CNS germinoma …

Neuro-Oncology

Updated 09.25.2024
Released 08.29.1995
Expires For CME 09.25.2027

CNS germinoma

Authors: Isaac Yang MD, Sanah Vohra PhD MPH

See Contributor Disclosures

Editor: Deric M Park MD FACP

CNS germinoma

In This Article

Quick Link

Introduction

Overview

Intracranial germinomas are relatively rare tumors that most often occur in childhood, adolescence, or early adulthood. They typically arise in the pineal and suprasellar regions and frequently present with signs of increased intracranial pressure, endocrine abnormalities, and visual changes. In this article, the author expands our view of the molecular pathogenesis of this neoplasm, highlights novel markers used in the diagnosis of this tumor, and reviews modifications in treatment strategies.

Key points

	• Chemotherapy alone is toxic and inferior to modest chemoradiation therapy regimens.
	• Treatment considerations are different for adults than for skeletally and neurologically immature children (generally younger than 12 years old).
	• For localized disease, the recommended radiotherapy volume is whole ventricular field plus boost to the primary tumor site regardless of whether or not chemotherapy is given.
	• For metastatic disease, the recommended radiotherapy volume is craniospinal plus boost to the primary tumor site regardless of whether or not chemotherapy is given.
	• Chemoradiation therapy may allow radiation dose reduction but not volume reduction.
	• Long-term data are still needed to determine if chemoradiation therapy provides meaningful reductions in cognitive and endocrine toxicity in adults compared to radiation therapy alone.

Historical note and terminology

Tumors arising in the posterior third ventricular and suprasellar regions represent a variety of cell types, including those derived from ectopic primordial germ cells, and those derived from cellular elements intrinsic to the CNS (63). In addition, pineal and suprasellar metastases from systemic malignancies can occur. Tumors derived from primordial germ cells are designated primary CNS germ cell tumors (GCTs). Germ cell tumors can be divided into two major groups: germinomas and “nongerminomatous” germ cell tumors (NGGCTs). Nongerminomatous germ cell tumors include embryonal carcinoma, yolk sac (endodermal sinus) tumor, choriocarcinoma, mature and immature teratoma, teratoma with malignant transformation, and mixed germ cell tumors. Histologic, electron microscopic, immunohistochemical, and molecular biological studies have confirmed the similarity of intracranial germinoma and nongerminomatous germ cell tumors to their extraneural analogues (16).

Germinomas are the most common of the intracranial germ cell tumors, accounting for 50% to 70% of germ cell tumors (55; 123; 136; 65). Germ cell tumors, both neural and extraneural have a predilection for midline structures, occurring primarily in the pineal and suprasellar regions in the CNS and peripherally in the sacrococcygeal region, retroperitoneum, and mediastinum (141). Germinomas are most commonly seen in the pineal region among males and the sellar or suprasellar region among females (141). Uncommonly, germinomas may occur in the basal ganglia (5% to 10% of cases), thalamus, fourth and lateral ventricles, cerebellum, cerebellopontine angle, and spinal canal (55; 112; 45; 105). Although extremely rare, germinoma in the brainstem has also been described (92). Multifocal tumors involving both the pineal gland and neurohypophysis, and sometimes diffusely involving the third ventricle and adjacent structures, have been reported in 2% to 8% of cases. Case series using neuroimaging techniques, have recorded bifocal (pineal and suprasellar) or multifocal involvement in about 18% of cases (04; 11; 80; 121; 12; 17). Metastatic spread can occur through the subependymal space and cerebral spinal fluid (CSF) but can also spend along the ventricular surface (09). The incidence of CSF dissemination at presentation is difficult to determine because of various methods of assessment, but in the modern era about 14% of patients were diagnosed with disseminated disease by MRI scanning or CSF cytology (69; 26; 127; 11; 47; 123; 40; 07; 121; 12; 17; 19); the true incidence may be somewhat higher.

Clinical manifestations

Presentation and course

The clinical manifestations of germinomas depend on the location of the tumor. Pineal region tumors generally present with evidence of increased intracranial pressure secondary to ventricular obstruction at the aqueduct of Sylvius and are accompanied by signs related to compression or infiltration of the dorsal midbrain. Presenting symptoms secondary to this obstruction include headache, nausea, vomiting, and visual disturbance, and neurologic symptoms include vertigo, ataxia/dyskinesia, and asthenia (65). Parinaud syndrome (loss of upward gaze, abnormal pupillary reaction to light, and convergence-retraction nystagmus) is often present, and isolated Argyll Robertson pupils or diplopia are also common. Precocious puberty is seen occasionally both with pineal (more commonly) and neurohypophyseal tumors. When the tumor is located in the neurohypophyseal region, the most frequent presenting signs and symptoms are endocrinologic and visual. In a large series, 86% of patients presented with diabetes insipidus, 93% with primary or secondary amenorrhea, and 30% with growth retardation (80). Panhypopituitarism and elevations in prolactin may occur, and psychiatric disturbance as the sole presenting symptom has also been described. Chiasmal visual field defects and reduced visual acuity due to infiltration or compression of the anterior visual pathways are common (85% of patients). Diplopia is most often due to fourth or sixth nerve palsies. These symptoms (particularly the endocrinopathies) may precede the diagnosis of tumor by months or years, especially with neurohypophyseal tumors (55; 45). Basal ganglia and thalamic tumors may present with hemiparesis or choreoathetotic movements, dystonia, bradykinesia, dyskinesia, rigidity, personality changes, ocular disturbances, and hemisensory changes in speech (62; 15; 65). Amnesia and hearing loss have also been reported. In rare cases, patients can present with symptoms of myelopathy when the spinal cord is the primary site of involvement. When the tumor spreads in the CSF, a variety of symptoms can occur as seen with other leptomeningeal metastases (61; 44).

Clinical vignette

An 18-year-old man was involved in a motor vehicle accident and sustained a compression fracture in his midthoracic spine. As part of his trauma workup, he underwent a CT of the head, which incidentally showed calcification and enlargement of his pineal gland. His alpha-fetoprotein was 5 ng/mL and his beta HCG was less than 2 IU/L. As he was asymptomatic, the decision was made to follow him with serial imaging. Approximately 8 months later, a head MRI showed enlargement of the mass as well as evidence of early hydrocephalus. He was started on acetazolamide and underwent a third ventriculostomy with endoscopic biopsy of the pineal tumor. Pathology confirmed a germinoma.

The patient enrolled in a clinical trial and received two cycles of carboplatin + etoposide and external beam irradiation consisting of 23.4 Gy in 13 fractions to the whole ventricles followed by a boost of 30.6 Gy in 17 fractions to the tumor. He unfortunately suffered a relapse in the spinal region approximately 1 year later. At this point, he was enrolled in another clinical trial and was treated with four cycles of cisplatin + etoposide, which resulted in significant hearing loss. Subsequent imaging showed marked improvement in the spinal tumor with no evidence of intracranial recurrence, so he underwent conditioning with carboplatin + thiotepa followed by an autologous peripheral blood stem cell transplant. He then received radiation 20.4 Gy to the whole brain and spine in 12 fractions and a 23.4 Gy spinal boost.

In the posttreatment setting, the patient struggled with nausea, malnutrition, and failure to thrive to the point where he had to be admitted for nasogastric tube feeds. He eventually had a gastrostomy tube placed, which was then converted to a jejunal tube. Other complications included a varicella zoster infection with resulting neuropathic pain and significant depression. All of these issues resolved over time.

At the time of this report, the patient was 7 years out from completing therapy, and he remained disease-free. He continued to have bilateral hearing loss for which he wore hearing aids. With regard to endocrine issues, he had several low testosterone levels that subsequently normalized. Cognitively, he continued to struggle with attention and memory issues but was in the process of finishing college.

Biological basis

Etiology and pathogenesis

The etiology of germinoma is unknown. The striking association between the onset of puberty and the incidence of intracranial germ cell tumors suggests a possible relation between increased neuroendocrine activity in diencephalic structures, and the induction of malignant change in previously dormant primordial germ cell rests (55). A similar relationship is seen with mediastinal germ cell tumors.

During early embryogenesis, primordial germ cells migrate from the fetal yolk sac to the developing gonadal ridge. Whether by chance (“misinvolvement-misenfoldment” hypothesis) (116) or ontologic design (34), primordial germs cells also disseminate widely throughout the developing embryonic tissues, but in most instances are destroyed either through immune mechanisms or apoptosis. It remains unclear why these cells persist in certain extragonadal midline structures, including the pineal gland and neurohypophysis. The pineal gland and hypothalamus or neurohypophysis are themselves linked neuroanatomically for reasons that may relate to orchestration of gonadotrophin release.

Chromosomal abnormalities may also play a role in the development of CNS germ cell tumors (03; 28; 139). Genetic profiles of germ cell tumors overall include imbalances with gains of 12p, 8q, 1p, 2p, 7q, 10q, and X, as well as losses of 11q, 13, 15q, 10q, and 18q (111). An international study of 62 cases of CNS germ cell tumors showed that over 90% of pure germinomas exhibited chromosomal abnormalities with frequent amplification of chromosomes X, 21q, 12p, 1q, and 14q and deletions of 11q, 10q, 17p, and 13q (142). The presence of 12p abnormalities is independent of histology and does not seem to influence prognosis, but the average number of chromosomal abnormalities does correlate with the histologic aggressiveness of the germ cell tumor. Overrepresentation of 12p is hypothesized to act as an initiating event in tumor development through overexpression of cyclin D2. Pineal region germ cell tumors also frequently show an increased copy number of chromosome X or chromosome 21, suggesting that relevant oncogenes reside in both of these locations as well. Interestingly, patients with Klinefelter syndrome (excess copies of the X chromosome) and Down syndrome (trisomy 21) have an increased incidence of CNS germ cell tumors (see Epidemiology section).

In two studies, Iwato and colleagues evaluated various molecular changes in intracranial germ cell tumors (52; 53). They found that intracranial germ cell tumors overexpress p53 and MDM2 and that an incidence of MDM2 gene alteration higher than TP53 gene mutation is seen. This finding, also seen in testicular germ cell tumors, suggests a common origin. The researchers also found that pure germinomas have a higher frequency (90%) of INK4a/ARF gene deletions than nongerminomatous germ cell tumors (55%), a finding not seen in testicular germ cell tumors. Germinomas also exhibit increased expression of Bax, which inhibits Bcl-2 (an antiapoptotic protein) and may account for an increased sensitivity to treatment (85). Miyanohara and colleagues (84) found that germinomas express c-kit on their cell surface, a finding not seen in teratomas and syncytiotrophoblastic giant cell germinomas. Co-expression of c-kit and stem cell factor has been reported in germinomas (137). Analysis of c-kit mutational hotspots in germinomas revealed mutations in 4 of 16 cases (114). Asgharzadeh and colleagues, however, found no correlation between expression of CD117 (c-kit) and mutational analysis. They reported strong positive immunostaining for CD117 in 100% of cases whereas their mutational analysis revealed only 9% c-kit mutation rate (exon 17 [N822Y]) (10). In an international study led by Wang, 53% of CNS germ cell tumors exhibited somatic mutations in at least one of the genes involved in the KIT/RAS or AKT/mTOR pathways. CBL, which encodes a RING finger ubiquitin E3 ligase, was the third most frequently mutated gene (142). Another study that examined 124 CNS germ cell tumors observed alterations in the MAPK pathway in 64.3% of germinomas. The PI3K pathway was the second most common target of alteration, with the most frequently mutated gene being MTOR (48).

Diagnostic workup

Reliable differentiation of germinomas from nongerminomatous germ cell tumors or other CNS tumors cannot strictly be characterized by imaging alone. Evaluation of the patient with a suspected germinoma includes an MRI of the brain and spinal cord, assays for tumor markers (AFP, beta-HCG) in both serum and CSF, hypothalamic-pituitary hormonal function evaluation, and a large volume CSF cytology. Note that a full endocrine evaluation is also important in pineal tumors to help rule out occult multifocal disease. If possible, the spinal MRI and CSF studies should be performed prior to any surgical intervention. If the presence of obstructive hydrocephalus precludes the safe performance of a lumbar puncture, ventricular CSF sampling following the placement of a ventriculostomy or ventriculoperitoneal shunt, or intraoperatively during an internal shunting procedure, can be performed. Of critical importance for prognosis and treatment decisions is distinguishing pure germinomas from nongerminomatous germ cell tumors. The diagnosis and classification of germ cell tumors can be made on the basis of tumor markers, histology, or both. It is important to note that efforts are underway to determine a tumor marker threshold for beta-HCG-secreting germinomas, as Europe more commonly uses a threshold of 50 mIU/mL compared to 100 mIU/mL in North America. See Table 1 for classification of germ cell tumors according to tumor markers and immunohistochemical markers.

Table 1. Classification of Germ Cell Tumors According to Markers

Tumor Type	Beta-HCG	AFP	PLAP	c-kit
GERMINOMAS
Pure Germinoma	-	-	+/-	+
Germinoma (syncytiotrophoblastic)	+	-	+/-	+
NGGCTs
Mixed Germ cell tumor	+/-	+/-	+/-	+/-
Embryonal carcinoma	+	+	+	-
Yolk sac tumor	-	+	+/-	-
Choriocarcinoma	+	-	+/-	-
Immature teratoma	+/-	+/-	-	+/-
Mature teratoma	-	-	-	-
Beta-HCG= human chorionic gonadotropin; AFP= alpha-fetoprotein; PLAP= placental alkaline phosphatase; += positive; - = negative; +/- = equivocal Adapted from (30).

Unless there are characteristic increased tumor markers found in the serum, or CSF, or both, a diagnosis of germ cell tumors often requires a biopsy. When the tumor markers are negative or only mildly elevated, or if there is any noncharacteristic finding, a tumor biopsy for histologic diagnosis should be performed. Surgery can be avoided for patients with compelling clinical and radiographic evidence of nongerminomatous germ cell tumors. Aggressive removal of tumors prior to chemotherapy or radiotherapy is generally not recommended or required due to the effectiveness of therapy as well as concern for increasing endocrine, cognitive, and neurologic toxicity for tumors in the regions most commonly affected by germinoma.

Radiological findings characteristic of the various CNS germ cell tumors have been reported (35; 134; 72).

Pineal germinoma imaging

T1-weighted, gadolinium-enhanced coronal and axial MRI scans of a 16-year-old boy with a biopsy-proven pineal region germinoma before (A, B) and after (C, D) one course of chemotherapy with cis-platinum and etoposide. The lobulate...

MRI images of germinomas are isointense to slightly lower intensity than grey matter, especially solid components, on T1-weighted images and are isointense or (more commonly) hyperintense on T2-weighted images. The high intensity components on T1 correspond to hemorrhage, fat, or high protein and may assist in differentiating germinomas from nongerminomas (72). Earlier reports suggested that germinomas showed homogenous contrast enhancement, but heterogenous enhancement is seen in more than half of germinomas (72). Large suprasellar tumors with a “dural tail” may be suggestive of a neurohypophyseal germ cell tumor (72). In most cases, there is little, if any, peritumoral edema. Tumors show low apparent diffusion coefficient (ADC) values, which appear to normalize following treatment; robust normalization of low ADC may be predictive of improved response to chemotherapy (97). Calcifications are seen in slightly less than half of cases by CT scanning. Intratumoral cysts are identified by MRI in about half of patients with germinomas (134; 87; 72). MRI can also demonstrate teratomatous tissue components (especially fat) suggestive of mixed germ cell tumors (35). A few case reports have noted cerebral hemiatrophy by MRI as a presenting feature in cases where germinomas were localized to the basal ganglia, thalamus, or brainstem. (62; 99).

Multifocal intracranial disease is seen in 18% of patients with germinomas in modern series and is important to document for radiotherapeutic target delineation. Sites of involvement include the pineal and suprasellar region, hypothalamus, optic chiasm, cavernous sinus, third ventricle wall, and anterior half of the lateral ventricle wall. Some cases are radiographically occult at diagnosis but become more evident after chemotherapy response. Hypophyseal size and pineal “cyst” sizes are important to follow after induction chemotherapy as decrease in size of these initially normal-appearing structures suggests occult involvement. Disseminated disease is diagnosed in cases with a positive CSF cytology or cases in which MRI scanning reveals metastases within the spinal canal. This later situation occurs in about 15% of patients and affects treatment planning and disease monitoring.

The distinctive biochemical profiles of these tumors can be exploited diagnostically by evaluation of CSF and serum. AFP and beta-HCG remain the most useful tumor markers in CNS germ cell tumors, although other markers, such as placental alkaline phosphatase (PLAP) and c-kit, are being investigated (65). Pure germinomas frequently display increased levels of placental alkaline phosphatase in the CSF (51; 130; 101). Alpha-fetoprotein is absent such that any detectable alpha-fetoprotein rules out the diagnosis. Markedly elevated levels of alpha-fetoprotein (greater than 700 ng/ml) are diagnostic of yolk sac tumors, and more modest elevations are seen in embryonal carcinomas, immature teratomas, and mixed germ cell tumors containing a predominance of these histologic types. Modest elevations of human chorionic gonadotrophin (usually less than 100 mIU/ml) and beta-human chorionic gonadotrophin (usually less than 50 mlU/ml) may be seen in the serum, CSF, or both in about one quarter of patients with pure germinomas (04; 13; 80; 120; 19; 49) and have been attributed to the presence of syncytiotrophoblastic giant cells within the tumor (129; 49), though serum elevations greater than 500 mIU/L and CSF elevation greater than 2000 mIU/L have been reported in a child with a recurrent, disseminated, pathologically confirmed pure germinoma (32). Markedly increased levels of human chorionic gonadotrophin (greater than 2000 mIU/ml) are seen in choriocarcinomas. Mature teratomas demonstrate no marker elevations. These markers are useful both as diagnostic tools and as surrogates of disease progression and response to therapy.

Implementation of appropriate treatment modalities and ultimate prognostication are dependent on the accurate histological classification of CNS germ cell tumors. Macroscopically, germinomas may appear ill-defined due to a propensity to infiltrate neighboring brain structures. On cut surface, the tumors are generally pink-gray and solid, although these may occasionally display cystic change. Microscopically, intracranial germ cell tumors display similar histologic features and immunohistochemical staining properties as testicular seminomas and ovarian dysgerminomas. The architecture of the tumor typically shows a lobular arrangement with fibrovascular septa dividing aggregates of tumor cells. The tumor cells generally appear uniform, with large round nuclei, vesicular chromatin, and single prominent nucleoli. The presence of glycogen renders the cytoplasm clear, which can be demonstrated by strong positive Periodic Acid Schiff (PAS) staining, which is sensitive to diastase digestion. Mitoses are frequently present, and necrosis is occasionally encountered. The T-cell rich lymphocytic infiltrates are typically intermingled to variable degrees, often associated with the fibrovascular septa, and may be so prominent as to mask the underlying tumor cells. Both neoplastic cells and reactive astrocytes can be seen in intraoperative smear preparations. Multinucleated syncytiotrophoblast-like giant cells may also be present and may lead to consideration of a granulomatous inflammatory process such as sarcoidosis or tuberculosis. Immunohistochemistry for placental alkaline phosphatase and c-kit produce cytoplasmic and membrane staining in germinomas (63).

CNS germinoma histology and immunohistochemical properties

(A) H&E stained section of a CNS germinoma showing poorly differentiated tumor cells with uniform, large round nuclei with vesicular chromatin and single prominent nucleoli. Scattered groups of T-lymphocytes are present. (B) T...

OCT3/4, a transcription factor necessary for maintaining pluripotency in embryonic stem cells and primordial germ cells and a member of the POU class of homeobox genes, has emerged as a robust nuclear marker for gonadal and extragonadal (eg, CNS) germ cell tumors, specifically germinomas and embryonal carcinomas, and may be useful in establishing a germ cell origin for tumors that otherwise may remain unidentified (43; 74; 22; 93). Additionally, podoplanin, a transmembrane sialoglycoprotein, was found to be a sensitive marker for CNS germinomas and absent in nongerminomatous germ cell tumors except for some immature teratomas (83). NANOG, a homeodomain transcription factor, has been shown to be expressed in more than 90% of germinoma cells, even in cases of inconsistent expression of OCT3/4 and placental alkaline phosphatase, any may help tumor identification in small biopsy specimens (117). Additionally, immunohistochemistry is employed in the evaluation of intracranial germ cell tumors for additional elements such as embryonal carcinoma (CD30 positive), yolk sac tumor (alpha-fetal protein positive), choriocarcinoma (beta-human chorionic gonadotropin and human placental lactogen positive), and teratoma. SALL4 has been identified as a sensitive and specific immunohistochemical marker for primary CNS germ cell tumors (81).

Because germ cell tumors arising outside the CNS may metastasize to brain, some authors recommend whole-body [18F]-FDG PET to rule out a primary extracranial germ cell tumor (46).

Management

With success rates approaching 100% for curing CNS germinomas with radiation, it has long been considered standard treatment; however, the required dose and tumor volume remain controversial (65). Today, standard treatment of localized germinomas typically consists of whole ventricular field irradiation plus a boost to the primary tumor with or without neoadjuvant chemotherapy. In patients with metastatic disease, craniospinal irradiation is indicated. The most pressing therapeutic challenge today is to reduce the long-term side effects of treatment without compromising disease-specific survival. CNS irradiation is associated with frequent and significant late consequences, and this observation provides the rationale for innovative combined modality approaches to therapy employing surgery, radiation, and chemotherapy. Nevertheless, treatment innovations that reduce the likelihood of cure below that seen with conventional therapy are not acceptable.

Surgery. The role of surgery in the treatment of CNS germinomas has evolved over time. In the past, because of the high morbidity and mortality associated with pineal surgery, a nonhistologic diagnosis, based on the exquisite radiosensitivity of germinomas, was frequently accepted. In patients with suggestive epidemiologic and radiographic characteristics, a “test dose” of cranial irradiation of 2000 cGy was often administered. If complete or near-complete tumor shrinkage was documented, the lesion was presumed to be a germinoma, and the full course of radiation therapy was then completed (45). Because of the variety of tumors that can present in suprasellar or pineal locations, many with variable radio- and chemosensitivities, radiographic and biochemical characteristics, and natural histories, this approach is no longer considered acceptable. In experienced hands, stereotactic, endoscopic, and craniotomy procedures for biopsy entail minimal risk (1% to 5% morbidity and mortality) (109; 13; 80; 121; 12; 145). For pure germinomas, for which curative nonsurgical therapy is available, open, stereotactic, or endoscopic biopsy is sufficient. Compared with biopsy alone, long-term follow up suggests that patients undergoing more extensive surgical resection may experience worse cognitive function and quality of life without improving tumor outcome (78). If CSF diversion is necessary, endoscopic “internal shunting” (third ventriculostomy) should be considered, obviating the need for ventriculoperitoneal shunting, which itself may lead to extraneural dissemination of tumor (55; 106). This approach also permits the identification of surgically curable but radio-resistant tumors such as mature teratomas and pineocytomas, which can then be fully resected, sparing patients additional toxic therapy. Metastasis, along the route of endoscopy, has been reported (138).

A second-look surgery may be considered in patients with partial response or stable disease with greater than 1.5 cm residual tumor (33; 56; 20). Mature teratomas and pineocytomas are radio-resistant and should be ruled out because they can be cured surgically. A second-look surgery would also help identify occult mixed germ cell tumors, which may require more intense therapy than pure germinomas. With regard to safety, it has been demonstrated that the risk of complications from a second-look surgery are significantly less due to decreased vascularity after induction chemotherapy (18).

Radiation. Modifications are occurring in radiotherapy treatment strategies for the management of localized CNS germinoma. Historically, radiotherapy doses have included 4000 to 5500 cGy to the involved field, and 3000 to 3600 cGy of craniospinal irradiation. Over the last decade, due to the attainment of high survival and cure rates as well as the desire to reduce long-term side effects resulting from radiotherapy, a trend toward reducing field size and total dose of radiation has emerged. Cranial irradiation fields have been narrowed to include the local tumor plus the ventricular system generally to 24 Gy based on success for microscopic disease using this dose for CSI without chemotherapy (20), and doses to primary tumor were initially reduced to 4000 to 4500 cGy, dependent, in some institutions, on tumor size (128; 41; 131). One study showed a 92% 5-year survival rate and 88.8% relapse-free survival rate using craniospinal irradiation (3000 cGy in 150 cGy fractions) with a 1500 cGy boost to the tumor volume (12). Ogawa and colleagues studied the effects of further localization of radiotherapy by showing that selective radiotherapy alone in 70 patients with intracranial germinomas led to seven relapses, three of which occurred in six patients who received focal irradiation that involved the primary tumor plus a margin but did not include the ventricles (95). In another study of 35 patients with localized germinomas, none of the 21 patients who received whole-ventricle irradiation experienced a relapse whereas five of the 14 patients who received focal irradiation developed recurrent tumors within the ventricular system (39). As a result, whole-ventricle irradiation is considered the current standard of care for radiation-only treatment of localized germinoma. Shibamoto’s group proposes further dose reduction and substratification based on tumor size. Utilizing 36 Gy after gross total resection, 40 Gy for tumors smaller than 2.5 cm, 45 Gy for tumors 2.5 to 4.0 cm, and 40 Gy for larger tumors, they report a 10-year, relapse-free survival rate of 95%, equivalent to historical rates cited for uniform use of 50 Gy. Ogawa and colleagues conclude that 40 to 45 Gy is adequate to cure germinomas 4 cm or smaller (126).

One concern about omitting the craniospinal field of radiation is the perceived risk of cerebrospinal fluid relapse in patients with initially localized disease. In older series (where pre-treatment staging procedures were often incomplete), relapse in the CSF was seen in 23% of cases versus 8% when prophylactic craniospinal irradiation was used (73; 123). Other studies, however, suggest an incidence of CSF relapse of approximately 7.6% (11/145), somewhat greater in patients receiving only involved field radiation (6/33, 18%), but less in patients treated to the whole brain or ventricular system (2/56, 3.8%) and in those who received only involved field radiation with pre-radiation chemotherapy (3/56, 5.4%) (73; 26; 133; 13; 40; 07; 121; 19). A comprehensive review of published cases since 1988 evaluated disease relapse and cure rates between craniospinal radiotherapy and reduced volume irradiation alone (whole brain or whole ventricular followed by boost) in the setting of localized intracranial germinomas (110). Recurrence rates were found to be 7.6% after reduced volume radiotherapy and 3.6% after craniospinal radiotherapy with isolated spinal relapses of 2.9% versus 1.2% respectively. Based on these data, the authors argue that replacing craniospinal radiotherapy with reduced volume whole-brain or whole-ventricular radiotherapy plus boost is warranted for the management of localized disease and that such a modification can have significant impact on the late toxic effects that arise due to irradiation (110). Shibamoto reviewed data from two earlier studies published by his group and reported no significant difference in 10-year survival rates between patients receiving craniospinal radiation and focal radiation therapy, 95% and 88% respectively (126). Based on these results, some authors recommend reserving craniospinal irradiation for positive CSF cytology or clinical or radiographic evidence of CSF dissemination (126). However, reduced volume radiotherapy remains controversial, and a retrospective review of 21 patients treated with either focal irradiation plus chemotherapy or craniospinal radiotherapy suggested higher rates of failure in the focal radiation group (94).

Certain subgroups of CNS germinoma are at higher risk for spinal dissemination and, therefore, may benefit from craniospinal irradiation. Ogawa and colleagues showed that large intracranial disease (larger than 4 cm) is associated a higher rate of spinal recurrence whereas smaller tumors (smaller than 4 cm) are associated with a better prognosis (96). Ogawa and colleagues also showed that multifocal intracranial disease is an independent risk factor for spinal recurrence. In a retrospective analysis of 170 patients with intracranial germinomas, the spinal cord metastasis rate was 3.4% in patients with localized disease who did not undergo spinal cord irradiation compared to 16.7% in patients with bifocal disease who were treated with whole-ventricular or whole-brain irradiation (71).

In nonlocalized CNS germinoma, when CSF cytology or neuraxis MRI scanning reveals disseminated disease at diagnosis, craniospinal radiation is used. The optimal dose of craniospinal irradiation remains controversial. Long-term results of SIOP96 support 24 Gy CSI +16 Gy boost to primary site (with no benefit to additional chemotherapy) as event-free survival was 100% and overall survival was 98% (20). Similar results have been reported from other groups using doses of 2000 to 2400 cGy (125; 126; 56). In addition, advances in radiotherapy techniques such as proton beam irradiation, which eliminate exit dose associated with radiation beams, are expected to significantly reduce toxicities associated with both localized and nonlocalized germinoma treatment (77). Early reports suggest similar event-free and overall survival rates with significant reductions in dose to temporal lobes and eliminating radiation exposure of the organs and structures anterior to the spine. Lastly, radiosurgery has been used to treat intracranial germinomas, but the role of this type of radiotherapy is not clear (148; 42; 31; 88; 146).

Radiation isodose lines for pineal germinoma with leptomeningeal metastases

Radiation isodose lines for 20-year-old male treated with craniospinal proton radiotherapy and pineal region boost without chemotherapy for pineal germinoma with leptomeningeal metastases. (A) Isodose lines depicting dose of 23.4 ...
Effect of proton radiotherapy on leptomeningeal metastases from pineal germinoma

(A) Sagittal T1-MRI with contrast demonstrating leptomingeal disease (arrows) from pineal region germinoma. (B) T2-weighted MRI 2 years after proton radiotherapy demonstrates fatty marrow changes ending in midvertebral body consis...

Chemotherapy. A number of multi-institutional and multinational collaborative groups have studied the possibility of using postoperative systemic chemotherapy for patients with CNS germinomas, primarily in the pediatric setting, in order to further reduce the CNS radiation dose and treatment volume. CNS germinomas, like their extraneural counterparts, are extremely sensitive to multiple chemotherapeutic agents and regimens, including single-agent cisplatin; carboplatin; ifosfamide; cyclophosphamide; and etoposide; as well as combination regimens including cisplatin or carboplatin plus etoposide; carboplatin, etoposide, and cyclophosphamide or ifosfamide; and carboplatin, etoposide, and bleomycin. Radiographic, cytologic, and biochemical complete responses to a variety of chemotherapeutic regimens are seen in 74% of patients (range: 47% to 100%), including those with leptomeningeal dissemination (05; 04; 147; 21; 11; 13; 122; 17; 19; 132) (Tables 1 and 2). A clinical trial through Children’s Oncology Group (COG-ACNS1123, NCT01602666) tried to assess neoadjuvant chemotherapy (four cycles of carboplatin and etoposide) followed by response-based radiation therapy for localized germinomas. Although this trial failed to meet its primary efficacy threshold due to low sample size, results showed high rates of 3-year progression-free survival and overall survival among the neoadjuvant chemotherapy individuals who received reduced irradiation dose (14). For patients with complete response or residual disease of less than 1.5cm, patients undergo 18Gy whole-ventricle irradiation plus 12Gy boost to the primary site; it is too early to assess the outcome of this study as the germinoma stratum is closed to accrual and patient follow-up is ongoing.

Subsequent studies and long-term follow-up have shown, however, that most relapses with focal irradiation tend to occur in the ventricular system and that whole-ventricle irradiation may help prevent these relapses. In their final update of patients with localized CNS germinomas treated in the SIOP CNS GCT 96 trial, Calaminus and colleagues reported that of their 65 patients who received chemotherapy followed by focal irradiation, seven relapses were noted, and six of these were ventricular recurrences outside the primary radiotherapy field (20). Of note, although there was no difference in 5-year event-free or overall survival between patients treated with craniospinal irradiation alone versus combined therapy, there was a difference in progression-free survival (0.97 +/- 0.02 vs 0.88 +/- 0.04; P=0.04). In addition, late relapses are seen after chemoradiation therapy and long-term follow-up. A series of patients treated with chemotherapy plus focal radiation therapy demonstrates event-free survival of 88% at 5 years that declined to 80% at 10 years (56). A review of 10 relapsed CNS germinomas from a group of 60 patients initially treated with neoadjuvant chemotherapy followed by focal irradiation showed that nine patients had local or locoregional recurrence, eight of whom were periventricular (01). This is consistent with other similar reports noting the pattern of marginal relapses suggested that chemotherapy was not able to sterilize the ventricular CSF (29; 56). These findings suggest that expanding the radiation field to include the ventricles may help prevent the majority of relapses in patients with localized germinoma treated with chemotherapy followed by radiation.

The role of chemotherapy in disseminated patients is controversial. Historically, chemotherapy has been used with the rationale to allow radiation-dose reduction. Historic craniospinal doses were 36 Gy, and many modern chemoradiotherapy trials demonstrated doses can be lowered to 20 to 24 Gy in good responders without compromising outcomes. Aoyama and colleagues (06) published a promising report in which patients with pure germinomas treated with a combination of etoposide and cisplatin followed by a radiation dose of only 2400 cGy. They demonstrated that the actuarial relapse free survival at 5 years was 90%, and the overall survival rate at 5 years was 100%. Patients with B-HCG secreting tumors had rates of 75% and 44% (chemotherapy used-ifosfamide, cisplatin, and etoposide); hence, it was felt that they should be treated with higher doses of radiation therapy than 2400 cGy. The observation that elevated B-HCG levels may indicate treatment-resistant disease is supported by data from Inoue and colleagues (50). In their study of 21 patients with CNS germinomas treated with chemoradiation therapy, 19 had a complete response, and 17 of these patients did not have elevated B-HCG levels in their CSF or tumor tissue. The two patients who were refractory to treatment both had elevated B-HCG in their CSF and tumor tissue. Kortmann and colleagues additionally reviewed in abstract form the 24 Gy CSI + 16 Gy boost arm of SIOP GCT 96 to the 30 Gy CSI + 15 Gy boost employed in MAKEI 89. The 5-year event-free survival was 90% in MAKEI 89 and 91% in SIOP 96, again supporting the efficacy of reduced-dose craniospinal radiation therapy (64).

Kretschmar and colleagues reported on the results of a Phase II study employing chemotherapy and response-based radiotherapy in children with CNS germ cell tumors (66). Subjects were stratified as either low-risk (ie, pure germinoma with normal alpha-fetoprotein and HCG less than 50 mIL/ml in serum and CSF) or high-risk (ie, mixed germinoma or other malignant variant or elevated HCG or alpha-fetoprotein). Subjects were treated with alternating courses of chemotherapy etoposide plus cisplatin alternating with cyclophosphamide plus vincristine for four courses. High-risk subjects received double doses of cisplatin and cyclophosphamide. Radiotherapy was initiated after chemotherapy with the delivered dose determined by risk group, dissemination, and response status. Kretschmar and colleagues documented 91% objective radiographic response in their subjects with germinomas, and all germinoma patients were alive at a median 66 months after radiation therapy (66).

However, the long-term results of a prospective multinational trial (SIOP96) call the role of chemotherapy into question again (20). For patients with metastatic tumors (n = 45), progression-free survival was estimated to be 1.00. Event-free survival at 5 years was 0.98+0.02 among all patients, of whom 28 received craniospinal radiotherapy alone and 17 had received additional chemotherapy before craniospinal radiotherapy. This indicates that there is no difference in outcomes with chemotherapy. Overall survival at 5 years was 0.98+0.02 among all patients. Although it appears that the dose of radiation can be reduced safely without the addition of chemotherapy, the decision to utilize chemotherapy was not randomized, and it is certainly possible that patients with bulky disease may have been more likely receive neoadjuvant chemotherapy.

Studies utilizing neoadjuvant, inductive chemotherapy followed by dose- and volume-reduced irradiation appear to yield comparable cure rates to traditional full-dose, large volume radiation; however, longer follow-up will be required to determine if these newer regimens avoid the neurocognitive sequelae of radiation and improve the quality of life of long-term survivors. The primary goals of this approach are to reduce cognitive and endocrine toxicity after radiation therapy. The current recommended radiation dose without chemotherapy is 20 to 24 Gy for either CSI or WVFI. Both modalities are associated with less than 10% risk of long-term endocrine dysfunction with the exception of growth hormone (82), so this is primarily a risk for skeletally immature children. Chemotherapy allows for reduction of the primary tumor boost dose from 40 to 45 Gy down to 30 to 36 Gy for good responders, which is likely meaningful for suprasellar tumors, especially in young children for whom vascular or cognitive issues are well-defined and are generally dose dependent. Emerging data regarding hippocampal radiotherapy dose and cognitive outcomes would suggest that reducing the dose to the medial temporal lobes (as would be expected in suprasellar tumors) may also reduce short-term memory difficulties in adults (37; 75). In the pineal region there would be no impact on endocrine risks, and it is likely there would be less benefit from a cognitive and neurovascular toxicity standpoint as less of the frontal or temporal lobes would be in the boost field. Alapetite and colleagues addressed this concern in his report of results of SFOP-90 in which 60 nondisseminated, histologically proven germinomas were treated with four alternating courses of etoposide-carboplatin and etoposide-ifosfamide followed by 49 Gy to the tumor bed and followed for a median of 76 months (range 7 to 136 months) (02). The 5- and 8-year survival was 98%. Twenty percent of subjects had a neuropsychological evaluation that showed good preservation. A study of 15 patients by Tseng and colleagues utilized chemotherapy and low-dose radiation and found that most patients had favorable outcomes over a median follow-up period of 45 months (140). Cheng and colleagues showed that of the eight children in their study with CNS germinomas who were treated with chemotherapy and whole-ventricle irradiation, all exhibited stable full-scale IQ, albeit with a decline in processing speed, through a median follow-up period of 61 months (23).

One trial was designed to test the feasibility of entirely avoiding the use of radiation therapy, in favor of an intensive chemotherapy regimen consisting of high-dose carboplatin, etoposide, and bleomycin, with the addition of high-dose cyclophosphamide in patients without an initial complete response (11). Of 71 patients (45 with germinomas and 26 with nongerminomatous germ cell tumors) enrolled in this trial, 68 were evaluated and 39 (57%) demonstrated a complete response to initial chemotherapy. Of the remaining 29 patients, 16 patients became complete responders following re-operation or cyclophosphamide-intensified chemotherapy, for an overall complete response rate of 77% (55 patients out of 71 patients), including 38 of 45 patients with germinomas (84%). Histology did not influence the complete response rate but did impact survival. Unfortunately, 28 of the 55 complete responders (51%), and 26 of the 45 (58%) with germinomas have relapsed, with a median follow-up time of 18 months. The 2-year survival probability for patients with germinomas was only 84%. Chemotherapy-related morbidity and mortality were also substantial (seven patients died from chemotherapy-related complications). The Third International CNS Germ Tumor Study stratified subjects into low risk (n=11), intermediate risk (n=2), and high risk (n=12) based on serum/CSF levels of HCGbeta, alpha-fetoprotein, and the histologic presence of nongerminomatous malignant elements (25). This study also utilized a chemotherapy-only strategy, with low-risk subjects treated with four to six alternating cycles of carboplatin/etoposide and cyclophosphamide/etoposide. The intermediate- and high-risk groups received four to six cycles of carboplatin/cyclophosphamide/etoposide. This approach yielded a response rate of 76% after four cycles of chemotherapy and a 6-year event-free and overall survival of 46% and 75%, respectively. The authors concluded that this approach yielded results that were inferior to regimens utilizing some form of radiotherapy.

The results of the Second International CNS Germ Cell Tumor Study Group Protocol (the successor to the Balmaceda study) (60) largely mirror the findings of the original study. Patients received two cycles of cisplatin, etoposide, cyclophosphamide and bleomycin, followed (for complete responders) by two cycles of carboplatin, etoposide, and bleomycin, followed (for those whose complete responses came only after four courses of chemotherapy) by an additional cycle of each regimen. Twenty patients with germinomas were enrolled, and 16 out of 17 evaluable patients had a partial or complete response after the first two cycles of treatment. At a median follow-up of 6.3 years, 14 out of 20 patients were disease-free; eight of these patients had no relapse or progression whereas the other six are in second or third remission after additional chemotherapy and radiation therapy. A second paper by this group on the same regimen suggests that this regimen is effective in achieving remissions, but this approach had a high morbidity and mortality suggesting this approach may not be prudent (59). In both International Studies, relapses occurred predominantly at distant neuraxis sites (including the CSF). Also, in both studies, patients with diabetes insipidus tolerated chemotherapy less well than their unaffected counterparts.

Modak and colleagues evaluated the use of high dose chemotherapy with autologous stem cell rescue in patients with relapsing or progressive disease (86). They gave a high dose escalation regimen of various thiotepa-based regimens to nine patients with germinomas and 12 patients with nongerminomatous germ cell tumors. This was followed by autologous stem cell rescue. Of the nine patients with relapsed or progressive germinomas, seven had a median survival of 48 months whereas only four of the patients with nongerminomatous germ cell tumors survived with a median of 33 months. All patients developed grade 4 hematologic toxicity, but no patients died from toxic causes. Kubota and colleagues analyzed the data from six patients with recurrent CNS germinoma (67). All patients received between one and seven cycles of platinum-based chemotherapy and achieved a complete response prior to undergoing high-dose chemotherapy that consisted of one to three cycles of carboplatin, etoposide, and melphalan. This was followed by autologous stem cell transplant and resulted in five of six patients being alive and disease-free with a median survival of 65 months. These results warrant further investigation to see if high-dose chemotherapy followed by autologous stem cell transplant is a reasonable approach for patients with relapsing and progressive germinomas.

In summary, despite remarkable initial complete response rates, chemotherapy-alone treatment regimens have not translated into acceptable long-term survival rates for patients with germinomas, and the toxicity associated with aggressive regimes is substantial. High-dose chemotherapy without radiation cannot currently be considered a treatment option for patients outside of the protocol setting but can be an effective salvage regimen with or without salvage radiation.

Summary of chemoradiation therapy. Optimal chemoradiation therapy in patients with CNS germinomas entails individual risk assessment and consultation with both radiotherapy and chemotherapy to determine optimal treatment based on tumor risk factors, age, and location of tumor. Pediatric patients most commonly receive neoadjuvant chemotherapy with an active regimen, followed by whole-ventricle irradiation and radiation tailored to the pretreatment extent of disease and response to chemotherapy. Patients with localized disease are safely treated with 2400 cGy WVFI with boost to the primary tumors at doses around 3000 to 3600 cGy for complete chemotherapy responders and somewhat higher doses (4000 to 5400 cGy) for less than complete responders. For patients treated without chemotherapy (generally low-risk young adults) 2400 cGY WVFI with boost to 4000 to 4500 cGy to the primary tumor can be administered. Prophylactic craniospinal irradiation can be omitted in most patients with individualized risk assessment for patients with bifocal or multifocal disease. If CSF dissemination has been documented prior to treatment, craniospinal irradiation with or without neoadjuvant chemotherapy should be considered based on patient age, bulk of disease, and clinical risk factors. Doses of about 2000 to 2400 cGy for CSI appear adequate with or without chemotherapy. For boost volumes (both primary site as well as metastatic sites) response-based tumor boost volumes and dose are the same as localized guidelines. These guidelines should permit decreases in the dose and extent of nervous system irradiation and will hopefully translate into a reduction in the late consequences of CNS irradiation. Nevertheless, substantial additional research is necessary to validate the preliminary results on which these suggestions are based to determine what chemotherapeutic regimens are most active, to evaluate novel markers of disease responsiveness, and to see whether further reductions in CNS irradiation are possible.

Importantly, patients whose germinomas recur after chemotherapy and reduced-dose radiation may still be cured with additional chemotherapy and radiotherapy (147; 21; 11; 13; 80; 82; 122; 17; 19). The true recurrence rate of germinomas after initial therapy may be higher than traditionally reported. In one study with a median follow-up of 134 months, the median time to recurrence was 50 months, with 36% of subjects having recurrence at 60 months or later, and the latest occurrence occurred at 230 months (58). Platinum-based chemotherapy followed by wide-field, low-dose radiation, 18 to 25.2 Gy, has shown some efficacy (58). Moreover, myeloablative chemotherapy regimens with stem cell transplant have demonstrated some benefit in recurrent disease (57; 38). In addition, studies have emphasized the importance of second-look surgery for patients treated with chemotherapy and radiation in which CSF and serum markers, if any, have returned to normal, but follow-up MRI scans continue to show minimal residual enhancing tissue. Usually in these studies, necrosis, fibrosis, or mature teratoma has been identified (11; 19). In any case, further chemotherapy and radiotherapy are not indicated, and in the latter case, curative gross total resection can be undertaken.

A more novel approach to treating patients with recurrent GCT is the use of dendritic cells, in which a patient had a radiographic response and a decrease in serum beta-HCG before succumbing to septic shock from a urinary tract infection (102). Future approaches may consider the role of the c-kit proto-oncogene in the pathogenesis of CNS germinomas and will need to evaluate the use of molecular therapies, such as ST1571, that target c-kit (114; 143).

Dasatinib has been shown to be feasible in children with central nervous system germinoma as it is a potent inhibitor of c-KIT (103). Anti-PD-1/PD-L1 agents may also represent a potential therapeutic modality given that the expression of PD-1 in tumor infiltrating lymphocytes and PD-L1 in CNS germinoma tumors were 96% and 92% respectively in a study of 25 tumor samples by Liu and colleagues (70).

Table 2. Chemo-radiotherapy Trials in Patients with CNS Germinomas

Kellie, n=20
	Chemotherapy
		• cisplatin/VP-16/cytoxan/bleomycin X two cycles • carboplatin/VP-16/bleomycin X two cycles • complete responders: 15/15 (NED in five patients)
	Radiation
		• reserved for patients with recurrent disease
	Chemotherapy and radiation
		• reserved for patients with recurrent disease
	Progression-free survival
		• 10/20 remain in original CR at median 5.2 years • 15/20 survive in CR at median 5.2 years follow-up
	Overall survival
		• 15/20 (75%) at 5.2 years median follow-up (60)
Siffert, n=19
	Chemotherapy
		• carboplatin/VP-16 • cisplatin/cytoxan • complete responders: 20/21
	Radiation
		• reduced in chemoresponders
	Chemotherapy and radiation therapy
		• complete responders: 21/21
	Progression-free survival
		• 100%--12 months
	Overall survival
		• not available (132)
Buckner, n=9
	Chemotherapy
		• cisplatin/VP-16 • complete responders: 6/8
	Radiation
		• reduced in chemoresponders
	Chemotherapy and radiation therapy
		• complete responders: 9/9
	Progression-free survival
		• 100%--57 months*
	Overall survival
		• 100%--57 months* (19)
Bouffet, n=51
	Chemotherapy
		• cisplatin/VP-16 • ifosfamide/VP-16 • complete responders: 18/38
	Radiation
		• reduced in chemoresponders
	Progression-free survival
		• 96.4%--3 years
	Overall survival
		• 98%--3 years (17)
Sawamura, n=6, 11
	Chemotherapy
		• cisplatin/VP-16 • cisplatin/VP-16/ifosfamide • complete responders: 14/14
	Radiation
		• 24 Gy IF
	Chemotherapy and radiation therapy
		• complete responders: 14/14
	Progression-free survival
		• 94%--2 years
	Overall survival
		• 100%-2 years (121)
Balmaceda, n=45
	Chemotherapy
		• carboplatin/VP-16 • bleomycin • complete responders: 37/45
	Radiation
		• none
	Overall survival
		• 84%-2 years (11)
Allen, n=11
	Chemotherapy
		• carboplatin • complete responders: 7/11
	Radiation
		• 30 Gy IF • 21 Gy CS **
	Chemotherapy and radiation therapy
		• complete responders: 11/11
	Progression-free survival
		• 91%--2 years
	Overall survival
		• 91%-2 years (04)
Aoyama, n=16
	Chemotherapy
		• Etoposide • Cisplatin • Complete response 13/13
	Radiation
		• 24GY IF
	Progression-free survival
		• 86% at 5 years
	Overall survival
		• 100% at 5 years (06)
IF: involved field radiation; CS: craniospinal irradiation * 57-month median (range 10-76); no patient has yet recurred ** CS irradiation for patients who had documented CSF dissemination at diagnosis

Outcomes

The prognosis for patients with CNS germinoma has improved dramatically over the last 3 decades with refinements in neurosurgical, neuroradiologic, and oncologic techniques. Five-year and 10-year survival rates in most studies have been 90% or greater for patients with germinomas treated with conventional radiotherapy regimens (73; 27; 45; 21; 128; 144; 47; 13; 41; 80; 131; 121a; 12). Survival rates for patients treated prior to 1980 are difficult to interpret because surgical verification of tumor histology was often not undertaken and tumor staging was sometimes incomplete. Earlier series, therefore, probably include tumors of various histology, extent, and prognosis. In addition to the presence of nongerminoma histologic features, some studies have suggested that elevated serum or CSF HCG levels (11; 121a; 49), the presence of syncytiotrophoblastic giant cells (147; 80; 129; 121a), or the presence of a cystic component on pre-treatment MRI (87), are poor prognostic factors in patients with germinomas. Germinomas with HCG-producing syncytiotrophoblastic giant cells (STGCs) have been implicated as poor prognostic indicators in some early studies. However, Fujimaki and colleagues reported a study of 131 germinomas and 39 STGC- or HCG-producing germinomas (HCG 2 to 200 mIU/ml). After induction chemotherapy, the relapse-free rate for germinoma was 90.1% and 84.6% for HCG germinoma, and the 5-year survival rates were 98.3% and 100% respectively. There was no clinically significant difference in outcome between germinomas and HCG germinomas (36).

Despite the excellent survival of patients with CNS germinomas, tumor-related deficits frequently do not fully resolve (41; 98). Residual endocrine abnormalities in patients with neurohypophyseal tumors are extremely common, as are persistent eye movement deficits and visual field disturbances. Preoperative hormonal assessment can aide in determining the postoperative need for hormone replacement in patients with suprasellar germinomas (91). Of even greater concern are the long-term consequences of chemotherapy and CNS irradiation. Both adults and children are at risk, but late effects are more common, and more pronounced at both ends of the age spectrum. Chemotherapy alone can produce lasting deficits in physical, psychosocial, and intellectual functioning, all of which are more prominent when cranial irradiation is added to the treatment approach (115). Even low doses of irradiation can produce significant late effects (54; 98). In children and adolescents, hypothalamic and pituitary dysfunction, hearing loss, growth retardation, and progressive cognitive dysfunction are especially common. One study of neurocognitive function showed significant decline in working memory, processing speed, and visual memory over time (76). O’Neil and colleagues report that an approach utilizing chemotherapy followed by reduced-dose irradiation may lead to better neurocognitive outcomes in children and adolescents (100). If craniospinal irradiation is used, bone marrow suppression, gonadal and thyroid hypofunction, and growth deficiencies become additional concerns (121; 17; 124). Infertility and second malignancies are also a concern in long-term survivors who receive alkylating agent or topoisomerase II inhibitor-containing chemotherapy regimens. The exact incidence of these complications is difficult to determine, and published studies vary widely in reported complication rates, based partly on differing definitions and durations of follow-up, but reduced educational and occupational attainment, the need for special education, and compromised social and personal functioning have been reported in 30% to 100% of long-term survivors. Data from Sutton and colleagues showed that the long-term outcome of 22 patients with marker negative suprasellar germinomas treated with neuro-axis RT had no significant long-term effects, except short stature in females and the need for hormone replacement (135). There was no correlation with age at the time of radiation treatment and any adverse effects.

Another complication of intracranial germinomas is their ability to spread via ventriculo-peritoneal shunts. This suggests that abdominal imaging may be required for surveillance purposes. Dissemination into the abdominal cavity may occur months to years after shunt placement and necessitates abdominal therapies, such as radiation or chemotherapy.

Media

References

01: Alapetite C, Brisse H, Patte C, et al. Pattern of relapse and outcome of non- metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 2010;12(12):1318-25. PMID 20716594
02: Alapetite C, Patte C, Frappaz D, et al. Long-term follow-up of intracranial germinoma treated with primary chemotherapy followed by focal radiation treatment: the SFOP-90 experience. Neurooncol 2005;7:517.
03: Albrecht S, Armstrong DL, Mahoney DH, Cheek WR, Colley LD. Cytogenetic demonstration of gene amplification in a primary intracranial germ cell tumor. Genes Chromosomes Cancer 1993;6:61-3. PMID 7680224
04: Allen JC, DaRosso RC, Donahue B, Nirenberg A. A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 1994;74:940-4. PMID 8039122
05: Allen JC, Kim JH, Packer RJ. Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J Neurosurg 1987;67:65-70. PMID 2439668
06: Aoyama H, Shirato H, Ikeda J, et al. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20(3):857-65. PMID 11821471
07: Aoyama H, Shirato H, Kakuto Y, et al. Pathologically-proven intracranial germinoma treated with radiation therapy. Radiother Oncol 1998;47:201-5. PMID 9683370
08: Arens R, Marcus D, Engelberg S, Findler G, Goodman RM, Passwell JH. Cerebral germinomas and Klinefelter syndrome. A review. Cancer 1988;15:1228-31. PMID 3277702
09: Aridgides P, Janssens GO, Braunstein S, et al. Gliomas, germ cell tumors, and craniopharyngioma. Pediatr Blood Cancer 2020:e28401. PMID 32960496
10: Asgharzadeh S, Gonzalez-Gomez I, Tu YX, Gilles FH, Krieger M, Finlay JL. CD117 expression in CNS germinoma and correlation with c-kit mutational analysis. Neurooncol 2005;7:514.
11: Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. J Clin Oncol 1996;14:2908-15. PMID 8918487
12: Bamberg M, Kortmann RD, Calaminus G, et al. Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 1999;17:2585-92. PMID 10561326
13: Baranzelli MC, Patte C, Bouffet E, et al. C. Nonmetastatic intracranial germinoma. The experience of the French Society of Pediatric Oncology. Cancer 1997;80:1792-7. PMID 9351549
14: Bartels U, Onar-Thomas A, Patel SK, et al. Phase II trial of response-based radiation therapy for patients with localized germinoma: a Children's Oncology Group study. Neuro Oncol 2022;24(6):974-83. PMID 34850169
15: Bartels U, Singhal A. Central nervous system germ cell tumors (CNS-GCT). In: Scheinemann K, Bouffet, editors. Pediatric Neuro-oncology. New Yok: Springer, 2015:149-62.
16: Bentley AJ, Parkinson MC, Harding BN, Bains RM, Lantos PL. A comparative morphological and immunohistochemical study of testicular seminomas and intracranial germinomas. Histopathology 1990;17:443-9. PMID 2076869
17: Bouffet E, Baranzelli MC, Patte C, et al. Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Br J Cancer 1999;79:1199-204. PMID 10098759
18: Breen WG, Blanchard MJ, Rao AN, Daniels DJ, Buckner JC, Laack NN. Optimal radiotherapy target volumes in intracranial nongerminomatous germ cell tumors: long-term institutional experience with chemotherapy, surgery, and dose- and field-adapted radiotherapy. Pediatr Blood Cancer 2017;64(11). PMID 28695992
19: Buckner JC, Peethambaram PP, Smithson WA, et al. Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol 1999;17:933-40. PMID 10071287
20: Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013;15(6):788-96. PMID 23460321
21: Calaminus G, Bamberg M, Baranzelli MC, et al. Intracranial germ cell tumors: a comprehensive update of the European data. Neuropediatrics 1994;25:26-32. PMID 8208347
22: Cheng L, Sung MT, Cossu-Rocca P, et al. OCT4: biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol 2007;211(1):1-9. PMID 17117392
23: Cheng S, Kilday JP, Laperriere N, et al. Outcomes of children with central nervous system germinoma treated with multi-agent chemotherapy followed by reduced radiation. J Neurooncol 2016;127(1):173-80. PMID 26744133
24: Chik K, Li C, Shing MM, Leung T, Yuen PM. Intracranial germ cell tumors in children with and without Down syndrome. J Pediatr Hematol Oncol 1999;21:149-51. PMID 10206462
25: da Silva NS, Cappellano AM, Diez B, et al. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 2010;54(3):377-83. PMID 20063410
26: Dattoli MJ, Newall J. Radiation therapy for intracranial germinoma: the case for limited volume treatment. Int J Radiat Oncol Biol Phys 1990;19:429-33. PMID 2394620
27: Dearnaley DP, A’Hern RP, Whittaker, Bloom HJ. Pineal and CNS germ cell tumors: royal Marsden Hospital experience 1962-1987. Int J Radiat Oncol Biol Phys 1990;18:773-81. PMID 2323968
28: De Bruin TW, Slater RM, Defferrare R, et al. Isochromosome 12p-positive pineal germ cell tumor. Cancer Res 1994;54:1542-4. PMID 8137260
29: Douglas J, Rockhill J, Olson J, Ellenbogen R, Geyer JR. Cisplatin-based chemotherapy followed by focal, reduced-dose irradiation for pediatric primary central nervous system germinomas. J Pediatr Hematol Oncol 2006;28(1):36-9. PMID 16394891
30: Echevarria ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008;13(6):690-9. PMID 18586924
31: Endo H, Kumabe T, Jokura H, Tominaga T. Stereotactic radiosurgery followed by whole ventricular irradiation for primary intracranial germinoma of the pineal region. Minim Invas Neurosurg 2005;48(3):186-90. PMID 16015498
32: Finlay J, Saba da Silva N, Lavey R, et al. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolution. Pediatr Blood Cancer 2008;51:313-6. PMID 18421722
33: Friedman JA, Lynch JJ, Buckner JC, Scheithauer BW, Raffel C. Management of malignant pineal germ cell tumors with residual mature teratoma. Neurosurgery 2001;48(3):518-22. PMID 11270541
34: Friedman NB, Van de Velde RL. Germ cell tumors in man, pleiotropic mice, and continuity of germplasm and somatoplasm. Hum Pathol 1981;12:772-6. PMID 7309029
35: Fujimaki T, Matsutani M, Funada N, et al. CT and MRI features of intracranial germ cell tumors. J Neurooncol 1994;19:217-26. PMID 7807172
36: Fujimaki T, Matsutani M, The Japanese Pediatric Brain Tumor Study Group. HCG-producing germinoma: analysis of Japanese pediatric brain tumor study group results. Neurooncol 2005;7:518.
37: Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 2014;32(34):3810-6. PMID 25349290
38: Grodman H, Wolfe L, Kretschmar C. Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low-dose continuous intravenous etoposide along with dose-intensive chemotherapy followed by autologous hematopoietic stem cell rescue. Pediatr Blood Cancer 2009;53(1):33-6. PMID 19326417
39: Haas-Kogan D, Missett B, Wara W, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiation Oncology Biol Phys 2003;56(2):511-8. PMID 12738328
40: Haddock MG, Schild SE, Scheithauer BW, Schomberg PJ. Radiation therapy for histologically confirmed primary central nervous system germinoma. Int J Radiat Oncol Biol Phys 1997;38:915-23. PMID 9276355
41: Hardenbergh PH, Golden J, Billet A, et al. Intracranial germinoma: the case for lower dose radiation therapy. Int J Radiat Oncol Biol Phys 1997;39:419-26. PMID 9308946
42: Hasegawa T, Kondziolka D, Hadjipanayis CG, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for CNS nongerminomatous germ cell tumors. Report of four cases. Pediatr Neurosurg 2003;38(6):329-33. PMID 12759512
43: Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol. 2005;29(3):368-71. PMID 15725806
44: Hengstman GJ, Gons RA, Lenssen PP, Kappelle AC. Intracranial germinoma presenting as polyradiculopathy due to widespread spinal dissemination. J Neurooncol 2006;80(1):105-6. PMID 16937013
45: Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial germ-cell tumors in children. J Neurosurg 1991;74:545-51. PMID 1848284
46: Hoque R, Menon U, Gonzalez-Toledo E, Gu X, Jaffe SL. CNS germinoma of the pituitary and pineal regions, lateral ventricle and fourth ventricle presenting in adulthood. J La State Med Soc 2008;160(6):319-21. PMID 19283979
47: Huh SJ, Shin KH, Kim IH, Ahn YC, Ha SW, Park CI. Radiotherapy of intracranial germinomas. Radiother Oncol 1996;38:19-23. PMID 8850422
48: Ichimura K, Fukushima S, Totoki Y, et al. Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targetd for therapy. Acta Neuropathol 2016;131(6):889-901. PMID 26956871
49: Inamura T, Nishio S, Ikezaki K, Fukui M. Human chorionic gonadotrophin in CSF, not serum, predicts outcome in germinoma. J Neurol Neurosurg Psychiatry 1999;66:654-7. PMID 10209181
50: Inoue A, Ohnishi T, Kohno S, et al. Significance of human chorionic gonadotropin as a predictor of resistance to standard chemo-radiotherapy for pure germinoma. Neurosurg Rev 2018;41(2):557-65. PMID 28819802
51: Inoue HK, Naganuma H, Ono N. Pathobiology of intracranial germ-cell tumors: immunochemical, immunohistochemical, and electron microscopic investigations. J Neurooncol 1987;5:105-15. PMID 2822861
52: Iwato M, Tachibana O, Tohma Y, Nitta H, Hayashi Y, Yamashita J. Molecular analysis for p53 and mdm2 in intracranial germ cell tumors. Acta Neuropathol 2000a;99:21-5. PMID 10651023
53: Iwato M, Tachibana O, Tohma Y, et al. Alterations of the INK4a/ARF locus in human intracranial germ cell tumors. Cancer Res 2000b; 60(8):2113-5. PMID 10786670
54: Jenkin D, Danjoux C, Greenberg M. Subsequent quality of life for children irradiated for a brain tumor before age four years. Med Pediatr Oncol 1998;31:506-11. PMID 9835903
55: Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63:155-67. PMID 2991485
56: Jensen AW, Laack NN, Buckner JC, Schomberg PJ, Wetmore CJ, Brown PD. Long-term follow-up of dose-adapted and reduced-field radiotherapy with or without chemotherapy for central nervous system germinoma. Int J Radiat Oncol Biol Phys 2010;77(5):1449-56. PMID 20045266
57: Kadota RP, Mahoney DH, Doyle J, et al. Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma. Pediatr Blood Cancer 2008;51(5):675-8. PMID 18623206
58: Kamoshima Y, Sawamura Y, Ikeda J, Shirato H, Aoyama H. Late recurrence and salvage therapy of CNS germinoma. J Neurooncol 2008;90(2):205-11. PMID 18604473
59: Kellie SJ, Boyce H, Dunkel IJ, et al. Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach. Pediatr Blood Cancer 2004a;43(2):126-33. PMID 15236278
60: Kellie SJ, Boyce H, Dunkel IJ, et al. Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol. J Clin Oncol 2004b:22(5):846-53. PMID 14990640
61: Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin 2003;21(1):25-66 PMID 12690644
62: Kim CH, Paek SH, Park IA, et al. Cerebral Hemiatrophy of the Brain: Report of three cases. Acta Neurochir (Wien) 2002:144:145-50. PMID 11862514
63: Kleihues P, Cavenee WK. Pathology and genetics of tumours of the nervous system. Lyon: IARC Press, 2000:208-14.
64: Kortmann RD, Gobel U, Koch S, et al. Outcome after reduction of irradiation dosage in patients with intracranial nonmetastatic germinoma: a comparison between MAKEI 89 and SIOP CNS GCT 96. Neurooncol 2005;7:532.
65: Kremenevski N, Buchfelder M, Hore N. Intracranial germinomas: diagnosis, pathogenesis, clinical presentation, and management. Curr Oncol Rep 2023;25(7):765-75. PMID 37036624
66: Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the children’s oncology group. Pediatr Blood Cancer 2007;48:285-91. PMID 16598761
67: Kubota H, Umeda K, Kagehiro K, et al. High-dose chemotherapy with autologous stem cell transplantation spares re-irradiation for recurrent intracranial germinoma. Pediatr Blood Cancer 2018;65(8):e27104. PMID 29693779
68: Lee SH, Jung KW, Ha J, et al. Nationwide population-based incidence and survival rates of malignant central nervous system germ cell tumors in Korea, 2005-2012. Cancer Res Treat 2017;49(2):494-501. PMID 27554477
69: Legido A, Packer RJ, Sutton LN, et al. Suprasellar germinomas in childhood. A reappraisal. Cancer 1989;63:340-4. PMID 2910439
70: Liu B, Arakawa Y, Yokogawa R, et al. PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes. PLoS One 2018;13(4):e0194594. PMID 29617441
71: Lian X, Hou X, Yan J, et al. Treatment outcomes of intracranial germinoma: a retrospective analysis of 170 patients from a single institution. J Cancer Res Clin Oncol 2019;145(3):709-15. PMID 30209611
72: Liang L, Korogi Y, Sugahara T, et al. MRI of intracranial germ-cell tumours. Neuroradiology 2002:44:382-8. PMID 12012121
73: Linstadt D, Wara WM, Edwards MS, Hudgins RJ, Sheline GE. Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation. Int J Rad Oncol Biol Phys 1988;15:291-7. PMID 3403312
74: Looijenga LH. Human germ cell tumors: identification of relevant subgroups. Neurooncol 2005;7:516.
75: Ma TM, Grimm J, McIntyre R, et al. A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation. Radiother Oncol 2017;125(2):234-40. PMID 29128167
76: Mabbott DJ, Monsalves E, Spiegler BJ, et al. Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood. Cancer 2011;117(23):5402-11. PMID 21563173
77: MacDonald SM, Trofimov A, Safai S, et al. Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. Int J Radiat Oncol Biol Phys 2011;79(1):121-9. PMID 20452141
78: Martens T, Rotermund R, Zu Eulenburg C, Westphal M, Flitsch J. Long-term follow-up and quality of life in patients with intracranial germinoma. Neurosurg Rev 2014;37(3):445-50. PMID 24715277
79: Matsumoto F, Takeshima H, Yamashita S, et al. Epidemiologic study of primary brain tumors in Miyazaki prefecture: a regional 10-year survey in southern Japan. Neurol Med Chir (Tokyo) 2021;61(8):492-8. PMID 34148943
80: Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446-55. PMID 9046301
81: Mei K, Liu A, Allan RW, et al. Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases. Mod Pathol 2009;22(12):1628-36. PMID 19820689
82: Merchant TE, Davis BJ, Sheldon JM, Leibel SA. Radiation therapy for relapsed CNS germinoma after primary chemotherapy. J Clin Oncol 1998;16:204-9. PMID 9440744
83: Mishima K, Kato Y, Kaneko MK, et al. Podoplanin expression in primary central nervous system germ cell tumors: a useful histological marker for the diagnosis of germinoma. Acta Neuropathol 2006;111(6):563-8. PMID 16718353
84: Miyanohara O, Takeshima H, Kaji M, et al. Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J Neurosurg 2002;97:177-83. PMID 12134909
85: Mizoguchi M, Takanori I, Shono T, et al. A comparative study of apoptosis and proliferation in germinoma and glioblastoma. Neuro-Oncology 2000;2:96-102. PMID 11303626
86: Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors. J Clin Oncol 2004:22(10):1934-43. PMID 15143087
87: Moon WK, Chang KH, Han MH, Kim IO. Intracranial germinomas: correlation of imaging findings with tumor response to radiation therapy. Am J Roentgenol 1999;172:713-6. PMID 10063866
88: Mori Y, Kobayashi T, Hasegawa T, Yoshida K, Kida Y. Stereotactic radiosurgery for pineal and related tumors. Prog Neurol Surg 2009;23:106-18. PMID 19329865
89: Nakamura H, Makino K, Yano S, et al. Epidemiological study of primary intracranial tumors: a regional survey in Kumamoto prefecture in southern Japan--20-year study. Int J Clin Oncol 2011;16(4):314-21. PMID 21240684
90: Nakashima T, Nishimura Y, Sakai N, Yamada H, Hara A. Germinoma in cerebral hemisphere associated with Down syndrome. Childs Nerv Syst 1997;13:563-6. PMID 9403208
91: Nam DH, Wang KC, Shin CH, Yang SW, Cho BK. A simple method of predicting normal outcome in children with intracranial germinoma. Childs Nerv Syst 1999;15:179-84. PMID 10361968
92: Neelima R, Mathew A, Kapilamoorthy TR, Radhakrishnan VV. Germinoma of medulla. Neurol India 2010;58(5):768-70. PMID 21045508
93: Ngan KW, Jung SM, Lee LY, Chuang WY, Yeh CJ, Hsieh YY. Immunohistochemical expression of OCT4 in primary central nervous system germ cell tumours. J Clin Neurosci 2008;15(2):149-52. PMID 17997317
94: Nguyen QN, Chang EL, Allen PK, et al. Focal and craniospinal irradiation for patients with intracranial germinoma and patterns of failure. Cancer 2006;107(9):2228-36. PMID 17019739
95: Ogawa K, Shikama N, Toita T, et al. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 2004;58(3):705-13. PMID 14967424
96: Ogawa K, Yoshii Y, Shikama N, et al. Spinal recurrence from intracranial germinoma: risk factors and treatment outcome for spinal recurrence. Int J Radiat Oncol Biol Phys 2008;72(5):1347-54. PMID 18513888
97: Ogiwara H, Tsutsumi Y, Matsuoka K, Kiyotani C, Terashima K, Morota N. Apparent diffusion coefficient of intracranial germ cell tumors. J Neurooncol 2014;121(3):565-71. PMID 25413617
98: Oka H, Kawano N, Tanaka T, et al. Long-term functional outcome of suprasellar germinomas: usefulness and limitations of radiotherapy. J Neurooncology 1998;40:185-90. PMID 9892101
99: Okamato K, Ito J, Ishikawa K, et al. Atrophy of the basal ganglia as the initial diagnostic sign of germinoma in the basal ganglia. Neuroradiology 2002:44:389-94. PMID 12012122
100: O'Neil S, Ji L, Buranahirun C, et al. Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatr Blood Cancer 2011;57(4):669-73. PMID 21495164
101: Ono N, Isobe I, Uki J, Kurihara H, Shimizu T, Kohno K. Recurrence of primary intracranial germinomas after complete response with radiotherapy: recurrence patterns and therapy. Neurosurgery 1994;35:615-21. PMID 7528902
102: Osada T, Fujimaki T, Takamizawa M, Tsuno NH, Kirino T, Shibata Y. Dendritic cells activate antitumor immunity for malignant intracranial germ cell tumor: a case report. Jpn J Clin Oncol 2001;31:403-6. PMID 11574635
103: Osorio DS, Finlay JL, Dhall G, Goldman S, Eisenstat D, Brown RJ. Feasibility of dasatinib in children and adolescents with new or recurrent central nervous system germinoma. Pediatr Blood Cancer 2013;60(9):E100-2. PMID 23754592
104: Ostrum QT, Gittleman H, Truitt G, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro Oncol 2018;1;20(suppl_4):iv1-iv86. PMID 30445539
105: Ozelame RV, Shroff M, Wood B, et al. Basal ganglia germinoma in children with associated ipsilateral cerebral and brain stem hemiatrophy. Pediatr Radiol 2006;36(4):325-30. PMID 16463029
106: Pople IK, Athanasiou TC, Sandeman DR, Coakham HB. The role of endoscopic biopsy and third ventriculostomy in the management of pineal region tumours. Br J Neurosurg 2001;15:305-11. PMID 11599445
107: Prall JA, McGavran L, Greffe BS, Partington MD. Intracranial malignant germ cell tumor and the Klinefelter syndrome. Case report and review of the literature. Pediatr Neurosurg 1995;23:219-24. PMID 8835213
108: Queipo G, Aguirre D, Nieto K, et al. Intracranial germ cell tumors: association with Klinefelter syndrome and sex chromosome aneuploidies. Cytogenet Genome Res 2008;121(3-4):211-4. PMID 18758161
109: Regis J, Bouillot P, Rouby-Volot F, Figarella-Branger D, Dufour H, Peragut JC. Pineal region tumors and the role of stereotactic biopsy: review of the mortality, morbidity, and diagnostic rates in 370 cases. Neurosurgery 1996;39:907-12. PMID 8905744
110: Rogers SJ, Mosleh-Shirazi MA, Saran FH. Radiotherapy of localised intracranial germinoma: time to sever historical ties. Lancet Oncol 2005; 6(7):509-19. PMID 15992700
111: Rosenblum MK, Nakazato Y, Matsutani M, et al. Germ Cell Tumours. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System, Revised 4th Edition. France: IARC Pubilcations, 2016:286-91.
112: Rubinstein LJ. Tumors and tumor-like lesions of maldevelopmental origin. In: Russell DS, Rubinstein LJ, editors. Pathology of tumours of the nervous system. 5th ed. Baltimore: Williams and Wilkins, 1989:665-76.
113: Russell DS, Rubinstein LJ. Pathology of tumours of the nervous system, 5th ed. Baltimore: Williams and Wilkins, 1989:664-76.
114: Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. c-kit gene mutations in intracranial germinomas. Cancer Sci 2004:95(9):716-20. PMID 15471556
115: Sands SA, Kellie SJ, Davidow AL, et al. Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: from the first international CNS germ-cell tumor study. Neuro-oncology 2001;3:174-83. PMID 11465398
116: Sano K. Pathogenesis of intracranial germ cell tumors reconsidered. J Neurosurg 1999;90:258-64. PMID 9950496
117: Santagata S, Hornick JL, Ligon KL. Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG. Am J Surg Pathol 2006;30(12):1613-8. PMID 17122519
118: Satge D, Sommelet D, Geneix A, Nishi M, Malet P, Vekemans M. A tumor profile in Down Syndrome. Am J Med Genet 1998;78:207-16. PMID 9677053
119: Satoh E, Imai A, Furui T. Successful pregnancy in a woman with acquired hypogonadism after treatment with radiotherapy for cranial tumor. J Obstet Gynaecol. 2005; 25(5):523-5. PMID 16183605
120: Sawamura Y, de Tribolet N, Ishii N, Abe H. Management of primary intracranial germinomas: diagnostic surgery or radical resection. J Neurosurg 1997;87:262-6. PMID 9254091
121: Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H. Germ cell tumours of the central nervous system: treatment considerations based on 111 cases and their long-term clinical outcomes. Eur J Cancer 1998a;34:104-10. PMID 9624246
122: Sawamura Y, Shirato H, Ikeda J, et al. Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 1998b;88:66-72. PMID 9420074
123: Schild SE, Scheithauer BW, Haddock MG, et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 1996;78:2564-71. PMID 8952565
124: Schneider DT, Hilgenfeld E, Schwabe D, et al. Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. J Clin Oncol 1999;17:3226-33. PMID 10506623
125: Schoenfeld GO, Amdur RJ, Schmalfuss IM, et al. Low-dose prophylactic craniospinal radiotherapy for intracranial germinoma. Int J Radiat Oncol Biol Phys 2006;65(2):481-5. PMID 16530341
126: Shibamoto Y. Management of central nervous system germinoma: proposal for a modern strategy. Prog Neurol Surg 2009;23:119-29. PMID 19329866
127: Shibamoto Y, Oda Y, Yamashita J, Takahashi M, Kikuchi H, Abe M. The role of cerebrospinal fluid cytology in radiotherapy planning for intracranial germinoma. Int J Radiat Oncol Biol Phys 1994a;29:1089-94. PMID 8083078
128: Shibamoto Y, Takahashi M, Abe M. Reduction of the radiation dose for intracranial germinoma: a prospective study. Br J Cancer 1994b;70(5):984-9. PMID 7947108
129: Shibamoto Y, Takahashi M, Sasai K. Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated by radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:505-10. PMID 9112445
130: Shinoda J, Yamada H, Sakai N, Ando T, Hirata T, Miwa Y. Placental alkaline phosphatase as a tumor marker for primary intracranial germinoma. J Neurosurg 1988;68:710-7. PMID 3357030
131: Shirato H, Nishio M, Sawamura Y, et al. Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 1997;37:511-5. PMID 9112446
132: Siffert J, Robertson P, Jakacki R, et al. Multiagent neoadjuvant chemotherapy followed by reduced dose radiotherapy for newly diagnosed central nervous system germinoma: preliminary results of a multi-institutional phase II pilot. J Neurooncol 2000;2:294.
133: Sugiyama K, Uozumi T, Arita K, et al. Clinical evaluation of 33 patients with histologically verified germinoma. Surg Neurol 1994;42:200-10. PMID 7940105
134: Sumida M, Uozumi T, Kiya K, et al. MRI of intracranial germ cell tumors. Neuroradiology 1995;37:32-7. PMID 7708186
135: Sutton LN, Radcliffe J, Goldwein JW, et al. Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery 1999;45(6):1292-7. PMID 10598695
136: Takami H, Perry A, Graffeo CS, et al. Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo Clinic and Japanese consortium cohorts. J Neurosurg 2020:1-11. PMID 32005022
137: Takeshima H, Kahi M, Uchida H, Hirano H, Kuratsu J. Expression and distribution of c-kit receptor and its ligand in human CNS germ cell tumors: a useful histological marker for the diagnosis of germinoma. Brain Tumor Pathol 2004;21(1):13-6. PMID 15696963
138: Talamonti G, Ligarotti GK, Bramerio M, Imbesi F. Unusual behaviour of a pineal germinoma mimicking neurosarcoidosis and metastasising along the endoscopic route. BMJ Case Rep 2013;2013. PMID 23912659
139: Taylor MD, Mainprize TG, Squire JA, Rutka JT. Molecular genetics of pineal region neoplasms. J Neurooncol 2001;54:219-38. PMID 11767289
140: Tseng CK, Tsang NM, Jaing TH, Liau CT, Wu CT, Lin KL. Outcome of central nervous system germinoma treatment by chemoradiation. J Pediatr Hematol Oncol 2011;33(4):e138-42. PMID 21516012
141: Villano JL, Propp JM, Porter KR, et al. Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol 2008;10(2):121-30. PMID 18287340
142: Wang L, Yamaguchi S, Burstein MD, et al. Novel somatic and germline mutations in intracranial germ cell tumours. Nature 2014; 511(7508):241-5. PMID 24896186
143: Watanabe A, Horiksohi T, Naganuma H, Satoh E, Nukui H. Intramedullary spinal cord germinoma expresses the protooncogene c-kit. Acta Neurochir (Wien) 2005. PMID 15662572
144: Wolden SL, Wara WM, Larson DA, Prados MD, Edwards MS, Sneed PK. Radiation therapy for primary intracranial germ-cell tumors. Int J Radiat Oncol Biol Phys 1995;32:943-9. PMID 7607968
145: Yamamoto I. Pineal region tumor: surgical anatomy and approach. J Neurooncol 2001;54:263-75. PMID 11767292
146: Yang KY, Li Sh, Lin JW, Su TM, Ho JT, Chen WF. Concurrent chemoradiotherapy for primary cervical spinal cord germinoma. J Clin Neurosci 2009;16(1):155-8. PMID 19008102
147: Yoshida J, Sugita K, Kobayashi T, et al. Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16). Acta Neurochir 1993;120:111-7. PMID 7681619
148: Zissiadis Y, Dutton S, Kiernan M, et al. Stereotactic radiotherapy for pediatric intracranial germ cell tumors. Int J Radiation Oncology Biol Phys 2001;51:108-12. PMID 11516859

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Isaac Yang MD

Dr. Yang of David Geffen School of Medicine at UCLA received a consulting fee from Baxter and research grants from BrainLab and Stryker as an independent contractor.
See Profile
Sanah Vohra PhD MPH

Dr. Vohra of UCLA Health has no relevant financial relationships to disclose.
See Profile

Editor

Deric M Park MD FACP

Dr. Park of the University of Chicago has no relevant financial relationships to disclose.
See Profile

Former Authors

Russell Walker MD
Michael J Glantz MD
Jeffrey J Raizer MD
Sandro Santagata MD PhD
J Paul Duic MD
Santosh Kesari MD PhD
Jai Grewal MD
Harpreet K Grewal MD
John Shin MD
Nadia Laack MD
Aditya Raghunathan MD
Loren Herrera Hernandez MD
Nimish Mohile MD MS FAAN
Alicia Lenzen MD
Rimas V Lukas MD

Patient Profile

Age range of presentation: 2 to 44 years
Sex preponderance: There is an overall male predominance (approximately 1.8:1), though females more commonly have suprasellar lesions compared to males.
Heredity: Heredity may be a factor (Klinefelter Syndrome- 47 XXY; Down Syndrome – trisomy 21)
Population groups selectively affected: Japanese
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Neoplasm of uncertain or unknown behaviour of brain: D43.2
ICD-11: Primary neoplasm of brain of unknown or unspecified type: 2A00.5

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

CNS germinoma

Associated Disorders

Choriocarcinoma
Diabetes insipidus
Embryonal carcinoma
Endodermal sinus tumor
Hydrocephalus
- Immature teratoma
- Mature teratoma
- Pan-hypopituitarism
- Precocious puberty
- Radiation-induced nervous system injury

Differential Diagnosis

nongerminoma germ cell tumors
glioma
meningioma
primitive neuroectodermal tumor
craniopharyngioma
- ependymoma
- pineocytoma
- pineoblastoma
- metastatic tumors
- lymphoma

Also Relevant

Dermoid and epidermoid tumors
Intracranial nongerminomatous germ cell tumors
Optic pathway gliomas
Pituitary adenoma

CNS germinoma …

CNS germinoma

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Table 1. Classification of Germ Cell Tumors According to Markers

Management

Table 2. Chemo-radiotherapy Trials in Patients with CNS Germinomas

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Overview of neuropathology updates for infiltrating gliomas

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Vein of Galen malformations

Circumscribed astrocytic gliomas [Brief]

Adult-type diffuse gliomas [Brief]

Pediatric-type diffuse high-grade gliomas [Brief]

Glioneuronal and neuronal tumors [Brief]

CNS germinoma

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Table 1. Classification of Germ Cell Tumors According to Markers

Management

Table 2. Chemo-radiotherapy Trials in Patients with CNS Germinomas

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Overview of neuropathology updates for infiltrating gliomas

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Vein of Galen malformations

Circumscribed astrocytic gliomas [Brief]

Adult-type diffuse gliomas [Brief]

Pediatric-type diffuse high-grade gliomas [Brief]

Glioneuronal and neuronal tumors [Brief]

This is an article preview.
Start a Free Account
to access the full version.