. The result is augmentation of H type-2 expression in dysplasia and less-differentiated adenocarcinomas, and a loss of A, B, Le(a), and Leb expression in dysplasia and all carcinomas.
Assuntos
Adenocarcinoma/sangue , Antígenos de Grupos Sanguíneos , Lectinas de Plantas , Doenças Prostáticas/sangue , Neoplasias da Próstata/sangue , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Anticorpos Monoclonais , Humanos , Técnicas Imunoenzimáticas , Lectinas , Antígenos do Grupo Sanguíneo de Lewis , Masculino , Doenças Prostáticas/diagnóstico , Doenças Prostáticas/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Coloração e RotulagemRESUMO
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
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
We reviewed 351 cases of clear cell sarcoma of the kidney (CCSK), including 182 cases entered on National Wilms Tumor Study Group (NWTSG) trials 1-4 for which clinical follow-up information was available. Tumors were restaged using NWTS 5 criteria. Mean age at diagnosis in the NWTS group was 36 months with a range of 2 months to 14 years. The male to female ratio was 2:1. Typical gross features included large size (mean diameter 11.3 cm), a mucoid texture, foci of necrosis, and prominent cyst formation. Nine major histologic patterns were identified (classic, myxoid, sclerosing, cellular, epithelioid, palisading, spindle, storiform, and anaplastic); virtually all tumors contained multiple patterns that blended with one another. Immunohistochemical stains were performed on 45 cases; only vimentin was consistently immunoreactive. Consistently negative results with other antibodies helped exclude other tumors in the differential diagnosis; all CCSKs were cytokeratin-negative, including epithelioid tumors that mimicked Wilms tumor, and MIC2-negative, including cellular tumors that mimicked primitive neuroectodermal tumor. The p53 gene product was rarely overexpressed in non-anaplastic CCSKs, but strikingly overexpressed in two of three anaplastic CCSKs. Overall survival was 69%. Multivariate analysis revealed four independent prognostic factors for survival: treatment with doxorubicin, stage, age at diagnosis, and tumor necrosis. Of note, stage 1 patients had a remarkable 98% survival rate. No other histologic or clinical variable independently correlated with survival.
Assuntos
Neoplasias Renais/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Lactente , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Análise Multivariada , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/cirurgia , Nefrectomia , Prognóstico , Fatores Sexuais , Análise de Sobrevida , Fatores de TempoRESUMO
Fifty-five patients with atypical teratoid/rhabdoid tumors of the central nervous system were studied to define the clinical and pathologic features of this newly described neoplasm. The lesion occurred primarily in children younger than 2 (mean age at diagnosis, 17 months). The neoplasms were located in the posterior fossa (36 patients) and the supratentorial compartment (17 patients) or were multifocal in both compartments (2 patients) at presentation. Histologically, the tumors were composed of small cells and large, pale cells in a jumbled architectural arrangement. The small cell component resembled medulloblastoma and occasionally had cords of cells in a mucinous background, simulating chordoma. The cytoplasm of the larger cells was conspicuous with a somewhat "rhabdoid" appearance, although rhabdoid features were not always prominent. Epithelioid features in the form of poorly formed glands or Flexner-Wintersteiner rosettes were noted in a minority of lesions. The neoplasms showed striking polyphenotypic immunoreactivity, including that for vimentin, glial fibrillary acidic protein, epithelial membrane antigen, cytokeratins, synaptophysin, chromogranin, and smooth muscle actin. Using a probe for chromosome 22, seven of eight scorable cases showed a solitary signal by fluorescence in situ hybridization (FISH) consistent with monosomy 22. The eighth scorable case showed three signals by fluorescence in situ hybridization and had a translocation involving chromosome 22 reported by conventional cytogenetics. In contrast to patients with medulloblastoma, the neoplasm with which these lesions are often confused, the outcome of the patients was uniformly poor. The mean postoperative survival of patients with atypical teratoid/rhabdoid tumors was only 11 months. Local recurrence, seeding of the cerebrospinal fluid pathways, or both, were common terminal events. This study underscores the distinctive clinical, histopathologic, immunohistochemical, and cytogenetic character of this unusually aggressive tumor.
Assuntos
Neoplasias Encefálicas/patologia , Proteínas de Neoplasias/análise , Tumor Rabdoide/patologia , Teratoma/patologia , Neoplasias Encefálicas/química , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Tumor Rabdoide/química , Teratoma/químicaRESUMO
The clinical, pathologic, and immunohistochemical features of a widely disseminated tumor with rhabdoid phenotype are described in nine infants < or = 3 months of age. Five neonates had tumor evident at birth, two of which had placental metastases. The average survival following diagnosis was < 6 weeks. None of the infants had an apparent primary tumor in either the kidney or brain. In four cases, the dominant mass involved the head and neck region, and in two cases, the primary mass was paraspinal. The histologic features were those of a high-grade, round cell neoplasm with abundant cytoplasm and containing cells with cytoplasmic filamentous inclusions. Immunohistochemical studies revealed polyphenotypic antigen expression. Genetic information was available from eight of nine cases. Karyotype analysis revealed abnormalities of chromosome band 22q11-12 in three of six tumors. Fluorescence in situ hybridization studies or molecular studies demonstrated 22q11.2 deletions in all five cases with available frozen tissue, two of which had translocations involving 22q by karyotype analysis. The similar clinical and pathologic findings in these rapidly fatal tumors in infants and the demonstration of abnormalities of chromosome 22q11 in a majority of the cases supports their histogenetic and nosologic relationship to the family of malignant rhabdoid tumors that typically occur in young children in several anatomic sites, including kidney, soft tissues, liver, and brain. Like neuroblastoma and rhabdomyosarcoma, malignant rhabdoid tumor can appear as disseminated disease at birth or shortly thereafter.
Assuntos
Cromossomos Humanos Par 22/genética , Tumor Rabdoide/congênito , Tumor Rabdoide/genética , Citoesqueleto/ultraestrutura , Feminino , Deleção de Genes , Idade Gestacional , Neoplasias de Cabeça e Pescoço/congênito , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/ultraestrutura , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariotipagem , Masculino , Prognóstico , Tumor Rabdoide/patologia , Tumor Rabdoide/ultraestruturaRESUMO
BACKGROUND: We sought to compare the immunoreactive potential of human cord blood (CB) versus normal adult bone marrow (BM) versus mobilized blood (peripheral blood stem cells; PBSC) from cancer patients. METHODS: Forty mice were randomized to receive a range of doses of T cell-replete cell preparations from one of the above three cell sources. Twenty-eight control mice underwent transplantation with T cell-depleted cells. Mice were observed for 60 days for the development of fatal xenogeneic graft-versus-host disease-like syndrome (GVHDLS). RESULTS: For the mice that had received T cell-replete grafts of CB or BM or PBSC, the duration of GVHDLS-free survival of the chimeras was inversely proportional to the number of T cells transplanted. After adjustment for the number of T cells transplanted, the relative hazard of developing fatal GVHDLS was 62-fold higher for PBSC and 210-fold higher for BM as compared with CB. Flow cytometric and histologic analyses of selected chimeras that died of GVHDLS showed extensive proliferation of human T cells in multiple organs. In contrast, mice that survived to day 60 were engrafted with human myeloid and B lymphoid cells. CONCLUSIONS: The immunoreactive potential, as measured by this in vivo assay, differed among clinical grafts: BM > PBSC > CB.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Transplante Heterólogo/imunologia , Adulto , Animais , Linfócitos B/transplante , Transplante de Medula Óssea , Neoplasias da Mama/sangue , Quimera/imunologia , Feminino , Sangue Fetal/citologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Depleção Linfocítica , Camundongos , Gravidez , Valores de Referência , Análise de Sobrevida , Linfócitos T/patologia , Linfócitos T/transplanteRESUMO
We report on a group of 9 subjects who had a 46,XY karyotype, ambiguous genitalia, abnormalities of sexual duct formation, and lack of gonadal tissue on one or both sides. This is sometimes referred to as "embryonic testicular regression." Previous investigators have suggested that this condition results from loss of testes at a critical stage in development. We examined the possibility that the "embryonic testicular regression" is part of the clinical spectrum of 46,XY gonadal dysgenesis. Four subjects totally lacked gonadal tissue, three of them having ambiguous genitalia, and one a micropenis. The development of incongruous sexual ducts (presence of Müllerian ducts in the subject with micropenis, and absence of Müllerian and Wolffian ducts in two subjects with ambiguous genitalia) suggests that the embryonic gonads were intrinsically functionally abnormal before their disappearance. Five subjects had unilateral gonadal tissue, ambiguous genitalia, and a mix of Wolffian and Müllerian structures. The development of incongruous sexual ducts in 3 of them, the presence of ambiguous external genitalia in 5, and the presence of abnormal gonadal histology in 2 patients all indicate an underlying abnormality of gonadal differentiation in these subjects. The occurrence of testicular regression in several subjects in the family of one patient suggests a genetic basis for the condition. The presence of multiple congenital anomalies in other subjects in our study suggests either a mutation in a single gene that functions in several developmental pathways, or a defect of multiple genes that might be the result of a chromosome deletion.(ABSTRACT TRUNCATED AT 250 WORDS)