AUTHOR AND EDITOR INFORMATION

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• Introduction
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• Follow-up
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INTRODUCTION

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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).

Frequency

United States

Primary intracranial germ cell tumors account for only 2-5% of all CNS malignancies, and just over half of these are germinomas.

International

Primary intracranial germ cell tumors are more common in Asia, especially Japan, where they account for up to 10% of all CNS malignancies.

Mortality/Morbidity

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

• Significant morbidity is most often due to treatment rather than the tumor itself, but direct tumor effects can be significant.
• Spinal cord metastasis is observed in up to 10-15% of patients, but extraneural metastasis is very uncommon.
• The survival rate is remarkably better than that for the nongerminomatous CNS germ cell tumors.

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.

• Among pineal germinomas, males outnumber females by about 3:1.
• Among suprasellar germinomas, females slightly outnumber males.

Age

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

• Ninety percent of patients present when younger than 20 years, and 98% when younger than 30 years.
• The incidence peaks in children aged 10-12 years.
• Sixty-five percent or tumors arise in the second decade of life (age 11-20 years).

CLINICAL

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History

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

• The pineal region is the most common site for an intracranial germinoma, and 50-60% of cases present in this location. These tumors manifest with symptoms and signs of increased intracranial pressure, obstructive hydrocephalus, or both. Common nonspecific complaints include headache, nausea, vomiting, and Parinaud syndrome.
• • Compression of the quadrigeminal plate causes Parinaud syndrome.
  • Parinaud syndrome is characterized by an upward gaze palsy, loss of convergence, pupillary dilation with poor reactiveness to light, and nystagmus.
• Germinomas arising in the suprasellar region are observed more often in females than in males and are the site of approximately 30% of intracranial germ cell tumors. These may present with visual field defects due to impingement upon the optic chiasm or with endocrine manifestations due to effects upon the hypothalamic-pituitary axis.
• • Common endocrine manifestations include diabetes insipidus, retarded growth, precocious puberty, secondary amenorrhea, and panhypopituitarism.
  • The spectrum of visual symptoms includes deficits in visual acuity (84% of patients), failure of pupillary contraction to light, diplopia, and bitemporal hemianopsia.
• Case reports describe involvement of the ventricles, basal ganglia, cerebellum, brain stem, and spinal subarachnoid spaces. These tumors can also be involved in the production of site-specific features based on direct tumor effects at their location. Multifocal germ cell tumors are not uncommon, are usually bifocal, and most often involve the pineal and suprasellar compartments simultaneously.

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.

DIFFERENTIALS

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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.

WORKUP

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Lab Studies

• Serum electrolytes and serum and urine osmolality are useful to detect diabetes insipidus (impaired antidiuretic hormone [ADH] secretion), in which hypernatremia is present and urine osmolality is low.
• Thyroid function tests, growth hormone (GH), serum cortisol, serum testosterone level in men, and serum prolactin level may be useful to detect pituitary dysfunction.
• • Note that while multiple anterior pituitary hormones may be suppressed by a tumor, prolactin may be concomitantly or exclusively elevated due to the so-called stalk effect.
  • Unlike the other hormones that have stimulatory input from the hypothalamus, prolactin receives only inhibitory input. A lesion that interrupts this connection (eg, by compression of the pituitary stalk) may lead to hyperprolactinemia.
• Serum and cerebrospinal fluid tumor markers (ie, AFP and beta-HCG) may be helpful.
• • A pure germinoma is usually not associated with elaboration of these markers. Elevated tumor markers make a pure germinoma unlikely, but 10-15% of germinomas produce low levels of beta-HCG.
  • AFP is predominantly associated with endodermal sinus tumors (yolk sac tumors) but can also be expressed by embryonal cell carcinomas and immature teratomas.
  • Beta-HCG is a normal product of placental trophoblastic tissues, and its level is elevated in association with choriocarcinomas and some germinomas. These germinomas secrete beta-HCG at low levels and histologically contain a minor population of syncytiotrophoblast. HCG-secreting germinomas are thought to be more aggressive than nonsecreting germinomas, but this notion is controversial.
• Cerebrospinal fluid (CSF) cytology may be helpful in detecting craniospinal spread (intracranial germinomas tend to disseminate craniospinally). CSF cytologic status is important for staging and is critical for planning radiotherapy.

Imaging Studies

• Plain films are of limited value but may show the characteristic findings of pineal calcification and possible disruption of the normal appearance of the sella turcica. (However, destruction of the sella turcica is much more common in craniopharyngiomas than in germinomas.) One study reported that only 14 of 58 patients had any visible changes.
• On CT scan, more than 50% of germinomas are hyperdense to normal brain, while the remainder exhibit isodensity. Germinomas tend to be homogeneous, with moderate to marked contrast enhancement.
• MRI, with or without gadolinium, is the neuroimaging test of choice. MRI is critical in preoperative staging. Imaging should include screening the craniospinal axis for CSF dissemination and vertebral metastasis. On MRI, germinomas are isointense to hypointense on T1-weighted images and T2-weighted images. Marked homogeneous enhancement is typical. Cystic degeneration is seen in 33% and CSF seeding in 50% of pineal region germinomas. Often, the residual pineal gland is densely calcified. Characteristically, germinomas melt away within 2 weeks of starting radiation therapy, whereas nongerminomatous germ cell tumors may persist for months. A density corresponding to fat is a hallmark of teratomas, and choriocarcinomas tend to hemorrhage.
• Angiography is seldom indicated in the primary evaluation of germinoma. Angiographic evidence of a posterior suprasellar germinoma typically includes elevation of the anterior choroidal artery and posterior displacement of the basilar artery and pontomesencephalic vein. Pineal region tumors displace the posterior choroidal artery posteriorly and laterally and elevate the internal cerebral vein.

Procedures

• Biopsy remains crucial in the selection of an appropriate treatment and in the evaluation of prognosis. Treatment for germinomas differs significantly from that for nongerminomatous germ cell tumors. In addition, the chemotherapy regimens for pineal tissue tumors are different from those for germ cell tumors.

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.

• T1 tumor - Smaller than 5 cm in diameter and located in the suprasellar, intrasellar, or pineal region
• T2 tumor - Larger than 5 cm in diameter and located in the perisellar region
• T3 tumor - May be smaller than 5 cm in diameter but invades and encroaches on the third ventricle
• T4 tumor - Extends into the anterior, middle, or posterior fossa
• M0 - No evidence of gross subarachnoid or hematogenous metastasis
• M1 - Microscopic tumor cells found in the CSF
• M2 - Gross nodular seeding in the ventricular system or cranial subarachnoid spaces
• M3 - Gross nodular seeding in the spinal subarachnoid spaces
• M4 - Metastasis outside the cerebrospinal axis

TREATMENT

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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.

• Radiation therapy is a central component in the treatment of intracranial germinoma. Many advocate ventricular irradiation followed by a boost to the tumor bed.
• • The optimal dose is unclear, and while total doses as small as 30.6 Gy have proven effective, most recommend greater than 40 Gy.
  • Craniospinal radiation therapy is indicated in cases of documented leptomeningeal metastasis; however, it is of questionable benefit to those with normal CSF cytology and spinal MRI.
  • Long-term complications of cranial and craniospinal irradiation include intellectual deterioration, endocrine dysfunction, hearing loss, growth arrest, and increased likelihood of a secondary malignancy.
• Chemotherapy has been evaluated for germinomas in 3 settings: (1) chemotherapy without radiation therapy; (2) chemotherapy with reduced-dose radiation therapy; (3) chemotherapy after radiation therapy for tumors with incomplete response. Chemotherapy without radiation therapy preliminarily appears inferior and is not presently recommended. Chemotherapy in conjunction with radiotherapy has the benefit of reducing the brain's overall radiation exposure, while not impacting overall survival or the recurrence rate.
  • Platinum-based regimens appear most effective, and studies have focused particularly upon the PEB regimen (cisplatin, 20 mg/m²/d for 5 d; etoposide, 100 mg/m²/d for 5 d; and bleomycin, 15 mg/m² on day 1).
  • Cisplatin intensification (PEB in which the cisplatin dose is 40 mg/m²) has demonstrated improved outcome for patients with advanced disease.
• The primary role of surgery is to obtain tissue for histologic diagnosis. Primary resection should not be undertaken for germinomas; however, initial debulking may be indicated to decompress compromised CNS structures, such as the optic chiasm. Ventriculoperitoneal shunts may be beneficial in selected patients and are not specifically contraindicated. Finally, recurrent or recalcitrant disease should be completely removed for histologic assessment and exclusion of a nongerminomatous component.

Consultations

• General medical care of patients with germinomas focuses predominantly on careful screening for and correction of neuroendocrine abnormalities.
• Diabetes insipidus may persist following treatment and should be managed with correction of extracellular volume loss (taking care to avoid correction that is too rapid in patients with hypernatremia) and administration of desmopressin acetate.
• Depending on the extent of involvement of the germinoma, other manifestations, such as secondary hypothyroidism, adrenal failure or crisis, hypogonadism, and even panhypopituitarism, should be treated with appropriate hormone replacement therapy (eg, hydrocortisone, testosterone, thyroid hormone). These hormones may require lifelong replacement, and their use warrants consultation with an endocrinologist for assistance.

MEDICATION

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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 Category: Vasopressin analogs

These agents treat diabetes insipidus, a neuroendocrine abnormality associated with CNS germinomas.

FOLLOW-UP

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Further Inpatient Care

• Recommended follow-up after initial therapy involves monitoring for a response and for recurrence with a CT scan, MRI, and CSF cytologic studies. No clear follow-up schedule has been defined, but the general consensus is for follow-up evaluations with neuroimaging at 1- to 2-week intervals during treatment to assess for tumor response.
• Perform concomitant sampling of CSF prior to discharge and yearly thereafter. Interestingly, patients who have had tumor cell–positive CSF samples at the time of diagnosis do not have statistically different future CSF positivity, because they are more likely to have received larger initial radiation dosages, especially craniospinal irradiation.

Further Outpatient Care

• Long-term follow-up with neuroimaging is recommended approximately every 6-12 months for several years.
• Patients with neuroendocrine abnormalities are likely to need lifelong care in association with an endocrinologist.

Complications

See Complications of radiation and chemotherapy in Medical Care. 

Prognosis

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.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Pitfalls involved in the diagnosis and treatment of CNS germinomas are of significant concern because most of these tumors occur in adolescents with long life expectancy.
• • Failure to diagnose a CNS germinoma at an early stage given typical clinical history and appropriate laboratory and pathologic findings could result in an increased prevalence of metastasis and a poorer prognosis at the time of diagnosis, with legal or financial ramifications.
  • Even if the diagnosis is rapid and accurate, the process of consent for treatment must be exhaustive because long-term sequelae of successful irradiation, chemotherapy, or both include decreased intelligence, permanent panhypopituitarism, growth arrest, infertility, and increased risk of a second malignancy.

Special Concerns

• Although no specific mention of management of germinomas in pregnancy is found in the literature, these patients, with their endocrine disturbances, probably would have trouble both becoming pregnant and maintaining a pregnant state. Treatment of a pregnant patient also is not described specifically; however, because these tumors are significantly radiosensitive, local irradiation to the CNS with protection of the woman's abdomen is likely to represent a proposed treatment.

MULTIMEDIA

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Media file 1:  Germinoma (hematoxylin and eosin stain, magnification 200X). The tumor has nests of large cells with clear cytoplasm separated by fibrous septa, which contain an infiltrate of small lymphocytes.
	View Full Size Image
Media type:  Photo

Media file 2:  Germinoma (hematoxylin and eosin stain, magnification 500X). The neoplastic cells have a variable quantity of clear cytoplasm and large nuclei containing prominent eosinophilic nucleoli.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Nov 21, 2006