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Background
This a rare tumor that has been identified in patients with pure or mixed gonadal dysgenesis or in male pseudo-hermaphrodism.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE/
PREVALENCEAGE SEX GEOGRAPHY EPIDEMIOLOGIC ASSOCIATIONS
DISEASE ASSOCIATIONS CHARACTERIZATION ANDROGEN INSENSITIVITY SYNDROME
- Gonadoblastoma in androgen insensitivity syndrome: a case report.
Raspagliesi F, Ditto A, Cobellis L, Quattrone P, Fontanelli R, Kusamura S, Solima E.
Department of Gynecological Oncology, National Cancer Institute, Milan, Italy.
Tumori. 2003 Mar-Apr;89(2):196-8. Abstract quote
We report a case of androgen insensitivity syndrome (AIS) characterized by malignant degeneration of the testes consisting of gonadoblastoma and dysgerminoma. AIS is a rare inherited form of male pseudohermaphroditism that can manifest as a normal female phenotype without mullerian derivatives and absence of the upper third of the vagina.
A 32-year-old white 46,XY female with AIS underwent removal of the dysgenetic gonads at the Gynecological Oncology Department of the Istituto Nazionale Tumori, Milan, Italy. We investigated cytogenetic alterations, hormonal levels and the presence of neoplasia in the dysgenetic gonads.
Histological analysis revealed a gonadoblastoma mixed with dysgerminoma in the left gonad and a pure dysgerminoma in the right gonad. The patient's hormonal status matched that of a male. Second-look laparotomy after chemotherapy showed a complete pathological response.
AIS should be suspected in phenotypically female patients with primary amenorrhea; surgical removal of the gonads is mandatory to avoid malignant degeneration.TURNER SYNDROME
- Gonadoblastoma in Turner syndrome and Y-chromosome-derived material.
Mazzanti L, Cicognani A, Baldazzi L, Bergamaschi R, Scarano E, Strocchi S, Nicoletti A, Mencarelli F, Pittalis M, Forabosco A, Cacciari E.
Department of Pediatrics, Pediatric Clinic, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Am J Med Genet A. 2005 Jun 1;135(2):150-4. Abstract quote
The identification of Y-chromosome material is important in females with Ullrich-Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y-chromosome-derived material and the occurrence of gonadoblastoma in these patients.
The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y-chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1-34 years old), diagnosed cytogenetically, was studied for Y-chromosome markers (SRY and Y-centromeric DYZ3 repeats). The follow-up was of 2-22 years; 101 of these patients were followed during pubertal age. Y-chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8-25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y-material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y-positive material was of 33.3% (4/12).
Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y-chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y-chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.
- Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study.
Gravholt CH, Fedder J, Naeraa RW, Muller J.
Medical Department M (Endocrinology and Diabetes) and Medical Research Laboratories, Arhus Kommunehospital, Denmark.
J Clin Endocrinol Metab. 2000 Sep;85(9):3199-202. Abstract quote
The presence of Y chromosome material in patients with Turner syndrome is a risk factor for the development of gonadoblastoma. However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity, or mortality in Turner syndrome.
We examined 114 females with Turner syndrome for the presence of Y chromosome material by PCR. Initially, five different primer sets were used. Y Chromosome-positive individuals were further examined with an additional four primer sets. We found 14 (12.2%; 95% confidence interval, 6.9-19.7%) patients who had Y chromosome material. The karyotype in 7 of these patients did not suggest the presence of Y chromosome material. Seven of the patients had been ovariectomized before entering the study due to verified Y chromosome material, whereas three patients were operated upon after the DNA analysis. The histopathological evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three patients (age, >50 yr) positive for Y chromosome material chose not to have ovariectomy performed, and detailed ultrasonographies did not suggest the presence of gonadoblastoma.
The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7-10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies.
PATHOGENESIS CHARACTERIZATION GENERAL TSPY GENE
- Expression of a candidate gene for the gonadoblastoma locus in gonadoblastoma and testicular seminoma.
Lau Y, Chou P, Iezzoni J, Alonzo J, Komuves L.
Department of Medicine, VA Medical Center, University of California, San Francisco CA, USA.
Cytogenet Cell Genet. 2000;91(1-4):160-4. Abstract quote
The gonadoblastoma locus on the Y chromosome (GBY) predisposes the dysgenetic gonads of XY females to develop in situ tumors. It has been mapped to a critical interval on the short arm and adjacent centromeric region on the Y chromosome. Currently there are five functional genes identified on the GBY critical region, thereby providing likely candidates for this cancer predisposition locus.
To evaluate the candidacy of one of these five genes, testis-specific protein Y-encoded (TSPY), as the gene for GBY, expression patterns of TSPY in four gonadoblastoma from three patients were analyzed by immunohistochemistry using a TSPY specific antibody.
Results from this study showed that TSPY was preferentially expressed in tumor germ cells of all gonadoblastoma specimens. Additional study on two cases of testicular seminoma demonstrated that TSPY was also abundantly expressed in all stages of these germ cell tumors.
The present observations suggest that TSPY may either be involved in the oncogenesis of or be a useful marker for both types of germ cell tumors.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS BETA-HCG
- False-positive pregnancy test associated with gonadoblastoma.
Schanne FJ, Cooper CS, Canning DA.
Division of Pediatric Urology, Children's Hospital of Philadelphia, PA, 19104 USA.
Urology. 1999 Jul;54(1):162. Abstract quote
Gonadoblastomas are known to be hormonally active tumors that occur in streak or dysgenetic gonads of patients with intersex abnormalities.
Several reports document their ability to produce beta-human chorionic gonadotropin (HCG), but none have documented an elevated peripheral serum beta-HCG.
We report on the case of a patient with pure gonadal dysgenesis with XY karyotype who was found to have an elevated peripheral serum beta-HCG after a positive pregnancy test.
Knowledge of gonadoblastoma's potential to elevate serum beta-HCG levels may prevent unnecessary searches for other causes.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
- Identification of germ cells at risk for neoplastic transformation in gonadoblastoma.
Kersemaekers AM, Honecker F, Stoop H, Cools M, Molier M, Wolffenbuttel K, Bokemeyer C, Li Y, Lau YF, Oosterhuis JW, Looijenga LH.
Hum Pathol. 2005 May;36(5):512-21. Abstract quote
Summary Carcinoma in situ (CIS) is the precursor of malignant testicular germ cell tumors (GCTs) of adolescents and young adults, being the neoplastic counterpart of primordial germ cells/gonocytes. Carcinoma in situ cells will develop into invasive seminoma/nonseminoma.
Gonadoblastoma (GB) is the precursor of invasive GCTs in dysgenetic gonads, predominantly dysgerminoma (DG). In this process, part of the Y chromosome (GBY region) is involved, for which TSPY is a candidate gene. A detailed immunohistochemical survey was performed for the known diagnostic markers, germ cell/placental alkaline phosphatase (PLAP), c-KIT, and OCT3/4, as well as testis-specific protein on the Y chromosome (TSPY) on a series of GBs, and adjacent invasive DGs. All 5 patients were XY individuals (4 females and 1 male). In contrast to c-KIT, PLAP was positive in all cases. The immature germ cells of GBs were positive for OCT3/4, whereas the mature germ cells were negative for this marker, but positive for TSPY. In every GB, a minor population of germ cells positive for both markers could be identified, similar to most CIS cells and early invasive DG.
On progression to an invasive tumor, TSPY can be lost, a process that is also detectable in invasive testicular GCTs compared to CIS. These results indicate that GB is a heterogeneous mix of germ cells, in which the OCT3/4-positive cells have the potential to undergo progression to an invasive tumor. These early invasive stages are initially also positive for TSPY (like CIS), supporting a positive selection mechanism.
Therefore, OCT3/4 in combination with TSPY is valuable to identify malignant germ cells in dysgenetic gonads. This could allow better prediction of the risk of progression to a GCT. In addition, the data support the model that GB represents the earliest accessible developmental stage of malignant GCTs.ELECTRON MICROSCOPY
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
PROGNOSIS CHARACTERIZATION
TREATMENT CHARACTERIZATION GENERAL
- Management of males with 45,X/46,XY gonadal dysgenesis.
Muller J, Ritzen EM, Ivarsson SA, Rajpert-De Meyts E, Norjavaara E, Skakkebaek NE.
Department of Growth and Reproduction GR, Rigshospitalet, Copenhagen, Denmark.
Horm Res. 1999;52(1):11-4. Abstract quote
Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads.
We have studied gonadal tissue from 10 individuals, 0.3-17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3-15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found.
On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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