Extragonadal Germ Cell Tumors

Updated: Sep 10, 2018
  • Author: Kush Sachdeva, MD; Chief Editor: E Jason Abel, MD  more...
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Overview

Practice Essentials

Extragonadal germinal cell tumors (EGGCTs) are rare tumors that predominantly affect young males. Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include the following:

  • Yolk-sac tumors
  • Embryonal carcinomas
  • Choriocarcinomas
  • Teratomas
  • Nonteratomatous combined germ cell tumors

The most common site of extragonadal germ cell tumors is the mediastinum (50-70%) followed by the retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than 5%).

Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in 45%, sarcoma in 5%, and viable germ cell cancer in 26%. However, the smaller the residual mass, the lower the chance that it harbors viable tumor cells.

The only known risk factor for extragonadal germ cell tumors is Klinefelter syndrome (47XXY), which is associated with mediastinal nonseminomatous germ cell tumors, which are characterized by their location on the midline from the pineal gland to the coccyx. [1, 2] In extragonadal germ cell tumors, no evidence of a primary malignancy is present in either the testes or ovaries by radiologic imaging or physical examination.

Extragonadal germ cell tumors can produce a wide range of clinical manifestations; on the other hand, they may attain large volumes if they arise in silent areas. Histologically, they mirror their gonadal counterparts, with which they share the same chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result in high rates of long-term survival and even cure.

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Pathophysiology

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.

 

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Epidemiology

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 children, benign and malignant extragonadal germ cell tumors (EGGCTs) occur equally in males and females. 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 16 % among 15- to 19-year-olds. Up to one-third are extragonadal neoplasms and the most common sites are the sacrococcygeal or retroperitoneal region, and the pineal gland. [10]  

 

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Prognosis

A classification system developed by the International Germ Cell Collaborative Group (IGCCG) categorizes germ cell tumor (GCT) risk on the basis of the following11:

  • 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%. [11, 12]  

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.

Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

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. [13]

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 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%

 

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