Pediatric Annals

Pediatric Brain Tumors

Russell W Walker, MD; Jeffrey C Allen, MD

Abstract

Brain tumors are the most common solid tumors in children. Each year there are approximately 1200 new cases of primary childhood central nervous system tumors in the US.1'2 Most brain tumors in children are incurable, causing progressive neurological disability and leading to death within a few years. The intractability of childhood brain tumors often causes intense suffering in both patient and family, a situation which produces an attitude of despair in the pediatrician who makes the diagnosis as well as in the surgeons, neurologists and oncologists involved in the ongoing care. However, advances in diagnostic techniques and palliative treatment now often allow the physician to lengthen diseasefree survival, relieve disabling symptoms, and improve the quality of life for these patients.

The purpose of this article is to discuss the epidemiology, clinical assessment, diagnostic evaluation and therapeutic modalities of pediatric brain tumors. The goal is to help the physician choose the best approach to a given patient. The common tumors will be discussed individually. Finally, recent advances and new developments that permit some optimism about the future of brain tumor therapy will be reviewed.

GENERAL CONSIDERATIONS

The incidence of brain tumors in the US for children under 15 years of age is 23.9 per million per year (1969 to 197 1); the incidence is the same for both black and white children, and for boys and girls.3 However, in medulloblastoma and intracranial germ cell neoplasms there is a male preponderance of about 3:2. The peak age incidence in all childhood brain tumors is five to ten years (Figure 1). However, age-specific incidence rates depend on histologic type. Astrocytomas peak at age three years, whereas medulloblastomas and glioblastomas peak at ages five and seven respectively (Figure 2).

The majority of childhood tumors (approximately 60%) arise in the posterior fossa, unlike the situation in adults where approximately 75% of brain tumors are supratentorial. Of the supratentorial tumors inchildhood, roughly 10% to 15% are in the suprasellar, hypothalamic, and pineal region, that is, in the midline. The remaining 25% of supratentorial brain tumors in children are located in the cerebral hemispheres (Table 1 ).

The histologic types also differ from those seen in adults. In children, brain tumors of glial origin, astrocytomas of the cerebrum, the thalamus, brain stem, optic chiasm, and cerebellum (Table 2) constitute 60% of the total. The proportion of tumors of glial origin in adults is considerably smaller. Instead, in adults, there are relatively large numbers of meningiomas, nerve sheath tumors, and pituitary tumors.

The etiology of brain tumors is not known, but both hereditary and environmental factors are contributing causes. Hereditary diseases such as neurocutaneous syndromes are associated with intracranial neoplasms. Approximately 15% of children with neurofibromatosis develop intracranial tumors, which are usually cerebral, hypothalamic or optic gliomas. This is in contrast to adults with neurofibromatosis, in whom the commonest associated tumors are meningiomas and acoustic neurinomas. Children with tuberous sclerosis develop intracranial lesions as well. These are subcortical hamartomas and subependymal low grade astrocytomas. Von HippelLindau disease is seen in association with retinal angiomatosis and cerebellar hemangioblastoma. Families have been reported in which several siblings have developed brain tumors, suggesting a familial association.4 A less common occurrence is the association of medulloblastoma with the autosomal dominant basal cell nevus syndrome.5

The cell type from which this tumor is derived is debated. However, it is generally believed that the tumor arises from undifferentiated cells with both neurogenic and gliogenic capabilities.4 It is a highly malignant solid tumor. On histologic examination it is composed of densely packed small cells with pyknotic nuclei and scanty cytoplasm. Occasionally Homer-Wright rosettes are seen.…

Brain tumors are the most common solid tumors in children. Each year there are approximately 1200 new cases of primary childhood central nervous system tumors in the US.1'2 Most brain tumors in children are incurable, causing progressive neurological disability and leading to death within a few years. The intractability of childhood brain tumors often causes intense suffering in both patient and family, a situation which produces an attitude of despair in the pediatrician who makes the diagnosis as well as in the surgeons, neurologists and oncologists involved in the ongoing care. However, advances in diagnostic techniques and palliative treatment now often allow the physician to lengthen diseasefree survival, relieve disabling symptoms, and improve the quality of life for these patients.

The purpose of this article is to discuss the epidemiology, clinical assessment, diagnostic evaluation and therapeutic modalities of pediatric brain tumors. The goal is to help the physician choose the best approach to a given patient. The common tumors will be discussed individually. Finally, recent advances and new developments that permit some optimism about the future of brain tumor therapy will be reviewed.

GENERAL CONSIDERATIONS

The incidence of brain tumors in the US for children under 15 years of age is 23.9 per million per year (1969 to 197 1); the incidence is the same for both black and white children, and for boys and girls.3 However, in medulloblastoma and intracranial germ cell neoplasms there is a male preponderance of about 3:2. The peak age incidence in all childhood brain tumors is five to ten years (Figure 1). However, age-specific incidence rates depend on histologic type. Astrocytomas peak at age three years, whereas medulloblastomas and glioblastomas peak at ages five and seven respectively (Figure 2).

The majority of childhood tumors (approximately 60%) arise in the posterior fossa, unlike the situation in adults where approximately 75% of brain tumors are supratentorial. Of the supratentorial tumors inchildhood, roughly 10% to 15% are in the suprasellar, hypothalamic, and pineal region, that is, in the midline. The remaining 25% of supratentorial brain tumors in children are located in the cerebral hemispheres (Table 1 ).

The histologic types also differ from those seen in adults. In children, brain tumors of glial origin, astrocytomas of the cerebrum, the thalamus, brain stem, optic chiasm, and cerebellum (Table 2) constitute 60% of the total. The proportion of tumors of glial origin in adults is considerably smaller. Instead, in adults, there are relatively large numbers of meningiomas, nerve sheath tumors, and pituitary tumors.

The etiology of brain tumors is not known, but both hereditary and environmental factors are contributing causes. Hereditary diseases such as neurocutaneous syndromes are associated with intracranial neoplasms. Approximately 15% of children with neurofibromatosis develop intracranial tumors, which are usually cerebral, hypothalamic or optic gliomas. This is in contrast to adults with neurofibromatosis, in whom the commonest associated tumors are meningiomas and acoustic neurinomas. Children with tuberous sclerosis develop intracranial lesions as well. These are subcortical hamartomas and subependymal low grade astrocytomas. Von HippelLindau disease is seen in association with retinal angiomatosis and cerebellar hemangioblastoma. Families have been reported in which several siblings have developed brain tumors, suggesting a familial association.4 A less common occurrence is the association of medulloblastoma with the autosomal dominant basal cell nevus syndrome.5

Figure 1. Age-specific incidence rates of primary intracranial neoplasms in children (Connecticut 1935-1964).'

Figure 1. Age-specific incidence rates of primary intracranial neoplasms in children (Connecticut 1935-1964).'

Figure 2. Age-specific incidence rates of the most common primary intracranial neoplasms in children (Connecticut 19351964).'

Figure 2. Age-specific incidence rates of the most common primary intracranial neoplasms in children (Connecticut 19351964).'

Environmental factors that have been implicated in the etiology of brain tumors include ionizing radiation, presumed infectious agents in animals, and industrial toxic exposures. Kleriga et al reported a case of a cerebellar malignant astrocytoma at the site of a medulloblastoma treated with surgery and radiation J 1 years previously.6 Equally intriguing are reports of the increased incidence of brain tumors among children of parents who are employed in the chemical or aircraft industry.7

Clinical Findings Symptoms are determined by the location and histology of the tumor and the age of the child. Most childhood tumors are in the posterior fossa and cause their first symptoms by compression of the fourth ventricle, leading to increased intracranial pressure and hydrocephalus, which is often associated with signs of cerebellar dysfunction. In one series of 299 children, 86% presented with signs of increased intracranial pressure, such as headache, vomiting and episodic "greying out" of vision.2 Other common presenting symptoms of intracranial neoplasms include gait disturbance, hemiparesis, behavioral changes, dementia, diplopia, vertigo, and visual difficulties (Table 3).

The symptoms usually begin with a bifrontal or diffuse headache, which often occurs in the early morning upon awakening. Usually the headache is gone within one or two hours. The pathogenesis is unknown. Occasionally, however, the headache is abrupt in onset, short-lived, and precipitated by change in position, exercise or transient increases in intrathoracic pressure. This type of headache is thought to be due to sudden rises in intracranial pressure, called plateau waves, lasting 10 to 20 minutes.8

Cerebellar signs are dependent upon the location of the tumor within the cerebellum. Medulloblastomas and ependymomas are usually midline lesions, arising in the region of the fourth ventricle. Lesions in this location commonly produce a severe truncal ataxia which causes a staggering broad-based gait. Cerebellar astrocytomas are often confined to one hemisphere. A hemispheral lesion produces an ipsilateral ataxia in the limbs and in addition to clumsiness of fine manual movements, there is a tendency to sway or fall to the side of the lesion. Nystagmus is a frequent sign of cerebellar tumors and when present, although not necessary for diagnosis of a cerebellar tumor, is usually indicative of a lesion in the posterior fossa. Head tilt is yet another sign that may be seen in children with infratentorial tumors. The child frequently holds his neck flexed toward the side of the lesion, resisting attempts at passive movement. Whether this sign is a direct consequence of pressure on the eleventh cranial nerve in the region of the foramen magnum, or whether it is due to direct cerebellar compression, is not known. Brain stem gliomas generally infiltrate the brain stem without causing ventricular obstruction. Brain stem tumors more often show various cranial nerve abnormalities and long tract signs, such asa spastic gait, hemiparesis, and upgoing toes (Babinski's sign).

Supratentorial lesions, on the other hand, have varying clinical presentations depending on the hemispheral locations of the tumor, and whether or not there is obstruction of the cerebrospinal fluid pathways with consequent hydrocephalus. A rapidly growing cerebral glioma, for example, will produce focal neurologic deficits, seizures, or both, which are caused by pressure from the tumor and its surrounding edema on contiguous structures.

Table

TABLE 1LOCATION OF PEDIATRIC BRAIN TUMORS

TABLE 1

LOCATION OF PEDIATRIC BRAIN TUMORS

Table

TABLE 2INCIDENCE OF BRAIN TUMORS BY TUMOR HISTOLOGY ' °

TABLE 2

INCIDENCE OF BRAIN TUMORS BY TUMOR HISTOLOGY ' °

Table

TABLE 3COMMON PRESENTING SYMPTOMS OF BRAIN TUMORS2

TABLE 3

COMMON PRESENTING SYMPTOMS OF BRAIN TUMORS2

Temporal lobe lesions frequently produce focal seizures or visual field defects. Frontal lesions may produce hemiparesis if they impinge on the pre-central gyrus or its descending tracts in the internal capsule. Anterior frontal lesions may be silent until they become large and produce signs of increased intracranial pressure. Dominant temporoparietal lesions may result in aphasia and occipital lesions may produce a visual field defect. False localizing signs may be present. A unilateral or bilateral sixth nerve palsy with diplopia is commonly seen with increased intracranial pressure due to traction on the sixth cranial nerve. Frontal lesions with or without hydrocephalus may cause ataxis by compression of the fiber tracts leading from the frontal lobe to the cerebellum. Occasionally, the presence of ataxia leads to an erroneous diagnosis of a posterior fossa lesion.

Diagnostic Evaluation Computed axial tomography (CT scan) has revolutionized the diagnostic evaluation of the child suspected of having an intracranial neoplasm. Not only is the CT scan a more sensitive diagnostic tool than pneumoencephalography, isotope brain scan, or angiography, but it also gives more information about the nature of the mass. The unenhanced scan can determine whether the lesion is cystic or solid, and whether or not it is calcified or hemorrhagic. The presence of hydrocephalus or edema is also easily appreciated. Following the plain CT scan, the patient receives an intravenous injection of contrast material, such as iothalamate meglumine (Conray). The usual dose is 1.0 ml/ kg. Enhancement of the lesion by the contrast material implies breakdown of the blood -brain barrier and, in the case of supratentorial malignant tumor, the degree of enhancement is related to the degree of malignancy.9

When a positive scan is obtained, angiography gives further information about the blood supply of the tumor and the degree of vascularity. There may be a "tumor blush" or, in the case of a malignant glioma, there may be the presence of an early draining vein in the late arterial phase. The angiogram may also assist the neurosurgeon in planning his operative approach.

In patients with cerebral glioma, the EEG may reveal focal slowing over the tumor, at times even when the CT scan is negative. The EEG is often abnormal, but usually it is not helpful in the evaluation of posterior fossa lesions. Spinal fluid examination may or may not reveal abnormalities in protein, cell count, or cytology. Lumbar puncture is dangerous when there is increased intracranial pressure; thus, it is prudent to defer this procedure when increased intracranial pressure is suspected.

Figure 3. CT scan with contrast. Magnified view of the posterior fossa. Within the superior cerebellar vermis there isa cystic lesion with an enhancing mural nodule (arrow). The dilated third ventricle and lateral ventricles indicate hydrocephalus. At surgery the lesion proved to be a cerebellar astrocytoma.

Figure 3. CT scan with contrast. Magnified view of the posterior fossa. Within the superior cerebellar vermis there isa cystic lesion with an enhancing mural nodule (arrow). The dilated third ventricle and lateral ventricles indicate hydrocephalus. At surgery the lesion proved to be a cerebellar astrocytoma.

Figure 4. CT scan following intravenous contrast. There is a large enhancing lesion in the posterior fossa obliterating the fourth ventricle and obstructing cerebrospinal fluid pathways, causing dilation of the third and lateral ventricles. At surgery this was found to be a medulloblastoma.

Figure 4. CT scan following intravenous contrast. There is a large enhancing lesion in the posterior fossa obliterating the fourth ventricle and obstructing cerebrospinal fluid pathways, causing dilation of the third and lateral ventricles. At surgery this was found to be a medulloblastoma.

Treatment Once the diagnosis of an intracranial tumor is made, treatment modalities include surgery, radiation therapy, and chemotherapy. In addition, corticosteroids are given for control of the tumor edema. Not all of the above treatment modalities are necessary for each tumor; the treatment plan depends on the nature and location of the tumor as well as on the age of the child. Since astrocytomas (cerebral and cerebellar types), brain stem gliomas, medulloblastomas and ependymomas make up more than 75% of all pediatric brain tumors, management of these entities will be discussed individually.

SPECIFIC INFRATENTORIAL TUMORS

Cerebellar Astrocytomas Cerebellar astrocytomas make up about 20% of brain tumors in children. Males and females are affected equally; the mean age is six to seven years.10 The tumor is usually located laterally in one cerebellar hemisphere, but it may either arise in or extend to the midline region as well. When the lesion is limited to one cerebellar hemisphere, the child usually presents with a history of clumsiness of one hand and an awkward gait marked by stumbling to one side. There may be no headache or vomiting if the ventricular system is not blocked. With a midline lesion, the history is usually shorter. Symptoms of progressive truncal ataxia, headache and vomiting usually cause the child to be brought to the physician. The vomiting may predate other symptoms by several weeks.

The typical CT scan appearance is a cystic intra-axial lesion with an enhancing mural nodule (Figure 3). Occasionally, the tumor is solid. A definitive diagnosis can only be made by surgical exploration and histopathological examination. There are two histologic variants of this tumor. The juvenile microcystic cerebellar astrocytoma accounts for 70% of cases and the diffuse astrocytoma comprises the remaining 30%. The prognosis for the juvenile cerebellar astrocytoma is better than that for the diffuse type. The survival rates are 94% for juvenile cerebellar astrocytomas and 38% for diffuse astrocytomas, with folio wup more than 25 years following surgery." Survival is also related to the extent of surgical resection. In the series of Griffin et al, complete surgical excision was followed by a survival rate of 100%, with a mean followup time of seven years. Overall survival for partial resection was 79%.' The optimal treatment for a partially resected tumor is controversial, but Griffin's data suggest that adjuvant radiation therapy improves prognosis. Radiation is indicated for the diffuse type and for the rare malignant cerebellar astrocytoma. The usual dose to the posterior fossa is 5000 rad given over a period of six weeks.

Medulloblastomas Approximately 20% of brain tumors in children are medulloblastomas. They occur more frequently in males than in females. The primary age group affected is four to eight years, although the tumor may occasionally occur in young adults. Unlike the cerebellar astrocytoma, medulloblastomas are nearly always located in the cerebellar vermis, probably arising from the anterior medullary velum in the roof of the fourth ventricle.

Figure 5. Cross-section through the pons of a patient with a brain stem glioma. There is almost total replacement of normal structures by tumor (arrow). Note typical deformity of the fourth ventricle (double arrows).

Figure 5. Cross-section through the pons of a patient with a brain stem glioma. There is almost total replacement of normal structures by tumor (arrow). Note typical deformity of the fourth ventricle (double arrows).

Table

TABLE 4CLASSIFICATION OF BRAIN TUMORS*

TABLE 4

CLASSIFICATION OF BRAIN TUMORS*

The cell type from which this tumor is derived is debated. However, it is generally believed that the tumor arises from undifferentiated cells with both neurogenic and gliogenic capabilities.4 It is a highly malignant solid tumor. On histologic examination it is composed of densely packed small cells with pyknotic nuclei and scanty cytoplasm. Occasionally Homer-Wright rosettes are seen.

The clinical presentation of the child with medulloblastoma is usually similar to that of any midline cerebellar mass. The duration of symptoms prior to diagnosis is usually shorter than that of a cerebellar astrocytoma because medulloblastomas grow more rapidly and their location within the fourth ventricle leads to early ventricular obstruction and increased intracranial pressure. Headache and vomiting are the first symptoms, followed by truncal ataxia. Vomiting, like the headache, usually occurs in the early morning before breakfast. Many patients with recurrent vomiting and presumed gastrointestinal disease are referred for neurological consultation only upon later discovery of papilledema. Often patients will have nystagmus due to compression of the vestibular nuclei and a sixth nerve palsy due to increased intracranial pressure. Rarely, a child with medulloblastoma may present with a subarachnoid or intraparenchymal hemorrhage and signs of disseminated disease. In a review of a series of 1 1 3 unselected children with subarachnoid hemorrhage, 15% had intracranial tumors. Of these tumors, the majority were medulloblastoma and primitive neuroectodermal tumors.12

The CT scan usually reveals a midline cerebellar mass that enhances with contrast (Figure 4). Usually other diagnostic studies are not necessary prior to surgery. The optimal treatment goal is gross total resection which, with the aid of the operating microscope, is becoming more attainable. Following surgery, an extent-of-disease evaluation should be performed which should include a postoperative CT scan, myelogram, and examination of spinal fluid cytology and bone marrow smears. CSF and bone marrow examinations are necessary because of the known tendency of this tumor to seed the subarachnoid space and, rarely, to metastasize to bone. Patients whose disease is confined to the posterior fossa at the time of diagnosis have a much better prognosis than those who have any evidence of metastasis either within or outside the CNS. All patients, regardless of extent of disease, receive radiation therapy. This consists of radiation to the entire craniospinal neuraxis at a dose of 3500 rad and a full therapeutic dose of 5000 rad to the tumor bed and posterior fossa. Radiation is administered over a period of six weeks.

The five- and ten-year disease-free survival rates reported by Berry et al in 1981 were 56% and 43% respectively.13 They reviewed 122 patients over a 25-year period and found that improved survival rates were associated with an increased degree of resection and with radiation doses to the posteri or fossa of 5200 rad or more. In addition, they found a subset of 1 5 patients who had all received at least 5200 rad of radiation to the posterior fossa and had had a gross total resection. The survival rate for this group was 77% at both five and ten years. They did not find any survival advantage following administration of "adjuvant chemotherapy," although other investigators were able to produce palliation with chemotherapy given for relapse. The role of adjuvant chemotherapy remains uncertain. Two large cooperative studies, by the International Society of Pediatric Oncology (SIOP)'4 and by the Children's Cancer Study Group (CCSG),1 5 have failed to show a major benefit following chemotherapy with drugs such as vincristine and N -(2-chlorethyl)-N' -cyclo he xyl-N -nitrosourea (CCNU).

Brain Stem Gliomas Gliomas of the brain stem account for approximately 10% to 15% of all childhood brain tumors, usually occurring in the three- to eight-year age group. These neoplasms often grow to a very large size before becoming symptomatic, because they infiltrate the brain stem rather than compress the ventricular system and thus do not cause early hydrocephalus ( Figure 5). The commonest location for brain stem gliomas is in the pons, although the tumor sometimes arises in the medulla and midbrain.

The usual clinical presentation is diplopia, facial weakness and difficulty walking. Facial weakness and diplopia are secondary to cranial nerve palsies and are caused by compression of the nuclei within the brain stem. The facial nerve is the most commonly involved. Sixth nerve palsy results in lateral rectus weakness and diplopia and medullary involvement causes dysarthria and dysphagia as well as other lower cranial nerve signs. The gait disturbance is due to spasticity and weakness caused by compression of the descending corticospinal tracts. Ataxia may also contribute to difficulty walking and this is indicative of involvement of cerebellar connections within the brain stem. Sensory abnormalities are usually limited to the face, indicating trigeminal involvement. Sensory findings involving the trunk are not commonly seen and there are usually no behavioral changes or alterations of mood.

The histological pattern seen at diagnosis ranges from a low grade (grade I and II) to a frankly malignant astrocytoma (grade III and IV). In two reported biopsy series, only three of 19 and six of 26 specimens (nine of 45) were grade IV.16'17 Yet, in 25 autopsied patients, with brain stem gliomas reported by Mantravadi et al, grade IV represented 48% of the tumors.18 The discrepancy between malignancy of biopsy and autopsy specimens may reflect either a sampling problem or may indicate a tendency for these tumors to undergo malignant degeneration with time.

The diagnosis is made by the CT scan, which usually reveals an enlarged and hypodense brain stem. CT scan variations include areas of cystic formation, contrast enhancement, and exophytic extension. Often there is some contrast enhancement. The tumor may extend to include the midbrain or upper cervical cord as well. The fourth ventricle is posteriorly displaced and has a butterfly appearance. There is frequently mild hydrocephalus. Ordinarily, diagnosis does not require confirmation by angiography or air studies unless presence of an arteriovenous malformation or an extra-axial lesion is suspected.

Treatment of brain stem gliomas has changed very little over the years. It consists of radiation therapy, given at a dose of 5000 to 6000 rad to the brain stem. Although the role of surgery is controversial, improved surgical techniques and use of the operating microscope have made it possible for certain patients to benefit from the evacuation of cysts and debulking of exophytic components. Subarachnoid dissemination of tumor to the spinal cord and cauda equina sometimes occurs, but local subarachnoid extension rather than diffuse CNS dissemination is more common. Prophylatic irradiation of the spinal neuraxis is not recommended.18

The role of chemotherapy is unclear. Rosen et al reported a patient with a six-month remission following a course of high-dose methotrexate, given at a dose of 500 mg/ kg.19 The Children's Cancer Study Group, however, has recently completed a randomized trial of radiation therapy as compared with radiation therapy plus vincristine and CCNU. No significant benefit of chemotherapy was observed. Although long-term remissions have occasionally been obtained with radiotherapy and with chemotherapy, the median survival is 15 months. The overall five-year survival rate reported by most investigators is 20% to 30%. 16'18

Ependymomas Ependymomas represent about 9% of brain tumors in children.4 The incidence is probably equal among boys and girls, as it is in adults, although Mork and Loken in their series of 101 cases found a very slight preponderance of boys.20 The majority of intracranial tumors are in the two- to six-year age group, whereas the majority of spinal tumors occur during the teenage years. These tumors arise anywhere in the neuraxis where ependymal cells are found, as well as within the cerebral hemispheres not contiguous with any ependymal tissue. In children, the vast majority are located intracranially, in the posterior fossa, whereas in adults ependymomas are more often found in an intraspinal or cauda equina location. In their review of 74 ependymomas in children. Shuman et al found 67% in the fourth ventricle, 24% in the lateral ventricles and 8% in the cauda equina.21

Histologically, ependymomas are separated into two main groups. The first, the typical or cellular ependymoma, is a densely cellular tumor with a characteristic pattern of ependymal rosettes and pseudorosettes around blood vessels. The malignant ependymoma, however, is more pleomorphic, with mitotic figures, neovascularization and necrosis. The clinical presentation of these tumors reflects the location in which they arise. An ependymoma originating near the fourth ventricle may mimic a medulloblastoma, presenting with headache, vomiting and truncal ataxia.

The treatment of ependymomas is controversial. The goal of surgery is gross total resection. There is a difference of opinion as to the long-term value of radiation therapy. Mork and Loken reported improved short-term survival in their patients treated with postoperative irradiation, but they were unable to demonstrate any long-term benefit. ° There is debate as to whether to enlarge the radiation port to include the entire neuraxis. Some investigators propose radiation because approximately 10% of patients will develop tumor seeding in the subarachnoid space. Others believe that neuraxis irradiation should be reserved for those tumors which are anaplastic.21'22

Chemotherapy has been insufficiently evaluated in treatment of this tumor. Patients with recurrent tumors have shown favorable responses to chemotherapy in single agent phase II trials. In a study by the Children's Cancer Study Group which included patients with posterior fossa ependymomas, no benefit of adjuvant chemotherapy was observed.1S The projected five-year survival rate is only 25%. It appears that those with malignant ependymomas have an even worse prognosis.2'

CNS SIDE EFFECTS OF THERAPY

The treatment of brain tumors has always been complicated by the side effects of the therapy itself and gains made in diagnosis and treatment are often partially offset by complications of therapy. Each therapeutic modality has unique problems and complications associated with it. The goals of surgery are to remove as much of the tumor as possible without injury to adjacent normal tissue but inevitably in some patients the surgery increases neurologic disability. To avoid surgical complications, the surgeon must have as much information as possible prior to surgery concerning both the exact location and the nature of the tumor. Postoperative morbidity has been reduced in recent years because of better localization of the tumor by CT scanning, together with additional coronal views and preoperative angiograms. The operating microscope has permitted better planes of dissection, with less interruption of normal tissue and accordingly fewer postoperative deficits.

Radiation, which is a mainstay of brain tumor therapy, has acute, subacute and chronic side effects. Acute reactions occur within hours after a single treatment. An increase in cerebral edema may merely aggravate a focal neurological deficit, or, if the edema is severe, it may cause cerebral herniation. Adrenocorticosteroids may prevent or minimize cerebral edema. The radiation somnolence syndrome is a subacute reaction. Four to six weeks following the completion of cranial radiotherapy, these children may become somnolent, anorectic and lethargic.22 The drowsiness may be mild or children may sleep up to 20 hours per day. Low grade fever and vomiting may also be present. The symptoms may persist from four days to three weeks, followed by complete resolution. The syndrome is common, occurring in 78% of 98 leukemic patients in one study.22 Although cranial radiotherapy was generally thought to have no long-term sequelae, there is a recent report of subsequent learning disabilities in seven of 29 children who showed the somnolence syndrome following CNS prophylaxis for acute lymphoid leukemia which included 2400 rad of cranial radiotherapy.23 The pathophysiology of this syndrome is not known, but it is believed to be related to an impairment of myelin synthesis. There are reports of a severe form of this syndrome seen when higher radiation doses, 4000 to 5000 rad, are given. In these cases somnolence is accompanied by focal findings24 and these patients may be mistakenly diagnosed as having tumor recurrence until the symptoms recede.

Chronic or delayed radiation damage in its severe form consists of radiation necrosis. This usually follows high dose therapy, greater than 6000 rad. Symptoms appear from six months to several years following cranial irradiation and this entity may mimic a brain tumor both by clinical symptoms and on CT scan. There may be contrast enhancement on CT scan, yet at surgery no tumor, only necrotic tissue, is found. The damage may remain focal or become diffuse, resulting in progressive dementia and death due to swelling. The pathophysiology of delayed radiation damage is unknown, but on histopathological examination there is brain necrosis with hyalinization of vascular structures.

Probably the most worrisome, but least common, late complication is the development of a second cancer. The incidence of such second cancers is 1.5%.25 Thyroid carcinoma has occurred in patients following radiotherapy for medulloblastoma, where the measured dose of radiation to the thyroid gland is 2300 rad.26 In addition, later occurrence of fibrosarcomas and malignant astrocytomas within the brain have been reported.25

Endocrine dysfunction may follow irradiation of the hypothalamus and pituitary and include short stature due to growth hormone deficiency, primary or secondary hypothyroidism, and panhypopituitarism.25-27 A decrease in growth rate is usually the first sign of endocrine dysfunction and short stature may not be clinically apparent until years following radiation therapy.27

Behavioral and intellectual disorders following radiation therapy to the brain include low IQ, difficulties in visual perception, decreased attention span, and a decrease in short-term memory. Danoff studied 38 children with psychological and intelligence testing one to 21 years following radiation therapy. Of these children, 17% were found to be mentally retarded and 28% were classified as dull normal, and behavioral disorders were noted in 39% of the patients.25 It is generally agreed that when given under the age of three years, cranial radiation is more likely to result in intellectual impairment. In 13 patients who received localized radiation to the brain when they were less than two years of age, seven of 1 3 (54%) had IQ scores below 70."

Spinal neuraxis radiation later leads to growth retardation as measured by sitting height. The latter measures spinal growth whereas standing height measures overall linear growth. Probert et al found that of 22 children evaluated, ten (45%) had a sitting height more than two standard deviations below the mean, but only four of 22 (18%) had a standing height more than two standard deviations below the mean. Sixteen children had a discrepancy between sitting and standing height and the most marked was in those children who received spinal irradiation before the age of six years. It appears that during the adolescent growth spurt there is an increased sensitivity to irradiation, just as there is in the child under six.

Chemotherapy for brain tumors also has complications. The agents commonly used in brain tumors are the nitrosoureas (CCNU and N, NI-bis(2-chlorethyl)-Nlnitrosourea) vincristine, methotrexate, and cis-platinum. The nitrosoureas have been extensively used in adults with brain tumors. Their primary toxicity is to the bone marrow, thrombocytopenia and leukopenia occurring about four weeks after administration. Pulmonary toxicity has also been reported.

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TABLE 1

LOCATION OF PEDIATRIC BRAIN TUMORS

TABLE 2

INCIDENCE OF BRAIN TUMORS BY TUMOR HISTOLOGY ' °

TABLE 3

COMMON PRESENTING SYMPTOMS OF BRAIN TUMORS2

TABLE 4

CLASSIFICATION OF BRAIN TUMORS*

10.3928/0090-4481-19830501-05

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