Pediatric Brain Tumors —
Overall Review

TADANORI TOMITA, MD

aFall 2000

Brain tumors  are the most common solid malignancy in childhood. For several decades, brain tumors had been observed to be the second most common type of cancer in children, second only to leukemia. However, a recent study by the National Cancer Institute shows that a significant increase in childhood brain tumors brings them the dubious distinction as the most common pediatric tumor.

In 1974, brain tumors occurred at an annual rate of 2.35 per 100,000 children younger than 15 years, which increased to a corresponding value of 3.45 in 1994. Similar changes in incidence were noted in ALL, which showed a corresponding change in annual incidence from 2.74 to 3.33 per 100,000 children younger than 15 years. This rise in brain tumor incidence among children is attributed to improved diagnostic methods and more awareness of brain tumors among physicians. However, environmental factors cannot be completely ruled out.

TUMOR TYPES

Molecular cytogenetic techniques have helped researchers understand that brain tumors arise from genetic disruptions in cells, causing the cells to become neoplastic. However, despite extensive research, the causes of genetic disruption remain unclear. Brain tumors in the same family members are extremely rare. Furthermore, brain tumors can occur anywhere in the intracranial space. The tumor is named according to the cellular origin and the microscopic appearance.

Most childhood brain tumors arise in the supporting cells of the brain (glia) and are called “gliomas.” The most common is the “astrocytoma,” derived from astrocytes, which are major supportive cells. Astrocytes constitute nearly 40% of the total CNS cell population and are widely spread throughout the central nervous system including the optic nerves. The tumors are classified histologically from grade I through grade IV. Grade I and II are histologically benign, but grade III and grade IV are malignant, hence “glioblastoma.” Other tumors are ependymomas, gangliogliomas, choroid plexus papillomas, and oligodendrogliomas.

Other common brain tumors in childhood arise in the primitive nerve cells, and are much more common in children than in adults. When they occur in the cerebrum, they are called “primitive neuroectodermal tumor” (PNET). In the infratentorial location, they are called medulloblastomas, while those in the pineal gland are called pineoblastomas. They are malignant, grow rapidly, and tend to spread through the CSF. All gliomas and PNETs arise in the brain substance, so that the tumor cells often infiltrate adjacent brain structures, thus preventing total resection.

A third type of childhood brain tumor arises in the non-neuronal embryonal cells. They are germ cell tumors, craniopharyngiomas, or dermoids. Tumors arising in the meninges, nerve sheaths, or pituitary gland have an expansile nature with little or no infiltration to the brain or spinal cord. They are meningiomas, neurinomas, and pituitary adenomas, respectively. They usually occur in adults, but can appear in children.

BRAIN TUMORS’ WARNING SIGNS

Space-occupying lesions such as brain tumors and hydrocephalus increase the intracranial pressure. This causes the brain structures to shift within the intracranial space, which may be life-threatening. Many childhood tumors are found in the skull midline, which often produces hydrocephalus. In such cases, hydrocephalus is the primary cause of symptoms rather than tumor itself.

Initial symptoms are early morning intermittant headaches and nausea, lasting for several months or years. Then, the headaches become more frequent and intense with emesis accompanied by dizziness, weakness, unsteadiness, and double vision. Increasing sleepiness, gait disturbance, ocular changes (abduceus palsy in particular), visual disturbance, seizures, tremors or weakness of the extremities are more definitive signs for childhood brain tumor. Of course, patients present differently depending upon their age and the tumor’s location and histology. Infants and younger children typically present with irritability and rapidly expanding head size. Infants and young children may also present with lack of physical growth (failure to thrive) or precocious puberty.

Papilledema is another sign of hydrocephalus or a mass-induced rise in intracranial pressure. If papilledema is persistant and untreated, blindness may result. Shifts of brain contents through the tentorial opening or the foramen magnum may occur, causing twisting and compression of the brain stem, leading to bradycardia, hypertension, and irregular respirations. Because of compression of the third nerve, the ipsilateral pupil is enlarged and does not react to the light stimulation. Ultimately, the patient exhibits changes in body and limb tone and posture (decortication and decerebration), and stops breathing.

DIAGNOSIS

Developed in the mid 70’s, the computed tomography (CT) scan revolutionized the diagnosis of brain tumors. CT images show skull, blood clots, and the calcified mass appears white, while the brain is gray, and the CSF, fat and air appear black. Contrast dye injected intravenously enhances visualization of the blood vessels and most pathological conditions such as tumors. Thus, CT scan is capable of disclosing not only a tumor mass, its location and extension but also any associated pathological changes such as brain edema around the tumor, hydrocephalus, hemorrhage, cystic formation, calcification, etc. The risks, though minor, are the requirement of sedation for the young child, possible allergic reaction to the intravenous contrast dye, and radiation exposure. Published reports warn that more than 20 rads may cause later cataracts. The radiation doses required for CT are much lower, almost negligible, but nonetheless every effort is made to avoid exposing the eyes to radiation.

Magnetic resonance imaging (MRI), which involves a high-powered magnet, became available in the mid 1980’s. MRI images are quite distinct, allowing a more detailed examination than is possible with CT. Because MRI gives not only an axial view but also coronal and sagittal views, three-dimensional examination is possible.

Due to the risks involved in standard angiography (an invasive procedure carried out routinely before CT became available), MRA (magnetic resonance angiography) has replaced angiography in most situations. MRA uses a special software package along with MRI, which can provide relatively good answers about the vascularity of the tumor. MRS (magnetic resonance spectroscopy) is also relatively new. This diagnostic tool can show a chemical make-up of the tumor and differentiate tumor growth from other lesions. Recent technological advances have made it possible to locate the primary center of the brain (motor cortex, speech center, etc.) by functional MRI (fMRI).

Because some brain tumor cells spread through the CSF pathway, they may reach the spinal canal where they can proliferate. A lumbar puncture yields a CSF sample for study by the pathologist. However, spinal tap is contraindicated if the patient has a large mass in the intracranial space.

MRI can investigate the spinal canal for anatomical anomalies in the spinal cord, spine, and CSF. Spine MRI is a non-invasive method that has replaced myelography, an invasive test previously used.

THERAPY

When the patient is in acute distress, dexamethasone alleviates cerebral edema surrounding a tumor. However, the effects are temporary, and the prolonged use of the drug causes obesity, increased appetite, psychological changes, excess hair growth, gastric ulcers, increased infection rate, and steroid dependency. Long-term use suppresses the adrenal gland. Therefore, dexamethasone should be withdrawn cautiously over a period of time to prevent an acute adrenal crisis.

Surgery for childhood brain tumors is done for histological confirmation, maximum cytoreduction, neural decompression and CSF pathways restoration. Surgical resection is usually the primary treatment; in fact, most benign brain tumors can be cured by surgical excision alone. Patients with malignant tumors often get benefit from maximum debulking, which allows better response to radiation or chemotherapy.

Surgical resection has been improved by advances in surgical techniques and instrumentations such as microsurgery, surgical laser, and ultrasonic aspirator. Frameless stereotactic device and intraoperative ultrasonography can localize the brain tumor. The frameless stereotaxy guides the neurosurgeon precisely to the tumor based on preoperative CT or MRI images.

Even so, a certain group of tumors remain unresectable. Tumors involving or invading the brain stem, optic chiasm or diencephalon are operable but often unresectable.

The surgical mortality for brain tumors has been markedly reduced to less than 1% over the past 20 years. In fact, during the past ten years, a only one infant has died during surgery at Children’s Memorial Hospital. A pediatric neurosurgeon alone, however, is not the only key to successful surgery. Qualified pediatric anesthesiologists, well-equipped pediatric neurosurgical care facilities, and other staff members, such as well-trained nurses, dictate the success.

Complications include minor or major neurological deficits, postoperative hemorrhage, brain swelling and infection. Fortunately, young patients recover quite well with rehabilitation therapy even from major neurological postoperative deficits.

HYDROCEPHALUS

Approximately 80% of childhood midline brain tumors are associated with hydrocephalus.

Each ventricle has a choroid plexus that attaches to the wall of the ventricle and is the major site for CSF production, approximating 20cc/hour, or half a liter per day. The CSF circulates through the subarachnoid space over the surface of the brain and the spinal cord and subsequently is absorbed through arachnoid villi into the venous system. The production, circulation and absorption rates are normally well balanced. If an imbalance occurs between production and absorption, or if circulation is disturbed, the ventricle cavity expands and hydrocephalus develops. Most hydrocephalus associated with brain tumor is due to an obstruction in the ventricular system. Rarely, hydrocephalus occurs with normal communication of the CSF, due to obstruction in the subarachnoid space or obliteration of the arachnoid villi by diffuse tumor disseminations, postoperative hemorrhage in the subarachnoid space, or by over-production of the CSF.

Hydrocephalus usually resolves by resecting the mass lesion blocking the CSF pathway. However, in 15% of children this is not the case; they need a CSF diversion procedure. One of common methods is the placement of a shunt connecting the hydrocephalic ventricular cavity to the peritoneal space (ventriculoperitoneal shunt). Complications include shunt malfunction, infection or life-long shunt dependency. Another method to control obstructive hydrocephalus—particularly those with posterior fossa or pineal region tumors—is a bypass in the third ventricle. Ventriculoscopy allows the neurosurgeon to create a hole in the base of the third ventricle (third ventriculostomy), which drains the CSF directly into the subarachnoid space. The advantage of this method is the avoidance of shunting, but the procedure requires neurosurgical expertise. Acute hemorrhage, though rare, is sometimes fatal. Also, late failure of third ventriculostomy occurs in about 30 % of patients.

RADIATION THERAPY

Radiation therapy is often needed for children with malignant brain tumors and for unresectable benign tumors, because small microscopic cells are inevitably left in the surrounding brain, even when the entire visible tumor has been resected. Residual tumor cells become the source for future recurrence. Medulloblastomas and PNETs have a tendency to spread through the CSF pathway, so radiation therapy to not only the primary site but also the craniospinal axis is crucial.

In external beam radiation therapy, high-energy rays penetrate the skin and internal skull structures, exposing everything in the path of the ray to the radiation. It is, in general, delivered every day, five days a week, for five to six weeks. During the radiation treatment period, particularly the first week, children may tire easily, lack an appetite, have occasional dizziness and headaches, which usually subside spontaneously. These early radiation side effects often respond to dexamethasone therapy. In most cases, radiation therapy is done on an outpatient basis.

Though essential, radiation therapy has other side effects. Fast-growing cells such as neoplastic cells are more susceptible to irradiation, but normal tissues with rapid turnover and reproduction rates are also susceptible. Hair cells and bone marrow, for instance, are affected, resulting in transient hair loss and a decrease in the number of white blood cells, platelets, and red cells. Endocrine organs also are sensitive to irradiation. The pituitary functions are often disturbed. The thyroid gland is directly irradiated during the craniospinal irradiation therapy. Short stature and scoliosis may be related to irradiation of the spine.

Blood vessels, too, are sensitive to radiation, and occlusion of the blood vessels of the brain may occur. This complication is more common when the base of the brain, where major arteries compose a circle of Wills, receives a high dose of irradiation during infancy or young childhood. This can result in a progressive vascular stroke 10 to 20 years after irradiation. The occlusions of small vessels in the tumor however are beneficial because they suppress tumor growth due to the lack of blood supply.

A more serious concern of radiation therapy in infants and children is its effects upon intellectual development. The brain is maturing very rapidly during the early stage of life (approximately 80% of the brain is formed during the first two years of life), so radiation therapy given during this stage frequently causes psychomotor retardation. The younger the age and the higher the dose of irradiation, the more serious the effects. Because of the growing awareness of this complication, radiation therapy is often deferred during infancy, and instead chemotherapy is given until the child is older. This is, however, a controversial issue among the pediatric specialists.

Another concern is secondary tumors in the irradiated site, which can occur 5 to 15 years later and is benign or malignant.

Stereotaxic irradiation such as provided with the gamma knife and the linear accelerator delivers focally intensified radiation with minimum irradiation to the surrounding structures. The highly computerized technique delivers the desired target with exceedingly high doses of radiation while the surrounding areas receive a minimal dose. Stereotactic radio surgery delivers single large doses thus treatment requires only one day. However, a significant disadvantage, particularly in children, is the potential for latent sequelae to the brain from the use of the single large dose. Fractionated stereotactic radiation has combined advantages of precision of the steroetactic system to protection of the developing brain by fractionated radiation therapy.

Another method for irradiating tumor cells is through internal radiation therapy (brachytherapy or interstitial radiation therapy). Small radioactive seeds in a catheter are placed in the tumor intraoperatively or through stereotactic procedure. The seeds are removed after the desirable radiation dose is delivered to the tumor tissue, usually after four days. The radiation dose is calculated by a radiophysicist, so that a much higher dose of radiation is given to the tumor while minimizing the radiation exposure to the surrounding brain tissue. This technique provides radiation to a single region, therefore a large extensive tumor or tumors already spreading in the remote site are not candidates for this therapy. The internal radiation therapy using radioisotope has been largely replaced by stereotaxic radiosurgery. A promising intraoperative radiation device recently acquired at Children’s Memorial Hospital is a photon radiation system (PRS). The PRS uses x-rays as a radiation source, thus radiation control is less strict. Using PSR, a high dose of irradiation is delivered to the desired area at craniotomy while normal structures are shielded under direct vision.

CHEMOTHERAPY

Chemotherapeutic agents suppress the tumor growth by inhibiting the cell metabolism and further multiplication. Because each drug affects cell division to various extents, multiple agents are usually more effective than a single agent. Chemotherapeutic drugs affect rapidly dividing cells so that not only neoplastic cells but rapidly dividing cells in normal organs are also affected, including the bone marrow, hair follicles, gastrointestinal tract, and the reproductive system. Among them, the influence upon the bone marrow is the most serious. Other organs such as the liver and kidneys, which metabolize and excrete the drug may be affected. Some agents affect central and peripheral nervous system, resulting in often-transient encephalopathy and neuropathy, respectively.

Other forms of chemotherapy are intraarterial chemotherapy and intrathecal chemotherapy. Through the carotid or vertebral artery, chemotherapy is given to either side of the cerebral hemisphere or the posterior fossa. The arterial circulation can deliver a higher concentration of the drug to the desired area. Little has been reported about the use of this technique in children; it is currently under investigation. Intraarterial chemotherapy may be complicated by visual changes (blindness) and vascular changes (stroke).

Intrathecal chemotherapy is used to administer certain drugs directly to the CSF space and along the CSF pathway. The technique permits exposing the tumor cells in the

CSF pathway to higher concentrations of the chemotherapeutic agents. Two types of intrathecal chemotherapy have been used: one that employs frequent spinal taps and another that involves the placement of an Omaya reservoir. The later method involves surgical placement of a catheter into the lateral ventricle (occasionally cystic space of the tumor), which is connected to a subcutaneous reservoir. Administration of the drug through the Omaya reservoir allows for better flow through the CSF and is less painful than frequent spinal taps. When the concentration of the intrathecal drug is too high, brain toxicity can occur.

Most children who need chemotherapy for brain tumors are enrolled in national study group protocols. The response of the tumor to chemotherapy is evaluated by frequent neuroimaging studies such as CT scans and/or MRI, typically after two cycles of chemotherapy and shortly before the planned third cycle. If the tumor appears to be responding, the same protocol will be continued. If there is evidence of further tumor growth despite cycles of chemotherapy, the given protocol should be terminated and a different protocol with new chemotherapy agents will be considered. In such a case another experimental chemotherapy would be chosen.

INDIVIDUAL TUMORS

Posterior Fossa Tumors
In the posterior fossa, tumors of the cerebellum and fourth ventricle tend to present with signs of hydrocephalus. They are medulloblastomas, cerebellar astrocytomas, and ependymomas. On the other hand, brain stem tumors present with cranial nerve deficits and long tract signs such as pyramidal tract signs and cerebellar signs.

Medulloblastoma: Medulloblastoma, a malignant tumor that affects young children and presents in the cerebellar vermis and fourth ventricle, is thought to originate from the posterior medullary velum. Approximately 15% of medulloblastomas are located in the cerebellar hemisphere. Common symptoms, which occur because of the development of hydrocephalus, are morning headaches and nausea with progressive unsteadiness of gait. A CT scan clearly demonstrates a large hyperdense mass in the posterior fossa occupying the entire midline structure of the posterior fossa.

FIGURE 1  Sagittal MRI of a 6-year-old boy with medulloblastoma. Note a contrast-enhancing tumor (arrow) in the fourth ventricle and hydrocephalus. He had a successful tumor resection followed by radiation therapy and chemotherapy. Hydrocephalus was resolved after the tumor resection. It is now six years after diagnosis, and he has no evidence of disease.

Decades ago, children with medulloblastoma did not live more than five years (the five-year survival rate was approximately 20%). Survival has since improved, and recently approximately 70% to 80% of children with a medulloblastoma live longer than five years. The biggest factor in this improvement is the surgical removal of as much tumor as possible during the initial craniotomy and the advancement of adjuvant therapies.

Even when the tumor is visibly excised, patients with medulloblastoma require postoperative radiation therapy and chemotherapy. This is because of a high probability that residual cells remain in the surrounding brain tissue and also a high tendency of dissemination of the tumor cells in the spinal fluid. Studies done at Children’s Memorial Hospital indicate that more than 50% of medulloblastomas are already spread at the time of diagnosis. Irradiation is given using cranial spinal radiation therapy with a higher dose of the radiation to the posterior fossa (5000–5500 rad) and lower dose (2500–3600 rad) to the cranio/spinal axis. Patients who show evidence of disease in the spinal column or in the supratentorial region need a higher dose of radiation therapy to the brain and spine. Also, the intensity of chemotherapy is adjusted depending upon the evidence of tumor dissemination. Therefore, it is important to investigate extension of the tumor by a MRI of the head and spine and CSF cytology. If the tumor is removed totally at the time of surgery, and adequate radiation therapy and chemotherapy are provided, children with medulloblastoma typically have long-term survival. Because radiation on the brain during the first three years of life may not be well tolerated, radiation may be deferred by controlling the tumor initially with chemotherapy. This approach may be successful but is still controversial in terms of tumor control.

Even after successful surgery and adequate adjuvant therapy are given, the patients with medulloblastoma should be followed closely. We recommend surveillance MRI scans every three months for the first two years when the recurrence rate is the highest. Occasionally, a bone scan survey may be done to discover any bone metastases since this tumor has been known to metastasize. After three years, the incidence of recurrence of medulloblastoma diminishes markedly, but the tumor may occur five years or later. Although the incidence of recurrence at a later stage is rare, surveillance using a neuroimaging study should be continued for ten years after surgery. Patients who have incomplete resection, advanced stage medulloblastoma, an inadequate dose of radiation therapy because of their young age, or other extenuating factors (DNA-diploid medulloblastoma, expression of specific oncogenes) should be considered for advanced chemotherapy.

Cerebellar Astrocytomas: Cerebellar astrocytoma is as common as medulloblastoma, but it has a different prognosis. It is one of the most benign and favorable tumors among the pediatric brain tumors. Its presentation is similar to that of the medulloblastoma and is mainly due to hydrocephalus. Some present with a head tilt or pain in the occiput. Approximately half of cerebellar astrocytomas are cystic. Approximately 95% of the patients are cured surgically without radiation or chemotherapy. Because most of the tumors are located in the cerebellar hemisphere, a complete resection is often possible.

Occasionally, an extension of the astrocytoma to the brain stem or cerebellar peduncle may preclude a total resection of the tumor. Resectability has markedly increased by current techniques that use surgical lasers and the microscope. Radiation is not recommended even after incomplete resection because 50% of residual tumors are either stable or involute. Also, malignant transformation of cerebellar astrocytomas occur only among those who previously received radiation therapy. These patients need close follow-up by CT or MRI.

Even after total resection of the astrocytoma and medulloblastoma, some patients continue to be hydrocephalic. Approximately 15% of them need a CSF diversion shunt or third ventriculostomy.

Ependymomas: Ependymomas are the third most common histological type of tumors affecting the cerebellum and the fourth ventricle in children. Ependymomas tend to occur in very young children; 50% are diagnosed during the first three years of life. Ependymomas derive from the ependymal layer of the fourth ventricle, and extend into the fourth ventricle cavity or into the neighboring subarachnoid space. Approximately 20% of ependymomas originate from the floor of the fourth ventricle while others are from the lateral recess. The latter type of ependymoma often extends into the cerebellopontine angle where multiple cranial nerves are affected. The clinical presentations are similar to those of medulloblastomas and astrocytomas. Because they usually involve the brain stem or cranial nerves, complete resection is often difficult even by an experienced neurosurgeon. In our series, only 50% of children with ependymoma had gross total resection, though surgical respectability has improved over past ten years.

FIGURE 2  ICoronal MRI of an 11-year-old girl with a large ependymoma in the parietal location. Note a contralateral shift of the lateral ventricles (arrow). She had a total resection of the tumor and has done well without adjuvant therapy for 7 years.

Despite the use of radiation therapy and chemotherapy following an incomplete resection, recurrence rates in ependymomas are high (much higher than that of medulloblastomas), and patients should be followed closely with MRI. Spinal cord metastases occur in less than 10% of cases, which is much less than in medulloblastomas. Patients with ependymomas have been treated by postoperative radiation therapy to the posterior fossa, if the MRI shows evidence of disease. Furthermore, the long-term chemosensitivity of ependymomas remains doubtful. Although controversial, completely resected ependymomas can be observed without adjuvant therapies. For incompletely resected ependymomas, a second-look operation is recommended after a few months of chemotherapy, followed by stereotaxic radiation therapy.

Brain Stem Tumors: Resection of these tumors is difficult—often impossible. There are three portions in the brain stem, and tumor histology often differs in each depending upon the location. Tumors of the pons are almost invariably malignant astrocytomas, while tumors of the medulla oblongata and the midbrain tend to be benign astrocytomas.

Children with pontine tumors often present with multiple neurological signs that are rapidly progressive, sometimes within a few weeks. They often suffer from abducens and facial palsy, dysarthria, hemi paresis and ataxia. CT scans—and more recently, MRI scans—clearly demonstrate an enlarged pons, which may often extend into the neighboring brain stem and cerebellar structures. Approximately 90% of pontine tumors are malignant astrocytomas with a rapid growth rate. Unfortunately, none of the pontine glioblastomas are surgically resectable.

Current controversy exists as to whether this tumor should be biopsied or not. It is possible to do it by means of a stereotaxtic device, but the obtained sample is quite small and it does not necessarily represent the entire tumor. Because CT and MRI are able to predict pontine tumor’s histological features, most treatment plans can be made without a tumor biopsy. The patient’s symptoms often respond, at least temporarily, to dexamethasone treatment. Approximately one third of the patients develop hydrocephalus.

National and international protocols use radiation therapy and chemotherapy. They include hyperfractionated radiation or chemotherapy as a radiosensitizer. Despite all this, suvival rates have never improved. Most patients die within 12 months of diagnosis, and the two-year survival rate is only 8%. The value of systemic chemotherapy needs further investigation.

Tumors of the medulla oblongata rarely extend into the pons, but can extend into the cervical cord. Patients present with hemiparesis or quadriparesis. They may have dysarthria, dysphonia or central apnea. Most medulla oblogata tumors are benign astrocytomas. Significant tumor resection is possible, but total extirpations are often difficult due to changes of vital signs (bradycardia and hypertension) during tumor resection.

Tumors of the midbrain occur either in the tectum (quadrigeminal plate) or the cerebral peduncle. The former presents with hydrocephalus and rarely causes neurological disturbances. The latter, however, presents with progressive contralateral hemiparesis. Tectal tumors are often indolent and rarely require treatments beyond those needed for hydrocephalus. On the other hand, cerebral peduncle tumors, most of which are benign astrocytomas, often extend to the thalamus and must be treated. Most cerebral peduncle tumors can be resected by sophisticated microneurosurgery, and adjuvant therapy may not be necessary if total resection is achieved.

Other Posterior Fossa Tumors: Common adult tumors in the posterior fossa—acoustic neurinoma, meningioma, hemangioblastoma and metastatic carcinomas—are very rare in children. Acoustic neurinomas and meningimas are often associated with neurofibromatosis type 2 when they occur in childhood. In that case, multiplicity of these tumors in the central nervous system is a feature of the disease.

Suprasellar Tumors
Found in this location are the optic pathways (optic nerves, chiasm), the hypothalamus, the third ventricle, and the circle of Willis. Tumors that occur here present with visual disturbances, hydrocephalus, and/or endocrine dysfunctions. Surgical resections of suprasellar region tumors may be hindered if any of the structures above are involved. Two main tumors occur in this region during childhood. One is craniopharyngioma and the other is hypothalamic and/or optic chiasm astrocytoma. The former is surgically resectable, but the latter is not. Other suprasellar tumors in childhood are germ cell tumors and histiocytosis X, both of which often present with diabetes incipidus. Common adult tumors such as pituitary adenomas and meningiomas are rare in childhood.

Craniopharyngiomas: Craniopharyngiomas arise in embryonally misplaced cells of the craniopharyngeal duct in the base of the brain, so that the tumor itself is not neural in origin. It often presents with visual disturbances due to the compression of the optic nerves or the optic chiasm. Cystic changes and calcified masses are characteristic of childhood craniopharyngiomas. Although most of the tumors are sellar and suprasellar, the cystic component can extend into various directions into the subarachnoid spaces and third ventricle. About 50% of childhood craniopharyngiomas extend upward into the third ventricle and result in hydrocephalus. Most craniopharyngiomas are surgically resectable, however, endocrinological function is almost invariably disturbed. The most common endocrinological problem is diabetes incipidus. Other hormonal functions may be disturbed such as those affected by the growth hormone, adrenocorticoidal hormones, sex hormones, and thyroid hormones. Another undesirable endocrine dysfunction related to childhood craniopharyngioma is obesity as a result of hypothalamic damage.

FIGURE 3  Sagittal MRI of an 8-year-old boy with a massive craniopharyngioma. Note a large solid component (arrow) extending from the sella turcica to the posterior fossa. Also, multiple cysts (asterisks) are filling the third ventricle and causing hydrocephalus. Hydrocephalus was resolved following a successful tumor resection. He has required multiple hormonal replacement therapy since the tumor resection.

If the tumor adheres to the hypothalamus, to the visual pathway, or to a major artery such as internal carotid and basilar arteries, portions of the tumor may not be resectable. In that case, radiation therapy is indicated. Some neurosurgeons may choose to give radiotherapy irrespective of the extent of surgical resection because of the tumor’s relatively high recurrence rate (25%) despite gross total resection. Even after total resection, patients need serial monitoring by CT and MRI because of high recurrence rates. Systemic chemotherapy is not effective for eradicating craniopharyngiomas, but further tumor growth may be suppressed by intermittent injections of bleomysin into the cystic portion of the craniopharyngioma through the Omaya reservoir. Cystic recurrence of the craniopharyngioma may be treated with injection of P32 (radioisotope) into the cystic cavity. The intracystic injections of can be complicated; severe adhesive arachnoiditis or neurotoxicity can occur if the agents leak into the subarachnoid space.

Suprasellar astrocytomas: A great majority of these tumors are benign astrocytomas that grow slowly. Infants and children with optic pathway astrocytomas present with visual changes, nystagmus, and hydrocephalus. Infants with suprasellar astrocytomas may present with failure to thrive. Approximately 30% of optic pathway astrocytomas are associated with neurofibromatosis type 1, and 15% of children with neurofibromatosis type 1 develop optic pathway gliomas. Because of direct involvement of the optic pathway, the tumor cannot be excised without visual compromises. In certain tumors, the exophytic portion of tumor that protrudes from the optic pathway can be resected. However, the current treatment of choice for progressive optic pathway astrocytomas is chemotherapy. A great majority (60 to 70%) respond to carboplatin or vincristine chemotherapy, which often improves the child’s vision and reduces the failure to thrive. Radiation therapy, although effective, should be avoided especially in young children because of its latent adverse effects. When patients present with hydrocephalus, shunt placement is necessary. Due to a lack of communication between the lateral ventricles, the shunts are placed bilaterally.

Hypothalamic tumors may present differently from optic pathway astrocytomas. However, neuroimaging tends to fail to differentiate them due to a lack of anatomical separation between the optic chiasm and the hypothalamus. Usually hypothalamic tumors do not cause visual disturbances. Instead, two endocrinological presentations are typical: diencephalon syndrome and precocious puberty. The diencephalon syndrome caused by astrocytomas is characterized by loss of weight and little subcutaneous fat despite good appetite and increasing body height. Precocious puberty tends to be associated with hypothalamic hamartomas, which can be differentiated through MRI. Neither hypothalamic astrocytomas nor hamartomas can be resected, though debulking is possible. Chemotherapy is often effective for hypothalamic astrocytomas. Children with hamartomas are treated symptomatically and rarely require surgery for the tumor.

Thalamic Tumors: The thalamus is the major sensory relay center, but thalamic tumors rarely present with sensory abnormalities. Symptoms commonly associated with thalamic tumors are intentional tremor, hemiparesis and hydrocephalus. The thalamus is located in the depth of each cerebral hemisphere, conforming to the lateral wall of the upper third ventricle and floor of the body of the lateral ventricle. Therefore, surgical resections of the thalamic tumors are difficult and may be associated with postoperative motor weakness or speech difficulties. However, resectability has improved thanks to recent advanced surgical technology and techniques.

Half of all thalamic tumors are benign astrocytomas, and the other half malignant astrocytomas. After benign astrocytomas are successfully resected, no further treatment is necessary. Unresectable progressive benign astrocytomas are treated with limited-field radiation therapy, but increasing numbers of children have been treated with a combination of carboplatin and vincristine. Patients with malignant astrocytoma are treated by both radiation therapy and chemotherapy. The prognosis of children with malignant astrocytomas is poor, and most die within a year despite treatment. If the patient shows signs of hydrocephalus (which occurs in 80% of the cases), a shunt is required.

Cerebral Hemispheric Tumors
In the cerebral hemisphere, the most common tumor is the benign astrocytoma. Other common pediatric tumors are PNETs, ependymomas, gangliogliomas and ologodendroglomas. In the cerebral ventricle, choroid plexus papillomas are the most common in childhood. Glioblastomas, metastatic carcinomas and meningiomas, which are common in adults, are rare in children. Some cerebral hemispheric tumors in children may be very large despite relatively subtle presenting symptoms.

Cerebral astrocytomas: Cerebral astrocytomas occur in any lobe of the cerebral hemisphere; most are benign. Gross total resection is frequently possible though transient cerebral dysfunctions may occur. Following total, or sometimes, subtotal resection, cure is achieved without adjuvant therapy. Gangliogliomas and oligodendrogliomas are benign gliomas, and gross total resections are usually curative. Subependymal giant cell astrocytomas, often associated with tuberous sclerosis, are benign and occur in the lateral ventricle. They attach to the region of foramen of Monro, and total resection is usually possible. When patients present with seizure disorder, intraoperative monitoring using electrocorticography often helps to ensure removing not only tumor but associated seizure foci.

Malignant astrocytomas are rare, and they often further involve the basal ganglia and thalamus. Patients with malignant astrocytomas need adjuvant radiation therapy and chemotherapy. Radical tumor resection enhances adjuvant therapy. However, the prognosis of children with malignant astrocytomas is poor.

Cerebral PNET: Histologically, PNETs resemble medulloblastomas of the cerebellum; they are one of the most primitive and malignant tumors among pediatric CNS tumors and tend to be very large and vascular. They often extends to multiple lobes of the cerebral hemisphere or involve very deep structures of the cerebral hemisphere. Even if the neurosurgeon is able to totally resect the tumor, the patient still requires postoperative adjuvant therapy. Radiation therapy usually includes the whole neuroaxis because the tumors tend to spread along the spinal fluid pathway. Because surgical resection and radiation therapy never is totally successful, the patient needs further chemotherapy. Furthermore, the patient should be followed-up with serial MRI scans and CSF cytology. Despite aggressive therapy, patients with PNETs of the cerebral hemisphere have a poor prognosis; the tumors often recur within one year of surgery. Conventional chemotherapy may not be effective, so a great majority of patients need more aggressive adjuvant chemotherapy.

Choroid Plexus Papillomas: Choroid plexus papillomas arise in the choroid plexus, the major site of spinal fluid production. Consequently, patients with choroid plexus papillomas often present with hydrocephalus due to over-production of cerebral spinal fluid. The common site for these tumors in childhood is the lateral ventricle and occasionally the third ventricle. The fourth ventricle is an uncommon site for a choroid plexus papilloma in childhood. The best treatment is surgical excision of the tumor and appropriate care for the hydrocephalus. In most cases, after the papilloma is resected successfully, hydrocephalus subsides. Patients with choroid plexus papillomas are quite young; approximately two thirds of them are in their first two years of life. Because they are small, their blood volume is limited so blood transfusions for acute blood loss should be prepared in advance.

FIGURE 4  Axial MRI of a 10-year-old boy with a massive choroid plexus papilloma of the third ventricle and hydrocephalus. He had been known to have a large head, spastic diplegia and developmental delay since infancy. Because of recent onset of headaches, neuroimaging studies were obtained. The third ventricle papilloma was resected, and he has done well for almost 10 years since.

After benign papillomas are resected, their recurrence is rare. It is rare for them to become malignant. Malignant choroid plexus papillomas often affect very young children, and they need to be treated with chemotherapy.

Pineal Region Tumors
The posterior portion of the third ventricle is the pineal region, which is next to the aqueduct of the Sylvius. Therefore, hydrocephalus is present in virtually every case. Compression upon the tectum of the midbrain often causes upward gaze palsy and pupillary abnormalities (Parinaud’s signs). In this small area, tumors of variable histology can occur. The most common ones are germ cell tumors, and approximately 80% of those in the pineal region are malignant. Similar germ cell tumors can occur in the gonads.

Germ cell tumors exist as two different types: one is germinoma and the other non-germinomatous type. The non-germinomatous type tumor includes choriocarcinoma, embryonal cell carcinoma and teratocarcinoma. These tumors often produce specific tumor markers: alpha fetoprotein and/or beta HCG, in the blood and CSF. Elevated tumor markers can conclude the diagnosis of non-germinomatous germinomas. It is important to investigate the patients with staging MRI and CSF cytology along with tumor marker levels of the spinal fluid and serum. Only benign germ cell tumors are mature teratomas. Nearly all pineal germ cell tumors occur in males. Occasionally, germ cell tumors can occur concurrently in the pineal and hypothalamic locations. Other common pediatric pineal region tumors are pineoblastomas, which belong to PNET family, and extremely malignant and tend to disseminate through the CSF pathways. Pineoblastomas tend to occur in much younger children and affect both sexes equally.

The surgical resection of pineal region tumors may be difficult because of their deep location in the brain. Prior to the era of microneurosurgery, mortality rates reached nearly 50%. However, today most of them can be resected with minimum morbidity. Because the malignancy rate is high in this location and resection is difficulty, diagnostic radiation therapy had often been used. Germinomas, especially, which are by far the most common among pineal region tumors among teenage boys, respond to radiation therapy quite well and may totally dissolve after 1600 rad; they are one of the most radiosensitive tumors among CNS tumors. Until recently, a frequently used treatment method consisted of the following; after diagnostic radiation therapy ranging from 1500 rad to 2000 rad, subsequent MRI scans determined whether or not the tumor was shrinking. If the tumor shrank, the radiation was continued to its maximum dose; if the tumor did not respond, surgery was required.

However, due to the heterogeneous nature of pineal region tumors, and the risky nature of irradiation during childhood, this approach has been abandoned. New chemotherapy protocols for pineal region tumors of teenage boys take advantage of the fact that germinomas are extremely chemosensitive, and a single dose of chemotherapy (carboplatin) can reduce the tumor quite significantly.

Histological confirmation can now be achieved by stereotactic or ventriculoscopic biopsy. The advantage of the ventriculoscopic approach is that the third ventriculostomy permits directly visualizion of the tumor through the scope. However, these biopsy procedures may be complicated by intra- or postoperative hemorrhages. Also, tissue samples obtained for biopsy do not necessarily represent entire tumor histology.

Germ Cell Tumors: Children with teratomas are often cured with total tumor resection. However, children who show positive CSF cytology and who have concurrent pineal and hypothalamic tumors are treated with craniospinal irradiations. The prognosis of germ cell tumors is excellent, and approximately 90% of patients are cured. On the other hand, the five-year survival rate of youngsters with non-germinomatous germ cell tumors is 60%.

Pineoblastoma: Pineoblastomas tend to disseminate through the CSF pathways as other PNETs. If the tumor is present in the spinal column or if there are positive results of CSF cytology, surgical resection is usually not indicated. Patients with pineoblastomas need radiation therapy not only in the pineal region but also along the cranio/spinal axis. The prognosis of patients with pineoblastomas is poor due to the tumor’s tendency to disseminate and because of its occurrence among young children (for whom radiation therapy is very detrimental, leaving chemotherapy as the only alternative.) The five-year survival rate is only 15%.

THE BRAIN TUMOR CENTER AT CHILDREN’S MEMORIAL

Because of increasing medical sophistication and complex brain tumor therapy, no one physician can handle the problems presented by children with brain tumors. A team approach is the optimal treatment, and this is the approach of the Brain Tumor Center at Children’s Memorial Hospital. The center includes pediatric neurosurgeons, pediatric oncologists, pediatric neurologists, radiation oncologists, pediatric neuroradiologists, neuropathologists, endocrinologists, medical psychologists, nursing and social workers. In addition, other pediatric subspecialists in such as those in intensive care medicine, neonatology, and pediatric rehabilitation medicine are involved as needed for the best possible care of children with brain tumors.

Thanks to the team approach, the early recognition of recurrence after the individual treatment given for the brain tumor is much more likely. (In malignant tumors, the highest frequency of recurrence occurs within the first three years of diagnosis.) Furthermore, part of what makes early recognition possible are the frequent surveillance neuroimagings including CT and MRI scans along with CSF cytology. The timing of follow-up may vary depending on the patient’s tumor type and treatment given. Early detection of a recurrent tumor is crucial.

The Brain Tumor Center at Children’s Memorial also offers the best chance at identifying any serious early or late side effects caused by treatment. Physical, intellectual, and endocrinological handicaps should be detected early in order to initiate appropriate therapy. All of these measures are intended to maximize the potential of each and every child diagnosed with a brain tumor.

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