Excerpt from Gonadoblastoma

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Background

In 1953, Scully first described a unique gonadal neoplasm that strongly resembled a normally developing gonad and subsequently named the neoplasm gonadoblastoma. Gonadoblastoma is a rare benign tumor that has the potential for malignant transformation and affects a subset of patients with intersex disorders. The select intersex syndromes associated with a clear risk of developing gonadoblastoma are (1) complete androgen insensitivity/male pseudohermaphroditism (46,XY), (2) mixed gonadal dysgenesis (45,X/46,XY), and (3) a subset of patients with Turner syndrome (45,XO). The 2 essential findings that predispose these abnormal gonads to undergo neoplastic transformation into gonadoblastoma are (1) the karyotype has either macroscopic or molecular evidence of a Y chromosome and (2) the gonads nearly always are located intra-abdominally.

Histologically, the following 2 distinct cell types characterize these tumors: (1) large germ cells (similar to dysgerminoma and seminoma) and (2) small cells, which resemble immature Sertoli or granulosa cells. Additionally, in two thirds of patients, Leydig-type cells are found in the stromal component of the tumor and are thought to be responsible for frequent virilizing features in these patients. While gonadoblastoma has normal germinal and stromal characteristics, some of the germ cells are large and have numerous mitotic figures that resemble classic testicular seminoma. In fact, as these cells overgrow the surrounding stroma, the tumor gains the characteristics of a more aggressive lesion and acquires the potential for metastatic spread.

The diagnosis of gonadoblastoma can be challenging, but, 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.

Pathophysiology

Human development and sexual differentiation is a complicated but highly organized process. By the fifth week of fetal development, 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. In patients with complete androgen insensitivity/male pseudohermaphroditism (46,XY), mixed gonadal dysgenesis (45,X/46,XY), and a subset of patients with Turner syndrome (45,XO), 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.

Frequency

United States

Gonadoblastoma is an uncommon tumor occurring almost exclusively in patients with intersex disorders, 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, while the incidence of developing gonadoblastoma in individuals with androgen insensitivity/male pseudohermaphrodism (46,XY) has been reported to be 30-66%. In patients with Turner syndrome with a Y chromosome–negative karyotype (45,XO), as many as 39% have evidence of molecular Y chromosome when studied with polymerase chain reaction (PCR). The molecular presence of a Y chromosome predisposes an individual to a 7-10% risk of developing gonadoblastoma. Additionally, the rate of contralateral disease is substantial at 38.6%.

Mortality/Morbidity

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 an intersex disorder 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.

Race

No data are published on the race distribution of this disease.

Sex

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.

Age

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/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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