Cerebellar Astrocytomas

Low-grade astrocytomas occur throughout the CNS and constitute a fourth of all pediatric brain tumors. Cerebellar astrocytomas are common (12–17% of pediatric CNS tumors), and their treatment has the most favorable outcome of all intra-axial neoplasms in the CNS.⁵ Most of these tumors are found in children younger than the age of 10 years. The symptoms of cerebellar astrocytomas include headache (80%), vomiting (80%), gait disturbance, and decreased level of consciousness. Signs include ataxia in 80%, papilledema, cranial nerve palsies (including blindness and diplopia), and dysmetria. The rapid progression of signs and symptoms is often a function of cerebrospinal fluid (CSF) obstruction because the tumor occupies the fourth ventricle or the aqueduct, and causes hydrocephalus. Treatment of the hydrocephalus is often required urgently in very sick children. Temporary diversion of CSF via external ventriculostomies or shunts often precedes removal of the tumor.

Many of the signs and symptoms of posterior fossa neoplasms have an indolent progression. It is not unusual for headache and vomiting and ataxia to continue for many months in patients who are treated for otitis, viral syndromes, gastrointestinal disorders, or failure to thrive. It is the experience of many neurosurgeons that nearly all brain tumors in young children are misdiagnosed initially, sometimes for long periods of time. The relentlessness and progression of symptomatology is the decisive factor that leads to diagnostic studies.

Operative excision of these tumors is often possible, but new neurologic deficits can occur postoperatively in 30% of patients, although at least half of these new deficits are transient.⁶ Postoperative deficits occur because of the proximity of vital brain stem and delicate cranial nerve structures near the tumor, which is often large and firm. Postoperative pseudomeningoceles (the bulging of skin at the occipital incision site) and hydrocephalus are not uncommon (10–25%) and require additional treatment. Temporary continuation of postoperative CSF diversion via external ventriculostomy is favored by many surgeons to reduce the likelihood of permanent ventriculoperitoneal shunts.

The goal of operative therapy for low-grade tumors is complete removal. When total resection of these tumors is confirmed, the long-term survival without recurrence is about 90%, but much depends on the biologic aggressiveness of the tumor. Some histologic features such as mitosis, endothelial proliferation, and necrosis suggest a high-grade lesion with a much poorer prognosis. In cases of ‘low-grade’ astrocytomas with unanticipated rapid recurrence, additional treatment can be attempted, including further surgery and adjunctive chemotherapy and/or radiotherapy. Frequent follow-up scans are needed for at least five years after the operation.

Ependymomas

Ependymomas represent about 10% of pediatric brain tumors and are slightly less common than PNETs and astrocytomas. More than two-thirds of ependymomas in children occur in the posterior fossa (Fig. 19-1) and the symptoms they cause are similar to posterior fossa or cerebellar astrocytomas: headache, vomiting, lethargy, and ataxia. These symptoms result from a combination of compression along the dorsal brain stem and hydrocephalus. Many extend from the obex (in the inferior aspect of the fourth ventricle) and then extrude through the lateral opening of this ventricle (foramen of Luschka) into the cerebellopontine angle. Here they invade and compress cranial nerves with resulting facial weakness, diplopia, swallowing dysfunction, and hearing loss. When large, they often extend beyond the foramen magnum and can compress the cervical cord. In regard to their cell of origin, they are not limited to the ependymal layer of the ventricle but can arise from cerebellar, cerebral, or spinal cord parenchyma.

Aggressive surgical resection has been the goal of treatment of these difficult tumors, but there is high probability of new or worsening neurologic deficits as a result of the operative dissection. There is a correlation between postoperative residual tumor and tumor recurrence and/or progression. In the 30% of children where the tumor is totally resected, there is still a 20% to 40% possibility of recurrence, even after conventional radiotherapy.⁷ In cases of near-total resection, the rate of progression-free survival falls to 30%.⁸ Most of the recurrences are local and radiation therapy has become the mainstay of treatment, even with complete resection. Very small children, usually younger than age 3 years, are faced with comparatively greater morbidity from conventional radiotherapy, and radiation therapy is often deferred. Chemotherapy has been used with some success in this group of patients. The role of chemotherapy without irradiation has generally not been favorable in older age groups. Retrospective studies have failed to prove substantial benefit in survival when chemotherapy is added to surgery and radiation therapy for newly diagnosed ependymomas.

Treatment of ependymomas has remained problematic. Large, invasive tumors are clearly difficult to remove without significant risk to the patient, and residual tumors are largely refractory to chemotherapy and radiation. Some surgeons have suggested a staged operative approach with an initial subtotal debulking followed by a second aggressive operative exploration after chemotherapy. Whether this approach provides improved outcomes has not been established. Surveillance of treated patients with ependymomas must continue for many years, independent of histologic grading and extent of resection. Radiosurgery is also being used to treat focal areas of recurrent or unresectable tumor.

Medulloblastomas

Medulloblastomas are the most common malignant solid tumor in children and constitute 20% of pediatric brain tumors.⁹ They are usually located in the posterior fossa and they are also referred to as PNETs because they are histologically identical to tumors (pineoblastomas, neuroblastomas, and retinoblastomas) located in other locations that are believed to have derived from progenitor subependymal neuroepithelial cells undergoing malignant transformation. Nearly half of medulloblastomas have chromosomal abnormalities, particularly the deletion of 17p chromosome that contains the tumor suppressor gene TP53.¹⁰

Hydrocephalus often occurs with medulloblastomas because of their location within the cerebellar vermis (a midline structure), often filling the fourth ventricle (Fig. 19-2). Children with this tumor often have symptoms of elevated intracranial pressure (ICP) (obtundation, headache, nausea/vomiting, irritability) and have signs suggestive of posterior fossa compression (dysmetria, ataxia, diplopia, head tilt, and papilledema). Lumbar puncture should not be done after computed tomography (CT) or magnetic resonance imaging (MRI) has established the presence of a posterior fossa tumor and obstructive hydrocephalus. CSF diversion (usually via an external drain) is usually done either before or in conjunction with craniotomy. Conversion of these temporary devices to permanent ventriculoperitoneal shunts is not uncommon in children with large tumors and marked preoperative ventriculomegaly.

Complete resection of medulloblastomas is often possible, although permanent postoperative deficits can occur.⁶ The ‘posterior fossa syndrome’ can occur postoperatively in 10–15% of children and is characterized by mutism, drooling and swallowing difficulties, ocular palsies, and increasing ataxia.¹¹ These problems resolve entirely in most patients after several months. Improvement is thought to occur with resolution of swelling within the inferior vermis.

Staging is important with medulloblastomas because patients have a predictable outcome depending on age, metastases, pathology, and extent of surgical resection. Poor survival is correlated with age younger than 4 years, residual tumor measuring more than 1.5 cm,² and tumor dissemination, particularly ‘drop’ metastasis along the spinal column. After craniospinal radiation in eligible patients, survival occurs in 50–70% of patients with standard or low-risk medulloblastomas. Newer treatment protocols include chemotherapy first, which is followed by radiotherapy consisting of lowered cumulative craniospinal doses (24–36 Gy to the entire brain) with hyperfractionated delivery, usually 1 Gy twice daily. Survival in these ‘good risk’ patients is nearly 90% after five years. Survival in high-risk patients is 60–65% with current multimodality therapy, with the worst outcomes in affected infants. Children younger than 3 years of age are usually treated first with chemotherapy, with irradiation deferred for 1 to 2 years. Radiation is sometimes avoided altogether in the 40% with progression-free survival.¹²

Recurrent medulloblastoma after surgery and radiotherapy is not amenable to cure, but a combination of aggressive therapies can allow remission of disease. These treatments include reoperation, radiosurgery, and high-dose chemotherapy with autologous stem cell rescue. Each of these treatments carries significant morbidity, including loss of cognitive skills, growth retardation, endocrine problems, and the risk of second tumors and vascular malformations in previously irradiated areas.

Supratentorial Nonglial and Glial Neoplasms

There are multiple nonglial tumors involving the cerebral hemisphere. Supratentorial tumors are fairly common, and the majority of these are glial in origin, usually designated in ascending order of malignancy as astrocytomas, anaplastic astrocytomas, or glioblastoma multiforme. Nonastrocytic tumors include PNETs (including cerebral neuroblastomas), choroid plexus tumors (papillomas and carcinomas), and teratomas (including dysembryoplastic neuroepithelial tumors [DNETs]), germinomas, oligodendrogliomas, meningiomas, and gangliogliomas. In this latter grouping, operative resection is the requisite initial treatment. In the last three tumors, adjunctive therapies are not recommended after gross total resection if tumor histology is benign.

Seizures are much more common with supratentorial tumors because they affect the eloquent neocortex, particularly tumors in the medial or lateral temporal cortex. Older individuals are afflicted with these tumors and can present with personality changes, cognitive difficulties, headache, and growth deficits.

Germ cell tumors are composed of germinomas and teratomas, and arise in pineal and suprasellar regions predominantly. Germ cells tumors often metastasize and cannot be surgically cured. Therefore, they are often best treated with radiation and chemotherapy. This combination of therapies is often quite successful with the majority of germ cell neoplasms.

Ependymomas that occur in the cerebral hemispheres remain problematic in terms of treatment, although hemispheric tumors generally have comparatively better outcomes. Incomplete resection (often because of diffuse involvement within critical brain regions) and leptomeningeal spread are significant adverse risk factors. Age is also a factor. Children younger than 3 years of age have significantly diminished progression-free survival (10–15%) compared with older children.¹³

As with medulloblastoma, glial and nonglial tumors often have genetic abnormalities, with chromosomal abnormalities and gene mutations. Many low-grade lesions progress to become more malignant. The pathway to this malignant progression is complex. Chromosomal translocations and mutations occur as initiating events before the amplification of deleterious genes that support tumor progression.14–16

With most benign tumors, there exists a strong association between extent of resection and outcome. From the neurosurgical viewpoint, maximal resection should be attempted without inordinate surgical morbidity. The advent of frameless stereotaxy for precise tumor localization, ‘functional’ localization with intraoperative monitoring (e.g., somatosensory evoked potential mapping to determine the location of the motor cortex), presurgical functional MRI to determine location of speech areas, and intraoperative scanning (via real-time ultrasonography [US], CT, or MRI) have each added considerably to the safety of the operation. Nonetheless, the operative approach can only achieve resection of targeted areas. Infiltrative tumors (which typically extend well beyond the target borders) cannot be ablated using current surgical technology. The roles of chemotherapy, molecular manipulation, and conformal radiation therapy remain essential to the goal of controlling high-grade brain neoplasms partially treated with operation. Unfortunately, high-grade brain lesions remain stubbornly resistant to the intensive multimodality treatments that follow surgical resection. Survival curves for highly malignant brain lesions have not changed substantially in the past several decades.

Radiotherapy for Pediatric CNS Tumors

The target for radiation therapy is cellular DNA. Ionizing radiation damages double-stranded DNA, leading to cell death. Unlike normal cells, which have a preserved ability to repair radiation damage, neoplastic cells often are replicating at abnormally high rates and radiation interferes with their mitotic or proliferative ability. With slowly growing tumors such as craniopharyngiomas, the response to radiation is subtle and such tumors may take many months to show a clinical response. The critical sublethal dose required to preserve normal tissue but damage brain tumors, the so-called therapeutic window, is quite well understood and depends on a number of factors, including vulnerability of affected tissue (which can depend on the age of the patient and locale of the target; optic nerve radiation, as an example, is poorly tolerated), tumor vulnerability, volume irradiated, total dose, fraction size, and interfraction interval. As total volume of irradiation increases, the cumulative radiation dose must necessarily decrease to reduce the morbidity of treatment. The conventional cumulative radiation dose for most pediatric CNS tumors is in the 50–60 Gy range, although some tumors (e.g., germinomas) are much more sensitive to radiation and can respond to treatment in the 30–50 Gy range.¹⁷ Tumor type is therefore an important determinant of the effectiveness of radiation therapy, and biopsy is often a prerequisite for treatment.

Radiotherapy has enjoyed significant technologic advances with the advent of improved radiologic definition of tumors and sophisticated computer-assisted planning in three-dimensional systems. Stereotactic radiosurgery (SRS) has become routine in the USA, and single high-dose fractions can be delivered with great precision using high-energy photons produced either by linear accelerators or cobalt sources (gamma knife). Proton-beam therapy utilizes charged nuclear particles to deliver energy in discrete target points after the proton has nearly come to rest. As such, the proton can traverse normal brain without losing energy. As it comes to rest, it gives off most of its energy in less than 1 cm in the form of a Bragg ‘peak,’ providing a distinctively sharp rise in absorbed energy at the targeted tissue.

All these stereotactic methods are very precise and ideal for small targets, which are usually noninfiltrative lesions with well-delineated borders. The complications arising from targeting structures larger than 3.5 cm limit the radiosurgical approach. As such, the utility of treating small noninfiltrative tumors is optimal with single-fraction radiosurgery. For larger lesions in vulnerable areas of the brain (e.g., brain stem, retina, or cranial nerves), fractionation can be used with either repeat head fixation or localization systems to minimize complications of SRS therapy. In pediatric patients, SRS is mainly used as a boost to tumors that have recurred or persisted after conventional fractionated radiation therapy.

Finally, so-called conformal radiation provides the radiobiologic advantages of hyperfractionation along with the precision and control of SRS. Tumors typically treated in this manner are craniopharyngiomas, optic system tumors, and pituitary adenomas.