Topic Contents
- General Information About Childhood Central Nervous System (CNS) Germ Cell Tumors
- Cellular Classification of Childhood CNS Germ Cell Tumors
- Stage Information for CNS Germ Cell Tumors
- Treatment Option Overview
- Treatment of Newly Diagnosed Germinomas
- Treatment of Newly Diagnosed Teratomas
- Treatment of Newly Diagnosed Nongerminomatous Germ Cell Tumors
- Treatment of Recurrent Childhood CNS Germ Cell Tumors
- Long-Term Effects of Childhood CNS Germ Cell Tumors
- Current Clinical Trials
- Changes to This Summary (05 / 17 / 2012)
- About This PDQ Summary
- Get More Information From NCI
Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Childhood Central Nervous System Germ Cell Tumors Treatment
General Information About Childhood Central Nervous System (CNS) Germ Cell Tumors
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (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 childhood and adolescent cancer survivors.)
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. (Refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors for information about the general classification of childhood brain and spinal cord tumors.)
Anatomy
Central nervous system (CNS) germ cell tumors (GCTs) may arise from the pineal and/or suprasellar regions as solitary or multiple lesions. Pineal region tumors are twice as frequent as suprasellar tumors, but approximately 5% to 10% of patients have both suprasellar and pineal gland involvement at the time of diagnosis. Involvement of both sites is most commonly seen in pure germinomas. Males have a higher incidence of GCT than females, with males having a preponderance of pineal region primaries. Other areas that may be involved, though rare, include the basal ganglia, ventricles, thalamus, cerebral hemispheres, and the medulla.[2,3]
Diagnosis
Radiographic characteristics of CNS GCTs cannot reliably differentiate germinomas from nongerminomatous germ cell tumors (NGGCTs) or from other CNS tumors. The diagnosis of GCTs is based on clinical symptoms and signs, tumor markers, neuroimaging, and cytological cerebrospinal fluid (CSF) and histological confirmation. Patients with intracranial GCTs often present with pituitary dysfunction including diabetes insipidus (DI), with an increased presence in patients with tumors involving the suprasellar region. Two-thirds to 90% of patients with a GCT of the suprasellar region present with DI.[4,5] Patients with tumors in the pineal region may also present with DI without imaging evidence of third ventricular and suprasellar involvement. Visual loss, growth hormone deficiency, precocious puberty (suprasellar tumors), and Parinaud syndrome (pineal tumors) are also common.[5] Nonspecific symptoms such as enuresis, anorexia, and psychiatric complaints can lead to delays in diagnosis, whereas signs of increased intracranial pressure or visual changes tend to result in earlier diagnosis.[6]
Appropriate staging is crucial since patients with metastatic disease should receive different total radiation doses and more extended radiation fields. All patients with a suspected CNS GCT should have the following tests:
- Magnetic resonance imaging (MRI) of brain and spine with gadolinium.
- Alpha-fetoprotein (AFP) and beta subunit human chorionic gonadotropin (beta-HCG) in both serum and CSF. If pre-operative lumbar CSF can be obtained safely and tumor markers are elevated, this may obviate the need for upfront surgery. In cases where the patient presents with hydrocephalus requiring CSF diversion, CSF tumor markers can be obtained by ventricular CSF sampling at the time of surgery.
- CSF cytology.
- Evaluation of pituitary/hypothalamic function.
- Visual field examinations for suprasellar or hypothalamic tumors.
- Baseline neuropsychologic examination.
Diagnosis of GCTs often requires a tumor biopsy, except in cases with characteristic increased tumor markers in the serum and/or CSF. When the tumor markers are negative or mildly elevated but below diagnostic criteria, or if there is any noncharacteristic finding, a tumor biopsy should be done.
References:
Cellular Classification of Childhood CNS Germ Cell Tumors
Childhood central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that commonly arise from the pineal and/or suprasellar regions of the brain. In Western countries, GCTs represent less than 4% of primary brain tumors in children, while in series from Japan and Asia, CNS GCTs account for approximately 11% of pediatric CNS tumors.[1,2,3]
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. 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.[4,5] Recent investigations comparing the genomic alterations found in GCTs are very similar, whether they are tumors of CNS, gonadal, or extragonadal origin. These findings lend support that all GCTs have common pathogenetic mechanisms.[6]
The World Health Organization has classified CNS GCTs into the following major groups:[7]
- Choriocarcinoma.
- Embryonal carcinoma.
- Germinoma.
- Mixed germ cell tumors.
- Teratoma.
- Immature.
- Mature.
- Teratoma with malignant transformation.
- Yolk sac tumors.
Nongerminomatous germ cell tumors (NGGCTs), commonly referred to as secreting tumors, include embryonal carcinoma, yolk sac tumors, choriocarcinoma, and mixed GCTs. Alternative classification schemes have been proposed by others, including the Japanese Pediatric Brain Tumor Study Group for CNS GCTs, who base their stratification on the therapeutic grouping of the differing histologic variants as shown in Table 3.
The classification of a childhood brain tumor is based on both the histopathologic characteristics of the tumor and its location in the brain.[6] In addition to the microscopic appearance of the various CNS GCTs, tumor markers (proteins secreted by the tumor cells) found in the serum and cerebrospinal fluid (CSF) aid in diagnosis (see Tables 1 and 2).[1,8,9]
Table 1. Immunohistochemical Markers
| Tumor Type | Beta-HCG | AFP | PLAP | c-kit |
| AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; PLAP = placental alkaline phosphatase. | ||||
| Choriocarcinoma | + | - | ± | - |
| Embryonal carcinoma | - | - | + | - |
| Germinoma (syncytiotrophoblastic) | + | - | ± | + |
| Immature teratoma | ± | ± | - | ± |
| Mature teratoma | - | - | - | - |
| Mixed germ cell tumor | ± | ± | ± | ± |
| Pure germinoma | - | - | ± | + |
| Yolk sac tumor | - | + | ± | - |
Table 2. Serum and Cerebrospinal Fluid Markers
| Tumor Type | Beta-HCG | AFP |
| AFP = alpha-fetoprotein; HCG = human chorionic gonadotropin; + = positive; - = negative; ± = equivocal; +++ = strongly positive; (±) equivocal, not diagnostic; (+) = positive, not diagnostic. | ||
| Choriocarcinoma | +++ | - |
| Embryonal carcinoma | - | - |
| Germinoma | (±) | - |
| Teratoma | - | (+) |
| Yolk sac tumor | - | +++ |
For some CNS GCTs, elevations of tumor markers along with the imaging findings are diagnostic of a CNS GCT and may obviate the need for initial biopsy or resection of the tumor mass. The tumor markers alpha-fetoprotein (AFP) and beta subunit human chorionic gonadotropin (beta-HCG) are the most commonly followed, although other markers such as placental alkaline phosphatase (PLAP) and c-kit are being investigated. The laboratory tests used to detect tumor markers have become more reliable during the last decade, but the interpretation of specific results varies within study groups. Some European and Asian groups consider tumors with serum and/or CSF AFP ≥50 ng/ml and/or beta-HCG ≥100 IU/L to be secreting GCTs, whereas others in the United States and Europe consider tumors as secreting if serum and/or CSF AFP ≥10 ng/dl and/or serum and/or CSF beta-HCG ≥50 IU/L. Pure germinomas and teratomas usually present with negative markers, but very low levels of beta-HCG can be detected in germinomas (with syncytiotrophoblastic cells) and elevations of AFP can be seen in teratomas.[9] Both AFP and beta-HCG have predictable half-lives, making these markers useful in diagnosing some CNS GCTs, and in monitoring response and early detection of recurrence.
Alternative classification schemes for CNS GCTs have been proposed by others, including the Japanese Pediatric Brain Tumor Study Group, who base their stratification on the prognostic grouping of the differing histologic variants as shown in Table 3. Pure germinomas and mature teratomas fall into the good prognostic group; choriocarcinoma, yolk sac tumor, embryonal carcinoma, or mixtures of these three histologic subtypes fall into the poor prognostic group.[8]
Table 3. Japanese Pediatric Brain Tumor Study Group Classification
| Prognostic Group | Tumor Type |
| Good | Germinoma, pure |
| Mature teratoma | |
| Intermediate | Germinoma with syncytiotrophoblastic giant cells |
| Immature teratoma | |
| Mixed tumors mainly composed of germinoma or teratoma | |
| Teratoma with malignant transformation | |
| Poor | Choriocarcinoma |
| Embryonal carcinoma | |
| Mixed tumors composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma | |
| Yolk sac tumor |
References:
Stage Information for CNS Germ Cell Tumors
There is no universally accepted staging system for germ cell tumors (GCTs), but a modified Chang Staging System has been traditionally used. In addition to whole-brain magnetic resonance imaging (MRI), MRI of the spine is required. When medically permissible, lumbar cerebrospinal fluid (CSF) should be obtained for the measurement of tumor markers (alpha-fetoprotein [AFP] and beta subunit human chorionic gonadotropin [beta-HCG]) and for cytopathologic review. Serum tumor markers are often obtained for AFP and beta-HCG; however, they do not serve as a substitute for CSF tumor markers.[1] Patients with localized disease and negative CSF cytology are considered to be M0 (no metastasis); patients with positive CSF cytology or patients with drop metastasis in the spine or cranial subarachnoid space are considered to be M+ (metastatic-positive). Appropriate staging is crucial since patients with metastatic disease should receive different total radiation doses and more extended radiation fields.
GCTs can disseminate throughout the neuraxis at diagnosis or at any disease stage. Rarely, extracranial spread to lung and bone has also been reported.[2,3]
References:
Treatment Option Overview
Teratomas, germinomas, and nongerminomatous germ cell tumors (NGGCTs) have differing prognoses and may require different treatment regimens. For older children (aged >3 years) and adults, radiation therapy has been an important component of therapy for germinomas and NGGCTs, although the total dose and fields are debated. The addition of chemotherapy has shown central nervous system GCTs to be chemotherapy sensitive. Regimens that utilize both chemotherapy and radiation therapy have been investigated for germinomas and NGGCTs. These combined regimens have been adopted to increase survival (NGGCTs) or to allow for reduction in the field or dose of radiation therapy (germinomas and NGGCTs).[1,2,3,4]
References:
Treatment of Newly Diagnosed Germinomas
Treatment Options
Germinomas are highly radiosensitive and have been traditionally treated with radiation therapy alone; historically, craniospinal irradiation (CSI) with a boost to the region of the primary tumor has been utilized. This has resulted in 5-year overall survival rates greater than 90%.[1]; [2][Level of evidence: 2A]; [3,4][Level of evidence: 3iA] These excellent survival rates have allowed investigators to focus on reducing radiation treatment volume and intensity in an attempt to decrease late effects.[2,5] Patterns of relapse following CSI versus reduced-volume radiation therapy (whole brain or whole ventricular radiation therapy) have strongly suggested that CSI is not necessary for localized germinomas.[6,7] Based on these results, the treatment for patients with localized germinomas has been modified to cover the whole ventricular system followed by a boost to the primary site, rather than to deliver radiation therapy to the entire craniospinal axis or even to the whole brain. This change has not resulted in worse outcomes and is expected to minimize the acute and long-term toxicity of radiation therapy.
Chemotherapy has been explored in an effort to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach maintaining excellent survival rates, but the number of treated patients is still small.[8,9,10]; [11][Level of evidence: 2A]; [12][Level of evidence: 3iiiC] Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in central nervous system (CNS) germinomas. Management of patients receiving chemotherapeutics that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) are often quite challenging to manage because of the high prevalence of diabetes insipidus in this population.[13] An international group of investigators have explored a chemotherapy-only approach primarily for younger children. They were able to achieve a complete response in 84% of patients with germinomas treated with chemotherapy alone. Fifty percent of these patients relapsed or progressed; many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS requiring further therapy including radiation.[14] Subsequent studies have continued to support the need for irradiation following chemotherapy and the likely requirement for whole ventricular irradiation when chemoradiotherapy is used in order to avoid ventricular recurrence.[15][Level of evidence: 2A]; [16][Level of evidence: 3iiiA]
The appropriate dose and field of radiation therapy given following chemotherapy has not been established. The treatment options for localized pure germinoma include whole ventricular radiation therapy with 24 Gy followed by a boost to the primary tumor for a total dose of 45 Gy to 50 Gy. Chemotherapy followed by reduced-dose radiation therapy could also be considered. However, the extent of dose reduction of radiation therapy has not been established, and whether the whole ventricular irradiation dose (following chemotherapy) can be further reduced to primary tumor bed alone has not been established.
The following two standards of care exist for the treatment of newly diagnosed germinomas:
| 1. | Radiation therapy alone. |
|---|---|
| 2. | Neoadjuvant chemotherapy followed by response-based reductions in radiation therapy. |
References:
Treatment of Newly Diagnosed Teratomas
Teratomas are designated as mature or immature based on 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) for mature versus immature into the good- and intermediate-risk groups, respectively (see Table 3), while the Children's Oncology Group includes immature teratomas with other NGGCTs.
The treatment for teratomas should include maximal surgical resection. Adjuvant treatment in the form of focal radiation therapy and/or adjuvant chemotherapy for subtotally resected tumors is controversial, with small institutional series suggesting potential utility for the use of radiosurgery (stereotactic radiosurgery).[1,2][Level of evidence: 3iA]
References:
Treatment of Newly Diagnosed Nongerminomatous Germ Cell Tumors
Treatment Options
The prognosis for children with nongerminomatous germ cell tumors (NGGCTs) remains inferior in comparison to germinomas. While difficult to state definitively due to the small number of patients, it appears that patients with NGGCTs and higher elevations in tumor markers, particularly alpha-fetoprotein (AFP), have a worse prognosis.[1,2] With the current treatment regimens, the 10-year overall survival (OS) for NGGCTs is between 70% and 80%.[3,4] NGGCTs are radiosensitive; however, survival following standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years. The majority of NGGCTs relapse within 18 months. OS rates can be stratified by histologic subtypes. Patients with pure choriocarcinoma, yolk sac tumor, or embryonal carcinoma appear to have the worst outcomes compared with patients with pure germinoma or teratoma mixed with other NGGCT elements. The addition of chemotherapy has been shown to improve OS rates. Effective agents include carboplatin, etoposide, bleomycin, ifosfamide, and vinblastine.[3,4] As with patients with germinoma, the administration of chemotherapy requiring hyperhydration can be complex when the patient has a comorbidity of diabetes insipidus.[5]
The optimal treatment regimen for NGGCTs remains unclear. The addition of chemotherapy to radiation therapy has increased survival, but the specific chemotherapy regimen and length of therapy and the optimal radiation field, timing, and dose remain under investigation.[3,6,7] Some investigators have proposed radiation therapy fields that are smaller than craniospinal irradiation (e.g., focal or focal whole ventricular) for nondisseminated NGGCT patients. Results of these trials appear promising, although controversy exists over the pattern of relapse for patients treated with chemotherapy and focal radiation.[3,4,8]
Commonly, patients treated with chemotherapy may have normalization of tumor markers with a less than complete radiographic response. A second-look surgery can help determine if the residual mass contains teratoma or fibrosis versus residual NGGCT.[4] Occasionally, the mass continues to expand in size even though tumor markers may have normalized; this may be due to the growing teratoma syndrome and not a failure to treat the NGGCT component.[9,10] In such circumstances, surgery is usually required for debulking and histologic confirmation.
High-dose chemotherapy with autologous stem cell rescue has shown promise as consolidation therapy for some high-risk germ cell tumors.[11]
References:
Treatment of Recurrent Childhood CNS Germ Cell Tumors
The most common type of relapse is local recurrence at the primary tumor site, but 30% of relapses are outside the primary site and/or combined with leptomeningeal spread. The outcome for patients with relapse, especially those with nongerminomatous germ cell tumors (NGGCTs), remains poor.
Salvage therapies have included surgery, focal or craniospinal radiation, chemotherapy with re-irradiation, and myeloablative chemotherapy with autologous stem cell rescue (ASCR). Patients with germinoma that have been treated initially with chemotherapy only benefit from chemotherapy followed by radiation therapy.[1,2] Re-irradiation following chemotherapy at recurrence has been utilized.[2] For pure germinoma patients who previously received radiation therapy, myeloablative chemotherapy with stem cell rescue has been used.[3,4] High-dose chemotherapy and ASCR may also have curative potential for some relapsed systemic NGGCTs.[3,4,5,6]
Enrollment on clinical trials should be considered for all patients with recurrent disease. Information about ongoing clinical trials is available from the NCI Web site.
References:
Long-Term Effects of Childhood CNS Germ Cell Tumors
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 will need continued replacement therapy.[1,2,3]
Although significant improvements in the overall survival of CNS GCTs have occurred, patients still face significant late effects secondary to the location of their primary tumor and its treatment. Each chemotherapeutic agent has its own characteristic long-term side effects. Radiation therapy to the areas commonly affected by GCTs is known to cause visual field impairments, extraocular movement disturbances, endocrine disorders, decline in patients' performance status, and learning disabilities.[4,5] Second tumors have been identified in this population, some of which are felt to be related to prior irradiation.[6] Current clinical trials and therapeutic approaches are directed at minimizing the long-term sequelae of the treatment of CNS GCTs.
References:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood central nervous system germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Changes to This Summary (05 / 17 / 2012)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Childhood Central Nervous System (CNS) Germ Cell Tumors
Added text to state that if pre-operative lumbar cerebral spinal fluid (CSF) can be obtained safely and tumor markers are elevated, this may obviate the need for upfront surgery. In cases where the patient presents with hydrocephalus requiring CSF diversion, CSF tumor markers can be obtained by ventricular CSF sampling at the time of surgery.
Cellular Classification of Childhood CNS Germ Cell Tumors
Added text to explain the symbols used in Table 2.
Stage Information for CNS Germ Cell Tumors
Added Fujimaki et al. as reference 1.
Treatment of Newly Diagnosed Germinomas
Revised text to state that chemotherapy has been explored in an effort to reduce radiation therapy doses and associated neurodevelopmental morbidity (cited O'Neil et al. as reference 12 and level of evidence 3iiiC).
About This PDQ Summary
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 who care for cancer 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:
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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.
The lead reviewers for Childhood Central Nervous System Germ Cell Tumors Treatment are:
- Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
- Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Roger J. Packer, MD (Children's National Medical Center)
- Malcolm Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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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National Cancer Institute: PDQ® Childhood Central Nervous System Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/childCNS-germ-cell/healthprofessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-05-17
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