Gonadoblastoma Workup

• 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 are useful in diagnosing features of intersexuality in newborns but 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 retrograde genitography to delineate the urogenital anatomy. Often, the bladder, vagina, and any communication between the 2 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 ultrasonography, CT scanning, and MRI 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, ultrasonography can be helpful in visualizing the uterus, vagina, fallopian tubes, ovary, and a contralateral testicle.
• A flat abdominal radiograph can sometimes reveal gonadal calcification, which is a classic pathologic finding in gonadoblastoma.

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.

• Gross evaluation of gonadoblastoma usually reveals a small, slightly lobulated, 1-cm to 8-cm, soft to firm, gray-tan to brown, slightly lobulated tumor. The consistency has been described as gritty on cut sections because of the presence of multifocal calcification.^[15]
• 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, a third type of cell can frequently be observed in the stroma of the tumor and is nearly identical to Leydig cells, with the exception of having visible Reinke crystals, and are thought to be responsible for frequent virilizing features in these patients.^[15] 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 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.

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 to be appropriately staged depending on their histology.