Ependymomas, neuronal and mixed neuronal–glial tumors, dysembroblastic neuroepithelial tumors, pleomorphic xanthoastrocytomas, and pilocytic astrocytomas

Handbook of Clinical Neurology, Vol. 105 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 36

Ependymomas, neuronal and mixed neuronal–glial tumors, dysembroblastic neuroepithelial tumors, pleomorphic xanthoastrocytomas, and pilocytic astrocytomas HERBERT B. NEWTON,1* ROBERTA RUDA`,2 AND RICCARDO SOFFIETTI 2 Dardinger Neuro-oncology Center, Division of Neuro-oncology, Department of Neurology, The Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA

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Division of Neuro-oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy

INTRODUCTION The most common tumors in adults are high-grade astrocytomas and meningiomas, which account for approximately two-thirds or more of all newly diagnosed primary brain tumors (PBTs) each year in the USA (Newton, 1994; Louis et al., 2007). However, there are several other neuroepithelial tumors that, although less frequently diagnosed, are still clinically significant; they include ependymomas, neuronal and mixed glial– neuronal neoplasms, dysembryoblastic neuroepithelial tumors (DNETs), pleomorphic xanthoastrocytomas (PXAs), and pilocytic astrocytomas. The majority of these tumors are low to medium grade and do not behave in an aggressive fashion. However, more anaplastic and aggressive subtypes can occur. This chapter reviews the epidemiology and clinical presentation, pathology, neuroimaging, and treatment of this diverse group of brain tumors.

EPENDYMOMAS Ependymal tumors are tumors of neuroectodermal origin, arising from the ependymal cells that line the ventricles of brain and the central canal of the spinal cord. According to the World Health Organization (WHO) (Louis et al., 2007), ependymal tumors are classified as follows: myxopapillary ependymoma (grade I), occurring almost exclusively in the conus medullaris/cauda equina/filum terminale; subependymoma (grade I), a slowly growing intraventricular lesion, more commonly

asymptomatic and with a favorable prognosis; ependymoma grades II and III (anaplastic). This section focuses on intracranial ependymomas (grade II or III), as ependymomas of the spinal cord or cauda equina are described elsewhere in this volume. Ependymomas are most common in children, while rarely occurring in adults. They are the most common brain tumor in children younger than 5 years and the third most common brain tumor in patients younger than 20 years, accounting for 10% in the pediatric population. Tumors in the supratentorial compartment (50–60% of adult ependymomas, 30% of pediatric ependymomas) are most often hemispheric or occur in relationship to the third ventricle; tumors in the posterior fossa (60% of pediatric ependymomas, 40% of adult ependymomas) are medial (fourth ventricle) or lateral (cerebellopontine angle). Given the predominant location in the posterior fossa, the most common presenting symptoms and signs are due to raised intracranial pressure from obstructive hydrocephalus and cerebellar dysfunction. Symptoms include nausea, vomiting, headache, instability and lethargy (in young children), and gait disturbance. Neurological signs include increased head circumference or bulging fontanel (in young children), papilledema, ataxia, and nystagmus. Less common are lower cranial nerve palsies or torticollis, reflecting tonsillar herniation. Facial weakness, head tilt, and/or hearing loss may occur with tumors in the cerebellopontine angle. The duration of symptoms prior to diagnosis varies greatly, and ranges

*Correspondence to: Herbert B. Newton, MD FAAN, Dardinger Neuro-oncology Center, Department of Neurology, Ohio State University Medical Center, 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA. Tel: 614-293-8930, Fax: 614-293-6111, E-mail: [email protected]

552 H.B. NEWTON ET AL. from a few days to several months. Supratentorial higher in surgical series than in radiotherapy series; tumors may manifest as focal neurological deficits or overall, image-verified (MRI) gross total resection is seizures, reflecting the region of the brain infiltrated or achieved in 50–75% of patients. It can be hindered by compressed. anatomical factors, such as adherence of the tumor to the floor of the fourth ventricle, brainstem, lower cranial Pathology nerves, or major vascular structures. Reoperation following initial incomplete surgery or at tumor recurGrade II ependymoma is characterized by moderate cellurence is increasingly advocated, assuming that a comlarity, absent or rare mitoses, and lack of pleomorphism. plete resection is achievable (Healey et al., 1991; Van Key histological features are perivascular pseudoVeelen-Vincent et al., 2002; Metellus et al., 2007). There rosettes and ependymal rosettes. Four histological varare a number of reasons why gross total resection cannot iants are recognized: cellular ependymoma, papillary be accomplished at first surgery: patient in extremis ependymoma, clear cell ependymoma, and tanycytic immediately prior to surgery, imaging not matching with ependymoma. Anaplastic ependymoma (20–30%) is charfindings at operation, and expertise of the neurosurgeon. acterized by hypercellularity, pleomorphism (grade III), Currently, there is controversy regarding the optimal frequent mitoses, necrosis, and endothelial proliferations, time of second surgery after initial incomplete surgery: but the latter two criteria do not appear to be indepenShould it be as soon as possible or after a brief course dently related to prognosis. Ependymomas typically of chemotherapy? express glial fibrillary acidic protein (GFAP), especially Because a risk of CSF dissemination exists for all in pseudo-rosettes, and vimentin. The proliferation index patients with newly diagnosed ependymoma, disease is variable, and is higher when anaplastic features are staging, including craniospinal MRI and CSF cytology, present or the patient is old. The cytogenetic aberrations is mandatory following surgery. Regular surveillance differ between intracranial and spinal ependymomas, with MRI could discover asymptomatic recurrences (in but no single genetic change seems specific or prognostiup to 43% of patients with recurrence), and impact cally important so far (Gilbert et al., 2010). survival and subsequent treatment, in particular the ability to perform a reoperation with complete resection Imaging and treatment (Good et al., 2001). Several open questions related to Gadolinium-enhanced magnetic resonance imaging (MRI) follow-up remain. How often and for how long must demonstrates rather well circumscribed lesions with varysurveillance with MRI be performed? When is CSF ing degrees of contrast enhancement. Ventricular obstruccytology needed? tion or brainstem displacement and hydrocephalus are Radiotherapy is well established in the management frequent accompanying features. Supratentorial tumors of intracranial ependymomas, despite the lack of may exhibit cystic components. Intratumoral hemorrhage randomized clinical trials showing benefit and the general and extensive calcification are observed occasionally. opinion that ependymomas are relatively radioresistant, Gross infiltration of adjacent brain structures and edema without a clear dose–response relationship (Garrett and are rare. However, in supratentorial ependymomas, the Simpson, 1983; Taylor, 2004; Merchant and Fouladi, neuroradiological distinction from other glioma entities 2005). There is general consensus that postoperative radioconstitutes a diagnostic challenge. MRI appears particutherapy is part of the standard of care for patients with larly useful for determining the relationship to suranaplastic ependymoma. In the past, whole-brain radiorounding structures and invasion along the cerebrospinal therapy (WBRT) or craniospinal irradiation (CSI) have fluid (CSF) pathway and syrinx formation. been largely employed, but many recent papers have Surgery represents the most important treatment reported no improvement in outcome and/or reduction in modality for ependymomas (Ruda` et al., 2008). The frequency of CSF spread when larger treatment volumes goals of surgery are to make a histological diagnosis, have been used (Wallner et al., 1986; Vanuytsel and Brada, remove obstacles to CSF flow, and achieve a complete 1991; Vanuytsel et al., 1992; Merchant et al., 1997; Schild tumor resection. The majority of series report that comet al., 1998; Timmermann et al., 2000; Paulino, 2001; pleteness of surgical resection is significantly associated Rogers et al., 2005). Thus, localized ependymomas are with better overall and progression-free survival (Healey generally treated with limited-field radiotherapy to deliver et al., 1991; Schwartz et al., 1999; Paulino et al., 2002; doses up to 60 Gy, whereas CSI is reserved for the setting Kawabata et al., 2005; Rogers et al., 2005; Metellus of CSF dissemination. The role of radiotherapy in patients et al., 2007, 2008). In some reports, the extent of surgery with grade II ependymomas is more controversial also correlated with CSF dissemination and metastatic (Donahue and Steinfeld, 1998; Reni et al., 2004; Metellus rate (Rezai et al., 1996; Korshunov et al., 2004; Mansur et al., 2007). A number of retrospective series have et al., 2005). The frequency of complete resection is reported an advantage in terms of survival of patients

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS (mostly after incomplete resection) receiving adjuvant radiotherapy over those undergoing surgery alone (Salazar, 1983; Vanuytsel et al., 1992; Schild et al., 1998; Metellus et al., 2007), and a better local tumor control with doses above 50 Gy (Shaw et al., 1987). Moreover, a paper on posterior fossa ependymomas reported that even after gross total resection, confirmed by postoperative imaging, adjuvant radiotherapy significantly improved local control (Rogers et al., 2005). Conversely, other authors are in favor of deferring radiotherapy in patients with totally resected intracranial ependymomas until tumor progression (especially for supratentorial tumors) (Awaad et al., 1996; Hukin et al., 1998). In the absence of data from randomized clinical trials, reserving radiotherapy for recurrent disease may be an option in patients with intracranial grade II ependymoma after either total or subtotal resection, provided there is careful clinical and MRI monitoring. Stereotactic radiotherapy, by increasing the dose to the tumor (‘boost’), could overcome the radioresistance (Stafford et al., 2000; Mansur et al., 2004; Combs et al., 2006; Lo et al., 2006), but the superiority over conventional techniques remains to be proven by clinical trials. Few data are available regarding the role of chemotherapy. Chemotherapy has been employed at the time of relapse, and platinum-based regimens are considered the best available option, with response rates (31–67%) higher than those after nonplatinum-based regimens (11–13%) or nitrosourea-based regimens (25%) (Gornet et al., 1999; Brandes et al., 2005). Moreover, no significant differences regarding time to progression or overall survival have emerged among the various regimens. Anecdotal responses have been reported with irinotecan/topotecan, ifosfamide, diaziquone, idarubicin, and tamoxifen plus isotretinoin (Rojas-Marcos et al., 2003; Malkin, 2006). Temozolomide may have some role because xenograft models have documented activity of temozolomide against ependymoma (Friedman et al., 1995), and a patient with recurrent intracranial ependymoma, treated with temozolomide and in remission 10 years after completing chemotherapy, has been reported (Rehman et al., 2006). A phase II study with temozolomide in recurrent ependymoma is ongoing at the University of Turin, and preliminary results are promising (Ruda` et al., 2001).

NEURONAL AND MIXED GLIAL^ NEURONAL TUMORS Neuronal and mixed glial–neuronal tumors are composed of either a pure population of neoplastic neuronal cells, or neuronal tumor cells admixed with one or more subpopulations of neoplastic glial cells (Krouwer,

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1997). These are uncommon tumors, and as a whole comprise between 1% and 6.5% of all PBTs in adults, and up to 10% of brain tumors in children. In most cases, they are slow-growing, indolent tumors that present in children or young adults, with minimal signs and symptoms.

Gangliocytomas Gangliocytomas are tumors composed of a pure population of neoplastic neurons (Krouwer, 1997). They are rare tumors, with an estimated incidence of 0.1–0.5% across all age groups. The tumor can arise within the cerebrum, pituitary gland, hypothalamus (near the floor of the third ventricle), pineal region, brainstem, or upper spinal cord. In the cerebrum, the most common location is the temporal lobe, either as an isolated lesion, or with spread into the frontal or parietal lobes. Tumors confined to the cerebellum may also occur as dysplastic gangliocytomas (Lhermitte–Duclos disease; see below). The majority of gangliocytomas become symptomatic within the first three decades of life, with a mean of 25 years. However, there are reports of patients presenting with this tumor well into the sixth and seventh decades. Symptom duration prior to surgical intervention can be quite variable, but ranges from 3 to 4 years in the majority of patients. The most common neurological symptoms are headaches and seizures. Any type of seizure can occur, but they are most often of the complex partial variety. Other less common symptoms include nausea and emesis, visual loss, hemiparesis, and sensory deficits. Hydrocephalus may be noted in patients with tumors arising from the pineal or third ventricular regions.

PATHOLOGY Macroscopically, gangliocytomas are discrete lesions, with a clear cleavage plane at the interface with normal surrounding neural tissues (Krouwer, 1997; Shin et al., 2002; Louis et al., 2007). Regions of calcification and cyst formation may be noted. On microscopic examination, the hallmark feature is the presence of a population of well-differentiated or ‘mature’ neoplastic neuronal cells with a greater cellular density than normal surrounding brain. The neoplastic cells resemble pyramidal neurons or ‘ganglion’ cells, but have atypical features such as large vesicular nuclei, conspicuous nucleoli, abundant cytoplasm, vacuolation, dysplastic multipolar processes, and multinucleated forms. The abnormal neurons stain for synaptophysin, neurofilament epitopes, and various neuropeptides and biogenic amines (e.g., somatostatin, serotonin). These tumors are considered grade I within the current WHO classification scheme (Louis et al., 2007).

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Neuroimaging studies are clearly able to differentiate gangliocytomas from surrounding normal brain (Shin et al., 2002; Raizer and Naidich, 2007). Using computed tomography (CT), the tumor is either isodense or hyperdense in comparison to normal neural tissues, and often contains variable amounts of calcification and cyst formation. On MRI, the mass is usually hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, and may demonstrate punctate regions of calcification. On T1-weighted sequences, the tumor has a more mixed, heterogeneous appearance, with intermediate to decreased signal intensity. After contrast administration, there is usually mild to moderate heterogeneous enhancement. Surgical resection is the initial treatment of choice for gangliocytomas (Krouwer, 1997). If the tumor is accessible, a gross total resection should be performed, followed by observation. In two-thirds of gross totally resected cases, aggressive surgery will result in complete seizure control. After an incomplete resection, a conservative approach is still recommended – careful clinical observation and follow-up with serial MRI. For the majority of patients, further treatment with externalbeam radiotherapy, radiosurgical boosting, or chemotherapy will not be necessary (Krouwer, 1997; Mohile and Raizer, 2006). In the event of tumor recurrence, further resection is the preferred approach. Radiotherapy and/or chemotherapy would be appropriate to consider only for deep, inaccessible tumors with persistent recurrence and an aggressive clinical phenotype.

Dysplastic gangliocytoma (Lhermitte–Duclos disease) Dysplastic gangliocytoma of the cerebellum, or Lhermitte– Duclos disease (LDD), is a rare lesion that usually develops in a hemisphere and may extend into the midline vermis (Krouwer, 1997; Nowak and Trost, 2002). The mass typically becomes symptomatic between the third and fourth decades of life, with a mean age of approximately 35 years. However, cases have been reported in young children and adults above 70 years of age. The symptoms are chronic and have usually been present for 3–4 years before the diagnosis is made. Common symptoms include headache, visual loss, nausea and emesis, diplopia, dizziness, tinnitus, slurred speech, clumsiness, and unsteady gait. Many of the symptoms are related to raised intracranial pressure secondary to hydrocephalus. Compression or rotational displacement of the brainstem can produce less common clinical manifestations such as cranial nerve dysfunction and pyramidal tract signs. In some patients developmental lesions can also be noted, including megalencephaly,

neuronal heterotopias in the white matter, hypertrophy of the olivary nuclei, cervical syrinx, and vascular malformations (Nowak and Trost, 2002). Recent studies have linked the occurrence of LDD to Cowden’s disease, an autosomal dominant developmental syndrome that appears to be caused, at least in some families, by germline loss or mutation of the PTEN tumor suppressor gene (Krouwer, 1997; Nowak and Trost, 2002; Derrey et al., 2004; Abel et al., 2005). Some studies suggest that 40% of patients with LDD have the clinical manifestations of Cowden’s disease. However, the actual percentage of linked cases is likely to be much higher, and some authors feel that the two diseases are a single phakomatosis, with variable clinical manifestations (Nowak and Trost, 2002; Derrey et al., 2004).

PATHOLOGY On macroscopic evaluation, the lesions are firm, rubbery, and poorly circumscribed masses, lying immediately underneath the surface of the cerebellum (Krouwer, 1997; Nowak and Trost, 2002). The mass is composed of thickened and enlarged folia, with multiple foci of myelination in the outer zones, within the site of the molecular layer, with thickening of the underlying gray matter. On microscopic examination, the enlarged folia demonstrate an inner layer of abnormal ganglion cells that either replace or disrupt the normal Purkinje cell layer or internal granular cells. Within the adjacent white matter, edema and axonal swelling are present, with a variable amount of demyelination. In addition, there is an upper layer of large, abnormally myelinated, processes lying within and distending the molecular layer. The abnormal ganglion cells are composed of two subpopulations: large polygonal-shaped cells with numerous mitochondria and prominent nucleoli, and smaller cells with more hyperchromatic nuclei and fewer mitochondria. LDD are considered WHO grade I lesions within the current classification scheme (Louis et al., 2007).

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On neuroimaging studies of LDD, the mass is typically well circumscribed and easily identified (Krouwer, 1997; Kulkantrakorn et al., 1997; Nowak and Trost, 2002; Raizer and Naidich, 2007). Using MRI, T2-weighted and FLAIR sequences demonstrate a homogeneous and hyperintense mass, with a striated or ‘corduroy’ pattern. On T1 sequences, the lesion is more heterogeneous, and either isointense or hypointense in comparison to adjacent brain. The mass does not enhance after contrast administration. On CT, the mass is more ill-defined and appears hypodense, without calcification or enhancement. The preferred approach to treatment is complete surgical resection and decompression of the posterior

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS fossa (Krouwer, 1997; Nowak and Trost, 2002). In some cases, complete removal of the mass may not be possible, due to ill-defined margins. After an incomplete resection, a conservative approach is still recommended, including careful clinical observation and follow-up with serial MRI scans. Rarely, LDD can recur within the cerebellum, usually in the context of a patient who has had a subtotal resection. A permanent ventriculoperitoneal shunt may be necessary in selected patients. There is no role for radiotherapy or chemotherapy in the initial treatment of LDD (Krouwer, 1997; Mohile and Raizer, 2006). If there is recurrent growth of the mass, a re-resection should be attempted. Irradiation should be considered only for patients with persistent, recurrent disease.

Central neurocytoma Central neurocytoma is a rare tumor that has been officially recognized as a separate clinicopathological entity only since 1982 (Krouwer, 1997; Schild et al., 1997; Schmidt et al., 2004; Zhang et al., 2004). It comprises 0.1–0.5% of all PBTs, and has no gender predilection. The tumor usually presents between the third and fourth decades, with a mean of 29 years and a range that spans from 8 to 69 years (Schild et al., 1997; Schmidt et al., 2004). Central neurocytomas typically develop within the ventricular walls or septum pellucidum, with more than 50% of cases arising in the lateral ventricles adjacent to the foramen of Monro. Another 15% involve both the lateral and third ventricles, or are bilateral. On occasion, the tumor can develop within the fourth ventricle. The clinical course is usually brief (mean 3 months), because of the frequent development of obstructive hydrocephalus and raised intracranial pressure. Common symptoms include headache, nausea and emesis, visual disturbances including diplopia, loss of visual acuity, and visual field defects, and frontal lobe dysfunction, with alterations of personality, cognition, and memory. Less often, hormonal abnormalities can occur with large tumors that impinge on the pituitary gland and/or hypothalamus. Rapid clinical deterioration can be noted on occasion, in the setting of intratumoral hemorrhage or the acute onset of complete ventricular obstruction.

PATHOLOGY On gross inspection, the tumor appears as a lobulated, well-circumscribed, gray-colored mass, in the proximity of the foramen of Monro and lateral ventricles (Krouwer, 1997; Schmidt et al., 2004). Necrosis and cyst formation may be noted. The microscopic appearance is reminiscent of classical oligodendrogliomas, with the presence of a homogeneous population of uniform small

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cells with rounded to slightly lobulated nuclei and scant cytoplasm. A characteristic feature is the presence of densely packed tumor cells alternating with variably sized ‘islands’ that are relatively anuclear and contain a dense fibrillary matrix. The tumors are typically quite vascular and reveal a diffuse open branching network of vessels. Features suggestive of anaplasia (i.e., mitoses, necrosis) are uncommon. The neuronal phenotype of the tumor is consistent with the immunohistochemical profile, which is positive for synaptophysin, microtubule-associated protein 2 (MAP2), neuronal cytoskeletal proteins, and neuron-associated adhesion molecules. GFAP reactivity is variable, but is usually present in only a small fraction of tumor cells. Central neurocytoma is classified as a WHO grade II tumor in the current schema (Louis et al., 2007). A more aggressive variant of central neurocytoma has now been described, and is designated as ‘atypical central neurocytoma’ (Kuchiki et al., 2002; Schmidt et al., 2004; Louis et al., 2007). These tumors display more anaplastic features, such as regions of necrosis, microvascular hyperplasia, and increased mitotic activity. In addition, they are more likely to have a MIB-1 (mindbomb homolog-1) labeling index greater than 2%, which has been correlated in some studies with a higher recurrence rate.

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On neuroimaging studies, the tumor is usually in the region of the foramen of Monro and septum pellucidum, often in contact with the wall of one or both lateral ventricles (Krouwer, 1997; Schmidt et al., 2004; Zhang et al., 2004; Raizer and Naidich, 2007). Hydrocephalus is usually present, and can easily be documented by CT or MRI. CT demonstrates a heterogeneous, multicystic, hyperdense mass with amorphous foci of calcium. Deposits of calcium are present in 50–60% of all cases. The tumor margins are sharply demarcated from surrounding brain. Contrast enhancement is noted to a variable degree in the solid portion of the mass. On T2weighted and FLAIR MRI, the mass is either isointense or hyperintense compared with brain parenchyma, with sharply demarcated borders. Similarly, T1-weighted images also demonstrate an isointense or hyperintense mass, which displays a moderate to marked degree of enhancement after contrast administration. The initial approach to treatment for a patient with a central neurocytoma is always an aggressive surgical resection (Krouwer, 1997; Schild et al., 1997; Schmidt et al., 2004). A preoperative shunt or ventriculostomy is usually not necessary. Although several surgical techniques are available, many surgeons prefer the interhemispheric, transcollosal approach, from the nondominant side (Schmidt et al., 2004). Following a gross

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total resection, many reports suggest excellent longterm outcomes, with 5-year local control and survival rates of 100% and 80%, respectively (Schild et al., 1997). However, a more recent study from the same group at the Mayo Clinic, with longer follow-up on a larger cohort, noted less favorable results (Leenstra et al., 2007). After gross total resection, the 10-year local control rate was only 61%. Nonetheless, most authors would recommend that, after a gross total surgical resection, the patient be followed closely without further adjuvant treatment (Krouwer, 1997; Schmidt et al., 2004). This approach also applies to tumors with a more aggressive phenotype (i.e., MIB-1 labeling index > 2%). Adjuvant radiotherapy and chemotherapy should not be used if the patient has had radical tumor removal. For patients with recurrent or progressive tumors, a re-resection should be attempted initially, if feasible. If there is continued residual tumor, especially in cases with a short interval of stability or if the tumor is biologically aggressive (i.e., anaplastic features and/or a MIB-1 labeling index > 2%), conformal irradiation should be performed (Krouwer, 1997; Schild et al., 1997; Schmidt et al., 2004; Leenstra et al., 2007). A dose of at least 5400 cGy is recommended to maximize local control rates (Rades et al., 2003). In the experience of Schild and colleagues (1997), the 5-year local control rate was 100% after subtotal resection plus irradiation. In comparison, the 5-year local control rate after subtotal resection was only 50% without the use of radiotherapy (p < 0.02). Recently, some authors have begun to report the use of radiosurgery for patients with central neurocytoma who have small, residual or recurrent tumors (Anderson et al., 2001; Schmidt et al., 2004). Although the number of patients reported remains small and follow-up has been limited, the technique appears to be safe and effective at improving local control, and should be considered in selected patients. Chemotherapy has been used in only a handful of patients with progressive or recurrent central neurocytoma (Krouwer, 1997; Schmidt et al., 2004; Mohile and Raizer, 2006). However, objective responses and stabilization of disease have been noted with the use of several different chemotherapy drugs in various combinations, including carmustine, PCV (procarbazine, CCNU, vincristine), cisplatin, carboplatin, etoposide, ifosfamide, and cyclophosphamide (Brandes et al., 2000; von Koch et al., 2003; Mohile and Raizer, 2006; Leenstra et al., 2007).

Gangliogliomas Gangliogliomas are the most common mixed glial– neuronal neoplasm, and are defined by the presence of two clearly delineated histological components: atypical ganglion cells and neoplastic glial cells (Krouwer et al.,

1993; Hakim et al., 1997; Krouwer, 1997; Im et al., 2002). The incidence ranges from 0.5% to 6.25% of all PBTs in adults, and up to 10% of central nervous system (CNS) tumors in children. Although the age range can vary from very young children to elderly adults, the majority of cases present in the second and third decades of life, with a median age of approximately 20 years. Some larger series would suggest a slight male predilection for the disease. Gangliogliomas can arise anywhere within the CNS, including the spinal cord. However, the most common location is the supratentorial brain, usually within one of the temporal lobes. The duration of symptoms prior to diagnosis is often quite long (> 15 years in some patients), with a median of approximately 4 years. Seizures are the most common presenting symptom, affecting between 65% and 85% of patients (Krouwer, 1997; Im et al., 2002). Most often, partial complex seizures are noted, which is consistent with the predilection of the tumor for the temporal lobes. Symptoms related to raised intracranial pressure, such as headache, nausea and emesis, and lethargy, are uncommon due to the slow, indolent growth of these tumors. When they do occur, it is usually in the setting of a cerebellar tumor with associated hydrocephalus. Other infrequent symptoms and signs include personality changes, gait ataxia, visual loss, and focal motor deficits.

PATHOLOGY On macroscopic examination, the tumor can be solid or cystic, with foci of calcification; regions of hemorrhage and necrosis are rare. Histologically, the tumor reveals an admixture of atypical ganglion cells and gliomatous cells, similar to an astrocytoma (Krouwer et al., 1993; Krouwer, 1997; Im et al., 2002; Luyken et al., 2004). The atypical ganglion cells are unevenly distributed throughout the tumor, and display neoplastic features such as heterotopic locations, cytological pleomorphism, and nuclear atypia (e.g., binucleation). The glial component demonstrates a variable degree of hypercellularity, cellular pleomorphism, and nuclear pleomorphism. In typical tumors, signs of anaplasia are rare (e.g., mitoses, necrosis, vascular hyperplasia) within the glial component. Calcification can be noted in up to 50% of cases. Focal leptomeningeal tumor extension may be noted, but does not appear to have prognostic implications. If a cyst is present, the cyst wall is composed of non-neoplastic, compressed brain parenchyma. Neuronal markers (e.g., MAP2, synaptophysin, neurofilament protein) are positive in the atypical ganglion cell population. The most common varieties of ganglioglioma are classified as WHO grade I or II in the current system, depending on the degree of cellularity and atypia (Louis et al., 2007).

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS Anaplastic gangliogliomas are more aggressive tumors and display malignant features in the glial component of the neoplasm (Krouwer, 1997; Luyken et al., 2004). These tumors will have prominent cellular and nuclear atypia, hypercellularity, frequent mitoses, vascular proliferation, and necrosis. MIB-1 and Ki-67 labeling indices often reveal high proliferative activity (> 5%). Anaplastic gangliogliomas are classified as WHO grade III in the current system (Louis et al., 2007).

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On CT, the tumor usually presents as a cystic isodense or hypodense mass with a mural nodule (Castillo et al., 1990; Krouwer et al., 1993; Hakim et al., 1997; Krouwer, 1997; Im et al., 2002; Raizer and Naidich, 2007). Calcifications are noted within the nodule in approximately 50% of cases. Edema and mass effect are uncommon. Enhancement is negligible to mild in typical (low grade) tumors. Indentation or erosion of the inner table of the skull may be noted on bone window sequences, with large tumors involving the cortical surface. On MRI, T2weighted and FLAIR images will demonstrate a wellcircumscribed, hyperintense mass that may be solid or cystic. T1-weighted images consistently show the mass to be hypointense in comparison to surrounding brain. After contrast administration, the degree of enhancement is variable, but is often mild in typical low-grade tumors. Anaplastic gangliogliomas will often be more infiltrative on MRI, and can also demonstrate a higher degree of enhancement and peritumoral edema. Similar to other neuronal CNS tumors, surgical resection is the preferred initial treatment approach for gangliogliomas (Krouwer et al., 1993; Hakim et al., 1997; Krouwer, 1997; Im et al., 2002). Because the tumors are usually noninfiltrative and well delineated from surrounding neural tissues, gross total resection is often possible. In addition, some authors recommend intraoperative electrocorticography (IECoG) during surgery of these lesions, to allow the mapping and potential resection of seizure foci in patients with longstanding chronic epilepsy (Awad et al., 1991). The surgeon should not assume that the epileptogenic focus is within or immediately contiguous to the tumor boundaries. In the series by Awad and coworkers, the seizure focus was within the structural lesion in 23% of patients, contiguous within 2 cm of the tumor in 38% of patients, and remote or noncontiguous in the remaining cases (Awad et al., 1991). The surgical team will need to decide whether or not resection of the tumor is adequate for seizure control, or whether further resection of adjacent epileptogenic cortex will be necessary. In the study by Luyken et al. (2004), patients who had undergone complete resection had a significantly higher 7.5-year recurrence-free survival rate than

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those who had received a partial resection (99% versus 92%; p ¼ 0.027). Overall, for patients who have had a gross total resection, the 5-year survival rate is greater than 90%. Radiotherapy is not indicated for patients who have had complete tumor removal. This is supported by recent data that do not demonstrate any benefit for postoperative irradiation in patients with WHO grade I and II tumors (Luyken et al., 2004). However, other authors contend that radiotherapy can be effective at improving local control for subtotally resected, lowgrade and malignant gangliogliomas (Liauw et al., 2007). Most authors would suggest withholding adjuvant irradiation or chemotherapy, after a complete or subtotal resection, if the lesion is low grade. For persistent recurrent low-grade tumors, especially those not amenable to further surgery, and for all high-grade tumors, the use of conformal radiotherapy is indicated (Krouwer 1997; Liauw et al., 2007). For low-grade tumors, a total dose of 5400 cGy is indicated. A higher dose of approximately 6000 cGy is recommended for high-grade lesions. Similarly, chemotherapy should be considered for persistent low-grade tumors not amenable to re-resection, and for residual and recurrent high-grade lesions (Mohile and Raizer, 2006). Several case reports in children and adults suggest that chemotherapy can be of benefit in this setting, including various combinations of nitrosoureas, cis-retinoic acid, etoposide, carboplatin, and cyclophosphamide.

Cerebellar liponeurocytoma Cerebellar liponeurocytoma is a rare tumor of the cerebellum that has been recognized only recently as a specific neuropathological entity (Alkadhi et al., 2001; Amina et al., 2003; Mohile and Raizer, 2006; Louis et al., 2007). The mass typically arises within a hemisphere or the vermis of the cerebellum. The age of onset is somewhat older than central neurocytoma, with a mean of 50 (range 36–77) years. No gender predilection has been noted thus far.

PATHOLOGY On macroscopic examination, the tumor has regions of patchy bright yellow admixed with more typical soft, gray–reddish tissue (Mohile and Raizer, 2006; Louis et al., 2007). The hallmark feature on microscopic inspection is the presence of uniform small cells with scant cytoplasm and round to oval hyperchromatic nuclei intermingled with varying amounts of lipid-laden cells. The small uniform cells are similar to the ‘small blue’ cells characteristic of medulloblastoma. Anaplastic features, such as mitoses, microvascular hyperplasia, and regions

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of necrosis are rare or absent. Immunohistochemical staining for neuronal markers, including synaptophysin, MAP2, and neuron-specific enolase, are positive in the small cell and lipidic cell populations. Labeling indices with MIB-1 or Ki-67 suggest low proliferative activity, with a mean of 3%. Cerebellar liponeurocytoma is classified as a WHO grade I or II tumor in the current system (Louis et al., 2007).

IMAGING

AND TREATMENT

The tumor is usually well demarcated within the cerebellum on neuroimaging studies (Alkadhi et al., 2001; Raizer and Naidich 2007). On CT, the tumor appears hypodense to isodense compared with brain parenchyma, with scattered regions exhibiting the attenuation values of fatty tissue. After contrast administration, the tumor demonstrates a moderate amount of heterogeneous enhancement. On T2-weighted and FLAIR MRI, the mass is heterogeneous and appears slightly hyperintense compared with normal brain. The amount of peritumoral edema is quite variable. On T1-weighted images, the tumor is generally hypointense and has a clear cleavage plane, with numerous scattered foci of high signal intensity consistent with lipid. Gadolinium enhancement is typically patchy and very mild. Surgical resection is the treatment of choice for this rare tumor (Alkadhi et al., 2001; Raizer and Naidich, 2007). After a gross total resection, adjuvant treatment with irradiation or chemotherapy is not warranted. For recurrent or progressive tumors, conformal externalbeam radiotherapy should be considered. Due to the rarity of this tumor, the appropriate dose of radiation remains unclear. To date, there have not been any reports on the use of chemotherapy for patients with recurrent or progressive cerebellar liponeurocytoma.

DYSEMBRYOBLASTIC NEUROEPITHELIAL TUMORS This tumor entity was originally identified in patients who had undergone epilepsy surgery for the treatment of longstanding drug-resistant partial seizures (Prayson, 2010). It showed unusual morphological features including cortical topography, multinodular architecture, a ‘specific glioneuronal element’ with columnar structure, and foci of cortical dysplasia. Long-term follow-up demonstrated no clinical or radiological evidence of recurrence, even in patients with incomplete surgical removal. Moreover, several factors strongly suggested that these tumors might have a dysembryoplastic origin. Therefore, the term ‘dysembryoplastic neuroepithelial tumor’ (DNET) was proposed for these distinctive lesions (Daumas-Duport et al., 1988). It has been suggested that DNETs include a large spectrum of

tumors that cannot be distinguished histologically from ordinary gliomas, and that the diagnosis of such ‘nonspecific histological forms’ requires that clinical presentation and imaging features be taken into consideration (Daumas-Duport, 1993; Honavar and Janota, 1994; Daumas-Duport et al., 1999; Pasquier et al., 2002). Large variations are observed in the reported incidence of DNETs according to the surgical protocol and/or the criteria used for their diagnosis. Among all neuroepithelial tumors diagnosed in a single institution, DNETs were identified in 1.2% of the patients under 20 years of age and in 0.2% of those aged more than 20 years (Rosemberg and Vieira, 1998). Patient age at the onset of symptoms is an important diagnostic criterion. In about 90% of cases the first seizure occurs before 20 years of age. At diagnosis, the patients are often in the second or third decade of life, but detection of DNETs by imaging in children or young adults with recent-onset seizures has become more common, and these tumors are increasingly operated on in the setting of pediatric neurosurgery (Bourgeois et al., 1999; Fernandez et al., 2003; Nolan et al., 2004; Cataltepe et al., 2005; Giulioni et al., 2005). Males are more frequently affected. DNETs may be located in any part of the supratentorial cortex, but they show a predilection for the temporal lobe, preferentially involving the mesial structures (Daumas-Duport et al., 1988, 1999; Prayson and Estes, 1992; Daumas-Duport, 1993, 1995; Honavar and Janota, 1994; Degen et al., 2002; Pasquier et al., 2002; Chan et al., 2006). Patients who harbor supratentorial DNETs typically present with drug-resistant partial seizures, with or without secondary generalization and no neurological deficit (Ruda` et al., 2010). The duration of seizures prior to surgical intervention can vary from weeks to decades, leading to variability in the age of the patients at pathologic diagnosis.

Pathology DNETs may vary in size from some millimeters to several centimeters (Pasquier et al., 2002). The leptomeninges are not involved. The appearance of DNETs on cut sections may reflect the complex histoarchitecture of the lesion. The most typical feature is the viscous consistency of the glioneuronal component. This may be associated with multiple or single firmer nodules. The affected cortex is often expanded. The histological hallmark of the classical DNET is the ‘specific glioneuronal element’, characterized by columns oriented perpendicularly to the cortical surface. They are formed by bundles of axons lined by small oligodendroglia-like cells. Between these columns, neurons

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS with normal cytology appear to float in a pale eosinophilic matrix. Associated are scattered GFAP-positive stellate astrocytes. Several histological forms of DNETs have been described, but this subclassification has no clinical or therapeutic implication. In the simple form, the tumor consists of unique glioneuronal elements. In the complex form, glial nodules, which lend the tumor a characteristic multinodular architecture, are seen in association with the specific glioneuronal element. In association with the tumor, a dysplastic disorganization of the cortex may be observed in up to 80% of cases with adequate sampling (Pasquier et al., 2002; Valenti et al., 2002; Sakuta et al., 2005; Takahashi et al., 2005). Supratentorial cortical DNETs contain mature neurons. Both in the tumor itself and in the area of cortical dysplasia, the neurons may show various degrees of cytological abnormality. However, DNETs do not contain atypical neurons that resemble dysplastic ganglion cells, such as those found in gangliogliomas. The limits of the tumor most often coincide with that of the cortex. In other instances, the tumor seems also to involve the adjacent white matter. The histological diagnosis of DNETs may be difficult, particularly with limited material. It is thus important that the diagnosis of DNET be taken into consideration whenever all of the following criteria are present: (1) partial seizures with or without secondary generalization, usually beginning before the age of 20 years; (2) no progressive neurological deficit; (3) predominantly cortical topography of a supratentorial lesion, best demonstrated on MRI; and (4) no mass effect on CT or MRI, except if related to a cyst, and no peritumoral edema (DaumasDuport, 1995; Daumas-Duport et al., 1999).

Neuroimaging and treatment Cortical topography of the lesion, the absence of mass effect, and no peritumoral edema are important criteria for differentiating between DNETs and gliomas. The cortical location of the lesion is seen better on MRI than on CT. DNETs appear hyperintense on T2-weighted and hypointense or, less often, isointense on T1-weighted images. These tumors may look like macrogyri but often have a pseudocystic or multicystic appearance (DaumasDuport, 1993, 1995; Kuroiwa et al., 1995; DaumasDuport et al., 1999; Stanescu et al., 2001). Calcifications are often seen on CT, and may be voluminous. About one-third of DNETs show contrast enhancement on CT or MRI, which often appears as multiple rings rather than homogeneous enhancement (Stanescu et al., 2001; Nolan et al., 2004). Ring-shaped contrast enhancement may occur in a previously nonenhancing tumor (Stanescu et al., 2001), and increased lesion size, with or without peritumoral edema, may also be observed

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on imaging follow-up. However, in DNETs, these changes are not signs of malignant transformation but are usually due to ischemic and/or hemorrhagic changes (Ostertun et al., 1996; Daumas-Duport and Varlet, 2003; Jensen et al., 2006). DNETs are benign (Stanescu et al., 2001). Long-term clinical follow-up usually demonstrates no evidence of recurrence, even in patients with partial surgical removal. Risk factors for the development of recurrent seizures after operation at long-term follow-up were longer preoperative history of seizures and the presence of cortical dysplasia adjacent to the DNET.

PLEOMORPHIC XANTHOASTROCYTOMAS PXA is a low-grade form of astrocytic neoplasm, initially described by Kepes (1993), that usually develops within the supratentorial brain, and has a more favorable prognosis than infiltrative gliomas (Kepes, 1993; van Roost et al., 1996; Giannini et al., 1999; Christoforidis, 2007). Within the cerebrum, PXA has a predilection for the temporal lobes, but has also been described elsewhere, including other lobes of the brain, the sella turcica, cerebellum, spinal cord, and retina. The tumor is usually very superficial and associated with the leptomeninges, and has a distinct interface with surrounding brain parenchyma. Rarely, the tumor is located deep within the brain and does not have a connection with the leptomeninges. PXA is an uncommon tumor, comprising less than 1% of all astrocytic neoplasms. The age of onset is typically in the first three decades of life, with a median age of 22 years. However, a few older patients have been reported. The incidence appears to be equal between males and females. Because of its superficial location and propensity to irritate nearby cerebral cortex, the majority of patients with PXA present with seizure activity (van Roost et al., 1996; Giannini et al., 1999; Crespo-Rodriguez et al., 2007). The seizures are usually of longstanding duration, with a mean of 7–10 years. Partial complex seizures are typically noted, but other types have been described. Headache is another common symptom; additional signs of raised intracranial pressure (e.g., nausea and emesis, diplopia, somnolence) are less frequent. Focal neurological deficits (e.g., mild hemiparesis, visual loss) can occur in 35–40% of patients.

Pathology On gross inspection, PXAs often have a rubbery consistency and yellow–tan appearance. Histologically, the tumor may seem very aggressive, due to the degree of cellular pleomorphism (similar to glioblastoma) (Kepes, 1993; Giannini et al., 1999; Korshunov and Golanov,

560 H.B. NEWTON ET AL. 2001; Louis et al., 2007). The predominant cells are The molecular biology of PXAs continues to be pleomorphic astrocytes that can display tremendous elucidated. Thus far, it is clear that they have a differvariability in cell density, size, and shape from case to ent spectrum of oncogene and tumor suppressor gene case. Their distribution within the tumor is variable – abnormalities compared with more common diffuse they may be present diffusely or in a more focal astrocytomas (Giannini et al., 1999; Korshunov and pattern. The typical tumor cells are enlarged, with large Golanov 2001; Nasuha et al., 2003). There can be p53 nuclei and a copious amount of cytoplasm. The nuclei mutations; however, they are not as widespread as in often display significant atypia, including irregular diffuse astrocytomas and have a different mutational and multilobulated forms, and occasional multinucleaspectrum. Typical abnormalities, such as epidermal tion. Similar to other astrocytic tumors, the cytoplasm growth factor receptor (EGFR) and MDM2 gene amplitends to be eosinophilic and stain with GFAP. Interfication, loss or mutation of the PTEN tumor suppressor mixed with the pleomorphic astrocytes is another popugene, and allelic loss of chromosomes 9, 10, and 19q, lation of lipidized or xanthomatous cells that contain have not been identified. Some higher grade tumors lipid droplets in the cytoplasm. The droplets are usually have been noted to express significant amounts of multiple and moderate in size. These xanthomatous vascular endothelial growth factor (VEGF) and the cells also have astrocytic differentiation, because they tumor suppressor gene p27. consistently stain with GFAP within the cytoplasm around the lipid droplets. Although the presence of Imaging and treatment the xanthomatous cell component is usually prominent, PXA generally appears as a solid mass with a cystic they can be rare in some tumors, scattered among the component, without any other specific characteristics pleomorphic cell population. (van Roost et al., 1996; Christoforidis, 2007; CrespoAdmixed with the pleomorphic and xanthomatous Rodriguez et al., 2007). On CT, the tumor will appear astrocytes are other cells, including spindled forms as a discrete, mixed high- and low-density lesion with and large ganglion-like cells. When the ganglion cell relatively well-defined margins. In some cases, the population is prominent, they can be considered as tumor will be low density and rather ill-defined. CalcifiPXA with ganglionic differentiation. Most PXAs have cation may be noted, but is usually not prominent. a dense reticulin network, within the solid portions of After contrast administration, there is homogeneous the tumor and surrounding individual cells or cell enhancement of the solid components of the tumor, clusters, especially when the tumor is present in the subincluding mural nodules. On rare occasions, there may arachnoid space. Lymphocytes are often noted in the be contrast enhancement in a gyral pattern. In addition, perivascular spaces and within the tumor parenchyma. some PXAs will cause bony erosion and remodeling of Most of these are of the T-cell phenotype and may be the inner table of the skull. With MRI, T2-weighted and accompanied by plasmacytes. Eosinophilic granular FLAIR sequences usually show the cortical-based mass bodies (EGBs) are small clusters of eosinophilic, to be hyperintense in comparison with brain. However, hyaline spheroids that are often seen to aggregate there may be some variability, with occasional tumors among tumor cells. Although EGBs are not specific appearing more isointense. On T1-weighted images, the for PXA, they are helpful in differentiating this tumor lesion typically appears slightly hypointense to isointense from more aggressive neoplasms, such as giant cell compared with gray matter, with clear differentiation of glioblastoma. The majority of cells within PXAs will the solid portion and cyst. After contrast administration, stain positive for GFAP and S-100 protein (Korshunov the solid portions of the tumor, including any mural and Golanov, 2001). Many cells will also be positive nodules, demonstrate homogeneous and strong enhancefor neuronal markers such as synaptophysin and neuroment. In some cases, enhancement will be evident in the filament proteins. Some the large, bizarrely shaped, nearby leptomeninges or may have a gyriform pattern. cells will stain for both glial and neuronal markers. Rarely, superficially located solid PXAs with dense The tumor in proximity to the brain surface can spread enhancement will have a ‘dural tail’, which can easily along the subarachnoid space and into the perivascular be confused with a meningioma (Pierallini et al., 1999; (i.e., Virchow–Robin) spaces. In addition, there may be Crespo-Rodriguez et al., 2007). Regions of hemorrhage a minor degree of infiltration of the tumor into surare also rare. rounding brain, similar to low-grade infiltrating astroThe focus of initial therapy is an attempt at radical cytomas. Classical PXA is considered a WHO grade II resection of the lesion, with clean margins (van Roost tumor in the current classification scheme (Louis et al., 1996; Tonn et al., 1997; Giannini et al., 1999). et al., 2007). Tumors with more prominent anaplastic Due to the cortical location of most PXAs, proximity features, such as frequent mitoses and necrosis, should to eloquent regions of cortex may make this approach be classified as a WHO grade III neoplasm.

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS difficult in selected tumors. However, the use of functional MRI, cortical mapping techniques, and awake craniotomy will allow neurosurgeons to remove the majority of these lesions completely. In addition, the use of IECoG may be helpful to ensure removal of associated epileptogenic foci. Following gross total resection of the tumor, radiotherapy and chemotherapy are not indicated. In tumors with anaplastic features and/or a high labeling index (> 4%), adjuvant treatment with radiotherapy and chemotherapy should be considered. Conformal irradiation may be of benefit in selected patients with higher grade or recurrent tumors, although there are few published data demonstrating efficacy. Radiosurgical approaches can also be used, in addition to or instead of conventional irradiation, in selected tumors of the appropriate size (< 3.0 cm). Chemotherapy has been attempted in a few patients with PXA, using regimens such as PCV and carboplatin plus vincristine (Giannini et al., 1999; Cartmill et al., 2001; Christoforidis, 2007). Similar to other gliomas, temozolomide may also be an active agent, but studies have yet to be reported.

PILOCYTIC ASTROCYTOMAS Pilocytic astrocytomas (PAs) are a low-grade form of glioma that are most common in children and young adults (Forsyth et al., 1993; Burkhard et al., 2003; Christoforidis, 2007; Newton, 2007). They are relatively uncommon overall, comprising only 1.9% of all PBTs across all age groups, with an incidence of 0.23 cases per 100 000 person-years. However, in the pediatric age group, PAs occur more frequently and represent the most common primary CNS tumor, accounting for 23.5% of all neoplasms in a recent survey (Rickert and Paulus, 2001). In patients under the age of 20 years, PAs have an incidence of 0.57 cases per 100 000 personyears. The mean age at diagnosis is approximately 17 years, with a wide range that includes infants and adults beyond the seventh decade. Cerebellar PAs tend to be diagnosed in a younger age group (mean 9–10 years) than cerebral PAs, which have a mean age of approximately 22 years. PAs have been reported in all regions of the CNS, and tend to favor locations in or near the midline. The cerebellum is the most common location, with PAs arising either in the roof of the fourth ventricle or just off the midline within the cerebellar hemispheres. The tumor is usually well circumscribed, but in some cases may extend through the peduncle into the brainstem. Brainstem PAs typically arise within the midbrain tectum, pons, or cervicomedullary junction. Tumors of the dorsal pons and cervicomedullary junction will often have an exophytic component. Supratentorial PAs also tend to occur in

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the midline, usually along the optic nerves and chiasm, but also in other regions such as the hypothalamus and thalamus and, rarely, the medial aspects of the temporal and parietal lobes. At presentation, the signs and symptoms of PA will vary considerably depending on the location of the mass (Forsyth et al., 1993; Christoforidis, 2007; Newton, 2007). Within each location, the tumor can infiltrate and cause regional dysfunction or destruction of neural tissues, as well as mass effect on nearby structures. In addition, the tumor may cause a general increase in intracranial pressure. Tumors arising in the cerebellum usually cause raised intracranial pressure, especially when there is associated obstructive hydrocephalus. Common symptoms and signs include headache, lethargy, nausea and emesis, nystagmus, papilledema, and imbalance. Tumors in the midline will cause truncal ataxia, whereas more lateral, hemispheric lesions will present with ipsilateral dysmetria and appendicular ataxia. The mean duration of symptoms for most patients is 5.5–6 months. Rarely, the tumor can present acutely with spontaneous hemorrhage. PAs of the midbrain tectum and dorsal pons have a different presentation than more diffuse brainstem tumors, with an absence of long tract signs and cranial nerve palsies. More often, they present with raised intracranial pressure secondary to obstructive hydrocephalus. Similar to PA of the cerebellum, the mean duration of symptoms is rather prolonged, with a mean of 7 months. Tumors of the cervicomedullary junction have a similar presentation to those in the pons, with an even longer mean duration of symptoms, of approximately 2 years. PAs of the optic apparatus present with slowly progressive visual field defects, decreased acuity, and/or proptosis. Tumors of the chiasm, third ventricle, or hypothalamus can also induce endocrine deficiencies such as diabetes insipidus, the syndrome of inappropriate antidiuretic hormone release, and precocious puberty. Obstructive hydrocephalus can occasionally be caused by a large tumor affecting the third ventricle. Cerebral PAs usually present with headache, seizures, and/or focal deficits that slowly progress over 12–18 months. Leptomeningeal spread of tumor is very uncommon, affecting approximately 3% of patients with PA, with symptoms such as paraparesis, sphincter dysfunction, ataxia, seizures, and cognitive dysfunction.

Pathology On macroscopic inspection, PAs appear as wellcircumscribed, yellowish to grayish pink, and translucent masses that often contain multiple small or singular large cysts (Malik et al., 2006; Louis et al., 2007; Newton, 2007). Tumors with large cysts are usually

562 H.B. NEWTON ET AL. located in the cerebrum or cerebellum, and typically 2007). Using CT, PAs typically appear as welldemonstrate a single, solid, mural tumor nodule along demarcated cystic masses that are isodense or hypodense the cyst wall. The cyst may contain a variable amount in comparison with brain. The solid portion of the tumor of clear to yellowish fluid. Small hemorrhages or regions enhances strongly after contrast administration. On of calcification may be noted within solid portions of the T2-weighted and FLAIR MRI, PAs are hyperintense tumor. On microscopic examination, PAs exhibit two compared with brain. On T1-weighted images, the mass distinct forms: the more frequently diagnosed classical is hypointense and displays dense enhancement with con‘juvenile’ form and an ‘adult’ variant (Malik et al., trast. Most PAs do not cause significant edema or 2006; Newton, 2007). Various mixtures of these two regional mass effect. The cystic portion of the tumor is forms can also be seen. The juvenile form of PA demonwell delineated; if a mural nodule is associated with the strates a biphasic pattern in which mild to moderately cyst, it will also enhance vigorously. If the cyst wall cellular areas of elongated, fusiform unipolar and bidoes not enhance, it may be devoid of neoplastic cells. polar ‘piloid’ cells are interspersed with hypocellular, However, with any degree of cyst wall enhancement, microcystic regions. Within the pilocytic zones, the piloid neoplastic cells are likely to be present in the cyst wall cells form streams, whorls, parallel arrays, and other patlining. Although the margins of PAs are usually fairly terns (often with interdigitating processes), and often lonsharp, the tumors may exhibit some regional infiltration gitudinally sheath nearby blood vessels. Piloid cells and into normal brain. This capacity is more pronounced with their processes stain with GFAP, demonstrating their PAs of the optic apparatus, which are well known to astrocytic lineage. The amount of cellular and nuclear infiltrate and grow along the optic nerves, chiasm, and pleomorphism is mild to moderate, whereas mitoses are optic tracts. Dissemination of PAs, especially leptogenerally uncommon (i.e., fewer than one or two mitoses meningeal spread, is an uncommon finding on MRI that per high-power field). Regions of necrosis and florid has been well documented (Buschmann et al., 2003; Faria endothelial proliferation are rare. Occasional tumors will et al., 2006). display robust vascularization (5–12%). The adult variant All patients with a PA should undergo a neuroof PA does not demonstrate a biphasic pattern. Instead, surgical evaluation for potential tumor resection these tumors display more densely packed bundles of (Forsyth et al. 1993; Newton, 2007). If the mass is broad, bipolar, fibrillated cells that form monotonous, accessible, the treatment of choice is gross total resecinterweaving, intersecting patterns. The tumor cells do tion of the lesion. In the report of Forsyth and conot sheath blood vessels and have no predilection for workers, the 10-year survival rate for patients microcystic degeneration. Rosenthal fibers may be following complete resection was 100%, compared with numerous, whereas granular bodies are generally unonly 74% for those who had undergone a subtotal reseccommon. The mean age of patients with the adult variant tion or biopsy (Forsyth et al., 1993). Following a gross tends to be older than that of patients with the more total resection, adjuvant treatment with irradiation or classical juvenile form: 29.9 versus 20.3 years. PAs are chemotherapy is not indicated, and patients should be classified as WHO grade I by the current schema (Louis followed with serial MRI. Even after a subtotal resecet al., 2007). tion, most authors would recommend that careful The molecular biology of PA continues to be elucifollow-up and serial MRI was appropriate, and that furdated, and appears to be quite different from that of ther treatment should be withheld. It is well known that, higher grade astrocytomas and other gliomas (Ichimura after surgery, residual PAs can be stable for months to et al., 2004; Louis et al., 2007; Newton, 2007). PAs have years, and may even exhibit spontaneous regression. If a different oncogenic (e.g., EGFR, PDGFR, MDM2, there is evidence of progressive disease, re-resection Akt) and tumor suppressor gene (e.g., p53, PTEN) proshould be the first choice in accessible tumors, especially file from that which is commonly noted in glioblastoma when the lesion is in the cerebral hemispheres or cerebelmultiforme and other high-grade gliomas. However, lum. The role of surgery becomes more complicated for one similarity is that PAs also express high levels of PAs in delicate locations such as the optic apparatus, VEGF and its receptors, which is consistent with the brainstem, and cervicomedullary junction. Resection of vascularity noted on histological examination and tumors from the optic nerve, chiasm, and optic tracts is MRI (Leung et al., 1997). often very difficult and can result in significant loss of vision. More conservative approaches, such as decompression of the optic canal or partial tumor debulking, Imaging and treatment may be useful alternative options. Brainstem and cervicoOn neuroimaging, PAs are usually solitary lesions medullary tumors with an exophytic component can be with well circumscribed margins (Forsyth et al., 1993; partially debulked, and the patient then either followed Arslanoglu et al., 2003; Christoforidis, 2007; Newton, closely or evaluated for radiotherapy. It should be noted

EPENDYMOMAS, NEURONAL AND MIXED NEURONAL–GLIAL TUMORS 563 that tumors that arise in these locations in patients with respectively ( p ¼ 0.013). For those patients in whom neurofibromatosis type 1 can be very indolent and benign, irradiation is deemed appropriate, some authors would and should be observed carefully for a while before any recommend using stereotactically guided conformal surgical intervention is entertained. CSF diversion may techniques to minimize radiation exposure to normal be necessary in selected patients, especially those with surrounding brain structures (Saran et al., 2002). This tumors in the upper brainstem. Ventriculoperitoneal technique can also be used effectively to treat tumors shunting is the most common procedure, although endolocated in eloquent regions of the brain, with minimal scopic third ventriculocisternostomy is an alternative risk of morbidity. approach. Stereotactic radiosurgery with a linear accelerator or The role of conventional external-beam radiation gamma knife is another option for selected patients, therapy remains unclear for patients with PAs. Although including those with tumors in the brainstem (Boethius no large controlled clinical trials are available on which et al., 2002; Hadjipanayis et al., 2002). In two series to base definitive conclusions, most authors agree that totaling 56 patients, including many adults and teenradiation is not indicated for patients after a complete agers, growth control rates following radiosurgery surgical resection (Forsyth et al., 1993; Newton, 2007). ranged from 70% to 90%. Tumor shrinkage was noted These patients should be followed long-term with in many tumors on follow-up MRI. neurological examinations and CT and MRI for evidence Conventional radiation therapy should also be of recurrence. However, whether or not radiation considered for the uncommon patient with PA who therapy should be administered following a biopsy or develops leptomeningeal metastases (Mamelak et al., subtotal or partial resection remains controversial. Some 1994). The patient with symptomatic disease affecting authors have been unable to demonstrate a significant the cerebrum or cranial nerves might benefit from difference in survival between groups of patients that whole-brain treatment, whereas meningeal tumor have undergone radiation therapy versus surgical resecaffecting the lumbosacral nerve roots or cauda equina tion alone. In a study of PAs of the cerebellum, Hayostek might respond to focal spinal irradiation. and colleagues (1993) found a 10-year survival rate of On rare occasions, chemotherapy has been used 80% for 55 patients who had received postoperative for patients with aggressive, multifocal, or inaccessible radiation (27 of 55 received > 4500 cGy) versus 82% PAs (Lesser, 2001; Newton, 2007). The majority of expefor 50 patients who had undergone surgical resection rience has been in children with chiasmatic or hypothaalone. Similarly, radiation therapy, after incomplete lamic tumors. Packer and colleagues treated 13 resection of supratentorial PAs failed to demonstrate patients under 5 years of age with progressive disease improved survival over incomplete resection alone in using six 8-week cycles of actinomycin D and vincristine a number of studies, many of which contained adult (Packer et al., 1988). After a median follow-up of 4.3 patients (Forsyth et al., 1993). Conversely, other years, 9 of 13 patients had no evidence of progressive authors suggest that radiation therapy administered to disease. In a similar study of older children, six patients a total dose of 4500–6000 cGy in 180–200-cGy daily were treated with a regimen of 6-thioguanine, procarbafractions should be considered following subtotal zine, dibromodulcitol, lomustine, and vincristine (Petroremoval of tumor or at the time of recurrence (Shaw nio et al., 1991). Four of six patients had a partial et al., 1989; Janny et al., 1994). In the study by Shaw response (mean time to progression, 122 weeks or and colleagues (1989), which evaluated 41 patients with more), whereas another had stable disease (mean time pilocytic tumors, the overall survival was not signifito progression, 252.3 weeks or more). In a study of cantly different between irradiated and nonirradiated seven older children, including four with progressive groups; however, in an analysis of the subgroup of pilocytic astrocytomas, using either carboplatin 31 patients who underwent subtotal resection or biopsy, plus vincristine or thioguanine, procarbazine, lomustine, the trend in survival seemed longer in the 27 patients and vincristine, Heath and coworkers noted objective who were irradiated. Wallner and colleagues (1988) responses in two (1 partial response, 1 minor response, stated that radiation therapy should be given to all 2 stable disease) (Heath et al., 2003). The progressionpatients with incomplete resections, based on the concept free survival rate was 71%, with a median follow-up of that irradiation will be more efficacious when adminis32 months. Brown and colleagues (1993) used various tered to a smaller residual tumor volume. In a recent chemotherapy regimens to stabilize 11 patients with clinstudy of 19 patients with PA, all of whom had undergone ically aggressive PAs that had progressed after surgical incomplete resection or biopsy, radiation therapy was resection, with radiation therapy in 7 patients. Five of considered more effective when used immediately the 11 patients had radiographic improvement after versus after disease progression (Kidd et al., 2006). The therapy, 3 had stable disease, and another 3 progressed 5-year progression-free survival rate was 77% and 50% despite therapy. The overall response rate was 75%

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for either regression or stabilization of disease. However, the median time to progression following chemotherapy, regardless of response, was only 7.5 months. In a study of 12 children with progressive cerebellar pilocytic tumors, Chamberlain (1997) used daily oral etoposide. Six of the patients responded with tumor shrinkage or stabilization with a median duration of 7 months. In a series of 46 patients (median age 41 years) with progressive low-grade gliomas, Quinn and coworkers included 5 patients with pilocytic astrocytomas in a phase II trial of temozolomide (200 mg/m2 daily for 5 days, every 28 days) (Quinn et al., 2003). Three patients had a partial response and two had stable disease, with a median progression-free survival of 14 months. In a recent case report, McLaughlin and colleagues (2003) treated a patient with a progressive, refractory PA with imatinib mesylate (STI-571, Gleevec), a platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor. The patient had a transient, but significant, regression of the tumor. It is interesting to note that on pathological examination the tumor did not express a significant concentration of PDGFR. An inhibitor of epidermal growth factor receptor (EGFR), gefitinib, has also been tested against PA cells generated in short-term primary culture (Foreman et al., 2006). All five PA cell lines were inhibited by gefitinib. However, the activity of gefitinib did not correlate with the expression of EGFR.

ACKNOWLEDGMENTS The authors would like to thank Julia Shekunov and Andrew Campbell for research assistance. H.B.N. was supported in part by National Cancer Institute grant, CA 16058, and the Dardinger Neuro-Oncology Center Endowment Fund.

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