Paulino et al provide an excellent summary of the literature on primary germinoma of the central nervous system (CNS). As the authors note, germ-cell tumors of the CNS are rare, comprising about 1% of all brain tumors in patients in the Western hemisphere. These tumors develop in the midline of the brain, primarily in the suprasellar-hypothalamic and pineal regions, and occur predominantly in males and the majority of these tumors are germinomas.
This commentary will highlight and review two important issues related to the management of these tumors: (1) the importance of a histologic diagnosis, and (2) the roles of radiation and chemotherapy in treatment.
Histologic Confirmation of the Diagnosis
The diagnosis of germinoma must be established histologically. Historically, diagnosis was based on radiologic evaluation and assessment of serum and/or cerebrospinal fluid levels of beta-human chorionic gonadotropin and alpha-fetoprotein. If these findings supported a diagnosis of germinoma, an empiric course of radiation therapy was given, followed by observation. Further evaluation, such as biopsy, was pursued to definitively establish the diagnosis only if the tumor recurred or progressed.
This approach was used in the past primarily because of the relative risk of morbidity and mortality associated with the performance of neurosurgery in the suprasellar and pineal regions. However, outcome in any patient with a malignant tumor correlates with diagnosis-based risk factors and optimal treatment approaches. Our current understanding of CNS germinoma may be limited because most of the information on risk factors and outcome is based on historical data from retrospective single- or limited-institution studies that included data on patients without a histologically confirmed diagnosis.
A specific diagnosis of CNS germinoma cannot be established based solely on clinical signs and symptoms, serologic/cerebrospinal fluid markers, and radiologic evidence of an intracranial tumor. The differential diagnosis of a lesion in these areas of the brain includes low-grade lesions that are curable with gross total resection, such as juvenile pilocytic astrocytoma and low-grade astrocytoma, as well as malignant lesions that require intensive treatment regimens incorporating both radiation therapy and chemotherapy, such as nongerminomatous germ-cell tumors, primitive neuroectodermal tumors (PNETs), and, rarely, malignant gliomas.
Technological advances in the development of image-guidance systems for stereotactic neurosurgical procedures and the development of intraoperative monitoring devices have improved the safety of neurosurgery in the suprasellar-hypothalamic and pineal regions. However, since neurosurgical outcome is still operator-dependent, the neurosurgeon must be experienced in the application of this technology and in the surgical oncologic approach to these anatomic sites.
Open biopsy or resection is favored over stereotactic biopsy of these lesions because of their anatomic location and because microscopic morphology may be heterogeneous. In addition, tumor specimen in excess of that needed for diagnosis may be banked for laboratory studies.
Controversy continues regarding the appropriate therapy for patients with CNS germinoma. Therapeutic decisions must be based on the histologic diagnosis and a complete diagnostic evaluation that includes magnetic resonance imaging of the brain and spine, cerebrospinal fluid cytology, and quantitation of both alpha-fetoprotein and beta-human chorionic gonadotropin in cerebrospinal fluid and/or serum. With regard to radiation therapy in patients with localized disease, data from contemporary reports support limiting treatment to whole-brain irradiation with a local field boost when this modality is used alone.
As noted by Paulino et al, the risk of spinal cord metastasis is less than 9% among patients reported in these studies. Some clinicians may have concerns about this failure rate, but they must balance those concerns against the risk of delayed adverse effects of spinal cord irradiation. In addition, significant late sequelae have been associated with cranial irradiation. Several groups have shown that outcome in patients with localized disease after chemotherapy and reduced-dose radiation therapy is similar to outcomes reported from trials of radiation alone.[4,5] However, patients with disseminated disease definitely require more aggressive therapy.
In the First International Central Nervous System Germ Cell Tumor Study, 28 of 71 patients (45 with germinoma and 26 with nongerminomatous germ-cell tumors) remained in continuous complete remission after chemotherapy (carboplatin [Para-platin]-based) alone. Therefore, these 28 patients were not at risk for radiation-associated late effects. However, significant treatment-related toxicities were noted in the whole group of 78 patients; these included hematologic toxicities (86% incidence of thrombocytopenia, platelet count < 50,000/µL) and toxic deaths (7/71 patients).
Additional, prospective, multi-institution trials are necessary to further evaluate this approach to the treatment of germinoma, as well as other germ-cell tumors. Such trials must include long-term follow-up to identify adverse late effects and to determine the risk of those effects. The investigators who design these trials will need to decide whether to initially evaluate the combination of modalities (ie, chemotherapy plus reduced-dose radiation therapy) or chemotherapy alone, as described by Balmaceda et al.
In summary, germinoma is a very chemosensitive and radiation-sensitive tumor compared with other primary CNS tumors. The major therapeutic advance is the evolution of multimodality treatment approaches incorporating chemotherapy with reduced-dose radiation therapy. Preliminary data suggest that chemotherapy alone may be an effective treatment, but this observation must be confirmed.
Non-Germinomatous Germ-Cell Tumors
Although the specific topic of the review article by Paulino et al was germinoma, some discussion of nongerminomatous germ-cell tumors should have been included. Unlike germinomas, the nongerminomatous germ-cell tumors are relatively chemoresistant and radiation-resistant. Matsutani et al established a risk-based classification system for all CNS germ-cell tumors. Using this system, clear differences in outcome are predictable among the nongerminomatous germ-cell tumors, based on primary histology of the tumor. Hopefully, this classification system will be incorporated into and validated in future prospective treatment trials of this rare, heterogeneous group of tumors.