22 Germ Cell Tumors
Abstract
Germ cell tumors (GCTs) of the central nervous system (CNS) are a heterogeneous group of tumors, which primarily occur in childhood, arising predominantly at midline and involving areas such as the pineal and suprasellar regions. The diagnosis of CNS GCTs is based on clinical symptoms and signs, cerebrospinal fluid (CSF) and serum tumor markers, neuroimaging characteristics, and cytologic (CSF) and histologic assessments; however, biopsy of the tumor is required for diagnosis. All GCTs present a certain degree of radiosensitivity, and most of them are chemosensitive. However, the possibility of achieving surgical access to intracerebral GCTs is of utmost importance in order to obtain tissue sampling, eventually perform CSF diversion, and decompress vital neurovascular structures with cytoreduction. Surgical approach to GCTs located in the suprasellar area utilized different transcranial and transfacial routes in the past. Nowadays, endoscopic endonasal techniques can be considered a viable surgical option for the management of GCTs, providing the possibility of achieving either tissue sampling via a minimally invasive biopsy or decompression of neurovascular structures. In this regard, first-line surgery with the aim of a conspicuous mass reduction helps increase the effectiveness and safety of radiochemotherapy, which can be addressed on a more affordable target.
22.1 Introduction
Germ cell tumors (GCTs) of the central nervous system (CNS) are a heterogeneous group of tumors that primarily occur in childhood, arising predominantly at midline and involving areas such as the pineal and suprasellar regions.
These tumors are morphologic, immunophenotypic, and genetic homologs of gonadal and other extraneuraxial germ cell neoplasms. CNS GCTs are divided into germinomas, the most frequent form, and nongerminomatous GCTs. The current World Health Organization (WHO) classification of CNS GCTs identifies the following major forms, according to histologic elements:
Germinoma: pure and with syncytiotrophoblasts.
Nongerminomatous GCTs:
Teratoma: mature, immature, and exhibiting malignant transformation.
Yolk sac tumor.
Embryonal carcinoma.
Choriocarcinoma.
Neoplasms harboring multiple histologic types are called mixed GCTs; CNS GCTs are also classified according to the secretion of tumor marker. Blood and CSF levels of α-fetoprotein (αFP) and β-human chorionic gonadotropin (βHCG) could be considered as important factors to be ruled out in the diagnostic workup. αFP elevation is associated with yolk sac tumor, dysgerminoma or seminoma, embryonal carcinoma, and immature teratoma. β-human chorionic gonadotropin (βHCG), normally secreted by placental trophoblastic tissue, is elevated in choriocarcinoma or embryonal carcinoma. Secreting tumors present CSF αFP level greater than 10 ng/mL (or a level higher than the institutional normal) and/or CSF β-HCG level greater than 50 IU/L (or a level higher than the institutional normal). 1 Germinomas are frequently positive for placental alkaline phosphatase (PLAP), optical coherence tomography 4 (OCT-4) and c-kit. Pure germinomas usually do not secrete appreciable tumor markers.
22.2 Epidemiology
CNS GSTs account for 3 to 4% of brain tumors in the first two decades, with a peak of incidence reported around the time of puberty. Nongerminomatous GCTs are more frequently diagnosed earlier in life, while germinomas are usually diagnosed between 10 and 21 years of age; an overall male preponderance is described. 2
Gender is predictive of tumor localization: the pineal region accounts for the great majority of this tumors in males, while suprasellar lesions occur predominantly in females. 3
22.3 Etiology
The issue of histogenesis of CNS GCTs is controversial. It is assumed that CNS GCTs arise from nests of primordial germ cells, migrated aberrantly during embryonic development and subsequently undergone malignant transformation. They either differentiate into a germinoma, mismigrational pluripotent embryonic cells, or give rise to other types of GCTs. 4 Current studies show matches in messenger RNA (mRNA) profiles of GCTs and pluripotent embryonic stem cells. This may confirm that GCTs originate from primordial germ cells. 5 , 6 GCTs that arise from gonadal and extragonadal sites are histologically, clinically, and genetically similar. Chromosomal comparative genomic hybridization analysis suggests that genomic alterations in CNS GCTs are almost indistinguishable from their extracranial counterparts. 7
CNS GCTs arising after early childhood show characteristically aneuploid profiles and complex chromosomal anomalies. Cytogenetic abnormalities include loss of 1p and 6q, increased copies of the X chromosome, and rarely abnormalities in 12p. 8 Gain of an extra X chromosome is a frequent genotype abnormality. Individuals with Klinefelter’s syndrome (XXY) are prone to develop intracranial GCTs, as are those with Down’s syndrome and those with neurofibromatosis type 1. 9
The most common abnormality in adult-onset CNS GCTs is duplication of the short arm of chromosome 12 due to isochromosome (i(12p)) formation. 10 c-kit mutations and increased kit expression have been seen in 23 to 25% of intracranial germinomas, and somatic mutations in AKT/mTOR pathway were found in 19% of patients. C-myc and N-myc amplifications were found in a minority of tumors. Distinct mRNA and micro-RNA profiles revealed with genomic analysis may be correlated with histologic differentiation and clinical outcome and, in the future, serve as novel therapeutic targets. 11 , 12 Otherwise, pure intracranial teratomas presenting as congenital or infantile growth have a typically diploid status and a general chromosomal integrity, and resemble teratomas of infant testis.
22.4 Clinical Features
The great majority of CNS GCTs arise along a midline axis extending from the pineal gland (the most common site) to the suprasellar region (the second most common site), where tumors originate from the neurohypophyseal infundibular region. Intraventricular, diffuse periventricular, thalamostriate, cerebral hemispheric, cerebellar, bulbar, intramedullary, and intrasellar localizations have been described. Multifocal CNS GCTs usually involve the pineal and suprasellar regions, either simultaneously or sequentially. The significance of these lesions is controversial; actually, it is debated if they are synchronous lesions or metastasis. The bifocal presentation of these tumors may be a poor prognostic sign and should alert clinicians to the possibility of a disseminated disease. 13 The initial clinical presentation in CNS GCTs is dependent upon the patient’s age, tumor location, tumor size, and disease duration.
Congenital tumors, often teratomas, detectable by ultrasound as a heterogeneous echogenic mass with cystic and solid components, can produce polyhydramnios and obstructive hydrocephalus. CNS GCTs in young infants can cause irritability, listlessness, failure to thrive, macrocephaly, and bulging fontanelle; teratoma and choriocarcinoma are the most common CNS GCTs in this age group. Beyond infancy, clinical presentation depends on tumor location.
22.4.1 Pineal Region Tumor
Lesions in the pineal region compress and obstruct the cerebral aqueduct, resulting in progressive hydrocephalus and intracranial hypertension. Symptoms include headache, nausea and vomiting, papilledema, somnolence, ataxia, seizures, and behavioral abnormalities. Compression and invasion of the tectum cause Parinaud’s syndrome, seen at presentation in up to 50% of pineal GCTs and characterized by paralysis of upward gaze, loss of light perception and accommodation, nystagmus, and failure of convergence. Endocrinopathies and disturbances in sexual development are less common in patients with isolated pineal region tumors.
22.4.2 Suprasellar Region Tumors
GCTs of the suprasellar region usually cause hypothalamic/pituitary axis dysfunction: diabetes insipidus and enuresis and anterior hypopituitarism, with thyroid and/or cortisol deficiency, growth failure, delayed puberty, regression of sexual development, or sexual dysfunction. Tumors secreting β-HCG may cause precocious puberty due to increase in testosterone production (isosexual pseudoprecocity in boys). Optic chiasm impingement can cause visual field defects, bilateral temporal hemianopia overall, diplopia, blurred vision, and vision loss.
22.4.3 Rare Presentation
Psychiatric abnormalities such as psychosis and behavioral changes are atypical presentations in patients with multiple lesions or GCTs in the pineal gland. Midbrain outflow tremor (Holmes’ tremor) has been reported in patients with germinoma. It is a hyperkinetic movement disorder that presents as mild to severe tremors, dystonia, and cerebellar deficits.
22.5 Diagnosis
The diagnosis of CNS GCTs is based on clinical symptoms and signs, CSF and serum tumor markers, neuroimaging characteristics, cytologic CSF, and histologic assessments. Both CT and MRI are very sensitive in detecting suprasellar and pineal region masses, but the radiographic characteristics are very similar in all GCTs, limiting their usefulness in determining the exact histology of these tumors. Therefore, biopsy of the tumor is required for diagnosis, unless characteristic serum or CSF tumor marker elevation coexists.
22.6 Management Options
All GCTs present a certain degree of radiosensitivity, and most of them are chemosensitive. However, the possibility of achieving surgical access to intracerebral GCTs is of utmost importance in order to obtain tissue sampling, eventually perform CSF diversion, and decompress vital neurovascular structures with cytoreduction.
It should be said that the definition of the histologic subtype is crucial to define the most appropriate therapeutic strategy, because sensitivity to radiation and/or chemotherapy varies among different histotypes.
In addition, GCTs have a significant risk of spreading throughout the CNS, so the investigation of the entire neuroaxis, eventually by means of MRI, is mandatory for treatment planning and prognostic purposes. Patients with confined disease and negative CSF cytology are considered to be metastatic negative; patients with positive CSF cytology or patients with drop metastases are considered to be metastatic positive. Appropriate staging is crucial because patients with metastatic disease may receive higher total doses of radiation and more extended radiation fields.
Therefore, in patients with marker-positive GCTs, measurement trends of the markers can also be useful to monitor therapeutic response and as a sensitive early sign of tumor recurrence.
22.6.1 Radiotherapy
Patients with malignant GCTs require radiation therapy. The recommended radiation strategy delivers daily doses to the whole ventricular system and an additional boost to the tumor bed. 14 Craniospinal irradiation is controversial, and the current trend is to reserve it to tumors with documented spinal seeding. Pediatric patients are particularly vulnerable to adverse radiation effects. In order to reduce radiation-related toxicity, recent therapeutic strategies combine reduced radiation doses with chemotherapy. Germinomas are highly sensitive to both radiotherapy and chemotherapy and have an excellent prognosis, with an overall survival of 90% at 10 years. 15
In contrast, nongerminomatous germ cell tumors (NGGCTs) are less responsive to radiation, with 5-year overall survival rates of 30 to 50%. 1
22.6.2 Chemotherapy
Most of the germ cell chemotherapy regimens have been extrapolated from experience with treating extracranial GCTs, in which success has been remarkable. Currently, a regimen with etoposide and carboplatin or cisplatin is the most widely used. Chemotherapy has been explored for germinomas in an effort to reduce radiation therapy doses and associated neurodevelopmental morbidity. Patients affected by NGGCTs have an inferior outcome compared with patients affected by germinomas; therefore, chemotherapy is typically used with radiation to improve prognosis, resulting in reasonable expectation for long-term survival. 16
22.6.3 Surgery: The Role of Endoscopic Endonasal Surgery
Surgical approach to GCTs located at the suprasellar area relied mostly on different transcranial and transfacial routes. Nowadays, the evolution of endoscopic endonasal techniques has permitted the extension of the indications to a variety of lesions involving the suprasellar area 17 , 18 , 19 in pediatric patients. 20 , 21
We have been employing the endoscopic endonasal technique since 1997 on more than 2,000 patients aiming to remove, first, different sellar lesions and, then, lesions involving the surrounding skull base areas. In fact, the endonasal corridor provides a direct, multiangled, and close-up view of the inferior aspects of the suprasellar neurovascular structures without any brain retraction. 17 , 19 , 21 Early devascularization of the tumor can be obtained, thus limiting intraoperative blood loss and the risk of postoperative visual loss, which is strictly related to the integrity of the vascularization of the optic chiasm. Furthermore, the endoscopic approach permits a clear visualization of the pituitary gland and stalk, thereby reducing the risks of harming endocrine and hypothalamic functions, which is of utmost importance in the pediatric population. 20 , 21
Remarkably, when dealing with GCTs at the suprasellar area, first-line surgery via the endoscopic endonasal approach increases the effectiveness and safety of radiochemotherapy via cytoreduction and a lower target volume. 22 , 23 , 24 , 25 , 26
However, in most cases tumors are not treated surgically, so this approach represents a viable and easy technique to achieve tissue sampling with minimal morbidity. In this chapter, we present a case of a pediatric patient affected by a large, intra- and suprasellar mixed GCT which was removed via a transplanum/transtuberculum endoscopic endonasal approach.
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