Hydrocephalus.

Hydrocephalus is the most common clinical presentation of posterior fossa brain tumors, which are the most common pediatric brain tumors. Historically the initial evaluation of children suspected of harboring a posterior fossa brain tumor has been via CT scan. However with improved technologies and more recent concerns regarding the long-term effects of radiation exposure, there is a trend toward less utilization of CT scans. If possible the initial assessment should be an MRI of the brain, which can provide the dual information regarding the brain tumor and the extent of hydrocephalus. The cause of the hydrocephalus is obstruction to the CSF flow as a result of the tumors in and around the fourth ventricle. The evaluation should consist of assessing the severity of the hydrocephalus (via the presence of periventricular capping/edema and tonsillar herniation) and the need for immediate intervention. High-dose steroids will often produce significant relief in symptoms as peritumoral edema is suppressed, and they are often utilized as a temporary measure for symptom relief. In infants, hydrocephalus can be asymptomatic and only evidenced by a rapidly enlarging head circumference. Supratentorial brain tumors can also produce hydrocephalus by causing mass effect on the ventricles, as well as by obstructing CSF flow through the ventricular system. Patients with suprasellar tumors can also have inadequate cortisol production or electrolyte disturbances, which need to be addressed as quickly as possible and often in concert with preparation for surgery.

Raised ICP is a medical emergency. Immediate relief can be accomplished by temporary placement of a catheter (drainage tube) in the ventricles, although this step is rarely needed, primarily because of the fact that steroids in the preoperative period followed by surgery to remove the tumors within 24 to 48 hours after diagnosis usually relieves the obstruction. Permanent techniques of hydrocephalus treatment include the placement of a ventriculoperitoneal (VP) shunt that drains CSF around the obstruction into the peritoneal space via a permanently implanted tube and more recently via an endoscopic third ventriculostomy (ETV). The latter has become the treatment of choice in the management of obstructive hydrocephalus and is not associated with the long-term complications of shunt revisions and infections. Most pediatric centers with sufficient expertise now routinely perform ETVs as the primary management of hydrocephalus in children with brain tumors. In addition the overall incidence of shunting for brain tumors has decreased during the past two decades. Like all complex procedures, rare but significant neurologic risks are associated with this procedure in approximately 1% of cases. The possibility of closure of a third ventriculostomy and resultant acute hydrocephalus requires long-term follow-up with neurosurgery, as with all children who have had placement of shunts for the management of the hydrocephalus.

Visual and Endocrine Evaluation.

Children with tumors in the sellar and suprasellar area can present with blindness, which rarely can be acute in onset. In those circumstances, although extremely rare, it is possible to obtain some recovery of vision by immediate treatment of the tumor. If a large mass or cyst is causing compression, acute drainage in conjunction with steroid administration can lead to some recovery of vision. Tumors in this location can also interfere with endocrine function and may lead to electrolyte disturbances and decreased steroid production, and these effects can be critical if they are unrecognized, especially if acute surgical intervention is indicated.

Advances in Surgical Techniques.

Recent advances in image-guided neurosurgical techniques have been considerable. Endoscopic procedures provide minimally invasive techniques to address not just obstructive hydrocephalus but also biopsy or resection of intracranial masses, with minimal morbidity in experienced hands. New techniques using intraoperative ultrasound have been developed and are being used in pediatric patients. 3D laser-guided maps can assist in the orientation and surrounding environment of the tumor during a procedure. More recently intraoperative MRI facilities now allow surgeons to use MRI procedures with the same magnet strength as that used for diagnostic imaging while operating. Real-time MRIs can assist the neurosurgeon in the detection of residual disease or hemorrhage before closure of the resection site.

The surgical approach used by the neurosurgeon will depend on a number of factors that must balance the need for diagnosis with the potential risks of operating in a given area. While the relative risks of general anesthesia and neurosurgical procedures continue to diminish with improving techniques, it is now common to perform staged operations in which a limited resection is performed to confirm the diagnosis. Based on the pathologic results obtained, decisions about more complicated or risky surgery can be considered for lesions in which complete resection is a critical component of improved outcome and can be deferred in lesions in which additional resection would not significantly alter prognosis but could cause significant morbidity. Specialized techniques such as endonasal endoscopic approaches can allow a minimally invasive approach, with excellent outcome in centers that have expertise in this approach.

The need of neurosurgeons to be aware of the evolving treatment strategies for children reinforces the role of the multidisciplinary team. During the past 5 years this need has become even more important, because many pediatric brain tumors now require molecular classification to guide therapy. For example in spite of their similar appearance, the treatment of posterior fossa medulloblastoma now differs significantly from posterior fossa ATRT. Treatment on national protocols therefore requires submission of fresh-frozen material obtained at the time of surgery for proper stratification on the basis of therapy protocols. As our molecular classification of pediatric brain tumors expands and newer and better molecular inhibitors of specific pathways become available, the role of the neurosurgeon and neuropathologist in ensuring the proper processing of these samples will continue to expand.

Perioperative Issues.

A number of factors must be considered for a child after a tumor-based procedure has been completed. The rate of weaning steroids after an operation will depend on many factors, including the histology, degree of resection, postsurgical edema, and patient status. Although most patients can be weaned off steroids rapidly after an operation, it is important that the members of the team have a coordinated structure so that as children pass from neurosurgical care to the radiation therapist or oncologist, overall management of these issues is seamless. A similar discussion holds true for anticonvulsant agents. Whereas many patients will receive preoperative or perioperative anticonvulsant therapy, most can be weaned rapidly, and communication among team members will therefore be required.

Seizures can be a presenting symptom for many patients with brain tumors or a result of electrolyte disturbances in the perioperative period. Management includes anticonvulsant agents and surgical resection geared not only toward the tumor but also toward dealing with the seizures. Intraoperative electrocorticography is particularly useful in the management of temporal and frontal lobe tumors with seizures and requires a multidisciplinary approach, which can lead to excellent overall outcomes. Choices of antiepileptic drugs (AEDs) are important because some may interfere with metabolism of chemotherapeutic agents, which requires a comprehensive approach toward the management of the patient’s seizures and tumor.

Hyponatremia is a common problem that can occur after neurosurgical intervention and requires immediate recognition. Two common conditions, both resulting in hyponatremia but needing different interventions, can occur. Cerebral salt wasting (CSW) occurs because of excess renal loss of sodium with volume depletion and has been associated with abnormally high atrial natriuretic peptide or brain natriuretic peptide levels, which block all stimulators of zona glomerulosa steroidogenesis, resulting in mineralocorticoid deficiency. CSW usually occurs 1 to 2 days after neurosurgical intervention, and patients typically demonstrate polyuria, dehydration, a serum sodium level less than 130 mEq/L, and excess urine sodium or urine osmolarity. Duration of CSW was 1 to 9 days in a study of 12 pediatric patients. CSW is generally treated with salt repletion, although fludrocortisone supplementation has also been successful. Syndrome of inappropriate diuretic hormone (SIADH), by contrast, results when water is preferentially retained, causing dilution of serum sodium. Patients present with hyponatremia and an elevated urine sodium level. The major clinical difference between CSW and SIADH is that in the former, dehydration is common, whereas in SIADH, symptoms of dehydration are lacking. SIADH is treated with water restriction. CSW was much more common than SIADH in one study of 30 patients.

Posterior fossa syndrome (or cerebellar mutism syndrome) is a complex and heterogeneous disorder that tends to occur 24 to 48 hours after resection of a posterior fossa tumor, usually medulloblastoma, ependymoma, or low-grade astrocytoma. Posterior fossa syndrome will develop in up to 25% of patients undergoing surgical resection in the posterior fossa and, in most patients, it will be severe. The pathophysiologic basis for this syndrome is unclear, with many hypotheses proposed. It is likely related to pressure effects on the deep cerebellar nuclei and is more frequently associated with large tumors extending into those areas. Gross total resection (GTR) of most posterior fossa brain tumors is associated with better long-term outcomes, and it is thought that the more aggressive surgical resections for those reasons are associated with the perceived increase in the frequency of this syndrome. The exact clinical patterns of posterior fossa syndrome can vary among patients both in constellation and severity. Usually the disorder includes loss of speech in patients who were capable of talking immediately after surgery. Other symptoms include irritability, which may relate to difficulties in communication, emotional withdrawal, and motor difficulties with ataxia. In a review of 450 children from two large Children’s Cancer Group (CCG) protocols for high-risk and standard-risk medulloblastoma, 107 patients (24%) had posterior fossa syndrome. It was classified as severe in 43%, moderate in 49%, and mild in 8%. As with many neurologic insults, most patients demonstrated significant improvement, although neurologic abnormalities persisted in a large proportion of patients. No uniform diagnostic criteria exist for posterior fossa syndrome, and radiologic imaging with SPECT has failed to define a specific controlling neurologic region.

Venous thrombosis in adults with brain tumors is common, especially when compared with adults undergoing operations for causes not related to brain tumors, and typically requires therapy. A similar predilection to significant symptomatic thrombosis in children with CNS tumors has not been identified. Because of the risks of spontaneous hemorrhage in patients taking anticoagulants, their routine use is discouraged for pediatric patients. When thromboses in this patient population are identified, other precipitating factors such as the presence of a central venous access device are usually evident. CNS hemorrhage is rare in pediatric patients undergoing tumor resection. Use of recombinant factor VIIa has been used successfully when bleeding was difficult to control.

Photon Therapy.

Photons are packets of high energy that enter tissue, depositing their energy as they pass through both normal tissue and the tumor, eventually exiting the brain. The presence of an exit dose is one of the major differences between this modality and proton therapy. The generation of photon beams is easily achieved with a large array of commercially available machines and, with more than 60 years of clinical experience, photon radiotherapy remains the most widely used form of radiation therapy. Significant advances in this modality have occurred through the development of better imaging (MRI and functional imaging such as PET and metaiodobenzylguanidine), planning algorithms, and machine delivery that has allowed the radiation oncologist to target tumors more accurately and to minimize the dose delivered to normal tissue.

Proton Radiotherapy.

The use of proton beam radiation therapy as an alternative to high-energy x-rays (photons) has the potential to limit some of the late effects of radiation therapy by reducing the exposure of normal tissue to the radiation. Physically, photon beams deliver their maximum radiation dose near the surface, followed by a continuously reducing dose with increasing depth. Tissues outside the target area receive an exit dose of the radiation beams. For example when a single posterior field is used to treat the spinal axis, critical organs along the path such as the heart, lung, bowel, and ovaries may receive significant exposure. In contrast in proton beam radiotherapy, while the charged particles—namely, protons—move through tissue, they ionize particles and deposit their radiation dose along the path. The maximal dose, called the Bragg peak, occurs shortly before the point of greatest tissue penetration, which is dependent on the energy of the proton beam. Because the energy can be precisely controlled, the Bragg peak can be placed within the tumor targeted to receive the radiation dose. Because the protons are absorbed at this point, normal tissues beyond the target receive little irradiation. Proton beam radiotherapy is becoming more readily available but remains a more limited and costly modality. Children most likely to benefit from proton beam treatment are those with favorable or curable brain tumors such as craniopharyngiomas, medulloblastomas, LGGs, ependymomas, and GCTs. With the increasing complexity of radiation planning, a dedicated pediatric radiation oncology team is required to ensure appropriate care for the pediatric patient.

Small-Molecule Inhibitors.

The sequencing of the human genome and the identification of a number of critical signaling pathways, especially the receptor tyrosine kinases, have provided the basis for a whole new class of anticancer agents. Normal cells transmit signals from the external environment to the nucleus via receptor tyrosine kinases. These molecules sit on the cell surface and homodimerize or heterodimerize in the presence of ligand, which results in a conformational change in the intracellular domain of the receptor. This process allows a phosphorylation event on the cytoplasmic component of the receptor that begins a complex cascade that results in the alteration of cell function. Many tumors use these receptors or their pathways to drive cell proliferation and migration, as well as decouple cell repair and apoptosis.

The activation of receptor tyrosine kinases results from the phosphorylation of a tyrosine residue in the intracellular domain of the receptor. This process can be blocked by the steric interference of small molecules designed to fit into the phosphorylation pocket. By carefully designing the shape of these molecules, the ability to define the specificity of these drugs to related receptors means that some inhibitors can disrupt only a single receptor or entire families of receptors. A number of experimental studies of these inhibitors have been tested in children with brain tumors, including those targeting the platelet-derived growth factor receptor (PDGFR) and ras pathways. One problem with small-molecule inhibitors, as with other agents targeting the CNS, is the need to get drugs across the BBB; small molecules are ideally suited for this purpose, but efflux pumps are present that may expel the agents, resulting in limited activity. Unfortunately this mechanism must be evaluated on a drug-by-drug basis.

Supratentorial, Cerebellar Pilocytic, and Other Low-Grade Astrocytomas.

LGGs represent the most frequent group of brain tumors that develop during childhood. According to the latest statistical report from the Central Brain Tumor Registry of the United States, the annual incidence of pediatric LGGs in the United States is 2.1 per 100,000 persons. PAs, which make up the majority of LGGs, are well-circumscribed tumors classified as WHO grade I. These tumors were formally referred to as juvenile PAs but are now classified simply as PAs. Grade I tumors are the most common LGGs found in children, representing 20% to 30% of all childhood brain tumors. PAs typically appear in the first two decades, with no clear gender predominance. They usually grow slowly, although their presentation can occur as acute deterioration as a result of obstructive hydrocephalus. NF-1 is the best example of a condition associated with an increased risk of PA in up to 15% of these patients. The localization of PAs in the context of NF-1 and their improved long-term prognosis is well established, although the molecular basis for this difference is unclear. Other predisposing factors such as common cytogenetic abnormalities are uncommon. Low-grade astrocytomas typically lack epidermal growth factor receptor (EGFR) amplification, although defects in the BRAF pathway have recently been reported and are present in the majority of cases.

Imaging and Histology.

The typical MRI appearance of a grade I astrocytoma is that of an intensely homogeneous, well-circumscribed, contrast-enhancing lesion with minimal surrounding edema. Lesions are typically bright on both T1- and T2-weighted images. Tumoral cysts are more prevalent in the cerebellum than in the cerebrum ( Fig. 57-18 ) and often possess a contrast-enhancing mural nodule. Apparent diffusion coefficient imaging may be useful in differentiating PAs from higher grade astrocytomas. Imaging characteristics can help with the differential diagnosis of low-grade lesions preoperatively but are not specific enough to be used without biopsy confirmation.

Posterior fossa pilocytic astrocytoma (juvenile pilocytic astrocytoma). A, A sagittal T1-weighted image without use of contrast material. B, An axial T1-weighted image with use of contrast material. C, An axial T2-weighted image.

Histologic examination reveals a biphasic pattern, with a compacted component containing bipolar cells ( Fig. 57-19 ) and Rosenthal fibers and a loose cellular array containing microcysts and eosinophilic granular bodies. Rosenthal fibers and eosinophilic granular bodies are pathologic hallmarks of pilocytic astrocytomas, although they can be observed in other diseases of the CNS. Rosenthal fibers are brightly eosinophilic, hyaline masses composed of alpha-B-crystalline and are best seen on tumor smear preparations ( Fig. 57-20 ). Eosinophilic granular bodies are globular aggregates within astrocytic processes and are also best visualized with smear pre­parations. PAs stain intensely with the GFAP immunoreagent. Invasion of the overlying meninges and adjacent brain parenchyma is commonly observed. Mitoses are rare, and the MIB1 labeling index is usually lower than 4%. Although the pathologic criteria for anaplastic astrocytoma include the identification of mitoses, their presence in PAs does not indicate a higher grade. Inexperienced pathologists can often misinterpret these mitoses, resulting in a diagnosis of a malignant rather than an LGG. Similarly PAs can have vascular proliferation, a hallmark of glioblastoma multiforme (grade IV astrocytoma), although, again similar to that of the presence of mitoses, this does not indicate transformation to a more malignant phenotype. Rarely PAs can present with diffuse leptomeningeal dissemination, especially in the variant of pilomyxoid astrocytoma. Characteristic of the unique biology of PAs, each of the metastatic lesions continues to behave as a low-grade astrocytoma with a slow, indolent course. These tumors therefore are not difficult to treat as a result of their metastatic phenotype but rather as a result of their slow, persistent recurrences.

Pilocytic astrocytoma. Shown is a biphasic pattern of compact, fiber-rich (FR) tumor and hypocellular (HC) areas with microcysts (×200).

Rosenthal fiber (arrow) in a pilocytic astrocytoma (hematoxylin and eosin; ×1000).

Molecular and Genetic Characteristics of Pediatric LGGs.

Recent efforts in the characterization of genomic alterations in pediatric LGGs have significantly expanded our understanding of the biology of those tumors. Genomic alterations of the BRAF gene, resulting in alteration of the MAPK pathway, are prominent in pediatric but not adult LGGs. Other genomic alterations affecting PI3K/AKT, EGFR, PDGFRa, FGFR1, TrkB, MybL1 and VEGF signaling pathways have been described in a subset of pediatric LGGs.

Importantly pediatric LGGs present distinct molecular alterations compared with adult LGGs. Tumor protein p53 (TP53) mutations are frequent in adult LGGs (up to 60% to 70%) but are rare in pediatric LGGs. Deletion of 1p and 19q is the most frequent copy number alteration in adult oligodendrogliomas. In contrast very few 1p-19q codeletions have been reported in pediatric LGGs. IDH1 and IDH2 mutations occur in about 70% of adult LGG, whereas these mutations are very rarely described in the pediatric population.

Prognosis.

The prognosis for surgically resectable tumors is excellent after GTR. For patients with PAs whose tumors can be completely surgically resected, depending on location, the 10-year PFS approaches 90%. Even in patients with incompletely resected lesions, treatment is not always required and, depending on the patient and clinical scenario, observation can be considered unless tumor or symptom progression is documented. The most critical variable in the treatment of PAs is the anatomic location of the tumor. Complete resections are most difficult for tumors located in the brainstem, spinal cord, optic pathways, thalamus, and hypothalamus. As such, the PFS of children with centrally located tumors (e.g., in the optic chiasm, thalamus, or hypothalamus) is less than 50%. Given the favorable toxicity profile of chemotherapy versus radiation therapy in young children, chemotherapy is preferred as the first therapeutic modality in young patients with tumors not amenable to gross total resection. The use of chemotherapy as initial treatment in patients with centrally located or unresectable lesions allows for the delay of radiation therapy until the child is less likely to incur the serious developmental and neuropsychological sequelae of radiation therapy. Patients demonstrating radiographic response to chemotherapy have PFS similar to those whose tumors remained stable. Ultimately the quality of survival depends on multiple factors, including the tumor location, the extent to which the tumor can be resected, timing of any radiotherapy, and adverse effects of surgery, chemotherapy, and radiotherapy. Transformation of PAs into higher grade malignant gliomas is highly unusual.

Clinical Presentation.

Most OPGs consist of PAs (WHO grade I). The clinical course of OPGs can vary considerably, from an indolent mass in a child with NF-1 to a relatively aggressive, invasive, and expansile diencephalic tumor. Unilateral optic nerve gliomas often present with the classic triad of visual loss, proptosis, and optic atrophy. Optic nerve tortuosity, which can be present alone or in the context of OPGs in children with NF-1, does not necessarily define the presence of disease or the need for therapy. Chiasmatic involvement may lead to unilateral or bilateral visual loss, a bitemporal visual field defect, and obstructive hydrocephalus as the tumor grows dorsally to obstruct CSF flow in the third ventricle. Further invasion into brain parenchyma may result in more pronounced visual field deficits, as well as hemiparesis. Chiasmatic tumors in infants present as large suprasellar masses that may also extend into the hypothalamus and third ventricle, producing hydrocephalus and endocrine abnormalities. In cases of hypothalamic extension, in addition to nystagmus, visual loss, and hydrocephalus, the diencephalic syndrome may occasionally be seen. This syndrome consists of hyperkinesia, euphoria, and emaciation, with preserved normal linear growth. Failure to thrive is a common presentation of this syndrome, but in the context of a number of other conditions that may also cause failure to thrive during infancy, a delay in diagnosis of a brain tumor is not uncommon. Endocrine deficiencies commonly accompany PAs in this location, and these tumors are more likely to have CSF dissemination in association with diencephalic syndrome, in spite of their histopathologic classification as benign. Many patients with NF-1 will have long-standing, subtle ophthalmologic abnormalities, and thus regular visual evaluation is required. For these patients routine surveillance MRI scans are not indicated because many asymptomatic and clinically irrelevant tumors will be diagnosed, creating a treatment dilemma.

Imaging and Histology.

The clinical diagnosis of an OPG is suspected when a child presents with visual impairment, nystagmus, and/or optic atrophy. MRI of the brain or orbits typically shows a solid, cystic, or mixed type of tumor, with strong gadolinium enhancement. The imaging characteristics of LGGs of the optic pathway are similar to those of low-grade astrocytomas in other locations. The typical MRI appearance of a grade I astrocytoma is an intensely homogeneous, well-circumscribed, enhancing lesion with minimal surrounding edema ( Fig. 57-21 ). Lesions are typically bright on both T1- and T2-weighted images. A higher ADC may predict a greater chance of progression. MRI studies and clinical presentation may distinguish an OPG from other childhood tumors that arise in the suprasellar location, such as a GCT or craniopharyngioma. Histologically OPGs are usually grade I PAs or, less frequently, grade II fibrillary astrocytomas. Mixed LGGs have been reported in this region, but the overall therapeutic approach is not altered, because most of these lesions are not resectable at diagnosis. Tumors with an elevated MIB1 labeling index of more than 1% and p53 expression were more likely to be WHO grade II and had a worse outcome compared with tumors with an MIB1 and p53 labeling index less than 1%, all of which were PAs. PAs with a more aggressive behavior had an MIB1 labeling index of 2% to 3% but retained a low p53 labeling index of less than 1%. Like LGGs in other locations, patients with sporadic OPGs have both BRAF V600E and truncated fusion KIAA1549 abnormalities. BRAF abnormalities are rare in patients with NF-1 because of the existence of constitutive activation of the ras/raf/mek/MAPK pathway.

A large optic pathway glioma in a 2-year-old boy who does not have neurofibromatosis type 1. A, An axial T2-weighted fluid-attenuated inversion recovery image that demonstrates bilateral involvement of the optic tracts posterior to the chiasm (arrows). B, A T1-weighted gadolinium-enhanced coronal image demonstrating the enhancing tumor expanding the optic chiasm (arrow). The patient has no functional vision and is legally blind.

Management.

The unpredictable clinical course of patients with optic pathway tumors has led to controversy regarding the optimal management of these tumors. The clinical course, age of onset, severity of symptoms, size and extent of the tumor, and presence of NF-1 may all affect management decisions. Treatment is frequently started promptly in younger patients, in patients with progressive symptoms, and in those with more extensive CNS involvement, with the paramount concern being preservation of vision. Although progression can be easily quantified on an MRI scan, correlation between MRI findings and visual outcome is poor. The initial treatment of choice is chemotherapy (see Table 57-5 ), which may cause stabilization or regression even in older children and adolescents and is not associated with the neurocognitive decline observed with radiation therapy. Surgery can be used upfront in selected cases, but the tumor may not be removed from the optic nerve without sacrificing vision. Combination therapy with carboplatin and vincristine or with TPCV has been considered to have comparable beneficial effects. TPCV should not be used in children with NF-1 because of the increased risks of secondary tumors associated with alkylator-based treatment. When progression of the tumor occurs after treatment with vincristine and carboplatin, vincristine and actinomycin can be considered for patients with NF-1 to avoid further risks of alkylator therapy. As for other LGGs, a number of new chemotherapy regimens are being developed (see Table 57-5 ) and can include bevacizumab and irintoecan, vinblastine, metronomic therapy, and low-dose cisplatin and etoposide. Current clinical trials targeting the mTOR pathway are under way, as is a phase II trial of lenalidomide. Although delaying radiation therapy is paramount in young children, older patients may also benefit from these chemotherapy approaches and from delaying or avoiding radiation therapy.

A randomized phase III COG study comparing the two regimens, carboplatin and vincristine versus TPCV for the treatment of progressive low-grade astrocytoma in children younger than 10 years, closed to accrual in 2005. The results have shown that both regimens are well tolerated and can delay or obviate the need for radiation therapy in most patients, and that some patients will show improvement in vision with therapy. Newer chemotherapy clinical trials for OPGs combine a number of agents such as TMZ with vincristine and carboplatin, and vinblastine and carboplatin. Although a definitive role for radiotherapy exists for the management of OPG, current trends in treatment favor a delay in the initiation of radiotherapy in young patients. Newer surgical techniques with direct administration of radiotherapy are also being explored and have demonstrated usefulness for selected patients. Unlike LGGs in other areas, optic pathway tumors affect vision directly, and changes in visual fields and acuity can be a better determinant of both disease response or progression than are changes on MRI. Recent consensus criteria for the assessment of visual function in patients with NF-1 have been reported, and these criteria should provide a useful platform for the assessment of therapies that target OPGs.

Prognosis.

Although optic pathway tumors are almost always of low-grade histology, their location often results in serious morbidity. In patients with significant visual deterioration, progressive vision loss can continue for many years after the tumor has become stable on routine surveillance imaging. The growth rate of these tumors, however, often slows during late childhood so that by adulthood, tumors may become quiescent and do not require further therapy. Children with NF-1 have been shown to have a better PFS, although an age of younger than 1 year is clearly associated with a higher risk of tumor progression. Patients with NF-1 appear to be at high risk for the development of moyamoya disease, as well as radiation-induced second malignancies. Patients with NF-1–associated optic nerve gliomas may remain stable for several years. Close observation and symptomatic management are recommended for these patients.

Presentation.

Patients with brainstem lesions can present with various clinical symptoms, depending on the location of the tumor. Medullary tumors are more common than midbrain tumors, and the male to female ratio is approximately 1 : 1. In spite of the eloquent function of the brainstem, most patients with low-grade astrocytomas in this location have an indolent course with subtle neurologic findings. Most commonly patients present with cranial nerve dysfunction or head tilt. Lower motor weakness with subtle hemiparesis is also seen. Most parents have difficulty defining the start of the symptoms and refer to their child as having always been clumsy or weak. Rarely these tumors can be multifocal in nature.

Histology and Imaging.

Most low-grade brainstem tumors are either grade I or II astrocytomas; fewer than 20% are malignant astrocytomas. Imaging characteristics are similar to those of other LGGs; PAs (grade I) tend to be bright on T1- and T2-weighted images and enhance after administration of contrast material. Edema tends to be minimal. Fibrillary astrocytomas (grade II), by comparison, enhance to a lesser degree after administration of contrast material. The considerable overlap and variability in the imaging characteristics of grade I versus grade II astrocytomas, however, prevents accurate diagnosis based on MRI characteristics alone. The histologic features of brainstem low-grade astrocytomas are identical to grades I and II astrocytomas in other locations.

Management.

Brainstem low-grade astrocytomas that remain focal can often be surgically resectable if they possess a plane between the brainstem and tumor. If the tumor is completely resected, these patients are unlikely to need additional therapy. Given the good long-term outcome of this patient population, aggressive surgery should not risk damage in areas with poor tumor boundaries. Incompletely resected brainstem low-grade astrocytomas have a high recurrence rate, and most of these patients will need additional therapy, usually chemotherapy rather than radiation therapy, given the good long-term prognosis of these patients (see Table 57-5 ). White matter tracts are often displaced by these tumors, and preoperative DTI can assist the neurosurgeon regarding the optimal approach to maximize resection while minimizing morbidity in this patient population. Although postsurgical morbidity such as problems with swallowing can be significant, many patients eventually recover function, although this process can take many months and requires extensive physical and occupational therapy. The chemotherapy options for these tumors are identical to those for low-grade astrocytomas in other locations and include vincristine and carboplatin or TPCV chemotherapy. Recurrence and need for retreatment are common, but most tumors will eventually stop growing while these patients enter adulthood.

Prognosis.

Because most patients with a low-grade brainstem glioma will be long-term survivors, it is important that the workup and treatment of these patients be adapted with this likely outcome in mind. Differentiation from DIPGs is usually easily made on the basis of imaging and clinical criteria. Surgical intervention must be based on the expectation that minimal long-term morbidity will result, given the large number of other treatment options available for these patients.

Clinical Presentation.

Thalamic tumors can present with a number of different clinical findings. Raised ICP, tremors, motor deficits, seizures, and mood changes are the most commonly observed presenting symptoms. Unlike in adult tumors, dementia is a rare presenting symptom.

Imaging and Histology.

Imaging characteristics of thalamic tumors are similar to those of gliomas in other locations ( Fig. 57-22 ). Low-grade and high-grade histologies are approximately equally distributed, although pathologic classification of these tumors can be influenced by sampling error from small biopsy specimens. The use of PET or SPECT imaging can help identify areas to be biopsied. Although astrocytic histologies predominate, oligodendroglial tumors have also been identified.

Bithalamic astrocytoma. A, An axial fluid-attenuated inversion recovery image. B, An axial T2-weighted image.

Management.

The presence of tumor in the thalamus presents a number of management difficulties. Because of their location, complete resection is difficult, although surgery can result in symptom improvement in selected cases. Even attempts at biopsy can result in significant morbidity. The small amount of surgical material often raises concerns of sampling error in attempting to determine the histopathologic grade of the tumor. Biopsy of the most malignant component of these deep-seated lesions can be guided with PET imaging. This guidance is particularly important for astrocytic tumors, for which samples of sufficient size and content are needed to define the elements of tumor grade. In the analysis of children with thalamic lesions, most tumors are unilateral in nature, and approximately 50% to 60% are low-grade astrocytomas; the remaining 40% are high-grade lesions. Some tumors are amenable to significant resection. The response of low-grade thalamic tumors to chemotherapy and radiation is not known to be different from that of similar tumors in other locations. Thus younger patients are often treated initially with chemotherapy used for other low-grade astrocytomas ( Table 57-5 ). In those with rapid progression or histologic verification of high-grade features, radiotherapy can be used, although a significant portion of the brain will receive a substantial dose, resulting in long-term toxicity for survivors.

Prognosis.

Contrary to some reports of very poor outcome for bithalamic astrocytomas of any grade, five of nine patients were long-term survivors in one retrospective series. Part of the difficulty in assigning an accurate prognosis to these tumors is the limited biopsy material available for assessment. With a number of reports of survivors now available, even in the context of bilateral disease, all young patients should be given a trial of chemotherapy.

Clinical Presentation.

Diencephalic low-grade astrocytomas are differentiated from other LGGs in children by their presence around the hypothalamus–optic chiasm and a unique constellation of symptoms, including the three “E’s”—emaciation, emesis, and euphoria. In spite of severe failure to thrive that is often seen, most infants retain normal growth rates and maintain normal pituitary secretion prior to surgical resection. Although an accurate clinical picture for these patients continues to be defined, because many lack the typical constellation, their management is difficult because of the deep-seated nature of these lesions and the frequent presence of leptomeningeal dissemination at diagnosis. As such, these patients require full craniospinal imaging at diagnosis, along with CSF analysis. Any patient presenting with symptoms of spinal disease needs to undergo immediate restaging.

Imaging and Histology.

The imaging characteristics of diencephalic LGGs do not differ from those of low-grade astrocytomas in other locations. Lesions are centered around the hypothalamus and chiasm, are bright on T2-weighted images, and usually show homogeneous enhancement after administration of contrast material. The lesions are typically PAs or fibrillary astrocytomas, although the pilomyxoid variant can also be observed in this location. These tumors cannot be differentiated by mutational status of BRAF because some patients have the BRAF V600E mutation, some have the BRAF truncated fusion KIAA1549, and other patients have neither.

Management.

The approach to therapy follows that used for other low-grade astrocytomas. Because of the young patient age and deep location of these tumors, radiation therapy is usually contraindicated and will result in significant cognitive impairment over the long term. Most patients undergo maximal safe surgery, followed by chemotherapy with vincristine and carboplatin or TPCV (see Table 57-5 ). Radiographic response or stable disease accompanied by weight gain is common. High-dose chemotherapy has also been used successfully as an investigational approach. Radiographic responses and improvement is weight have also been reported with bevacizumab and irinotecan.

Prognosis.

In spite of the low-grade nature of diencephalic tumors, patients with these tumors do less well than do patients with similar tumors located in the optic pathway, brainstem, or cerebellum. In addition to the continued progression of these tumors, which leads to compression of vital structures, patients are at high risk for surgery-induced hypothalamic damage resulting in obesity.

Clinical Presentation.

The initial symptoms of fibrillary astrocytomas vary, depending on the location of the tumor. Patients with medullary tumors may present with a long history of dysphagia, hoarseness, ataxia, and hemiparesis. Cervicomedullary tumors may cause medullary or upper cervical symptoms such as neck discomfort, weakness or numbness of the hands, and an asymmetrical quadriparesis. Patients with midbrain tumors such as a tectal glioma often present with signs and symptoms of raised ICP. Other symptoms include diplopia and hemiparesis. In children with dorsally exophytic brainstem glioma, a component of the tumor arises in the medulla and expands in a dorsal direction, resulting in noncommunicating hydrocephalus. Supratentorial fibrillary astrocytomas more commonly present with seizures, although thalamic lesions present with motor deficits. Hypothalamic lesions can present as diencephalic syndrome. Low-grade astrocytomas in the brainstem are usually focal rather than diffuse. They tend to arise in the midbrain, cerebellar peduncles, medulla, or cervicomedullary region. Because of the slow rate of progression of these lesions, most patients have subtle neurologic changes that only become evident over a long period. Unlike adult fibrillary astrocytomas, with which degeneration to malignant gliomas is common, pediatric fibrillary astrocytomas remain low grade, even after multiple recurrences. Symptoms may exist for months to years prior to the diagnosis of a low-grade astrocytoma.

Imaging and Histology.

Most low-grade fibrillary astrocytomas appear isodense on CT without significant contrast enhancement. The tumors are hypointense on T1-weighted and hyperintense on T2-weighted MRI, with minimal or no gadolinium enhancement ( Fig. 57-23 ) except for dorsally exophytic brainstem tumors. This appearance is in contrast to that of most PAs, in which homogeneous contrast enhancement is common. Pathologic examination may demonstrate some cellular pleomorphism, but no mitoses, necrosis, or endothelial proliferation are present (i.e., no histologic features of malignancy are present). Although PAs are usually well-circumscribed lesions with a biphasic pattern of areas of bipolar cells and Rosenthal fibers and other areas with microcysts, fibrillary astrocytomas have greater cellularity and infiltrating boundaries. In contrast to grade III or IV astrocytomas, fibrillary astrocytomas must lack features of malignancy, such as significant atypia and pleomorphism, mitoses, vascular proliferation, and palisading necrosis. A number of other subtypes of grade II astrocytomas have been identified, including the lipoastrocytic, protoplasmic, gemistocytic, and xanthomatous types. These subtypes are much less common in pediatric patients compared with adults, and may have a worse outcome compared with fibrillary astrocytomas and PAs. The rarity of these lesions prevents formal studies of these subtypes.

Grade II fibrillary astrocytoma. A, An axial fluid-attenuated inversion recovery image. B, An axial T1-weighted image with use of contrast material showing a noncontrast-enhancing fibrillary tumor.

Management.

Management of most fibrillary astrocytomas is similar to that of PAs and depends on the clinical prodrome, age, and location of the primary tumor. Rapidly evolving clinical symptoms in the setting of an operable tumor usually warrant prompt neurosurgical intervention. On the other hand, a lesion with a long history of indolent and mild symptoms is often managed with close MRI and clinical surveillance. In patients who subsequently show progressive neurologic symptoms and for whom MRI studies suggest tumor growth, therapeutic intervention is required. Diffuse fibrillary astrocytomas in eloquent locations such as the thalamus or motor regions are often biopsied to confirm the diagnosis and to exclude higher grade glial tumors. They do not lend themselves to radical resections, as is commonly performed for PAs. However in certain cases, such as dorsally exophytic brainstem astrocytomas, radical resection can often confer a long symptom-free outcome. In cases in which resection is not feasible, chemotherapy or radiotherapy may be indicated. As in the case of progressive or unresectable PAs, chemotherapy is the preferred first approach for patients (see Table 57-5 ). Patients respond well to either vincristine and carboplatin or TPCV chemotherapy. A recent randomized clinical trial of grades I and II astrocytomas has been completed in which these two treatment regimens were compared. Although recurrences occur in most patients, necessitating retreatment with other chemotherapeutic agents, the overall prognosis remains good. Experience with novel combinations of agents or high-dose chemotherapy is limited. Radiotherapy is reserved for older children or younger patients whose tumors progress and are refractory to chemotherapy. Reduced radiation doses to adjacent normal tissue, with equivalent tumor control to that of standard photon therapy, can be achieved with conformal proton therapy. Radiation therapy delivered at the time of initial diagnosis does not appear to provide additional benefit for OS.

Prognosis.

The long-term survival rate for completely resected pediatric supratentorial low-grade astrocytomas is excellent, especially when compared with similar tumors in adults. Even partially or unresected fibrillary astrocytomas may remain stable for many years. An example of this is the focal midbrain or tectal glioma, which is rarely biopsied or resected. Response to chemotherapy appears to be similar to that observed in PAs, although most patients will experience one or more episodes of progression, requiring retreatment with additional chemotherapy. However children with primary tumors arising in the pons or thalamus have a worse prognosis. The presence of a gemistocytic component characterized by a predominance of large astrocytes, with thick processes and dramatic accumulation of GFAP, represents a histologic variant of low-grade fibrillary (grade II) astrocytoma. This variant may be associated with p53 mutations and may also convey a higher predisposition to malignant transformation.

Although most patients with low-grade astrocytomas will survive, patients with fibrillary astrocytomas have a poorer outcome than patients with grade I astrocytomas. Because PAs are more focal and easier to resect than are fibrillary astrocytomas, prognosis may be related to the ease of resection rather than to biologic differences between these histologic variants. Overall survival after chemotherapy of children and adolescents with low-grade astrocytomas at 10 years is 70% to 80%. The role of MIB1 expression in the prognosis of low-grade astrocytomas is not established as a prognostic factor, after age and degree of resection are excluded. Survivors of low-grade astrocytomas still have a number of limitations. Future treatment efforts for these tumors therefore will need to combine effective therapy with improved quality of survivorship in these patients.

Presentation.

Most patients with tectal gliomas present with the symptoms of obstructive hydrocephalus because of expansion of these lesions adjacent to the periaqueductal space. When the presence of these tumors is picked up incidentally, many patients will demonstrate prolonged periods of stability and do not require treatment.

Imaging and Histology.

The radiographic appearance of most tectal gliomas is similar to that of other LGGs. Most tumors lack contrast enhancement ( Fig. 57-24 ). Based on their location and presenting symptoms, histologic verification is not required to make the diagnosis and can cause significant morbidity if attempted.

Tectal glioma. A, An axial T1-weighted image with use of contrast material showing a noncontrast-enhancing tectal tumor (arrow). B, An axial T2-weighted image shows T2 hyperintense lesion in the tectum (arrow) .

Management.

Biopsy or resection of tectal gliomas is usually not required. Rather, most patients require immediate CSF diversion through a third ventriculostomy. Failures of third ventriculostomies have been reported, even many years after the initial procedure, necessitating the proper education of families regarding symptoms that should precipitate immediate evaluation. Reduction in ventricular size is often incomplete and the ventricular size continues to change during the first year after diversion. Rarely tectal gliomas larger than 10 cm at presentation will continue to progress over time and may require surgical debulking and chemotherapy. Tumors that have atypical radiographic features, rapid progression, or repeated recurrence may require a biopsy. Tumors with asymptomatic progression can often be observed carefully. When treatment is required, approaches similar to those used for other low-grade astrocytomas are recommended. Chemotherapy is usually initiated. Radiation therapy is not required for most patients, and continued progression of these lesions into adulthood is rare.

Prognosis.

The long-term outcome for patients with tectal gliomas remains excellent, which is surprising given the unresectable nature of the lesion and the absence of therapy for most patients. Overall survival approaches 100% in this population, and thus avoidance of unnecessary surgical or radiation-related long-term morbidity is critical.

Clinical Presentation.

Although pilomyxoid astrocytomas present in a manner similar to that of other LGGs, the incidence of metastatic disease at presentation appears higher and requires a full workup, including spinal MRI and CSF for cytologic evaluation. Patients with pilomyxoid astrocytomas may be at greater risk for spontaneous hemorrhage at the time of diagnosis or resection or during follow-up.

Imaging and Histology.

On MRI pilomyxoid astrocytomas appear similar to PAs, with well-circumscribed margins and little peritumoral edema. They are usually found in the midline, including the brainstem and spine, and can be solid or solid and cystic. They are usually bright on T1- or T2-weighted and FLAIR sequences, and they enhance with administration of contrast material. In approximately 50% of cases, the contrast enhancement is heterogeneous. Adjacent areas of brain can demonstrate elevated choline-to-creatinine ratios suggestive of an infiltrative margin. Although their location, young patient age, and increased presence of dissemination provide clues to the diagnosis before a biopsy is performed, imaging characteristics do not clearly differentiate these tumors from other LGGs in the pediatric population. Histologically these lesions lack many features of PAs, such as Rosenthal fibers and a biphasic pattern. Rather a monophasic pattern and myxoid background is seen, with strong GFAP and synaptophysin staining. Like other glial tumors, mixed lineages may also be possible for pilomyxoid astrocytoma. The variable histologic appearance compared with PAs, MRS signal changes, and a higher incidence of progression and dissemination support their distinction from PAs. A predilection for younger age appears to exist when the tumor is localized to the pituitary-hypothalamic region.

Management.

Because of the more aggressive nature of these tumors compared with PAs, pilomyxoid astrocytomas are now classified as grade II gliomas. Treatments typically follow those of other LGGs, including vincristine and carboplatin and TPCV chemotherapy. Other therapies used for PLGGs have also been used for patients with pilomyxoid astrocytomas ( Table 57-5 ). Upfront chemoradiation therapy combinations have also been tried for these tumors. Formal clinical trials for this rare subtype are not possible, however. Because of the young age of the patient and the deep location of these tumors in many patients, radiation-based strategies will lead to significant long-term morbidity in most survivors. Many patients with pilomyxoid astrocytomas are infants and have diencephalic syndrome with dissemination, and thus complete surgical resection is not possible. Thus most patients will start with LGG chemotherapy. The use of intrathecal therapy for patients with disseminated disease who are unable to receive craniospinal radiation can be considered.

Prognosis.

Without well-defined studies, the prognosis of pilomyxoid astrocytoma is difficult to assess with certainty. Confounding issues of deep-seated lesions, especially around the hypothalamic region in which surgical options are limited, along with the young age of these patients and the presence of metastatic disease, likely affect the overall poor prognosis. A mean OS of 60 months for patients with pilomyxoid astrocytoma versus 220 months for patients with grade I PAs has been reported. Whether their unique biology affects survival is unknown, although these tumors can recur as typical grade I pilocytic astrocytomas. As in other LGGs, nestin expression may correlate with a worse prognosis.

Clinical Presentation.

Seizures are the first manifestation in 50% of cases of ganglioglioma, and many patients have a prolonged history of seizures of longer than 2 years. Complex partial seizures are common because gangliogliomas are frequently located in the temporal lobe, particularly the temporomesial region, although they can occur anywhere in the brain or spine.

Imaging and Histology.

Gangliogliomas are typically contrast-enhancing cystic lesions on CT scans. The MRI appearance of these tumors can be variable but is frequently hypointense on T1-weighted sequences and hyper­intense on T2-weighted images. Gadolinium enhancement varies in intensity from absent to significant and can be nodular, solid, or circumferential. An infantile variant of ganglioglioma, desmoplastic infantile ganglioglioma (DIG), can occur (discussed later). Pathologic studies show synaptophysin and neuronal nuclear antigen (NeuN)–positive ganglion cells, as well as a GFAP-positive astrocytic component. Lesions associated with the ganglion cell but lacking the astrocytic component are called gangliocytomas. Gangliogliomas are frequently WHO grade I tumors, although some may show anaplastic features in the glial or neural component. MIB1-positive cells are usually localized to the astrocytic component. Glial-neuronal tumors likely represent a spectrum of LGGs that include gangliogliomas and may also have PI3K pathway activation.

Management.

Complete or near-total resection is the treatment of choice and, in most cases, can eliminate or significantly improve seizure frequency in this patient population. Recurrent or unresectable tumors may be treated with radiation therapy, although these lesions may respond to LGG chemotherapy, and thus patients may avoid some of the long-term toxicity of radiation. In the case of recurrent or unresectable ganglioglioma, response to LGG chemotherapy has been demonstrated. Treatment for recurrent or unresectable gangliogliomas is included in current LGG chemotherapy trials. It should be noted that these tumors have been shown to undergo malignant transformation over time, usually involving the astrocytic component. Clinical trials of BRAF V600E inhibitors are under way for persons with this mutation, and significant durable responses have been reported.

Prognosis.

GTR is often curative, making tumor location and extent of resection the most important prognostic factors. Most patients are rendered seizure-free after GTR. Gangliogliomas of the posterior fossa have also been reported, and their outcomes appear to be similar to those for supratentorial lesions. Patients whose tumors can be fully resected to remove the enhancing components are likely to remain disease free, although persons with subtotal resected disease often require additional resection, chemotherapy, and/or radiation therapy. The uncommon presentation of these tumors in the infratentorial location and the limited sample sizes in case reports limit the confidence with which therapeutic approaches can be recommended. Spinal cord ganglioglioma appear to have an indolent course. Patients with subtotal resection can remain stable for prolonged periods. Therefore treatment should be deferred until lesions show clear evidence of progressive disease. Very rarely, gangliomas and glial neuronal tumors can degenerate into a CNS PNET (the neural component) or into a malignant glioma (the astrocytic component).

Clinical Presentation.

Most patients present with increasing head circumference, bulging fontanelle, and lethargy. Older patients present with focal motor deficits.

Imaging and Histology.

DIGs are large cystic structures on CT scans, with contrast enhancement of the solid component. T1-weighted MRI sequences demonstrate an isointense tumor; T2-weighted intensity of the tumor is variable. The tumors usually enhance after administration of contrast material. Peritumoral edema is uncommon. DIGs possess a desmoplastic stromal background, with neoplastic neurons and astrocytes. They often have areas with an elevated MIB1 labeling index, although this characteristic does not usually represent transformation to a more malignant phenotype. Tumors lacking the neural component are called desmoplastic infantile astrocytomas.

Management.

Cure can be achieved with complete resection. Many patients have remained progression-free after total resection without additional treatment. Chemotherapy, as for other low-grade astrocytomas, can be considered for patients with symptomatic or progressive cases for whom surgical removal is not feasible.

Prognosis.

Most patients will be long-term survivors if a complete resection is achieved. Lesions that are more deep-seated may have a poorer outcome, and initiation of chemotherapy may be considered at the first signs of progression in these unresectable tumors. Metastatic lesions have been reported, suggesting that in rare cases, a more malignant phenotype can occur.

Clinical Presentation.

The diagnosis of DNET should be a consideration in children and young adults with new-onset seizures or a long history of epilepsy. Patients with these tumors typically present with a long history of complex partial seizures, with an average age of onset of 9 years. In many patients the seizures are refractory to anticonvulsant medications. The superficial cortical location of DNETs may account for the high risk of seizures.

Imaging and Histology.

Contrast-enhanced cranial MRI typically shows a temporal or frontal lobe lesion, absent peritumoral edema, and only minimal, if any, gadolinium enhancement. The tumors are bright on T2-weighted sequences and hypointense on T1-weighted images ( Fig. 57-25 ). Mass effect is minimal to absent. Although routine fluorine 18–labeled deoxyglucose–PET imaging has not been helpful in the preoperative identification of these lesions, Carbon 11–methionine–PET was able to distinguish these lesions from other low-grade lesions. The pathologic findings include a specific glioneuronal element manifested by GFAP-negative oligodendroglia-like cells and neurons in a mucinous eosinophilic background that give the appearance of floating neurons. Because oligodendrocytes, astrocytes, or both are found on histopathologic analysis, the pathologic differential diagnosis often includes oligodendroglioma, mixed oligoastrocytoma (OA), and ganglioglioma. Like gangliogliomas and PXAs, DNETs have been reported to have the BRAF V600E mutation in approximately 30% of cases. Differentiation of DNETs from other LGGs can be difficult.

Left frontal dysembryoplastic neuroepithelial tumor. A, An axial T1-weighted image with use of contrast material showing a large nonenhancing tumor. B, An axial T2-weighted image.

Management.

Although these tumors have a benign course, the associated seizures may be refractory to antiepileptic drugs because of the increased expression of multidrug transporters. Gross total resection is often curative and typically alleviates the seizures, especially if the areas of cortical dysplasia can also be removed, although some case series have shown a significant number of patients who continue to have residual seizures. Adjuvant chemotherapy or radiation therapy is not recommended. Rare cases of malignant transformation of DNETs after radiation and chemotherapy have been reported.

Prognosis.

The stable behavior of these tumors over time results in an excellent prognosis after gross total or partial resection. Patients often have improved seizure control after surgery, especially if a complete resection was achieved, and some improvement in neuropsychologic functioning has been observed.

Clinical Presentation.

PXAs are typically large and superficially located, especially in the temporal lobes. Seizures are the most common presenting feature. For tumors of the cerebellum, pineal region, or spine, direct nerve compression results in focal deficits, and obstruction of CSF flow results in raised ICP. Rare cases of dissemination have been reported.

Imaging and Histology.

PXAs typically manifest enhancement on MRI, with occasional intratumoral cysts and calcification ( Fig. 57-26 ). Peritumoral edema is uncommon. Tumors usually extend to the meninges. The typical histopathologic picture includes a pleomorphic appearance of the astrocytic component, with significant cellular atypia and bizarre multinucleated giant cells with intracellular lipid accumulation. The proliferative indices are usually low, although necrosis, endothelial proliferation, and mitoses have been described. PXA can be confused with glioblastoma multiforme because of the presence of multinucleated cells and occasional foci of necrosis. The expression of CD34 on most tumors may be useful in the histologic classification of difficult or atypical cases. Prognosis appears to correlate with MIB1 expression. In lesions with mitoses, an elevated MIB1 labeling index, and necrosis, the term “pleomorphic xanthoastrocytoma with anaplastic features” is used.

Pleomorphic xanthoastrocytoma. A, A coronal T1-weighted image with use of contrast material (arrow). B, An axial T2-weighted image (arrow). C, A noncontrast computed tomography image (arrow).

Management.

The clinical diagnosis of PXA should be suspected in children who present with new-onset seizures, focal deficits, and a large, enhancing cortical mass on brain imaging. The goal of surgery is to achieve a GTR, which is usually curative. Adjuvant therapy can be deferred, although the patient should be followed expectantly. Tumors that recur and incompletely resected lesions with anaplastic features may be treated with chemotherapy or radiotherapy, although significant activity for these modalities has not been demonstrated. Few formal clinical trials for this rare subtype have been performed.

Prognosis.

Several series have reported a 5-year PFS of greater than 70%. However the presence of mitoses, endothelial proliferation, or necrosis on the pathologic specimen, although rare, may significantly alter the clinical behavior and prognosis. Cases of anaplastic PXA with subsequent malignant transformation have been reported. Radiation therapy does not alter the poor outcome in these cases.

Clinical Presentation.

SEGA is sometimes the presenting feature of TS in patients without the typical physical stigmata of the syndrome. Because of the variable phenotype of TS, a consensus on diagnostic criteria has been developed. Presentation in older children and adolescents is common. Although patients with TS typically have multiple periventricular SEGAs, those that produce symptoms of hydrocephalus arise in close proximity to the foramen of Monro, although lesions around the pineal gland can also result in symptoms. Most patients with known TS are followed up with regular neuroimaging and the SEGAs are removed serious neurologic syndromes, such as headaches, altered sensorium, or weakness are present. Of note, patients with TS may have other significant neurologic symptoms, such as seizures and cognitive deficiency related to cortical tubers.

Imaging and Histology.

CT and MRI are essential for early and accurate diagnosis. Although CT is superior to MRI for detecting small calcified lesions, MRI is superior to CT for identifying areas of gliosis, heterotopia, and SEGAs, which have the typical radiographic appearance of candle dripping. SEGAs typically show diffuse contrast enhancement on CT and MRI studies ( Fig. 57-27 ). SEGAs are considered grade I astrocytomas. They are well-circumscribed tumors that are positive for GFAP, neurofilament, neuron-specific enolase, and synaptophysin. Mitoses can be identified but do not indicate a higher grade or more malignant phenotype. They can occasionally be associated with bleeding.

Subependymal giant cell astrocytoma. A, An axial T1-weighted image with use of contrast material showing an enhancing tumor (arrow) . B, An axial T2-weighted image showing an area of dark signal corresponding to tumor.

Management.

The management of patients with TS is complex and requires adherence to recent consensus conference guidelines. GTR is the treatment of choice for SEGAs that are progressive, and cause obstructive hydrocephalus or seizures. The major risk of surgery is injury to the forniceal columns, resulting in memory disturbance. The benign behavior of these tumors warrants reoperation in the case of recurrence or progression after subtotal resection. Inhibition of the mTOR pathway in SEGAs has resulted in a very high response rate, and mTOR inhibitors have now been approved for the treatment of these lesions.

Prognosis.

SEGAs are essentially benign tumors, and gross total resection is generally curative. However multiple tumors may arise in some patients with TS, requiring ongoing radiologic surveillance. The overall prognosis for patients with TS is good, despite increased susceptibility to other tumor types, including rhabdomyomas of the myocardium and angiomyomas of the kidney, liver, adrenals, and pancreas.

Clinical Presentation.

Obstruction of CSF flow is the primary reason for symptomatology in patients with VHL disease who are diagnosed with hemangioblastomas. Headaches, morning vomiting, and long tract signs are therefore common. Ataxia and cranial nerve dysfunction can also be observed.

Imaging and Histology.

Hemangioblastomas are typically well-circumscribed cystic lesions with a solid tumor nodule. The solid component tends to enhance brightly with contrast and is usually located peripherally within the cyst ( Fig. 57-28 ). Flow voids are commonly observed on MRI and can be well delineated with angiography. Peritumoral edema is commonly observed. Tumors are usually composed of two elements—the stromal cells, which express vimentin and VEGF, and the endothelial cells, which express the VEGF receptor VEGFR2. Hemangioblastomas typically have low proliferative levels based on MIB1 immunoreactivity and are considered grade I tumors.

Cerebellar hemangioblastoma. A, A coronal T1-weighted image with gadolinium. B, A computed tomography image.

Management.

The management of these tumors requires specialized neurosurgical expertise because of the high risk of bleeding. The primary approach to these lesions, which tend to occur most commonly in the posterior fossa and cervicomedullary area, is maximal surgical resection. This approach provides long-term control in most patients, although, because of the underlying genetic predisposition, new tumors may continue to develop throughout the life of the patient. Embolization can reduce the intraoperative risks of bleeding. Radiosurgery can successfully treat the mural component of these tumors, although control is negatively influenced by the presence of the cysts. VEGF inhibitors have been tested in this population with initial encouraging results, although follow-up of these reports is still pending. A case of prolonged stable disease with thalidomide treatment was reported, although whether this outcome was related to its antiangiogenic or immune modulatory effects is unknown.

Prognosis.

Because of the genetic basis of these lesions, recurrences are common and likely represent new tumors rather than recurrences of previously resected ones, which indicates the importance of continued careful evaluation in this patient population.

Tanycytic Astrocytomas.

Tanycytic astrocytomas are rare and poorly characterized tumors. They are most common in adults and usually occur in the hypothalamic region. Their malignant potential is not well defined, although recurrences after complete resection have been observed. One reported case occurred in the context of an adolescent with NF-2.

Lipoastrocytomas.

Lipoastrocytomas are rare cortical tumors that, as the name suggests, possess fat droplets that give them the appearance of adipocytes in the context of a low-grade astrocytic lesion. These tumors express GFAP. Recurrences can occur and are treated with resection. Malignant transformation has not been reported in this tumor type, although one case was identified on autopsy in a patient with diffuse intrinsic pontine glioma.

Dysplastic Cerebellar Gangliocytomas.

Dysplastic cerebellar gangliocytomas are rare tumors of the cerebellum and fourth ventricle region that are of limited proliferative potential. They have a characteristic imaging pattern on MRI, with an abnormal laminated pattern in the cerebellum, although this pattern is not pathognomonic and can be mimicked by medulloblastoma. As such biopsy is recommended to differentiate the two entities. Dysplastic cerebellar gangliocytomas do not typically require therapeutic intervention, although seizure activity can occur as a result of their presence.

Disseminated Oligodendroglial-Like Leptomeningeal Tumor of Childhood.

Disseminated oligodendroglial-like leptomeningeal tumor of childhood is a newly described entity that typically demonstrate leptomeningeal enhancement on MRI and associated cystic or nodular T2 hyperintense lesions within the spinal cord/brain along the subpial surface. A discrete intraparenchymal lesion, usually in the spinal cord, is found in the majority of cases. These tumors are thought to have a greater risk of malignant transformation.

Supratentorial HGAs (Excluding DIPG).

Although adult and pediatric HGAs are similar histologically, increasing evidence indicates key biologic differences, even within shared pathways of tumorigenesis. Common pathways include the overexpression or mutation of EGFR, although both changes are less frequent in pediatrics, activation of the PI3K signaling pathway via silencing of the PTEN tumor suppressor, most often by methylation in pediatrics, and the MGMT DNA repair pathway, which is commonly methylated in adult HGAs but is more often overexpressed in pediatric tumors, perhaps helping to explain TMZ resistance in children with HGAs.

Recent findings have also demonstrated involvement of new pathways and features of pediatric HGA, further distinguishing them from adult tumors. These new pathways include overexpression of PDGFRα and novel histone mutations in H3F3A (observed in a minority of these tumors vs. a majority of DIPGs). Comprehensive profiling of HGA genetics has shown gains in chromosome 1q in pediatric HGA on copy number analyses, which is unusual in adults; fewer cases show chromosome 7 gain and 10q loss, two features seen in the majority of adult HGAs. One study appeared to show two distinct gene expression profiles in pediatric HGA, one that is similar to adult HGA, and one that is divergent. The PARP DNA repair pathway is also overexpressed in many pediatric HGAs, and this feature is associated with a poor prognosis ; PARP inhibitors may be useful as radiosensitizers. Aurora kinase B is overexpressed in a majority of pediatric HGAs. Unlike in adults, IDH1 mutations have not been found in pediatric HGAs. Pediatric tumors have demonstrated abnormalities in the Ras and Akt pathways, as well as Y-box protein-1. Microsatellite instability, which has been associated with a number of adult tumors, is very rare in pediatric HGAs.

Overexpression of many proteins distinguish pediatric HGAs from LGGs, including the DNA repair protein insulin-like growth factor binding protein 2 (IGFBP2), the cancer-testis antigen and possible immunotherapy target NY-ESO-1, the p53 inhibitor HDMX, the angiogenic marker endoglin, and the catalytic subunit of human telomerase reverse transcriptase (HTERT) ; the differentiation marker NF1A is underexpressed in pediatric HGA compared with LGG. In the CCG study of children with malignant HGGs (CCG945), p53 status was an important independent prognostic variable, with a 5-year PFS of 44% in tumors expressing a low level of p53 versus 17% in those overexpressing p53. Finally new epigenetic findings in pediatric HGAs include hypermethylation of the LIM homeobox 9 (LHX9) transcription factor, downregulation of class II and IV histone deacetylases (HDACs), acetylation of histone H3.3, and a decrease in adenosine deaminase, ribonucleic acid (RNA)-specific, 2 (ADAR2)–mediated RNA editing.

Imaging and Histology.

Typical HGAs have an MRI appearance of heterogeneous enhancement or diffuse nonenhancing tumor with significant edema on the T1-weighted image, compressing or displacing adjacent ventricular structures and occasionally causing hydrocephalus. The T2-weighted signal is often more diffuse, consistent with both infiltrative tumor and edema ( Fig. 57-29 ). MRS demonstrates a markedly elevated choline-to-NAA ratio; a 40% increase in choline over normal brain tissue indicates an HGA with 90% sensitivity and specificity. Lesions tend to be ¹⁸ F-labeled deoxyglucose–PET avid, although F-fluoro-ethyl-tyrosine (FET)–PET may be superior for treatment planning and distinguishing between LGGs and HGAs. Technetium 99m–sestamibi SPECT (MIBI SPECT) imaging can also detect HGAs and can be used to follow up for response or recurrence, as can serial diffusion weighted assessment. Areas of hemorrhage within pediatric HGAs at diagnosis are not uncommon. The presence of an HGA within the volume of a previously irradiated field is difficult to differentiate from a radiation-induced high-grade transformation of a low-grade astrocytoma, although preliminary studies have identified some molecular differences distinguishing radiation-induced glioblastoma. Malignant features on histopathologic examination of HGA include nuclear pleomorphism, mitoses, palisading necrosis ( Fig. 57-30 ), endothelial proliferation ( Fig. 57-31 ), and a high Ki-67 or MIB1 labeling index (see Fig. 57-17 ), although high interobserver variability exists between pathologists in judging these features. Most pediatric HGAs are nestin-positive on immunohistochemistry. Distinguishing between grade III and IV tumors relies on differences in histologic features; all HGAs must demonstrate nuclear atypia and mitoses, whereas grade IV tumors must also show either endothelial proliferation, necrosis, or both. It has now been shown that a proportion of CD133+ HGA cells costain for CD105 (endoglin), an angiogenesis marker, suggesting that vasculogenic mimicry occurs in pediatric HGAs, which may help increase angiogenesis in HGA through the formation of fluid-conducting vessels of tumor cells. CD105 staining is an unfavorable prognostic marker.

Right frontal glioblastoma. A, An axial T1-weighted image without use of contrast material showing the tumor (arrow). B, An axial fluid-attenuated inversion recovery image showing peritumoral edema and infiltrating tumor (arrow). C, An axial T1-weighted image with use of contrast material.

Palisading necrosis in a child with glioblastoma (hematoxylin and eosin; ×400).

Vascular proliferation with a glomeruloid tuft in a child with glioblastoma (hematoxylin and eosin; ×400).

Clinical Presentation.

The clinical presentations of children with brainstem tumors appear to fall into two groups. Patients with fewer than 3 months of symptoms, multiple cranial neuropathies (unilateral or bilateral), long tract signs (e.g., Babinski sign, hyperreflexia, and weakness), and cerebellar signs (e.g., ataxia, dysmetria, and dysarthria) are likely to have DIPG. Symptomatic hydrocephalus is present in fewer than 10% of patients with DIPG at presentation. Although the pons is not typically associated with behavior changes, pathologic laughter or separation anxiety have been symptoms noted in persons with DIPG. In contrast children with low-grade brainstem gliomas tend to manifest a more insidious history of isolated cranial nerve palsy or weakness, usually for longer than 3 months.

Imaging and Histology.

The diagnosis of DIPG may be made on the basis of the classic MRI appearance of a diffusely expanded pons with encirclement of the basilar artery. Most DIPGs appear to be hypointense on T1-weighted MRI and hyperintense on T2-weighted imaging. A prominent edema signal is common ( Fig. 57-32 ). The ventral pons may appear swollen and infiltrated. Contrast enhancement is variable, from homogeneous rim enhancement to patchy enhancement to complete absence of enhancement. In contrast to DIPGs low-grade focal lesions of the brainstem present with a more circumscribed appearance and associated contrast enhancement that occupies less than 50% of the axial diameter of the brainstem. These tumors may be composed of cystic and solid components. Leptomeningeal dissemination at diagnosis and recurrence may be more common in DIPGs than previously understood, and given the negative effect on prognosis, spine MRI at diagnosis should be considered. Diagnosis by imaging alone puts DIPG in a unique category, apart from nearly every other pediatric tumor, and some studies showing variability in reading of MRIs have called the practice into question. Another study of MRI-biopsy correlation showed that all diffuse, nonenhancing tumors were DIPG pathologically, whereas the diagnosis was more variable with focal or enhancing tumors.

Diffuse intrinsic pontine glioma. A, An axial T1-weighted image with use of contrast material with minimal enhancement (arrow). Note the tumor encroachment around the basilar artery. B, A sagittal T1-weighted image without use of contrast material. This is a large, diffusely expanding, low T1-weighted lesion of the pons with little encroachment into the midbrain or medulla. C, An axial T2-weighted image with little to no edema. D, Axial and sagittal diffusion tensor imaging showing posterior displacement of the corticospinal tract ( blue color and arrows ).

New MRI techniques have been found to have specific roles in diagnosing DIPGs. DTI is helpful in differentiating DIPG from demyelinating disease when the diagnosis is in question. Susceptibility-weighted imaging appears to be the best technique for detecting hemorrhages in DIPGs, which appear to be present in 47% of patients at diagnosis, although most hemorrhages are petechial and asymptomatic. MRS has identified a specific spectrum consistent with the malignant potential of DIPG. More importantly this method can detect positive responses in patients after radiation therapy, as well as changes indicative of progression in advance of MRI changes. The Cho : NAA ratio and lactate measurement on MRS appear to correlate with the length of survival. Elevated tumor perfusion on MRI after radiation therapy appears to predict a longer OS, and perfusion has been shown to decrease prior to clinical progression. Serial measurement and estimation of response may be best achieved with FLAIR imaging, although no radiologic methodology is optimal for disease assessment or response. Time to progression or OS, rather than radiographic response, may therefore be the best determination of treatment activity in clinical trials for this population. Ventriculomegaly without obstruction appears to be a common finding after radiation therapy in persons with DIPG, suggesting communicating hydrocephalus.

The histologic appearance of DIPG is similar to that of other HGAs. Most biopsy samples show evidence of atypia and mitoses and qualify as grade III anaplastic astrocytomas. Differentiation between anaplastic astrocytoma and glioblastoma in the pons is not relevant because all these patients appear to have an equally poor outcome.

Management.

During the past 30 years, little progress has been made in the treatment of DIPG. Radiation therapy has improved the median OS from weeks to months, but it can at best be considered palliative therapy. Despite many clinical trials, no chemotherapeutic agent has shown an improvement compared with radiation alone. Few patients survive more than 2 years.

Corticosteroids are generally started at the time of diagnosis, because peritumoral edema may contribute significantly to symptoms, and steroids may therefore offer some relief. Patients with DIPG often require steroids for a long duration, and investigation of agents that can offer relief from peritumoral edema without the adverse effects of steroids is ongoing.

The tide is clearly shifting toward diagnostic biopsy in patients with suspected DIPG. Several retrospective studies of open and stereotactic biopsy showed that the procedure is feasible and safe. A prospective trial of 24 patients undergoing stereotactic biopsy showed that transient cranial nerve palsies in two children were the only complications, with tissue obtained in all patients, including two for whom the biopsy results changed the management approach. A consensus statement in support of biopsy on behalf of a large group of DIPG experts has now been published. The procedure still carries risk, however, and should be performed at experienced centers by experienced neurosurgeons. The ideal locations for stereotactic biopsy appear to be areas of focal anaplasia, represented by T2 hypointensity, contrast enhancement, and diffusion restriction.

Radiation therapy remains the mainstay and standard treatment for DIPG. The tumor volume and a 1- to 2-cm volume of surrounding brainstem are generally included in the field, and conventional doses range from 5400 to 5940 cGy given over 6 weeks. This treatment is generally effective at decreasing tumor size, decreasing symptoms, and allowing patients to stop taking steroids, but these effects generally last only a matter of months, and the treatment is still considered palliative instead of curative. Multiple studies have attempted hyperfractionation techniques, ranging from 6600 to 7800 cGy, without improvement in survival ; this outcome may relate to the inherent resistance of these tumors. More recently in an attempt to reduce the impact of the radiation therapy schedule for these children with a limited life span, hypofractionation schedules have been tested, usually 3900 to 4500 cGy over 3 to 4 weeks, with a noninferior response rate and duration. Reirradiation is also the only therapy that has shown any potential efficacy at recurrence: two retrospective reports showed transient responses of some patients to reirradiation doses of 1800 to 2000 cGy, with children who had a prolonged duration of response from initial radiation therapy most likely to benefit.

Many adjuvant chemotherapy agents and strategies have been tried and have failed to improve outcomes in patients with DIPG compared with radiation therapy alone. Many recent phase II trials have centered on the use of TMZ, given that this agent is now standard of care in adults with HGG. However three phase II trials of TMZ given with radiation therapy, followed by TMZ alone, have failed to show an increase in survival time compared with historic standards from radiation therapy alone, and the addition of TMZ worsened toxicity. Other recent phase II trials have shown no benefit of tamoxifen, pegylated interferon α-2b, a regimen of cisplatin, etoposide, ifosfamide, vincristine, and valproate, and inhaled carbogen as a radiosensitizer. Other past failed agents and strategies have included preirradiation multiagent chemotherapy, topotecan as a radiosensitizer, etanidazole as a radiosensitizer, chemotherapy concurrent with radiation therapy including thalidomide, trofosfamide and etoposide, car­boplatin, carboplatin and etoposide, TMZ and cis-retinoic acid, chemotherapy with BBB disruption, intraarterial bevacizumab injection, and a postradiation high-dose chemotherapy regimen. New strategies that have been the subject of recent phase I reports include the use of the PDGFR inhibitor dasatinib in combination with the VEGFR2 inhibitor vandetanib, vandetanib alone, and the use of arsenic trioxide. The development of nonhuman primate models of direct drug delivery into the brainstem opens another avenue for developing improved therapies for these tumors.

Prognosis.

DIPG remains the most challenging of pediatric tumors to cure. Despite all approaches most survival curves are superimposable with regard to OS. Meta-analyses of numerous clinical reports indicate that median PFS ranges from 5 to 9 months, with a median OS of 6 to 16 months. One-year and 2-year survival ranges from 17% to 50% and 7% to 29%, respectively, with less than 10% survival at 3 years. Neither MRI characteristics nor WHO grade has an impact on prognosis in persons with DIPG. Poor performance at diagnosis on the FMH health status scale correlates with a worse prognosis. The size of the treating medical center has no effect on prognosis. One report indicated an improved prognosis for patients with DIPG who are younger than 3 years, although questions of misclassification of patients with low-grade brainstem glioma as having DIPG inevitably arise with reports of improved survival—yet another reason for the use of diagnostic biopsy. Very few cases of neonatal DIPG have been reported, and outcomes in these reports have been inconsistent, ranging from spontaneous regression to death within weeks. Retrospective studies have shown worse prognoses for patients initially treated with dexamethasone or rofecoxib, raising the question of whether tumor inflammation may be important to treatment. Patients with leptomeningeal dissemination at diagnosis appear to have a shorter PFS than do patients who do not have this finding. It is hoped that with time, the greatly improved understanding of DIPG biology and promising preclinical models will soon lead to successful clinical trials and an improved outlook for patients afflicted with this terrible disease.

Imaging and Histology.

Gliomatosis cerebri is diagnosed on MRI scan and demonstrates a characteristic diffuse infiltrative pattern. T1-weighted sequences are usually isointense to hypointense and underestimate the extent of disease, whereas T2-weighted sequences are hyperintense and highlight the full extent of the disease ( Fig. 57-33 ). Signal abnormality usually involves multiple lobes. The presence of contrast enhancement is strongly correlated with a poorer prognosis in both adult and pediatric patients. A solid area of tumor is usually not evident. MRS demonstrates elevation of choline and a decrease in NAA levels. Although the hallmark of gliomatosis cerebri is an infiltrative astrocytic tumor, areas of oligodendroglial cells are not uncommon for adult and pediatric patients. Most tumors are consistent with grade III histology, and mitoses are often present. MIB1 staining can vary considerably. The absence of mitoses is more likely to be because of sampling error. GFAP and S-100 can be positive or negative. Nestin and vimentin can be positive. Because of their infiltrative growth and co-opting of existing blood vessels, these tumors lack the abundant neovascularization observed in other malignant gliomas, which suggests that they will not be effectively treated with antiangiogenic agents.

Gliomatosis cerebri. This coronal fluid-attenuated inversion recovery image demonstrates the diffuse infiltration. Note that a solid uniform mass is absent.

Management.

Currently patients with gliomatosis under­go biopsy to confirm the diagnosis. Given the diffuse nature of these tumors, complete resection is rarely feasible. The mainstay of therapy is irradiation to the involved region, which, for pediatric patients, may require almost complete whole-brain therapy. In addition to significant morbidity, large-volume radiation therapy for gliomatosis cerebri has not been proven to be effective, although it may delay the time to progression. Objective responses to TMZ have been documented in adults and, in oligodendrogliomas, correlate with chromosome 1p and/or 19q loss. The impact of MGMT expression on response and outcome has not yet been determined.

Prognosis.

Pediatric patients with gliomatosis cerebri have a poor outcome. In a large series of pediatric and adult patients, a median survival of 14.5 months was demonstrated. Younger age, lower grade histology, and chemoresponsiveness were associated with slightly longer survival times. Although long-term survival is unlikely, adults whose tumors have chromosomal 1p and/or 19q loss can show more chemoresponsiveness to agents such as TMZ. Similar activity in pediatric patients has not been reported because of the rarity of these tumors in this population.

Clinical Presentation.

The presenting symptoms of infratentorial ependymomas are a result of their origin from ependymal tissue lining the fourth ventricle. Hydrocephalus results when the tumor fills the fourth ventricle, causing obstruction of the normal spinal fluid flow and subsequent development of headache, irritability, nausea, vomiting, and ataxia. Papilledema can often be found on physical examination. Tumors that extend out of the foramen of Luschka may compromise lower cranial nerve function and cause hearing impairment, hoarseness, and/or dysphagia. If the tumor extends through the foramen of Magendie, the patient may report neck discomfort or be noted to have torticollis. The most common signs of the tumor in infants are irritability, decreased oral intake, vomiting, ataxia, head pain, lethargy, and increased head circumference. Supratentorial ependymomas which represent approximately one third of ependymomas, are more common in older children and adults. These patients present with focal neurologic deficits and seizures. Spinal ependymomas are typically located in the cervical region. The most common presenting symptom is pain or motor deficits localized to the level of the spinal cord lesion. The pain is typically described as being worse at night, presumably because of congestion of the spinal venous plexus that occurs when the patient is in the recumbent position. The second most common symptom is radicular dysesthesias, and a late manifestation of this symptom is progressive spastic quadriparesis. Thoracic ependymomas are associated with scoliosis. Myxopapillary ependymomas of the conus medullaris and filum terminale may cause low back pain, radicular pain, saddle anesthesia, and sphincter dysfunction. When these tumors disseminate, they usually remain in the spine, although cranial metastases have been reported; therefore craniospinal imaging at diagnosis should be undertaken. Pediatric myxopapillary ependymoma may have a higher propensity to spread compared with adult tumors.

Imaging and Histology.

A typical MRI appearance of a fourth ventricular ependymoma is that of a homogeneously enhancing well-circumscribed solid mass, extending out one of the foramina of Luschka or Magendie with obstructive hydrocephalus. These tumors classically wrap around the brainstem or herniate through the foramen magnum ( Fig. 57-34 ). Hemorrhage and calcifications can be observed and are more common in supratentorial lesions. Ependymomas may occasionally spread via CSF, seeding the leptomeninges or ventricles, either at diagnosis or at recurrence. Careful attention to staging of patients is therefore important.

Posterior fossa ependymoma. A, An axial T1-weighted image with use of contrast material. B, A sagittal T1-weighted image with use of contrast material. C, A coronal T1-weighted image with use of contrast material. D, An axial T2-weighted image showing a T2 isodense lesion (arrow).

The characteristic microscopic feature of a classic ependymoma is that of dense cellularity, intermixed with perivascular pseudorosettes consisting of tumor cells and surrounding a neoplastic blood vessel ( Fig. 57-35 ). True ependymal rosettes representing abortive canals are relatively uncommon. Histologically the anaplastic variant is recognized by the presence of mitoses, necrosis, and vascular proliferation. They tend to be more cellular than grade II ependymomas but usually remain well demarcated. MIB1 rates greater than 5% in incompletely resected tumors or greater than 15% in completely resected tumors correlate with more aggressive behavior. GFAP and S-100 are positive in most ependymomas, and epithelial membrane antigen (EMA) stains are positive in anaplastic variants. The presence of perivascular elastic fibers may also be a diagnostic feature of these tumors. In patients in whom the diagnosis of ependymoma is indeterminate, electron microscopic analysis of cilia structure and junctional complexes, which are found in most ependymomas, can be used to confirm or exclude the diagnosis. Myxopapillary ependymomas have a mucinous appearance and arise almost exclusively in the cauda equine. Their MIB1 labeling index is typically low. Tanycytic ependymomas are a rare subtype of ependymoma that can occur throughout the brain or spine. Other rare subtypes include cellular ependymoma, papillary ependymoma, and clear cell ependymoma variants.

Ependymal pseudorosette (hematoxylin and eosin; ×600).

Management.

Evaluation of patients at diagnosis or recurrence should include an MRI of the brain and spinal cord, as well as cytologic evaluation of the CSF, usually performed at least 14 days after the operation. Attempting CSF analysis during the surgery or shortly after could give false-positive results. The usefulness of CSF sampling in patients may not be particularly sensitive. A number of factors have been associated with an unfavorable outcome, including younger age at diagnosis, subtotal resection, and a high MIB1 labeling index. Anaplastic histology remains controversial as a negative prognostic factor. Of these factors the single most important factor in the determination of prognosis appears to be whether a complete resection can be accomplished.

The first line of treatment is surgery with the goal of GTR. If a complete resection with clear margins of a grade II spinal cord or supratentorial ependymoma can be achieved, adjuvant therapy can be deferred in some patients. Technologic advances such as the operating microscope, Cavitron ultrasonic aspirator, intraoperative ultrasound, and intraoperative MRI, as well as electrophysiologic monitoring, have facilitated the safety of resections of intraaxial spinal cord tumors while reducing operative morbidity. Overall, spinal cord ependymomas are more easily resectable than astrocytomas because of the presence of a better demarcated cleavage plane. Tumors with an infiltrative boundary, or those with anaplastic histology, require adjuvant therapy. All posterior fossa tumors, independent of grade and degree of resection, should also receive adjuvant treatment. Spinal myxopapillary ependymomas with a complete surgical resection have an excellent prognosis and do not usually require adjuvant therapy even in the presence of drop metastases in the thecal sac. Given the overall good prognosis of these tumors, the need for radiation in incompletely resected disease is unclear, and careful surveillance imaging is needed. Early radiation therapy is not always routinely used but is recommended by some persons.

Regarding radiation therapy, there is a long history of deferring radiation therapy for infants and young children who have posterior fossa ependymomas, with use of various conventional chemotherapy regimens instead. Previous treatment recommendations included radiation therapy for patients in whom gross resection was not achieved or for patients with recurrent disease. However partially resected tumors almost invariably recur, requiring further surgery, radiotherapy, and conventional chemotherapy. As such, in the United States the current strategy for ependymoma is to recommend deferral of adjuvant therapy in persons with completely resected supratentorial ependymoma, use of radiotherapy in the involved fields alone for completely resected posterior fossa ependymoma, and use of multiagent chemotherapy for subtotally resected ependymoma, followed by second-look surgery and involved field radiation therapy. The benefit of hyperfractionation has not been established. Wide-field pulsed reduced dose rate radiotherapy is currently being evaluated. Craniospinal radiation therapy does not appear to be superior to focal radiation therapy. Several studies have suggested that radiotherapy prolongs PFS after subtotal resection of an ependymoma. Deferral of radiation therapy after initial complete resection can result in reduced cure, even when complete resection is achieved a second time. Proton radiation therapy appears to have equal efficacy when compared with photon therapy; it can reduce the potential long-term toxicity by decreasing the volume of normal brain tissue that is also targeted and is therefore recommended over photon therapy if it is available locally.

Until recently there was no clear role for chemotherapy in the management of ependymomas outside of clinical trials. Several small series in newly diagnosed and recurrent disease have shown objective responses to the following drugs: carboplatin, cisplatin, ifosfamide, and etoposide. Chemotherapy is more often used for infants and younger children with incompletely resected or disseminated disease. Encouraging results have been reported from the most recent cooperative group clinical trial involving preirradiation chemotherapy, which showed a 40% complete response (CR) rate in patients who received preirradiation chemotherapy for residual postoperative tumor. The two factors associated with a favorable outcome were the achievement of a complete resection and supratentorial disease. Chemotherapy should therefore be used to achieve a CR or improve the chances of a complete surgical resection at second-look surgery. It is not highly effective as sole treatment for this disease, and recurrences occur relatively rapidly in a significant percentage of patients if radiotherapy is not administered early. Infants may be more responsive, and 23% to 40% can be cured with chemotherapy alone. The use of high-dose chemotherapy and stem cell rescue in infants with ependymoma has failed to demonstrate a significant advantage compared with standard modalities in most, although not all, studies. Although uncommon, up to 10% of patients can have leptomeningeal spread of ependymoma. Response to intrathecal liposomal cytarabine has been reported.

Recurrences of intracranial ependymoma can occur throughout the first decade after initial therapy, although most recur within the first few years. Surveillance scanning is important because it allows smaller asymptomatic tumors to be identified that may be more amenable to reresection. Most recurrences are within the original radiation field and do not appear to be related to marginal failures.

Prognosis.

The most important prognostic factors for intracranial and spinal cord ependymoma are age, tumor grade, extent of surgical resection, and delivery of radiation therapy with doses of at least 5400 cGy. Children younger than 3 years, those with WHO grade III disease, or those with less than a GTR have been shown to have lower survival rates. The 5-year PFS and OS for patients with subtotal versus total resection of posterior fossa ependymomas is 25% and 66%, respectively. The prognosis of patients with disseminated disease is worse. Patients with a supratentorial nonanaplastic ependymoma can be treated with surgery only if the tumor can be completely resected. Recently a molecular assay for HTERT expression has been shown to predict the likelihood of progression and survival of pediatric intracranial ependymoma. Additional studies on the molecular profile of ependymomas will likely lead to improved stratification and prognostication of patients as previously discussed. Patients with an elevated MIB1 labeled index of more than 5% in incompletely resected ependymomas or of more than 15% in completely resected ependymomas were reported to have a worse prognosis in one study. Patients with a deletion of 6q15.3 appear to have an improved outcome. Molecular profiling has identified that the group A ependymomas (posterior fossa, infants) have a more aggressive biologic behavior and worse prognosis when compared with the group B ependymomas (supratentorial), although this classification is not currently being used to guide therapy intensity at the present time.

Most patients with completely resected ependymoma followed by focal radiation therapy will be long-term survivors. Consideration of advanced radiation planning and the type of radiation delivered (i.e., proton vs. photon) are critical to minimize long-term neurocognitive morbidity in this population.

At the time of recurrence, no standard salvage regimen has been proven to be effective. Reoperation to achieve a complete resection has been curative in some patients and is typically the first modality considered ; this approach can be combined with reirradiation. SRS has also been used with some success for focal recurrences of ependymoma. Patients with metastatic disease or infiltration into the brainstem or other critical structures have a poor salvage rate, presumably because of the lack of good therapies for recurrent disease and the inoperable nature of the lesions. Oral etoposide alone or in combination as a metronomic therapy combination has demonstrated responses in this disease. Bevacizumab in combination with irinotecan did not show any significant activity. A single case report of a response to the mTOR inhibitor sirolimus has also been published.

Recurrence of myxopapillary ependymoma can occur after complete resection and can be associated with dissemination. Although cranial metastases have been reported, most cases result in regional metastases of the spine but not beyond the foramen magnum. Many of these patients can undergo salvage therapy with radiation. Consequently frequent surveillance scanning of patients with myxopapillary ependymoma is recommended to identify recurrent disease early.

Clinical Presentation.

Oligodendrogliomas are diffusely infiltrating tumors that tend to occur in the white matter of the cerebral hemispheres. Patients frequently present with seizures, although higher-grade tumors may present with evidence of increased ICP because of more rapid growth. Other symptoms at presentation can include headache, visual field defect, paresis, and cranial nerve palsy. Although uncommon, oligodendrogliomas can also occur throughout other areas of the brain, including the posterior fossa, brainstem, and spine.

Imaging and Histology.

MRI evaluation of oligodendrogliomas typically reveals increased T2-weighted signal and decreased T1-weighted signal. Gadolinium contrast enhancement is more common in tumors that grow as solid masses and less common in purely infiltrative tumors. Contrast enhancement is also more common in grade III than in grade II oligodendrogliomas. Although oligodendrogliomas bear morphologic similarity to oligodendrocytes, the cellular origin of these tumors has remained difficult to prove. Histologic examination of fixed specimens of oligodendrogliomas reveals a monotonous pattern of cells with round nuclei and clear perinuclear halos (a “fried egg” appearance). This appearance is an artifact of formalin fixation and is not seen in frozen sections or tumor smears. Higher-grade anaplastic oligodendrogliomas (WHO grade III) are characterized by increased nuclear variability, increased mitotic activity, and/or microvascular proliferation. These features can occur diffusely throughout the tumor or in discrete foci. The differentiation between oligodendrogliomas and other diffuse gliomas such as astrocytomas and OAs is difficult because of a lack of reliable molecular markers that distinguish oligodendroglial tumors from astrocytic tumors. Mature oligodendrocyte-specific markers such as myelin basic protein, 2′3′−cyclic-nucleotide 3′-phosphodiesterase, and myelin-associated glycoprotein are not expressed in oligodendrogliomas, although astrocytic markers such as GFAP and S-100β are expressed in both astrocytomas and oligodendrogliomas. More recently the lineage markers OLIG1 and OLIG2 have been evaluated in the hope that they may enable specific identification of oligodendroglial tumors. However despite the restriction of OLIG2 expression to normal oligodendrocytes and their precursors, OLIG2 stains all diffuse gliomas and precludes specific immunohistochemical classification of these tumors. The loss of chromosome 1p and/or 19q is commonly seen in adult oligodendrogliomas and correlates strongly with chemotherapy responsiveness and outcome. Pediatric oligodendrogliomas have a much lower incidence of chromosomes 1p and/or 19q deletions. Even in children in whom these deletions are identified, the greater chemoresponsiveness observed in adults is less evident.

Management.

Treatment of pediatric oligodendrogliomas, like other glial tumors, involves surgical resection, radiation therapy, and chemotherapy. The goal of surgery is to facilitate accurate diagnosis and to remove as much of the tumor as safely possible. In the adult literature, there is uncertainty as to whether the extent of resection correlates with OS. Although some larger case series have shown no prognostic value in the extent of resection, most evidence seems to indicate that the extent of resection may be associated with better prognosis. In pediatric patients, it appears that the extent of resection is a sensitive predictor of outcome. Fewer pediatric low-grade oligodendroglial tumors progress to high-grade tumors, so it is possible that patients with subtotally resected tumors may still have a good outcome. For example in one series of 20 patients with oligodendrogliomas treated with surgery only, 70% remained progression-free at a median of 5 years.

Despite the fact that oligodendroglial tumors are radiosensitive, the use of adjuvant radiation therapy in asymptomatic children with incompletely resected oligodendrogliomas is not favored because of the well-described late effects of radiation therapy. Children who are symptomatic, who have tumors in critical locations such as the brainstem, or who have progressive disease despite resection and/or chemotherapy may benefit from radiotherapy. However it is now clear that a subset of these children can be effectively treated with chemotherapy, allowing for a delay in, or avoidance of, radiation therapy. The combination of carboplatin and vincristine chemotherapy has demonstrated activity in various low-grade astrocytomas, regardless of histologic subtype. This therapy should therefore be considered for patients with oligodendroglioma. Older children may also benefit from chemotherapy. Based on overlapping activity in children with low-grade astrocytomas, the combination of TPCV might also be of use in patients who do not respond to or have disease progression after vincristine and carboplatin therapy. The combination of procarbazine, lomustine, and vincristine or TMZ monotherapy could also be considered based on the responses seen in adults, but these treatments have not yet been adequately tested in children.

In patients with anaplastic oligodendroglioma or progressive disease, despite surgery and adjuvant chemotherapy, the risks of radiation therapy may be offset by the risk of further tumor growth. A recent survey of adult neurooncologists has found that the most commonly recommended treatment for anaplastic oligodendroglioma is the use of concurrent TMZ and radiotherapy followed by adjuvant TMZ. In rare cases of dissemination, the overall prognosis for these patients is poor, although transient chemotherapy responsiveness can be achieved. Patients with oligodendroglial gliomatosis cerebri have a very poor prognosis.

Prognosis.

Overall long-term survival from low-grade oligodendrogliomas appears comparable with that of other LGGs. It should be noted, however, that only limited numbers of case series are available, making comparisons among studies difficult. Bowers and colleagues have reported an OS of at least 5.5 years in a series of 20 patients with low-grade oligodendrogliomas treated initially with surgical resection alone. Six of 20 patients in this series had disease progression at a median of 2.2 years after initial resection. Other studies have reported 5-year OS rates of 65% to 84.4%, although the proportion of patients treated with radiation therapy and/or chemotherapy differed among these studies. Children younger than 3 years and children with incompletely resected tumors may do worse. The rarity of anaplastic oligodendroglioma in children makes specific estimates of survival in pediatric patients difficult. Oligodendrogliomas that are more centrally located do not appear to do as well as those located more peripherally in the cortex.

A number of studies from adult patients have indicated that allelic losses at chromosomes 1p and 19q, typically involving the entire chromosomal arm at both sites, correlate with histologic classification, response to treatment, and prognosis. Loss at chromosome 1p is a predictor of chemosensitivity, and loss at combined chromosomes 1p and 19q is associated with both chemosensitivity and longer recurrence-free survival. Recent evidence has indicated that loss at chromosomes 1p and 19q is associated with MGMT promoter methylation and lower expression of MGMT. Interestingly these chromosomal features appear to be less common in pediatric oligodendrogliomas. One study has reported the lack of allelic loss in children younger than 9 years, although a modest number of tumors from children older than 9 years had losses of chromosome 1p (45%) and/or 19q (27%). Nevertheless the incidence of chromosomal losses is significantly less than that seen in adults (50% to 90%). Taken together these studies suggest that the oncogenesis of these tumors is distinct from their adult counterparts.

Management.

A high level of clinical suspicion is critical for an early diagnosis of medulloblastoma. Neuroimaging is usually the first step, with CT or MRI scanning of the brain frequently performed in the acute setting. MRI of the brain and spine should be performed as soon as is feasible. In children in whom the diagnosis of medulloblastoma is suspected, an MRI of the spine should be obtained because the incidence of CSF dissemination at diagnosis ranges between 20% and 30%. Corticosteroids are usually used to control increased ICP. A lumbar puncture should be deferred until after intracranial hypertension has been relieved by surgery. Because extraneural spread of medulloblastoma is possible, bone marrow aspiration and biopsy should be considered for the complete evaluation of patients with medulloblastoma, although these procedures are no longer required for participation in cooperative clinical trials. Although the exact incidence of extraneural metastases is evolving, current estimates suggest that such metastases occur in fewer than 5% of patients. Because patients will require general anesthesia for insertion of a central line for the administration of chemotherapy, bone marrow samples and a baseline lumbar sample can be easily obtained with minimal trauma to the child or family. CSF obtained from the ventricular or cisternal fluid is not considered an adequate sample upon which to base staging decisions; thus lumbar sampling is recommended for all patients in whom such sampling is not contraindicated pretherapy.

At present risk stratification and treatment assignment are based primarily on clinical factors, although this will change with greater reliance on molecular profiling. Recently histology has been added in the risk assignment of medulloblastoma. The modified Chang criteria are based on the extent of tumor and the degree of metastasis ( Box 57-3 ). After completion of the staging evaluation (i.e., MRI of the brain and spine, CSF cytology, and bone marrow studies), histology, and degree of resection, patients are stratified to the standard-risk, high-risk, or infant-risk groups. The major determinants of clinical risk categorization are age at diagnosis (younger than 3 years vs. 3 years or older), metastasis or M stage (M0 versus higher than M0), volume of residual postoperative disease (less than 1.5 cm ³ residual disease vs. greater than 1.5 cm ³ residual disease), and histology (anaplastic–large cell versus other). Although these criteria are widely used in the staging of medulloblastoma, the role of complete resection versus less than 1.5 cm ³ residual disease, the age of the patient, and the significance of anaplastic histology are still in question, and entry criteria may vary from those indicated.

Histology has just recently begun to be considered in risk stratification. Most prior published series of patients with medulloblastoma had incorporated patients with anaplasia–large cell medulloblastoma into standard-risk treatment if they met the other criteria for standard risk. The recognition that infants with the desmoplastic variant may do better than infants with the nondesmoplastic variant may provide an opportunity to deescalate therapy in this particular group. Newer protocols are now incorporating these variables. Tolerability of therapy has also recently come to light as more adult programs begin to treat older patients with regimens similar to those that have produced significant advances in pediatric patients. Older patients, including adolescents, do not tolerate therapy as well as younger children or infants, which provides an argument for dose modifications in this group.

ATRTs of the posterior fossa often resemble medulloblastomas. In prior cooperative group studies, up to 30% of patients with ATRTs were misclassified as having a medulloblastoma. With the use of INI1 immunohistochemical analysis of the tumor sample, rapid differentiation of these two histologies is required because the treatment for ATRT differs from that of medulloblastoma in most large cooperative groups.

Treatment

Clinical Presentation.

Like other pineal region lesions, pineocytomas often present with a constellation of symptoms related to their location. This constellation includes obstructive hydrocephalus and Parinaud syndrome, a cluster of abnormalities of eye movements and papillary dysfunction characterized by paralyzed upgaze, pseudo–Argyll Robertson pupils, convergence-retraction nystagmus, eyelid retraction, and a conjugate downgaze “sunsetting” sign. Impairment of hypothalamic-pituitary, brainstem, and cerebellar function is also possible. Unlike malignant pineoblastomas, metastases are rare.

Imaging and Histology.

On neuroimaging, pineocytomas are typically small focal lesions that can contain cysts and/or calcifications; they are best seen by CT. They are similar to other low-grade tumors on MRI, with strong contrast enhancement, hypointensity on T1-weighted sequences, and high signal intensity on T2-weighted sequences. Surgically these tumors tend to be well demarcated from surrounding tissue. Areas of hemorrhage are not uncommon. Microscopically pineocytomas are made up of small, round, mature-looking cells that have maintained features of pinocytes, including rosettes. These tumors demonstrate characteristic pineocytomatous rosettes that differentiate them from pineoblastomas. Mitoses are rare, as are other features of malignancy. Pineocytomas are usually strongly synaptophysin and neuron-specific enolase (NSE)–positive. If areas of pineoblastoma are identified with a pineocytoma, treatment is dictated by the most malignant element (i.e., pineoblastoma).

Management.

Surgery remains the mainstay of the therapeutic approach for these lesions. Treatment directed at the hydrocephalus with third ventriculostomy may provide an opportunity to obtain a biopsy before aggressive and potentially morbid surgical resection is attempted. Tumors with persistent growth can be irradiated, although the benefit of this treatment has not been clearly demonstrated. A role for chemotherapy has not been defined. Patients with incompletely resected tumors do not require therapy unless clear progression is demonstrated. Even patients with metastatic disease can remain untreated. The overall benign course observed with pineocytomas is in stark contrast to that of pineoblastomas.

Prognosis.

The long-term prognosis remains excellent, even with incompletely resected disease. Conservative management should be followed with regard to attempted surgical resection and radiation therapy. Because almost all patients with pineocytomas will be long-term survivors, the need to avoid toxicity is paramount.

Clinical Presentation.

The presentation of patients with PPTID is similar to that of pineocytomas and includes obstructive hydrocephalus, as well as Parinaud syndrome, a cluster of abnormalities of eye movements and papillary dysfunction characterized by paralyzed upgaze, pseudo–Argyll Robertson pupils, convergence-retraction nystagmus, eyelid retraction, and conjugate downgaze. Impairment of hypothalamic-pituitary, brainstem, and cerebellar function is also possible. Unlike pineocytomas, metastatic disease appears to be slightly more frequent.

Imaging and Histology.

Imaging characteristics are similar to those of other lesions of pineal origin. They are cellular lesions with moderate nuclear atypia and a low mitotic index. Because of sampling error, diagnosis can be difficult with limited tissue, especially tissue obtained via third ventriculostomy.

Management.

Because of the increasing degree of malignant potential when compared with pineocytomas, attempts at surgical resection should be considered. Although formal pediatric studies are lacking, radiation therapy and chemotherapy should be considered. Intensity of treatment can be based on the localization of the tumor (focal, invasive, or disseminated), as well as the proportion of mitoses, necrosis, atypia, and possibly neurofilament protein expression.

Prognosis.

A definite prognosis for PPTID has not been clearly established. Grade is likely to play an important part in the long-term outcome of patients, as is the size and metastatic stage of patients. Because these tumors span all age groups, large homogeneous studies are difficult to perform.

Clinical Presentation.

Presenting symptoms of pineoblastoma are virtually identical to those for pineocytomas, although the duration of symptoms may be shorter than that seen for other tumors in this location. Pineoblastomas often present with a constellation of symptoms related to their location, including obstructive hydrocephalus in most patients, as well as Parinaud syndrome, a cluster of abnormalities of eye movements and papillary dysfunction, as previously described. Impairment of hypothalamic-pituitary, brainstem, and cerebellar function is also possible. Pineoblastomas have a much greater propensity to metastasize and thus may demonstrate symptoms beyond the pineal region.

Imaging and Histology.

The neuroimaging characteristics of pineoblastomas are not pathognomonic for these tumors, but they are differentiated from pineocytomas by a significant increase in the volume of the tumor and the presence of much less distinct boundaries. MRI characteristics include low signal on T1-weighted sequences and heterogeneous areas of contrast enhancement ( Fig. 57-40 ). T2-weighted signals may be lower than in pineocytomas because of the higher nuclear-to-cytoplasmic ratio evident in these more malignant tumors. On histologic analysis these tumors are similar to other small round blue cell tumors, composed of sheets of cells but lacking the characteristic pineocytomatous rosettes of pineocytomas. Pineoblastomas are typically synaptophysin- and NSE-positive and other markers, including those for photoreceptor pathways, can be present, consistent with the developmental role of the pineal gland. Homer-Wright rosettes (i.e., cells with a central zone of cytoplasm; see Fig. 57-39 ) and Flexner-Wintersteiner rosettes (i.e., cells with a central zone of cytoplasm and a central space; Fig. 57-41 ) are common, but these rosettes can be seen in a large number of other embryonal tumors. These tumors often have significant atypia, and mitotic activity can be high. When additional pathways of differentiation are present (e.g., melanin, cartilage, and muscle), the tumors are called pineal anlage tumors. Regions of pineoblastoma can also be identified as part of a pineocytoma and are treated as a pineoblastoma. Although sporadic pineoblastoma has no clear genetic association, patients with hereditary (bilateral) retinoblastoma have a significant incidence of pineoblastoma (trilateral retinoblastoma). The clinical course of retinoblastoma-associated pineoblastoma can differ from that of sporadic pineoblastoma.

A large contrast-enhancing pineoblastoma. A, An axial T1-weighted image with use of contrast material. B, An axial fluid-attenuated inversion recovery image demonstrating a bright T2-weighted signal.

Flexner-Wintersteiner rosette in a patient with pineoblastoma (hematoxylin and eosin; ×600).

Recent profiling of genomic alterations have reported copy number alterations observed in pineoblastoma. These alterations include loss of chromosome 16q and amplification of PCDHGA3, and FAM129A. In addition DNA copy number profiles have reported more similarities between sPNETs and pineoblastoma than between these tumors and the lower grade tumors of the pineal region. The development of pineoblastoma has also been reported in a young patient with a germline mutation of DICER1 , which is also associated with the development of pleuropulmonary blastoma.

Management.

The therapeutic approaches for pineoblastoma have followed those of other embryonal seeding tumors of the CNS. The workup of patients with pineoblastoma includes immediate intervention for obstructive hydrocephalus and assessment of risk for herniation. A rapid CT or MRI scan, in conjunction with the examination and presenting history, will permit the neurosurgeon to assess these risks. If urgent CSF shunting is not required, then completion of the imaging baseline workup, including MRI of the brain and spine, can be performed and surgical resection can be planned. Unlike medulloblastoma, the location of pineoblastomas with adjacent vascular structures makes exploratory surgery much more risky, and referral to a highly specialized center should be considered. A third ventriculostomy or VP shunt should be deferred prior to initial surgery but may be necessary if sufficient resection with reestablishment of CSF flow is not achieved. In many patients an endoscopic biopsy of the tumor to confirm the diagnosis and concurrent third ventriculostomy can be performed with a planned open craniotomy and resection once the patient is clinically stable, the disease has been defined, and possible presurgical chemotherapy has been provided. Patients with metastatic disease at diagnosis should not undergo upfront aggressive surgery because adjuvant therapy will be required. For patients with focal disease at diagnosis based on initial MRI and documentation of negative results of a lumbar puncture, complete removal of the tumor ultimately will be an important component of long-term prognosis but should not be undertaken at any costs. Consideration for staged surgeries (second- and even third-look approaches) may be equally effective without causing permanent neurologic damage.

As with other embryonal seeding tumors of the CNS, craniospinal radiotherapy is an important modality in treating microscopic metastatic disease at presentation. Unlike medulloblastoma, pineoblastomas do not have a standard-risk category. All patients require aggressive therapy, including a craniospinal dose of 3600 cGy and a focal boost to the primary site of 5400 to 5940 cGy. Sites of metastatic disease require radiation boosts as well. Even with focal resectable disease, the prognosis for pineoblastoma falls significantly below that of medulloblastoma. In persons with disseminated disease, especially diffuse leptomeningeal spread, and infants, for whom craniospinal radiotherapy is contraindicated, the prognosis remains especially poor. The use of SRS or other similar modalities to deliver single-fraction ablative radiation therapy may provide added disease control of unresectable tumor, although these approaches are limited to small areas of disease.

Chemotherapy is an important modality for patients with pineoblastoma, and significant responses to chemotherapy have been observed, including in patients with trilateral retinoblastoma. Results from infant studies, which deferred radiotherapy, demonstrated that although chemotherapy can be effective at reducing bulk disease, few patients are long-term survivors with this modality alone. Because of the rarity of this entity most protocols have combined these patients with patients who have other embryonal tumors, including CNS PNETs and, occasionally, medulloblastoma. Specific estimates of survival from different therapies have therefore been difficult to determine. Current approaches continue to include initial craniospinal radiotherapy in combination with chemotherapy, followed by postradiation chemotherapy. Most regimens have used combinations of vincristine, cyclophosphamide, cisplatin, and etoposide. Because of the chemoresponsiveness of these tumors, pilot clinical trials with high-dose chemotherapy with stem cell transplantation have also been undertaken. The results of the German HIT2000 clinical trial, which included children with CNS PNET and pineoblastoma, recently reported 5-year EFS and OS of 24% ± 10% and 40% ± 12%, respectively, with multiagent chemotherapy and radiation therapy. Children with high-risk disease received intensified therapy.

The concurrent use of craniospinal radiation therapy and multiagent chemotherapy for pineoblastoma has resulted in a significant impairment of nutrition during therapy for these patients. A large number of patients will require nutritional support through a nasogastric tube or, more commonly, a gastric tube. Constant surveillance of nutrition is important because these issues are often dismissed early and are only recognized when severe weight loss has occurred. Patients with persistent vomiting usually initiate therapy in a negative nutritional state.

Prognosis.

The outcome of patients with pineoblastoma remains poor. Patients with focal disease that can be completely resected have 3- and 5-year EFS of approximately 50%. Infants, patients with incompletely resected disease by the end of therapy, or patients with metastatic disease continue to do poorly, with 3- and 5-year EFS estimates of 20% or lower. Progression tends to occur early and can occur at the primary site, throughout the CNS, or both. A recent study of recurrence patterns in children with embryonal intracranial tumors noted a high rate of relapses that involved the spine in children with pineoblastoma. Extracranial metastases are uncommon. Some patients with metastatic disease, however, are long-term survivors. After recurrence, no standard therapy has been documented to be effective, and most patients will succumb to their disease, usually within months.

Clinical Presentation.

The clinical presentation of PTPRs is similar to that of other lesions of the pineal area. Hydrocephalus is present in almost all patients, and Parinaud syndrome is common. Impairment of hypothalamic-pituitary, brainstem, and cerebellar function is also possible. Metastatic disease does not appear to be as prevalent as in pineoblastomas.

Imaging and Histology.

PTPRs are well-circumscribed, often cystic lesions. They are hyperintense on T1- and T2-weighted sequences and enhance with administration of contrast material. Histologically these tumors stain strongly for keratins and are usually negative or weakly positive for GFAP (in contrast to ependymomas) and synaptophysin. Most of the tumor cells show strong expression of NSE, cytokeratins (particularly CK18), S-100 protein, and vimentin. The mitotic index and MIB1 labeling index are intermediate but of unclear prognostic significance.

Management.

In spite of their differentiated appearance, PTPRs are aggressive tumors that are not highly responsive to therapy. In a recent report of 31 patients, 21 of whom achieved a gross total resection, adjuvant radiation therapy alone resulted in a PFS rate of only 27%. The ability of achieve a gross total resection has been reported in some studies to be associated with improved PFS.

Prognosis.

In spite of complete resection and focal radiation therapy, local recurrences are common, although patients with complete removal of these tumors may do better. Dissemination appears rare, and craniospinal radiation therapy therefore does not appear to be required. Patients with an elevated MIB1 labeling index or mitotic rate may tend to do worse.