In 1953, Scully first described a unique gonadal neoplasm that strongly resembled a normally developing gonad and subsequently named the neoplasm gonadoblastoma. [1, 2] Gonadoblastoma is a rare benign tumor that has the potential for malignant transformation and affects a subset of patients with an intersex disorder or disorder of sex development (DSD).
The diagnosis of gonadoblastoma can be challenging; however, once the diagnosis is identified, the potential risk of malignant transformation warrants prophylactic removal of the abnormal gonad. Gonadoblastoma per se does not demonstrate invasive behavior; however, 50% of the specimens demonstrate evidence of local overgrowth by the germinal component, and approximately 10% of these germinomas/seminomas arising within this context have demonstrated metastases.
Human development and sexual differentiation is a complicated but highly organized process. By 5 weeks' gestation, the path of gonadal differentiation is directed by the chromosomal sex of the fetus and, thereafter, the phenotypic sexual development of the individual. Although surprisingly accurate, this complex multistep process is not universally perfect, and errors in sexual differentiation can occur. In individuals with anomalies of the sex chromosome, the gonads frequently are dysgenic, and sexual phenotype is unpredictable. As these patients mature into adulthood, the risk of developing benign and malignant gonadal tumors increases. Initially, the abnormal gonad can develop the histologic characteristics of gonadoblastoma. As the germinal component overgrows the stroma, the benign characteristic histology of gonadoblastoma progresses to a locally infiltrating pattern that predisposes the patient to the malignant spread of the lesion.
Gonadoblastoma can arise in dysgenetic gonads as part of a variety of DSD with a part of the Y chromosome as described further in Causes. It was originally postulated that a gene on the Y chromosome (gonadoblastoma locus on the Y chromosome, GBY) acted as an oncogene in the microenvironment of the dysgenetic gonad.  In 1995, Tsuchiya et al localized the gonadoblastoma susceptibility region (GBY) to a small region near the centromere of the Y chromosome, using a panel of DNAs from sex-reversed and gonadoblastoma patients.  This locus contains several known genes including amelogenin Y (AMELY), RNA-binding motif (RBM), protein kinase Y (PRKY), protein tyrosine phosphatase (PTP)-BL related Y (PRY), testis transcripts Y1 and Y2 (TTY1 and TTY2), and testis-specific protein Y-encoded (TSPY).
More recently, studies have revealed that the most promising molecular event that may contribute to gonadoblastoma development involves the TSPY gene. Although the exact functional role of the protein product is unknown, upregulation of the protein has been detected in numerous malignancies, including gonadoblastoma, other testicular tumors, and prostate cancer.
More recent studies point to its role as an active oncogene [5, 6] and further establish the candidacy of TSPY as the gene for GBY for the following reasons: (1) TSPY is expressed in adult spermatogonia and fetal gonocytes and seems to have vital functions in male stem/germ cell proliferation, (2) it has been mapped to the GBY region as described above, (3) it is ectopically expressed in gonadoblastomas and other testicular germ cell tumors (ie, the premalignant carcinoma in situ, seminoma, and some nonseminomatous germ cell tumors), and (4) expression of TSPY is correlated with expression of other established germ cell tumor markers including placental alkaline phosphatase, c-Kit, and OCT3/4. 
Furthermore, the TSPY promotor has been recently shown to direct gene expression, specifically in the germ cells of murine gonads.  In vitro and in vivo studies have demonstrated that ectopic expression of TSPY favors cell proliferation and growth and predisposes cells to further genetic “hits” resulting in carcinogenesis. 
Gonadoblastoma is an uncommon tumor occurring almost exclusively in patients with DSD, who have either molecular evidence of a Y chromosome or a Y chromosome on karyotype analysis. The karyotype of these individuals is most often 46,XY; 45,X/46,XY; or 45,XO. Phenotypically, 80% of patients with gonadoblastoma are females and 20% are males.  The exact prevalence of gonadoblastoma is not known. Patients with mixed gonadal dysgenesis (45,X/46,XY) have a 55% incidence, whereas the incidence of developing gonadoblastoma in individuals with androgen insensitivity and male pseudohermaphrodism (46,XY) has been reported to be 30-66%.
A normal or partially deleted Y chromosome or marker chromosome derived from Y has been found in 6-9% of patients with Turner syndrome (TS). The molecular presence of a Y chromosome in individuals with TS results in as high as a 43% incidence of developing gonadoblastoma.  Additionally, the rate of contralateral disease for all patients is substantial at 36%. 
Gonadoblastoma is not a malignant tumor, and no studies evaluating the associated morbidity from this lesion have been reported. A study from the Danish National Registry of Patients demonstrated that in patients with Turner syndrome who develop gonadoblastoma, no mortality from the disease occurred. 
The current recommendation for patients with a DSD or with Turner syndrome is to proceed with prophylactic removal of the dysgenic gonad prior to developing gonadoblastoma.
Minimal data evaluate the consequences associated with gonadoblastoma transformation into a malignant germinoma. If the gonadoblastoma is not detected early and if it develops into a malignant germinoma (seminoma), the current chemotherapy regimens are highly successful at curing patients with this tumor. In women who develop dysgerminoma of the ovary, a high cure rate with platinum-based adjuvant chemotherapy has been demonstrated. In men with metastatic testicular germ cell tumors, the cure rate approaches 80% with platinum chemotherapy for patients with extensive disease, and the results are even better for less advanced stages of the disease.
The results of treating germ cell tumors can be extrapolated to estimate the success expected in men with malignant germinoma (seminoma). With the advancements made in treating a germ cell tumor, the present topic of debate often focuses on long-term adverse effects and toxicity associated with the current chemotherapeutic regimens rather than improving the cure rate of the actual disease.
No data are published on the race distribution of this disease.
Approximately 80% of patients with gonadoblastoma are phenotypic females, and 20% are males. Nearly all of the patients who develop gonadoblastoma have a chromosomal anomaly consistent with an intersex syndrome, and the genotypic sex is frequently inconsistent with the phenotypic appearance. The karyotype analyses demonstrate the most common genotypes to be 45,X/46,XY and 46,XY in patients at risk of developing gonadoblastoma.
A person's predisposition to develop gonadoblastoma exists early in life; most of these tumors are identified within the first 2 decades of life. A review of the literature noted that 94% of cases of neoplasia that arise in dysgenic gonads are diagnosed when the patient is younger than 30 years; in one case, a neoplasm was diagnosed when the individual was aged 6 months.  Patients with complete male pseudohermaphrodism (46,XY) present after puberty, with primary amenorrhea often the initial clue leading to the diagnosis. However, in patients with partial androgen insensitivity and male pseudohermaphrodism (46,XY), abnormal appearance of genitalia at birth allows for earlier detection. Unless diagnosed soon after birth, most gonadoblastomas are identified in postpubertal individuals when they present with primary amenorrhea.
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