January 16, 2007

Extragonadal Germ Cell Tumors

Synonyms and related keywords: EGGCT, seminomas, germinomas, nonseminomatous germ cell tumors, NS-GCT, nongerminomas, nongerminomatous germ cell tumors, mediastinal germ cell tumors, MGCT, retroperitoneal germ cell tumors, RGCT, sacrococcygeal germ cell tumors, SCGCT, intracranial germ cell tumors, ICGCT


Background: Extragonadal germinal cell syndromes are rare tumors affecting predominantly young males. They are characterized by their location on the midline from the pineal gland to the coccyx. They 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 classical 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 GCTs may be explained by differences in the cellular environment between the gonad and the anterior mediastinum. Some retroperitoneal EGGCTs may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumour.

To explain the origin of CIS 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) or as tandem duplications of chromosome arm 12p. This abnormality is found in CIS 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 frequently are associated with MGCTs. Embryologically, hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up 30% of MGCTs, providing a possible basis for this association.

Recently the balance of the p53-mdm2 interaction was 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 ICGCTs, 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.


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).

Sex: In children, benign and malignant EGGCTs occur equally in males and females. In adults, only benign EGGCTs (teratomas) occur at equal frequency in both sexes; more than 90% of malignant EGGCTs occur in males.


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.

  • Retroperitoneal germ cell tumors
    • The second most common site of EGGCTs (30-40%), after the mediastinum, is the retroperitoneum. Retroperitoneal germ cell tumors (RGCTs) represent 10% of all malignant primary retroperitoneal tumors.
    • Often patients with RGCTs present late, after their tumors have reached large dimensions.
    • Presenting symptoms are abdominal mass with or without pain, backache, and weight loss. Loss of ejaculation was reported in one case.
  • Intracranial germ cell tumors
    • Very rare tumors of the adolescent and young adult, ICGCTs are localized preferentially to the pineal and suprasellar regions. However, other midline structures can be involved. Although seminomas (60% of ICGCTs) have a predilection for the suprasellar region, embryonal carcinomas, yolk-sac tumors, and choriocarcinomas mainly occur in the pineal region.
    • Pineal tumors present with headache, nausea, and vomiting because of increased intracranial pressure; they require early ventriculoperitoneal (VP) shunting. Deterioration of intellectual functions, gait abnormalities with frequent falls, and sphincteric incontinence are common. Choreic movements and ataxia of the limbs with spastic weakness appear in later stages of Parinaud syndrome.
    • In suprasellar tumors, precocious pseudopuberty, diabetes insipidus with or without anterior pituitary dysfunctions (eg, adrenocorticotropic hormone [ACTH] deficiency), central hypothyroidism, growth hormone (GH) deficiency, and hypogonadism may be seen. Decreased visual acuity, visual field defect, diplopia, obesity, psychosis, and obsessive-compulsive symptoms also have been reported.
    • Recently, a case of primary spinal seminoma was reported in a patient with Klinefelter syndrome.
  • Sacrococcygeal germ cell tumors
    • In the literature to date, 17 cases have been reported.
    • Pain and bowel habit change are the main symptoms. Severe arthropathy of peripheral joints and evidence of hypertrophic osteoarthropathy were reported in one case.
  • Extragonadal germ cell cancer syndrome
    • Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in young males. Histologically, these tumors are poorly differentiated carcinomas with atypical features.
    • The germ cell origin of these tumors is suggested by the typical abnormalities of chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG) and/or alpha-fetoprotein (AFP).

Physical: Complete physical examination is required.

  • 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 RGCTs.
  • In suprasellar 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.

Causes: See Pathophysiology.


Lymphoma, Mediastinal
Lymphoma, Non-Hodgkin

Other Problems to be Considered:

Mediastinal germ cell tumors
Thymic tumors
Mesenchymal tumors
Neurogenic tumors

Retroperitoneal germ cell tumors
Soft tissue sarcoma
Poorly differentiated carcinoma

Intracranial germ cell tumors
Pinealoma (pinealocytoma and pinealoblastoma)


Lab Studies:

Imaging Studies:

Other Tests:

Histologic Findings: EGGCTs show the same histologic features as gonadal GCTs.

Staging: Clinical staging of MGCT


Medical Care: Treatment modality is determined by the site and the histologic type of the primary tumor. Seminomas are very sensitive to chemotherapy and radiotherapy. NS-GCTs are less sensitive to these modalities and may require surgery for resection of a postchemotherapy residual mass. Prior to the availability of cisplatin-based chemotherapy, cure rates for NS-GCTs were less than 10%. Surgery is the only treatment for teratomas.

Surgical Care: Surgery is the primary and only effective modality in teratomas. It also is used as primary or secondary treatment of NS-EGGCTs. The current standard of care is surgery if a residual mass is present after neoadjuvant chemotherapy. Used in this setting, chemotherapy allows translation of PRs into CRs and evaluation of the chemosensitivity of the tumor.

However, the size of residual mass for which surgery is indicated remains controversial. In the experience at the Memorial Sloan-Kettering Cancer Center, 5 of 20 patients underwent surgery for residual mass after receiving chemotherapy or radiotherapy for retroperitoneal seminoma. No viable seminoma was found in masses less than 3 cm. Therefore, they recommend surgical resection for residual tumors greater than 3 cm to ascertain the need for subsequent chemotherapy.

No further chemotherapy is recommended if the final pathology is consistent with mature teratoma or necrotic tissue. Additional postoperative chemotherapy is given if the patient is found to have viable tumors. Although the same chemotherapy used preoperatively may be used after surgery, it is reasonable to switch to another drug combination.

The surgical resection should include all gross disease with en bloc resection of all involved structures that can be sacrificed. Orchiectomy or testicular biopsy is not required unless testicular examination and/or ultrasound findings are suggestive or frankly abnormal.


The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Chemotherapeutic agents -- Regardless of the tumor location and whenever chemotherapy is considered, a BEP combination is the treatment of choice (BEP for 4 cycles at 3-wk intervals). VIP has been used as salvage therapy for progressive disease or as postoperative therapy following resection of residual mass containing viable tumor. Vinblastine occasionally has replaced etoposide if the latter was used in the initial regimen.
Drug Name
Cisplatin (Platinol) -- Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to produce cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell it binds to DNA, resulting in interstrand and intrastrand cross-linking.
Modify dose on basis of CrCl. Avoid use if CrCl less than 60 mL/min.
Adult Dose20 mg/m2/d IV infusion over 20-60 min for 5 d q21d
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
InteractionsIncreases toxicity of bleomycin and ethacrynic acid; aminoglycosides and amphotericin B increase nephrotoxicity; bleomycin, cytarabine, methotrexate, and ifosfamide may accumulate because of decreased renal excretion; may enhance cytotoxicity of etoposide; mesna and sodium thiosulfate directly inactivate cisplatin; dipyridamole increases cytotoxicity by enhancing cellular uptake
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; adverse effects include bone marrow suppression, nausea, vomiting, mucositis, and high-frequency hearing loss; major dose-limiting toxic effect is peripheral neuropathy; can cause acute or chronic renal failure in as many as one third of patients treated, but usually can be prevented by vigorous hydration and saline diuresis; renal tubular wasting of potassium and magnesium are common (monitor closely); cellulitis and fibrosis rarely have occurred after extravasation; avoid aluminum needles
Drug Name
Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle. Prodrug activated by dephosphorylation.
Reduce dose in hepatic (increased total bilirubin [TB]) and renal (decreased CrCl) impairment.
Adult Dose100 mg/m2 IV daily for 5 d; repeat cycle every 3 wk
TB 1.5-3 mg/dL: 50% dose reduction
TB 3.1-4.9 mg/dL: 75% dose reduction
TB >5 mg/dL: Avoid use
CrCl 15-50 mL/min: 25% dose reduction
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration may cause death
InteractionsMay prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells; clearance decreased by high dose of cyclosporine (serum concentration >2000 ng/mL), leading to increased risk of neutropenia; zidovudine increases serum concentration, resulting in increased toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsBleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur
Drug Name
Bleomycin (Blenoxane) -- Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single- or double-stranded DNA breaks by ability to form oxygen free radicals.
Test dose is optional: 1-2 U IV/IM prior to full dose.
Adult Dose30 U IV bolus weekly on days 2, 9, and 16; repeat q21d; modify dose based on CrCl
CrCl 20-30 mL/min: 50% of normal dose
CrCl less than 20 mL/min: 40% of normal dose
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; significant renal function impairment; compromised pulmonary function
InteractionsMay decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; erythema, rash, vesiculations, hyperpigmentation, stomatitis, alopecia, and nail changes may occur
Drug Name
Ifosfamide (Ifex) -- Alkylating agent—2 major metabolites are produced after its activation in liver. Ifosfamide mustard, by its ability to cross-link DNA strands, responsible for therapeutic effect. Acrolein related to bladder toxicity.
Adult Dose1200 mg/m2/d IV continuous infusion d 1-5
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; depressed bone marrow function; uncontrolled infection
InteractionsPhenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P-450 activity may alter effects
Pregnancy D - Unsafe in pregnancy
PrecautionsMay cause hemorrhagic cystitis and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve; nausea, vomiting, diarrhea, and occasionally constipation may occur; CNS toxic effects include somnolence, confusion, depressive psychosis, and hallucinations; seizures and coma occasionally may occur; use mesna concomitantly at dose of 1200 mg/m2/d IV continuous infusion days 1-6
Drug Name
Vinblastine (Velban) -- Vinca alkaloid, inhibits microtubule formation, which in turn disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Reduce dose by 50% in patients with TB >3 mg/dL. Dose reduction not required in impaired renal function.
Adult Dose0.11 mg/kg IV days 1 and 2
Pediatric Dose3 mg/m2 IVP every 2-4 wk
ContraindicationsDocumented hypersensitivity; bone marrow suppression
InteractionsMay reduce plasma phenytoin levels; mitomycin-C may increase toxicity significantly; avoid heparin and furosemide
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in impaired liver function and neurotoxicity; when patient is receiving mitomycin-C, monitor closely for shortness of breath and bronchospasm; very irritating (a vesicant) and should be given exclusively via side port of freely flowing IV; if extravasation occurs, antidote is hyaluronidase (Wydase); warm compresses should be applied at site of extravasation; adverse effects include myelosuppression, alopecia, nausea, vomiting, anorexia, constipation, and paresthesia


Further Outpatient Care:



Patient Education:

No comments: