Primary intracranial germ cell neoplasms are rare in the United States and Europe, accounting for only 0.3 to 0.5% of all primary intracranial tumors. In contrast, they comprise at least 2% of primary intracranial tumors in Asian countries, up to 15% in some case series from Taiwan and Japan. 90% of intracranial germ cell tumors occur in patients younger than 20 years, with the peak incidence in patients between the ages of 10 and 12 years. Males are more commonly affected (M:F 2-2.5:1) when the CNS is considered as a whole, but pineal lesions are more common in males and suprasellar lesions occur more frequently in females.
More than 80% of intracranial germ cell tumors occur in midline structures; the pineal gland is the most common location, followed by the suprasellar region. These lesions are contrast-enhancing and usually appear hypointense or isointense on T1-weighted MRI images and hyperintense on T2-weighted images.
The clinical presentation is dependent upon the location of the lesion. Patients with tumors of the suprasellar region often present with diabetes insipidus, hypopituitarism, and visual field deficits. The sudden onset of diabetes insipidus in a young patient strongly suggests the presence of a suprasellar germ cell tumor; other suprasellar neoplasms, such as craniopharyngioma and juvenile pilocytic astrocytoma, tend to cause endocrine abnormalities only after surgical resection or in advanced untreated disease. In the pineal region, tumors may cause increased intracranial pressure by obstructing the cerebral aqueduct, producing headache, nausea, vomiting, and lethargy. Pineal tumors may compress and/or invade the tectal plate of the midbrain, resulting in paralysis of upward conjugate gaze (Parinaud's syndrome).
Germinoma, or intracranial seminoma, comprises approximately 60% of intracranial germ cell tumors and is the most common histologic type in the suprasellar region. In about half of cases, germinomas involve the suprasellar region and the pineal gland simultaneously. Germinomas are often difficult to resect because of high collagen content. Microscopically, they consist of nests, lobules, and/or sheets of large round tumor cells with well-defined borders, clear to pale cytoplasm with artifactual vacuolization, and round nuclei with open chromatin and prominent round or bar-shaped nucleoli. The neoplastic cells typically show surface staining for placental alkaline phosphatase (PLAP) and are positive for c-kit in over 90% of germinomas. A dense lymphocytic infiltrate and abundant macrophages are often present. The inflammatory response may be problematic in reaching a histologic diagnosis, especially in small biopsies, as macrophages can be difficult to distinguish from a non-seminomatous component. Prominent granulomatous inflammation may also mislead the pathologist into diagnosing sarcoidosis or infection, especially if a limited amount of tissue is provided for sampling.
Quantitative CSF beta-hCG and alpha-fetoprotein levels are commonly obtained in the work-up of intracranial germ cell tumors. Germinomas often contain isolated syncytiotrophoblastic-type cells that secrete low levels of beta-hCG (<100 mIU/mL) into CSF. Some literature indicates that the presence of these cells may be associated with a higher rate of recurrence, but these tumors do not behave as aggressively as choriocarcinomas. Alpha-fetoprotein may be positive in the CSF or serum in the presence of either endodermal sinus tumor (yolk sac tumor) or immature teratomatous components. In comparison to testicular and ovarian germ cell tumors, intracranial germ cell tumors with mixed morphology are infrequent. Germinomas with rare syncytiotrophoblastic-type cells are not considered mixed germ cell tumors.
The clinical management of intracranial germ cell tumors is complicated by risk of injury to the patient in resecting or performing biopsies of lesions near the third ventricle. The differential diagnosis of pineal lesions also includes parenchymal tumors such as pineocytoma and pineoblastoma; positive CSF beta-hCG and/or alpha-fetoprotein levels exclude pineal parenchymal tumors and suggest the presence of a germ cell neoplasm. If one or both of these markers are positive, the patient is often treated empirically for the histologic subtype suggested by the tumor marker pattern, without a tissue diagnosis. Stereotactic biopsy is recommended if CSF beta-hCG and AFP are normal, if beta-HCG is <50 mIU/mL, or if another invasive procedure such as ventricular shunt placement is necessary. As stated above, the amount of tissue obtained in a biopsy is often quite limited, and identification of other germ cell morphologic elements can be very challenging, especially if the biopsy is crushed or contains a large number of macrophages or granulomas.
The treatment of intracranial germ cell tumors depends on the certainty of the diagnosis, the histologic subtype, and location of the lesion. Surgical excision is recommended if the biopsy is nondiagnostic or suggestive of mature teratoma. Germinomas have a high cure rate with external beam radiation therapy alone, but adjunctive chemotherapy is often used to reduce the adverse cognitive and neuroendocrine effects produced by high-dose radiation. The role of protein tyrosine kinase inhibitors in the treatment of germinoma is currently under investigation. Non-seminomatous germ cell tumors are less radiosensitive and therefore more difficult to treat; high-dose chemotherapy and surgical resection are used more frequently in the management of these tumors.
Contributed by Manuel Zarandona, MD and Geoffrey Murdoch, MD