Extragonadal Germ Cell Tumors

Controversy remains regarding the origin of extragonadal germ cell tumors. These tumors can be found anywhere on the midline, particularly the retroperitoneum, the anterior mediastinum, the sacrococcyx, and the pineal gland. Other less common sites include the orbit, suprasellar area, palate, thyroid, submandibular region, anterior abdominal wall, stomach, liver, vagina, and prostate. The classic theory suggests that germ cell tumors (GCTs) in these areas are derived from local transformation of primordial germ cells misplaced during embryogenesis.

A recent alternative theory suggests that primary mediastinal presentations represent reverse migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in origin. According to this theory, the differences in phenotypes expressed by mediastinal germ cell tumors (MGCTs) and gonadal germ cell tumors may be explained by differences in the cellular environment between the gonad and the anterior mediastinum. Some retroperitoneal extragonadal germ cell tumors may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumor.

To explain the origin of occult carcinoma in situ cells, 2 models have been proposed. The first suggests that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotrophin stimulation.

 The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. In occasional cells, this crossing over may lead to increased 12p copy number and overexpression of cyclin D2. The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of cell cycle and genomic instability.

Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p)—an isochromosome of the short arm of chromosome 12—or as tandem duplications of chromosome arm 12p. ^[3] This abnormality is found in occult carcinoma in situ lesions as well as more advanced disease. Further studies indicate that the CCND2 gene is present at chromosome band 12p13 and CCND2 is overexpressed in most GCTs, including CIS. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

Hematologic malignancies are frequently associated with mediastinal germ cell tumors. ^[4] Embryologically, hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up 30% of mediastinal germ cell tumors, providing a possible basis for this association.

The balance of the p53-mdm2 interaction has been shown to be disrupted in intracranial germ cell tumors (ICGCTs), in which mdm2 sequesters p53 and inhibits its function as G1-S checkpoint controller and apoptosis inducer. In normal cells, mdm2 availability is controlled by ARF, the product of the p14ARF gene located on INK4a/ARF locus, which binds with mdm2 and induces its degradation. ^[5] Mutation of ARF, reported in 71% of intracranial germ cell tumors, results in mdm2 accumulation and functional impairment of p53. This abnormality was reported in 90% of seminomatous and 55% of nonseminomatous intracranial germ cell tumors (NS-ICGCTs) examined.

 

Frequency

United States

Extra-gonadal germ cell tumors (EGGCTs) represent 5-10% of all germ cell tumor (GCTs) with an incidence around 1/ in 1,000,000 population. ^[6]  

International

In Norway, a study by Dueland et al estimated the incidence of extra-gonadal germ cell tumor (EGGCTs) at 0.5 per 100,000 population per year. ^[7] This represents about 2% of the number of testicular cancers reported for the same period. Intracranial germ cell tumors represent 0.3-3.4% of primary intracranial tumors in Western countries and 2.1-12.7% in Japan. ^[8] In Germany, Rusner et al studied more than 16,000 patients with malignant GCTs from 1998-2008. They concluded that differences in age-specific and age-standardized incidence rates may be the result of different etiologies. ^[9]

Sex

In young children, benign and malignant extragonadal germ cell tumors (EGGCTs) occur equally in males and females. However, the incidence in older children and adolescents reaches 11.4 in 1,000,000 population for males, compared with 1 in 1,000,000 population for females. ^[10]

In adults, only benign extragonadal germ cell tumors (teratomas) occur at equal frequency in both sexes; more than 90% of malignant extragonadal germ cell tumors occur in males.

Age

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males. Pediatric germ cell tumors (GCTs) account for approximately 3.5% of cancers in children under the age of 15 years and increase in frequency to 13.9% among 15- to 19-year-olds. ^[10] Up to one-third are extragonadal neoplasms and the most common sites are the sacrococcygeal or retroperitoneal region and the pineal gland. ^[11]  

 

A classification system developed by the International Germ Cell Collaborative Group (IGCCG) categorizes germ cell tumor (GCT) risk on the basis of the following ^[12] :

• Histologic type (seminomas have a better prognosis than nonseminomas)
• Localization of metastases (retroperitoneal and testicular portend better prognosis than mediastinal and intracranial)
• Initial serum alpha fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) levels (the higher the tumor marker levels, the worse the effect on survival)

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates. ^[6]  Overall survival of patients with seminomatous extragonadal GCTs has been reported to range from 88%-100%, whereas suvival of patients with mediastinal nonseminomatous extragonadal GCTs is 40-45%. ^{[13, 14]}  

Patients with mediastinal GCTs have a poor prognosis owing to at least the following 3 factors: mediastinal germ cell tumors are not as sensitive as other germ cell tumors to chemotherapy, bulky disease increases the risk of poor outcome in the short term owing to respiratory failure, and hematologic malignancies are linked to a very unfavorable prognosis.

Racial disparities in mortality rates among males with GCTs have been reported. In a review of Surveillance, Epidemiology, and End Results (SEER) Program data, mortality rates were significantly higher in Hispanic and Asian/Pacific Island males than in white males. ^[15]

Nonseminoma

Ganjoo analyzed the data from 75 patients treated at Indiana University for nonseminomatous mediastinal germ cell tumors (NS-MGCTs) with chemotherapy followed by surgery. Tumor marker elevation prior to or after chemotherapy was not found to be an independent prognostic variable for survival. However, the presence of visceral metastases and especially postchemotherapy pathology were the most important predictors of survival. ^[16]

Good prognosis is indicated by all of the following:

• Testis/retroperitoneal primary
• No nonpulmonary visceral metastases
• Good tumor marker levels - AFP < 1000 ng/mL, β-hCG < 1000 IU/L, and LDH < 1.5 times the upper limit of normal

These features are found in 56% of nonseminomas, which have a 5-year progression-free survival rate (PFS) of 89% and 5-year overall survival rate of 92%.

Intermediate prognosis is indicated by all of the following:

• Testis/retroperitoneal primary
• No nonpulmonary visceral metastases
• AFP between 1000 and 10,000 ng/mL, β-hCG between 5000 and 50,000 IU/L, or LDH between 1.5 and 10 times the upper limit of normal

These features are found in 28% of nonseminomas, which have a 5-year PFS of 75% and 5-year survival rate of 92%.

Poor prognosis is indicated by any of the following:

• Mediastinal primary
• Nonpulmonary visceral metastases
• Poor markers -  AFP >10,000 ng/mL, β-hCG >50,000 IU/L, or LDH >10 times the upper limit of normal

These features are found in 16% of nonseminomas, which have a 5-year PFS of 41% and 5-year survival rate of 48%

Seminoma

No patients with seminoma are classified as having a poor prognosis. Good prognosis is indicated by the following:

• Any primary site
• No nonpulmonary visceral metastases
• Normal AFP, any β-hCG, any LDH

These features are found in 90% of seminomas, which have a 5-year PFS of 92% and 5-year survival rate of 88%

Intermediate prognosis is indicated by the following:

• Any primary site
• Nonpulmonary visceral metastases
• Normal AFP, any β-hCG, any LDH

These features are found in 10% of seminomas, which have a 5-year PFS of 67% and 5-year survival rate of 72%