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Ewa Rajpert-de Meyts - One of the best experts on this subject based on the ideXlab platform.
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266 PUBLICATIONS 11,846 CITATIONS SEE PROFILE
2016Co-Authors: John E Nielsen, Ewa Rajpert-de Meyts, Kristian Almstrup, See ProfileAbstract:Heterogeneity of chromatin modifications in testicular Spermatocytic Seminoma point toward an epigenetically unstable phenotyp
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Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.2919
2016Co-Authors: J Pathol, Andrew O M Wilkie, Ewa Rajpert-de MeytsAbstract:OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of Spermatocytic Seminoma reflecting distinct subpopulations of spermatogoni
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Heterogeneity of chromatin modifications in testicular Spermatocytic Seminoma point toward an epigenetically unstable phenotype
Cancer genetics, 2012Co-Authors: Dina G. Kristensen, G K Jacobsen, Olga Mlynarska, John Nielsen, Ewa Rajpert-de Meyts, Kristian AlmstrupAbstract:Testicular Spermatocytic Seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche.
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oct2 ssx and sage1 reveal the phenotypic heterogeneity of Spermatocytic Seminoma reflecting distinct subpopulations of spermatogonia
The Journal of Pathology, 2011Co-Authors: Anne Goriely, G K Jacobsen, Gareth D H Turner, Katherine A Ewen, Niels Graem, Andrew O M Wilkie, Ewa Rajpert-de MeytsAbstract:Spermatocytic Seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in Adark spermatogonia, SSX2-4 was present in Apale and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from Adark spermatogonia. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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carcinoma in situ in the testis
Scandinavian Journal of Urology and Nephrology, 2000Co-Authors: Mikael Rorth, Leendert H. J. Looijenga, Ewa Rajpert-de Meyts, Sophie D. Fosså, Lennart Andersson, Klaus Peter Dieckmann, Kenneth M Grigor, W F Hendry, Harry W Herr, Wolter J OosterhuisAbstract:Carcinoma in situ (CIS) of the testis is a common precursor of germ-cell tumours in adults and adolescents, with the exception of Spermatocytic Seminoma. This article reviews existing knowledge on the pathobiology, genetic aspects and epidemiology of CIS, discusses current hypotheses concerning pathogenesis and invasive progression of germ-cell neoplasms and provides guidelines for diagnosis and clinical management of CIS.
Leendert H. J. Looijenga - One of the best experts on this subject based on the ideXlab platform.
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Spermatocytic Seminoma: toward further understanding of pathogenesis.
The Journal of pathology, 2011Co-Authors: Leendert H. J. LooijengaAbstract:Human germ cell tumours comprise a heterogeneous group of neoplasms which, based on pathobiological, genetic and clinical characteristics, can be subdivided into different entities. One of these subgroups relates to the so-called Spermatocytic Seminomas, benign tumours only found in the testis, preferentially in elderly men. Various developmental models for this type of germ cell tumour have been proposed and it is clear that Spermatocytic Seminoma has a pathogenesis independent from that of Seminoma. A recent study examining expression of spermatogonial markers shows that Spermatocytic Seminomas are a heterogeneous group of tumours, with a supposed difference in origin, ie the majority from A or B spermatogonia, and a minority from A spermatogonia. However, this does not exclude an earlier cell of origin, possibly explaining the unique properties of this type of human germ cell tumour, with various counterparts in animals. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Genome-wide BAC array-CGH and expression profiling of human Seminomas, dysgerminomas, embryonal carcinomas and Spermatocytic Seminomas
Cancer Research, 2005Co-Authors: Leendert H. J. Looijenga, Hans Stoop, A. D. Gillis, Remco Hersmus, Wolter OosterhuisAbstract:1650 Human germ cell tumors (GCTs) comprise various entities, which are characterized by age of the patient at clinical presentation, clinical behavior, anatomical location, histology and chromosomal constitution of the tumor. Within the testis, Seminomas and nonSeminomas (including the stem cell component embryonal carcinoma) of adolescents and adults can be identified, as well as Spermatocytic Seminoma of elderly. In the ovary, the Seminoma-like tumors are known as dysgerminoma. We performed a genome wide screen for genomic imbalances using 3.7 and 32 K BAC-array CGH on testicular Seminomas (4), embryonal carcinomas (4), Spermatocytic Seminomas (5), ovarian dysgerminomas (n=4) and embryonal carcinoma (1). Known changes were identified, like gain of 7, 8, 12p and X and loss of 4, 5, and 13 in Seminoma/dysgerminoma and embryonal carcinoma, as well as a consistent gain of chromosome 9 in Spermatocytic Seminoma. The shortest regions of overlap (SRO) could be identified, and novel gains and losses were found, including a restricted high-level amplification of 9p in a Spermatocytic Seminoma. This genomic profile was combined with data from a genome-wide expression analysis using Affymetrix U133 Plus 2.0 arrays. Hierarchical clustering (Omniviz, after K-mean analyses, 2.75 fold expression difference) based on 1354 genes dividing the subtypes of tumors correctly. SAM analyses showed no differences between Seminoma and dysgerminoma. In contrast, these tumors were significantly different from embryonal carcinomas (241 positively and 6 negatively correlated genes) and Spermatocytic Seminomas (150 positively and 235 negatively correlated genes). These included previously identified diagnostic markers, like KRT8/18, BCAT1, GDF3, c-KIT, NANOG, OCT3/4 and SSX. In addition, novel differentiating genes were identified, like C6orf148, MST4, TNFRSF1A, GAGE4/8, PARD, PRSS21, and TUBA. Moreover, strong candidate genes for the SRO were identified, in particular for the high level amplification on 9p in Spermatocytic Seminoma. Ingenuity analysis revealed the pathways in with these genes act in the different tumor types, like cell cycle control, cell morphology etc. This combined high through-put genomic and expression investigation on a limited set of well-defined tumors allowed identification of chromosomal regions, genes and pathways involved in the development of the cancer. This data set is informative to identify diagnostic markers, as well as determine the cell of origin of these tumors.
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Reactivity of Germ Cell Maturation Stage-specific Markers in Classical and Spermatocytic Seminoma
Germ Cell Tumours V, 2002Co-Authors: Leendert H. J. Looijenga, Ruud J.h.l.m. Van Gurp, Ronald R De Krijger, H. Stoop, J. W. OosterhuisAbstract:This paper presents data supporting the model that classical Seminoma originates from a primordial germ cell/gonocyte in which maturation is blocked. Although Spermatocytic Seminoma might also originate from an embryonic germ cell, it retains the capacity to undergo further maturation, including partial meiosis. Moreover, we identified immunohistochemical markers helpful in the diagnosis of Spermatocytic Seminomas.
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reactivity of germ cell maturation stage specific markers in Spermatocytic Seminoma diagnostic and etiological implications
Laboratory Investigation, 2001Co-Authors: Hans Stoop, Wolter Oosterhuis, Ruud J.h.l.m. Van Gurp, Ronald R De Krijger, Ad Geurts Van Kessel, Beate Koberle, Leendert H. J. LooijengaAbstract:It is generally accepted that testicular Seminomas and Spermatocytic Seminomas have separate pathogeneses, although the origin of these two types of germ cell tumors of the adult testis remains a matter of debate. Although an embryonic germ cell origin seems to be most likely for Seminomas, a spermatogonia-spermatocyte origin has been suggested for Spermatocytic Seminoma. To shed more light on the etiology of Spermatocytic Seminomas, we undertook an immunohistochemical and molecular approach using SCP1 (synaptonemal complex protein 1), SSX (synovial sarcoma on X chromosome), and XPA (xeroderma pigmentosum type A) as targets. Although a stage-specific expression pattern has been reported for SCP1 and SSX in normal spermatogenesis, we demonstrate here that it also exists for XPA. In fact, immunohistochemistry shows that the proteins of SCP1 and XPA are specifically present in the stage of primary and pachytene spermatocytes. In contrast, SSX was found in spermatogonia and primary spermatocytes, as well as in germ cells, from at least the 17th week of intrauterine development onward. Although no protein encoded by any of these genes was detected in tumor cells of a series of testicular Seminomas, all tested Spermatocytic Seminomas were positive, in agreement with expression analysis. These data support the model that Seminomas originate from an embryonic germ cell, and they imply that the cell of origin of Spermatocytic Seminomas is at least capable of maturing to the stage of spermatogonia-pachytene spermatocyte.
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carcinoma in situ in the testis
Scandinavian Journal of Urology and Nephrology, 2000Co-Authors: Mikael Rorth, Leendert H. J. Looijenga, Ewa Rajpert-de Meyts, Sophie D. Fosså, Lennart Andersson, Klaus Peter Dieckmann, Kenneth M Grigor, W F Hendry, Harry W Herr, Wolter J OosterhuisAbstract:Carcinoma in situ (CIS) of the testis is a common precursor of germ-cell tumours in adults and adolescents, with the exception of Spermatocytic Seminoma. This article reviews existing knowledge on the pathobiology, genetic aspects and epidemiology of CIS, discusses current hypotheses concerning pathogenesis and invasive progression of germ-cell neoplasms and provides guidelines for diagnosis and clinical management of CIS.
G K Jacobsen - One of the best experts on this subject based on the ideXlab platform.
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Heterogeneity of chromatin modifications in testicular Spermatocytic Seminoma point toward an epigenetically unstable phenotype
Cancer genetics, 2012Co-Authors: Dina G. Kristensen, G K Jacobsen, Olga Mlynarska, John Nielsen, Ewa Rajpert-de Meyts, Kristian AlmstrupAbstract:Testicular Spermatocytic Seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche.
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oct2 ssx and sage1 reveal the phenotypic heterogeneity of Spermatocytic Seminoma reflecting distinct subpopulations of spermatogonia
The Journal of Pathology, 2011Co-Authors: Anne Goriely, G K Jacobsen, Gareth D H Turner, Katherine A Ewen, Niels Graem, Andrew O M Wilkie, Ewa Rajpert-de MeytsAbstract:Spermatocytic Seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in Adark spermatogonia, SSX2-4 was present in Apale and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from Adark spermatogonia. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of Spermatocytic Seminoma reflecting distinct subpopulations of spermatogonia.
'Wiley', 2011Co-Authors: Lim J, G K Jacobsen, Goriely A, Gd Turner, Ka Ewen, Graem N, Ao Wilkie, Rajpert-de Meyts EAbstract:Spermatocytic Seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from A(dark) spermatogonia
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the immunohistochemical expression pattern of chk2 p53 p19ink4d mage a4 and other selected antigens provides new evidence for the premeiotic origin of Spermatocytic Seminoma
Histopathology, 2003Co-Authors: Rajpertde E Meyts, G K Jacobsen, J Bartkova, Florence Aubry, Michel Samson, Jiri Bartek, N. E. SkakkebækAbstract:Aims: Spermatocytic Seminoma is a rare germ cell derived tumour of the testis that occurs mainly in older men. We analysed the expression of recently discovered markers for germ cell differentiation and the mitosis–meiosis transition in order to define the antigen profile for diagnostic purposes and to clarify the biology and histogenesis of Spermatocytic Seminoma. Methods and results: Twenty-five Spermatocytic Seminomas were examined for immunohistochemical expression of germ cell-specific onco-fetal antigens and proteins involved in regulation of germ cell division, DNA repair and differentiation. The panel included Chk2, p19INK4d, p53, MAGE-A4, KIT, TRA-1-60, neurone-specific enolase and placental-like alkaline phosphatase. Four of these proteins/antigens have never before been investigated in Spermatocytic Seminoma. Proteins highly expressed in gonocytes and spermatogonia, such as Chk2, MAGE-A4 and neurone-specific enolase, were consistently present in Spermatocytic Seminoma. Antigens expressed in embryonic germ cells but not in the normal adult testis, e.g. TRA-1-60, were undetectable, with the exception of p53 protein, which was demonstrated in 80% of cases. A proto-oncogene p19INK4d, which is involved in the transition from mitotic to meiotic division in germ cells, was not detected in Spermatocytic Seminoma. Conclusions: The investigation provided new information concerning the expression of Chk2, MAGE-A4, neurone-specific enolase and p19INK4d in Spermatocytic Seminoma. The pattern of expression is highly consistent with the origin of Spermatocytic Seminoma from a premeiotic germ cell, which has lost embryonic traits and has committed to spermatogenic lineage but has not yet passed the meiotic checkpoint, most probably from the spermatogonium of the adult testis.
Alberto G. Ayala - One of the best experts on this subject based on the ideXlab platform.
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An Overview of Testicular Germ Cell Tumors
Archives of Pathology & Laboratory Medicine, 2007Co-Authors: Armita Bahrami, Alberto G. AyalaAbstract:Abstract Context.—More than 90% of testicular neoplasms originate from germ cells. Testicular germ cell tumors (GCTs) are a heterogeneous group of neoplasms with diverse histopathology and clinical behavior. Objective.—To help the readers distinguish various subtypes of GCTs, to highlight the clinical manifestations and pathologic features of these tumors, and to review several newly developed immunohistochemical markers for GCTs. Data Sources.—Review of the pertinent literature and our experience. Conclusions.—The etiology of GCTs is largely unknown. Cytogenetic studies suggest a different pathogenesis for each group of infantile/prepubertal GCTs, postpubertal GCTs, and Spermatocytic Seminoma. Unclassified intratubular germ cell neoplasia is the precursor of all GCTs, excluding Spermatocytic Seminoma and infantile/prepubertal GCTs. Seminoma, the most common GCT in adults, does not occur before 5 years of age. Spermatocytic Seminoma, a tumor of elderly men, typically has an indolent clinical behavior, but rarely it undergoes sarcomatous transformation associated with an aggressive behavior. Embryonal carcinoma is the most common component in mixed GCTs. Eighty percent or more of embryonal carcinoma component and vascular invasion are recognized predictors of occult metastasis for clinical stage I mixed GCTs. Most patients with prepubertal yolk sac tumor, the most common pediatric GCT, have stage I disease at presentation. Most choriocarcinomas present with metastatic symptoms because of the propensity for rapid hematogenous dissemination. Teratomas in children regardless of maturity and dermoid cysts in adults are benign; in contrast, teratomas in adults have a malignant behavior. With appropriate therapy, the majority of testicular GCTs are curable.
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An Overview of Testicular Germ Cell Tumors
Archives of pathology & laboratory medicine, 2007Co-Authors: Armita Bahrami, Alberto G. AyalaAbstract:Abstract Context.—More than 90% of testicular neoplasms originate from germ cells. Testicular germ cell tumors (GCTs) are a heterogeneous group of neoplasms with diverse histopathology and clinical behavior. Objective.—To help the readers distinguish various subtypes of GCTs, to highlight the clinical manifestations and pathologic features of these tumors, and to review several newly developed immunohistochemical markers for GCTs. Data Sources.—Review of the pertinent literature and our experience. Conclusions.—The etiology of GCTs is largely unknown. Cytogenetic studies suggest a different pathogenesis for each group of infantile/prepubertal GCTs, postpubertal GCTs, and Spermatocytic Seminoma. Unclassified intratubular germ cell neoplasia is the precursor of all GCTs, excluding Spermatocytic Seminoma and infantile/prepubertal GCTs. Seminoma, the most common GCT in adults, does not occur before 5 years of age. Spermatocytic Seminoma, a tumor of elderly men, typically has an indolent clinical behavior, but...
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Anaplastic variant of Spermatocytic Seminoma
Human pathology, 1996Co-Authors: Jorge Albores-saavedra, Hank Huffman, Isabel Alvarado-cabrero, Alberto G. AyalaAbstract:Four examples of Spermatocytic Seminoma with a predominant anaplastic component occurred in men 33 to 43 years of age, without histories of cryptorchidism. The Seminomas presented with painless testicular masses recognized 3 to 18 months before orchiectomy. Preoperative serum measurements of human chorionic gonadotropin and alpha-fetoprotein were negative. All tumors contained areas (10% to 30% of the tumor) in which the three cell types characteristic of conventional Spermatocytic Seminoma could be identified under light microscopy. The predominant anaplastic component also contained the three cell types, but the nuclei had prominent nucleoli with granular and filamentous chromatin. In addition, sheets of cells with vesicular nuclei and prominent nucleoli superficially resembling embryonal carcinoma were found. There were numerous large mononuclear and multinucleated giant cells with bizarre nuclei and prominent nucleoli, but no sarcomatous elements. Many normal and abnormal mitotic figures were present. Tunical and vascular invasion and extensive necrosis were constant features. Immunohistochemistry documented p53 protein overexpression in two tumors, but neoplastic cells were negative with immunostains for placenta-like alkaline phosphatase, leukocyte common antigen, neuron-specific enolase, alpha-fetoprotein, human chorionic gonadotropin, vimentin, and cytokeratins. Ultrastructural examination of the anaplastic component showed large rope-like nucleoli, but the cytoplasmic features were similar to those of conventional Spermatocytic Seminoma. Despite the presence of a major anaplastic component, no patient has developed metastasis. Larger series and longer follow-up are needed to understand the natural history of these neoplasms.
Hans Stoop - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide BAC array-CGH and expression profiling of human Seminomas, dysgerminomas, embryonal carcinomas and Spermatocytic Seminomas
Cancer Research, 2005Co-Authors: Leendert H. J. Looijenga, Hans Stoop, A. D. Gillis, Remco Hersmus, Wolter OosterhuisAbstract:1650 Human germ cell tumors (GCTs) comprise various entities, which are characterized by age of the patient at clinical presentation, clinical behavior, anatomical location, histology and chromosomal constitution of the tumor. Within the testis, Seminomas and nonSeminomas (including the stem cell component embryonal carcinoma) of adolescents and adults can be identified, as well as Spermatocytic Seminoma of elderly. In the ovary, the Seminoma-like tumors are known as dysgerminoma. We performed a genome wide screen for genomic imbalances using 3.7 and 32 K BAC-array CGH on testicular Seminomas (4), embryonal carcinomas (4), Spermatocytic Seminomas (5), ovarian dysgerminomas (n=4) and embryonal carcinoma (1). Known changes were identified, like gain of 7, 8, 12p and X and loss of 4, 5, and 13 in Seminoma/dysgerminoma and embryonal carcinoma, as well as a consistent gain of chromosome 9 in Spermatocytic Seminoma. The shortest regions of overlap (SRO) could be identified, and novel gains and losses were found, including a restricted high-level amplification of 9p in a Spermatocytic Seminoma. This genomic profile was combined with data from a genome-wide expression analysis using Affymetrix U133 Plus 2.0 arrays. Hierarchical clustering (Omniviz, after K-mean analyses, 2.75 fold expression difference) based on 1354 genes dividing the subtypes of tumors correctly. SAM analyses showed no differences between Seminoma and dysgerminoma. In contrast, these tumors were significantly different from embryonal carcinomas (241 positively and 6 negatively correlated genes) and Spermatocytic Seminomas (150 positively and 235 negatively correlated genes). These included previously identified diagnostic markers, like KRT8/18, BCAT1, GDF3, c-KIT, NANOG, OCT3/4 and SSX. In addition, novel differentiating genes were identified, like C6orf148, MST4, TNFRSF1A, GAGE4/8, PARD, PRSS21, and TUBA. Moreover, strong candidate genes for the SRO were identified, in particular for the high level amplification on 9p in Spermatocytic Seminoma. Ingenuity analysis revealed the pathways in with these genes act in the different tumor types, like cell cycle control, cell morphology etc. This combined high through-put genomic and expression investigation on a limited set of well-defined tumors allowed identification of chromosomal regions, genes and pathways involved in the development of the cancer. This data set is informative to identify diagnostic markers, as well as determine the cell of origin of these tumors.
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reactivity of germ cell maturation stage specific markers in Spermatocytic Seminoma diagnostic and etiological implications
Laboratory Investigation, 2001Co-Authors: Hans Stoop, Wolter Oosterhuis, Ruud J.h.l.m. Van Gurp, Ronald R De Krijger, Ad Geurts Van Kessel, Beate Koberle, Leendert H. J. LooijengaAbstract:It is generally accepted that testicular Seminomas and Spermatocytic Seminomas have separate pathogeneses, although the origin of these two types of germ cell tumors of the adult testis remains a matter of debate. Although an embryonic germ cell origin seems to be most likely for Seminomas, a spermatogonia-spermatocyte origin has been suggested for Spermatocytic Seminoma. To shed more light on the etiology of Spermatocytic Seminomas, we undertook an immunohistochemical and molecular approach using SCP1 (synaptonemal complex protein 1), SSX (synovial sarcoma on X chromosome), and XPA (xeroderma pigmentosum type A) as targets. Although a stage-specific expression pattern has been reported for SCP1 and SSX in normal spermatogenesis, we demonstrate here that it also exists for XPA. In fact, immunohistochemistry shows that the proteins of SCP1 and XPA are specifically present in the stage of primary and pachytene spermatocytes. In contrast, SSX was found in spermatogonia and primary spermatocytes, as well as in germ cells, from at least the 17th week of intrauterine development onward. Although no protein encoded by any of these genes was detected in tumor cells of a series of testicular Seminomas, all tested Spermatocytic Seminomas were positive, in agreement with expression analysis. These data support the model that Seminomas originate from an embryonic germ cell, and they imply that the cell of origin of Spermatocytic Seminomas is at least capable of maturing to the stage of spermatogonia-pachytene spermatocyte.