History:

• Patients often report a history of illness for more than 3 months prior to diagnosis.
• Increased intercranial pressure

• Initial symptoms are usually nonspecific, nonlocalizing, and related to increased intracranial pressure (ICP). These signs occur in up to 75% of patients regardless of tumor location.
• The classic triad of a raised ICP consists of morning headaches, vomiting, and lethargy. The headache is characterized by pain upon arising that is relieved by vomiting and lessens during the day.

• School-aged children more commonly report vague intermittent headaches and fatigue. They may have a declining academic performance and may exhibit personality changes.

• Infants may present with irritability, anorexia, developmental delay, or regression.

• Seizures: Seizures are present at diagnosis in at least 25% of patients with supratentorial astrocytomas. They may precede diagnosis by several months to 1-2 years.

• Signs related to tumor location

• Focal motor deficits occur in up to 40% of patients with hemispheric and central diencephalic tumors.

• Hypothalamic tumors may be associated with neuroendocrine abnormalities, growth hormone deficiency, diabetes insipidus, and precocious pubertal development. These tumors may also impinge on the optic chiasm, resulting in optic atrophy and visual deficits.

• Patients with diencephalic tumors may present with the classic diencephalic syndrome (ie, emesis, emaciation, unusual euphoria), but the syndrome is rare in children older than 3 years.

• Patients with astrocytomas of the cerebellum may present with weakness, dysmetria, tremor, and ataxia.

• Astrocytomas of the brain stem are characterized by the presence of isolated cranial nerve deficits and contralateral hemiparesis.

• Astrocytomas of the visual pathways may be brought to medical attention because of strabismus, proptosis, nystagmus, or developmental delay. Young children rarely report the slow and progressive visual loss characteristic of these tumors. Infants frequently display head tilt, head bobbing, and nystagmus.

• Patients with astrocytomas of the spinal cord most frequently present with pain (70% of patients have pain localized to the vertebral segments adjacent to the tumor), weakness, gait disturbance, and sphincter dysfunction. Paresthesias and loss of sensation occur later in the disease course.

Physical:

• Increased intercranial pressure

• A funduscopic examination reveals papilledema. Infants may have only optic pallor.

• Palsy of cranial nerve VI is common and results in the inability to abduct one or both eyes.

• Infants may demonstrate the setting sun sign, observed as an impaired upgaze and a forced downward deviation of both eyes. Measurement of head circumference in infants with open sutures may reveal macrocephaly.

• Other signs

• Strength and motor testing may reveal weakness and monoplegia or hemiplegia.

   

• Localized deficits in truncal steadiness, upper extremity coordination, and gait may be observed with tumors of the posterior fossa and basal ganglia.

• Multiple and bilateral cranial nerve deficits, especially VI and VII; long tract signs; and ataxia are associated with brainstem tumors.

• Visual acuity is frequently reduced to less than 20/200 with optic gliomas. The pattern of visual loss in those patients with intraorbital tumors is most commonly a decrease in central vision, whereas bitemporal hemianopsia is most often noted in those patients with chiasmatic tumors. The involved eye generally shows optic pallor and nystagmus. Mild proptosis is usually present with primary intraorbital tumors.

• Spinal astrocytomas often cause weaknesses of a variable extent and severity, ranging from monoparesis to quadriparesis. Pain along the involved vertebral segment may occur when the patient sneezes or coughs. Papilledema and hydrocephaly are present in 15% of patients and are attributed to increased CSF viscosity from an elevated protein content.

Causes:

• Epidemiologic studies investigating parental occupational exposure, environmental exposure, and maternal nutritional intake failed to identify linkages with any of the childhood brain tumors.

• An association with NF1 is present in 50-80% of patients with isolated optic nerve astrocytomas and in as many as 20% of those with chiasmal or deeper optic tract tumors. NF1 and tuberous sclerosis are also associated with other low-grade astrocytomas.

• Astrocytoma is the most frequent CNS tumor in people with the Li-Fraumeni syndrome (germline mutation of the p53 tumor suppressor gene on the short arm of chromosome 17).

• Ionizing radiation to the head for prior malignancies causes secondary supratentorial malignant astrocytomas in a small number of patients.

Imaging Studies:

• Head computed tomography imaging with and without contrast

• CT imaging has higher than 95% sensitivity for the detection of brain tumors.

• On CT scans, most supratentorial low-grade astrocytomas are hypodense with variable contrast enhancement. Calcifications may be present. High-grade tumors show a more heterogeneous density pattern and a more diffuse contrast enhancement.

• Patients with cerebellar astrocytomas may demonstrate hydrocephalus and contrast enhancement on CT scans. A prominent cystic component is often present.

• Brainstem astrocytomas typically enhance poorly after contrast and lack calcifications on CT scans. They may appear isodense or hypodense.

• Head and spine magnetic resonance imaging with and without gadolinium

• Magnetic resonance imaging (MRI) is the imaging modality of choice for brainstem astrocytomas.
• MRI of the head must be performed in all patients with CT scan or clinical findings consistent with astrocytoma. Other tumors, such as medulloblastoma and ependymoma, may have a similar appearance on CT scans. MRI is useful in such instances by better demonstrating the anatomic origin and extent of tumor.

• MRI is the imaging modality of choice for detecting primary or disseminated spinal cord lesions. Perform an MRI of the spine in all tumors with malignant characteristics.

• A postoperative MRI is required to measure the extent of surgical resection and the detection of residual disease. Postoperative MRI evaluation must be performed within 72 hours of surgery in order to delineate residual tumor from the postsurgical inflammatory changes that are visualized on MRI at this time.

Procedures:

• CSF cytological examination: This examination is useful in malignant astrocytomas for the detection of microscopic leptomeningeal dissemination.

• Lumbar puncture: CT imaging or MRI must be performed prior to the lumbar puncture (LP) to rule out the presence of hydrocephaly in those patients suspected of having a brain tumor. Hydrocephaly places the patient at risk for herniation as a consequence of the procedure. In general, the LP is deferred up to 2 weeks postoperatively in order to avoid identifying tumor cells that may have disseminated as a result of surgery.

Histologic Findings: Childhood astrocytomas represent different histopathologic entities, such as pure astrocytoma (commonly pilocytic and fibrillary type in children), oligodendroglioma, and mixed tumors of both cell types. Astrocytomas are composed of glial fibrillary acidic protein (GFAP)–positive bipolar or stellate cells. Oligodendrogliomas are characterized by monotonous collections of spheroidal cells. Classification of gliomas is based primarily on their degree of anaplasia, rather than on histologic type.

Tumors that are modestly cellular and contain few or none of the histologic criteria of malignancy are designated low-grade or grade I and II lesions, according to the WHO. Unifying features are their slowly evolving nonaggressive clinical behavior and relatively benign histological appearance. Grade I is primarily designated for the typical pilocytic astrocytoma, accounting for 85% of cerebellar low-grade gliomas. It is composed of astrocytes interwoven with a fine fibrillary background and often has a characteristic microcystic component and Rosenthal fibers. Grade II is reserved for diffuse astrocytomas composed of moderately cellular astrocytes, oligodendrocytes, or both.

High-grade tumors are characterized by the presence of several histologic features of malignancy that include hypercellularity, cytologic and nuclear atypia, mitoses, necrosis, and endothelial proliferation. These tumors are clinically aggressive, regionally invasive, and capable of neuraxial dissemination. Grade III refers to anaplastic astrocytoma and grade IV is designated for glioblastoma multiforme.

The most common lesions of the brain stem are diffuse intrinsic pontine gliomas (80%). They are not amenable to biopsy except in about 25% of cases, in which an exophytic portion exists. Autopsy reveals that the majority of these cases are found to be high-grade tumors. Tumors arising in other areas of the brain stem are more likely to be low-grade and may be focal (<2 cm), cystic, or dorsal exophytic from the floor of the fourth ventricle, or they may arise from the cervicomedullary junction.

Medical Care:

• General
  • Treatment of astrocytomas depends on the location and grade of the tumor. Tumor location and associated morbidity may limit resection or render the tumor inoperable.
  • Patients who develop significant obstructive hydrocephaly that does not resolve may require the placement of a ventriculoperitoneal shunt.

• Chemotherapy
  • Chemotherapy has a limited role and limited success in the treatment of astrocytoma.
  • For low-grade astrocytomas that are inoperable because of location or have demonstrated early recurrence or progression, chemotherapy with carboplatin and vincristine has been used in prepubertal children in an effort to avoid or delay irradiation.
  • Chemotherapy has little impact on the overall survival of patients with high-grade tumors despite several regimens showing significant tumor response rates. To date, nitrosoureas (ie, bischloroethylnitrosourea [BCNU], cyclohexylchloroethylnitrosurea [CCNU]) and cisplatin show the most efficacy against these tumors. The alkylating agent, temozolomide, shows promising results in recent clinical trials as a single-agent therapy for astrocytoma.
  • Admit for treatment those patients with high-grade astrocytomas who are eligible for available investigational chemotherapy. Investigational chemotherapy for low-grade tumors is currently administered in an outpatient setting.

• Low-grade astrocytoma
  • Surgical resection is the primary treatment modality. If feasible, a complete resection is the goal of surgery in order to minimize the risk of local recurrence. However, long-term progression-free intervals may ensue even after partial resection. Low-grade tumors that recur or progress may be re-resected, and patients can undergo observation without further treatment if the risk of neurologic impairment from further growth is low and the tumor has undergone a significant interim period of dormancy.
  • Low-grade tumors that (1) are inoperable (diencephalic, brain stem), (2) are partially resected and posing a high risk of neurologic impairment if allowed to regrow, or (3) demonstrate early progression or recurrence may be treated with local radiotherapy to the area of the tumor plus a 2-cm margin. Alternatively, chemotherapy may be used in young children (prepubertal) in whom the clinician wishes to avoid or to delay radiotherapy because of its potential neurologic sequelae in this age group. To date, the most active chemotherapy regimen for these tumors is carboplatin and vincristine. These agents show objective response rates of 50-80% and produce prolonged stable disease.

• High-grade astrocytoma
  • Following surgical resection, patients are treated with local irradiation to 50-60 Gy with a 2- to 4-cm margin around the area of edema defined by imaging.
  • The addition of single-agent or multiple-agent chemotherapy following radiotherapy has little or no impact on the overall survival rate (0-30%) in this group of patients, in spite of producing response rates as high as 45%.

• Astrocytoma of the brain stem
  • Surgery has no role in those patients with diffuse pontine lesions (eg, malignant brainstem glioma), the most common brainstem tumor. Surgery is feasible for many patients with exophytic and cystic tumors, and extensive resection may prolong survival even without further treatment. However, a surgical approach to focal midbrain, medulla, and tectal plate regions is hazardous and resections are generally limited.
  • Local radiotherapy to 54 Gy is used for patients with inoperable tumors and for those who have high-grade lesions or early recurrence/progression of low-grade tumors. Radiotherapy for diffuse pontine lesions and high-grade tumors usually results in early and significant neurologic improvement, although the overall outlook remains dismal.
  • Despite ongoing clinical trials, a chemotherapeutic role in the management of patients with brainstem tumors has yet to be established.

• Astrocytoma of the visual pathway
  • The natural history of visual pathway astrocytomas is erratic. Some patients experience long-term stabilization without treatment, whereas others develop progressive disease with neurologic deterioration culminating in death. In contrast to those with chiasmatic lesions, patients with isolated optic nerve tumors rarely die of their disease; therefore, treatment efficacy must be based on visual outcome and freedom from treatment sequelae.
  • A period of observation without treatment is recommended in cases without severe proptosis, rapidly progressive visual decline, or extensive chiasmal tumors (with distortion or invasion of optic tracts, hypothalamus, or the third ventricular area).
  • Surgery is warranted only in those with chiasmatic or deeper intracranial involvement in order to rule out the possibility of an uncommon high-grade lesion. For these patients and for those with an isolated optic nerve tumor whose clinical characteristics do not meet the criteria above, the preferred treatment is local radiotherapy to 55 Gy. With radiotherapy, up to 90% of patients show at least stabilization of visual decline and 10-year progression-free survival rates of 70-90%.
  • Chemotherapy with carboplatin and vincristine may be used as an initial therapy or to delay irradiation in prepubertal children. This combination chemotherapy has produced complete or partial responses in 45% of newly diagnosed patients.
• Intramedullary spinal cord astrocytomas
  • Complete surgical resections are difficult in astrocytomas because a distinct tumor-cord interface is often absent; however, nearly 80-90% of resections may be performed in most cases.
  • Treatment with radiotherapy is the same as that for other CNS astrocytomas. Lower radiation doses to 50 Gy are used because of radiation intolerance of the spinal cord. Treatment of low-grade tumors with radiotherapy yields 5-year survival rates of 65-70%. Patients with high-grade tumors generally die of their disease within months of diagnosis despite radiation and chemotherapy.

Consultations:

• Radiation oncologist for high-grade, recurrent and/or progressive, or visual pathway tumors

• Neuroendocrinologist evaluation

• Occupational and/or physical therapist for rehabilitation
  Regular team members, including the following:

• Neurosurgeon

• Pediatric oncologist

• Neuro-oncologist
• Neurologist
• Neuropsychologist

Diet:

• No specific dietary requirements or restrictions exist.

• Patients who develop severe anorexia or weight loss as a result of therapy (particularly infants) may need supplemental nutrition to maintain daily requirements.

Activity:

• No restrictions in activity exist unless dictated by underlying neurological deficits.

• Patients with ventriculoperitoneal shunts may be restricted from high-impact sports, such as diving.

Current investigational dosing chemotherapy regimens for the treatment of low-grade astrocytomas with carboplatin and vincristine and for the treatment of high-grade astrocytomas with carmustine (BCNU) and cisplatin are provided below.
Drug Category: Antineoplastic agents -- These agents disrupt DNA replication, which inhibits tumor growth and promotes tumor cell death. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), then finally a mitotic cell division (phase M).

The cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Further Outpatient Care:

• Chemotherapy: Chemotherapy for low-grade tumors is currently administered in an outpatient setting for approximately 1 year.

• Radiotherapy: Begin daily outpatient local radiotherapy after recovery from surgery for a high-grade astrocytoma or early recurrent and/or progressive low-grade astrocytoma. This is generally administered over 6 weeks (usual dose is 160-180 Gy/d).

• Physical and neurologic examination

• For resected low-grade astrocytomas, outpatient examinations every 1-3 months are sufficient.

• For patients requiring radiotherapy, perform weekly monitoring of clinical response and potential treatment-related adverse effects during radiotherapy and then every 1-3 months thereafter for at least 1 year.

• Protocols using investigational chemotherapy in place of, or following, radiotherapy dictate how frequently these examinations are conducted.

• After 12-18 months from completion of therapy, these examinations are generally reduced to every 6 months for the next 2 years and annually thereafter, provided no interim complications occur.
• Routinely perform baseline neuropsychology and developmental testing at the completion of therapy and annually thereafter.

• Imaging studies

• Postoperative MRI evaluation must be performed within 72 hours of surgery in order to delineate residual tumor from the postsurgical inflammatory changes that are visualized on MRI at this time.
• MRI with contrast of the head should be performed every 3 months for the first 12-18 months after surgery and 4-6 weeks following the completion of radiotherapy. Subsequent imaging may be performed in conjunction with the physical and neurologic examination schedule, unless clinically indicated sooner. If a child is treated on an investigational clinical trial regimen, the protocol dictates the frequency of the imaging studies required.
• Perform MRI of the spine annually in those patients with high-grade tumors unless evidence of leptomeningeal spread exists at diagnosis, in which case the frequency of such examination is increased in accordance with the response to treatment.

• Laboratory studies
  • Weekly complete blood cell (CBC) counts and annual neuroendocrine studies (eg, thyroid function tests, growth hormone, luteinizing hormone [LH]/follicle-stimulating hormone [FSH], estradiol) are all that is required during radiotherapy unless otherwise dictated by investigational regimens or if clinically indicated.
  • The CBC count is used to monitor hematopoietic toxicity and determine whether intervention should be carried out to maintain hemoglobin levels at or above 10 g/dL in order to maximize radiation efficacy.

In/Out Patient Meds:

• Dexamethasone and antiseizure medications may be necessary to reduce the respective inflammatory response (edema) and seizure activity associated with the tumor and/or therapy.

• Investigational protocols may dictate other medications, including chemotherapy.

Transfer:

• Transfer patient to a pediatric center that can provide appropriate MRI imaging studies; pediatric neurosurgery; and pediatric hematology, oncology, or neuro-oncology. Pediatric radiation oncology and neurology may also be necessary for treatment and follow-up.

Complications:

• Obstructive hydrocephaly

• Neurologic impairment

• Radiation-induced effects

• Neurocognitive decline

• Endocrinologic dysfunction

• Mineralizing microangiopathy with ischemia or infarct

• Secondary CNS malignancies

• Transient headaches, fatigue, nausea, vomiting, and anorexia

• Chemotherapy-induced effects

• Myelosuppression, infection, nausea, vomiting, anorexia, renal damage, hepatic damage, hearing damage, neurotoxicity, and secondary malignancies may occur.
• Investigational chemotherapy for either high-grade or low-grade tumors may cause complications such as fever, neutropenia, or suspected infection; therefore, hospitalization may be necessary.
• Infertility and impairment of growth may also be long-term sequelae of therapy.

Prognosis:

• Low-grade astrocytoma

• The 10-year survival rate for completely resected low-grade cerebellar astrocytomas is near 100%, with little or no morbidity. It is 60-95% for all low-grade tumors, including those incompletely resected and treated with radiotherapy.
• Supratentorial tumors may result in residual motor deficits or seizure disorder. Radiotherapy may lead to neurocognitive impairment, neuroendocrine dysfunction, or ischemia and infarct.

• High-grade astrocytoma: Those who survive (<30%) are often left with some degree of motor, neurocognitive, or endocrinologic dysfunction.

• Astrocytoma of the brain stem

• Patients with dorsal exophytic and cervicomedullary tumors treated by complete surgical resection have survival rates over 90%.
• Survival may be 50-100% for those with small focal tumors of the midbrain or tectal region treated with surgery and/or radiotherapy. In sharp contrast, patients with diffuse pontine lesions rarely survive.
• Surgery to these areas can result in paralysis of multiple cranial nerves, mutism, and a compromised respiratory effort.

• Astrocytoma of the visual pathway

• The 10-year survival rate for patients with intracranial tumors (chiasm or deeper) is 40-85%, in contrast to the 90-100% for those with intraorbital tumors.
• Fewer than half of all patients have improvement in their visual deficits noted at diagnosis.
• Up to 50% of prepubertal children develop endocrinologic dysfunction from radiotherapy.

• Astrocytoma of the spinal cord: The overall survival rate for patients with low-grade astrocytomas with various degrees of resection and postoperative radiotherapy is 67% at 20 years, while those with high-grade tumors rarely survive.

Patient Education:

• Refer patients and their family members for psychosocial counseling.