January 17, 2007

Germinoma, Central Nervous System

Synonyms and related keywords: intracranial germinoma, pinealoma, ectopic pinealoma, atypical teratoma, germ cell tumor, germ-cell tumor, GCT, CNS germ cell tumor, CNS germinoma, atypical teratomas, pinealomas, ectopic pinealomas, CNS malignancy, malignant CNS tumor, central nervous system germinoma


Background: The central nervous system is the second most common site of extragonadal germ cell tumors, after the mediastinum. Germ cell tumors are broadly divided into germinomas and nongerminomatous germ cell tumors. Germinomas originate from a primordial germ cell, demonstrate no histologic differentiation, and with treatment have a relatively favorable overall prognosis. Nongerminomatous germ cell tumors (yolk sac tumors, choriocarcinomas, embryonal carcinomas, and teratomas) display various forms of differentiation and are more refractory to treatment. Most intracranial germ cell tumors arise in the midline, and they account for about 50% of all pineal region tumors. A slight majority of these (60%) are germinomas.

Pathophysiology: Germ cell tumors arise in midline locations, including the gonads, mediastinum, retroperitoneum, and CNS from neoplastic transformation of embryonic germ cells that inappropriately migrated into or failed to migrate out of these locations during development.

While the underlying etiology remains unknown, approximately 90% of germ cell tumors are associated with structural chromosomal anomalies, especially an isochromosome on chromosome arm 12p known as i(12p). The i(12p) is often seen in germ cell tumors of adults (male or female) and male adolescents. The i(12p) has also been found in germ cell tumors associated with hematolymphoid neoplasms. Central nervous system germinomas in particular often display sex chromosome abnormalities, usually an increased number of copies of chromosome X.

Several lines of evidence lead to the belief that that germ cell tumors are gonadotropin-driven. Klinefelter syndrome (XXY genotype), for example, in which gonadotropin levels are chronically elevated, is associated with an increased risk of germ cell tumors. However, this association may have more to do with chromosomal anomalies.

From several lines of evidence, it is thought that germ cell tumors are gonadotropin-driven. Klinefelter syndrome (XXY genotype), for example, in which gonadotropin levels are chronically elevated, is associated with an increased risk of germ cell tumors. However, this association may have more to do with chromosomal anomalies.

Lastly, it is now recognized that most germinomas contain c-kit mutations. C-kit is a tyrosine kinase whose mutations may result in constitutive activation and which has been implicated in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST).


Mortality/Morbidity: For germinomas, the estimated survival rate is 75-95% at both 5 and 10 years.

Race: Prevalence rates vary worldwide, with the highest frequency in Japan and Taiwan.

Sex: Males are affected more commonly than females, with an estimated male-to-female ratio of 2.5:1.

Age: Intracranial germ cell tumors are seen primarily in children and adolescents.


History: As with intracranial tumors generally, the clinical presentation depends upon the tumor location and rate of growth.

Physical: Focus the physical examination on identification of cranial nerve deficits, visual-field cuts, and visual acuity. Be aware of the physical manifestations of endocrinopathies such as hypothyroidism, precocious puberty, and hypogonadism.

Causes: Specific causes of germ cell tumors have not been identified.


Colloid Cysts
Metastatic Cancer, Unknown Primary Site
Pineal Tumors
Pituitary Macroadenomas

Other Problems to be Considered:

An intracranial germ cell tumor is high on the differential for any pineal region or suprasellar mass. Other tumors common to the area of the diencephalon, hypothalamus, and third ventricle include pituitary adenomas, craniopharyngiomas, true pineal tumors (pineocytomas, pineoblastomas), glial tumors (especially pilocytic astrocytoma), meningeal tumors, nongerminomatous germ cell tumors, Langerhans cell histiocytoses, and metastatic tumors. Nonneoplastic processes in the differential diagnosis include colloid cysts of the third ventricle, sarcoidosis, and cysticercosis.

Once a biopsy is performed and a pathologist has rendered the diagnosis of germinoma, it is important to remember that a small biopsy of a large tumor may rarely fail to disclose a minor nongerminomatous component. Such components are crucial, as they may render the tumor less responsive to radiation and chemotherapy. While an elevated alpha-fetoprotein (AFP) implies the presence of yolk sac elements, low levels of beta–human chorionic gonadotropin (beta-HCG) do not necessarily exclude a choriocarcinomatous component. Very high levels of beta-HCG, however, are unusual in pure germinoma and should raise concern for choriocarcinoma, which produces the highest levels of this hormone.

Finally, since germ cell tumors arising outside the brain have a high predilection to metastasize to the brain, the possibility that an intracranial germ cell tumor is a metastasis should be considered.


Lab Studies:

Imaging Studies:


Histologic Findings: CNS germinomas are histologically identical to gonadal seminomas and dysgerminomas. They are composed of neoplastic cells arranged in nests that have abundant clear cytoplasm. The cytoplasmic clearing is due to abundant glycogen that stains intensely red with a periodic acid-Schiff (PAS) stain. Their nuclei are large, vesicular, and contain one to several prominent eosinophilic nucleoli. The nests of neoplastic cells are separated by fibrous septa that usually contain an infiltrate of small reactive T lymphocytes.

Syncytiotrophoblastic giant cells, capable of producing HCG, are seen in approximately 14% of germinomas. A combination of malignant cytotrophoblastic cells and syncytiotrophoblastic cells typifies a choriocarcinoma, and the presence of syncytiotrophoblast in isolation does not impact tumor classification. However, cases with syncytiotrophoblast are thought to possibly be slightly more refractory to treatment.

With immunohistochemical staining, the neoplastic germ cells express placental-like alkaline phosphatase (PLAP) and c-kit (CD117). They are usually negative for HCG; however, isolated syncytiotrophoblastic giant cells may stain positive for HCG. Alpha-fetoprotein (AFP) is negative in the tumor cells.

Staging: Germinomas are staged according to CSF cytology and preoperative neuroimaging findings. Staging can be modified based on findings directly observed at the time of surgery. While the TNM (Tumor, Node, Metastasis) staging format is used, note that for all intracranial primary tumors, the involvement of lymph nodes is not applicable; therefore, the N is absent.


Medical Care: Germinomas are extremely radiosensitive, and radiation therapy is the standard treatment for intracranial germinoma. However, 3 questions remain controversial: optimal dosing, the extent of radiation, and whether combining other therapeutic modalities provides an advantage. Radiation therapy administered to the brain is capable of producing a host of undesirable long-term sequela.

The role of chemotherapy as a means of limiting the cumulative dose of radiation is the subject of active research. There has been an overall trend towards the use of combined chemotherapy with progressively decreasing doses of radiotherapy and smaller radiation fields.

Either radiation alone or combined chemotherapy and radiotherapy, results in a recurrence rate as high as 30%. Most patients achieve a complete response with additional chemotherapy, radiation, or both, and overall survival rates remain approximately 90% for pure germinomas.



Chemotherapeutic agents (eg, cisplatin, bleomycin, etoposide, cyclophosphamide) are used to treat germinomas. They are discussed below along with desmopressin acetate, which is used for the treatment of diabetes insipidus.

Drug Category: Chemotherapeutic agents -- These agents are chemical substances or drugs that treat neoplastic diseases by interfering with DNA synthesis.
Drug Name
Cisplatin (Platinol) -- Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix.
Adult Dose20-120 mg/m2 IV q3-4wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
InteractionsIncreases toxicity of bleomycin and ethacrynic acid
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur
Drug Name
Bleomycin (Blenoxane) -- Glycopeptide antibiotic that inhibits DNA synthesis. For palliation in management of several neoplasms.
Adult Dose0.25-0.5 U/kg (10-20 U/m2) IV/IM/SC 1-2 times/wk; reconstitute 15-U vial with 1-5 mL of sterile water or isotonic saline for injection
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; significant renal function impairment; compromised pulmonary function
InteractionsMay decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity when administered systemically
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; may cause vasoocclusive phenomenon with distal necrosis of digits; permanent damage to nail matrix may occur
Drug Name
Etoposide, VP-16 (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 phase of cell cycle.
Adult Dose100 mg/m2 IV d 1-5
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration may cause death
InteractionsMay prolong effects of warfarin and increase clearance of methotrexate; cyclosporine has additive effects in cytotoxicity of tumor cells
Pregnancy D - Unsafe in pregnancy
PrecautionsBleeding and severe myelosuppression may occur
Drug Name
Cyclophosphamide (Cytoxan, Neosar) -- Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose50-100 mg/m2/d PO or 400-1000 mg/m2 PO in divided doses over 4-5 d; alternatively, 400-1800 mg/m2 (30-40 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals; alternatively, administer 10-15 mg/kg IV q7-10d or 3-5 mg/kg bid
Pediatric DoseAdminister as in adults
ContraindicationsDocumented hypersensitivity; severely depressed bone marrow function
InteractionsAllopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy D - Unsafe in pregnancy
PrecautionsRegularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Drug Category: Vasopressin analogs -- These agents treat diabetes insipidus, a neuroendocrine abnormality associated with CNS germinomas.
Drug Name
Desmopressin acetate (DDAVP, Stimate) -- Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.
Adult Dose2-4 mcg IV/SC divided bid
Pediatric Doseless than 3 months: Not established
3 months to 12 years: 5-30 mcg/d intranasally qd or divided bid
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity; platelet-type von Willebrand disease
InteractionsDemeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsAvoid overhydration if patient is to benefit from its hemostatic effects


Further Inpatient Care:

Further Outpatient Care:


  • See Complications of radiation and chemotherapy in Medical Care.


  • The prognosis of germinomas is generally very good. The 5-year survival rate is higher than 75%, and the a 10-year survival rate is higher than 70%, with most estimates approaching 95% in patients who receive the more aggressive treatments described in Medical Care. This increased survival rate is offset by increased morbidity in patients who develop long-term cognitive difficulty following increased intracranial irradiation.


Medical/Legal Pitfalls:

Special Concerns:

No comments: