AUTHOR INFORMATION

Section 1 of 11

Authored by Joseph L Lasky III, MD, Pediatric Hematology/Oncology, Assistant Professor of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles

Coauthored by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; 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, Department of Health Care, Capital District Physicians' Health Plan

Joseph L Lasky III, MD, is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Joseph L Lasky III, MD
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, June 22 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 11

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:

• In the US: 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.

CLINICAL

Section 3 of 11

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. 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 exist, 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 detected easily 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 are 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 usually not 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. 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-candidate 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 a number of malignancies, including gonadoblastoma, other testicular tumors, and prostate cancer. It has been hypothesized to play a key role in germ cell proliferation in the testis, and, indeed, the TSPY promotor has been recently shown to direct gene expression, specifically in the germ cells of murine gonads.

DIFFERENTIALS

Section 4 of 11

17-Hydroxylase Deficiency Syndrome
5-Alpha-Reductase Deficiency
Ambiguous Genitalia and Intersexuality
Amenorrhea
Congenital Adrenal Hyperplasia
Genital Anomalies
Hydrocele and Hernia in Children
Hypospadias
Menstruation Disorders
Seminoma
Teratomas and Other Germ Cell Tumors
Turner Syndrome

WORKUP

Section 5 of 11

Lab Studies:

• Chromosome analysis


• • Chromosome analysis is the most important laboratory study in the diagnosis of gonadoblastoma.
  
  
  
  • The karyotype at birth is used as a screening test in neonates with abnormal genitalia.
  
  
  
  • The karyotype may also be used at a later age to detect patients who have androgen insensitivity/male pseudohermaphroditism (46,XY) and who present with primary amenorrhea.
  
  
  
  • The karyotype confirms the diagnosis of Turner syndrome and can differentiate the many other chromosomal abnormalities that have been described.
  
  
  
  • The presence of a Y chromosome has clearly been linked to the risk of developing gonadoblastoma in the intersex population. However, because the karyotype is not able to detect the molecular presence of a Y chromosome in patients with Turner syndrome, the absence of a Y chromosome does not exclude the patient from developing gonadoblastoma.
  
  
  
  • In patients with Turner syndrome (45,XO), the karyotype analysis lacks the sensitivity to detect the molecular presence of a Y chromosome, which has been confirmed and well documented with the use of the PCR and fluorescence in situ hybridization (FISH).
  
  
  
• Serum electrolyte panel


• • In newborns with clitoromegaly, obtain a serum electrolyte panel to exclude life-threatening electrolyte disturbances.
  
  
  
  • Elevated serum potassium and low serum sodium are observed in patients with 21-hydroxylase deficiency, and other abnormalities of androgen synthesis are observed in patients with congenital adrenal hyperplasia.
  
  
  
• Endocrinologic evaluation: Concomitant endocrine abnormalities should be delineated, including measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), testosterone/dihydrotestosterone (after gonadotrophin chorionic hormone [GCH] stimulation), 17-OH progesterone, and cortisol.

Imaging Studies:

• Imaging studies are useful in diagnosing features of intersexuality in newborns, but they have a limited role in the diagnosis gonadoblastoma. All of these studies help to identify patients at risk of developing gonadoblastoma in addition to characterizing the specific intersex disorder of the individual.


• • Most patients with ambiguous genitalia usually undergo a retrograde genitogram to delineate the urogenital anatomy. Often the bladder, vagina, and any communication between the two structures can be identified.

  • If a diagnostic surgical procedure is planned, cystourethroscopy and vaginoscopy can be performed to better visualize the anatomy.
  
  
  
• In patients that present later in life, localization studies such as ultrasound, computed tomography imaging, and magnetic resonance imaging may be useful.


• • Ultrasonographic evaluation of the gonads and other pelvic organs is frequently used to identify and characterize any persistence of müllerian duct structures.
  
  
  
  • Particularly in patients with mixed gonadal dysgenesis, ultrasound can be helpful in visualizing the uterus, vagina, fallopian tubes, ovary, and a contralateral testicle.
  
  
  
• A flat abdominal radiograph can sometimes depict gonadal calcification, which is a classic pathologic finding in gonadoblastoma.

Procedures:

• The role of exploratory laparotomy and gonadal biopsy is not well defined. More often in the past, it has been used for diagnostic purposes to help identify and characterize the anatomy of patients with mixed intersex disorders. Currently, the diagnosis can be made with the use of karyotype identification and molecular techniques, minimizing the need for a diagnostic biopsy. Today, an exploratory laparotomy is reserved for patients who undergo predominately a therapeutic and not a diagnostic gonadectomy.

The 2 main cell types form discrete solid aggregates that often contain calcifications. If the germ cells invade the margins of these discrete aggregates, the lesion is no longer considered benign and is termed a dysgerminoma/seminoma. With advanced local growth, the dysgerminoma/seminoma nearly obliterates the architecture that characterizes the benign histologic features of the gonadoblastoma. Approximately 17% of germinomas arising in gonadoblastomas are bilateral.

The pathologic diagnosis of gonadoblastoma can be challenging. Gonadoblastoma is often misdiagnosed as a nonseminomatous germ cell tumor. Only a few cases of nonseminomatous germ cell tumors (eg, yolk sac, embryonal cell carcinoma, teratoma, mucinous adenoma) have been reported in patients with gonadoblastoma.

In patients with Turner syndrome, the gonads are streaks, made up of fibrous stroma arranged in whorls similar to those in ovarian stroma but lacking primordial follicles.

Staging: Gonadoblastoma is not staged because it is not a malignant tumor. However, not removed early, at least 30% of these lesions develop into a higher grade malignancy, usually dysgerminoma or seminoma. These, of course, need staged appropriately depending upon their histology.

TREATMENT

Section 6 of 11

Medical Care: After the intersex disorder is characterized, the treatment of gonadoblastoma is surgical. Thereafter, patients must be observed by an endocrinologist, who supplements any deficiencies in gonadal or adrenal function.

Surgical Care:

• In patients with mixed gonadal dysgenesis, perform bilateral gonadectomy soon after establishing the diagnosis.


• • In a review of 140 patients with dysgenic gonads, Troche and Hernandez (1986) found that the neoplastic transformation of abnormal gonads was common, and bilateral involvement occurred in 38.6% of patients.

  • Patients with mixed gonadal dysgenesis (45,X/46,XY) have an incidence of developing gonadoblastoma of 30-66%. Therefore, most authorities recommended performing bilateral gonadectomy as soon as the diagnosis of gonadal dysgenesis is made.
  
  
  
• In patients with complete androgen insensitivity/male pseudohermaphroditism (46,XY) with normal phenotypic genitalia, Rutgers and Scully (1991) recommended that gonadectomy be performed after puberty but before the individual is aged 20 years.


• • This opinion is based on the negligible risk of finding gonadoblastoma in these patients before puberty. However, the overall risk of developing a seminoma/dysgerminoma is 9%; therefore, perform gonadectomy before the individual is aged 20 years.

  • In patients with partial androgen insensitivity/male pseudohermaphrodism (46,XY), the phenotypes are frequently unpredictable, and gonadectomy is recommended early in conjunction with any other procedure that may be required.
  
  
  
  • Additionally, 2 other reasons explain why patients with the complete form of androgen insensitivity should have gonadectomy performed after puberty. The reasons are as follows:
    • First, these patients usually receive the diagnosis after puberty when they present with primary amenorrhea.

    • Second, intra-abdominal testicular tissue allows for normal breast development, which allows these phenotypic (46,XY) girls to go through "normal" puberty. This mechanism is initiated when the pituitary release of gonadotropic hormones stimulates the production of testosterone by the testes. Being completely androgen insensitive, the ability to recognize the elevated testosterone concentration does not exist, and the biofeedback mechanism fails to function appropriately, resulting in constant elevated levels of serum LH and testosterone. In the peripheral adipose tissues, testosterone is converted by aromatase to 17-beta-estradiol. The high levels of 17-beta-estradiol allow for normal breast development and the overall feminization of the individual.
  
  
  
• Patients with Turner syndrome have been reported to have anywhere from 5-12% incidence of XY mosaicism. Debate remains as to whether screening all patients with Turner syndrome stigmata for the presence of Y chromosome mosaicism is worthwhile. No consensus exists regarding the necessity of performing prophylactic gonadectomies on all Turner syndrome patients. However, in the presence of virilizing symptoms in a Turner syndrome patient, looking for a Y chromosome is probably indicated. If found, these patients should undergo prophylactic gonadectomy, as the incidence of gonadoblastoma development in these patients has been reported to be as high as 30%.



• Individualize the surgical approach to gonadectomy based on the patient's particular anatomy.


• • After clearly defining the intersex syndrome, a transscrotal/translabial, inguinal, or transabdominal approach can be used to perform the gonadectomy.
  
  
  
  • If the intersex syndrome or the patient’s anatomy has not been established clearly, a transabdominal exploration can help to delineate the unpredictable anatomic variability of each individual.
  
  
  

Consultations:

• Obtain a consultation with a pediatric urologist when any suspicion of an intersex disorder is noted. Often the neonatal anatomy is difficult to diagnose with imaging studies alone, and cystoscopy and vaginoscopy may need to be performed.



• A consultation with a clinical geneticist can also be useful in patients who do not have a clearly defined genotype.



• Obtain an endocrinology evaluation to manage life-long hormone replacement needs.



• Patients with complete androgen insensitivity/male pseudohermaphroditism (46,XY) who receive the diagnosis late (eg, after puberty) should have a consultation with a surgeon for removal of the abnormal gonadal tissue.



• Although not directly pertaining to gonadoblastoma, an ethics consultation is often needed to help define the best treatment plan for children with intersex disorders.

Diet: After surgery, start a clear liquid diet as soon as the patient regains normal bowel function and advance the diet appropriately.

Activity: Patients are out of bed on postoperative day 1 and resume full normal activity 4 weeks after surgery.

MEDICATION

Section 7 of 11

Hormone replacement is initiated in a patient-by-patient basis. The endocrinologist manages the dosing and frequency of administration.

FOLLOW-UP

Section 8 of 11

Further Outpatient Care:

• After gonadectomy, discharge patients home with pain medication.



• Schedule a return visit in the clinic within 2 weeks to make sure the incision has healed well.

Complications:

• Treatment for an individual with gonadoblastoma is surgical, and the main complications observed are related to the wound (eg, infection).

Prognosis:

• The prognosis of patients with gonadoblastoma is excellent if the tumor is removed before the transformation to a malignant germinoma/seminoma occurs.



• With platinum-based chemotherapy, success rates of curing dysgerminoma/seminoma can be greater than 90%.



• Identify and treat patients at risk of developing these lesions early in life to reduce the possibility of sustaining morbidity and mortality from these lesions.



• Successful pregnancy has been achieved in patients with gonadal dysgenesis (45,XO; 46,XY; and others) following stimulation of uterine growth with cyclical hormone replacement. Patients with a Y chromosome should have prophylactic gonadectomies, if they have not had one previously. These can often be at the same time as delivery, which usually requires a Cesarean section.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• The exclusive occurrence of this unique malignancy in patients with intersex disorders has been well established. Although some forms of intersexuality can be difficult to diagnose, most patients at risk of developing gonadoblastoma can be treated appropriately in a timely fashion. In families and patients with Turner syndrome (45,X), gonadal dysgenesis (45,X/46,XY), or androgen insensitivity/male pseudohermaphrodism (46,XY), provide counseling regarding the risk of developing gonadoblastoma and clearly state the appropriate treatment. Failure to inform and treat these individuals in a timely fashion can lead to unnecessary morbidity and can place the institution and staff at liability.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 17-year-old girl presents to the office reporting primary amenorrhea. Which of the following findings would not make this patient at risk of developing a gonadoblastoma?

A: Excessive hirsutism
B: Mental retardation
C: Short hypoplastic vagina on the genitourinary examination
D: Absence of axillary and genital hair
E: Bilateral inguinal hernias

The correct answer is A: 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 complete androgen insensitivity/male pseudohermaphroditism (46,XY), mixed gonadal dysgenesis (45,X/46,XY), and a subset of patients with Turner syndrome (45,XO). Excessive hirsutism is not a characteristic of a patient with Turner syndrome (45,XO), male pseudohermaphrodism/androgen insensitivity syndrome (46,XY), or mixed gonadal dysgenesis (45X,46XY). Patients with male pseudohermaphrodism/androgen insensitivity syndrome (46,XY) have normal external anatomy but have a short hypoplastic vagina and an absence of axillary and genital hair.

CME Question 2: Which of the following screening tests should be used to monitor patients with an intersex disorder who are at risk of developing a gonadoblastoma?

A: Ultrasound
B: Computed tomography imaging
C: Annual pelvic examination
D: Magnetic resonance imaging
E: None of the above

The correct answer is E: None of these tests are adequate to screen patients who are at risk of developing 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 complete androgen insensitivity/male pseudohermaphroditism (46,XY), mixed gonadal dysgenesis (45,X/46,XY), and a subset of patients with Turner syndrome (45,XO). Any patient with Turner syndrome (45,XO) with Y mosaicism, male pseudohermaphrodism/androgen insensitivity syndrome (46,XY), or mixed gonadal dysgenesis (45X,46XY) should have both gonads removed prophylactically.

Pearl Question 1 (T/F): Gonadoblastoma is not a malignant tumor.

The correct answer is True: Gonadoblastoma is a benign lesion that can transform into a malignant dysgerminoma (seminoma).

Pearl Question 2 (T/F): Only patients who have a Y chromosome on a karyotype analysis are at risk of developing a gonadoblastoma.

The correct answer is False: Patients with Turner syndrome (45,XO) do not have a Y chromosome but can still develop a gonadoblastoma. Routine cytogenetic screening may not be able to detect molecular evidence of a Y chromosome using routine peripheral blood analysis. Patients with Turner syndrome have molecular evidence (ie, on polymerase chain reaction analysis) of a Y chromosome that is not detected on a karyotype. Thus, for patients with Turner syndrome who experience virilizing symptoms, a search for Y chromosomal material by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) is necessary as part of an evaluation for possible gonadoblastoma. After these investigations, prophylactic gonadectomy may be warranted.

Pearl Question 3 (T/F): Newborn girls with inguinal hernias should undergo a karyotype analysis.

The correct answer is True: Patients with male pseudohermaphrodism/androgen insensitivity syndrome (46,XY) often have normal female external anatomy but frequently have evidence of an inguinal hernia. People with complete androgen insensitivity/male pseudohermaphroditism (46,XY) are at risk of developing gonadoblastoma.

Pearl Question 4 (T/F): The most important test for identifying a patient at risk of developing a gonadoblastoma is a karyotype analysis.

The correct answer is True: Because only patients with Turner syndrome (45,XO), male pseudohermaphrodism/androgen insensitivity syndrome (46,XY), or mixed gonadal dysgenesis (45X,46XY) are at risk of developing gonadoblastoma, the karyotype is the only test that identifies and distinguishes these individuals from those with other forms of intersex disorders.

BIBLIOGRAPHY

Section 11 of 11

• Brant WO, Rajimwale A, Lovell MA, et al: Gonadoblastoma and Turner syndrome. J Urol 2006 May; 175(5): 1858-60[Medline].
• Chen MJ, Yang JH, Mao TL, et al: Successful pregnancy in a gonadectomized woman with 46,XY gonadal dysgenesis and gonadoblastoma. Fertil Steril 2005 Jul; 84(1): 217[Medline].
• Frias JL, Davenport ML: Health supervision for children with Turner syndrome. Pediatrics 2003 Mar; 111(3): 692-702[Medline].
• Gourlay WA, Johnson HW, Pantzar JT, et al: Gonadal tumors in disorders of sexual differentiation. Urology 1994 Apr; 43(4): 537-40[Medline].
• Gravholt CH, Fedder J, Naeraa RW, Muller J: Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study. J Clin Endocrinol Metab 2000 Sep; 85(9): 3199-202[Medline][Full Text].
• Kido T, Lau YF: A Cre gene directed by a human TSPY promoter is specific for germ cells and neurons. Genesis 2005 Aug; 42(4): 263-75[Medline].
• Lau YF: Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet 1999 Apr; 64(4): 921-7[Medline][Full Text].
• Levin HS: Tumors of the testis in intersex syndromes. Urol Clin North Am 2000 Aug; 27(3): 543-51, x[Medline].
• Mendes JR, Strufaldi MW, Delcelo R, et al: Y-chromosome identification by PCR and gonadal histopathology in Turner's syndrome without overt Y-mosaicism. Clin Endocrinol (Oxf) 1999 Jan; 50(1): 19-26[Medline].
• Pena-Alonso R, Nieto K, Alvarez R, et al: Distribution of Y-chromosome-bearing cells in gonadoblastoma and dysgenetic testis in 45,X/46,XY infants. Mod Pathol 2005 Mar; 18(3): 439-45[Medline].
• Rutgers JL, Scully RE: Pathology of the testis in intersex syndromes. Semin Diagn Pathol 1987 Nov; 4(4): 275-91[Medline].
• Rutgers JL, Scully RE: The androgen insensitivity syndrome (testicular feminization): a clinicopathologic study of 43 cases. Int J Gynecol Pathol 1991; 10(2): 126-44[Medline].
• Scully RE: Gonadoblastoma. A review of 74 cases. Cancer 1970 Jun; 25(6): 1340-56[Medline].
• Sultana R, Myerson D, Disteche CM: In situ hybridization analysis of the Y chromosome in gonadoblastoma. Genes Chromosomes Cancer 1995 Aug; 13(4): 257-62[Medline].
• Tewari K, Cappuccini F, Disaia PJ, et al: Malignant germ cell tumors of the ovary. Obstet Gynecol 2000 Jan; 95(1): 128-33[Medline].
• Troche V, Hernandez E: Neoplasia arising in dysgenetic gonads. Obstet Gynecol Surv 1986 Feb; 41(2): 74-9[Medline].
• Tsuchiya K, Reijo R, Page DC, Disteche CM: Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995; 57(6): 1400-7[Medline].
• Vlasak I, Plochl E, Kronberger G, et al: Screening of patients with Turner syndrome for "hidden" Y-mosaicism. Klin Padiatr 1999 Jan-Feb; 211(1): 30-4[Medline].

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