lunes, 26 de septiembre de 2016

Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®)–Health Professional Version


General Information About Childhood Central Nervous System (CNS) Germ Cell Tumors

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary onChildhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancerfor specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Primary central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of neoplasms that account for 0.5% of all primary brain tumors, with approximately 90% of the cases occurring before age 20 years. They are broadly classified as germinomatous and nongerminomatous germ cell tumors (NGGCTs) based on clinicopathologic features. Alternatively, in Europe and Asia, these tumors are broadly classified into secreting and nonsecreting tumors, dependent on elevation of serum and cerebrospinal tumor markers.[1,2]


In Western countries, GCTs represent less than 4% of primary brain tumors in children, while in series from Japan and Asia, CNS GCTs account for approximately 11% of pediatric CNS tumors.[4-6]


CNS GCTs usually arise in the pineal and/or suprasellar regions of the brain, as solitary or multiple lesions. Pineal region tumors occur twice as frequently as suprasellar tumors, but approximately 5% to 10% of patients have both suprasellar and pineal gland involvement at the time of diagnosis.[7] Involvement of both sites is most commonly seen in pure germinomas. Males have a higher incidence of GCT than do females, with males having a preponderance of pineal region primary tumors. Other areas that may be involved, though rare, include the basal ganglia, ventricles, thalamus, cerebral hemispheres, and the medulla.[8,9]
ENLARGEDrawing of the inside of the brain showing the supratentorium (the upper part of the brain) and the infratentorium (the lower back part of the brain). The supratentorium includes the cerebrum, ventricles (fluid-filled spaces), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium includes the cerebellum and brain stem (pons and medulla). The spinal cord is also shown.
Figure 1. Anatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.

Tumor Biology

In a study of 62 cases of intracranial GCT, next-generation sequencing, single nucleotide polymorphism array, and expression array have shown frequent mutations in the KIT/RAS signaling pathway (50% of cases) and the AKT/mTOR pathway (19% of cases).[10]

Clinical Features

Signs and symptoms of CNS GCTs depend on the location of the tumor in the brain, as follows:
  • Suprasellar region. Tumors arising in the suprasellar region often present with subtle or overt hormonal deficiencies and a protracted prodrome often lasting months to years. Diabetes insipidus caused by antidiuretic hormone deficiency occurs in 70% to 90% of patients and is the most common sentinel symptom; patients can usually compensate for this deficiency for months to years by drinking excessive amounts of fluid. Eventually, other hormonal symptoms and visual deficits emerge as the tumor expands dorsally and compresses or invades the optic chiasm.[6,11]
  • Pineal region. Patients with tumors in the pineal region usually have a shorter history of symptoms than do patients with tumors of the suprasellar or basal ganglionic region, with weeks to months of symptoms that include raised intracranial pressure and diplopia related to tectal and aqueductal compression. Symptoms and signs unique to masses in the pineal and posterior third ventricular region include Parinaud syndrome (vertical gaze impairment, convergence nystagmus, and light-near pupillary response dissociation), headache, and nausea and vomiting.
  • Multifocal or bifocal tumors. Patients with multifocal or bifocal primaries may present with both suprasellar and pineal region syndromes.[6]
Nonspecific symptoms such as enuresis, anorexia, and psychiatric complaints can lead to delays in diagnosis, whereas signs of increased intracranial pressure or visual changes tend to result in earlier diagnosis.[12]

Diagnostic Evaluation

Radiographic characteristics of CNS GCTs cannot reliably differentiate germinomas from NGGCTs or other CNS tumors. The diagnosis of GCTs is based on the following:
  • Clinical signs and symptoms.
  • Tumor markers.
  • Neuroimaging.
  • Cytological cerebrospinal fluid (CSF) and histological confirmation.
Patients with a suspected CNS GCT are diagnosed using the following tests:
  • Magnetic resonance imaging (MRI) of brain and spine with gadolinium.
  • Alpha-fetoprotein (AFP) and beta subunit human chorionic gonadotropin (beta-HCG) in both serum and CSF. If preoperative lumbar CSF can be obtained safely and tumor markers are elevated, this may obviate the need for upfront surgery. Lumbar CSF is preferred and is more sensitive than serum markers for beta-HCG.[13] When the patient presents with hydrocephalus requiring CSF diversion, CSF tumor markers can be obtained by ventricular CSF sampling at the time of surgery. (Refer to the Cellular Classification of Childhood CNS Germ Cell Tumors section of this summary for more information.)
  • Lumbar CSF cytology.
  • Evaluation of pituitary/hypothalamic function.
  • Visual-field examinations for suprasellar or hypothalamic tumors.
A baseline neuropsychologic examination is also performed when symptoms of endocrine deficiency and raised intracranial pressure are resolved.
Diagnosis of GCTs often requires a tumor biopsy, except in cases with characteristic increased tumor markers in the serum and/or CSF. When the tumor markers are negative or mildly elevated but below diagnostic criteria, or if there is any noncharacteristic finding, a tumor biopsy is performed.
It is crucial that appropriate staging is determined and that pure germinomas are distinguished from NGGCTs. The chemotherapy and radiation treatment plan differs significantly depending on GCT category and extent of disease.
  1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.
  2. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. Matsutani M, Sano K, Takakura K, et al.: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 86 (3): 446-55, 1997. [PUBMED Abstract]
  5. Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]
  6. Hoffman HJ, Otsubo H, Hendrick EB, et al.: Intracranial germ-cell tumors in children. J Neurosurg 74 (4): 545-51, 1991. [PUBMED Abstract]
  7. Weksberg DC, Shibamoto Y, Paulino AC: Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 82 (4): 1341-51, 2012. [PUBMED Abstract]
  8. Goodwin TL, Sainani K, Fisher PG: Incidence patterns of central nervous system germ cell tumors: a SEER Study. J Pediatr Hematol Oncol 31 (8): 541-4, 2009. [PUBMED Abstract]
  9. Villano JL, Propp JM, Porter KR, et al.: Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol 10 (2): 121-30, 2008. [PUBMED Abstract]
  10. Wang L, Yamaguchi S, Burstein MD, et al.: Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511 (7508): 241-5, 2014. [PUBMED Abstract]
  11. Afzal S, Wherrett D, Bartels U, et al.: Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy. J Neurooncol 97 (3): 393-9, 2010. [PUBMED Abstract]
  12. Crawford JR, Santi MR, Vezina G, et al.: CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis. Neurology 68 (20): 1668-73, 2007. [PUBMED Abstract]
  13. Allen J, Chacko J, Donahue B, et al.: Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer 59 (7): 1180-2, 2012. [PUBMED Abstract]
  • Updated: September 23, 2016

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