A 10 year old female with intermittent headaches for 3-4 months, complains of blurry vision. She is referred to a pediatric ophthalmologist for her blurry vision, when she is noted to have medial deviation (adduction) of her left eye. An MRI scan is done and this shows a pituitary mass. She is referred to a pediatric neurosurgeon who performs a gross total resection of the primary tumor. The tumor pathology is consistent with the diagnosis of craniopharyngioma. A follow-up MRI scan done within 48 hours of her tumor resection demonstrates no residual tumor. While she continues to have no recurrent tumor 2 years after her resection, she has persistent clinical problems related to the craniopharyngioma and its resection. Vision in her left eye is severely impaired. Cognition, concentration and memory appear to be adversely affected with decreased school performance. Growth has decreased and she requires growth hormone and thyroid hormone replacement. Neuropsychiatric testing is performed by a clinical psychologist. An individualized education plan is developed and she receives support services/tutoring.
Central nervous system (CNS) tumors have the dubious distinction of being the most common solid tumor of childhood. They represent the second most common malignancy in children (17%). There are approximately 2500 new brain tumor cases per year nationally. Infratentorial cerebellar and brain stem tumors are more common in children than adults. In contrast, cerebral tumors, mostly astrocytomas, are most common in adults. Of the pediatric brain tumors, 35-50% are astrocytomas, 10-20% medulloblastomas/primitive neuroectodermal tumors (PNET), 10-20% brain stem gliomas, 5-10% ependymomas, 5-10% craniopharyngiomas, 1-2% pineal tumors, and 10-15% other. Many of these tumors are undifferentiated and defy standard histologic classification. The incidence is higher in males versus females. There appears to be a small peak in embryonal tumors with a relative paucity of adult type gliomas until adolescence. One third of all brain tumors in children younger than 15 years of age occur in children under 5 years of age. The overall incidence of childhood brain tumors has been increasing over the past several decades, with some of this increase due to improved detection with computed tomography (CT) and magnetic resonance imaging (MRI) scans. Overall mortality and morbidity likely exceeds that of other common solid tumors and leukemia. Long term side effects of CNS tumors account for high rates of morbidity due to the location of primary lesions and aggressive therapy received by patients.
Factors that are associated with an increased risk of pediatric brain tumors include being male (medulloblastoma/PNET, ependymomas), ionizing radiation, and genetic conditions (neurofibromatosis, tuberous sclerosis, Turcot syndrome, and Li-Fraumeni syndrome). Cured meats and polyomaviruses (simian virus 40, JC, BK) have been also been implicated in the development of brain tumors. In general though, the majority of pediatric brain tumors arise with no obvious risk factors present.
Despite the progress made over the last 20-30 years in treating childhood cancer, pediatric brain tumors have demonstrated only modest improvements in survival. While from 1975-1995 the mortality rate for leukemia and all other non-central nervous system (CNS) cancers declined by over 50%, CNS cancers had only a 20% improvement in survival. The lack of improvement in brain tumor treatment is dependent on many factors which include: 1) the presence of the blood brain barrier, 2) the low regenerative capacity of the brain, and 3) the inability to intensify CNS toxic treatment without unacceptable long term developmental side-effects (pronounced in younger children). Despite the development and use of chemotherapy agents and radiation therapy over the last 20 years, the primary determinant of survival for the majority of pediatric brain tumors remains the degree of surgical excision. Improvements in the delivery of localized radiation therapy (conformal radiation), stereotactic radiation (gamma knife), dose-intensified treatment with bone marrow transplantation, and the development of new, targeted anti-tumor therapies hold promise for future improvement in treatment.
The most common presentations of brain tumors in children include flu-like symptoms; frequent headaches that are worse in the morning and associated with nausea and vomiting; seizure activity (more likely in slowly growing supratentorial tumors); unsteady gait; vision changes; and deterioration of school performance without explanation. Age of children also affects diagnosis, with younger children and infants suffering from more nonspecific symptoms. Infants with open fontanelles and cranial sutures that are not fused may be very nonspecific signs of tumor progression. The nonspecific nature of these symptoms are often misleading to the general practitioner so that care must be taken in evaluating children with persistent or worsening symptoms.
For older children infratentorial tumors generally present with problems of truncal steadiness, coordination, gait, or cranial nerve function. Nonlocalizing presenting signs suggestive of increased intracranial pressure are often found with tumors that fill the posterior fossa, while infiltrative tumors of the cerebellar hemispheres often present with an asymmetric inability to coordinate and direct limb movements. Seizures are most frequently found in slow growing supratentorial gliomas so that CT or MRI scans are indicated for all children with new onset focal and complex seizures, and most children with unexplained generalized seizures to rule out a brain tumor. Children with metastatic tumors (some primitive neuroectodermal or germ cell tumors) often present with metastases to the spinal cord and cauda equina, and may have back pain, urinary incontinence, or focal extremity weakness or sensory loss.
CNS symptoms associated with brain tumors can be used to determine brain tumor location. Brain stem tumors often result in motor and sensory changes, and the impairment of vital functions (cardiac, respiratory, vasomotor). Cerebellar lesions often present with abnormalities in balance, posture, or motor coordination (including eye movements). Frontal lobe tumors may affect attention, behavior, abstract thought, reflection, problem solving, creative thought, emotion, intellect, judgment, initiative, inhibition, coordinated movements, generalized and mass movements, some eye movements, muscle movements, skilled movements, sense of smell, physical reaction, or sexual urges. Parietal tumors may affect the appreciation of form through touch (stereognosis), tactile sensation, response to internal stimuli (proprioception), sensory combination and comprehension, some language and reading functions, or some visual functions. Occipital lobe lesions may affect reading or vision. Pituitary gland lesions affect hormonal body processes, physical maturation, growth (height and form), sexual maturation, and/or sexual function. Spinal cord tumors result in sensory and motor defects. Temporal lobe defects may affect auditory memories, hearing, visual memories, visual pathways, memory, music, fear, language, speech, or behavior.
Common findings within more general classifications of brain tumors occur as follows:
INFRATENTORIAL (Brain stem and cerebellar).
Brain stem: 1) inability to deviate both eyes conjugately, 2) problems with adducting an eye on lateral gaze, 3) cranial nerve V, VII, and IX defects.
Cerebellopontine angle: facial weakness, hearing loss, unilateral cerebellar deficits.
Brain stem or posterior fossa: peripheral VII nerve palsy (upper and lower facial weakness).
Above pons: central VII nerve palsy (lower facial weakness).
Hypothalamic, brain stem, or upper cervical cord: partial Horner's syndrome (ipsilateral ptosis and miosis).
Upper motor neuron signs: hemiparesis, hyperreflexia, clonus and sensory losses.
Frontal or parietal-occipital, third ventricle: may have no focal deficits (present with increased ICP).
Optic nerve or chiasmal defect: visual deficits, Marcus Gunn pupil (afferent pupillary defect), bitemporal hemianopsia (classic chiasmal tumor), unilateral or bilateral nystagmus with head tilt (chiasmal).
Hypothalamic: "diencephalic syndrome" (failure to thrive and emaciation in a happy and hungry child).
Pineal tumors: Parinaud's syndrome - poor upward gaze, slightly dilated pupils that don't react to light but react to accommodation, retraction or convergence nystagmus, lid retraction.
The initial diagnosis is largely based on imaging. A CT scan is often used in initial screening because of its relative speed or in cases where MRI is not available. MRI scan is the neuroimaging scan of choice. T2 weighted images enhance the differences between normal and tumor tissues. Gadolinium-DPTA, given as a contrast agent, further improves the sensitivity of MRI. MRA (magnetic resonance angiography) is useful if tumor vascularity is a concern.
Cerebrospinal fluid examination in conjunction with MRI will help to demonstrate spinal cord lesions caused by PNETs, anaplastic gliomas, and germinomas. PET scanning is useful in distinguishing between radionecrosis/scar tissue and recurrent or residual tumor. Neuropathologists experienced in pediatric brain tumor histopathology and cytology add considerably to the accuracy of pathologic diagnosis.
Specific tumor types tend to occur in specific areas of the brain, which can provide useful information in determining the tumor diagnostic type. Infratentorial tumors are likely to be brain stem gliomas, cerebellar astrocytomas, primitive neuroectodermal tumors (medulloblastomas), or ependymomas. Supratentorial tumors are likely to be choroid plexus tumors, otic/hypothalamic astrocytomas, or high grade gliomas. Pineal tumors are likely to be pineoblastoma, germ cell tumors, or astrocytoma. Craniopharyngiomas tend to occur in the suprasellar or intrasellar region. Gliomas in the visual pathway are likely to be a low grade pilocytic astrocytoma, or fibrillary astrocytoma. Intramedullary spinal cord tumors are likely to be astrocytomas, ependymomas, oligodendroglioma, gangliogliomas, or malignant gliomas. Disseminated brain tumors (15% of primary tumors) are likely to be medulloblastoma, germ cell tumors, ependymoma, or high grade gliomas.
Treatment options include neurosurgery, radiotherapy (radiation therapy) and/or chemotherapy. Acute complications of radiotherapy include: alopecia (temporary or permanent), erythema and desquamation of skin, otitis externa/media, hearing loss, and bone marrow suppression. Late complications include: radiation necrosis, headache, personality change, seizures, lethargy, hemiparesis, ataxia, increased ICP, focal neurologic signs, vasculitis with transient ischemic attacks and infarction, second malignancies (soft tissue sarcomas, meningiomas, others), somnolence syndrome (4-8 weeks after radiation therapy), necrotizing leukoencephalopathy (4-12 months after therapy), neuropsychologic damage (peaks 3 years after treatment), and endocrine dysfunction. Chemotherapy is limited by the blood brain barrier. In the majority of studies utilizing post-operative chemotherapy, overall survival is most directly related to the degree of primary resection. Efforts to delay radiotherapy by using chemotherapy first have generally resulted in poorer outcomes. High dose chemotherapy, often in conjunction with autologous bone marrow transplantation and reduced radiotherapy doses, in infants and younger children is being investigated. Future use of immunotherapy, gene transfer therapy, blood brain barrier disruption, and novel molecularly targeted therapy hold hope for future treatment efforts.
In general, prognosis is worsened by younger age (particularly infants), increased tumor size, metastatic disease, subtotal resection, unresectability, histologic aggressiveness, decreased radiotherapy, and molecular markers associated with poor outcomes. Side effects are probably most pronounced in children who are the youngest at diagnosis and treatment. IQ decreases, memory problems, fine motor, and visual disturbances may cause long term problems. Cognitive deficits, learning problems, and behavioral problems often occur.
Routine MRI surveillance should be performed every 3 to 6 months during the first 2 years, every 6 to 12 months for the next 2 to 3 years, and every 3 to 5 years thereafter to detect late events (meningiomas from radiation therapy). Medulloblastoma and other embryonal tumors should have spinal MRIs done for the first 2 years. Neuroendocrine problems include growth retardation from impaired growth hormone secretion, hypothyroidism, premature or delayed puberty, all of which may not be immediately obvious. Yearly endocrine and neuropsychologic testing is highly recommended for all CNS tumor patients. Evaluation and/or services for children with special health care needs should be initiated for all brain tumor patients to deal with long term sequelae.
1. Which statement(s) about pediatric brain tumors are true:
. . . . . a. Most common childhood solid tumor.
. . . . . b. Brainstem and cerebellar locations more common than adults.
. . . . . c. Incidence rate appears to be increasing.
. . . . . d. Overall survival has not kept pace with other childhood tumors.
. . . . . e. All of the above.
. . . . . f. b and d only.
2. Which of the following is not a common presenting sign of brain tumors?
. . . . . a. Visual problems
. . . . . b. Fever
. . . . . c. Seizure
. . . . . d. "flu-like" symptoms
. . . . . e. Headaches with early morning emesis
3. Brain stem tumors:
. . . . . a. Should always be biopsied
. . . . . b. Are infratentorial
. . . . . c. Can be cured with aggressive resection
. . . . . d. May present with cranial nerve abnormalities
. . . . . e. All of the above
. . . . . f. b and d only
4. Which of the following is most consistent with improved long-term survival in children with brain tumors?
. . . . . a. Young age at diagnosis
. . . . . b. Subtotal tumor resection
. . . . . c. Brain stem location
. . . . . d. Gross total tumor resection
. . . . . e. The use of regular-dose chemotherapy
5. Long term sequelae of brain tumors in children include:
. . . . . a. Decreased cognition
. . . . . b. Impaired memory
. . . . . c. Growth hormone deficiency
. . . . . d. Delayed puberty
. . . . . e. All of the above
1. Strother DR, Pollack IF, Fisher PG, et al. Tumors of the central nervous system. In: Pizzo P, Poplack DG (eds). Principles and Practice of Pediatric Oncology, 4th edition. 2001, Philadelphia: Lippincott Williams & Wilkins, pp. 751-824.
2. Messing-Junger AM, Janssen G, Pape G, et al. Interdisciplinary treatment in pediatric patients with malignant CNS tumors. Child's Nervous System 2000;16:742-750.
3. Packard RJ. Brain tumors in children. Arch Neurol 1999;56:421-425.
Answers to questions
1.e, 2.b, 3.f, 4.d, 5.e