eMedicine Specialties > Pediatrics: General Medicine > Oncology

Gonadoblastoma

Author: Joseph L Lasky III, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, Mattel Children's Hospital UCLA
Coauthor(s): Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA; Dimitri Kuznetsov, MD, Staff Physician, Department of Surgery, Section of Urology, University of Chicago; Nejd F Alsikafi, MD, Clinical Associate, Department of Urology, Mount Sinai Hospital; William J Cromie, MD, MBA, President and Chief Executive Officer, Health Care, Capital District Physicians' Health Plan
Contributor Information and Disclosures

Updated: Nov 26, 2008

Introduction

Background

In 1953, Scully first described a unique gonadal neoplasm that strongly resembled a normally developing gonad and subsequently named the neoplasm gonadoblastoma.¹ 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 include (1) complete androgen insensitivity and 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 are nearly always 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. Although 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; 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.

Pathophysiology

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. In patients with complete androgen insensitivity and 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, whereas the incidence of developing gonadoblastoma in individuals with androgen insensitivity and 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 at38.6%.

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.²

• 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.³ 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.

Clinical

History

• Any history of abnormal genitourinary anatomy at the time of delivery is most helpful in identifying patients with an intersex disorder who are at risk of developing gonadoblastoma.
• If the diagnosis is not established in the neonatal period, the most pertinent findings in the medical history are the individual's age, physical examination findings, mental developmental history, and family history.
  • Obtain any history of maternal exposure to androgens, drugs, alcohol, or illness during the first trimester of pregnancy.
  • Additionally, obtain a thorough family history regarding any existence of genital ambiguity, infertility, or amenorrhea because some evidence suggests that a hereditary component has a role in intersex disorders.
  • A family history can also be useful for screening purposes because a number of reports have documented the occurrence of gonadoblastoma and/or dysgerminoma in siblings of patients with male pseudohermaphrodism (46,XY) or in individuals with mixed gonadal dysgenesis (45,X/46,XY).
• In patient history, a symptom of primary amenorrhea is often the first clue to the diagnosis of an intersex disorder.
• Additionally, any developmental delay of the genitalia or secondary sexual characteristics should also initiate a prompt search for an intersex abnormality with a karyotype analysis. Troche and Hernandez (1986) found that approximately 10% of patients younger than 10 years with dysgenic gonads already had a gonadoblastoma or a dysgerminoma.³ The study further underscored the importance of karyotype analysis in patients with primary or secondary amenorrhea and abnormal sexual development.
• In Turner syndrome, persistence of infantile external genitalia and/or developmental delays can often be elicited from a medical history. Most of these individuals never have menstruated and have primary amenorrhea; however, exceptions are recognized, and, in 10% of women with Turner syndrome, puberty, menarche, and (rarely) pregnancy may occur.

Physical

• In patients at risk of developing gonadoblastoma, the tumor can frequently be diagnosed at birth by performing a careful physical examination. The unique abnormal physical findings of intersex syndromes are characteristic and can be easily detected by examining the genitalia.
• However, infants with pure forms of an intersex disorder can appear completely normal on the physical examination, and these disorders are difficult to diagnose in the neonatal period. These individuals are more frequently discovered after puberty when abnormalities become more apparent with subtle developmental delays.
• In addition to the genitourinary examination, a full physical examination is important to detect any gross abnormalities that can occur when gonadoblastoma transforms into a malignant dysgerminoma/seminoma and metastasizes. For example, a palpable abdominal mass can be found in approximately 50% of patients with metastatic disease.
• In females with a normal phenotype but with virilizing features (eg, clitoromegaly, abnormal hirsutism) and in all phenotypic males with undescended testis and hypospadiac urethra, obtain a karyotype analysis to exclude an intersex disorder.
• Other important physical findings include phallic size, the existence of an inguinal hernia, and the presence of a uterus on the bimanual examination. In the first few days of life, the maternal stimulatory effects of placental human chorionic gonadotropin facilitate the search for a uterus.
• The diagnosis of complete androgen insensitivity/male pseudohermaphroditism (46,XY) can be difficult in the neonate period; sometimes, the only clue to suggest the diagnosis is an inguinal hernia in these females who display a normal phenotype. Newborn girls with inguinal hernias have a 1.6% incidence of being male pseudohermaphrodites (46,XY) and should undergo a prompt karyotype analysis.
• Gonadoblastoma that is not identified in neonates is not usually diagnosed until after patients begin puberty when they present with primary amenorrhea. These teenagers have normal breast development, but secondary sexual characteristics are abnormal, with a complete absence of genital and axillary hair growth and a short and hypoplastic vagina.
• Patients with an incomplete or partial form of androgen insensitivity present with numerous variations of genital ambiguity, and, unlike patients with a pure form of androgen insensitivity/male pseudohermaphrodism (46,XY), these individuals receive the diagnosis soon after birth. The initial genitourinary examination reveals obvious abnormalities at birth. The physical examination findings are unpredictable and hard to interpret. A careful examination of the scrotum, labia, or the presence of an inguinal hernia often demonstrates gonadal tissue and leads to a karyotype analysis that establishes the individual's genotype and helps to characterize the intersex disorder.
• Patients with Turner syndrome (45,XO) typically present with short stature, a short webbed neck, widely spaced nipples, sparse pubic and axillary hair distribution, and infantile genitalia. Their skin is thick from lymphedema, and many nevi are present. The head and neck examination demonstrates a low hairline with low-set ears and hearing that is frequently impaired.
• The physical examination of patients with mixed gonadal dysgenesis (45,X/46,XY) is noteworthy for ambiguous genitalia with varying degrees of phallic enlargement, undescended testis, and a urogenital sinus with labioscrotal fusion. Nearly all of these patients have a uterus, vagina, and fallopian tubes in addition to an ovary/streak and a contralateral testicle. One half of these patients are short, and one third can appear similar to individuals with Turner syndrome.

Causes

• The etiology of intersex disorders is complicated, stemming from errors that occur during gametogenesis.
• The following 2 findings are universally present in patients with these lesions:
  • First, the karyotype has either macroscopic or molecular evidence of a Y chromosome.
  • Second, the gonads are undescended and are found in the abdomen.
• 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.⁴ 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).
• One of the most promising molecular events 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 It has been hypothesized to play a key role in germ cell proliferation in the testis; in fact, the TSPY promotor has been recently shown to direct gene expression, specifically in the germ cells of murine gonads.

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