Central nervous system tumors

Supratentorial lesions

• 1.

  Cerebral hemisphere: low- and high-grade glioma, ependymoma, meningioma, primitive neuroectodermal tumor (PNET), lymphoma, schwannoma

• 2.

  Sella or chiasm: craniopharyngioma, pituitary adenoma, germ cell tumors (GCTs), optic nerve glioma

• 3.

  Pineal region: pineoblastoma, pineocytoma, GCTs, astrocytoma

Infratentorial lesions

• 1.

  Posterior fossa: medulloblastoma, glioma (low more frequent than high grade), ependymoma, meningioma

• 2.

  Brainstem tumors: low- and high-grade glioma, PNET

Ventricular lesions

• 1.

  Choroid plexus papilloma, choroid plexus carcinoma, neurocytoma

The most useful pathologic classification for brain tumors is based on embryonic derivation and histologic cell of origin. Tumors are further classified by grading the degree of malignancy within a particular tumor type. This grading is useful in astrocytoma and ependymoma. Criteria that are useful microscopically in grading the degree of malignancy include:

• cellular pleomorphism,

• mitotic index,

• anaplasia and necrosis, and

• proliferative index.

Molecular pathology of CNS neoplasms

The majority of CNS neoplasms are sporadic. Only a small percentage is associated with inherited genetic disorders.

Chromosomal abnormalities have been identified in many pediatric brain tumors. These chromosomal abnormalities can be helpful in determining the pathologic classification of certain tumors. For example, a mutation or deletion of the tumor suppressor gene INI-1 is often used to help distinguish atypical teratoid/rhabdoid tumors (AT/RTs) from PNET or medulloblastoma. Identification of the genes involved and how they contribute to tumor genesis is ongoing. Recent discoveries regarding the molecular variation among tumors of the same pathologic classification have caused a major shift in the treatment of these tumors, as targeted therapies and unique approaches to these molecular subtypes are being explored.

Table 22.2 describes common cytogenetic abnormalities identified in brain tumors.

Intracranial tumors

Symptoms and signs are related to the location, size, and growth rate of tumor:

• Slow-growing tumors produce massive shifts of normal structures and may become quite large by the time they first become symptomatic.

• Rapidly growing tumors produce symptoms early and present when they are relatively small.

The most common presenting signs and symptoms of an intracranial neoplasm are increased intracranial pressure (ICP) and focal neurologic deficits.

If symptoms and signs of increased ICP precede the onset of localized neurologic dysfunction, a tumor of the ventricles or deep midline structures is most likely. If localizing signs (seizures, ataxia, visual field defects, cranial neuropathies, or corticospinal tract dysfunction) are predominant in the absence of increased ICP, it is more probable that the tumor originates in parenchymal structures (cerebral hemispheres, brainstem, or cerebellum).

Spinal tumors

Spinal tumors in children may be found anywhere along the vertebral column. They cause symptoms by compression of the contents of the spinal canal. Localized back pain in a child or adolescent should raise suspicion of a spinal tumor, especially if the back pain is worse in the recumbent position and relieved when sitting up. The major signs and symptoms of spinal tumors are listed in Table 22.3 . Most spinal tumors have associated muscle weakness and the muscle group affected corresponds to the spinal level of the lesions.

Spinal tumors can be divided into three distinct groups:

• Intramedullary : these tumors tend to be glial in origin and are usually gliomas or ependymomas.

• Extramedullary–intradural: these tumors are likely to be neurofibromas often associated with neurofibromatosis. If they arise in adolescent females, meningiomas are more likely.

• Extramedullary–extradural: these tumors are most often of mesenchymal origin and may be due to the direct extension of a neuroblastoma through the intervertebral foramina or due to a lymphoma. Tumors of the vertebra may also encroach upon the spinal cord, leading to epidural compression of the cord and paraplegia (e.g., PNET or Langerhans cell histiocytosis occurring in a thoracic or cervical vertebral body).

Computed tomography

The computed tomography (CT) scan is an important procedure in the detection of CNS malignancies. Scans performed both with and without iodinated contrast agents detect 95% of brain tumors. However, tumors of the posterior fossa, which are common in children, are better evaluated with magnetic resonance imaging (MRI). CT scans should be performed using thin sections (usually 5 mm). Sedation is often necessary to avoid motion artifacts. CT is more useful than MRI in:

• evaluating bony lesions,

• detection of calcification in tumor, and

• investigating unstable patients because of the shorter imaging time.

Magnetic resonance imaging

MRI provides the following additional advantages:

• no ionizing radiation exposure (especially important in multiple follow-up examinations);

• greater sensitivity in the detection of brain tumors, especially in the temporal lobe and posterior fossa (these lesions are obscured by bony artifact on CT);

• the ability to directly image in multiple planes (multiplanar), which is of value to neurosurgical planning (CT is usually only in axial planes, though reconstructions may be performed);

• the ability to apply different pulse sequences, which is useful in depicting anatomy (T1-weighted images) and pathology (T2-weighted images, diffusion-weighted images); and

• the ability to map motor areas with functional MRI.

MRI specificity is enhanced with the contrast agent gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) dimeglumine, which should be used in the evaluation of childhood CNS tumors and has the following advantages:

• highlights areas of blood–brain barrier breakdown that occur in tumors,

• useful in identifying areas of tumor within an area of surrounding edema,

• improves the delineation of cystic from solid tumor elements, and

• helps to differentiate residual tumor from gliosis (scarring).

The major difficulty with MRI in infants and children is the long time required to complete imaging and for this reason adequate sedation is required.

Magnetic resonance angiography

Magnetic resonance angiography has been utilized in the preoperative evaluation of the normal anatomic vasculature (e.g., dural sinus occlusion) but has not been particularly useful in the assessment of tumor vascularity.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy may be helpful in both diagnosing pediatric brain tumors and during follow-up investigations. This technique has been shown to be able to distinguish between malignant tumors and areas of necrosis by comparing creatine/choline ratios with n-acetyl aspartate/choline ratios. This technique, in combination with tumor characteristics as identified by MRI, tumor site, and other patient characteristics, may be able to more accurately predict the tumor type preoperatively. In addition, it may be helpful in identifying postoperative residual tumor from postoperative changes.

Positron emission tomography

Positron emission tomography (PET) is a potentially useful technique for evaluating CNS tumors. The fluorine-18-labeled analog of 2-deoxyglucose is used to image the metabolic differences between normal and malignant cells. Astrocytomas and oligodendrogliomas are generally hypometabolic whereas anaplastic astrocytomas and glioblastoma multiforme (GBM) are hypermetabolic.

PET is useful to determine:

• degree of malignancy of a tumor;

• prognosis of brain tumor patients;

• appropriate biopsy site in patients with multiple lesions, large homogeneous and heterogeneous lesions;

• recurrent tumor from necrosis, scar, and edema in patients who have undergone radiation therapy and chemotherapy; and

• recurrent tumor from postsurgical change.

The utility of recently developed PET–MRI scanning requires evaluation, though preliminary data demonstrate utility in astrocytomas. Evaluation of the spinal cord MRI and Gd-DTPA has replaced myelography in the evaluation of meningeal spread of brain tumors in the spinal column and delineating spinal cord tumors.

Cerebrospinal fluid examination

The cerebrospinal fluid (CSF) should have the following studies performed:

• cell count with cytocentrifuge slide examination for cytology of tumor cells,

• glucose and protein content,

• CSF α-fetoprotein (AFP), and

• CSF β-human chorionic gonadotropin (β-hCG).

Polyamine assays in the CSF are of value in the evaluation of tumors that are in close proximity to the circulating CSF (medulloblastoma, ependymoma, and brainstem glioma). The assay is not useful in GBM and not predictive in astrocytomas. AFP and β-hCG of the CSF may be elevated in CNS GCTs.

Bone marrow aspiration and bone scan

These studies are indicated in medulloblastoma and high-grade ependymomas with evidence of cytopenias on the blood count because a small percentage of these patients have systemic metastases at the time of diagnosis.

Surgery

The purpose of neurosurgical intervention is threefold.

• 1.

  to provide a tissue biopsy for purposes of histopathology, cytogenetics, and genomics;

• 2.

  to attain maximum tumor removal with fewest neurologic sequelae; and

• 3.

  to relieve associated increased ICP due to CSF obstruction

The use of preoperative dexamethasone can significantly decrease peritumoral edema, thus decreasing focal symptoms and often eliminating the need for emergency surgery. For patients with increased hydrocephalus that is moderate to severe, endoscopic or standard ventriculostomy can decrease ICP. Tumor resection is safer when performed 1–2 days following the reduction in edema and ICP by these means.

Technical advances in pediatric neurosurgery have led to less invasive surgical approaches with diminished surgical morbidity and mortality. These adjuncts include:

• Improved intraoperative stereotaxic image guidance allowing three-dimensional mapping of the brain and the tumor with increased precision.

• Functional mapping of the brain, including functional MRI and intraoperative electrocorticography allowing enhanced pre- and intraoperative differentiation of normal from tumor tissue.

• Neuroendoscopy allowing improved visualization and access to deeper regions.

• Ultrasonic aspiration allowing resection of tumors with reduced manipulation of the surrounding normal tissue.

• Robotic assistance and laser interstitial thermal therapy have allowed biopsy and treatment of previously inaccessible deep-seated and midline tumors.

Intraoperative MRI and CT scanning are useful in limited circumstances to verify the extent of resection and intraoperative real-time localization. The ideal goal remains a gross total resection of tumor when feasible with preservation of normal tissue. Due to the invasive nature of most pediatric tumors, microscopic residual is typically present as the removal of a margin of normal tissue could cause devastating neurologic sequelae. The application of intraoperative tumor fluorescence shows promise for further delineation neoplastic from normal tissue.

Radiotherapy

Most patients with high-grade brain tumors require radiotherapy to achieve local control of microscopic or macroscopic residual. Radiation therapy for intracranial tumors consists of external beam irradiation using conventional fields or three-dimensional conformal radiotherapy. The latter decreases radiation to normal brain tissue by up to 30%.

Intensity-modulated radiation therapy (IMRT) uses more complex computerized planning and intensity modulation of the radiation to further decrease radiation to normal tissue under certain circumstances. Proton beam radiation virtually eliminates exit dose, sparing some tissue-unwanted radiation. It is particularly useful in tumor adjacent to sensitive areas such as the pituitary gland and spinal cord. Proton beam radiation remains available at relatively few centers nationwide.

The wider use of ionizing radiation in pediatric brain tumors has resulted in improved long-term survival. However, the significant long-term effects on cognition and growth, especially in patients requiring craniospinal irradiation (CSI) (e.g., PNET), can be devastating (please see Chapter 33 : Evaluation, Investigations, and Management of Late Effects of Childhood Cancer).

The total dose of radiotherapy depends on:

• tumor type (which also influences volume of treatment),

• age of the child, and

• amount of residual tumor after surgery or chemotherapy

• volume of the brain or spinal cord to be treated.

Current efforts seek to decrease radiation by conforming better to the tumor and by using chemotherapy in addition. Children 3 years of age are most drastically affected. In this group, newer strategies that avoid or delay radiation therapy, by initial treatment with chemotherapy, have promising preliminary results. In medulloblastoma therapy, this approach allows up to 50% cure without ionizing radiation.

Brachytherapy, stereotactic radiosurgery, and fractionated stereotactic radiosurgery are alternatives to conventional radiation therapy presently under continuing study and may prove useful in relapsed patients.

Chemotherapy

Chemotherapy plays an expanding role in the management of recurrent disease and in many newly diagnosed patients.

Two anatomic features of the CNS make it unique with respect to the delivery of chemotherapeutic agents.

• 1.

  the tight junction of the endothelial cells of the cerebral capillaries—the blood–brain barrier and

• 2.

  the ventricular and subarachnoid CSF.

The blood–brain barrier inhibits the equilibration of large polar lipid-insoluble compounds between the blood and brain tissue, while small nonpolar lipid-soluble drugs rapidly equilibrate across the blood–brain barrier. The blood–brain barrier is probably not crucial in determining the efficacy of a particular chemotherapeutic agent, since in many brain tumors the normal blood–brain barrier is impaired. Factors such as tumor heterogeneity, cell kinetics and drug administration, distribution, and excretion play a more significant role in determining the chemotherapeutic sensitivity of a particular tumor than the blood–brain barrier. Tumors with a low mitotic index and small growth fraction are less sensitive to chemotherapy; tumors with a high mitotic index and larger growth fraction are more sensitive to chemotherapy.

The CSF circulates over a large surface area of the brain and provides an alternate route of drug delivery; it can function as a reservoir for intrathecal administration or as a sink after systemic administration of chemotherapeutic agents. The rationale of instillation of chemotherapy into the CSF compartment is that significantly higher drug concentrations can be attained in the CSF and surrounding brain tissue. This mode of administration is most applicable in cases of meningeal spread or in those tumors in which the risk of spread through the CSF is high.

Adjuvant chemotherapy is used in select primary brain tumors in addition to recurrent disease. In certain cases, chemotherapy allows for decreased radiation doses with equal or improved cure rates. In others, adjuvant chemotherapy improves outcome with standard radiation therapy. Disease-specific regimens will be discussed later. Trials of new agents, combinations of agents, and standard drugs as radio-sensitizing agents are ongoing.

High-dose chemotherapy with autologous stem cell rescue

Most infants and very young children with brain tumors have a worse prognosis than older children. They are also at higher risk for neurotoxicity, including mental retardation, growth failure, and leukoencephalopathy. Due to these factors, there is a reluctance to treat infants and young children with radiation therapy. Treatment approaches using postoperative chemotherapy cycles with agents such as cyclophosphamide, vincristine, cisplatin, etoposide, and high-dose methotrexate, followed by high-dose chemotherapy with autologous stem cell rescue, are used in young children in an attempt to avoid radiation altogether or at least delay its use until the patient is older ( Table 22.4 ).

In children with nonmetastatic medulloblastoma treated on the Head Start III protocol, the 5-year event-free survival (EFS) and overall survival (OS) rates for all patients were 61±8% and 77±7% (please see “Further reading and references”). Patients with nodular/desmoplastic medulloblastoma had outcomes of 89±6% and 89±6%, respectively. AT/RTs are very aggressive tumors of infancy that present similarly to medulloblastoma and are at times indistinguishable pathologically except for monosomy 22 (lack of expression of INI-1). While uniformly fatal if treated with conventional medulloblastoma therapy, the recently published COG ACNS0333 study demonstrates a 4-year EFS of 37 ±12% and OS of 43 ±12% for AT/RT patients when treated with high-dose chemotherapy followed by triple autologous stem cell rescue and focal radiation (see “Further reading and references”).

Astrocytomas

Astrocytomas account for approximately 50% of the CNS tumors with peaks between ages 5–6 and 12–13 years. They arise from astrocytic glial cells and are a subtype of glioma. The WHO grades these tumors I–IV in increasing malignancy. Low-grade tumors (WHO grades I and II) are distinguished histologically from high-grade astrocytomas (WHO grades III and IV) by the absence of cellular pleomorphism, high cell density, mitotic activity, and necrosis. The following are the histologic subtypes:

• Pilocytic astrocytoma has a fibrillary background, rare mitoses, and classically Rosenthal fibers. It usually behaves in a benign fashion. These tumors are well circumscribed and grow slowly (WHO grade I).

• Diffuse or fibrillary astrocytoma is more cellular and infiltrative and more likely to undergo anaplastic change (WHO grade II).

• Pleomorphic xanthoastrocytomas are usually classified as WHO grade II subtype, but often behave more aggressively.

• Pilomyxoid astrocytomas have variable predictability and may present with diffuse disease. They generally respond as WHO grade II tumors but commonly relapse.

• Anaplastic astrocytoma is highly cellular with significant cellular atypia. It is locally invasive and aggressive (WHO grade III).

• GBM demonstrates increased nuclear anaplasia, pseudopalisading, and multinucleate giant cells (WHO grade IV).

• Diffuse midline glioma, H3K27M mutant is a new integrated mutation-location defined WHO category grade IV tumor that encompasses most diffuse pontine and thalamic gliomas. It involves mutation of the Histone 3.3 or 3.1 genes in predominantly high-grade gliomas through a small number of morphologically grade II–III gliomas are H3K27M mutant as well. It overwhelmingly confers a poor prognosis.

The majority of cerebellar astrocytomas remain confined to the cerebellum. Very rarely do they have neuraxis dissemination.