Germ Cell Tumor, Extragonadal

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males. Literature suggests that the only known risk factor for extragonadal germ cell tumors (EGCTs) is Klinefelter syndrome (47XXY), which is associated with mediastinal nonseminomatous germ cell tumors They are characterized by their location on the midline from the pineal gland to the coccyx. 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 produce a rich symptomatology and may reach 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.

Pathophysiology

Controversy remains regarding the origin of extragonadal germ cell tumors (EGGCTs). 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 tumour.

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 or more copies of i(12p) or as tandem duplications of chromosome arm 12p.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.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). 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.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)

International

In Norway, a recent study by Dueland et al estimated the incidence of extra-gonadal germ cell tumor (EGGCTs) at 0.5 per 100,000 population per year.This represents about 2% of the number of testicular cancers reported for the same period. Intracranial germ cell tumors (ICGCTs) represent 0.3-3.4% of primary intracranial tumors in Western countries and 2.1-12.7% in Japan.

Mortality/Morbidity

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates. Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

• Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include yolk-sac tumors, embryonal carcinomas, choriocarcinomas, teratomas, and nonteratomatous combined germ cell tumors.
• The most common site of extragonadal germ cell tumors (EGGCTs) 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.

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.

Clinical History

Symptoms vary depending on the site and the size of the tumor. Those arising in nonvital organs can reach large sizes before becoming symptomatic, but small tumors may result in significant symptoms if they obstruct, compress, or rupture into important structures.

Physical

Complete physical examination is required.

• Mediastinal germ cell tumors (MGCTs) may be silent. Dullness caused by atelectasis or pleural effusion and localized wheezes because of airway compression may be present.
• A large abdominal mass may be palpated in retroperitoneal germ cell tumors (RGCTs).
• In suprasellar intracranial germ cell tumors (ICGCTs), decreased visual acuity and visual field defects, obesity, or signs of endocrine deficiencies may be present.
• In pineal tumors, Parinaud syndrome (ie, paralysis of conjugate upward gaze, slightly dilated pupils that react on accommodation but not to light, with a lesion at the level of the superior colliculi) can be present. Gait abnormalities, papilledema, and grasp reflex because of hydrocephalus are present variably. Plantar reflexes are sometimes extensor.

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