Background

Primitive neuroectodermal tumors, or embryonal CNS tumors, are the most common group of malignant brain tumors in children and include medulloblastomas, supratentorial PNETs, pineoblastomas, and atypical teratoid/rhabdoid tumors. There have been several changes to the categorization of embryonal tumors in the 2007 revised WHO classification of CNS tumors (Brat et al., 2008). Four distinct variants of medulloblastoma are now defined: large cell medulloblastoma, anaplastic medulloblastoma, medulloblastoma with extensive nodularity, and desmoplastic/nodular medulloblastoma. In addition, supratentorial PNETs, ependymoblastomas, and medulloepitheliomas have been consolidated under the same designation, CNS PNET. Medulloblastoma represents approximately 85% of intracranial PNETs and 15% of all pediatric brain tumors. The incidence in males is twice that of females, and the median age at diagnosis is 5 to 7 years. Taken as a group, 80% of all pediatric intracranial PNETs are diagnosed before age 10. According to the incidence data generated by the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry, the incidence of primitive neuroectodermal tumors has remained fairly stable over the past 20 years (Linabery and Ross, 2008).

Etiology

Although histological similarity unites the various PNET subtypes, laboratory-based studies have identified a diverse and complex range of molecular biological subtypes of PNET. The regulation of signaling pathways that control brain development is abnormal in medulloblastoma and supratentorial PNET. In addition, the use of DNA microarray analysis indicates clear molecular distinctions between different embryonal CNS tumors (Pomeroy et al., 2002). This allows classification based on gene expression patterns, a more detailed understanding of the cellular origin of the various tumors in this class, and better prediction of outcome (Gilbertson and Ellison, 2008; Rossi et al., 2008).

Original reports by Bailey and Cushing in 1925 suggested that medulloblastomas originated from multipotential “medulloblasts” thought to be capable of generating both glial and neuronal cells. Experimental evidence now indicates that the two main histopathological subtypes of medulloblastoma, desmoplastic and nondesmoplastic (formerly “classic”), originate from two distinct germinal zones within the cerebellum—that is, the external granular layer, which contains committed granule cell precursors, and the ventricular zone, which contains multipotential stem cells that give rise to the majority of cerebellar neurons (Gilbertson and Ellison, 2008; Rossi et al., 2008). Whereas desmoplastic medulloblastoma tends to express markers of granule cell lineage, suggesting an origin from granule cell precursors, nondesmoplastic medulloblastoma more frequently expresses markers associated with nongranule neurons, suggesting an origin in the ventricular zone of the developing cerebellum (Read et al., 2006). Gene expression analysis supports these data by demonstrating separate expression profiles, with desmoplastic medulloblastoma cells expressing genes more closely associated with proliferating granule cell precursors, and the expression profiles of nondesmoplastic medulloblastoma revealing a more heterogeneous set of markers not clearly associated with any particular cerebellar cell type (Ehrbrecht et al., 2006; Northcott et al., 2010).

There is limited understanding of the etiology of the other embryonal CNS tumors. Supratentorial PNETs originate from multipotential cells that have the capacity for differentiation along multiple lineages (Li et al., 2005). However, specific markers for supratentorial PNETs have not yet been defined, making further histopathological classification difficult. Among the less common embryonal CNS tumors, medulloepitheliomas appear to be derived from primitive cells in the subependymal layer, whereas ependymoblastomas presumably arise from periventricular neuroepithelial precursor cells. There are no convincing data to support a dietary or environmental etiology of PNETs from various epidemiological studies. However, a genetic predisposition for the development of medulloblastoma, supratentorial PNET, and pineoblastoma exists in rare cancer-susceptibility syndromes such as Turcot syndrome, nevoid basal cell carcinoma syndrome (Gorlin syndrome), and Li-Fraumeni syndrome (Attard et al., 2007; Hottinger and Khakoo, 2009). These syndromes, along with observations from the genomic profiling of pediatric brain tumors, have shed light on the molecular pathways involved in tumorigenesis. Several groups have independently used this information to separate medulloblastomas into four or five different categories (Kool et al., 2008; Northcott et al., 2011; Thompson et al., 2006). These categories include medulloblastomas resulting from dysregulation along the wingless (WNT) pathway, abnormal sonic hedgehog (SHH) pathway signaling, and two or three additional subsets that are less well characterized.

The clinical manifestations of Turcot syndrome include the development of colon cancer and brain tumors. This syndrome has been further classified into type 1 and type 2. Patients with Turcot syndrome type 1 have mutations in the mismatch repair gene, bMLH1, which leads to the formation of gliomas. Those with type 2 disease have germline mutations in the adenomatous polyposis coli (APC) gene that leads to development of medulloblastomas through the WNT pathway (Attard et al., 2007). Patients with sporadic medulloblastomas have been found to have mutations in several genes involved in the wingless pathway, including inactivation of the tumor suppressor genes, APC (3%) and AXIN (2%), and/or activating mutations in CTNNB1 gene (8%) (Baeza et al., 2003; Yokoto et al., 2002).

Nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome, is an autosomal dominant disorder characterized by the development of basal cell carcinomas, multiple bony cysts, and malignant tumors including medulloblastomas in young children (Kimonis et al., 1997). Patients with this disorder have mutations involving the ptc1 (Patched 1) gene (Hahn et al., 1996). This gene encodes for the protein which is the receptor of SHH. The SHH pathway is critically involved in the normal development of the cerebellum (Lewis et al., 2004). Approximately 10% to 20% of patients with sporadic medulloblastoma have mutations involving the SHH pathway. The ptc1 gene is the most commonly affected gene within this pathway, but mutations in other genes along this pathway including smoothened, fused, and suppressor of fused (SUFU) have also been identified (Raffel et al., 1997; Taylor et al., 2002; Zurawel et al., 2000). Although mutations in the WNT and SHH pathways are important in the development of medulloblastoma, they account for only 30% to 40% of the sporadic cases of medulloblastoma. Abnormal signaling along other pathways, such as Notch, has also been implicated in the development of medulloblastomas (Lasky and Wu, 2005).

Trilateral retinoblastoma is a well-recognized syndrome characterized by bilateral retinoblastomas occurring concurrently with a pineoblastoma with retinoblastic features (Finelli et al., 1995). Although approximately half of the cases of trilateral retinoblastoma are associated with the familial form of retinoblastoma, one analysis indicates that most children with trilateral retinoblastoma have ordinary hereditary retinoblastoma that is complicated by trilateral disease by chance, thus dispelling the notion that trilateral retinoblastoma is caused by a different allele than that which causes ordinary retinoblastoma (Kivela, 1999).

Although reports of supratentorial PNET and medulloblastomas have occurred in patients with the Li-Fraumeni syndrome (mutations in the TP53 gene on chromosome 17), no compelling evidence exists to suggest that TP53 mutation alone is sufficient to promote development of a PNET (Weber et al., 1998). In addition, isolated TP53 mutations appear to be less common in sporadic medulloblastoma than would be expected (Burns et al., 2002; Portwine et al., 2001). However, evidence exists that alterations in p53 function may influence the effect of PTCH1 mutations in promoting the growth of medulloblastoma (Wetmore et al., 2001). Although most medulloblastomas are sporadic, familial cases unrelated to the mentioned syndromes have also been reported (von Koch et al., 2002).

Clinical Presentation

Many of the clinical manifestations of a medulloblastoma that arises in close proximity to the fourth ventricle are the result of increased intracranial pressure (ICP) due to obstructive hydrocephalus. Headache is the most common initial symptom and usually precedes diagnosis by 4 to 8 weeks. Intractable nausea and vomiting occur frequently, characteristically in the morning. Personality changes, namely irritability, are an early feature but may be difficult to recognize as a sign of a brain tumor. Other features that can lead to diagnosis include lethargy, diplopia, head tilt, and truncal ataxia. The common signs on physical examination are papilledema, ataxia, dysmetria, and cranial nerve involvement. Abducens nerve palsy secondary to increased ICP is a cause of diplopia and head tilt. Torticollis can be a sign of cerebellar tonsil herniation.

Although contrast-enhanced magnetic resonance imaging (MRI) identifies leptomeningeal metastases in 10% to 30% of children with intracranial PNETs at the time of diagnosis, clinical manifestations are uncommon. Back pain and radicular pain indicate the rare complication of spinal dissemination. Less commonly, intratumoral hemorrhage may lead to acute onset of confusion, headache, and loss of consciousness. Among infants with posterior fossa tumors, diagnosis can be more challenging; thus, important features include changes in mood and personality as well as macrocephaly. Delay in achieving milestones or loss of previously achieved milestones and failure to thrive are characteristic. Similar to medulloblastoma, the presenting features of supratentorial PNETs include progressive headache, nausea, vomiting, and lethargy secondary to increased ICP. Alternatively, children with pineoblastomas often present with dorsal midbrain compression (Parinaud syndrome) and obstructive hydrocephalus secondary to aqueductal occlusion.

Diagnosis

A high level of clinical suspicion is critical to make an early diagnosis of PNET. Neuroimaging is usually the first step, with computed tomography (CT) scan of the brain frequently obtained in the acute setting. Contrast-enhanced cranial MRI provides definitive imaging of the tumor. Certain MRI features may help distinguish the various types of posterior fossa tumors (medulloblastoma, ependymoma and pilocytic astrocytoma) of childhood. Although no single radiological feature is pathognomonic of a medulloblastoma, certain common characteristics exist. On CT, a medulloblastoma is generally hyperdense and homogeneously enhancing, filling the fourth ventricle (Fig. 52E.1, A). On contrast-enhanced cranial MRI, medulloblastomas are often isointense or hypointense to surrounding normal brain on T1-weighted images (see Fig. 52E.1, B). The uniform hypercellularity of most medulloblastomas typically results in a relatively homogeneous image appearance. On T2-weighted images, medulloblastoma can appear to be hyperintense or more frequently can display mixed signal characteristics indicative of small intratumoral cysts, calcification, or small areas of hemorrhage (see Fig. 52E.1, C). Because medulloblastoma typically arises in the roof of the fourth ventricle, a cleft of cerebrospinal fluid (CSF) beneath the tumor in the fourth ventricular canal helps distinguish this tumor from an ependymoma, which typically arises from the floor of the fourth ventricle. Ependymomas can fill the fourth ventricle and calcify more frequently than medulloblastomas. In addition, ependymomas often contain cysts, making their overall image appearance more heterogeneous. Because these tumors typically arise near the obex, ependymomas frequently extend out the foramen of Magendie over the dorsal surface of the cervical spinal cord or through the foramen of Luschka. Pilocytic astrocytomas typically arise in the cerebellar hemispheres and have the appearance of a cystic mass with an enhancing mural nodule. On T2-weighted MRI, these tumors often appear as areas of homogenous high signal intensity, with the fluid collections defining the less intense tissue components of the tumor (see Fig. 52E.1, D).

Fig. 52E.1 A, This 3-year-old girl presented with 3 weeks of worsening headaches that awakened her at night. Contrast-enhanced cranial computed tomography (CT) scan shows a large dense mass within the posterior fossa, containing internal calcifications. Surrounding edema can be seen. Compression of the quadrigeminal plate cistern and fourth ventricle led to obstructive hydrocephalus. B, Axial T1 postcontrast magnetic resonance image (MRI) of the same patient, showing heterogeneous enhancement of the lesion. MR spectroscopy showed a markedly depressed NAA peak, with elevation of the choline peak consistent with high-grade tumor. Diffusion-weighted imaging showed restricted diffusion indicative of a highly cellular lesion. Resection of the mass showed it to be a medulloblastoma. C, A 13-month-old child presented with unsteady gait and vomiting over several days. MRI showed a large nonenhancing posterior fossa mass filling the fourth ventricle. Resection showed tumor consistent with ependymoma. Axial T2 FLAIR image shows T2 prolongation. D, Sagittal T1 image after the infusion of gadolinium, showing the ependymoma filling the fourth ventricle. Note the lack of contrast enhancement. The lesion extends out of the foramen of Magendie over the dorsal surface of the cervical spinal cord.

Management

In children in whom the diagnosis of intracranial PNET is suspected, a contrast-enhanced spinal MRI should be obtained at the time of diagnosis to assist in neurosurgical planning and staging (Cohen et al., 1995). After radiological diagnosis, corticosteroids are frequently used to control increased ICP. Most often the child will require admission for observation and pediatric neurosurgical consultation. If the child has unstable mental status or vital signs, emergency external ventricular drainage may be required before surgery. The goals of surgery are to control ICP, achieve a gross total resection (if feasible), establish a histological diagnosis, and bank frozen tumor for molecular analysis prior to protocol therapy. Placement of a ventriculoperitoneal (VP) shunt before surgery is no longer commonly practiced but may be necessary after surgery. A lumbar puncture for CSF cytological evaluation should only be performed after ICP has been relieved after surgery. Potential complications of posterior fossa surgery include cerebellar mutism and aseptic meningitis. The posterior fossa, or cerebellar mutism, syndrome may occur in as many as 40% of children undergoing posterior fossa surgery (Wells et al., 2010). The characteristics include reduced speech output or mutism, personality changes, hypotonia, ataxia, and reduced oral intake. Symptoms typically appear 1 to 2 days after surgery and may last for a few months, with varying degrees of recovery (Catsman-Berrevoets and Aarsen, 2010).

Risk stratification of PNET is currently based on clinical staging and certain neuropathological features, although molecular observations will most probably be incorporated into the next generation of clinical trials. Clinical staging follows the completion of perioperative brain and spine MRI and lumbar CSF cytological analysis. The M (metastasis) staging criteria include: M0, no metastases; M1, positive CSF cytology alone; M2, intracranial metastases; M3, spinal metastases; and M4, systemic metastases. The major determinants of clinical risk categorization are age at diagnosis, metastasis (M stage), primary tumor site, and volume of residual postoperative disease. In addition, the presence of large-cell anaplasia has recently emerged as a risk factor (Von Hoff et al., 2010). Distinction is made between age younger than 3 years versus older than 3 years, stage M0 versus stages higher than M0, cerebellar versus non-cerebellar primary tumor, postoperative residual tumor volume of less than 1.5 cm² versus greater than 1.5 cm², and presence or absence of large-cell anaplasia (Von Hoff et al., 2010; Zeltzer et al., 1999).

Patients are currently stratified into either standard-risk or high-risk prognostic groups. Standard-risk patients are those who are older than age 3 at diagnosis, have residual tumor volume of less than 1.5 cm², have a primary tumor in the cerebellum, have no evidence of metastasis (M0), and do not have anaplastic medulloblastoma. Children younger than age 3 are always at high risk because of higher rates of recurrence (McNeil et al., 2002). In addition, patients with residual tumor volume greater than 1.5 cm², any metastatic disease, or large-cell/anaplastic medulloblastoma are at high risk for recurrence. Treatment of intracranial PNETs usually consists of surgery, radiation therapy, and chemotherapy, with specific therapies guided primarily by age and risk stratification. The current recommended therapy for standard-risk patients includes craniospinal irradiation (23.4 Gy) with a boost to the primary tumor site to 54 Gy. Vincristine is usually administered weekly with radiation therapy. Following radiation therapy, adjuvant chemotherapy is given, with the most common regimen consisting of 8 cycles of cisplatin, lomustine, and vincristine (Packer et al., 2006). Current research in this group of patients consists of identifying adjuvant chemotherapy with less ototoxicity than cisplatin and less myelosuppression than lomustine.

In addition to developing effective chemotherapy regimens with less toxicity, several groups are trying to decrease the toxicity associated with radiation therapy. The use of proton-beam radiation therapy as an alternative to high-energy x-rays (photons) has been studied and found to have the potential to limit late effects of radiation therapy by reducing the exposure of normal tissue to radiation (Durante and Loeffler, 2010). The basis for the interest in proton irradiation in the treatment of pediatric malignancies is the differences between charged particle beams (photons) and proton beams. Standard photon (x-ray) beams deliver a maximum radiation dose near the surface, followed by a continuously reducing dose with increasing depth. As a result, tissues outside the target area receive an exit dose of the radiation, which can lead to significant morbidity in patients receiving craniospinal irradiation. In contrast, as protons move through tissue, they ionize particles and deposit a radiation dose along their path. The maximum 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 is precisely controlled, placement of the Bragg peak within the tumor and tissues targeted to receive the radiation dose is possible. Because the protons are absorbed at this point, normal tissues beyond the target receive very little radiation (MacDonald et al., 2006). Thus, the use of proton radiation can spare adjacent critical structures such as the optic apparatus, cochlea, and hypothalamus when they are not adjacent to tumor volume, potentially resulting in fewer long-term sequelae (Merchant et al., 2008b).

All newly diagnosed patients younger than 3 years of age at diagnosis are classified as high risk. The frequency of leptomeningeal dissemination is also increased at the time of diagnosis in young children (27%-43%) versus older children (20%-25%) with similar histological diagnoses (Heideman et al., 1997), and there is a higher incidence of aggressive tumor variants such as atypical teratoid/rhabdoid tumor (Hilden, 2004). After surgical resection, chemotherapy—alone or with involved-field radiation therapy—often follows in an effort to reduce the high incidence of developmental and neuropsychological sequelae in young children and infants treated with craniospinal irradiation. The risks of radiation therapy in infants and young children are significantly greater than the benefits of therapeutic response in terms of neurocognitive development. Consequently, several chemotherapy regimens designed to delay or eliminate the need for craniospinal irradiation are undergoing evaluation, including regimens employing intraventricular chemotherapy (Rutkowski et al., 2005) and high-dose chemotherapy with autologous stem cell rescue (Dhall et al., 2008; Fangusaro et al., 2008). Several different approaches are being used to try to improve survival in older children with high-risk disease (M+, >1.5 cm² residual tumor volume, anaplasia, supratentorial location). These include the use of autologous hematopoietic progenitor cells to shorten the interval between chemotherapy cycles, as well as the addition of high-dose methotrexate (Chi et al., 2004; Gajjar et al., 2006). The Children’s Oncology Group is currently studying the use of carboplatin as a radiosensitizer, as well as 13-cis-retinoic acid during and following adjuvant chemotherapy.

Prognosis

Standard-risk medulloblastoma patients have a 5-year survival of approximately 80%; 5-year survival in high-risk medulloblastoma patients is approximately 30% to 40% (Oyharcabal-Bourden et al., 2005; Packer et al., 2006). The presence of CNS dissemination is the single most important factor that correlates with outcome (Helton et al., 2002). Most initial recurrences occur at the primary site. Salvage therapy is rarely curative, but long-term disease control may occur with high-dose myeloablative chemotherapy (Dunkel et al., 2010; Gardner, 2004). Lifelong serial surveillance imaging is required in anticipation of radiation-induced secondary malignancies such as meningioma or high-grade glioma (Kantar et al., 2004). Radiation therapy, particularly in young children, can also cause significant adverse late effects in cognitive development, growth, and endocrine function (Mulhern et al., 1999; 2005).

Background

Pilocytic astrocytomas (PAs) are well-circumscribed, slow-growing tumors classified as WHO grade I (Luis et al., 2007). These tumors are the most common gliomas found in children and represent approximately 20% of all childhood brain tumors. Pilocytic astrocytomas are typically diagnosed in the first 2 decades, with no clear gender predilection. Neurofibromatosis type 1 (NF1) is associated with an increased risk of PA (Rodriguez and Berthrong, 1996). No other definite predisposing factors are known. Histologically, PAs consist of bipolar cells with long “fiberlike” processes, hence the name pilocytic. Other distinctive histological features of PAs include Rosenthal fibers, eosinophilic granular bodies, and microcysts. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway through specific gene fusions and activating mutations has recently been identified in the majority of PAs, as well as other pediatric low-grade astrocytomas (Tatevossian et al., 2010), and may provide an opportunity for the future development of molecular targeted therapies.

Clinical Presentation

Pilocytic astrocytomas can arise anywhere in the CNS, but most commonly occur in the optic pathways, the optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, midbrain, and medulla. Pilocytic astrocytomas of the spinal cord are less common. The spectrum of clinical manifestations depends on the structures involved and may include visual deficits, obstructive hydrocephalus, macrocephaly in younger patients, ataxia, endocrine dysfunction, focal neurological deficits, long-tract signs, cranial nerve dysfunction, and seizures if the tumor involves cortical structures. Cerebellar PAs usually present with symptoms indicative of increased ICP, such as headache, nausea, and vomiting. Similarly, because brainstem PAs are usually dorsal and exophytic, obstructive hydrocephalus is often the presenting feature. The diencephalic syndrome is unique to low-grade gliomas, usually juvenile PAs arising in infants in the hypothalamus or optic pathways, and consists of emaciation with normal linear growth, frequently accompanied by hyperemesis, hyperkinesis, and nystagmus (Fleischman et al., 2005).

Diagnosis

This diagnosis should be suspected when any of the mentioned features are observed in a young patient. The history of illness is usually long; other signs of chronicity such as bone remodeling, scoliosis, or hemihypotrophy may be present, depending on the primary tumor location. The typical MRI appearance is a homogeneously enhancing mass with only minimal associated edema. Intratumoral cysts are common depending on location—that is, cerebellum, cerebrum, midbrain, and spinal cord (Fig. 52E.2). Rarely, PAs present with diffuse leptomeningeal dissemination, especially the infant variant (pilomyxoid astrocytoma) (Komotar et al., 2005).

Fig. 52E.2 A 9-year-old boy who presented with a short history of headache and nausea. Contrast-enhanced cranial magnetic resonance imaging was obtained because of the severity of his headaches, which demonstrated an enhancing tumor with a solid portion in the anterior aspect of the posterior fossa, adjacent to the dorsal midbrain. A large cyst can be seen posterior to the solid mass. Resection revealed a pilocytic astrocytoma.

Management

The mainstay of therapy for PAs is surgery. If feasible, gross total resection is “curative” even though residual microscopic disease always remains, and radiation and chemotherapy are typically not required. Surgical intervention is typically not required for clinically and radiologically diagnosed optic pathway gliomas, especially in NF1 patients, except under unusual circumstances such as very large exophytic tumors that are affecting vital neurological function or producing hydrocephalus by extension dorsally in the third ventricle. Progressive or unresectable PAs, or those arising in infants or young children causing visual symptoms, may require adjuvant treatment.

Chemotherapy is assuming an increasingly important role in the management of diencephalic low-grade gliomas in younger patients and in children with unresectable and progressive tumors. Various regimens such as carboplatin and vincristine or thioguanine, procarbazine, lomustine, and vincristine (TPCV protocol), have produced consistent durable responses (Packer et al., 1997; Prados et al., 1997; Shaw and Wisoff, 2003). Both regimens were compared in a randomized phase III trial by the Children’s Oncology Group, and final study results are expected to be published in the near future. Temozolomide, an oral alkylating agent with a favorable side-effect profile, has been effective in uncontrolled studies as monotherapy in adult low-grade gliomas (Kesari et al., 2009; Quinn et al., 2003). Temozolomide also appears to be active in children with low-grade gliomas, achieving stable disease in 41% of patients in a Children’s Oncology Group study (Nicholson et al., 2007). Other regimens that have shown evidence of activity in small patient series include vinblastine (Lafay-Cousin et al., 2005) and irinotecan/bevacizumab (Packer et al., 2009). “Anti-angiogenic” regimens with oral medications given at a low dose on a daily “metronomic” schedule are also under investigation (Samuel et al., 2009). BRAF, which is constitutively active in the majority of PAs, has recently emerged as a novel, promising target for small-molecule inhibitors (Tatevossian et al., 2010). Because of concern for adverse effects including neurocognitive and endocrine effects as well as secondary malignancies, radiation therapy is usually deferred in children with low-grade gliomas, especially in those with diencephalic tumors and NF1. Additional late effects of radiation when used in younger children with diencephalic gliomas include strokes related to a moyamoya-like syndrome (Arita et al., 2003; Merchant et al., 2009, Serdaroglu et al., 2000).

Prognosis

The prognosis for resectable tumors is excellent, with 5-year recurrence-free survival of greater than 90% after gross total resection (Shaw and Wisoff, 2003). The most critical variable in the treatment of PAs is the anatomical location of the tumor. Complete resections are most difficult for tumors located in the brainstem, spinal cord, and hypothalamus. As such, the progression-free survival of children with centrally located tumors (e.g., optic chiasm, thalamus, hypothalamus) is reduced. The proliferative index of pediatric PAs does not appear to be associated with outcome (Horbinski et al, 2010). Given the risk of long-term sequelae of radiation therapy, especially in young children, chemotherapy is now usually preferred as the first therapeutic modality in most patients with progressive tumors not amenable to gross total resection (Sievert and Fisher, 2009). The use of chemotherapy as initial treatment in patients with centrally located or unresectable tumors allows for the delay of radiation therapy until the child is less likely to suffer major developmental and neuropsychological sequelae. Ultimately, the quality of survival depends on multiple factors including tumor location, extent of tumor resection, timing of any radiation therapy, and side effects of surgery, chemotherapy, and radiation. Malignant transformation of PA and other low-grade astrocytomas in children is rare (Broniscer et al., 2007).

Background

Optic pathway gliomas (OPG) may be considered a subset of PAs, but their unique features and management requirements warrant a separate discussion. OPG represent approximately 4% to 6% of all primary pediatric brain tumors. These tumors may involve various parts of the optic pathway, such as the optic nerves, optic chiasm, optic tract, and optic radiations. The tumor may also infiltrate the adjacent hypothalamus and temporal lobes. Optic nerve gliomas are strongly associated with NF1, and NF1 patients represent about 50% of patients treated for DPG. Although approximately 20% of NF1 children scanned prospectively from birth will acquire MRI abnormalities suggestive of an anterior or posterior OPG, less than half of those will develop progressive neurological and radiological disease, and the occasional tumor may undergo spontaneous regression (Parsa et al., 2001). OPGs in NF1 patients have been suggested to have a more indolent course than those arising in patients without NF1 (Deliganis et al., 1996). In a recent series however, progression-free survival for NF1 patients requiring treatment appeared similar to non-NF1 patients (Nicolin et al., 2009).

Clinical Presentation

Most OPGs are low-grade astrocytomas, primarily PAs (WHO grade I) (Cummings et al., 2000). Although most OPGs are of lower histological grade, the clinical course of these tumors may be aggressive when the optic pathways and hypothalamus are invaded. Age is an important prognostic factor: children younger than 5 years of age experience a more aggressive course. Unilateral optic nerve gliomas present with the classic triad of vision loss, proptosis, and optic atrophy. Chiasmatic involvement may lead to unilateral or bilateral vision loss, optic tract involvement may lead to a visual-field deficit, and large dorsally exophytic or hypothalamic components of the tumor may lead to obstructive hydrocephalus. Further invasion into brain parenchyma may result in visual-field defects and hemiparesis. The diencephalic syndrome is unique to infant presentations of OPG and hypothalamic PA and presents with irritability, failure to thrive, nystagmus, visual loss, and hydrocephalus in the first or second year of life (Fleischman et al., 2005).

Diagnosis and Management

The clinical diagnosis of an OPG should be suspected when a child presents with visual impairment associated with nystagmus and optic atrophy. It is very difficult to ascertain visual loss in younger children, but close behavioral observation during play may raise suspicion. Contrast-enhanced cranial or orbital MRI typically shows a solid, cystic, or solid and cystic tumor with enhancement (Fig. 52E.3). MRI studies and clinical presentation may distinguish an OPG from other childhood tumors that arise in the suprasellar location, such as a germ cell tumor or craniopharyngioma. The unpredictable clinical course of patients with OPGs 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 the presence of NF1 may all impact management decisions. Treatment usually starts promptly in young patients, those with progressive symptoms, and those with extensive CNS involvement; preservation of vision is paramount. The initial treatment of choice is chemotherapy, which may cause stabilization or regression of the tumor (Silva et al., 2000). Combination therapy with carboplatin and vincristine (Kato et al., 1998; Packer et al., 1997) is most commonly used as first-line therapy, but the TPCV protocol (Lancaster et al., 2003) and other low-grade glioma protocols are also used. Although a definitive role for radiation therapy exists in the management of OPG, most favor a delay in initiating radiation in young patients (Jahraus and Tarbell, 2006). Recovery of visual deficits is unpredictable even if a radiographic tumor response is observed (Moreno et al., 2010).

Fig. 52E.3 A -year-old girl with a history of neurofibromatosis type 1 (NF1) who was seen after an ophthalmological evaluation revealed a left eye deviation and visual-field loss. A, Magnetic resonance imaging (MRI) reveals T2 prolongation in the optic chiasm. B, There is significant enlargement of the left optic nerve. C, Coronal T1 postgadolinium imaging shows the lesion to be contrast enhancing. The combined findings were highly suggestive of an optic pathway glioma.

Prognosis

Although OPGs are usually low-grade tumors, the location of these neoplasms often results in serious morbidity. The growth rate of OPGs often slows in older children and young adults. The most robust adverse prognostic factor across multiple studies has been age younger than 1 year at diagnosis, although some suggest that children with NF1 may have a longer progression-free survival (Opocher et al., 2006). Patients with OPGs associated with NF1 may remain stable for several years. Close observation and symptomatic management are appropriate for this subpopulation.

Background

Subependymal giant cell astrocytomas (SEGA) usually originate in the ependymal lining of the lateral ventricles and are associated almost exclusively with tuberous sclerosis (TS) (Kumar and Singh, 2004). Sporadic SEGAs are rare. TS is an autosomal dominant genetic syndrome caused by mutations in either TSC1 (hamartin) or TSC2 (tuberin), which are regulators of key cellular signaling pathways including the mammalian target of rapamycin (mTOR) pathway (Jozwiak et al., 2008).

Clinical Presentation

Subependymal giant cell astrocytoma is sometimes the presenting feature of TS in patients without the typical physical stigmata of the syndrome. Although patients with TS typically have multiple periventricular SEGAs, the tumors that produce symptoms of hydrocephalus arise in close proximity to the foramina of Munro. Most patients with known TS have been followed with serial MRI scans, and newly identified SEGAs are typically removed in anticipation of more serious neurological syndromes such as headaches, altered sensorium, or weakness. These children may have other neurological symptoms such as seizures related to cortical tubers and cognitive deficiency.

Diagnosis and Management

Contrast-enhanced cranial CT and MRI are essential for early and accurate diagnosis. Whereas the former is better for detecting small calcified lesions, MRI is superior to CT in identifying areas of gliosis, heterotopia, and SEGA, which gives the typical radiographic appearance of candle dripping (Nabbout et al., 1999). SEGAs typically demonstrate diffuse contrast enhancement on both CT and MRI studies. Gross total resection is the treatment of choice for SEGAs that are large, progressive, and causing obstructive hydrocephalus. This can be accomplished by a transcallosal craniotomy and rarely after an endoscopic procedure. The main surgical risk is injury to the forniceal columns, resulting in memory disturbance. Alternatively, a VP shunt can provide symptomatic relief. The benign behavior of these tumors warrants re-operation in the case of recurrence or progression after subtotal resection. Pharmacological inhibition of mTOR with rapamycin is emerging as a promising alternative to surgery for these and other TS-related conditions (Franz et al., 2006). SEGA may respond dramatically to mTOR inhibitors, but the tumors will recur once mTOR inhibition is terminated. The long-term use of these inhibitors, which are also immunosuppressive, is unknown and will require further study.

Prognosis

Subependymal giant cell astrocytomas are usually benign tumors, and gross total resection may be curative. However, multiple tumors may arise in some patients with TS. 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 (Crino et al., 2006).

Background

Diffuse astrocytomas (DAs, WHO grade II) are a common variant of low-grade astrocytoma (LGA), composed primarily of fibrillary neoplastic astrocytes and distinct from PAs. The most typical histological subtype is also termed fibrillary astrocytoma. DAs represent 12% to 18% of all pediatric intracranial tumors. No gender predilection exists, and the peak age at diagnosis is 6 to 10 years. DAs may arise in any location within the CNS but are most commonly diagnosed in the frontal and temporal lobes. Brainstem and spinal cord are less common locations, and cerebellar DAs are rare. TP53 gene mutations are a genetic hallmark of DAs and can be found in more than 60% of tumors (Okamoto et al., 2004).

Clinical Presentation

Initial symptoms vary depending on the location of the tumor and may exist for months to years before a definitive diagnosis (Table 52E.3). DAs within the brainstem have a different clinical course compared to DAs in other locations and will be discussed under Diffuse Intrinsic Pontine Glioma. Brainstem DAs often undergo malignant transformation within months. This transformation is much less likely in other locations. 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 increased ICP. Other symptoms include diplopia and hemiparesis.

Diagnosis and Management

Most DAs appear isodense on CT scan, without significant contrast enhancement. The tumor is hypointense on T1-weighted and hyperintense on T2-weighted MRI, with minimal or no contrast enhancement with the exception of dorsally exophytic brainstem tumors (Fig. 52E.4). The risk of malignant transformation appears to be much higher in adults than in children, although the molecular abnormalities observed during transformation in children are similar to those observed in adult high-grade gliomas. These abnormalities include p53 overexpression, as well as RB1 and/or CDKN2A and PTEN deletions. Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, which is found in more than 80% of adult DAs (Yan et al., 2009), appears to be rare in pediatric DAs. Management of DAs depends on the clinical prodrome and location of the primary tumor (Ernestus et al., 1996). Rapidly evolving clinical symptoms in the setting of a resectable tumor usually warrant prompt neurosurgical intervention. In patients with incidental diagnoses or lesions with a long history of indolent and mild symptoms, deferral of radical surgery is an option, with close MRI and clinical surveillance. If the tumor is surgically well accessible, some physicians and patients prefer a preemptive strategy with the hope of averting ultimate neoplastic transformation. Patients who show progressive neurological symptoms or MRI evidence of tumor growth require therapeutic intervention (Jallo et al., 2001). The likelihood of gross total resection of a diffuse fibrillary astrocytoma is low, especially when the tumor is located in an eloquent location such as the medulla. However, in patients with supratentorial tumors, radical resection may confer a long symptom-free interval. Chemotherapy or radiation therapy is indicated when radical resection is not feasible (Sievert and Fisher, 2009) or the tumor shows early signs of neoplastic transformation.

Fig. 52E.4 A-B, A 4-year-old girl with a several-week history of headache and a left cranial nerve VII palsy. Axial and sagittal magnetic resonance imaging (MRI) evaluation shows a dorsally exophytic mass in the medulla that is hyperintense on T2 FLAIR images. Biopsy showed the lesion to be consistent with a fibrillary (WHO grade II) astrocytoma. C, A 6-year-old boy with a several-week history of headache who subsequently developed right hand weakness along with a right-sided limp and ataxia. MRI demonstrates a diffusely infiltrating lesion of the pons that is hyperintense on T2-weighted images. Of note, the basilar artery is entirely surrounded by tumor. The lesion was noted to be strongly enhancing when contrast was administered. The radiological features of this tumor are consistent with a diffuse pontine glioma.

Prognosis

Long-term survival is possible for children with completely resected supratentorial DAs, with the notable exception of those with diffuse pontine gliomas, in whom the prognosis is poor (Jallo et al., 2004; Mauffrey, 2006). Gemistocytic astrocytoma, a variant of DA characterized by the presence of gemistocytic neoplastic astrocytes with eosinophilic cytoplasm, has a less favorable clinical course because of the propensity of these tumors to rapidly progress to higher-grade lesions such as anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV). The prognosis for focal midbrain tumors is also favorable in spite of the fact that complete resection is not possible (Hamilton et al., 1996; Stark et al., 2005). No convincing evidence of a prognostic value of molecular markers such as TP53 mutations or the proliferative index has been shown for pediatric DAs to date.

Background