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Liang Cheng - One of the best experts on this subject based on the ideXlab platform.
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Gonadoblastoma versus ovarian mixed germ cell sex cord stromal tumor in women or girls with no evidence of a disorder of sex development a problem in differential diagnosis
Pathology Research and Practice, 2020Co-Authors: Lawrence M Roth, Bernard Czernobilsky, Steven A Mann, Liang ChengAbstract:Gonadoblastoma occurring in a normal girl or woman has been confused with ovarian mixed germ cell-sex cord stromal tumor (MGC-SCST) due to a lack of knowledge that the former occurs occasionally in a normal woman or girl. In this article, we develop histological criteria that facilitate the distinction of Gonadoblastoma in an individual with a normal karyotype and no evidence of a disorder of sex development from ovarian MGC-SCST. We reviewed the histological findings of Gonadoblastoma occurring in normal individuals and compared them to cases of ovarian MGC-SCST in our files. The histological findings of Gonadoblastoma differ substantially from those of ovarian MGC-SCST. Importantly, Gonadoblastoma contains two types of transformed germ cells, some histologically benign and others premalignant, whereas MGC-SCST contains only a single type, typically premalignant in the ovary and benign in the testis. Furthermore, degenerative changes of hyalinization and calcification are common in Gonadoblastoma, whereas they are extremely rare in MGC-SCST. Although the great majority of cases of Gonadoblastoma occur in an individual with a disorder of sex development and an abnormal karyotype, a substantial number arise in a normal woman or girl with no evidence of a disorder of sex development. In the latter circumstance, it is important to distinguish Gonadoblastoma from ovarian MGC-SCST. It is very likely that those Gonadoblastomas arising in a normal individual develop through a different molecular pathway than the ones that occur in the dysgenetic gonads of an individual with a disorder of sex development.
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Gonadoblastoma: origin and outcome
Human pathology, 2019Co-Authors: Lawrence M Roth, Liang ChengAbstract:Classical Gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development; however, a small number of cases arise in individuals with a normal peripheral karyotype and no evidence of a disorder of sex development. Those Gonadoblastomas that occur in an individual who has a Y chromosome or part thereof express testis specific protein Y-encoded 1 (TSPY1). If a gonad in those individuals contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical Gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular stroma that sometimes contains steroid cells. Classical Gonadoblastoma can be interpreted as a noninvasive or an in situ neoplasm that is the precursor of germinoma in some individuals and, indirectly, of other more aggressive germ cell neoplasms. The "dissecting" variant is derived from classical Gonadoblastoma and is characterized by unusual growth patterns. Undifferentiated gonadal tissue is the precursor of Gonadoblastoma; however, if all germ cells in an individual with undifferentiated gonadal tissue involute, the result is a secondary streak gonad. Undifferentiated gonadal tissue is a non-neoplastic condition resembling a streak gonad but additionally contains germ cells with delayed maturation that express octamer-binding transcription factor 4; however, other germ cells, show normal maturation and express TSPY1.
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Classical Gonadoblastoma: its relationship to the 'dissecting' variant and undifferentiated gonadal tissue.
Histopathology, 2017Co-Authors: Lawrence M Roth, Liang ChengAbstract:Classical Gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all Gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical Gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical Gonadoblastoma can be interpreted as a noninvasive neoplasm that is the precursor of germinoma, and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical Gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be clearly distinguished from “dissecting Gonadoblastoma,” a neoplasm derived from classical Gonadoblastoma that is the precursor of some germinomas. “Dissecting Gonadoblastoma” is a variant of classical Gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of “dissecting Gonadoblastoma”. This article is protected by copyright. All rights reserved.
Lawrence M Roth - One of the best experts on this subject based on the ideXlab platform.
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Gonadoblastoma versus ovarian mixed germ cell sex cord stromal tumor in women or girls with no evidence of a disorder of sex development a problem in differential diagnosis
Pathology Research and Practice, 2020Co-Authors: Lawrence M Roth, Bernard Czernobilsky, Steven A Mann, Liang ChengAbstract:Gonadoblastoma occurring in a normal girl or woman has been confused with ovarian mixed germ cell-sex cord stromal tumor (MGC-SCST) due to a lack of knowledge that the former occurs occasionally in a normal woman or girl. In this article, we develop histological criteria that facilitate the distinction of Gonadoblastoma in an individual with a normal karyotype and no evidence of a disorder of sex development from ovarian MGC-SCST. We reviewed the histological findings of Gonadoblastoma occurring in normal individuals and compared them to cases of ovarian MGC-SCST in our files. The histological findings of Gonadoblastoma differ substantially from those of ovarian MGC-SCST. Importantly, Gonadoblastoma contains two types of transformed germ cells, some histologically benign and others premalignant, whereas MGC-SCST contains only a single type, typically premalignant in the ovary and benign in the testis. Furthermore, degenerative changes of hyalinization and calcification are common in Gonadoblastoma, whereas they are extremely rare in MGC-SCST. Although the great majority of cases of Gonadoblastoma occur in an individual with a disorder of sex development and an abnormal karyotype, a substantial number arise in a normal woman or girl with no evidence of a disorder of sex development. In the latter circumstance, it is important to distinguish Gonadoblastoma from ovarian MGC-SCST. It is very likely that those Gonadoblastomas arising in a normal individual develop through a different molecular pathway than the ones that occur in the dysgenetic gonads of an individual with a disorder of sex development.
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Gonadoblastoma: origin and outcome
Human pathology, 2019Co-Authors: Lawrence M Roth, Liang ChengAbstract:Classical Gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development; however, a small number of cases arise in individuals with a normal peripheral karyotype and no evidence of a disorder of sex development. Those Gonadoblastomas that occur in an individual who has a Y chromosome or part thereof express testis specific protein Y-encoded 1 (TSPY1). If a gonad in those individuals contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical Gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular stroma that sometimes contains steroid cells. Classical Gonadoblastoma can be interpreted as a noninvasive or an in situ neoplasm that is the precursor of germinoma in some individuals and, indirectly, of other more aggressive germ cell neoplasms. The "dissecting" variant is derived from classical Gonadoblastoma and is characterized by unusual growth patterns. Undifferentiated gonadal tissue is the precursor of Gonadoblastoma; however, if all germ cells in an individual with undifferentiated gonadal tissue involute, the result is a secondary streak gonad. Undifferentiated gonadal tissue is a non-neoplastic condition resembling a streak gonad but additionally contains germ cells with delayed maturation that express octamer-binding transcription factor 4; however, other germ cells, show normal maturation and express TSPY1.
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classic and dissecting Gonadoblastoma in a phenotypic girl with a 46 xx peripheral karyotype and no evidence of a disorder of sex development
International Journal of Gynecological Pathology, 2019Co-Authors: Lawrence M Roth, Mary M Davis, Bernard CzernobilskyAbstract:Herein, we report a case of a 9-yr-old girl who had a 46, XX peripheral karyotype and apparent developmentally normal ovaries. She presented with abdominal pain and a right adnexal mass. No clinical or pathologic evidence of gonadal dysgenesis or undifferentiated gonadal tissue was detected. She underwent right salpingo-oophorectomy with rupture of the tumor at the time of operation due to recent adnexal torsion. The original pathologic diagnosis was Gonadoblastoma and mixed germ cell tumor. Most significantly in our study, we identified a rare and novel pathway for the development of malignant mixed germ cell tumor from Gonadoblastoma in the absence of identifiable dysgerminoma. The histologically identifiable steps of progression in our case were as follows: (1) residual islands of classic Gonadoblastoma, (2) overgrowth by "dissecting" Gonadoblastoma composed of transformed germ cells with clear cytoplasm and sex cord elements surrounded by a basement membrane, (3) stromal infiltration by dedifferentiated germ cells with loss of basement membrane, (4) formation of malignant mixed germ cell tumor. The dedifferentiated areas were composed of anaplastic germ cells with amphophilic cytoplasm that gradually replaced the sex cord elements by clonal expansion. Both the original transformed and the anaplastic germ cell components strongly expressed OCT4. We believe that the mixed germ cell tumor arose from the dedifferentiated germ cell component through neoplastic progression. This premise suggests that the germ cell component of "dissecting" Gonadoblastoma rarely undergoes anaplastic change in the absence of transition to germinoma and can be the direct precursor of mixed germ cell tumor.
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Classical Gonadoblastoma: its relationship to the 'dissecting' variant and undifferentiated gonadal tissue.
Histopathology, 2017Co-Authors: Lawrence M Roth, Liang ChengAbstract:Classical Gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all Gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical Gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical Gonadoblastoma can be interpreted as a noninvasive neoplasm that is the precursor of germinoma, and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical Gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be clearly distinguished from “dissecting Gonadoblastoma,” a neoplasm derived from classical Gonadoblastoma that is the precursor of some germinomas. “Dissecting Gonadoblastoma” is a variant of classical Gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of “dissecting Gonadoblastoma”. This article is protected by copyright. All rights reserved.
Yunfai Chris Lau - One of the best experts on this subject based on the ideXlab platform.
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Gonadoblastoma locus and the tspy gene on the human y chromosome
Birth Defects Research Part C-embryo Today-reviews, 2009Co-Authors: Yunfai Chris Lau, Tatsuo KidoAbstract:The Gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of Gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.
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testis specific protein y encoded gene is expressed in early and late stages of Gonadoblastoma and testicular carcinoma in situ
Urologic Oncology-seminars and Original Investigations, 2007Co-Authors: Eric Vilain, Felix A Conte, Ewa Rajpertde Meyts, Yunfai Chris LauAbstract:The testis-specific protein Y-encoded gene (TSPY) is a tandem repeat gene located at the critical region for the Gonadoblastoma locus on Y chromosome that predisposes the dysgenetic gonads of intersex individuals to oncogenesis. The expression and molecular properties of TSPY suggest that it is the putative gene for the Gonadoblastoma locus on Y chromosome. In this study, we examined the expression of TSPY and other germ cell tumor markers in 4 cases of Gonadoblastoma using immunostaining techniques. Our results showed that TSPY expression was closely associated with initiation and various stages of Gonadoblastoma development. TSPY protein localized with established germ cell tumor markers, such as the placental alkaline phosphatase, c-KIT, and OCT3/4, in the same tumor cells of both Gonadoblastoma and adjacent carcinoma in situ, the precursor for germ cell tumors. These findings support the candidacy of TSPY as the gene for the Gonadoblastoma locus on Y chromosome and suggest that TSPY could be a significant marker for these types of germ cell tumors.
Michael J Gaffey - One of the best experts on this subject based on the ideXlab platform.
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Gonadoblastomas in 45 x 46 xy mosaicism analysis of y chromosome distribution by fluorescence in situ hybridization
American Journal of Clinical Pathology, 1997Co-Authors: Julia C Iezzoni, Christopher Von Kapherr, Wendy L Golden, Michael J GaffeyAbstract:Gonadoblastomas are composed of nests of neoplastic germ cells and sex cord derivatives surrounded by ovarian-type stroma. These tumors are found almost exclusively in persons with gonadal dysgenesis associated with a Y chromosome or Y chromosome fragment, and accordingly, the Y chromosome has been implicated in Gonadoblastoma oncogenesis. To evaluate this association, we used two-color fluorescence in situ hybridization with chromosome-specific probes to determine the distribution of the X and Y chromosomes in the tumor nests and surrounding stromal cells in paraffin tissue sections of three Gonadoblastomas in two patients with gonadal dysgenesis and 45,X /46,XY mosaicism. Statistical analysis of the data from the fluorescence in situ hybridization demonstrated that in all three Gonadoblastomas, the proportion of nuclei with a Y chromosome signal was significantly higher in the tumor cells than in the nontumoral cells of the surrounding stroma ( P <.001). These results suggest that Y chromosome material participates in Gonadoblastoma tumorigenesis.
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Gonadoblastomas in 45,X/46,XY mosaicism: analysis of Y chromosome distribution by fluorescence in situ hybridization.
American journal of clinical pathology, 1997Co-Authors: Julia C Iezzoni, Wendy L Golden, Christopher Von Kap-herr, Michael J GaffeyAbstract:Gonadoblastomas are composed of nests of neoplastic germ cells and sex cord derivatives surrounded by ovarian-type stroma. These tumors are found almost exclusively in persons with gonadal dysgenesis associated with a Y chromosome or Y chromosome fragment, and accordingly, the Y chromosome has been implicated in Gonadoblastoma oncogenesis. To evaluate this association, we used two-color fluorescence in situ hybridization with chromosome-specific probes to determine the distribution of the X and Y chromosomes in the tumor nests and surrounding stromal cells in paraffin tissue sections of three Gonadoblastomas in two patients with gonadal dysgenesis and 45,X /46,XY mosaicism. Statistical analysis of the data from the fluorescence in situ hybridization demonstrated that in all three Gonadoblastomas, the proportion of nuclei with a Y chromosome signal was significantly higher in the tumor cells than in the nontumoral cells of the surrounding stroma ( P
R Sultana - One of the best experts on this subject based on the ideXlab platform.
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In situ hybridization analysis of the Y chromosome in Gonadoblastoma.
Genes chromosomes & cancer, 1995Co-Authors: R Sultana, David Myerson, Christine M. DistecheAbstract:Gonadoblastoma is a rare tumor arising in the streak gonads of about 30% of 46, XY sex-reversed females. Because Gonadoblastoma develops only in patients who have Y-chromosome material and dysgenetic gonads, it has been hypothesized that positive expression of a gene (or genes) on the Y chromosome (GBY) is involved in the etiology of the tumor. To examine the Y chromosome directly in tumors, we performed nonisotopic in situ hybridization of a biotin-labeled Y-specific probe for the DYZI locus on formalin-fixed, paraffin-embedded sections of tumor samples from four different patients. After hybridization to DYZI, the Y chromosome was found to be present in all Gonadoblastoma foci in the four patients studied, and the Gonadoblastoma foci showed an average of 85% cell nuclei positive for the Y chromosome on tissue sections. Normal male and female control tissues showed an average of 78% and 0% positive nuclei, respectively. One patient with bilateral Gonadoblastoma had previously been shown to be mosaic, with a 45, X/46, XY karyotype in lymphocytes, skin fibroblasts, and cultures from both gonads. Examination of sections of this patient's gonads showed 79% positive nuclei within the Gonadoblastoma foci, whereas the nontumor stromal tissue had 19% positive nuclei. These results indicate that, in this mosaic gonad, tumor foci developed only from cells that had a Y chromosome. Our results support the hypothesis that there is a GBY locus on the Y chromosome and that the Y chromosome is retained in the Gonadoblastoma foci during the development of the tumor. © 1995 Wiley-Liss, Inc.
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Analysis of the Y chromosome in Gonadoblastoma
American Journal of Human Genetics, 1994Co-Authors: R Sultana, David Myerson, D AdlerAbstract:Gonadoblastoma is a rare tumor arising in the streak gonads of about 30% of 46,XY sex-reversed females. As Gonadoblastoma develops only in patients with Y-chromosome material and dysgenetic gonads, it has been hypothesized that positive expression of a gene (or genes) on the Y chromosome (GBY) is involved in the etiology of Gonadoblastoma. To examine the Y chromsome directly in the tumors, we performed in situ hybridization of a Y-chromosome-specific probe to formalin-fixed, paraffin-embedded tumor samples from four different patients. A biotin-labeled probe for the repeated DYZ1 locus, which maps to interval 7 (band q12) of the Y chromosome was hybridized to gonadal sections and detected by antibodies and a peroxidase reaction. After hybridization to DYZ1, Gonadoblastoma foci showed an average of 85% positive cells. The Y chromosome was found to be present in all Gonadoblastoma foci in the four patients studied. Normal male and female control tissues showed an average of 83% and 0% positive cells, respectively. One patient with bilateral Gonadoblastoma had been previously shown to be mosaic with a 45,X/46,XY karyotype in lymphocytes, skin fibroblasts, and cultures from both gonads. Examination of sections of this patient`s gonads showed 77% positive cells within the Gonadoblastoma foci, while themore » nontumor stroma tissue had 19% positive cells. These results indicate that in this mosaic gonad tumor foci exclusively developed from cells having a Y chromosome. Our results support the hypothesis that there is a GBY locus on the Y chromosome and that the Y chromosome is retained in Gonadoblastoma foci during the progression of tumor.« less
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Gonadoblastoma: Molecular definition of the susceptibility region on the Y chromosome and role of TSPY
American Journal of Human Genetics, 1994Co-Authors: K. Tsuchiya, R Sultana, M. DonlanAbstract:Gonadoblastomas are gonadal neoplasms that arise almost exclusively in the dysgenetic gonads of 46,XY sex-reversed females. The frequency of Gonadoblastoma in patients who have dysgenetic gonads and a Y chromosome is at least 30%. In contrast 45,X Turner females who also have dysgenetic gonads do not develop this tumor. The high frequency of Gonadoblastoma in sex-reversed females compared to Turner females has led to the hypothesis that there is a gene on the Y chromosome that is involved in the development of the tumor. This gene has been called the Gonadoblastoma locus on the Y chromosome, or GBY. Deletion mapping of sex-reversed females with Gonadoblastoma and partial Y chromosomes has previously localized the GBY gene to a region near the centromere. Using sequence-tagged sites, we have further sublocalized GBY in a patient with Gonadoblastoma and a minute Y-derived marker chromosome. This region includes parts of intervals 3 and 4 of the Y chromosome. Based on the overlapping YAC contig map of the Y chromosome, this critical region is approximately 3 Mb. Using sex-reversed females with different deletions of Yp we have also localized the testis-specific protein, Y-encoded (TSPY) gene to interval 3D, which is within the Gonadoblastoma critical region. TSPYmore » consists of a repetitive gene family that is part of the DYZ5 locus. Expression of this gene has previously been shown to be limited to the testis. We have found expression of TSPY by RT-PCR in Gonadoblastomas from two different individuals. In one of these patients, expression was observed in a unilateral Gonadoblastoma, but not in the contralateral streak gonad. These findings suggest that TSPY may play a role in the development of Gonadoblastomas.« less