Primary brain tumors, including germ cell tumors (GCTs), are a diverse group of diseases that together constitute the most common solid tumors of childhood. The most recent classification of CNS tumors implements some molecular parameters for the first time, in addition to histology, to define brain tumor entities.[
CNS GCTs are broadly classified as germinomatous (commonly referred to as germinoma) and nongerminomatous germ cell tumors (NGGCTs) on the basis of clinicopathological and laboratory features, including tumor markers.[
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization Classification of Tumors of the Central Nervous System.[
In Western countries, GCTs represent 3% to 4% of primary brain tumors in children, with a peak incidence from age 10 to 19 years.[
Overall, males have a higher incidence of GCTs than do females. Male patients have a preponderance of pineal-region primary tumors.[
CNS GCTs usually arise in the pineal and/or suprasellar regions of the brain as solitary or multiple lesions (refer to Figure 1). The most common site of origin is the pineal region (45%), and the second most common site is the suprasellar region (30%) within the infundibulum or pituitary stalk. Both of these sites are considered extra-axial or nonparenchymal CNS locations. Approximately 5% to 10% of patients present with synchronous tumors arising in both the suprasellar and pineal locations. Germinoma is the most frequently observed histology.[
Figure 1. Anatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.
The signs and symptoms of CNS GCTs depend on the location of the tumor in the brain, as follows:
Nonspecific symptoms such as enuresis, anorexia, and psychiatric complaints [
Diagnostic Evaluation and Prognostic Factors
Radiographic characteristics of CNS GCTs cannot reliably differentiate germinomas from NGGCTs or other CNS tumors. The diagnosis of GCTs is based on the following:
The diagnosis of a suspected CNS GCT and an assessment of the clinical deficits and extent of metastases can usually be confirmed with the following tests:
If possible, a baseline neuropsychological examination should be performed after symptoms of endocrine deficiency and raised intracranial pressure are resolved.
CNS GCTs can be diagnosed and classified on the basis of histology alone, tumor markers alone, or a combination of both.[
Distinguishing between different GCT types by CSF protein marker levels alone is somewhat arbitrary, and standards vary across continents. Patients with pure germinomas and teratomas usually present with negative markers, but low levels of beta-HCG can be detected in patients with germinomas.[
The use of tumor markers and histology in GCT clinical trials is evolving. For example, in the COG-ACNS1123 (NCT01602666) trial, patients were eligible for assignment to the germinoma regimen without biopsy confirmation if they had one of the following:
|AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; PLAP = placental alkaline phosphatase; + = positive; +++ = highly positive (elevated); - = negative; ± = equivocal.|
|Yolk sac tumor||-||+++||±||-|
|Immature teratoma with malignant components||±||+||+||±|
|Mixed germ cell tumor||±||±||±||±|
There is also an effort to use tumor markers to determine prognosis on the basis of the presence and degree of elevation of AFP and beta-HCG. This is an evolving process, and cooperative groups in North America, Europe, and Japan have adopted slightly different criteria.[
Alternative classification schemes for CNS GCTs have been proposed by groups such as the Japanese Pediatric Brain Tumor Study Group for CNS GCTs. This group based their stratification on the prognostic grouping of the differing histological variants, as shown in Table 2.[
|Prognostic Group||Tumor Type|
|Intermediate||Germinoma with syncytiotrophoblastic giant cells|
|Mixed tumors mainly composed of germinoma or teratoma|
|Teratoma with malignant transformation|
|Mixed tumors mainly composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma|
|Yolk sac tumor|
It is crucial that appropriate staging is determined and that germinomas are distinguished from NGGCTs. Chemotherapy and radiation treatment plans differ significantly depending on GCT category and extent of disease.
Cellular and Molecular Classification
The pathogenesis of intracranial GCTs is unknown. The germ cell theory proposes that CNS GCTs arise from primordial germ cells that have aberrantly migrated and undergone malignant transformation. A genome-wide methylation profiling study of 61 GCTs supports this hypothesis.[
An alternative hypothesis, the embryonic cell theory, proposes that GCTs arise from a pluripotent embryonic cell that escapes normal developmental signals and progresses to CNS GCTs.[
The WHO has classified CNS GCTs into the following groups:[
NGGCTs can consist of one malignant NGGCT type or contain multiple elements of GCT components, including teratomatous or germinomatous constituents.
Recurrent mutations in KIT, genes in the MAPK pathway, and genes in the PI3K/mTOR signaling pathway have been identified in CNS GCTs.[
Global hypomethylation that mirrors primordial germ cells in early development has also been observed in CNS GCTs.[
In an evaluation of 21 cases of CNS germinomas diagnosed between 2000 and 2016, programmed death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1) expression was assessed by immunohistochemistry. Ninety percent of germinomas had germ cell components that stained positively for PD-L1. In addition, tumor-associated lymphocytes stained positive for PD-L1 in more than 75% of cases.[
There is no universally accepted clinical staging system for germ cell tumors (GCTs), but a modified Chang staging system has traditionally been used.[
Ventricular tumor markers are obtained for AFP and beta-HCG in the presence of obstructive hydrocephalus and a necessary CSF diversion. However, ventricular CSF does not serve as a substitute for CSF tumor staging and cytopathological review. Both serum and CSF tumor markers should be obtained for a thorough staging and diagnostic evaluation.[
Patients with localized disease and negative CSF cytology are considered to be metastatic negative (M0). Patients with positive CSF cytology or patients with drop metastasis (spinal or cranial subarachnoid metastases) are considered to be metastatic positive (M+). Appropriate staging is crucial because patients with metastatic disease require extended radiation fields.
GCTs may be disseminated throughout the neuraxis at the time of diagnosis or at any disease stage. Several patterns of spread may occur in germinomas, such as subependymal dissemination in the lateral or third ventricles and parenchymal infiltration. Extracranial spread to lung or bone is rare but has been reported.[
Teratomas, germinomas, and other nongerminomatous germ cell tumors (NGGCTs) have differing prognoses and require different treatment regimens. Studies have observed the following:[
Table 3 outlines the treatment options for patients with newly diagnosed and recurrent childhood CNS GCTs.
|Treatment Group||Treatment Options|
|Newly diagnosed childhood CNS germinomas||Neoadjuvant chemotherapy followed by response-based radiation therapy|
|Newly diagnosed childhood CNS nongerminomatous GCTs||Chemotherapy followed by radiation therapy|
|Surgery, if incomplete response to chemotherapy before irradiation|
|Newly diagnosed childhood CNS teratomas||Gross-total resection|
|Recurrent childhood CNS GCTs||Chemotherapy followed by additional radiation therapy|
|High-dose chemotherapy with stem cell rescue with or without additional radiation therapy|
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[
Treatment options for newly diagnosed childhood central nervous system (CNS) germinomas include the following:
Neoadjuvant Chemotherapy Followed by Response-Based Radiation Therapy
Chemotherapy has been explored to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach for maintaining excellent survival rates.[
Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in CNS germinomas. Managing patients receiving chemotherapy agents that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) can be quite challenging because of the possibility of diabetes insipidus in patients with primary tumors of the suprasellar region.[
An international group of investigators explored a chemotherapy-only approach primarily for younger children. A complete response was achieved in 84% of patients with germinomas who were treated with chemotherapy alone. However, 50% of these patients suffered tumor relapse or progression. Many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS, which required additional therapy, including radiation.[
Subsequent studies have continued to support the need for radiation therapy after chemotherapy and the likely requirement for whole-ventricular irradiation (24 Gy) with local tumor site–boost radiation therapy (total dose, 40 Gy).[
Optimal management of bifocal lesions is less clear, but most investigators consider this presentation a form of metachronous primary disease to be staged as M0. A meta-analysis of 60 patients demonstrated excellent progression-free survival after craniospinal irradiation alone. Chemotherapy plus localized radiation therapy, including whole-ventricular irradiation, also resulted in excellent disease control.[
CNS germinomas are highly radiosensitive and have been traditionally treated successfully with radiation therapy alone. Historically, patients with nondisseminated disease have been treated with craniospinal irradiation plus a boost to the region of the primary tumor. The dose of craniospinal irradiation has ranged from 24 Gy to 36 Gy, although studies have used lower doses. The local tumor dose of radiation therapy has ranged between 40 Gy and 50 Gy. Studies of lower-dose craniospinal irradiation have shown excellent outcomes.[
Patterns of relapse after craniospinal irradiation versus reduced-volume radiation therapy (whole-brain or whole-ventricular radiation therapy) have supported the omission of craniospinal irradiation for localized germinomas.[
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS Germinomas
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Treatment options for newly diagnosed childhood central nervous system (CNS) nongerminomatous germ cell tumors (NGGCTs) include the following:
The optimal treatment regimen for CNS NGGCTs remains unclear.
The prognosis for children with CNS NGGCTs is inferior to that for children with germinomas, but the difference is diminishing with the addition of multimodality therapy. NGGCTs are radiosensitive, but patient survival rates after standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years.[
Chemotherapy Followed by Radiation Therapy
The use of chemotherapy before radiation therapy has increased survival rates. However, the specific chemotherapy regimen, length of therapy, and the optimal radiation field, timing, and dose remain under investigation.[
Evidence (chemotherapy followed by radiation therapy):
Patients in this study received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide. If a CR or PR with or without second-look surgery was achieved, the patient was eligible for reduced radiation therapy, defined as 30.6 Gy to the whole-ventricular field and a 54-Gy boost to the tumor bed, compared with 36 Gy of craniospinal irradiation plus a 54-Gy tumor-bed boost used in the ACNS0122 trial.[
The current and prevailing controversy in the management of patients with newly diagnosed, localized NGGCTs—who have no evidence of dissemination and either a complete radiographic response to chemotherapy or have no evidence of disease before and after the initiation of chemotherapy—is the radiation volume. The SIOP-CNS-GCT-96 (NCT00293358) trial employed involved fields of radiation only for these patients with no radiographic evidence of residual or disseminated disease. Two COG protocols used either craniospinal or whole-ventricular fields of radiation plus a boost to the primary tumor. The incidence of isolated spinal relapses was similar in all of these studies, ranging from 8% to 11%.
Patients with relapsed NGGCTs are difficult to treat with curative intent, and their prognosis is guarded. Whether craniospinal irradiation or whole-ventricular plus spinal radiation should be included for all newly diagnosed NGGCT patients is an unresolved controversy and a major question for future clinical trials.
A small percentage of patients treated with chemotherapy may have normalization of tumor markers with a less-than-complete radiographic response. Occasionally, a mass continues to expand in size even though tumor markers may have normalized. This condition, designated as growing teratoma syndrome, represents an accelerated growth of the mature teratoma components during or after treatment.[
A SIOP trial identified a significant OS advantage for patients without residual disease (5-year PFS rate, 85% ± 0.04% vs. 48% ± 0.07%), which underscores the important role of second-look surgery after chemotherapy and before irradiation.[
A second-look surgery can help determine whether the residual mass contains teratoma, fibrosis, or residual NGGCT.[
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS NGGCTs
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Teratomas are designated as mature or immature on the basis of the absence or presence of differentiated tissues. The Japanese Pediatric Brain Tumor Study Group stratifies teratomas for classification and intensity of treatment (chemotherapy and radiation) into a good-prognosis group (mature teratomas) and an intermediate-prognosis group (immature teratomas) (refer to Table 2), while the Children's Oncology Group includes immature teratomas with other nongerminomatous germ cell tumors.
Treatment options for newly diagnosed childhood central nervous system (CNS) teratomas include the following:
The primary treatment for teratomas is gross-total resection.[
Adjuvant treatment in the form of focal radiation therapy and/or adjuvant chemotherapy for patients with subtotally resected tumors is controversial. Small institutional series suggested a potential utility of stereotactic radiosurgery.[
Treatment options for recurrent childhood central nervous system (CNS) germ cell tumors (GCTs) include the following:
For patients who had localized germinomas at diagnosis and were treated with craniospinal and local boost radiation therapy, the most common form of relapse is at the primary site.[
Patients with disseminated germinomas and nongerminomatous germ cell tumors (NGGCTs) also may have complex patterns of relapse, including local and/or disseminated intracranial or intraspinal relapse after treatment with craniospinal radiation therapy alone or preirradiation chemotherapy with various volumes and doses of radiation therapy.[
Enrollment on clinical trials should be considered for all patients with recurrent disease. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.
Chemotherapy Followed by Additional Radiation Therapy
Patients with germinomas that were treated initially with chemotherapy only can benefit from chemotherapy followed by radiation therapy at the time of relapse.[
High-Dose Chemotherapy With Stem Cell Rescue With or Without Additional Radiation Therapy
For patients with pure germinomas who previously received radiation therapy, myeloablative chemotherapy with stem cell rescue has been used. High-dose chemotherapy and autologous stem cell rescue may also have curative potential for some patients with relapsed systemic NGGCTs.[
Treatment Options Under Clinical Evaluation for Recurrent Childhood CNS GCTs
There are limited clinical trials available for patients with recurrent NGGCTs. Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
A significant proportion of children with central nervous system (CNS) germ cell tumors (GCTs) present with endocrinopathies, including diabetes insipidus and panhypopituitarism. In most cases, these endocrinopathies are permanent despite tumor control, and patients will need continuous hormone replacement therapy.[
Although significant improvements in the overall survival of patients with CNS GCTs have occurred, patients face significant late effects based on the location of the primary tumor and its treatment. These sequelae are not only limited to children, but they can also occur in adolescents and young adults. Treatment-related late effects include the following:
Current clinical trials and therapeutic approaches are directed at minimizing the long-term sequelae that result from the treatment of CNS GCTs.
Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in survivors of childhood and adolescent cancer.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system germ cell tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389498]
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Last Revised: 2022-01-27
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