Classification and Epidemiology

Germ cell tumors can be categorized according to histology, location, and the presence or absence of dissemination. The World Health Organization histologic classification recognizes six subtypes (Table 204-1), although from a therapeutic standpoint these lesions are generally categorized as germinomas, nongerminomatous germ cell tumors (NGGCTs), and teratomas. The NGGCT group includes embryonal carcinoma, endodermal sinus (yolk sac) tumor, choriocarcinoma, and mixed tumors, which often also contain both germinomatous and teratomatous elements. Pure germinomas account for more than 50% of all germ cell tumors, mixed tumors and teratomas each account for 10% to 20%, and the remaining NGGCT subgroups each account for 5% to 10% of tumors.^2–7 It has been suggested by Teilum that the individual histologic subsets reflect the transformation of different embryonic (e.g., germinoma, teratoma) and extraembryonic (e.g., NGGCT) cell rests.⁸ From this perspective, germinoma would theoretically reflect the most undifferentiated of the germ cell tumors, although contrary to the situation with other tumor types, they are the most treatment-responsive germ cell neoplasms. Because many tumors contain both germinomatous and nongerminomatous elements, the latter of which can adversely affect outcome, adequate tissue sampling and histologic assessment or evaluation of tumor markers or both, are essential in guiding therapy.

TABLE 204-1 World Health Organization Classification of Germ Cell Tumors

Germ cell tumors are also commonly categorized according to their site of origin, with the vast majority of lesions originating in the pineal or suprasellar regions (Fig. 204-1A and B).^1,4,9 The former outnumber the latter by a ratio of 2 : 1,^1,2 although this distribution is influenced by patient age and sex. Suprasellar tumors are more common in females than males, whereas pineal region tumors are overwhelmingly more common in males.^1,7 Although germ cell tumors as a group are most frequently detected around the time of puberty or shortly thereafter,² suprasellar lesions often occur earlier in childhood and more commonly contain nongerminomatous elements.³ In up to 10% of patients, tumor is simultaneously detected in both the pineal and suprasellar regions (Fig. 204-1C).^1,2 It is unclear whether this represents bifocal tumor onset or metastatic spread from a single site. However, the frequent endoscopic detection of metastatic deposits within the third ventricular floor in patients with pineal region germinomas suggests that the latter explanation is more likely.¹⁰ In addition to the pineal and suprasellar regions, germ cell tumors have also been reported to arise in a number of atypical intracranial locations, including the basal ganglia and posterior fossa.^1,9

FIGURE 204-1 A, Sagittal magnetic resonance image of a suprasellar germinoma showing a thickened infundibulum. B, Sagittal image of a pineal region germinoma. C, Axial computed tomographic scan of a tumor with combined suprasellar and pineal region involvement and extensive ventricular metastases.

Clinical Findings

The clinical signs and symptoms leading to the diagnosis of a germ cell tumor are largely determined by the location of the lesion, but they are also influenced by tumor histology and patient age. Germ cell tumors arising in the pineal region typically cause symptoms associated with increased intracranial pressure resulting from obstructive hydrocephalus, such as headache, nausea, and vomiting. Patients may exhibit a Parinaud syndrome, with impairment of both upgaze and pupillary constriction to light, as well as retraction nystagmus on attempted convergence. Papilledema and ataxia are also commonly seen on examination.

Suprasellar lesions typically cause symptoms of hypothalamic-pituitary axis dysfunction,^1,2,6,9 particularly diabetes insipidus, which is almost universally seen. Disturbances in visual acuity and visual fields are likewise common.^1,11 Diabetes insipidus is also observed in a small percentage of patients who seem to have purely pineal lesions, possibly reflecting microscopic spread of tumor to the anterior third ventricular floor.^1,2,10 Similarly, precocious puberty may be observed in patients with pineal as well as suprasellar lesions as a result of secretion of β-human chorionic gonadotropin (β-hCG) by the tumor.

Because NGGCTs tend to be biologically more aggressive than germinomas, these lesions typically have a shorter natural history. In some patients with germinomas, the duration of symptoms before detection can be extremely protracted, with isolated diabetes insipidus occasionally being present for years before diagnosis.^1,2,11,12 Germinomas arising in the basal ganglia or thalamus have also been reported to be accompanied by an extended interval of seizures, hemiparesis, and dementia before diagnosis.¹³ Among the NGGCTs, choriocarcinomas have a particular propensity to enlarge rapidly and undergo hemorrhage, thereby leading to a precipitous onset of symptoms and clinical deterioration.^1,3

Germ cell tumors that arise in infancy and early childhood pose particular diagnostic challenges. Frequently, the sole initial sign is increased intracranial pressure manifested as macrocephaly, split sutures, and a bulging fontanelle.^1,2,6 In some cases, the mode of manifestation can be even more nonspecific and consist of failure to thrive and loss of developmental milestones. Accordingly, such tumors are often extremely large at the time of diagnosis.¹⁴

Diagnostic Evaluation

Apart from teratomas, which can have a mixture of cystic and solid elements, frequently with fat and bone visible on imaging,¹⁵ most germ cell tumors can resemble other pineal region and suprasellar tumors radiologically. In the past, patients with lesions of the pineal and suprasellar regions that were thought to possibly be germ cell tumors were often given a “test dose” of irradiation, and if a complete response was achieved, the tumors were presumed to have been germinomas and treated empirically with additional radiotherapy, with biopsy reserved for nonresponding lesions.¹⁶ Because lesions other than germinomas may respond rapidly to irradiation but ultimately require different management approaches, this strategy has fallen out of favor. Accordingly, appropriate diagnostic evaluation incorporates a combination of blood and cerebrospinal fluid (CSF) marker analysis for α-fetoprotein (AFP) and β-hCG, and in patients lacking significant elevation of these markers, histologic examination of a biopsy sample is warranted.^1,3,6,9

AFP is a marker for tumors with yolk sac components (endodermal sinus tumor, teratoma with endodermal sinus elements, and occasionally embryonal carcinoma), whereas β-hCG is commonly expressed by choriocarcinomas, malignant teratomas, and embryonal carcinomas containing trophoblastic tissue (Table 204-2). Expression of high levels of either AFP or β-hCG is diagnostic of an NGGCT, and histologic confirmation is not required. Low-level expression of β-hCG (<50 to 100 mIU/mL) is often observed in germinomas with syncytiotrophoblastic cells, and in this setting, some investigators will treat patients empirically as though they have a germinoma,¹⁷ although this approach remains controversial. In situations in which neither AFP nor β-hCG is elevated, biopsy is required to establish the diagnosis. Although germinomas can express placental alkaline phosphatase histologically, this marker has not proved widely useful for noninvasively establishing the diagnosis of germinoma by blood or CSF marker analysis.^2,6,18 Similarly, soluble c-kit has been suggested as a CSF marker of germinomas,¹⁹ although the sensitivity and specificity of this marker have not been independently confirmed in the clinical diagnostic setting.

TABLE 204-2 Patterns of Tumor Marker Production

AFP, α-fetoprotein; β-hCG, β-human chorionic gonadotropin.

* Small amounts of AFP may be secreted by intestinal glandular components.

† Levels less than 50 to 100 mIU/ml may be secreted by syncytiotrophoblastic components.

Because germ cell tumors can disseminate within the neuraxis, staging by CSF cytology and magnetic resonance imaging (MRI) of the spine also constitutes an important component of the diagnostic evaluation. The reported frequency of dissemination varies widely between studies. Even excluding patients with bifocal pineal and suprasellar lesions, at least 10% of patients have evidence of leptomeningeal or intraventricular tumor spread based on imaging, positive CSF cytology, or a combination of both.^7,20

Surgical Management

The role of surgery in the management of germ cell tumors is principally determined by the underlying histologic diagnosis and location of the tumor. Tumors of the pineal region typically manifest with obstructive hydrocephalus, which often requires timely intervention for diversion of CSF. Historically, diversion was commonly accomplished by insertion of a ventriculoperitoneal shunt, which allowed prompt relief of the elevated pressure, as well as sampling of CSF for marker analysis. However, because obstruction of CSF pathways often resolves rapidly with treatment, particularly in patients with germinomas, and shunting places the patient at risk for shunt-related metastases,^4,6,21 this approach has become less common as a primary management strategy.

Endoscopic third ventriculostomy has emerged as a more popular alternative for CSF diversion in recent years because it allows biopsy in many cases, permits sampling of CSF for markers and cytologic examination, and achieves internal CSF diversion. This strategy for CSF management is not applicable in patients with significant involvement of the third ventricular floor by tumor, a situation that applies in most suprasellar germ cell tumors, and in such cases, shunt insertion remains a valuable option. A third approach to CSF diversion is temporary external ventricular drainage, which may be useful for patients with germinoma, in whom the tumor can regress significantly within days of beginning irradiation or chemotherapy (Fig. 204-2), and for situations in which open surgical resection is being considered as an initial component of management.

FIGURE 204-2 Coronal enhanced magnetic resonance images of a germinoma at diagnosis (left) and 1 week after beginning therapy (right).

A second neurosurgical issue in initial management involves establishing a tissue diagnosis. For tumors that exhibit significantly elevated levels of AFP or β-hCG, the diagnosis of NGGCT is already established, thus obviating the need for tissue sampling. However, for pineal and suprasellar tumors of uncertain etiology that are presumed to be germ cell tumors, biopsy is warranted to confirm the diagnosis and define the histology. Acquisition of tissue can often be accomplished with stereotactic or endoscopic techniques, although in view of the risk for hemorrhage associated with these approaches, some neurosurgeons prefer to perform an open biopsy.¹⁵

A third aspect of neurosurgical management relates to the issue of cytoreduction, which has therapeutic benefit in selected situations. One such scenario involves patients in whom the tumor is thought to be a benign teratoma at diagnosis, because these lesions respond poorly to either chemotherapy or irradiation and require removal as definitive therapy. This approach would apply to the small subset of tumors that have imaging characteristics consistent with a teratoma but lack significant elevations of AFP or β-hCG, hence suggesting that there are no malignant elements or evidence of metastatic spread.

Because germinomas are extremely responsive to radiotherapy and chemotherapy, there is usually no indication for surgical debulking.²² The situation is more complex for NGGCTs, which may contain treatment-resistant teratoma admixed with germinomatous and nongerminomatous elements (Fig. 204-3). Most recent cooperative group protocols have favored proceeding with initial adjuvant therapy in an effort to eradicate the malignant components of the tumor, with the understanding that in many cases a teratomatous remnant will remain and eventually require additional intervention. Thus, a second scenario in which resection may be appropriate relates to so-called second-look surgery for biopsy and resection of this residual tissue.^{1,2,9,23–28} Despite the lack of definitive evidence that this delayed approach improves survival, there is strong anecdotal evidence that it spares many children with treatment-responsive NGGCTs the risks associated with surgical intervention and, by eliminating the very aggressive components of the tumor and decreasing tumor size, may reduce the risk related to resection in patients with teratomatous elements who ultimately require surgical intervention.^25–30 Management of patients with NGGCTs who continue to have elevated markers after initial adjuvant therapy remains controversial because this implies the existence of residual malignant elements, and in such cases, the benefit of second-look surgery remains uncertain.²⁶

FIGURE 204-3 Nongerminomatous germ cell tumor admixed with teratomatous components. A, Initial tumor appearance. After biopsy diagnosis, the patient was treated with chemotherapy followed by second-look resection. Craniospinal irradiation was then administered. B, A small focus of residual tumor was treated with a stereotactic radiosurgical boost and has remained stable at 6 years of follow-up.

For patients who are appropriate candidates for tumor resection, options for the surgical approach and technical caveats are in large part influenced by the location and extent of the tumor. For lesions in the pineal region, supracerebellar infratentorial, suboccipital transtentorial, and interhemispheric transventricular approaches may each be appropriate, depending on whether the tumor predominantly extends above or below the vein of Galen and the degree to which the lesion fills the posterior third ventricle.^15,31 Similarly, a variety of options are available for suprasellar lesions, including the pterional, subfrontal, anterior interhemispheric, and transventricular routes, as determined by the growth pattern of the tumor.³²

Adjuvant Therapy and Prognostic Considerations

The strongest determinant of prognosis for patients with central nervous system (CNS) germ cell tumors is the histologic subtype of the tumor. Germinomas are extremely responsive to both radiation therapy and chemotherapy, with long-term survival rates in the range of 90% as long as radiation is included in the treatment.^1,6,33 Although the presence of disseminated disease and elevated levels of β-hCG (a marker of syncytiotrophoblastic elements) have been found to be adverse prognostic features in some studies,^33–35 other reports have noted that these factors do not preclude excellent survival rates in the setting of pure germinoma, provided that therapy is appropriately tailored.^17,36 In contrast, outcome results for patients with nongerminomatous tumors have been much less favorable, with 5-year survival rates in the range of 40% to 70%, even with intensive multimodality therapy.^1,2,6,9,33 Accordingly, the treatment strategies that have been used in recent years for these two subgroups of tumors have focused on reducing the morbidity of treatment and long-term sequelae in children with germinomas while maintaining excellent survival rates, and enhancing long-term disease control in children with NGGCTs.