Introduction
Background
Medulloblastoma is the most common malignant brain tumor in children, accounting for 10-20% of primary CNS neoplasms and approximately 40% of all posterior fossa tumors. It is a highly invasive embryonal neuroepithelial tumor that arises in the cerebellum and has a tendency to disseminate throughout the CNS early in its course.
Morphologically similar tumors arising in the pineal region are termed pineoblastomas, and those arising in other CNS locations are called primitive neuroectodermal tumors (PNETs).
With aggressive surgery, craniospinal radiotherapy and chemotherapy, more than 50% of children with medulloblastoma can be expected to be free of disease 5 years later. Using current treatments, 80-90% of those without disseminated disease can be cured; however, treatment for this disease often results in significant endocrinological and intellectual sequelae.
Pathophysiology
Medulloblastoma is a cerebellar tumor arising predominantly from the cerebellar vermis. The histogenesis of medulloblastoma remains controversial.
One view suggests that the cell of origin derives from the external granular layer of the cerebellum. This is supported by the finding that the proliferation of precursor neurons in this layer is controlled by sonic hedgehog (shh), whose receptor PTCH is mutated in a subset of sporadic medulloblastomas. Furthermore, suppression of shh was recently shown to eliminate medulloblastoma that spontaneously develops in the PTCH +/- heterozygote mouse.
Another hypothesis proposes that medulloblastomas have more than one cell of origin. This is based on studies showing differential immunoreactivity to a neuronal calcium-binding protein that is not expressed in the external granular layer and to a beta-tubulin isotype that is expressed in the neuronal cells of the ventricular matrix and external granular layer. Numerous molecular alterations that appear to modulate the biological behavior of medulloblastoma or its response to therapy have been reported. For example, studies suggest that medulloblastoma expression of neurotrophin (NT3) and its cognate receptor, Trk C, may modulate the behavior of these tumors by inducing apoptosis, thereby retarding tumor progression and resulting in a more favorable prognosis.1
Other studies have shown that overexpression of the oncogenes ERBB2 and MYCC are associated with worse outcome, and that MYCC can induce the potentially more aggressive large cell anaplastic variant of medulloblastoma. Finally, amplification of the oncogene OTX2 has been most recently described in association with medulloblastoma.
As the tumor grows, obstruction of cerebrospinal fluid (CSF) passage through the fourth ventricle generally occurs, resulting in hydrocephaly. The tumor may spread contiguously, to the cerebellar peduncle and/or the floor of the fourth ventricle; anteriorly, to the brainstem; inferiorly, to the cervical spine; or superiorly, above the tentorium. It also may spread via the CSF intracranially or to the leptomeninges and spinal cord. Of all the pediatric CNS neoplasms, medulloblastoma has the greatest propensity for extraneural spread, especially to bone and bone marrow; however, the rate of such events is less than 4%.
Frequency
United States
Approximately 250 new patients are diagnosed annually.
International
Exact figures are unknown. In general, brain tumors occur at a rate of 2.5-4 per 100,000 at-risk children per year. Of these, approximately 18% are medulloblastoma.
Mortality/Morbidity
Risk group stratification is continuing to evolve but is currently based on 3 principal features, including age, extent of postoperative residual disease, and the metastasis stage (M stage) derived from the Chang classification staging system. The M stage classification is as follows:
- M0 - No gross subarachnoid or hematogenous metastasis
- M1 - Microscopic tumor cells found in CSF
- M2 - Gross nodular seeding in cerebellum, cerebral subarachnoid space, or in the third or fourth ventricles
- M3 - Gross nodular seeding in spinal subarachnoid space
- M4 - Extraneuraxial metastasis.
The specific risk groups based on this classification scheme are defined below.
- Average-risk disease: This risk group is defined as patients older than 3 years who are at stage M0 with less than 1.5 cm2 of residual tumor postoperatively. The 5-year survival rate for this group is currently more than 80%
- Poor-risk disease: This risk group is defined as patients older than 3 years who are at stage M1-M4 and/or with more than 1.5 cm2 of residual tumor postoperatively. The 5-year survival rate for this group is currently 30-60%.
- Infants: This group is defined as patients younger than 3 years. This group has the worst prognosis, regardless of M stage and extent of postoperative residual disease. The 5-year survival rate is approximately 30%; however, patients with metastatic disease do considerably worse. Those infants with desmoplastic tumors are more likely to survive.
Various biologic parameters have been related to outcome. In retrospective studies, children with tumors that have increased expression of TRKC and WNT are more likely to survive, whereas those with increased amplification of MYCC oncogene or increased ERBB2 expression have a poorer prognosis. Real-time biologic tumor analysis will likely supplement, if not supplants, clinical parameters used for stratification in the future. In addition, histologic features of severe anaplasia have been associated with poorer survival.
Despite successful treatment, a significant number of patients have neurocognitive and endocrinologic deficits. Although most long-term survivors have normal intelligence, many subsequently develop learning difficulties that require individualized educational programs. Biochemical growth deficiency is observed in 70-80% of patients, and some degree of growth impairment is present in well over half of patients after treatment. Thyroid and gonadotropin hormonal deficiency may also occur. Craniospinal radiation, a mainstay of treatment, has been implicated as a major cause of these deficits.
Race
No racial predisposition is noted. The latest data from the Surveillance, Epidemiology, and End Results (SEER) program showed that patients aged 0-14 years in the United States have an incidence rate per million population of 5.7 in whites and 5 in blacks.2
Sex
US incidence per 1 million population for patients aged 0-14 years is 6.1 for boys and 4.5 for girls.
Age
Peak age of incidence is 3-5 years. Approximately 80% of patients are diagnosed in the first 15 years of life.
Clinical
History
Although 70-90% of patients with medulloblastomas present with a history of headaches, emesis, and lethargy, these symptoms are generally intermittent and subtle. Duration of symptoms for 3 months or more before diagnosis is common.
- Increased intracranial pressure (ICP)
- Early symptoms are secondary to increased ICP. The classic triad consists of morning headaches, vomiting, and lethargy. Headache consists of head pain present upon arising that is relieved by vomiting and gradually lessens during the day. Cushing triad (ie, hypertension, bradycardia, and hypoventilation), an uncommon finding in children with increased intracranial pressure, usually indicates impending herniation.
- Initial signs of increased ICP are usually subacute, nonspecific, and nonlocalizing.
- School-aged children may complain of vague intermittent headaches and fatigue. They may demonstrate declining academic performance and personality changes.
- Infants may present with irritability, anorexia, and developmental delay.
- Cerebellar dysfunction
- With increasing tumor size and invasion into the surrounding brain tissue, more characteristic symptoms appear.
- One symptom is progressively worsening ataxia involving the lower extremities, often with relative sparing of the trunk and upper extremities.
- Brain stem deficits: Tumor infiltration of the brain stem or increased ICP may result in diplopia and multiple other cranial nerve findings, such as facial weakness, tinnitus, hearing loss, head tilt, and stiff neck.
- Metastatic disease: Uncommonly, patients may present with back pain or leg weakness secondary to spinal metastasis.
Physical
The earliest signs are nonlocalized and caused by increased ICP. Later signs are generally due to tumor invasion of the surrounding tissue.
- Increased ICP
- Funduscopic evaluation reveals papilledema or optic pallor in infants.
- Palsy of cranial nerve VI resulting in the inability to abduct one or both eyes is common.
- Infants may have the "setting sun" sign. This is demonstrated by impaired upgaze and seemingly forced downward deviation of the eyes.
- Measurement of head circumference in infants with open cranial sutures also may reveal macrocephaly.
- Cerebellar findings: Localized deficits in truncal steadiness, upper extremity coordination, and gait are common.
- Brain stem findings
- Invasion into the brain stem may cause loss of conjugate gaze (gaze palsy) or the inability to adduct one eye on attempted lateral gaze. This is observed most commonly in combination with deficits of cranial nerves V, VII, and IX.
- Invasion into the cerebellopontine angle results in facial weakness and hearing loss, often with associated unilateral cerebellar deficits.
Causes
- Environmental: Epidemiological studies investigating parental occupational exposures, environmental exposures and maternal nutritional intake have not proven a direct link between such factors and the development of childhood brain tumors.
- Familial and heritable disease
- Medulloblastoma is associated with recessively inherited Turcot and ataxia-telangiectasia syndromes.
- As many as 5% of patients with autosomal dominant nevoid basal cell carcinoma (Gorlin) syndrome develop medulloblastoma. These tumors demonstrate loss of heterozygosity at band 9q22-q23, the region containing the PTCH tumor suppressor gene associated with Gorlin syndrome.
- Genetic associations: The most frequent cytogenetic abnormality in sporadic medulloblastoma is an isochromosome 17q [i(17q)]. Of tumors analyzed, 40-50% have a deletion of the short arm of chromosome 17, implicating the presence of a tumor suppressor gene that maps to 17p, which is distinct from the p53 gene. Alternatively, a gene on 17q may be related to transformation because of increased copy number.
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References
Kieffer-Renaux V, Bulteau C, Grill J, et al. Patterns of neuropsychological deficits in children with medulloblastoma according to craniospatial irradiation doses. Dev Med Child Neurol. Nov 2000;42(11):741-5. [Medline].
Deorah S, Lynch CF, Sibenaller ZA, Ryken TC. Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. Neurosurg Focus. Apr 15 2006;20(4):E1. [Medline].
Tait DM, Thornton-Jones H, Bloom HJ, et al. Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer. Apr 1990;26(4):464-9. [Medline].
Robertson PL, Muraszko KM, Holmes EJ, Sposto R, Packer RJ, Gajjar A, et al. Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. J Neurosurg. Dec 2006;105(6 Suppl):444-51. [Medline].
Brown HG, Kepner JL, Perlman EJ, et al. "Large cell/anaplastic" medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol. Oct 2000;59(10):857-65. [Medline].
Cohen BH, Zeltzer PM, Boyett JM, et al. Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol. Jul 1995;13(7):1687-96. [Medline].
Albright AL, Wisoff JH, Zeltzer PM, Boyett JM, Rorke LB, Stanley P. Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery. Feb 1996;38(2):265-71. [Medline].
Boon K, Eberhart CG, Riggins GJ. Genomic amplification of orthodenticle homologue 2 in medulloblastomas. Cancer Res. Feb 1 2005;65(3):703-7. [Medline].
Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors [see comments]. N Engl J Med. Jun 17 1993;328(24):1725-31. [Medline].
Dunkel IJ, Finlay JL. High dose chemotherapy with autologous stem cell rescue for patients with medulloblastoma. J Neurooncol. Jul 1996;29(1):69-74. [Medline].
Dupuis-Girod S, Hartmann O, Benhamou E, et al. Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma?. J Neurooncol. Jan 1996;27(1):87-98. [Medline].
Eberhart CG, Burger PC. Anaplasia and grading in medulloblastomas. Brain Pathol. Jul 2003;13(3):376-85. [Medline].
Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. Oct 2006;7(10):813-20. [Medline].
Gajjar A, Fouladi M, Walter AW, et al. Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors. J Clin Oncol. Jun 1999;17(6):1825-8. [Medline].
Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol. Oct 20 2005;23(30):7621-31. [Medline].
Grotzer MA, Hogarty MD, Janss AJ, et al. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res. Aug 2001;7(8):2425-33. [Medline]. [Full Text].
Grotzer MA, Janss AJ, Fung K, et al. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol. Mar 2000;18(5):1027-35. [Medline].
Hallahan AR, Pritchard JI, Hansen S, et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. Nov 1 2004;64(21):7794-800. [Medline]. [Full Text].
Hernan R, Fasheh R, Calabrese C, et al. ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma. Cancer Res. Jan 1 2003;63(1):140-8. [Medline].
Jenkin D. The radiation treatment of medulloblastoma. J Neurooncol. Jul 1996;29(1):45-54. [Medline].
Kim JY, Sutton ME, Lu DJ, et al. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res. Feb 1 1999;59(3):711-9. [Medline]. [Full Text].
Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. Jan 15 2000;46(2):269-79. [Medline].
MacDonald TJ, Brown KM, LaFleur B, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet. Oct 2001;29(2):143-52. [Medline].
Merchant TE, Kun LE, Krasin MJ, et al. Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys. Mar 1 2008;70(3):782-7. [Medline].
Oliver TG, Grasfeder LL, Carroll AL, et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci U S A. Jun 10 2003;100(12):7331-6. [Medline]. [Full Text].
Packer RJ. Brain tumors in children. Arch Neurol. Apr 1999;56(4):421-5. [Medline].
Packer RJ, Finlay JL. Medulloblastoma: presentation, diagnosis and management. Oncology (Huntingt). Sep 1988;2(9):35-45, 48-9. [Medline].
Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. Sep 1 2006;24(25):4202-8. [Medline].
Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol. Jul 1999;17(7):2127-36. [Medline].
Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg. Nov 1994;81(5):690-8. [Medline].
Pizzo PA, Poplack DG. Tumors of the central nervous system. In: Principles and Practice of Pediatric Oncology. 3rd ed. 633-97.
Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002;415(6870):436-42.
Reddy AT, Packer RJ. Pediatric central nervous system tumors. Curr Opin Oncol. May 1998;10(3):186-93. [Medline].
Romer JT, Kimura H, Magdaleno S, et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell. Sep 2004;6(3):229-40. [Medline].
Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med. Mar 10 2005;352(10):978-86. [Medline].
Siu IM, Lal A, Blankenship JR, et al. c-Myc promoter activation in medulloblastoma. Cancer Res. Aug 15 2003;63(16):4773-6. [Medline]. [Full Text].
Stearns D, Chaudhry A, Abel TW, et al. c-myc overexpression causes anaplasia in medulloblastoma. Cancer Res. Jan 15 2006;66(2):673-81. [Medline].
Strother D, Ashley D, Kellie SJ, et al. Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study. J Clin Oncol. May 15 2001;19(10):2696-704. [Medline].
Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: final analysis of trial comparing standard- dose with reduced-dose neuraxis irradiation. J Clin Oncol. Aug 2000;18(16):3004-11. [Medline].
Thorarinsdottir HK, Rood B, Kamani N, et al. Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer. Mar 2007;48(3):278-84. [Medline].
Thorarinsdottir HK, Rood B, Kamani N, et al. Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer. Feb 2 2006;[Medline].
Yachnis AT. Neuropathology of pediatric brain tumors. Semin Pediatr Neurol. Dec 1997;4(4):282-91. [Medline].
Zeltzer PM, Boyett JM, Finlay JL, et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol. Mar 1999;17(3):832-45. [Medline].
Zerbini C, Gelber RD, Weinberg D, et al. Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol. Apr 1993;11(4):616-22. [Medline].
Further Reading
Keywords
medulloblastoma, posterior fossa primitive neuroectodermal tumor, PNET, brain tumor, hypertension, bradycardia, hypoventilation, Cushing triad, facial weakness, tinnitus, hearing loss, head tilt, papilledema, optic pallor, stiff neck, gaze palsy, Turcot syndrome, ataxia-telangiectasia, Gorlin syndrome, nevoid basal cell carcinoma syndrome
