Intracranial GCT may present in an insidious manner, and many patients show a long symptomatic period before definite diagnosis [23, 24]. Symptoms in patients with intracranial GCT include headache, nausea and vomiting, polyuria and/or polydipsia, visual disturbances, fatigue, weight loss or poor growth, and precocious puberty. The initial clinical presentation varies according to patient’s age, tumor location, and size. Pineal GCT usually manifest with signs of increased intracranial pressure/CSF obstruction (headache, nausea, vomiting, and papilledema) and often require shunting. Somnolence is seen in up to half of patients and ataxia, seizures, and behavioral changes in a subset. Endocrinopathies and disturbances in sexual development such as precocious puberty in patients with isolated pineal region tumors are less common [17, 18]. The cause of precocious puberty in pineal GCT is only partially understood. Interestingly, choriocarcinomas are more likely to present with precocious puberty than any other type of GCT [10, 24].

Conversely, suprasellar tumors usually present with an endocrinopathy, such as central diabetes insipidus, hypopituitarism, hypothyroidism, adrenal insufficiency, precocious puberty, delayed sexual development, or retarded growth. Patients rarely present with signs of increased intracranial pressure. Ophthalmic symptoms are quite common in all patients. Pineal region tumors usually cause photosensitivity or diplopia, with up to a third of patients having a component of Parinaud syndrome (impaired upward gaze, convergence nystagmus, and impaired papillary response). A subset of patients with suprasellar tumors develop visual changes due to tumor entrapment of the optic nerve or chiasm [1, 17]. In patients with GCT of the basal ganglia, progressive hemiparesis is also a common complaint [23, 24]. A sudden onset of intracranial bleeding is often an initial, dramatic presentation of choriocarcinoma.

Germinomas usually appear as masses with relatively uniform density (or signal intensity) except for variable intratumoral cysts. They show increase density on computed tomography (CT) scans, with a somewhat blurred border. Pineal calcification, uncommon in children less than 10 years of age, is a useful clue to the diagnosis of a GCT [10]. On MRI, germinoma appears as a well-defined mass with slightly low signal intensity on T1-weighted images and high intensity on T2-weighted images. Pineal teratomas appear as heterogeneous well-demarcated masses with occasional calcifications, irregular cysts, or fatty tissue and thus are identifiable on both CT and MRI. Differentiation from pineal parenchymal tumors is not always easy [1]. Pituitary GCT may affect the neurohypophysis exclusively or extend into the intrasellar region. Signal characteristics are quite similar to those of pineal tumors. Loss of the posterior pituitary “bright spot” is useful in the assessment and monitoring of suprasellar germinoma.

For pineal lesions, the main differential diagnoses are pineal parenchymal tumors and low-grade gliomas. For sellar GCT, differential diagnoses are craniopharyngioma, Langerhans cell histiocytosis, hypophysitis, sarcoidosis, and low-grade gliomas [1, 2].

Currently, stereotactic or endoscopic biopsy is the gold standard for diagnosing CNS GCT. However, some NGGCT produce tumor markers that are helpful to identify the histological subtype, such as alpha-fetoprotein (AFP) and beta-subunit human chorionic gonadotropin (β-HCG). These secreted markers can be measured both in serum and CSF [1, 3, 5, 18]. Even when the role of ventricular CSF oncoprotein assays is evolving; lumbar CSF remains the most useful and reliable source of fluid for clinical guidance in the diagnosis, management, and tumor response of CNS GCT, since it is more sensitive than radiologic changes [30].

Any detectable elevation of AFP (serum >5–10 ng/dL; CSF >2–5 ng/dL) or marked CSF elevation of β-HCG (typically more than 100–200 IU) may be considered diagnostic of NGGCT without histologic confirmation [5]. Germinomas with syncytiotrophoblastic giant cells also produce hCG, but the CSF titer is lower than that of choriocarcinoma in most cases. Mixed GCT, according to the histological elements they contain, produce variable amounts of tumor markers [1, 5]. sKIT, a soluble form of the c-KIT has been proposed as a useful tumor marker for CNS germinomas, since the levels in this tumor are significantly higher, and its CSF concentration is particularly increased in patients with subarachnoid dissemination.

Pure germinomas account for most CNS GCT and are histologically identical to their gonadal counterparts of seminoma (testes) and dysgerminoma (ovaries). They are composed of large, undifferentiated cells arranged in monomorphous sheets, nests, or lobules outlined by thin fibrovascular septa. Germinoma cells have an abundant clear cytoplasm due to glycogen accumulation, as well as round, vesicular, and centrally positioned nuclei with prominent, squared, or rectangular-shaped nucleoli (Figs. 9.1 and 9.2). These cytological features are retained in lumbar or ventricular CSF samples. Mitoses are easily identified and may be conspicuous, but necrosis is infrequent. Strands of connective tissue variably infiltrated by non neoplastic lymphocytes are common. However, some germinomas show an extensive lymphoplasmacytic reaction or granulomatous response. A subset of germinomas may contain variable amounts of syncytiotrophoblastic giant cells which express β-HCG, human placental lactogen (hPL), and cytokeratins. Germinomas with syncytiotrophoblastic elements are not as aggressive as choriocarcinomas and therefore should not be confused (Fig. 9.3). Nonetheless, they seem to have a higher recurrence rate following radiation therapy than germinomas without these cells [5].

The most consistent immunohistochemical pattern in germinomas includes a strong nuclear labeling for SALL4 [31] and OCT4 [32], cell membrane staining for CD117 (KIT), and membrane/cytoplasmic positivity for PLAP (See Chap. 4). Some markers await validation, for example, HESRG [33].

NGGCT comprise a unique group of neoplasms displaying several forms of differentiation. They include pure or mixed populations of teratoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma [5, 34].

Embryonal carcinomas are composed of large, mitotically active cells that proliferate in cohesive nests and sheets, sometimes forming papillae or irregular gland-like spaces, and frequent areas of coagulative necrosis (Fig. 9.4). Tumor cells show enlarged, irregular nuclei with prominent nucleoli, as well as abundant, clear cytoplasm, the latter being strongly and diffusely positive for cytokeratins and for CD30. They also share immunoreactivity for PLAP and OCT4 with germinomas, but KIT is negative [18].

Yolk sac/endodermal sinus tumors are composed of primitive epithelial cells in a myxoid matrix resembling extraembryonic mesoblast. Epithelial elements may demonstrate several growth patterns but are more commonly arranged about an intervening meshwork of irregular tissue spaces (reticular pattern) (Fig. 9.5). Infrequently, cuboidal yolk sac tumor cells line delicate fibrovascular projections to form distinctive papillae known as Schiller-Duval bodies [18]. A diagnostic feature that is not always seen is the presence of brightly eosinophilic, PAS-positive/diastase-resistant hyaline globules within the cytoplasm of tumor cells or in the stroma. Mitotic activity varies considerably, but necrosis is uncommon. AFP, SALL4, and Glypican-3 immunoreactivity is characteristic. Conversely, yolk sac tumors are negative for KIT and OCT 4.

Teratomas differentiate along ectodermal, mesodermal, and/or endodermal lines, usually with tissues representing all three germ cell layers. They are classically divided into mature, immature, and teratoma with malignant transformation. Distinction may be therapeutically relevant [18].

Mature teratomas are exclusively composed of differentiated “adult-like” tissue elements representing ectoderm, mesoderm, and endoderm, with scant or absent mitotic activity. The most common ectodermal components identified include skin with appendages and brain, while mesodermal constituents include the cartilage, bone, fat, and muscle (Fig. 9.6). Cysts lined by respiratory or enteric epithelia are usually the endodermal elements, with some lesions also containing pancreatic or hepatic tissue [18]. Immature teratomas contain incompletely differentiated elements that resemble fetal tissue. Teratomas are classified as immature even if only a minority is composed of these less differentiated tissues, and mitotic activity is evident. Hypercellular and mitotically active stroma, reminiscent of embryonic mesenchyme, and primitive neuroectoderm mimicking neuroepithelial structures and developing neural tube are particularly common (Fig. 9.7). Clefts lined by melanotic neuroepithelium, representing abortive retinal differentiation, may also be encountered. The differential diagnosis of the latter involves the enigmatic pineal anlage tumor (Fig. 9.8). Teratoma with malignant transformation refers to teratomas containing a conventional somatic cancer. Rhabdomyosarcoma, undifferentiated sarcoma, squamous cell carcinoma, or adenocarcinoma are the most frequent (see also chapter 12).