Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development

Some patients with disorders of sex development (DSDs), previously known as intersex disorders, have abnormal gonadal development and an increased risk of germ cell tumors. Because of their relative rarity, however, many pathologists are unfamiliar with the morphological findings in the gonads of DSD patients and their clinical significance. This review concentrates on some of the most common DSDs where gonadal specimens may come to the attention of pathologists. It highlights the findings in gonadal dysgenesis, a DSD with a spectrum of clinical, pathologic, and molecular features but with the shared attributes of having both Y chromosomal material (even if in very limited amounts) in the gonad and also having mutations or deletions in genes necessary for normal gonadal development, mostly in those upstream of the SOX9 gene. This situation results in testicular tissue lacking normal Sertoli cells, which are now considered an essential element for the normal maturation of the primordial germ cells that migrate to the gonad from the embryonic yolk sac. Germ cells with delayed maturation mimic neoplastic germ cells, but there are both morphological and immunohistochemical differences. If the gonad having germ cells with delayed maturation also harbors the TSPY gene on the GBY locus of the Y chromosome, the cells may undergo neoplastic transformation and result in the distinctive gonadoblastoma, whose pathologic features are explored at length herein, including its potential for variant morphologies, such as a “dissecting” pattern. Another important DSD, the androgen insensitivity syndrome (AIS), is discussed at length, including the varied appearances of the testis and its distinctive lesions—hamartomas and Sertoli cell adenomas. The potential for germ cell neoplasia in the partial AIS is also discussed and contrasted with that of the complete AIS. A third major topic is ovotesticular DSD (true hermaphroditism). The clinical features and morphology of this condition are reviewed, including the arrangements of the tissue components in an ovotestis. Several other DSDs with distinctive gonadal findings are also considered, including Klinefelter syndrome, 5α-reductase deficiency, 17β-hydroxysteroid dehydrogenase deficiency, and female adrenogenital syndrome.     

Dysgerminoma in a 10-Year Old with 45X/46XY Turner Syndrome Mosaicism

BackgroundTurner syndrome is a genetic disorder resulting from the absence of or structural abnormality of one X chromosome. The presence of Y chromosome material in girls with Turner syndrome confers an increased risk of benign and malignant germ cell tumor and prophylactic bilateral gonadectomy is recommended.CaseA 10-year-old Turner mosaic syndrome (45X/46XY) patient underwent prophylactic gonadectomy after unremarkable preoperative pelvic imaging. Histopathology showed a streak right gonad, and left gonad with gonadoblastoma with limited degree of infiltrating germinoma.Summaryand ConclusionGonadoblastoma and dysgerminoma have been reported in girls with Turner mosaic who carry Y chromosome material. Prophylactic gonadectomy should be considered in these girls without delay.     

Atypical Presentation of Swyer Syndrome

BackgroundSwyer syndrome is a rare type of disorder of sex development and typically presents with delayed puberty and primary amenorrhea. We describe an unusual presentation of this condition.CaseA 17-year-old female patient with typical thelarche and adrenarche presented with primary amenorrhea. Pelvic ultrasound showed normally developed uterus and bilateral ovoid hypoechoic structures suggestive of gonads. Laboratory investigations revealed highly elevated gonadotrophins with estradiol level within a range typical for a female of reproductive age and chromosome analysis showed a 46,XY karyotype. Histopathological examination of the gonadectomy specimens revealed gonadoblastoma and dysgerminoma with no functional ovarian or testicular tissue.Summary and ConclusionThis report reminds us the possibility of diagnosis of Swyer syndrome in the presence of normal pubertal development and normal sex steroid levels considered to be produced by gonadoblastoma.     

Gonadoblastoma bilateral y disgerminoma asociados en un síndrome de Swyer

Swyer syndrome is a pure gonadal dysgenesis with female phenotype and 46 XY karyotype. Affected individuals have dysgenetic and non-functioning gonads. The risk of gonadal neoplasia is high at between 25% and 30%. The most frequently reported malignancies are gonadoblastoma and disgerminoma. We report a case of bilateral gonadoblastoma and dysgerminoma in a female patient with this syndrome.     

Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: an immunohistochemical study for OCT3/4 and TSPY

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.     

Frasier syndrome: A case report

IntroductionFrasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions.Clinical findingsIt is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common.Main diagnosesMutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome.Therapeutic interventionsIt is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary.ConclusionFrasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.     

Short stature as the only presenting feature in a patient with an isodicentric (Y)(q11.23) and gonadoblastoma. A clinical and molecular cytogenetic study

A 13-year-old phenotypically female patient presented with short stature (height SDS –2.6), but without any Turner stigmata or other dysmorphic features. Chromosome analysis showed mosaicism for an isodicentric (idic) (Y)(q11.23) containing cell line and a 45,X cell line. Subsequent gonadectomy revealed a left streak ovary and a right ovary of abnormal appearance, which on histological examination appeared to contain a gonadoblastoma. DNA analysis showed that the proposed critical region of the gonadoblastoma locus on the Y chromosome was contained within the patient's idic (Y). Conclusion The case described here shows that patients with 45,X/46,X, isodicentric (Yp) mosaicism and a female phenotype (1) can lack external virilisation but still have a gonadoblastoma and (2) do not necessarily have Turner stigmata but can present with only short stature. This case also underlines the importance of karyotyping patients with unexplained short stature to enable gonadectomy if Y-derived material is detected. Received: 12 July 2000 / Accepted: 20 September 2000     

45,X/46,XY mosaicism

The clinical findings in ten patients with 45,X/46,XY mosaicism are described. Three girls presented with short stature, delayed sexual development or Turner-like stigmata without signs of virilization. Bilaterally gonadoblastomas were found in two girls, and the gonads in one of these girls also contained mucinous cystadenomas. The remaining seven patients were raised as boys. Three had scrotal hypospadias and mixed gonadal dysgenesis. Three presented as male pseudohermaphrodites with scrotal or penoscrotal hypospadias and bilateral testes. One male was diagnosed in adulthood because of gynecomastia, but had normal male external genitals. The clinical findings illustrate the wide spectrum of phenotypic manifestations of 45,X/46,XY mosaicism, ranging from females with Turner-like phenotypes, phenotypic males and females with mixed gonadal dysgenesis, male pseudohermaphroditism to almost phenotypic normal males.