Gonadoblastoma

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 Etiology. 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.[3] 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).

More recently, studies have revealed that the most promising molecular event that may contribute to gonadoblastoma development involves the TSPY gene.[5] 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[6, 7] 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.[8]

Furthermore, the TSPY promotor has been recently shown to direct gene expression, specifically in the germ cells of murine gonads.[9] 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.[8]

The select DSDs associated with a clear risk of developing gonadoblastoma include the following:

• Complete androgen insensitivity (46,XY)

• Pure gonadal dysgenesis or Swyer syndrome (46,XY)[10]

• Mixed gonadal dysgenesis (45,X/46,XY)

• A subset of patients with Turner syndrome (45,XO usually with evidence of XY mosaicism)

• Frasier syndrome (a rare 46,XY DSD caused by a mutation in the Wilms tumor 1 gene [WT1])[11]

• Denys-Drash syndrome (associated with disorder of sexual development, nephropathy, and Wilms tumor development, also caused by WT1 mutations)[12]

• 9p Partial monosomy (syndrome with trigonocephaly, minor anomalies, and intellectual disability)[13]

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 (or a small piece) and (2) the gonads are nearly always located intra-abdominally. However, a limited number of cases of gonadoblastoma have been reported in patients with a 46,XX karyotype, suggesting that other molecular events besides the existence of a Y-chromosome remnant may lead to gonadoblastoma.[14]  To the author's knowledge no environmental or dietary exposures predispose to gonadoblastoma development.

United States statistics

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.[8] 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.[15] Additionally, the rate of contralateral disease for all patients is substantial at 36%.[16]

Race-, sex-, and age-related demographics

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.[17] 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.

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 delivery.

Morbidity/mortality

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.[18]

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.

Complications

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

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 the 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.[17] 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.

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.

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 of 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 who 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. However, more recently some groups are advocating a lower threshold for testicular biopsy (particularly in patients with DSD) given improvements in techniques and diagnostic testing and the possibility of preserving endocrine function if gonadectomy can be avoided.[19]  Exploratory laparotomy is still generally reserved for patients undergoing 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.[20]

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.[20] 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.

Dr. Scully's original work on gonadoblastoma also revealed some other histologic variants, one of which was termed "dissecting" gonadoblastoma (DGB). The significance of this subtype is that it is often mistaken for malignant germinomas. A recent review of these lesions suggested methods by which to differentiate these two entities so that more aggressive treatment can be reserved for true germinomas.[21]

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.

Immunohistochemical stain results for OCT3/4, TSPY, and SCF are generally positive.[22]

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.

A study by McCann-Crosby et al found that in patients older than 1 year with gonadal dysgenesis, expression of OCT 3/4, PLAP, CD117 may be instrumental in the decision-making process for gonadectomy, even in the absence of overt germ cell malignancy.[23]

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.

After the DSD or other high-risk condition 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.

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.[17]  Patients with mixed gonadal dysgenesis (45,X/46,XY) have an incidence of developing gonadoblastoma of 30-66%.[24] Therefore, most authorities recommended performing bilateral gonadectomy as soon as the diagnosis of gonadal dysgenesis is made.[25]

In patients with complete androgen insensitivity and 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.[26]  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 and 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 6-9% 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 has been reached regarding the necessity of performing prophylactic gonadectomies on all patients with Turner syndrome. However, in the presence of virilizing symptoms in a patient with Turner syndrome, 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 43%.

Individualize the surgical approach to gonadectomy based on the patient's particular anatomy. After clearly defining the DSD, a transscrotal/translabial, inguinal, or transabdominal approach can be used to perform the gonadectomy. If the DSD or the patient's anatomy has not been established clearly, a transabdominal exploration can help to delineate the unpredictable anatomic variability of each individual.

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 and 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 appropriately advance the diet.

Activity

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

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

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