Intracranial germ cell tumors

INTRODUCTION — Intracranial germ cell tumors (GCTs) are a subset of extragonadal GCTs that arise within the central nervous system (CNS), without evidence of a primary tumor in either the testes or the ovaries. Like other extragonadal GCTs, intracranial GCTs typically arise in midline locations, such as the pineal and suprasellar regions. They affect primarily adolescents and young adults, with a peak incidence in the second decade of life.

Treatment and prognosis vary based on histology and localization, and most tumors require a multidisciplinary approach that includes surgical biopsy or resection, chemotherapy, and/or radiation therapy (RT).

Intracranial GCTs are discussed here. Sacrococcygeal teratomas and extragonadal GCTs arising in the mediastinum and retroperitoneum are discussed separately. (See "Sacrococcygeal teratoma" and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

EPIDEMIOLOGY — Intracranial GCTs occur with increased frequency in East Asia, for reasons that are not known. GCTs make up approximately 15 percent of pediatric central nervous system (CNS) tumors in Japan and Korea, for example, compared with 0.5 to 3 percent of CNS tumors in North America and Europe [1,2].

The age-adjusted annual incidence rate of intracranial GCTs in Japan is 0.45 cases per 100,000 population aged <15 years [3]. Rates in Germany and the United States (US) are approximately one-third as high [4]. In the US, Surveillance, Epidemiology, and End Results (SEER) and Central Brain Tumor Registry of the United States (CBTRUS) data show that Asian/Pacific Islanders have a two- to threefold higher risk of intracranial GCT compared with White Americans, suggesting that genetic factors may be more important than environmental factors in the etiology of GCTs [5].

The peak incidence of intracranial GCT is during the second decade of life, with a median age at diagnosis of 10 to 14 years [6-8]. GCTs constitute approximately one-third of all CNS tumors in this age group [9]. There is a male preponderance of between 2:1 and 3:1, especially with tumors in the pineal region [10,11].

Risk factors are not well established aside from young age, male sex, and geography. Like other extragonadal GCTs, intracranial GCTs occur with increased frequency in males with Klinefelter syndrome (47,XXY) and possibly in individuals with trisomy 21 (Down syndrome) compared with the general pediatric population [12-14].

PATHOLOGY

Histologic classification — The World Health Organization (WHO) classification of tumors of the central nervous system (CNS) recognizes seven histologic types of intracranial GCTs (table 1) [4]. Because germinomas have distinct treatment and prognostic implications, they are typically considered separately from the other GCT subtypes, which are referred to as nongerminomatous GCTs (NGGCTs).

NGGCTs include six tumor subtypes. Most commonly, NGGCTs are composed of more than one subtype and are therefore termed "mixed GCTs":

●Mature teratoma

●Immature teratoma

●Teratoma with somatic-type malignancy (eg, rhabdomyosarcoma, undifferentiated sarcoma)

●Embryonal carcinoma

●Yolk sac tumor

●Choriocarcinoma

●Mixed GCT

Germinomas comprise 60 to 65 percent of all pediatric intracranial GCTs. Mixed GCTs make up approximately 25 percent of NGGCTs and are most commonly a combination of germinoma and teratoma [10,11].

Histologically, pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue. The histologic appearance of NGGCTs varies depending upon the specific cell types present [4]. Infiltrating small lymphocytes are often present and can obscure the diagnosis, especially in small biopsy specimens. Immunophenotypic staining for a variety of molecular markers also contributes to categorization and pathologic diagnosis (table 2).

Secretory characteristics (AFP, hCG) — Some intracranial GCTs secrete alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) into the cerebrospinal fluid (CSF) and/or serum. Tumors may secrete AFP, hCG, or both, depending on the subtype [15]:

●AFP – AFP is mainly secreted by yolk sac tumors; lower levels may be detected from embryonal carcinomas, immature teratomas, and mixed GCTs.

●hCG – hCG is secreted by choriocarcinomas; lower levels may be detected from embryonal carcinomas, immature teratomas, mixed GCTs, and some germinomas with syncytiotrophoblasts (also called hCG-secreting germinomas).

Highly elevated AFP (>500 ng/mL) and hCG (>1000 milli-international units/mL) levels suggest the presence of pure yolk sac tumor or choriocarcinoma, respectively. Although the correlation between magnitude of tumor marker elevation and histology is imperfect, particularly for cases with a limited biopsy or subtotal resection, AFP and hCG levels in embryonal carcinomas, immature teratomas, and mixed GCTs are much lower compared with pure yolk sac tumors or choriocarcinomas.

Pure germinomas generally are associated with absent AFP and hCG levels in both CSF and serum. Although an elevated AFP in either the serum or CSF effectively rules out a pure germinoma, a minority of germinomas are associated with elevated hCG levels in the CSF and/or serum [16,17]. The source of the elevated hCG is thought to be syncytiotrophoblasts that are associated with germinomas. There is, however, no consensus on a threshold hCG level that reliably distinguishes an hCG-secreting germinoma from a choriocarcinoma or a mixed GCT without tumor tissue confirmation [15]. (See 'hCG-secreting germinomas' below.)

Measurement of AFP and hCG in serum and CSF, when safe and appropriate, is part of the diagnostic evaluation of all suspected intracranial GCTs. Thresholds for defining elevations are reviewed below. (See 'Evaluation and diagnosis' below.)

Relationship to gonadal GCTs — The pathologic similarity of CNS and gonadal GCTs, including histology and molecular genetics, suggests that CNS and other extragonadal GCTs derive from primordial germ cells and embryonic stem cells that migrate to the CNS during development [18]. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Pathogenesis'.)

Molecular biology — The molecular pathogenesis of intracranial GCTs is under active investigation. Early studies highlighted frequent chromosomal instability, isochromosome 12p [19-23], and gain-of-function variant of KIT proto-oncogene, receptor tyrosine kinase (KIT) [24,25].

Subsequent next-generation sequencing efforts point to frequent abnormalities in the KIT/Ras and mitogen activated protein kinase (MAPK)/AKT/mechanistic target of rapamycin (mTOR) signaling pathways [7,26-28]. Variants in KIT/Ras and phosphoinositide 3-kinase (PI3K)/AKT pathway genes occur in all subtypes but are most common in germinomas. Germline variants in jumonji domain containing 1C (JMJD1C) were also highly enriched in Japanese patients with intracranial germ cell tumors, suggesting a genetic association [26]. Germinoma cells also highly express programmed cell death ligand 1 (PD-L1) [29].

This emerging genomic information offers promise that therapies targeting the MAPK and PI3K pathways could prove useful in refractory intracranial GCTs or in the newly diagnosed setting as part of a strategy to further reduce or eliminate radiation in some patients.

CLINICAL PRESENTATION

Location — Intracranial GCTs arise almost exclusively from midline locations. The two most frequent sites are the pineal gland and the suprasellar regions, with each accounting for approximately one-third of tumors [8]. Intracranial GCTs can also arise in the basal ganglia, thalamus, cerebral hemisphere, and cerebellum [30,31].

In 5 to 15 percent of cases, patients present with tumors at both pineal and suprasellar locations (referred to as bifocal disease) [8,10,11]; these tumors are usually pure germinomas, especially if serum and CSF human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) levels are normal [7,32].

Evidence of central nervous system (CNS) dissemination, with tumor seeding or multiple tumor nodules along the lateral and third ventricles and/or spine, is observed in up to 20 percent of patients at the time of presentation [8].

Symptoms — Presenting symptoms of patients with intracranial GCTs depend upon the location of the tumor. Delays in diagnosis are common and are associated with a higher incidence of disseminated disease [33]. In particular, symptoms related to endocrinopathy (delayed vertical growth, arginine vasopressin deficiency [AVP-D, previously called central diabetes insipidus], etc) are associated with delays of greater than 12 months.

Pineal tumors — Pineal tumors typically cause obstructive hydrocephalus. Patients present with signs of increased intracranial pressure (headache, vomiting, papilledema, lethargy, somnolence) in 25 to 50 percent of cases. Other symptoms associated with pineal GCTs and obstructive hydrocephalus include ataxia, behavioral changes, and decline in academic performance. (See "Pineal gland masses".)

Neuro-ophthalmologic abnormalities (especially paralysis of upward gaze and convergence) are present in up to 50 percent of cases. (See "Ocular gaze disorders", section on 'Parinaud syndrome'.)

Endocrinopathies are rarely associated with pineal tumors at diagnosis, although AVP-D is sometimes observed and may indicate occult tumor involvement of the floor of the fourth ventricle and the suprasellar area [34].

Suprasellar tumors — Suprasellar GCTs most commonly present with hypothalamic/pituitary dysfunctions, including AVP-D, delayed pubertal development or precocious puberty, isolated growth hormone deficiency, or other aspects of hypopituitarism (central hypothyroidism, adrenal insufficiency). (See "Causes, presentation, and evaluation of sellar masses".)

Suprasellar GCTs can also cause ophthalmologic abnormalities such as decreased visual acuity from chiasmic or optic nerve compression or visual field deficit (classically, bitemporal hemianopsia). Patients with suprasellar GCTs often have chronic subtle symptoms, and their tumors are diagnosed incidentally on imaging studies performed for unrelated reasons.

EVALUATION AND DIAGNOSIS — The diagnosis of intracranial GCTs is suspected based on clinical signs, neuroimaging, and measurement of tumor markers in serum and cerebrospinal fluid (CSF). Histologic examination is needed to establish a definitive diagnosis in almost all cases.

Neuroimaging — Magnetic resonance imaging (MRI) is the preferred imaging technique for diagnosis and staging, although computed tomography (CT) is also fairly sensitive in detecting suprasellar and pineal GCTs because of their hypercellular nature, which results in a hyperdense signal on CT.

On MRI, intracranial GCTs appear isointense or hypointense on T1 sequences and hyperintense on T2 sequences. These tumors typically show homogeneous enhancement with gadolinium or heterogeneous enhancement if cysts are present. Imaging characteristics of the histologic subtypes are similar, and MRIs cannot reliably distinguish germinomas from nongerminomatous GCTs (NGGCTs) [35-37].

MRI of the entire spine is imperative for adequate staging of intracranial GCTs, since 10 to 15 percent of patients will have leptomeningeal spread at the time of diagnosis [10,34].

Tumor markers — The distinction between germinomas and NGGCTs is critical since patients with germinomas have a more favorable prognosis and require less intensive therapy than those with NGGCTs. Tumor markers, such as alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG), are helpful in making this distinction, although histologic examination is required for a definitive diagnosis.

Both markers should be measured in serum and CSF preoperatively, as long as it is safe to perform a lumbar puncture (LP). Ventricular CSF can sometimes be sampled at the time of biopsy if an LP is not feasible preoperatively. Levels of hCG tend to be higher in CSF than serum, whereas levels of AFP tend to be more elevated in serum than CSF. Elevation in either compartment is considered abnormal. The usual cutoffs for elevation are AFP >10 microg/L (or above the institutional normal range) and hCG >50 international units/L.

Patterns of elevation help to narrow the diagnostic possibilities as follows:

●Normal AFP and hCG in both serum and CSF – Pure germinomas and mature teratomas are expected to show normal AFP and hCG in serum and CSF. All of the other NGGCT subtypes (classically embryonal carcinoma), except yolk sac tumor or choriocarcinoma, can also present with normal tumor markers if they are nonsecretory, as can all of the other central nervous system (CNS) tumors and nonneoplastic etiologies on the differential diagnosis. Histologic diagnosis in these cases is critical.

●Elevated hCG in serum or CSF, normal AFP – Choriocarcinoma is the classic NGGCT associated with hCG secretion, either as pure choriocarcinoma or as part of a mixed GCT. Levels can be highly elevated (eg, >1000 milli-international units/mL) in pure choriocarcinoma. Lower-level elevations of hCG can be seen in hCG-secreting germinomas (although some have levels >100 milli-international units/mL) [16,17]. Uncommonly, immature teratoma, embryonal carcinoma, and mixed GCTs can present with elevated hCG but normal AFP. There lacks an international consensus on the magnitude of hCG that reliably distinguishes an hCG-secreting germinoma from choriocarcinoma or other NGGCTs, and therefore a tissue diagnosis is necessary to guide treatment. (See 'hCG-secreting germinomas' below.)

●Elevated AFP in serum or CSF, normal hCG – Any tumor with an elevated AFP (>10 ng/mL or higher than the institutional normal range) can be assumed to contain a yolk sac tumor component, and high-level AFP elevation (>500 ng/mL) is characteristic of a pure yolk sac tumor. Less dramatic elevations of AFP with normal hCG can also been seen with immature teratomas, embryonal carcinomas, and mixed GCTs.

If a histologic diagnosis is not possible because surgery is contraindicated, patients with an elevated AFP and normal hCG should be treated as they would for an NGGCT with a yolk sac component. A serum AFP >1000 ng/mL has been identified as a poor prognostic indicator [38], but since a significant proportion of these tumors have mixed components, using tumor markers alone for risk stratification without a tissue diagnosis (whether retrospectively or prospectively) would likely lead to unreliable or biased results.

●Elevated AFP and hCG – Elevation of both tumor markers is most commonly seen with immature teratoma, embryonal carcinoma, and mixed GCTs. In the absence of a tissue diagnosis, these tumors are treated as NGGCTs, although risk stratification based on histologies will likely be more informative and possibly practice changing in the future.

CSF cytology — CSF cytology should be obtained during staging of an intracranial GCT whenever an LP can be safely performed. Even if MRI of the spine does not show evidence of tumor involvement, patients with positive CSF cytology are considered to have metastatic intracranial GCTs and should receive craniospinal irradiation (CSI) as part of their treatment. (See 'Management of germinomas' below.)

If CSF cytology cannot be obtained preoperatively or if ventricular CSF cytology is positive at the time of surgery, an LP should be performed two weeks later for staging [15]. Ventricular fluid obtained perioperatively should not be used for determining metastatic status.

Biopsy and initial surgical management — The initial surgical management of suspected intracranial GCTs differs from that of many other primary brain tumors in that maximal safe resection is usually not undertaken as the initial procedure. GCTs arise in deep, midline locations, which may not be amenable to radical resection without high risk of surgical morbidity [39]. In addition, more than one-half of GCTs are germinomas, which do not require surgical debulking because they are exquisitely sensitive to radiation and chemotherapy.

A biopsy is therefore the initial procedure of choice in most cases. Consensus guidelines recommend against surgical resection of germinomas [2,15]. "Second-look" surgery is used to resect residual NGGCTs after radiation and/or chemotherapy, when possible. (See '"Second-look" surgery' below.)

The biopsy approach depends on the location of the tumor, the need for concomitant ventriculostomy, and surgeon preference. Pineal region tumors can often be accessed endoscopically, which allows for biopsy and third ventriculostomy, if needed for hydrocephalus, during the same procedure. Suprasellar masses may be accessed transsphenoidally or via frontal craniotomy.

There are two potential exceptions to the need for a tissue diagnosis, which are only applicable in select cases and are not uniformly accepted.

●Suspected bifocal germinoma – Patients with an enhancing mass in both the suprasellar region and the pineal region who have negative serum and CSF tumor markers may be treated empirically for germinoma in selected cases. Practice varies, however, and some expert groups favor biopsy even for patients with suspected bifocal germinoma [2]. In a Japanese study of 89 bifocal tumor cases with arginine vasopressin deficiency (AVP-D) and negative tumor markers who underwent biopsy, germinoma was confirmed in the majority (96 percent); three NGGCTs were identified (two mixed GCTs and one embryonal carcinoma) [32].

●Suspected NGGCT with elevated AFP and/or hCG – Selected patients with a high AFP and/or hCG and a clinical presentation and imaging suggestive of NGGCT may be treated for NGGCT without confirmatory tissue. This exception primarily applies to patients who do not have a separate indication for surgery (eg, hydrocephalus) and in whom a biopsy would pose significant risk. Without tissue, and because there lacks an international consensus on the magnitude of hCG that reliably distinguishes an hCG-secreting germinoma from an NGGCT, there remains a risk of overtreatment of an hCG-secreting germinoma as an NGGCT.

A biopsy to obtain tissue for diagnosis is always necessary for patients with a possible GCT who have normal CSF and serum AFP and hCG, as a pure germinoma, mature teratoma, and other tumor marker-negative NGGCTs must be distinguished from other benign and malignant lesions. (See 'Differential diagnosis' below.)

Integrated diagnosis and staging — Final pathologic results should always be considered in the context of the preoperative diagnostic evaluation and the limitations of the diagnostic technique. Surgical biopsies often yield only a small sample, and this can lead to an inaccurate tissue diagnosis. As an example, in a mixed GCT that contains both germinoma and nongerminomatous components, a small biopsy may only include an area of pure germinoma.

When the tissue diagnosis is discordant from the CSF and/or serum markers, treatment should be based upon the result that is associated with the most malignant histology and worst prognosis. As an example, a tissue diagnosis of a pure germinoma would be inconsistent with an elevated AFP, and such a patient should be considered as having an NGGCT with a yolk sac component. Conversely, if the tissue diagnosis reveals elements of an NGGCT, despite normal AFP and/or hCG levels, the patient should be treated as having an NGGCT and not a pure germinoma. (See 'Management of nongerminomatous GCTs' below.)

Intracranial GCTs are classified as localized (M0) or disseminated/metastatic (M+), similar to other pediatric CNS tumors. Metastatic disease includes patients with positive cytology and/or evidence of intracranial and/or spinal metastases on neuroimaging. Bifocal lesions in the pineal and suprasellar region without other evidence of metastasis are considered nondisseminated. Patients with documented or suspected extra-CNS findings (eg, enlarged testicle, intra-abdominal pain/mass on examination) should undergo systemic imaging studies.

Differential diagnosis — Intracranial GCTs must be distinguished from other benign and malignant lesions, including:

●Pineal location – CNS embryonal tumors (most common), pineal parenchymal tumors, ependymoma (rare)

●Suprasellar location – Langerhans cell histiocytosis (most common), craniopharyngioma

●Either location – Low-grade glioma (most common), hamartoma, or metastatic disease from extracranial tumors

MANAGEMENT OF GERMINOMAS

Localized germinoma

Selection of therapy — Intracranial germinomas are exquisitely sensitive to radiation therapy (RT) but have the potential to disseminate and recur throughout the craniospinal axis. For localized germinoma, the highest risk of recurrence is locally and along the walls of the ventricles, and high cure rates (>90 percent) are achieved with RT-alone approaches that include the whole ventricular system [40-47].

Chemotherapy is also associated with high response rates in germinoma but is not curative as responses are not durable [48-50]. Therefore, its role is primarily to allow for a reduction in RT dose in the hopes of decreasing long-term neurocognitive and endocrine side effects of RT. Contemporary cooperative group clinical trials for localized germinoma aim to identify optimal combinations of chemotherapy and response-adapted RT that maintain excellent survival of RT alone while decreasing late toxicities among survivors.

Outside of clinical trials, current treatment approaches for patients with localized germinoma include the following:

●Radiation alone, consisting of whole-ventricle RT (21 to 24 Gy) plus a tumor boost for a total dose of 40 to 45 Gy (see 'Radiation alone approach' below)

●Neoadjuvant platinum-based chemotherapy and response-adapted RT consisting of whole-ventricle RT plus a tumor boost; RT doses are determined by response to neoadjuvant chemotherapy, and patients with a complete response (CR) to chemotherapy receive reduced doses of RT compared with those used for RT alone (see 'Combined chemotherapy and radiation' below)

Both approaches are associated with long-term survival exceeding 90 percent but have not been compared directly in randomized trials given the rarity of the tumor and the iterative nature of cooperative group trials exploring combination therapy. Although there is a reasonable expectation that lower doses of RT will translate into better neurocognitive and endocrine outcomes in children with germinomas, this theoretical benefit will need to be validated with long-term follow-up, and the reductions in RT dose after neoadjuvant chemotherapy are relatively small (ie, <10 to 15 Gy). Furthermore, multiagent chemotherapy extends treatment time by at least three months and exposes patients to additional systemic toxicities.

The choice is therefore individualized based on patient age, access to clinical trials, and patient and caregiver preferences. Because the potential gains from reduced doses of RT vary inversely with age, we favor neoadjuvant chemotherapy plus response-adapted RT in younger patients (eg, <10 years), ideally in the context of a clinical trial. In older patients, the advantages and disadvantages are more closely balanced, and RT alone remains a reasonable and commonly used approach [47].

International consensus guidelines increasingly favor combination therapy for localized germinoma in patients of any age [2,15]. There is broad agreement that craniospinal irradiation (CSI) and chemotherapy-alone approaches are not recommended for localized germinoma.

Radiation alone approach — Patients with localized germinoma who are selected for RT alone (without neoadjuvant chemotherapy) should receive whole-ventricle RT (21 to 24 Gy) and an additional boost to the tumor for a total dose of 40 to 45 Gy [51].

Historically, patients with localized germinomas received full CSI (36 Gy) and a boost to the primary tumor for a total dose of 50 to 54 Gy. Subsequent observational studies comparing CSI with whole brain or whole-ventricle RT found that the number of spinal relapses remained low (<10 percent) in patients who received brain-only RT, suggesting that spinal RT prophylaxis could be omitted [42,52-59]. Thereafter, whole-ventricle RT plus tumor boost replaced CSI as the standard of care for RT alone.

In observational studies, patients treated with whole-ventricle RT plus tumor boost have progression-free and long-term survival rates exceeding 90 percent [40-47]. Outcomes are illustrated by a retrospective, single-center study of 213 consecutive patients with intracranial germinoma treated over a 50-year period [47]. From 2012 onward, standard of care for localized germinoma consisted of whole-ventricle/whole brain RT plus tumor boost without chemotherapy. Among 33 patients treated in this manner, five-year disease-free and overall survival rates were 94 and 100 percent, respectively, with a median follow-up of 55 months.

Further reduction in the volume of RT from tumor plus whole-ventricle to tumor-only (involved field) is not recommended for localized germinoma, as recurrence rates increase significantly. This was demonstrated in a series of 35 patients with localized germinomas who received either whole-ventricle or focal tumor RT [57]. Among 21 patients treated with whole-ventricle RT, none developed recurrent disease. By contrast, 5 of 14 (36 percent) who received only focal tumor RT had recurrent tumors within the ventricular system but outside the primary treatment field. Similarly, in a second series, the recurrence rate for patients receiving localized RT without ventricular coverage was higher than in those receiving CSI (28 versus 2 percent) [40].

Studies using neoadjuvant chemotherapy in localized germinoma have also reinforced the importance of whole-ventricle RT rather than focal RT, as discussed below.

Combined chemotherapy and radiation — Germinomas are known to be highly sensitive to chemotherapy, although responses are not durable. Thus, clinical research has focused on use of neoadjuvant chemotherapy as a means to further reduce the dose of RT administered to the whole ventricle and tumor, without compromising the excellent survival rate of RT alone [60-67].

Based on cooperative group clinical trials over the past several decades, the current approach to combination therapy for localized germinoma consists of multiagent platinum-based chemotherapy followed by whole-ventricle RT plus a tumor boost, with RT doses determined by best response to chemotherapy. Patients with a CR to chemotherapy receive reduced doses of RT (eg, 18 Gy to the whole ventricle plus 12 Gy tumor boost). Patients with a partial response (PR) or stable disease receive 24 Gy to the whole ventricle and a tumor boost up to a total of 36 to 45 Gy.

Results of this approach are illustrated by results of Stratum 2 of the Children's Oncology Group (COG) trial for localized germinoma (ACNS1123), which studied the efficacy of four 21-day cycles of carboplatin/etoposide followed by, in patients with a CR, reduced-dose whole-ventricle RT (18 Gy) and local tumor boost (12 Gy) [68]. Patients with a PR or stable disease with <1.5 cm residual tumor received standard-dose whole-ventricle RT (24 Gy) plus local tumor boost (12 Gy). Results were as follows:

●The median age of 137 eligible patients was 14 years (range 4.9 to 21.5 years), and 73 percent were male. Most tumors were either pineal (47 percent) or suprasellar (31 percent).

●Seventy-four out of 88 patients who achieved CR and received reduced-dose RT were considered evaluable for the primary outcome; among these patients, three-year progression-free survival (PFS) and overall survival (OS) were 94.5 and 100 percent, respectively. For 16 evaluable patients who received 24 plus 12 Gy after PR or stable disease, three-year PFS and OS were both 93.8 percent.

●Eight relapses occurred among all 137 patients, including three along the biopsy track and three in the spine. All four progressions in the reduced-dose RT cohort were outside the radiation field.

●While the long-term neurocognitive data will require more maturation, those children who received 18 Gy of whole-ventricle RT showed better concentration/attention scores and a nonsignificant trend towards higher mean estimated IQ scores at 30 months compared with those who received 24 Gy of whole-ventricle RT. Importantly, however, this was not a randomized comparison, and the two groups had differential responses to chemotherapy in addition to receiving different doses of RT.

While this trial and other studies support neoadjuvant chemotherapy with response-adapted doses of whole-ventricle RT plus tumor boost as an acceptable alternative to RT alone [60-67], further reductions in RT volume or dose are not recommended outside of clinical trials. This is based on results of both prospective and retrospective studies showing inferior results compared with historical benchmarks when whole-ventricle RT is eliminated, even when neoadjuvant chemotherapy is included in the regimen [69-71]. As examples:

●In a series of 60 patients with localized germinomas, neoadjuvant chemotherapy followed by 40 Gy focal RT to the tumors resulted in an eight-year event-free survival (EFS) of 83 percent [70]. Eight of 10 recurrences occurred outside the RT field, in the periventricular area.

●In the International Society of Paediatric Oncology (SIOP) central nervous system (CNS) GCT 96 prospective nonrandomized study, 190 patients with localized germinomas received either neoadjuvant chemotherapy plus 40 Gy focal RT or 24 Gy CSI with a 16 Gy tumor boost without chemotherapy [71]. The five-year EFS for patients receiving chemotherapy and focal RT was lower than for those receiving RT to a larger field without chemotherapy (88 versus 94 percent). In the patients who received chemotherapy plus focal RT, six of seven recurrences (86 percent) were ventricular, either alone or in combination with local tumor recurrence. In the patients who received CSI, all four relapses were at the original tumor site.

A chemotherapy-only approach is also not recommended [2,15]. Although nearly all patients with localized germinomas respond to chemotherapy, responses are not durable, and chemotherapy alone has resulted in unacceptable tumor recurrence rates. In two series that included a total of 64 patients with pure germinomas, recurrent disease eventually developed in 48 and 58 percent [48,49]. The Third International CNS Germ Cell Tumor Study also confirmed that a chemotherapy-only approach led to inferior EFS compared with radiation-containing regimens [50].

hCG-secreting germinomas — Pure germinomas can contain syncytiotrophoblasts that produce and secrete human chorionic gonadotropin (hCG). Early reports suggested that hCG-secreting germinomas had a higher relapse rate than nonsecreting pure germinomas [45,69]. However, subsequent reanalysis of the data found that the increased rate of recurrence of hCG-secreting germinomas was primarily related to elimination of whole brain and/or whole-ventricle RT [16,17,72,73], and no recurrences were observed in patients with hCG-secreting germinomas who received at least whole-ventricle RT.

The major concern in patients with a presumed hCG-secreting germinoma without tissue diagnosis is whether an element of choriocarcinoma, embryonal carcinoma, and/or immature teratoma is also present. There also lacks an international consensus on a threshold of hCG that would reliably distinguish an hCG-secreting germinoma from a nongerminomatous GCT (NGGCT). Therefore, in patients with an intracranial GCT with elevated hCG and normal alpha-fetoprotein (AFP), a tissue confirmation of germinoma with syncytiotrophoblasts would be needed to establish the diagnosis of an hCG-secreting germinoma; otherwise, patients without tissue diagnosis should be treated as NGGCTs.

Disseminated germinoma — While CSI is no longer considered necessary for children with localized germinomas, CSI continues to be recommended for patients with disseminated germinomas based upon MRI and/or cerebrospinal fluid (CSF) findings. Existing recommendations include treating bifocal tumors as localized tumors if the MRI of the spine and the CSF cytology are negative [2,15].

A change from the historical approach of using 36 Gy CSI was initially supported by a series of 49 patients, in which the dose of CSI was reduced to 30 Gy and the dose of radiation to the primary tumor was decreased from 50 to 45 Gy [40].

Additional data supporting the efficacy of a reduced dose of CSI come from the SIOP CNS GCT 96 study [71]. For patients with metastatic germinoma, the five-year PFS was 98 percent after neoadjuvant chemotherapy, 24 Gy CSI, and a 16 Gy tumor boost (total RT dose to the primary tumor 40 Gy), suggesting that the dose of CSI can be further reduced when given in combination with chemotherapy, even for patients with metastatic germinomas.

Recurrent germinoma — In contemporary series of patients with pure germinomas, recurrences are most commonly encountered in patients who received neoadjuvant chemotherapy and a reduced dose and/or volume of RT. The majority of these patients can be salvaged with radiation with or without chemotherapy [50,70,71,74]. Salvage PFS and OS are reported to be as high as 85 percent [8].

Most recurrent germinomas remain sensitive to chemotherapy, and retreatment with the original regimen is a viable strategy to reinduce a complete remission. For patients who receive RT to a reduced volume and for whom disease recurs outside of the radiation field, CSI alone is a reasonable salvage strategy. If disease recurs in the radiation field, then additional chemotherapy to reinduce a CR/near CR is warranted before consolidating with additional RT.

For patients who have already received CSI, salvage is still possible, with either standard chemotherapy and reirradiation, or an aggressive approach of myeloablative high-dose chemotherapy with autologous stem cell rescue with or without additional RT, if it can be safely tolerated [75-79].

MANAGEMENT OF NONGERMINOMATOUS GCTS — NGGCTs are less common than germinomas, include several histologic subtypes (table 2), and have a worse overall prognosis compared with germinomas. Multimodality therapy is therefore required in all patients. Based on the available data, the standard of care includes neoadjuvant chemotherapy and radiation therapy (RT) that consists of both craniospinal irradiation (CSI) and a tumor boost. Whether a reduced field of RT can be used for certain subgroups of NGGCTs remains controversial, as discussed below.

Mature teratoma — Maximal safe resection is recommended for patients with a histologic diagnosis of mature teratoma by biopsy and normal tumor markers.

In contrast to germinoma and all other NGGCTs, complete resection of a mature teratoma is considered definitive treatment without further adjuvant therapy. For patients with residual tumor after maximal safe resection, adjuvant focal RT has been used, although given the rarity of the tumor, treatment decisions should be individualized [2,15,80].

Multiple retrospective series describe long recurrence-free survival for patients with mature teratoma after surgical resection alone without adjuvant treatment [7,52,72,81,82]. In addition, poor sensitivity to chemotherapy and radiation is demonstrated in patients with growing teratoma syndrome. (See 'Growing teratoma syndrome' below.)

All other histologies — For NGGCTs other than mature teratoma, multimodality therapy is required for optimal local control and recurrence-free survival. Contemporary cooperative group clinical trials continue to investigate the feasibility of de-escalating radiation to minimize long-term sequelae of treatment while not sacrificing overall survival (OS).

Chemotherapy plus CSI — NGGCTs are relatively insensitive to radiation alone. In historical series, patients with NGGCTs treated with RT alone (CSI and a boost to the tumor) had OS rates of 20 to 40 percent [10,11,72,83]. Combining neoadjuvant chemotherapy with CSI significantly improves outcomes, with OS rates exceeding 70 percent [38,71,72,84-88], regardless of localized versus metastatic disease, although results remain inferior to those for patients with germinoma.

Almost all of the chemotherapy regimens for NGGCT contain a platinum compound (either cisplatin or carboplatin) and etoposide [72,85,86], and some groups add ifosfamide or cyclophosphamide to this combination [84,87]. The most common approach uses four to six cycles of chemotherapy prior to "second-look" surgery. This is followed by RT, including CSI (30 to 36 Gy) and a tumor boost (for a total of 54 to 60 Gy).

Results of this approach are illustrated by the Children's Oncology Group (COG) ACNS0122 trial, which enrolled 102 children with newly diagnosed NGGCT (median age 12 years) [87]. The majority of patients had either pineal or suprasellar tumors (54 and 24 percent, respectively). After initial surgery, patients were treated with neoadjuvant carboplatin/etoposide alternating with ifosfamide/etoposide for six cycles, followed by 36 Gy CSI and local tumor boost to 54 Gy. A "second-look" surgery was permitted prior to RT and performed in 15 patients. With a median follow-up of 5.1 years in the entire cohort, five-year progression-free survival (PFS) and OS were 84 and 93 percent, respectively. Among the 49 patients with localized disease who achieved a complete response (CR) or partial response (PR) after neoadjuvant chemotherapy with or without "second-look" surgery, five-year PFS and OS were 92 and 98 percent, respectively. These results led to the subsequent COG NGGCT trial (ACNS1123), which examined the feasibility of reducing the field of radiation from CSI to whole-ventricle with tumor boost. (See 'Potential role of reduced radiation' below.)

The presence of residual disease upon completion of neoadjuvant chemotherapy is a risk factor for worse outcomes. In ACNS0122, those with no residual tumors before radiation had five-year PFS and OS of 100 percent, compared with 81 and 92 percent, respectively, among those with residual tumors; of those patients with residual masses after chemotherapy, 15 patients underwent "second-look" surgery, and five patients had residual elements of NGGCT (one embryonal carcinoma, one mixed GCT, three malignant teratomas) [87]. In the International Society of Paediatric Oncology (SIOP) central nervous system (CNS) GCT 96 trial, the prognostic significance of residual disease after neoadjuvant chemotherapy was even more pronounced; PFS was 85 percent for those with no residual tumors versus 48 percent for those with residual tumors [38]. These data suggest that, while a gross surgical resection at the time of diagnosis may not be necessary, a "second-look" surgery in patients with residual tumors after neoadjuvant chemotherapy (before starting radiation) may significantly improve their long-term outcome. (See '"Second-look" surgery' below.)

The magnitude of alpha-fetoprotein (AFP) elevation is also an adverse prognostic indicator in children with intracranial NGGCTs. In the SIOP CNS GCT 96 study, patients with AFP >1000 microg/L had PFS of 32 percent versus PFS of 76 percent in patients with AFP levels <1000 microg/L [38]. By contrast, the degree of beta-hCG (human chorionic gonadotropin) elevation in children with intracranial NGGCTs does not appear to have an impact on survival [38,65,87].

Potential role of reduced radiation — In selected patients with localized NGGCT, the feasibility of reducing the field of RT has been explored in an effort to reduce long-term toxicities of treatment [38,89-91]. However, results have been mixed, and decisions to omit CSI in patients with NGGCT should continue to be individualized for patients being treated outside of a clinical trial.

●In the SIOP CNS GCT 96 study, 116 patients with localized NGGCT received neoadjuvant chemotherapy followed by local RT (omitting ventricular or spinal irradiation) [38]. This approach showed inferior five-year PFS (72 percent) compared with results from ACNS0122 (neoadjuvant chemotherapy followed by CSI), in which five-year PFS was 92 percent [87]. In one retrospective series, local RT was associated with a 32 percent distant recurrence rate at 10 years [90]; in a second series, local RT with or without ventricular radiation was associated with a four-year PFS of 81 percent [91].

●In ACNS1123, 74 of 137 patients with localized NGGCT achieved a CR or PR after chemotherapy with or without "second-look" surgery and received whole-ventricle RT plus tumor boost [89]. Among these patients, three-year PFS and OS were 88 and 92 percent, respectively [89,92]. All eight recurrences involved distant relapses (six spinal alone, two combined local and spinal). Although the preponderance of spinal relapses prompted early closure of the study and was most likely attributable to the elimination of CSI, the majority of children with localized NGGCT after achieving a PR or CR with neoadjuvant chemotherapy appeared to be cured without CSI. Neurocognitive outcomes have not yet been reported and will be critical to confirm the presumed benefit with reduced RT volume.

●As a follow-up to ACNS1123, ACNS2021 is studying the survival of children with localized NGGCT who achieve a CR or PR with neoadjuvant chemotherapy and who then proceed to receive whole-ventricle and spinal canal irradiation (instead of CSI), hopefully to reduce the incidence of spinal cord-only recurrence seen during ACNS1123.

A retrospective pooled analysis of four large trials in children with NGGCT showed that in 73 patients with localized NGGCT, there was no association between focal whole ventricular irradiation and increased risk of metastatic recurrences, adding further to the controversy of whether CSI can be safely eliminated in patients with localized NGGCT [93].

Pending further prospective data, a definitive recommendation that CSI is not required for children with localized NGGCT who achieve a PR or CR after neoadjuvant chemotherapy may be premature. ACNS1123 had a relatively short median duration of follow-up of three years, so late recurrences beyond three years are possible. In addition, out of the 74 patients who achieved PR or CR and received whole-ventricle RT and tumor boost on ACNS1123, there were 16 patients who were included without tissue diagnosis (five had bifocal disease, 11 had elevated hCG levels). Since these patients may have hCG-secreting germinomas that have a better prognosis compared with NGGCTs [16,17], their inclusion could have contributed to the favorable survival outcomes.

A more detailed breakdown of the patient subgroups in ACNS1123, based on tumor markers and histology, is needed to confirm whether patients classified as "intermediate prognosis" (eg, patients with predominantly germinoma and/or immature teratoma, with minor elements of more aggressive entities), who have shown favorable survival without CSI [72,86], can be safely treated with reduced RT volume. A future trial mandating upfront surgery and tissue diagnosis may be required to accurately determine whether CSI can be eliminated for certain subgroups of NGGCT.

"Second-look" surgery — Although more definitive data are needed, strong consideration should be given to "second-look" surgery in patients who have residual tumors after chemoradiotherapy [39].

There are no definitive data that suggest that gross total resection of NGGCT at the time of diagnosis improves either PFS or OS [38,72]. Instead of pursuing a macroscopic resection of an NGGCT at the initial surgery, such a procedure may be performed more safely as a "second-look" surgery after tumor reduction by neoadjuvant chemotherapy and/or RT. A few early small series have shown that gross total resection of residual NGGCT may improve survival [86,94,95]. At resection, the majority of residual masses in patients with intracranial NGGCTs after chemotherapy and/or RT are mature teratoma and/or necrotic/scar tissue [39], although viable tumor cells have also been observed [86,87,94-98].

In the SIOP CNS GCT 96 trial, five-year PFS was 85 percent for those with no residual tumors versus 48 percent for those with residual tumors [38]. In ACNS0122, those with no residual tumors before radiation had five-year PFS and OS of 100 percent compared with 81 and 92 percent for those with residual tumors [87].

Growing teratoma syndrome — The "growing teratoma syndrome" is defined as a solitary enlarging tumor, with normal or declining AFP and/or beta-hCG, which upon resection proves to be composed entirely of a mature teratoma. This is a well-defined event that occurs in up to 10 percent of patients with extracranial NGGCTs [99] and more rarely in patients with intracranial NGGCTs [100-106]. A contemporary review of 777 cases of pediatric intracranial GCTs identified only 39 cases of growing teratoma syndrome [107]. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Growing teratoma syndrome' and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Rationale for resection of residual masses in patients with NSGCT'.)

Surgical resection of a probable growing mature teratoma should be attempted in patients with intracranial NGGCTs who experience an enlarging solitary tumor during or shortly after chemotherapy or RT despite normalization of tumor markers. This approach avoids subjecting patients to more intensive treatments due to a mistaken diagnosis of tumor recurrence or progression.

Surgical resection for a growing mature teratoma is the only curative intervention, since these lesions do not respond to chemotherapy or RT. Definitive treatment for the underlying NGGCT that gave rise to growing teratoma (ie, RT and chemotherapy) must also be completed, regardless of the definitive surgery undertaken for the growing teratoma.

Recurrent NGGCTs — The prognosis for patients with recurrent intracranial NGGCTs is poor. Nearly all will have received chemotherapy and RT as their initial treatment.

High-dose chemotherapy with autologous stem cell rescue has been attempted with variable success [75-79], and prognosis for recurrent NGGCT is much worse compared with that for recurrent germinoma. Identification of novel effective agents for intracranial NGGCTs is urgently needed to improve clinical outcome for children with these heterogeneous and challenging tumors.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Intracranial germ cell tumors (GCTs) are rare brain tumors that typically arise in midline locations, such as the pineal or suprasellar regions. They affect primarily adolescents and young adults, with a peak incidence in the second decade of life. (See 'Epidemiology' above.)

●Pathology – Intracranial GCTs include a number of histologic tumor types (table 1); the primary distinction is between germinomas and nongerminomatous GCTs (NGGCTs), since NGGCTs require more intensive chemotherapy and craniospinal irradiation (CSI). (See 'Pathology' above.)

●Clinical presentation – Presenting symptoms of patients with intracranial GCTs depend upon the location of the tumor. Pineal tumors often cause obstructive hydrocephalus. Suprasellar tumors commonly present with hypothalamic/pituitary dysfunction including arginine vasopressin deficiency (AVP-D) and delayed or precocious puberty. (See 'Clinical presentation' above.)

●Evaluation and diagnosis – The initial evaluation of a patient with a suspected intracranial GCT should include (algorithm 1):

•Neuroimaging with MRI with and without contrast to include the head and the entire spine (see 'Neuroimaging' above)

•Measurement of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) in both serum and cerebrospinal fluid (CSF) (see 'Tumor markers' above)

•Cytology from CSF, either preoperatively if a lumbar puncture (LP) can be safely performed, or two weeks postoperatively (see 'CSF cytology' above)

•Biopsy of the tissue mass to establish a histologic diagnosis, especially in patients with normal tumor markers (see 'Biopsy and initial surgical management' above)

●Management of germinomas (algorithm 2)

•Localized germinoma – For patients with localized germinoma, we recommend treatment that includes whole-ventricle radiation therapy (RT) with a boost field to the primary tumor, rather than CSI or chemotherapy alone (Grade 1B).

RT can either be given alone or in combination with neoadjuvant platinum-based chemotherapy, which allows for lower doses to be administered in patients with a complete response (CR). For most younger patients (eg, <10 years), we suggest neoadjuvant chemotherapy plus response-adapted RT (Grade 2C). In older patients, the advantages and disadvantages are more closely balanced, and RT alone remains a reasonable alternative to combination therapy. (See 'Selection of therapy' above.)

Recommended doses of RT vary depending upon whether neoadjuvant chemotherapy is administered. (See 'Radiation alone approach' above and 'Combined chemotherapy and radiation' above.)

•Disseminated germinoma – CSI remains the standard of care for disseminated germinoma. (See 'Disseminated germinoma' above.)

●Management of NGGCTs (algorithm 2)

•Mature teratoma – Maximal safe resection should be undertaken for patients with a histologic diagnosis of mature teratoma by biopsy and normal tumor markers. Complete resection of a mature teratoma is considered definitive treatment without further adjuvant therapy. (See 'Mature teratoma' above.)

•All other NGGCTs – For patients with all other NGGCTs, we recommend treatment that includes both platinum-based chemotherapy and RT, rather than RT or chemotherapy alone (Grade 1B). For RT, we suggest CSI plus tumor boost rather than more limited fields (Grade 2B). (See 'Chemotherapy plus CSI' above.)

Although early data from the ACNS1123 trial suggest that the vast majority of patients with localized NGGCT who achieve a CR or partial response (PR) with neoadjuvant chemotherapy appear to be cured with whole-ventricle RT and tumor boost only, further data maturation is needed. The role of reduced-field RT in patients with localized NGGCT therefore remains controversial. (See 'Potential role of reduced radiation' above.)

•Role of "second-look" surgery – In patients with residual masses after chemotherapy and RT, "second-look" surgery should be strongly considered. (See '"Second-look" surgery' above.)