Gonadoblastoma
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]
Synonyms and keywords: Gonadoblastomas; Gonadoblastomata
Overview
Historical Perspective
Gonadoblastoma was first discovered by Dr. Robert E. Scully, an American pathologist, in 1953 following studying the pathology of a series of tumors suspected of being dysgerminomas. This tumor is called gonadoblastoma since it looks like embryonic tissue, but in an indifferent way regarding sexual development.[1][2] The association between GBY gene (GonadoBlastoma on Y chromosome) and gonadoblastoma was made in 1986. Page hypothesized that the GBY gene predispose the gonads with disgenetic abnormality to gonadoblastoma development, however, it plays a physiologic role in normal male.[3] In 1995, Tsuchiya found that the GBY gene located near the centromere of Y chromosome and contains multiple genes including Testis-specific protein Y-encoded (TSPY) gene.[4]
Classification
Gonadoblastoma may be classified according to its pathologic features into following forms:[5]
- Classical
- Dissecting
- Burnt-out
Pathophysiology and Associated Conditions
The exact pathogenesis of gonadoblastoma is not fully understood. Gonadal development starts at 5 weeks of gestation and continues according to sex chromosomal contents. Any defects in this complicated process lead to defective gonadal development and gonadal dysgenesis and subsequently, it can be converted to gonadoblastoma in 20% to 30% of the cases. [6][7] Gonadoblastoma develop almost exclusively in dysgenetic gonads containing the Y chromosomal contents. The GBY gene locus, localized near the centromere of the Y chromosome, is hypothesized to be the culprit gene in the pathogenesis of gonadoblastoma. TSPY gene product is observed to be overexpressed in the gonadoblastoma and other germ cell tumors, although its exact role is still unclear.[8] Gonadoblastoma occurs bilaterally in 50% of the cases. It can be accompanied by dysgerminoma in 50% of cases as well as with other more malignant germinomatous neoplasms in 10%.[9] Other conditions associated with gonadoblastoma are as follows:
Gross Pathology
Gross pathology of tumor greatly depends on the degree of germ cells overgrowth and calcification. The tumor is firm and cartilaginous with a yellow to a brown-grey color. It can be calcified partly or almost completely. It can be very large especially with when ccompanied by a dysgerminoma or be hardly detectable in gross examination.[2]
Microscopic Pathology
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Gonadoblastoma is formed from two different types of cells: larger cells resembling immature germ cells and smaller cells resembling the sex-cord stroma (Granulosa or Sertoli-like cells). another kind of stromal cells (Leydig cells or Lutein-like cells) can also exist, but their presence is not essential for the diagnosis. The two essential type of cells forms a nest-like space in which, immature germ cells surrounded by sex-cord stromal cells. This nested arrangement is characteristic of gonadoblastoma. The Leydig-like cells, large polygonal cells in the interstitium, tend to be present greatly after puberty. The nest is encircled by a basement membrane which can be hyalinized or even calcified. Calcification can be focal or extensive. Focal calcification is found in more than 80% of the individuals. The nodular pattern of hyalinized basement membrane encircled by stromal cells can also be present. Germ cells within the tumor have varied degrees of atypia and they must be differentiated from the simultaneous invasive germ cell tumor.[11] Gonadoblastoma classified pathologically into three forms:[2][5]
- Classical form which is described above thoroughly.
- Burnt-out form, in which the cells regress and the remnant is calcified and forms a mulberry-shaped calcification.
- Dissecting form which has a infiltrative and cord like pattern rather than a nested arrangement. The clinical relevance of this pathologic feature is that, it should be differentiated from germinoma.[12]
Causes
The following disorders are associated with the development of gonadoblastoma.[13] [14][15][16]
Differentiating Gonadoblastoma from Other Diseases
Gonadoblastoma must be differentiated from:[17][18]
- dysgerminoma
- Sex-cord stromal tumors
- Sertoli-cell nodules
Epidemiology and Demographics
The prevalence of gonadoblastoma varied depend on the chromosomal content, presence or absence of mosaicism, gonadal histology and age of the patient between 15% to 30%.[15] The incidence of gonadoblastoma varied according to the presence or absence of Y chromosomal content and age of the individual. Patients with Turner syndrome who have Y chromosomal content either completely or partially can develop gonadoblastoma with an incidence as high as 43%.[19] Phenotypical female with XY gonadal abnormalities have been observed to develop gonadoblastoma by 40%.[17] Gonadoblastoma affects individuals of any age but tends to present at a greater extent prior to 15 years of age. it commonly originated from dysgenetic gonad but has been seen in women with normal ovary and karyotypes, although rarely. Since this tumor affects gonads, there is no genotype-phenotype correlations. The majority of affected individuals appear phenotypically female, but in reality, they are intersex.[2] There is no racial predilection to gonadoblastoma.
Risk Factors
The most potent risk factor in the development of gonadoblastoma is gonadal dysgenesis. The risk of gonadoblastoma development increases with age. In individuals with XY gonadal abnormalities, it reaches 30% by thirty years of age. Other risk factors include being affected with Turner syndrome, and having Y chromosome materials. There are some rare reports of gonadoblastoma development in patients with 46 XX karyotype that suggest the presence of unknown pathophysiological mechanisms for this tumor.[20] [17]
Screening
There is insufficient evidence to recommend routine screening for gonadoblastoma. However, patients with XY gonadal abnormalities should be followed using sonography starting at age 2, every six months, until gonad can be removed.[15]
Natural History, Complications, and Prognosis
Gonadoblastoma per se is a benign tumor, however, it has the capacity to convert to dysgerminoma or other more malignant germ cell tumors and produce steroids with resultant virilization.[17] If complicated by an invasive germ cell tumor, then prognosis depends on the staging of the tumor.[9]
Diagnosis
Diagnostic Study of Choice
There are no established criteria for the diagnosis of gonadoblastoma. It is often found during a workup for ambiguous genitalia in infancy or sexual developmental disorder in puberty. Any clue to the presence of an intersex gonadal abnormality (gonadal dysgenesis) should raise the concern for the coexisting gonadoblastoma.[15]
History and Symptoms
Patients with gonadoblastoma present either during infancy with ambiguous genitalia or later with sexual developmental complaints. The hallmark of gonadoblastoma is gonadal developmental disorders. The majority of affected individuals are phenotypically women and may be discovered during a workup for virilization and/or primary amenorrhea. Others are phenotypically men with sex organs developmental problems such as cryptorchidism and hypospadias.[9]
Physical Examination
Gonadoblastoma has no characteristic physical feature, however, any clue to existence of an intersex disorder must raise the concern for diagnosing the coexisting gonadoblastoma. Patients with gonadoblastoma can appear phenotypically female or male. It is of particular note that clinical presentation may be varied considering the nature of abnormal gonad and the amount of steroid hormone in it. In phenotypic women, physical examination of patients can be remarkable for virilization or the presence of a pelvic mass.In phenotypic men, physical examination suggestive of gonadoblastoma are undescended testis and hypospadias. [2][9]
Laboratory Findings
Chromosomal analysis plays the most beneficial role in the diagnosis of conditions associated with gonadoblastoma. It can be used as the screening test in the infants with external genitalia ambiguity and later in life for individuals suspected of intersex disorders. Since the presence of Y chromosomal content in individuals with disgenetic gonads strongly suggests the development of gonadoblastoma in those with gonadal abnormalities, a karyotype analysis showing Y chromosome is helpful for diagnosis. However, sometimes the Y chromosome materials are present in molecular level and can not be diagnosed karyotypically. In theses individuals, molecular analysis of chromosomes using polymerase chain reaction (PCR) and/or fluorescence in situ hybridization (FISH) are suggested.[21] Some patients with gonadoblastoma may have elevated concentration of human chorionic gonadotropin (hCG), which is usually suggestive of dysgerminoma.[20] Gonadoblastoma has no specific laboratory feature, however, some immunohistochemistry staining can be positive including:[17][22]
- TSPY
- OCT3/4
- FoxL
- SF-1
- Sox9
X-ray
An abdominal x-ray may be helpful in the diagnosis of calcification in the gonads associated with gonadoblastoma. If the tumor is calcified a characteristic confined spotty pattern can be observed radiographically. This finding may be unilateral or bilateral.[15][23]
Ultrasound
There are no ultrasound findings associated with gonadoblastoma. However, an ultrasound may be helpful in the evaluation of a mass in the gonads and the exclusion of associated conditions. In one study, sonographic findings associated with testicular gonadoblastoma was a well-defined complex mass with a solid and interspaced cystic components. It should be mentioned that cystic component is not usual for gonadoblastoma, but its presence may suggest the existence of granulosa cells in the tumor. Additionally, calcification of tumor may not be present all the time.[24] It is also observed that gonadoblastoma may lead to an increase in echogenicity localized to the tumor location on the ultrasound imaging studies.[25]
CT scan and MRI
There are no CT scan or MRI findings associated with gonadoblastoma. However, an imaging study may be helpful in the diagnosis of associated conditions of this disorder, which include gonadal dysgenesis, Turner syndrome, and etc.
Treatment
The mainstay of treatment for gonadoblastoma is surgical removal of the tumor. Gonadectomy is applied only to those who have Y chromosome content and/or virilization. Hormonal replacement therapy may be done depending on the patient and presence or absence of vaginal bleeding and or virilization.[17] Bilateral gonadectomy should be considered when the contralateral gonad is abnormal or undescended. Since gonadoblastoma was also found in anatomically normal male, in case of gonadoblastoma in anatomically normal male, close monitoring of contralateral gonad is recommended if it is preserved.[26][25] Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3]. Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
Primary Prevention
There are no established measures for the primary prevention of [disease name]. Effective measures for the primary prevention of gonadoblastoma include [measure1], [measure2], and [measure3].
Secondary Prevention
There are no established measures for the secondary prevention of [disease name]. Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].
References
- ↑ Scully, Robert E. (1953). "Gonadoblastoma. A gonadal tumor related to the dysgerminoma (Seminoma) and capable of sex-hormone production". Cancer. 6 (3): 455–463. doi:10.1002/1097-0142(195305)6:3<455::AID-CNCR2820060303>3.0.CO;2-U. ISSN 0008-543X.
- ↑ 2.0 2.1 2.2 2.3 2.4 Scully RE (1970). "Gonadoblastoma. A review of 74 cases". Cancer. 25 (6): 1340–56. PMID 4193741.
- ↑ Page DC (1987). "Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads". Development. 101 Suppl: 151–5. PMID 3503713.
- ↑ Tsuchiya K, Reijo R, Page DC, Disteche CM (December 1995). "Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome". Am. J. Hum. Genet. 57 (6): 1400–7. PMC 1801429. PMID 8533770.
- ↑ 5.0 5.1 Ulbright, Thomas M.; Young, Robert H. (2014). "Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development". Seminars in Diagnostic Pathology. 31 (5): 427–440. doi:10.1053/j.semdp.2014.07.001. ISSN 0740-2570.
- ↑ Carcangiu, M. L. (2014). WHO Classification of Tumours of Female Reproductive Organs. Lyon: International Agency for Research on Cancer. ISBN 978-9283224358.
- ↑ Cools M, Stoop H, Kersemaekers AM, Drop SL, Wolffenbuttel KP, Bourguignon JP, Slowikowska-Hilczer J, Kula K, Faradz SM, Oosterhuis JW, Looijenga LH (June 2006). "Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads". J. Clin. Endocrinol. Metab. 91 (6): 2404–13. doi:10.1210/jc.2005-2554. PMID 16608895.
- ↑ Kido, Tatsuo; Lau, Yun-Fai Chris (2008). "The human Y-encoded testis-specific protein interacts functionally with eukaryotic translation elongation factor eEF1A, a putative oncoprotein". International Journal of Cancer. 123 (7): 1573–1585. doi:10.1002/ijc.23697. ISSN 0020-7136.
- ↑ 9.0 9.1 9.2 9.3 Saia, Philip (2018). Clinical gynecologic oncology. Philadelphia, PA: Elsevier. ISBN 978-0-323-40067-1.
- ↑ "Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Clinical Principles and Applications by Reed E. Pyeritz M.D., Ph.D., FACP, FACMG | | NOOK Book (eBook) | Barnes & Noble®".
- ↑ Cools, Martine; Stoop, Hans; Kersemaekers, Anne-Marie F.; Drop, Stenvert L. S.; Wolffenbuttel, Katja P.; Bourguignon, Jean-Pierre; Slowikowska-Hilczer, Jolanta; Kula, Krzysztof; Faradz, Sultana M. H.; Oosterhuis, J. Wolter; Looijenga, Leendert H. J. (2006). "Gonadoblastoma Arising in Undifferentiated Gonadal Tissue within Dysgenetic Gonads". The Journal of Clinical Endocrinology & Metabolism. 91 (6): 2404–2413. doi:10.1210/jc.2005-2554. ISSN 0021-972X.
- ↑ Kao, Chia-Sui; Idrees, Muhammad T.; Young, Robert H.; Ulbright, Thomas M. (2016). ""Dissecting Gonadoblastoma" of Scully". The American Journal of Surgical Pathology. 40 (10): 1417–1423. doi:10.1097/PAS.0000000000000704. ISSN 0147-5185.
- ↑ Milewicz, Tomasz; Mrozińska, Sandra; Szczepański, Wojciech; Białas, Magdalena; Kiałka, Marta; Doroszewska, Katarzyna; Kabzińska-Turek, Monika; Wojtyś, Andrzej; Ludwin, Artur; Chmura, Łukasz (2016). "Dysgerminoma and gonadoblastoma in the course of Swyer syndrome". Polish Journal of Pathology. 4: 411–414. doi:10.5114/pjp.2016.65876. ISSN 1233-9687.
- ↑ Quinonez, Shane C.; Park, John M.; Rabah, Raja; Owens, Kailey M.; Yashar, Beverly M.; Glover, Thomas W.; Keegan, Catherine E. (2013). "9p partial monosomy and disorders of sex development: Review and postulation of a pathogenetic mechanism". American Journal of Medical Genetics Part A. 161 (8): 1882–1896. doi:10.1002/ajmg.a.36018. ISSN 1552-4825.
- ↑ 15.0 15.1 15.2 15.3 15.4 "Yen & Jaffe's Reproductive Endocrinology | ScienceDirect".
- ↑ Patel, Payal R.; Pappas, John; Arva, Nicoleta C.; Franklin, Bonita; Brar, Preneet Cheema (2013). "Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy". Journal of Pediatric Endocrinology and Metabolism. 26 (9–10). doi:10.1515/jpem-2012-0409. ISSN 2191-0251.
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 Sperling, M (2014). Pediatric endocrinology. Philadelphia, PA: Elsevier/Saunders. ISBN 978-1-4557-4858-7.
- ↑ Eble, John (2004). Pathology and genetics of tumours of the urinary system and male genital organs. Lyon Oxford: IARC Press Oxford University Press (distributor. ISBN 9283224159.
- ↑ Brant WO, Rajimwale A, Lovell MA, Travers SH, Furness PD, Sorensen M, Oottamasathien S, Koyle MA (May 2006). "Gonadoblastoma and Turner syndrome". J. Urol. 175 (5): 1858–60. doi:10.1016/S0022-5347(05)00932-8. PMID 16600779.
- ↑ 20.0 20.1 Esin, Sertac; Baser, Eralp; Kucukozkan, Tuncay; Magden, Hasim Ata (2011). "Ovarian gonadoblastoma with dysgerminoma in a 15-year-old girl with 46, XX karyotype: case report and review of the literature". Archives of Gynecology and Obstetrics. 285 (2): 447–451. doi:10.1007/s00404-011-2073-9. ISSN 0932-0067.
- ↑ Brant, William O.; Rajimwale, Ashok; Lovell, Mark A.; Travers, Sharon H.; Furness, Peter D.; Sorensen, Mathew; Oottamasathien, Siam; Koyle, Martin A. (2006). "Gonadoblastoma and Turner Syndrome". Journal of Urology. 175 (5): 1858–1860. doi:10.1016/S0022-5347(05)00932-8. ISSN 0022-5347.
- ↑ Kao, Chia-Sui; Ulbright, Thomas M; Idrees, Muhammad T (2014). "Gonadoblastoma: an immunohistochemical study and comparison to Sertoli cell nodule with intratubular germ cell neoplasia, with pathogenetic implications". Histopathology. 65 (6): 861–867. doi:10.1111/his.12444. ISSN 0309-0167.
- ↑ Seymour, EQ; Hood, JB; Underwood, PB; Williamson, HO (1976). "Gonadoblastoma: an ovarian tumor with characteristic pelvic calcifications". American Journal of Roentgenology. 127 (6): 1001–1002. doi:10.2214/ajr.127.6.1001. ISSN 0361-803X.
- ↑ Luisiri, A; Vogler, C; Steinhardt, G; Silberstein, M (1991). "Neonatal cystic testicular gonadoblastoma. Sonographic and pathologic findings". Journal of Ultrasound in Medicine. 10 (1): 59–61. doi:10.7863/jum.1991.10.1.59. ISSN 0278-4297.
- ↑ 25.0 25.1 Hatano T, Yoshino Y, Kawashima Y, Shirai H, Iizuka N, Miyazawa Y, Sakata A, Onishi T (March 1999). "Case of gonadoblastoma in a 9-year-old boy without physical abnormalities". Int. J. Urol. 6 (3): 164–6. PMID 10226831.
- ↑ Chapman WH, Plymyer MR, Dresner ML (December 1990). "Gonadoblastoma in an anatomically normal man: a case report and literature review". J. Urol. 144 (6): 1472–4. PMID 2231948.