eMedicine Specialties > Oncology > Carcinomas of the Central and Peripheral Nervous System

Germinoma, Central Nervous System

Amani AlKofide, MBBS, Assistant Professor, Alfaisal University College of Medicine; Consultant, Department of Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh

Updated: Sep 2, 2009

Introduction

Background

Germ cell tumors (GCTs) in the central nervous system (CNS) can occur at any age, but the majority of CNS GCTs occur in the first and second decade of life¹ ; the peak incidence is from 10-19 years of age.^2,3 GCTs account for approximately 5% of all intracranial tumors seen in patients younger than 20 years of age.

Pathologically, intracranial GCTs are similar to GSTs in the gonads and other extragonadal areas.⁴ CNS GCTs are broadly divided into germinomas and nongerminomatous germ cell tumors (NGGCTs). The current World Health Organization classification of CNS GCTs, which is based primarily on histological elements, divides these tumors into the following major forms^5,6 :

• Germinoma
• Teratoma 
• Yolk sac tumor/endodermal sinus tumor
• Embryonal carcinoma
• Choriocarcinoma

Pathophysiology

The cell of origin of CNS GCTs remains controversial. The germ cell theory postulates that these tumors arise from primordial germ cells that have migrated aberrantly during embryonic development and subsequently undergone malignant transformation. In contrast, the embryonic cell theory suggests that GCTs arise from a mismigrational pluripotent embryonic cell. It has also been postulated that pure germinomas arise from germ cells while mixed NGGCTs are a result of misfolding and misplacement of embryonic cells into the lateral mesoderm, causing these cells to become entrapped in different areas of the brain. Current evidence suggests that GCTs arise from germinal elements at various stages of development.

Limited data exist in regard to the cytogenetics of CNS GCTs. Studies of malignant testicular tumors have shown that the most common chromosomal abnormality is an isochromosome of the short arm of chromosome 12 (12p). Chromosomal comparison of CNS GCTs with gonadal tumors using genomic hybridization analysis has found the two to be essentially identical.^9,10  In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12. In children, cytogenetic abnormalities include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. A study in children revealed that a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p.¹¹  The most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q.^9,10  Increased copies of the X chromosome are seen in CNS GCTs; the most frequent genotype abnormality isXXY, similar to that in Klinefelter syndrome. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with Down syndrome and those with neurofibromatosis, type 1.¹²
 
Frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas, suggesting that this gene plays an important role in the development of these tumors. Mutations of the c-kit gene have been found in 23–25% of intracranial germinomas.^13,14  These mutations are believed to promote the development of intracranial GCTs. C-myc and N-myc amplifications were seen in a minority of tumors.

Frequency

United States

• According to data from the Surveillance, Epidemiology and End Results (SEER) program, CNS GCTs were seen almost exclusively in individuals between birth and 34 years of age, with a peak incidence of 0.2 per 100,000 person-years at ages 15 to 19.^{1,3 5}
• Intracranial GCTs account for only 0.4-3.4% of all CNS tumors.
• Based on data from the Central Brain Tumor Registry of the United States, less than 93 GCTs are expected to be diagnosed annually in US males under age 19, and less than 38 diagnosed in females ¹ ,{Ref15} .
• Pineal lesions occur more commonly than suprasellar lesions, at a ratio of 2:1. Tumors of the pineal area comprise 50-60% of CNS GCTs; those of the suprasellar region, 30-40%. CNS GCTs may also occur in the basal ganglia, thalamus, and cerebral hemispheres.

International

Primary CNS GCTs are more common in Asia than in North America. They account for approximately 2-3% of all intracranial tumors and 8-15% of pediatric brain tumors in the Far East.^3,15,16

Mortality/Morbidity

• 5-year survival
• Patients with pure germinomas have a 5-year survival rate of 70-90%. Those with predominantly germinoma or teratoma mixed with other NGGCTs have a 5-year survival of approximately 70%.¹⁷  Patients with pure malignant NGGCT (embryonal carcinoma, yolk sac tumor, or choriocarcinoma) have a 5-year survival of 30-50%.¹⁸  
• Tumor-related morbidity 
  Diabetes insipidus, hypopituitarism, and visual field deficits are the most common presentation of CNS GCTs and may persist despite therapy. Parinaud syndrome is common in patients with pineal tumors and often persists even after therapy. 
• Treatment-related morbidity  
  • Surgery of deep-seated structures within the brain may be associated with significant morbidity. However, modern neurosurgical navigation techniques have minimized this risk. Tissue sampling by stereotactic biopsy is a safe and rapid method of determining tumor histology 
  • Late sequelae of radiation therapy to the CNS include growth effects, hearing loss, neuropsychological and cognitive impairments, and neuro-endocrine disorders.^19,20,21  
  • Risks of treatment-related secondary cancers are well described.

Race

Registry data and clinical series around the world show variation and discrepancies, which raises questions regarding the quality and reliability of the information available. However, the highest incidence of CNS GCTs has been reported in many Asian countries, including Japan, Taiwan, and Singapore.^18,16

Sex

There is an overall male predominance in CNS GCTs. Data from the NCI Surveillance, Epidemiology and End-Results (SEER) Program on CNS GCTs in the United States^3,1 showed that the incidence of CNS germ cell tumors in males, all ages combined, was 3.7 times that seen in females. Among adolescents and young adults, the incidence in males was more than 12 times that seen in females.
 
Location of CNS GCTs also varies by sex. In males, 70% of tumors occur in the pineal area; for GCTs in this region, the male:female ratio is 18:1. In females, 75% of CNS GCTs occur in the suprasellar areas.

Age

CNS GCTs may occur at any age; however, they are considered primarily a disease of adolescents and young adults.^{5 17,1} The peak incidence is from 10-19 years of age. Age distribution of CNS GCTs is as follows: 

• 0 – 14 years: 34% of cases
• 15 – 29 years: 57% of cases
•  30 – 44 years: 9% of cases.

Clinical

History

Clinical presentation varies, depending on age of patient and site of tumor.^{7  22}  

• Prenatal/neonate – Congenital teratomas produce polyhydramnios and hydrocephalus; ultrasound will show a heterogeneous echogenic mass with cystic and solid components.
•  Young infants -  The teratoma and choriocarcinoma subtypes of nongerminoma germ cell tumor are most common in this age group⁵³ . These patients may present with irritability, listlessness, failure to thrive, macrocephaly, and bulging fontanelle.
•  Beyond Infancy – Presentation depends on tumor location.

Pineal region tumors
 
Parinaud syndrome is the most common presentation, accounting for 34% of cases. It is due to compression on the tectum. The syndrome comprises paralysis of upward gaze, loss of light perception and accommodation, nystagmus, and failure of convergence.
  
Features of increased intracranial pressure may supervene. These include headache, nausea and vomiting, and papilledema. Somnolence, ataxia, seizures, and behavioral abnormalities may develop.
 
Precocious puberty may develop in a pre-pubertal child.
 
Diabetes insipidus and anterior hypopituitarism may occur.

Suprasellar region tumors
 
Patients with suprasellar GCTs usually present with endocrine deficits. These include the following:        

• Anterior hypopituitarism and Diabetes insipidus
• Thyroid and/or cortisol deficiency
• Growth failure from growth hormone deficiency
• Delayed puberty from gonadotrophin deficiency
• Regression of sexual development or sexual dysfunction
• Posterior pituitary dysfunction (vasopressin deficiency)
• Precocious puberty may develop in a pre-pubertal child (due to tumor-induced hypothalamic injury or secretion of human chorionic gonadotrophin by the tumor).

Visual disturbances may include diplopia, blurred vision, and diminished vision. Enuresis and psychiatric abnormalities may develop.^7,5,23  In general, patients with  symptoms of increased intracranial pressure and visual changes tend to present earlier in the disease course than patients with endocrine dysfunction.

Physical

The clinical evaluation should include the following:

• General physical examination
• Check of growth parameters
• Careful neurological evaluation, with assessment for neurocutaneous stigmata
• Assessment of primary and secondary sexual characteristics
• Ophthalmological exam. 

Causes

The exact cause of CNS GCTs is unknown. GCTs appear to arise from primordial germ cells that migrate to the germinal ridges in the developing embryo.^5,22,11,12 This process appears to be under the control of complex molecular events. Aberration in any of these molecular pathways may potentially give rise to GCTs.  
 
Important factors in cell migration include the extracellular matrix, which affects cell adherence and migration. Other factors, such as chemotropic factors, may also be involved in cell migration. In vitro studies have shown that tumor growth factor beta 1 may initiate the migration of primordial germ cells.  
 
Some primordial germ cells that have left the yolk sac endoderm migrate aberrantly cranially towards the diencephalic midline structures rather than laterally to genital ridges.
 
Maturation of the fetal hypothalamus coincides with the migration of primordial germ cells. The fetal hypothalamus may secrete chemotrophic factors that attract primordial germ cells to the diencephalon.
 
Germ cells migrate into the mesenchyme of the mesentery and stimulate blood vessel formation and may reach intracranial locations via the circulation. 

Once the primordial germ cells have reached their intracranial location through abnormal pathways, congenital or acquired aberrant molecular events occur in the primordial germ cell itself or in the surrounding microenvironment, leading to the formation of CNS GCTs.
 
The surge of the neuroendocrine functions of reproduction in the diencephalon may also be a cause or contributing factor to the development of CNS GCTs, as demonstrated by the location of these tumors and their predominance in the pubertal age group. 

Differential Diagnoses

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

Other Problems to Be Considered

Glial Tumors - astrocytomas, gangliomas
Granular cell tumor
Hamartomas
Meningiomas
Xanthogranuloma

Workup

Laboratory Studies

• Studies to detect hormonal dysfunction
  • Diabetes insipidus – measure serum sodium, serum osmolality, and urine osmolality
  • Hypopituitarism – thyroid function tests, growth hormone levels, cortisol levels
  • Gonadal dysfunction – testosterone level in males; prolactin level in females.
•  Tumor markers - in serum and CSF^24,25
  • Alpha-fetoprotein (AFP) may be normally elevated both in serum and CSF of neonates and infants. It has a wide variation. It reachs adult levels at the age of 8-12 months. Therefore accurate interpatation of rasied AFP must take into account the normal varation seen in this age group. In normal infants AFP in CSF is :

                 median 61kIU/L in infants less than 31 days
                 median 1.2kIU/L in infants 32-110 days

• AFP may be elevated in pure endodermal sinus tumor (yolk sac), embryonal carcinoma, and malignant teratoma.
• β-hCG levels above 50-100 IU/L indicate the presence of choriocarcinoma while lower levels may indicate pure germinoma that contain syncytotrophoblastic giant cells^12,39,53 .
• Carcinoembryonic antigen (CEA) levels may be increased in NGGCTs or their components.
• CSF tumor marker levels are usually higher than serum levels.²⁴
• Detection of elevated tumor markers may be sufficient for diagnosis in patients in whom endoscopic biopsy is not considered possible.
• CSF cytology – to detect malignant cells.²⁶

Imaging Studies

• CT scan of the brain
  • Germinomas show a homogeneous pattern and are hyperdense compared with brain tissue; with pineal gland tumors, calcification of the gland may be seen.
  • NGGCTs are irregular in shape, with edema, and are less dense than germinomas.
  • Mature teratomas have mixed densities, with large cysts and areas of calcification with distinct tumor margins. 
• Magnetic resonance imaging 
  • MRI of the brain and spine with and without gadolinium is the gold standard radiological imaging study (see Images 1-3).
  • Germinomas are homogeneous and show isointensity or slightly low signal intensity on T1-weighted images, and isointensity or high intensity on T2-weighted images.
  • NGGCTs are more heterogeneous and may have hemorrhage.
  • Malignant teratomas are heterogeneous, with small cysts and irregular tumor margins, and may demonstrate peri-tumor edema. 
  • MRI is excellent in delineating tumor anatomy and may suggest specific tumor type; however, the findings may be similar for germinomas, NGGCTs, and pineal parenchymal tumors. Therefore, imaging studies alone may not suffice for precise diagnosis.

Procedures

• Histological confirmation is accomplished by means of endoscopic/stereotactic biopsy or open biopsy. Advances in endoscopic techniques have led to less morbidity and mortality with this procedure.
• Adequate specimen size is important because in NGGCT, a specimen that is too small may miss a tumor component and thus may not be representative of the actual tumor type.
• Suprasellar tumors are generally more accessible to surgical biopsy than are pineal tumors.
• Currently the recommendation for all patients with pineal and suprasellar tumors is to undergo surgical biopsy for histological confirmation.
• Only patients with elevated serum or CSF levels of AFP or β-hCG >50-100 IU/ml do not warrant surgery for the sole purpose of tissue diagnosis^15,39,53 Diagnosis without tissue verification should be considered in such patients because high postoperative mortality has been reported after resection of secreting tumors.

Histologic Findings

The World Health Classification (WHO) system of CNS GCTs is based on histology, serum and CSF tumor markers, and protein markers on tumor cells.^6,12   

• Germinoma is composed of undifferentiated, uniform large cells with abundant glycogen-rich cytoplasm arranged in nests separated by bands of connective tissue along trophoblastic lines (see Image 4). Scattered β-hCG – secreting syncytiotrophoblasts may be present. 
• Embryonal carcinoma is composed of large cells with a high mitotic index that proliferate in cohesive nests and sheets demonstrating zones of coagulative necrosis.
• Choriocarcinoma is characterized by extraembryonic differentiation along trophoblastic lines with βHCG-secreting syncytiotrophoblasts.
• Endodermal sinus tumors are composed of primitive-appearing epithelial cells linked to extraembryonic mesoblast.
•  Mixed germ cell tumors have more than one histological component.
• Teratoma
  • Mature teratomas comprise fully differentiated tissue elements of ectoderm, mesoderm, and endoderm. 
  • Immature teratomas contain incompletely differentiated tissue elements.
  • Teratomas with malignant transformation usually contain rhabdomyosarcoma or undifferentiated sarcoma. 

Staging

The diagnostic work-up for CNS GCTs should include MRI of the brain and spine, measurement of the tumor markers β -hCG and AFP in both serum and CSF, and tissue confirmation by biopsy.^{24 25,27} .

• MRI of the brain and spine are essential for diagnosis, assessing extent of intracranial disease and detecting metastatic disease
• Postoperative MRI of the brain is essential to assess residual tumor
•  CSF cytology is used to  detect malignant cells²⁶
•  Measurement of serum and CSF tumor markers including AFP and β-hCG.^24,25
• Evaluation of the disease outside the CNS is usually unnecessary

Treatment

Medical Care

Radiation Therapy
 
In the past, patients with imaging findings typical of CNS germinoma were treated empirically with radiation therapy.² This approach has largely been abandoned, since current stereotactic biopsy techniques permit histological diagnosis with minimal risk of morbidity. Identification of the histological elements of the tumor is important in determining the most appropriate therapeutic strategy, because the different histological types vary in their sensitivity to radiation.^8,28,29 Germinomas are highly responsive to radiation therapy^30,17,31 ; a complete response rate with a 5-year survival of more than 90% is seen with radiation therapy alone.^2,32 NGGCTs are less radiosensitive than pure germinomas, with an overall 5-year survival of 30-50%.
 
Full-dose craniospinal radiation (CSI) was traditionally employed for patients with pure germinomas. Side effects of CSI may be significant, however. Studies comparing CSI with reduced-volume radiation, whether whole-brain or whole-ventricular, have shown no significant difference in the pattern of relapse in germinomas.^{33,8,16,34,35}  
Therefore, CSI is no longer used for localized germinomas.^33,36  
 
Trials to determine the best regimen for radiation therapy are ongoing.^37,32 Currently, patients with localized or multifocal disease may receive 24 Gy to the whole-ventricular system and a 21-Gy boost to all measurable disease. Most experts advocate a boost to the primary tumor bed in order to prevent local recurrence; 45 Gy appears to be a satisfactory upper dose limit.^38,39,40,41 Patients with disseminated disease may receive 24 Gy to the craniospinal axis.^37,30,42

Studies of radiation therapy alone versus neoadjuvant chemotherapy followed by response-based radiotherapy are currently under way.^{33,15,30,43,35}
 

Chemotherapy
 
In patients with germinomas, chemotherapy has been recently added to the treatment regimen in order to permit the use of a lower radiation dose, thereby reducing the long-term morbidity associated with radiation therapy while maintaining the excellent survival rates.^{32,5,8,29,43,39} .In patients with NGGCTs, the use of adjuvant chemotherapy with radiation therapy is intended to improve outcome, because even with surgery and CSI these patients have a poor prognosis.^{32,8,15,22,44} The increase in survival seen with combination therapy has made chemotherapy an integral part of treatment for NGGCTs.^16,34,45,38
 
As with gonadal germ cell tumors, the agents that to date have shown the best activity against CNS GCTs are cisplatin, etoposide, vinblastine, bleomycin, and carboplatin.³⁹
Ifosfamide and cyclophosphamide are also used.²⁹

Patients with relapsed or progressive disease, especially those with NGGCTs, have a poor prognosis. High-dose chemotherapy followed by autologous stem cell transplant may be effective in this group of patients.⁴⁶

Surgical Care

Currently the recommended practice is to acquire a tissue biopsy sample, with the exception of patients who have a characteristic elevation in tumor markers and in whom surgical intervention may lead to significant sequelae.^5,17 {Ref27}^38,39  

Surgical treatment of CNS GCTs varies according to the tumor type. Germinomas carry a relatively excellent prognosis and management has therefore focused on reducing morbidity. Partial and gross total resection of germinomas has no proven benefit and may lead to neurological or endocrinological deterioration. Therefore, most neurosurgeons limit surgical intervention to biopsy and instead treat these patients with radiation and chemotherapy.^33,8,43  

Patients with choriocarcinoma have an increased tendency to hemorrhage; current recommendation is for early and radical surgery.
 
Patients with NGGCTs have poor long-term survival, and surgery for these patients is aimed at improving outcome. Reduction of tumor burden by partial resection is often an option when removal of all tumor tissue is impossible. Adjuvant radiation therapy and chemotherapy are often incorporated in the treatment plan.^15,47,44
 
Patients presenting with obstructive hydrocephalus may require a ventriculoperitoneal shunt.
 
In patients who have had an incomplete response to initial chemotherapy, second-look surgery may be performed to remove the residual tissue and permit its histological verification. The remaining tissue may contain malignant elements; however, it may consist of fibrosis, necrosis, or a mature teratoma — the so-called growing teratoma syndrome.^38,39 . The growing teratoma syndrome is characterized by enlarging tumor mass during or after chemotherapy in the presence of normal or declining tumor markers. Surgical resection of the tumor is considered curative.^28,48

Consultations

• Endocrinology

Patients with CNS GCTs may have a range of endocrine dysfunctions, including diabetes insipidus, hypothyroidism, precocious or delayed puberty, sexual dysfunction, growth failure, adrenal crises, and panhypopituitarism. Proper monitoring of hormone levels and electrolytes is essential. Lifelong hormonal replacement may be required for most of these patients.

• Ophthalmology

Disturbance in vision is a common presenting feature. Evaluation by an ophthalmologist will identify the visual deficit.

• Audiometry

Audiogram studies should be performed, especially in patients expected to receive radiation therapy and ototoxic agents — specifically, cisplatin.

Medication

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.

Chemotherapeutic agents

These agents are chemical substances or drugs that treat neoplastic diseases by interfering with DNA synthesis⁴⁹

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix.

Dosing

Adult

20-120 mg/m² IV q3-4wk

Pediatric

Not established

Interactions

Increases toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Administer adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliation in management of several neoplasms.

Dosing

Adult

0.25-0.5 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

Not established

Interactions

May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity when administered systemically

Contraindications

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Caution 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

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.

Dosing

Adult

100 mg/m² IV d 1-5

Pediatric

Not established

Interactions

May prolong effects of warfarin and increase clearance of methotrexate; cyclosporine has additive effects in cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; IT administration may cause death

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Bleeding and severe myelosuppression may occur

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.

Dosing

Adult

50-100 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

Administer as in adults

Interactions

Allopurinol 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

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Vasopressin analogs

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

Desmopressin acetate (DDAVP, Stimate)

Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.

Dosing

Adult

2-4 mcg IV/SC divided bid

Pediatric

<3 months: Not established
3 months to 12 years: 5-30 mcg/d intranasally qd or divided bid
>12 years: Administer as in adults

Interactions

Demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects

Contraindications

Documented hypersensitivity; platelet-type von Willebrand disease

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Avoid overhydration if patient is to benefit from its hemostatic effects

Follow-up

Further Inpatient Care

• A repeat MRI of the brain should be performed within the first 48 hrs of surgery to assess for residual disease.
• During hospitalization, daily weights and intake/output should be measured.
• Care must be taken not to overcorrect fluid and sodium levels; repletion should be guided by fluid balance and electrolyte levels.

Further Outpatient Care

Neuropsychological assessment should  be provided — especially for adolescents, to ensure proper schooling and adjustment. 
 

Complications

• Patients may have persistent neurological deficits, even after tumor control.
• Endocrine abnormalities usually persist and require lifetime hormonal replacement 
• Chemotherapy related - see Medication, above
• Surgical

Pineal region tumors have a surgical morbidity of 2-5%, including transient movement abnormalities of eyes, ataxia, and cognitive dysfunction.

• Radiation Therapy
  • The deleterious effects of brain radiation therapy on intelligence have been well documented, particularly in children. In older patients, studies have shown a decline in neurocognitive function and performance IQs¹⁹ .
  • Brain injury including atrophy, multifocal encephalomalacia, focal necrosis, and cerebrovascular occlusion have been reported after radiation therapy.²⁰ .
• Secondary Neoplasms

Radiation therapy and chemotherapy may promote the development of secondary cancers, including acute myeloid leukemia and radiation-induced brain neoplasms.
 

Prognosis

• Germinomas are generally associated with an excellent prognosis. Even in those with syncytiotrophoblasts that secrete β -hCG, 5-year survival is 70-90% and 10-year survival is 70%.^3,1
• With mixed germ cell tumors, 5-year survival is 60-80%.
• With NGGCTs, 5-year survival is 30-50%.

Patient Education

Patients and their caregivers should receive education with regard to disease, treatment options, prognosis, and expected and anticipated complications.

Miscellaneous

Medicolegal Pitfalls

Patients can present with symptoms such as enuresis or psychiatric disturbances that may lead to delay in diagnosis.^7,23 This delay may have clinical consequences—continued tumor growth, and perhaps metastasis, and thus poorer outcome — with subsequent legal implications.

Special Concerns

• Fertility – Although no hard data are available in patients with CNS GCTs, fertility could be impaired via several mechanisms. The endocrine dysfunction from the tumor itself may cause infertility.^47,19 Chemotherapy, such as with ifosphamide and cyclophosphamide, may lead to infertility. Radiation therapy to the hypothalamic, pituitary and spinal areas may all lead to infertility.
• Pregnancy – As with cancer in general, the risk of treatment during pregnancy resulting in fetal death or malformations depends on the chemotherapeutic agents administered. The risk is greatest during the first trimester. Pregnant women who require radiation therapy for CNS GCTs may benefit from proper abdominal protection.
• Anesthesia – Proper monitoring of fluid balance and sodium levels is essential, particularly in patients with diabetes insipidus.

Multimedia

Media file 1: MRI of the brain - T1 weighted-image- coronal view- showing a heterogeneously enhancing, multicystic mass in the suprasellar region

Media file 2: MRI of the brain - axial view- heterogeneous mass lesion measuring approximately 3.2 x 2.9 x 4.0 cm.

Media file 3: MRI of the brain - T1-weighted image - post-gadolinium sagittal view- A suprasellar lesion that severely compresses the optic chiasm encases the posterior aspect of the optic nerves bilaterally and causes superior displacement of the third ventricle, with significant compression of the brain stem.

Media file 4: Biopsy specimen from an intracranial germ cell tumor - Large tumor cells with large nuclei; prominent nucleoli; and abundant, clear cytoplasm (rich in glycogen) are noted among reactive inflammatory cells--lymphocytes and histiocytes. Elsewhere there are well-formed granulomas, a well-known phenomenon in germinomas, especially of the pineal region.

References

1. Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X. Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol. Apr 2008;10(2):121-30. [Medline].

2. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. Aug 1985;63(2):155-67. [Medline].

3. Keene D, Johnston D, Strother D, Fryer C, Carret AS, Crooks B. Epidemiological survey of central nervous system germ cell tumors in Canadian children. J Neurooncol. May 2007;82(3):289-95. [Medline].

4. Bentley AJ, Parkinson MC, Harding BN, Bains RM, Lantos PL. A comparative morphological and immunohistochemical study of testicular seminomas and intracranial germinomas. Histopathology. Nov 1990;17(5):443-9. [Medline].

5. Echevarría ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist. Jun 2008;13(6):690-9. [Medline].

6. Rosenblum MK. CNS germ cell tumors: WHO Classification of Tumors of Central Nervous System ed 4. 4.

7. Crawford JR, Santi MR, Vezina G, Myseros JS, Keating RF, LaFond DA. CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology. May 15 2007;68(20):1668-73. [Medline].

8. Finlay J, da Silva NS, Lavey R, Bouffet E, Kellie SJ, Shaw E, et al. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolution. Pediatr Blood Cancer. Aug 2008;51(2):313-6. [Medline].

9. Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W. Comparative genomic hybridization in pineal germ cell tumors. J Neuropathol Exp Neurol. Sep 2000;59(9):815-21. [Medline].

10. Schneider DT, Zahn S, Sievers S. Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol. Jun 2006;19(6):864-73.

11. Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP. Malignant germ cell tumours of childhood: new associations of genomic imbalance. Br J Cancer. Feb 26 2007;96(4):667-76. [Medline].

12. Sato K, Takeuchi H, Kubota T. Pathology of intracranial germ cell tumors. Prog Neurol Surg. 2009;23:59-75. [Medline].

13. Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H. C-kit gene mutation: common and widely distributed in intracranial germinomas. J Neurosurg. Mar 2006;104(3 Suppl):173-80. [Medline].

14. Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. c-kit gene mutations in intracranial germinomas. Cancer Sci. Sep 2004;95(9):716-20. [Medline].

15. Frank Saran. Pineal Tumors: Germinomas and Non-germinomatous Germ Cell Tumor. In: Clinical Endocrine Oncology Second Edition. 2008 pp 310-317.

16. Matsutani M,. Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol. Sep 2001;54(3):311-6. [Medline].

17. Kaur H, Singh D, Peereboom DM. Primary central nervous system germ cell tumors. Curr Treat Options Oncol. Dec 2003;4(6):491-8. [Medline].

18. Matsutani M. Pineal germ cell tumors. Prog Neurol Surg. 2009;23:76-85. [Medline].

19. Sugiyama K, Yamasaki F, Kurisu K, Kenjo M. Quality of life of extremely long-time germinoma survivors mainly treated with radiotherapy. Prog Neurol Surg. 2009;23:130-9. [Medline].

20. Sutton LN, Radcliffe J, Goldwein JW, Phillips P, Janss AJ, Packer RJ, et al. Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery. Dec 1999;45(6):1292-7; discussion 1297-8. [Medline].

21. Yoshida J, Sugita K, Kobayashi T, Takakura K, Shitara N, Matsutani M, et al. Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16). Acta Neurochir (Wien). 1993;120(3-4):111-7. [Medline].

22. Jubran RF, Finlay J. Central nervous system germ cell tumors: controversies in diagnosis and treatment. Oncology (Williston Park). May 2005;19(6):705-11; discussion 711-2, 715-7, 721. [Medline].

23. Sonoda Y, Kumabe T, Sugiyama S, Kanamori M, Yamashita Y, Saito R. Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr. Aug 2008;2(2):118-24. [Medline].

24. Kim A, Ji L, Balmaceda C, Diez B, Kellie SJ, Dunkel IJ. The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors. Pediatr Blood Cancer. Dec 2008;51(6):768-73. [Medline].

25. Calaminus G, Bamberg M, Harms D, Jürgens H, Kortmann RD, Sörensen N, et al. AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics. Apr 2005;36(2):71-7. [Medline].

26. Shibamoto Y, Oda Y, Yamashita J, et al. The role of cerebrospinal fluid cytology in radiotherapy planning for intracranial germinoma. Int J Radiat Oncol Biol Phys. Jul 30 1994;29(5):1089-94. [Medline].

27. Shinoda J, Sakai N, Yano H, Hattori T, Ohkuma A, Sakaguchi H. Prognostic factors and therapeutic problems of primary intracranial choriocarcinoma/germ-cell tumors with high levels of HCG. J Neurooncol. Jan 2004;66(1-2):225-40. [Medline].

28. Friedman JA, Lynch JJ, Buckner JC, Scheithauer BW, Raffel C. Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery. Mar 2001;48(3):518-22; discussion 522-3. [Medline].

29. Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al. Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach. Pediatr Blood Cancer. Aug 2004;43(2):126-33. [Medline].

30. Haas-Kogan DA, Missett BT, Wara WM, Donaldson SS, Lamborn KR, Prados MD, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys. Jun 1 2003;56(2):511-8. [Medline].

31. Matsatani M. Clinical Management of Primary Central Nervous System Germ Cell Tumors. Semin Oncol. 2004;31:676-683.

32. Blakeley JO, Grossman SA. Management of pineal region tumors. Curr Treat Options Oncol. Nov 2006;7(6):505-16. [Medline].

33. Cho J, Choi JU, Kim DS, Suh CO. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol. Apr 2009;91(1):75-9. [Medline].

34. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O. Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Childs Nerv Syst. Jan-Feb 1998;14(1-2):59-62. [Medline].

35. Roberge D, Kun LE, Freeman CR. Intracranial germinoma: on whole-ventricular irradiation. Pediatr Blood Cancer. Apr 2005;44(4):358-62. [Medline].

36. Shikama N, Ogawa K, Tanaka S. Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer. Jul 1 2005;104(1):126-34.

37. Aoyama H. Radiation therapy for intracranial germ cell tumors. Prog Neurol Surg. 2009;23:96-105. [Medline].

38. Sawamura Y. Strategy of combined treatment of germ cell tumors. Prog Neurol Surg. 2009;23:86-95. [Medline].

39. Shibamoto Y. Management of central nervous system germinoma: proposal for a modern strategy. Prog Neurol Surg. 2009;23:119-29. [Medline].

40. Shim KW, Kim TG, Suh CO, Cho JH, Yoo CJ, Choi JU, et al. Treatment failure in intracranial primary germinomas. Childs Nerv Syst. Oct 2007;23(10):1155-61. [Medline].

41. Yasuda K, Taguchi H, Sawamura Y, Ikeda J, Aoyama H, Fujieda K, et al. Low-dose craniospinal irradiation and ifosfamide, cisplatin and etoposide for non-metastatic embryonal tumors in the central nervous system. Jpn J Clin Oncol. Jul 2008;38(7):486-92. [Medline].

42. Schoenfeld GO, Amdur RJ, Schmalfuss IM, Morris CG, Keole SR, Mendenhall WM, et al. Low-dose prophylactic craniospinal radiotherapy for intracranial germinoma. Int J Radiat Oncol Biol Phys. Jun 1 2006;65(2):481-5. [Medline].

43. Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group. Pediatr Blood Cancer. Mar 2007;48(3):285-91. [Medline].

44. Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al. Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol. J Clin Oncol. Mar 1 2004;22(5):846-53. [Medline].

45. Ogawa K, Toita T, Nakamura K, Uno T, Onishi H, Itami J. Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: a multiinstitutional retrospective analysis of 41 patients. Cancer. Jul 15 2003;98(2):369-76. [Medline].

46. Modak S, Gardner S, Dunkel IJ, Balmaceda C, Rosenblum MK, Miller DC, et al. Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol. May 15 2004;22(10):1934-43. [Medline].

47. Janmohamed S, Grossman AB, Metcalfe K, Lowe DG, Wood DF, Chew SL, et al. Suprasellar germ cell tumours: specific problems and the evolution of optimal management with a combined chemoradiotherapy regimen. Clin Endocrinol (Oxf). Oct 2002;57(4):487-500. [Medline].

48. Peltier J, Vinchon M, Baroncini M, Kerdraon O, Dhellemmes P. Bifocal mixed germ-cell tumor with growing teratoma syndrome and metachronous mature metastases: case report. J Neurooncol. Oct 2008;90(1):111-5. [Medline].

49. Skeel RT. Handbook of Cancer Chemotherapy. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:. 85, 91, 93, 105.

50. Nakamura H, Takeshima H, Makino K, Kuratsu J. Evaluation of residual tissues after adjuvant therapy in germ cell tumors. Pediatr Neurosurg. 2007;43(2):82-91. [Medline].

51. Ogino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara S, Yamada T. CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys. Jul 1 2005;62(3):803-8. [Medline].

52. Robertson Patricia. intracranial nongerminoma germ cell tumors. Available at www.medlink.com.

Keywords

Intracranial germ cell tumors, germinoma, nongerminomatous germ cell tumor, germ cell tumor, teratoma, pineal lesions, suprasellar lesions, gonadotrophines, tumor markers, alpha-fetoprotein (AFP),  beta-human chorionic gonadotrophins (β-hCG) , primordial germ cells, Klinefelter syndrome, syncytiotrophoblasts
 
 

Contributor Information and Disclosures

Author

Amani AlKofide, MBBS, Assistant Professor, Alfaisal University College of Medicine; Consultant, Department of Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh
Amani AlKofide, MBBS is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

Hindi N Al-Hindi, MD, FCAP
Consultant Anatomic Pathologist and Neuropathologist
Coordinator, Anatomic Pathology Residency Training Program
Director of Electron Microscopy Services
Department of Pathology and Laboratory Medicine
King Faisal Specialist Hospital & Research Center
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Riyadh 11211
Kingdom of Saudi Arabia

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email: hal-hindi@kfshrc.edu.sa

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