Central nervous system tumors

Handbook of Clinical Neurology, Vol. 112 (3rd series) Pediatric Neurology Part II O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 99

Central nervous system tumors JACQUES GRILL1* AND CORMAC OWENS2 Brain Tumor Program, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Villejuif, France

1

2

Department of Paediatric Oncology, Our Lady’s Children’s Hospital, Dublin, Ireland

BACKGROUND Epidemiology Central nervous system (CNS) tumors together with leukemia represent more than one half of all childhood malignant tumors. Brain tumors are the most frequently seen solid-type tumor and have the highest mortality amongst all forms of pediatric malignant tumor. For example, in the French National Register for Pediatric Solid Tumors (http://www.chu-nancy.fr/rntse) brain tumors make up one-third of all pediatric solid tumors and for the period 2000–2003 they had an annual incidence of 30 cases per million children per year. Similar figures are observed in other registries, with up to 47 cases per million children per year in the United States where benign tumors are also registered (http://www. cbtrus.org/factsheet). They also represent 20% of neurosurgical emergencies. The incidence decreases gradually with age and as a result the adjusted ratio for CNS tumors in infants is twofold that of older children. However, for the 10–14-year-old group, brain tumors are the most frequently seen type of tumor. These findings have not changed since the 1990s when magnetic resonance imaging (MRI) became widely used in clinical practice. Recently published detailed, epidemiological data relating to specific histological diagnosis using data provided by the database of the French National Brain Tumor Bank (Bauchet et al., 2009) shows that 52% of cases were gliomas, 31% were neuroectodermal or ependymal, and 5% were craniopharyngiomas. In addition, germinal tumors, meningiomas, and neurinomas each made up 3%. In terms of survival, CNS tumors are an extremely heterogeneous group of diseases with prognosis

depending on the precise location (potentially limiting surgical options) and on the histology (an important factor in terms of the efficacy of adjuvant therapy) of individual lesions. Half of all CNS tumors are glial tumors. The overall 5-year survival rate for malignant gliomas that infiltrate the brainstem is approximately 0% and for optical pathway low-grade gliomas is approximately 90%. Survival for CNS tumors improved significantly from 57% to 65%, with a risk reduction of 3% per year during the period 1983–1994 (Gatta et al., 2005). However, brain tumors represent the primary cause of death from disease in children and adolescents, malignant tumor in general being the second cause of death in this age group after accidents. With the exception of ionizing radiation and the predisposition syndromes there are very few clear-cut risk factors for the development of a brain tumor in childhood. In any case, these risk factors explain only a tiny proportion of cases. The main predisposition syndromes are listed in Table 99.1. Various epidemiological studies have investigated potential environmental risk factors, but so far have been unable to demonstrate reproducible results, and where a potential risk factor was identified the relative risk was rarely more than 2. Various risk factors have been identified: parental exposure to pesticides (Zahm and Ward, 1998), dietary exposure through the intake of nitrosamines which can be metabolized into a nitrosurea-type carcinogen (salted meat) (Dietrich et al., 2005), paternal exposure to excessive heat (saunas) in the 3 months preceding child conception (Bunin et al., 2006), the mother of the child having had a prior abortion for glial tumors (Mallol-Mesnard et al., 2008), increased birthweight for glial tumors (Von Behren et al., 2003), maternal consumption of tea or coffee (Plichart et al., 2008),

*Correspondence to: Jacques Grill, M.D., Ph.D., Brain Tumor Program, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, 114 Rue Edouard Vaillant, 94805 Villejuif, France. E-mail: [email protected]

Table 99.1 Main brain tumor predisposition syndromes Syndrome

Type of brain tumors

Transmission

Locus

Gene

Signs

Neurofibromatosis type 1

Optic pathway glioma, low-grade and high-grade astrocytomas.

Autosomal Dominant

17q11.2

NF1

Neurofibromatosis type 2

Meningioma, ependymoma, neurinoma frequently of the VIII nerve. Subependymal giant cell astrocytoma (SEGA) pilocytic astrocytoma, ependymoma.

Autosomal Dominant

22q12.2

NF2

Cafe´-au-lait spot, plexiform neurofibroma, Lish nodules, scoliosis, pseudarthrosis. Opacities of the lens, hamartomas of the retina, neurofibroma.

Autosomal Dominant

16p13 9q34

TSC1 TSC2

Von Hippel Lindau disease

Cerebellar and intramedullar hemangioblastomas

Autosomal Dominant

3p25-p26

VHL

Retinoblastoma Hereditary Ataxia - Telangiectasia

pinealoblastoma, high-grade glioma Lymphoproliferative disease

13q14

RB1

Turcot

Medulloblastoma

Lynch

High-grade glioma

Gorlin syndrome

Desmoplastic medulloblastoma, meningioma

Wermer syndrome (MEN1)

Pituitary adenoma

Tuberous Sclerosis (Bourneville)

Autosomal Recessive

11q22.3 11q21

Autosomal Dominant Autosomal Dominant Autosomal Dominant

5q21-q22

APC

various 9q22.3-q31

MMR genes PTCH

11q13

MEN1

Autosomal Dominant

Cortical tubers, achromiques spots, facial angiofibromas, epilepsy, mental retardation, retinopathy cardiac rhabdomyoma, renal angiomyolipoma. Retinal hemangioblastoma, clear cell renal cancer, neuroendocrine tumor of the pancreas. Bilateral retinoblastoma Osteosarcoma Cutaneo- mucous telangiectasias, immunodeficiency, lung telangiectasias Familial adenomatous polyposis Hereditary non-polyposis colon cancer (HNPCC) Macrocephaly, facial dysmorphism, basocellular naevi and carcinoma (adults), mandubilar cysts, costal abnormalities, uterine fibroma Parathyroı¨d adenomas, endocrines tumors of the pancreas

Rhabdoı¨d tumor predisposition syndrome Familial medulloblastomas

Rubinstein Taybi syndrome

Fanconi anemia

Cowden syndrome

Li Fraumeni syndrome

Atypical teratoı¨d and rhabdoid tumor (ATRT), schwannomas meningiomas Desmoplastic medulloblastoma

Medulloblastomas Gliomas Meningiomas Medulloblastoma Astrocytoma

Dysplastic gangliocytoma of the cerebellum (Lhermitte –Duclos) meningioma. High-grade glioma, choroı¨d plexus carcinoma, PNET

Autosomal Dominant

22q

INI 1

Rhabdoı¨d tumors outside the CNS (kidney most frequently).

Autosomal Dominant Incomplete Penetrance Sporadic

10q24.3

SUFU

Other neoplasms (brain and soft tissues)

16p13.3 22q13

CBP EP300

Autosomal Recessive

13q12-13

BRCA2

Autosomal Dominant

10q23.2

PTEN

Autosomal Dominant

17p13.1

TP53

Microcephaly Facial dysmorphism Large thumbs Skelettal malformation, hyperpigmentation, genito-urinary or cardiac malformations Multiple hamartomas, macrocephaly, oral papillomatosis, palmoplantar keratosis. Sarcoma and breast cancer in close relatives

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and exposure to antiretroviral medication during pregnancy (Benhammou et al., 2008). Mobile phones, hightension wires, and parental smoking cannot currently be considered as risk factors due to conflicting results available in the literature.

Principles of neuropathology The World Health Organization (WHO) classification was specifically developed for glial tumors presenting in adults. Due to the complexities of individual tumors across the entire spectrum of brain tumors, but especially in children, it is not always possible to classify a particular brain tumor using this classification. Due to this inability to classify pediatric tumors according to a preexisting system for adults, new entities are frequently described (Louis et al., 2007). Tumors are generally categorized according to the predominate cell type and graded appropriately from I to IV, ranging from the most benign to the more malignant. Other classification systems are used, notably that of Sainte Anne Hospital, which is based on the spatial structure of tumors, but this classification is not universally recognized (DaumasDuport et al., 2005). The complexities involved in making a diagnosis often require the use of multiple immunohistochemical markers: GFAP and Olig2 for glial tumors, synaptophysin and NeuN for neuroectodermal tumors, EMA for epithelial tumors and ependymomas, and so on. Cellular proliferation is measured according to a marker index using antibodies that target a cell cycle protein, MIB-1 or Ki-67. An index greater than 10% indicates rapid cell turnover (which correlates with a more aggressive tumor), but this value needs to be interpreted in association with the degree of tumor infiltration found in the tissue sample being analyzed. The advice of a panel of experts is frequently asked for, where there is difficulty in making a diagnosis, particularly when it comes to registering patients for a specific treatment protocol. The main tumor types described are glial tumors (astrocytomas, oligodendrogliomas, oligoastrocytomas, and ependymomas), primitive neuroectodermal tumors or PNET (medulloblastomas, pinealoblastomas, and ependymoblastomas), plexus choroid tumors (papillomas or carcinomas), craniopharyngiomas, meningiomas, sarcomas, and atypical teratoid rhabdoid tumors. Numerous other types have been described, but they are rare and should mainly be considered as alternatives in a differential diagnosis. Generally speaking the clinical presentation and the neurosurgical options are dependent on the location of the mass, and the adjuvant treatment strategies are dependent on the histological subtype of the tumor.

Principles of biology The reasons why a particular tumor develops in a patient are usually unknown and the development generally felt

to be a random process that spontaneously arises in one cell. Subsequent oncogenic events are necessary for the cell to acquire the full malignant tumor phenotype (selfrenewal, unrestricted growth, motility, etc.). According to two different, opposing theories, which were proposed more than 20 years ago, tumors originate either in a cell that has already begun to differentiate or in a communal type, undifferentiated precursor cell, i.e., a malignant tumor stem cell also called a tumor-initiating cell. The first hypothesis, proposed by Rubinstein, stipulates that tumors differ according to their location, even if they have a similar histology. In support of this theory, various biological properties have been identified that are related to the tumoral location, but independent of the histological subtype (Taylor et al., 2005; Rodriguez et al., 2008). The second theory, supported by Lucy Rorke, using the example of a PNET proposes that these tumors evolve from a more primitive cell, nowadays called a malignant tumor stem cell or an early progenitor. This latter view has been largely influenced by the theories and findings in hematological malignancies. In certain cases, a dedifferentiation can be demonstrated in vitro from a mature astrocytoma cell to a progenitor cell with stem cell properties; these cells are extremely susceptible to malignant transformation (Dufour et al., 2009). In this case, cells that are already committed to differentiation de-differentiate before malignant transformation, supporting Rubinstein’s view. Work done by numerous groups suggests that brain tumors are a hierarchical organization, with a fraction of the tumoral cells retaining stem cell properties (self-renewal, asymmetrical division, high expression of efflux pumps, unlimited growth, ability to differentiate in multiple lineage, etc.). However, one should consider stemness as a state of the tumor cell rather than a fate since under specific culture conditions stem cells can be grown from stem cell-free populations of cells. These malignant tumor stem cells have been found to be relatively resistant to conventional therapies, such as irradiation (Bao et al., 2006; Blazek et al., 2007) and chemotherapy (Liu et al., 2006). While tumoral stem cells play a significant role in the initiation and development of brain tumors, the microenvironment also has an important role (Tysnes et al., 1997). For example, in an optic pathway glioma murine model where the NF1 gene is specifically deleted in astrocytes, tumors develop only when there is a loss of heterozygosity of the NF1 gene in the cerebral microenvironment, i.e., in the background of an NF1þ/ mouse (Bajenaru et al., 2003). In this regard, the developing CNS in children is under the influence of numerous growth factors, particularly in infancy, and this may explain the extreme aggressiveness seen in brain tumors of the very young. With increasing regularity, the biological makeup of individual tumors is used in making diagnoses and

CENTRAL NERVOUS SYSTEM TUMORS

Fig. 99.1. Fluorescence in situ hybridization. Two fluorescent probes are used, the green labeling the centromere of chromosome 7 and the red one labeling the EGFR gene. High degree of amplification of the gene is shown here in a child with gliomatosis cerebri.

gives information on prognosis, even though histology continues to be the dominant factor considered. The various techniques used include: ●

●

●

Fluorescent in situ hybridization (FISH), which can be used to search for chromosomal losses or gains and chromosomal amplification or deletion. It uses probes specific for a given chromosomal segment (Fig. 99.1). Comparative genomic hybridization (CGH) by microarray, which is no longer a pure research tool, for the analysis of the entire genome, looking for chromosomal imbalances. It is now frequently used to classify risk groups among medulloblastoma. The search for specific oncogenetic mutations, such as the beta-catenin mutation seen in certain medulloblastomas, the V600E mutation of the BRAF gene in gangliogliomas, or the hSNF5/INI-1 gene in atypical teratoid rhabdoid tumors (ATRT).

In summary, improved understanding of the signaling pathways involved in the evolution of these tumors will permit the development of targeted therapies aimed at blocking the cellular functions that govern cell survival and proliferation. The targeted therapeutic approaches for different tumor types are discussed in the text pertaining to each individual tumor.

Principles of radiology MRI has now become indispensable in diagnosing and evaluating brain or spinal tumors. Certain lesions are visualized poorly when using computed tomography (CT) as they are difficult to differentiate from normal brain

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Fig. 99.2. Tractography in a child with a tumor lining the optic tract. Courtesy of Pr Nathalie Boddaert, Neuroradiology, Necker Hospital, Paris.

parenchyma, although the majority can be readily identified using this technique. CT imaging continues to be an important diagnostic tool as it is easier to perform, generally without the need for sedation or anesthesia. In addition, we can obtain information that is not available with MRI, such as detecting the presence of calcification in craniopharyngiomas or identifying that a lesion is hyperdense when compared to the normal parenchyma, suggesting that the lesion may be malignant. Various MRI sequences can be used to evaluate lesions such as diffusion sequences, used in preoperative assessment to identify nervous tracts abutting the tumor (Nimsky et al., 2006) (Fig. 99.2) or perfusion and permeability sequences used to determine the aggressiveness of the tumor (Law et al., 2008) (Fig. 99.3). MRI spectroscopy is used to analyze metabolites in cerebral tissue (choline, N-acetyl-aspartate, creatine, and lipids). Different metabolite profiles can suggest a preoperative diagnosis (Harris et al., 2007) or can help in the evaluating the response to treatment of a tumor (Dyke et al., 2007). It should be noted that these techniques remain the preserve of specialist centers. Angiography is used only in the case of a hypervascular tumor that is amenable to embolization (choroid plexus carcinomas, hemangioblastomas, or meningiomas).

Initial management Making the diagnosis of a brain tumor in children is frequently extremely difficult and the median delay is usually several months. In Edgeworth’s study performed in the UK in 1996, the delay was 20 weeks (Edgeworth et al., 1996). If the symptoms are taken together they often suggest the diagnosis, but they are generally not constant or progressive. Most commonly the signs are

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Fig. 99.3. Perfusion (left) and permeability (right) analysis after resection of a high grade glioma in a 14 year old child. Perfusion/ Permability maps are coregistered with morphological MRI (T1 + gado) with a single T2* dynamic sequence (see Meyzer et al., Radiat Oncol 2010, 5: 9.). The arrows shows a possible residue of active tumor (red) not clearly seen on the T1 + gado sequence.

psychological or gastrointestinal. A false diagnosis of migraine is made in more than a third of cases where the child presents with headaches. Where there is a progressive increase in the frequency and intensity of headaches, with a nocturnal pattern which may wake the child, and if they are not very responsive to analgesia, a diagnosis of tumor should be considered, all the more so if headaches are associated with other symptoms. A recent meta-analysis by the Nottingham team (Wilne et al., 2007) has shown that the most frequent symptoms/signs seen are: headaches (33%), nausea and vomiting (32%), problems with balance and coordination (27%), and papilledema (17%). In infants and young children the most common sign identified is an increase in head circumference (41%). Back pain, scoliosis, isolated limb weakness, or sphincter problems suggest a spinal tumor. An increase or loss of weight, an increase in head circumference, growth problems, visual difficulties, or precocious puberty are uncommon signs and should be investigated to rule out a tumoral cause. Once the diagnosis of a brain tumor has been made (9 times out of 10 a CT scan is all that is required to make the diagnosis) the child should be rapidly transferred to a neurosurgical unit, due to the risk of sudden deterioration. A medically supervised transfer should be organized where the presentation is associated with convulsions, symptomatic hydrocephalus, and signs of meningism or impaired consciousness. Where there are signs of raised intracranial pressure (ICP), it is important to maintain a sufficient blood pressure, to avoid stress, and to counteract the effects of the increased pressure by providing

supplementary oxygen, a degree of head elevation, and anti-edematous treatment, such as corticotherapy or a mannitol infusion where required. It is impossible to predict how quickly the signs of raised ICP will progress, but the goal should be to transfer the patient as quickly as possible. In infants the evolution of symptoms may be slower and hydrocephalus may only be indentified on the CT scan. Where the evolution of symptoms/signs is comparatively slow, suggesting a benign lesion, it is still important to transfer these patients promptly as they may have cystic lesions that could cause a rapid decompensation, resulting in coning of the cerebrum or amygdala.

POSTERIOR FOSSA TUMORS Posterior fossa tumors are most commonly detected (in 75%) due to the presence of signs of raised ICP – headaches, vomiting, and more rarely convulsions. Increased ICP in these cases develops due to an obstructive hydrocephalus, caused by a blockage of the fourth ventricle. Papilledema is not always present. Difficulty walking in the context of a cerebellar syndrome is often noted (60% of cases). Cranial nerve deficits or motor impairment indicate brainstem involvement. A general clinical deterioration may be present with dehydration due to recurrent vomiting and anorexia. Frequently (a third of cases), the diagnosis is delayed due to the erroneous assumption that the signs are due to a psychological problem.

CENTRAL NERVOUS SYSTEM TUMORS

Cerebellar pilocytic astrocytomas EPIDEMIOLOGY They represent approximately 10–15% of all brain tumors and 25–35% of pediatric posterior fossa tumors. The median age at diagnosis is 8 years, slightly older than the median age for other posterior fossa tumors.

PARTICULAR SYMPTOMS AND SIGNS AT PRESENTATION The diagnosis is sometimes made with the detection of neck pain, torticollis, or vertigo.

DIAGNOSIS On CT these lesions appear typically as cystic, hemispheric, and hypodense lesions which lack the imaging characteristics of malignant lesion. In general there is a nodular or “fleshy” component at the periphery of the cyst. Obstructive hydrocephalus may be present if the fourth ventricle or aqueduct is compressed. Tonsillar herniation constitutes an emergency and warrants urgent neurosurgical intervention. There is an intense uptake of contrast of the nodular component, but not always of the cystic wall. MRI is better at evaluating the limits of the lesion and its relationship with the fourth ventricle, cerebellar peduncle, and vermis. Lesions that partially involve the brainstem are referred to as transitional and do not generally have as good a prognosis as lesions that are entirely hemispheric (Pencalet et al., 1999).

PROGNOSIS AND QUALITY OF LIFE The risk of a local relapse is < 10% in cases of complete resection and almost 30% where the surgery was incomplete. Brainstem infiltration, often the cause of an incomplete resection, is the single most important risk factor in terms of progression-free survival (Pencalet et al., 1999; Due-Tonnessen et al., 2002). Residual tumor tissue may be the site of future relapse (Due-Tonnessen et al., 2002). Almost 90% of patients have a normal level of functioning, although moderate deficits are present in almost 20% of patients (Due-Tonnessen et al., 2002; Callu et al., 2009). A recent north-American study demonstrated an increased risk of cognitive and adaptive impairment in children treated for a cerebellar astrocytoma without showing that the site of tumor had an impact (Beebe et al., 2005). The long-term outlook for these patients is not without its problems as the majority of these patients have an impaired quality of life when compared to controls, particularly where social interaction is concerned (Pompili et al., 2002).

HISTOPATHOLOGY AND BIOLOGY The histological analysis is usually quite typical, with a biphasic appearance of lax microcystic glial tissue and a more compact component containing Rosenthal fibers. Although vascular proliferation may be present, there are no other signs of malignancy (Louis et al., 2007). The immunohistochemistry shows strong GFAP staining. The presence of an MIB-1 index > 5% suggests a more aggressive behavior (Bowers et al., 2003). Up until recently little was known of the oncogenetic pathways involved in these tumors, but several CGH microarray studies have demonstrated the duplication of the BRAF oncogene, which could become a therapeutic target (Bar et al., 2008; Pfister et al., 2008).

TREATMENT Generally these lesions are not found in the fourth ventricle, but they can compress it. In cases of tonsillar herniation, brainstem compression, or impaired consciousness, an urgent neurosurgical intervention is required. This may be either a ventriculocisternostomy or the insertion of an external ventricular drain before definitive surgery. In certain cases with the intention of relieving pressure,

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drainage of a posterior fossa cyst may be considered. In general anti-edematous medications are ineffective. The goal of surgery is the complete resection of the tumor, even if a second intervention is necessary to complete the clearance. Adjuvant therapy (chemotherapy for children younger than 10 years of age and radiotherapy for older children) is indicated only in cases where the surgeon is unable to resect the lesion completely.

Medulloblastoma EPIDEMIOLOGY Medulloblastomas are the most common form of brain tumor seen in children, comprising almost 25% of all CNS malignant tumors before the age of 15 years. This tumor may present at any age (birth up until adulthood), but the majority are diagnosed between 5 and 10 years of age. Most series report a male predominance of 2:1. Most cases are sporadic, although familial cases have been described, most notably in the context of Gorlin syndrome (see below).

SYMPTOMS AND SIGNS AT PRESENTATION In infants, medulloblastomas generally present with psychomotor regression, which can be present several months before other signs of a posterior fossa tumor are noted. Asking the parents about the maximum level of development attained by the child often reveals premorbid developmental retardation (Ashley et al., 2008). Clinical observations and animal models of medulloblastomas suggest that this type of tumor develops due to an anomaly in cerebellar embryogenesis (see below). An increase in head circumference is often

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noted in infants. In older children, the most frequent symptoms are vomiting, headaches, and changes in behavior, especially at school (Brasme et al., 2012).The presenting features may be those of meningism and this is strongly suggestive of a metastatic presentation. NonCNS metastases in brain tumors are extremely rare, and are really found only in cases of medulloblastoma. They usually present with bone pain, due to bone marrow infiltration. Diagnostic delay is highly variable and not linked to the patient’s age. In a recent population-based study in the region of Paris, we found a median delay between first signs and diagnosis of 65 days (interquartile range 31–121 days), which was significantly longer in children presenting with psychological symptoms (Brasme et al., 2012).

DIAGNOSIS CT imaging reveals a hyperdense tumor, with calcification in only 10% of cases. There may be a cystic component, but much less frequently than in cases of pilocytic astrocytoma. There is generally a marked and homogeneous uptake of contrast. Hydrocephalus is present in more than 90% of the cases. MRI is better at evaluating tumor extension, in particular the relationship between the tumor and the foramen of Lushka, and in detecting metastases (Fig. 99.4). Before surgery it is imperative to image both the cerebrum and the entire spine and spinal cord. T2 sequences can be very helpful when there is heterogeneous contrast uptake, particularly when assessing potential brainstem involvement. Disease extension is classified using the Chang system, which takes into account the local extension and the site of the metastases. This classification system was initially described in 1959, before the advent of CT or MRI. More recently, a classification system for metastatic disease based on the imaging characteristics of the metastases has been developed (Dufour et al., 2012). Nodular metastases have a better prognosis than linear lesions.

HISTOPATHOLOGY AND BIOLOGY In 1925, Bailey and Cushing gave these tumors the name medulloblastoma because the tumoral cells resembled developing neural tube cells. Eighty years later this hypothesis was confirmed (Singh et al., 2003, 2004; Sch€ uller et al., 2008; Yang et al., 2008). In 1985, Lucy Rorke included these tumors in the PNET category. In the last WHO classification (Louis et al., 2007), three subtypes of medulloblastoma were identified. The nodular/desmoplastic subtype has the best prognosis and is associated with neuronal differentiation nodules separated by undifferentiated zones with a raised index of

Fig. 99.4. Cranial MRI workout of a medulloblastoma in a 4 year old child. Tumor is evidenced as a posterior fossa mass obstructing the 4th ventricule with contrast enhancement on the T1 + gado sequence (upper left panel), the signal is similar to the one of the cerebellar cortex on T1 and on T2 (upper right panel) indicating a high cellularity on the contrary to pilocytic astrocytomas, the sagittal T2 sequence (lower left panel) shows the close relationship with the brainstem and the enlargement of the Sylvius aqueduct and third ventricule. After surgery, flow through the Sylvius is restored as shown on the sagittal T2 sequence (lower right panel), but the vermis is damaged.

proliferation and a reticulin network. Extensive nodularity can be seen in the very young (Giangaspero et al., 1999). This subtype is seen in 15–20% of cases, and generally in children younger than 3 years of age. The anaplastic/large cell subtype has the worst prognosis, but represents only a small proportion of medulloblastomas, around 10%. It can present at any age. The most common subtype is the standard form, found in 70% of cases. Using the genomic profile of medulloblastomas it is possible to identify five biologically distinct subtypes, each of which is characterized by a specific signaling pathway that plays a role in cerebellar development (Kool et al., 2008). The first group is characterized by a mutation in the beta-catenin oncogene, a monosomy 6 and an activation of the Wnt signaling pathway. The histological aspect of this group is of the standard subtype, although there is also a nuclear accumulation of the mutated beta-catenin protein which can be detected by immunohistochemistry. The prognosis of this subgroup is excellent (Ellison et al., 2005; Fattet et al., 2009). The second group is characterized by the PTCH1 or SUFU gene, a loss of the long arm of chromosome 9 and an activation of the Sonic Hedgehog pathway. This group corresponds with the

CENTRAL NERVOUS SYSTEM TUMORS desmoplastic histological form (McManamy et al., 2007). The other groups are less well defined biologically. They overexpress genes involved in neuronal differentiation or photoreceptor genes, and they are associated with anomalies of chromosome 17, such as an isochromosome 17q. They are more frequently metastatic at presentation. The amplification of the oncogene c-myc (or alternatively N-myc and L-myc) is strongly associated with the anaplastic/large cell subtype with a poor prognosis as a result.

TREATMENT The initial management consists of treating the hydrocephalus either by performing a ventriculocisternostomy (Fig. 99.5) several days before the definitive surgery (Sainte-Rose et al., 2001) or by insertion of an external ventricular drain directly prior to resection of the tumor. The benefits of the former are that it allows the posterior fossa to decompress, thereby limiting the peri- and

Monro

Ballon

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postoperative complications (Grill et al., 2004). Apart from certain cases, such as large, infiltrating tumors and metastatic disease, or when chemotherapy is indicated to reduce tumor bulk preoperatively (Grill et al., 2005c), surgical excision of the tumor is the first component of the treatment. It is extremely important to perform as extensive a resection as possible, particularly in younger children, as a complete resection in their case may avoid the need to use radiotherapy (Grill et al., 2005a; Rutkowski et al., 2005). In older children, a subtotal resection does not change the treatment program. It is essential to evaluate the extent of resection with imaging within 72 hours of the operation to avoid difficulties in interpreting a potential residue due to postoperative inflammation. Adjuvant therapy is based on the completeness of resection and the presence or not of metastases. Biological risk factors are increasingly used to stratify the treatment options. High-risk forms are treated with intensive chemotherapy and high-dose craniospinal irradiation (Gajjar et al., 2006; Grill et al.,

Landmarks

!

Fig. 99.5. Ventriculocisternostomy. The endoscope is introduced through one of the lateral horn of the ventricule and directed towards the foramen of Monro (upper left panel), mammilar bodies indicate the landmarks of floor of the third ventricule (upper right panel), the ballon is introduced in the puncture of the floor and inflated (lower left panel), and at the end of procedure, one can see the basilar artery just below the hole (lower right panel). Courtesy of Pr Christian Sainte-Rose, Neurosurgery, Necker Hospital, Paris.

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2006), whereas less high-risk forms are treated with chemotherapy and reduced-dose craniospinal irradiation (Packer et al., 2006). Due to the significant medium-term sequelae seen in children treated with chemotherapy and radiotherapy (Bull et al., 2007), the French study group successfully tested a treatment strategy based on hyperfractionating the radiotherapy without chemotherapy in older children with localized disease (Carrie et al., 2009); the neuropsychological outcome seems to be less impaired than in the other treatment strategies.

PROGNOSIS AND QUALITY OF LIFE Today, approximately 70% of localized forms and 50% of metastatic forms can be cured. Poor prognostic factors are: young age, incomplete resection, and the presence of metastases, including isolated CSF extension (Zeltzer et al., 1999; Sanders et al., 2008). In the studies using “sandwich” chemotherapy, that is administering the chemotherapy between the surgery and radiotherapy for high-risk medulloblastomas, the response to chemotherapy was shown to have a strong impact on progressionfree survival (Dufour et al., 2012). It is important to note that not all histological and biological characteristics proposed as features of good prognosis are universally accepted (Entz-Werle et al., 2008). Nevertheless, generally accepted factors of good prognosis include: desmoplastic histology (Rutkowski et al., 2005, 2010; McManamy et al., 2007) and the nuclear expression of beta-catenin (Ellison et al., 2005). The amplification of the c-myc oncogene (Scheurlen et al., 1998) is a biological marker of poor prognosis and the anaplastic/large cell subtype is a histological marker of poor prognosis (Giangaspero et al., 2006). These biological risk factors are frequently more important in terms of prognosis than standard clinical risk factors and should therefore be systematically analyzed, preferably on tumor tissue frozen at the time of resection. After treatment, the most important problems are generally cognitive and endocrine in origin. Risk factors for a significant degree of impairment after treatment are: young age at diagnosis (Suc et al., 1990), hydrocephalus at diagnosis (Grill et al., 2004; Merchant et al., 2004), postoperative complications such as classical akinetic mutism (Kao et al., 1994; Wells et al., 2008), the total dose of craniospinal irradiation received (Mulhern et al., 1998; Kieffer-Renaux et al., 2000), the administration of concomitant chemotherapy, particularly high-dose chemotherapy (Fouladi et al., 2004; Bull et al., 2007), cerebellar structure injury (Grill et al., 2004; Von Hoff et al., 2008; Puget et al., 2009a) (Fig. 99.6), and poor socioeconomic status of the parents (Beaugrand et al., 2009). Intelligence as measured by IQ decreases with time and is dependent on the treatment therapies and the

Fig. 99.6. Postoperative sequelae of a medulloblastoma. The arrows shows the hypersignal lining the dentate nuclei. This correspond the gliotic reaction after ischemic injury during surgery and is visible after several months/years after surgery. Note the artefact caused by a magnetic ventriculo-peritoneal shunt, hampering the analysis of the posterior fossa with MRI.

degree of residual cerebellar syndrome (KiefferRenaux et al., 2000).

Ependymomas EPIDEMIOLOGY Ependymomas are the third most frequently seen brain tumor in children. They are most often located in the posterior fossa, but they may also be supratentorial or spinal; the latter form is generally found only in adolescents or adults. The median age at presentation is 5 years. Extremely rare familial forms have been described.

SYMPTOMS AND SIGNS AT DIAGNOSIS As these tumors are most commonly encountered in young children they tend to present with nonspecific symptoms such as lethargy, irritability, and withdrawal. Torticollis is a frequent presentation sign, due to the tumor’s propensity to infiltration toward the foramen of Magendie and the foramen magnum. Radiologically these tumors are often isodense with the normal cerebellar cortex. They are often found to propagate toward the foramen of Lushka, the cerebellopontine angle, the foramen magnum, and the spinal cord. Contrast uptake is less homogeneous and more linear than when compared

CENTRAL NERVOUS SYSTEM TUMORS with medulloblastomas. Some parts of the tumor may not demonstrate any contrast uptake and are better seen using MRI T2 and FLAIR sequences. Initial spinal imaging is generally normal as metastatic disease at diagnosis is rare.

HISTOPATHOLOGY AND BIOLOGY Histologically these tumors are characterized by the presence of ependymal rosettes, they are GFAP (a glial marker) positive, and the cellular cytoplasm is positive in dots for EMA (epithelial membrane antigen). According to the WHO classification, there are two different entities. A differentiated form, which is classified as grade 2 and an anaplastic form, which is classified as grade 3 (Louis et al., 2007). The prognostic impact of the grading is debatable, even if it has been proven useful in older children in some studies. Another variant discussed in the literature, which is of particular interest, is the clear cell subtype. This is almost always found in a supratentorial location, extra-CNS metastases are not infrequent, and it is associated with specific genetic anomalies: a loss of 18q and a gain of 19q (Fouladi et al., 2003a; Rousseau et al., 2007). The oncogenesis of these tumors is becoming increasingly better understood and it is apparent that the Notch signaling pathway, which has an important role in the development of the CNS during embryogenesis, plays an integral role in the development of these tumors (Taylor et al., 2005; Modena et al., 2006; Puget et al., 2009b). It is also clear that the biology of the supratentorial/spinal tumors is quite different from those that are located in the posterior fossa, even if they are indistinguishable from a histological point of view (Taylor et al., 2005; Andreiuolo et al., 2010b).

TREATMENT Complete resection of the tumor is the mainstay of treatment, and should always be the goal, even if it requires several procedures. In nearly 50% of cases complete resection is not possible, and the risk of relapse is extremely high despite adjuvant therapies. Radiotherapy is the only really effective adjuvant treatment, although chemotherapy has been shown to be effective in certain forms of the disease, notably in children younger than 5 years of age (Grill et al., 2001; Grundy et al., 2007). Some groups even suggest that for completely excised, grade 2, supratentorial ependymomas no adjuvant therapy is required (Palma et al., 2000). The minimum dose of radiotherapy that needs to be administered to the tumor bed is 54 Gy over 6 weeks. Recent studies have demonstrated the futility of administering prophylactic craniospinal irradiation in the absence of metastases or of even extending the tumor bed irradiation to the entire posterior fossa (Paulino, 2001; Merchant et al., 2004).

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Treatment for patients who relapse, as commonly seen in cases where there was an incomplete resection, generally consists of further surgery and re-irradiation where possible (Merchant et al., 2008). Very few chemotherapeutic agents have been shown to be effective in treating ependymomas (Grill et al., 2003). The most effective appears to be etoposide, administered orally in small doses (Sandri et al., 2005), and the most effective combination is the association of vincristine, cyclophosphamide, and etoposide (Massimino et al., 2004).

PROGNOSIS AND QUALITY OF LIFE It is extremely difficult to analyze treatment efficacy and prognostic factors in ependymomas, as there is only one small randomized study in the literature. In addition the WHO classification for these tumors lacks definitive diagnostic criteria and reproducibility. Given the understandable reluctance to use radiotherapy in young children, there is a significant risk of relapse, with a progression-free survival at 5 years in these patients of 20–40% (Grill et al., 2001; Grundy et al., 2007; McGuire et al., 2009a). In contrast, when radiotherapy is administered as part of first-line treatment, there is a good level of disease control (Massimino et al., 2006). The best available results published demonstrate a progression-free survival at 5 years of 50–60% (Massimino et al., 2004; Merchant et al., 2004). Supratentorial tumors have been shown to be associated with a better prognosis in some studies (Grill et al., 2001; McGuire et al., 2009b). Metastases at diagnosis correlate with a much poorer outcome (Zacharoulis et al., 2008). Several new biological factors have been found to be associated with a poor prognosis: telomere maintenance and telomerase expression (Tabori et al., 2006b, 2008), the loss of nucleolin expression (Ridley et al., 2008), a high Ki67 index (Preusser et al., 2008), the overexpression of the epidermal growth factor (EGF) receptor and a gain of chromosome 1q (Mendrzyk et al., 2006), and the overexpression of tenascin-C (Korshunov et al., 2000; Andreiuolo et al., 2010a). These studies, however, require confirmation. Neurological and cognitive sequelae are dependent on the extent of surgical damage required to obtain a complete resection (van Veelen-Vincent et al., 2002; von Hoff et al., 2008). Other risk factors for cognitive deficits include: young age (von Hoff et al., 2008) and the presence of hydrocephalus at diagnosis (Merchant et al., 2004; Conklin et al., 2008; von Hoff et al., 2008). It appears that radiotherapy alone does not in itself cause major sequelae; IQ remains constant when compared before and after therapy (Kieffer-Renaux et al., 2005; von Hoff et al., 2008).

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Brainstem glioma EPIDEMIOLOGY AND DIAGNOSIS Brainstem gliomas represent 15–20% of all posterior fossa tumors. It is important to ascertain the rapidity with which symptoms appear and progress. Tumors that evolve quickly over a couple of months (between the first signs and diagnosis) are more likely to be malignant in nature. These tumors are generally classed in two surgical groups: the first are those tumors that are infiltrating and inoperable; the second are those that are exophytic and potentially operable. Radiologically there are four groups. Type 1 are diffuse, infiltrating, hypodense on CT imaging, “hypointense” on T1 sequences, and “hyperintense” on T2 MRI sequences (Fig. 99.7). Rarely, there is ring of contrast uptake. Type 2 has similar features, but is more localized. Type 3 is generally exophytique and protrudes posteriorly. There is an intense uptake of contrast and they often have a cystic appearance. The fourth type are bulbocervical. Some 40% of brainstem tumors are type 1. They are generally malignant, apart from bulbocervical or tectal plate tumors which most often tend to be pilocytic astrocytomas (Ternier et al., 2006). The diffuse, infiltrating types tend to evolve rapidly and they are diagnosed on the basis of imaging and evolution. The biological knowledge of these tumors comes only from autopsy cases, implicating the platelet-derived growth factor receptor (PDGFR) pathway (Zarghooni et al., 2010). They tend to be biopsied only if the presentation is atypical, or for the purpose of testing the suitability of therapeutic targets which may be offered in the context of a research protocol (Roujeau et al., 2007). For the remainder of tumor types, the diagnosis requires tissue confirmation.

TREATMENT AND PROGNOSIS Management is dependent on the type of tumor. The only treatment available for the diffuse type is radiotherapy at a dose of 54 Gy. None of the studies performed that attempted to improve outcomes by combining radiotherapy with additional forms of treatment has shown any benefit (Hargrave et al., 2006). Many teams have begun to study the potential of targeted therapies in these tumors, but to date no adjuvant treatment has shown any benefit. Median survival is 9 months, and very few children are still alive 2 years after the diagnosis is made. As the tumors progress the children generally develop complete motor palsy including cranial nerves and neurovegetative disturbances (bladder dysfunction), without loss of consciousness unless the fourth ventricle is obstructed resulting in hydrocephalus. Treatment of exophytic tumors is dependent on surgery. In general they are low-grade, glial-type tumors.

Fig. 99.7. Different MRI aspects of diffuse intrinsic pontine gliomas (type 1). A ring-like contrast enhancing part within a non-enhancing mass can be seen on the T1 + gado sequence (upper left panel). Usually, there is a massive enlargement of almost the entire pons; the extension through the cerebellar peduncles is frequently seen on FLAIR sequences (upper right panel). Sometimes the tumor is clearly in hyposignal on T1 images and may involve only part of the pons anteriorily with engulfment of the basilar artery (lower left panel) or posteriorily in the fourth ventricule (lower right panel).

Pilocytic astrocytomas have a better prognosis than gangliogliomas, which tend to be infiltrating and are rarely completely resectable (Baussard et al., 2007). Where resection is incomplete and the tumor has progressed, chemotherapy can be offered to the young and radiotherapy to older children. The prognosis is fair but there is a risk of malignant transformation.

Other diagnoses LHERMITTE–DUCLOS DISEASE This is a rare, benign condition of uncertain origin, which is characterized by disorganization of the cerebellar architecture; it is sometimes referred to as a gangliocytoma even though there is ongoing controversy as to whether it is a neoplastic lesion, a malformation, or a hamartoma (Lhermitte and Duclos, 1920). It can be found as part of Cowden syndrome – multiple hamartoma neoplasia syndrome (Pe´rez-Nu´n˜ez et al., 2004) – where there is a mutation of the gene suppressor PTEN, which has a direct action on the mTOR signaling

CENTRAL NERVOUS SYSTEM TUMORS pathway (Rosner et al., 2008). The cerebellum, as seen with MRI, has a striped or broad, leafy pattern. Functional MRI demonstrates a decrease in diffusion consistent with a hypercellular lesion and an increased vascular index without alteration of the blood–brain barrier (no contrast uptake) (Cianfoni et al., 2008). This lesion may also be the site of development for other tumors, such as a ganglioglioma (Takei et al., 2007).

Hemangioblastoma This vascular, cystic lesion is frequently associated with von Hippel–Lindau disease and the cerebellum is one of the most common locations where it may develop. Hemangioblastomas are often not detected until adulthood. They appear as cystic lesions with a nodule of extremely strong contrast enhancement. As part of the diagnostic workup for this tumor it is necessary to rule out a second renal or retinal tumor. It is due to the eponymous gene, for which there is a targeted therapy (Kaelin, 2008). A national register has been established by the National Cancer Institute (Richard et al., 2007).

CEREBRAL TUMORS Thalamic tumors There is little in the literature on tumors of the thalamus in children, with the largest studies enrolling fewer than 30 patients over an extended period. The most common symptoms are motor deficits and those related to intracranial hypertension. The presence of tremor is rare at diagnosis. Thalamic tumors are generally divided into three groups, depending on location: unilateral thalamic lesions (75%), thalamo-peduncular (10%), and bilateral lesions

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(15%) (Puget et al., 2007a). Analysis of studies performed shows that a slower evolution of symptoms (more than 2 months), presence of a cystic component, low-grade histology, and at least a 90% resection are all associated with better progression-free survival. Extension to the contralateral thalamus is considered as a factor of poor prognosis (Reardon et al., 1998). The presence of peritumoral edema and a tumor volume in excess of 30 mL are strongly indicative of a malignant tumor (Fig. 99.8). Some 60% of the lesions are low-grade gliomas, which is particularly true of the thalamo-peduncular lesions. The bithalamic lesions tend not to progress much, and can be classified as a gliomatosis cerebri type lesion (see below). The remaining thalamic tumors are mostly highgrade gliomas, although PNET or germinomas are occasionally found in this location. Prognosis is linked to extent of surgery, even for malignant lesions, with better outcomes demonstrated for subtotal resection (Puget et al., 2007a). The use of chemotherapy and radiotherapy is dependent on the histological diagnosis.

Hemispheric tumors Most (80%) of these tumors are neuroepithelial in origin and more than half of them are glial tumors, which may be of high or low grade. The histological diagnosis of these lesions can also be that of an ependymomas, particularly in children younger than 10 years of age. We will discuss only a certain number of these tumors.

DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR This tumor was first described in 1988 by DaumasDuport as a low-grade cortical lesion, often detected after a convulsion (Daumas-Duport et al., 1988). With

Fig. 99.8. Thalamic malignant glioma in an 8 year old girl with hemiplegia. A large tumor (>30 cc) is developed in the posterior part of the right thalamus with heterogenous contrast enhancement (figure 8a) with extension controlateraly and in the cerebral peduncle.

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J. GRILL AND C. OWENS detected with MRI. Recently, a very specific mutation of the BRAF oncogene has been found in more than half of the gangliogliomas (MacConnaill et al., 2009).Treatment consists of surgery alone, with an excellent survival rate of 90% and control of seizures in the majority of cases (Benifla et al., 2006). Certain studies have demonstrated the risk of malignant transformation after radiotherapy, although this may also happen spontaneously.

GLIOMATOSIS CEREBRI

Fig. 99.9. Dysembryoplastic neuro-epithelial tumor in a 7 year old boy with seizures.

MRI, this tumor has a hyposignal on T1 and a hypersignal on T2 (Fig. 99.9). Localized contrast uptake is possible, especially if there is an oligodendroglial or pilocytic nodule (Josan et al., 2007). Relapse after resection, even if incomplete, is rare and generally there is no indication for adjuvant therapy. Malignant transformation is an extremely rare occurrence. Seizure control tends to be better if the surgery is performed earlier (Bourgeois et al., 1999; Kameyama et al., 2001).

DESMOPLASTIC INFANTILE GANGLIOGLIOMA Also known as desmoplastic infantile astrocytoma, this rare, cystic tumor which tends to be attached to the meninges is nearly always found in children younger than 2 years of age (Mallucci et al., 2000). They do not tend to progress much, but they are often of massive volume at diagnosis. Surgical intervention is often complicated hemorrhage, especially when multiple procedures are required. Multifocal presentation, malignant transformation, and spontaneous regression have all been described. There is no role for chemotherapy or radiotherapy in the treatment program.

GANGLIOGLIOMA This tumor is characterized by the presence of tumoral astrocytes and neural ganglion cells. They are mostly of low grade, but malignant forms have been described (Louis et al., 2007). They account for up to 5% of pediatric brain tumors. They are diagnosed after the development of seizures, which are often refractory. With CT the lesion is hypodense, often calcified with little mass effect. They are generally found in the temporal lobe. There is often a cystic component and there is a strong uptake of contrast. No peritumoral infiltration is

This is defined by the presence of an infiltrating glioma that involves at least two lobes of the brain and that may or may not invade the deep gray matter. Bilateral thalamic involvement has been described (Chappe et al., 2013). Due to the infiltrating nature of these tumors it is difficult to classify them according to the WHO system. They tend to be resistant to treatment, resulting in refractory epilepsy, and patients have a median survival of less than 2 years. Poor prognostic factors include contrast uptake and age younger than 10 years at diagnosis (Armstrong et al., 2006).

PRIMITIVE NEUROECTODERMAL TUMORS Primitive neuroectodermal tumors should be included in the differential diagnosis for high-grade gliomas, and although they differ biologically when compared with medulloblastomas, their type of treatment is similar to that of the medulloblastomas (which is discussed in the section on pinealoblastoma). Compared with high-grade gliomas, these tumors are generally encountered in younger (less than 10 years old) children, whereas high-grade gliomas tend to be found in adolescents. Even with aggressive therapy, the outcome for these tumors is mediocre, particularly if the resection was incomplete.

LOW-GRADE GLIOMAS Low-grade gliomas account for 80% of all supratentorial gliomas. They tend to be diagnosed due to the presence of a motor deficit or refractory seizures. Apart from the gangliogliomas and pilocytic astrocytomas previously described, it is important to mention the subependymal giant cell astrocytoma which is associated with tuberous sclerosis (TS). They are generally diagnosed due to the patient developing signs of hydrocephalus (due to the tumor’s intraventricular location) or as a result of screening patients with TS. Tumors arising in the context of TS are often not completely resectable. They are, however, very sensitive to targeted therapy, through the use of the derivatives of rapamycin which is an mTOR blocker that acts directly on the oncogenetic pathway involving the TSC1 and TSC2 genes (Franz et al., 2006).

CENTRAL NERVOUS SYSTEM TUMORS

HIGH-GRADE GLIOMAS Some 20–40% of all supratentorial malignant gliomas and 10% of all brain tumors are high-grade gliomas. They generally arise sporadically, but they can be found in the context of neurofibromatosis type 1 (NF1), Li– Fraumeni syndrome, or Turcot syndrome. In contrast to those in adults, high-grade gliomas in children very rarely evolve from a low-grade glioma (Broniscer et al., 2007). They are one of the most frequent radiotherapy-induced tumors diagnosed (Carret et al., 2006). Progression is rapid, with the majority of tumors presenting within less than 2 months of symptoms. The most frequent symptoms are motor deficits, impaired consciousness, and seizures (a third of cases). Fundoscopy generally reveals bilateral papilledema. CT with contrast is sufficient to make the diagnosis, which may be confirmed with typical MRI findings, such as the presence of peritumoral edema and/or infiltration of a lesion, which is more extensive on T2-weighted imaging postcontrast than on T1. These lesions tend to invade multiple structures or lobes, often have a necrotic appearance, have a heterogeneous pattern of contrast uptake, and a tumor volume in excess of 30 mL. MR spectroscopy and positron emission tomography (PET) can also guide clinicians toward diagnosing a high-grade lesion or deciding whether to perform a biopsy, but these investigations are not universally available or practical in the context of a clinical situation that often requires an urgent surgical intervention. The histological and biological nomenclature of these tumors is complex, and widespread differences and inconsistencies exist between clinicians/researchers. Studies have shown that following central review 25–30% of cases were designated low-grade glioma (Pollack et al., 2003; Chastagner et al., 2007). Even if the terminology is the same as that used for adults, it is clear that pediatric tumors have some differences from their adult counterpart (Faury et al., 2007; Puget et al., 2012; De Carli et al., 2009; Qu et al., 2010). We now have proof that the ras/ AKT pathway is important for the development of malignant gliomas in children (Faury et al., 2007). Owing to the frequently infiltrating nature of these lesions, radical surgery is not always feasible. In these cases adjuvant radiotherapy is usually performed, except in very young children, for whom chemotherapy is preferred (Dufour et al., 2006). The treatment program is not dependent on the histological subtype or tumor grade. Numerous different chemotherapy protocols have been tried, including high-dose chemotherapy with stem cell rescue (Massimino et al., 2005), but the addition of chemotherapy has not resulted in improved survival. Due to the promising results seen with the use of temozolomide in adults, various groups have been

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investigating its use in children, often concomitantly with radiotherapy, as it is administered orally and is well tolerated, even if the response in relapsed patients is as poor as with the other commonly used medications (Verschuur et al., 2004). Despite a multimodality treatment program only 20% of children over 5 years of age with a malignant glioma are cured. It is noteworthy that there is a small subgroup of very young children who have a much better prognostic outlook, with survival in the region of 50% (Dufour et al., 2006).

Pineal tumors We generally talk of tumors located in the pineal region instead of pineal tumors, as we are often not able to confirm that the tumor is arising from the pineal gland. They represent 5% of all brain tumors and have a higher incidence in Japan compared to the rest of the world. Many different types of tumor can arise in this location, including glial tumors. We will discuss only the most common. They classically present with obstructive hydrocephalus, caused by compression or obstruction of the aqueduct of Sylvius (90% of cases) and oculomotor deficits, most notably Parinaud syndrome (paralysis of upward gaze, accommodative paresis, and mid-dilated pupils with little light reaction). Imaging plays a very important role at diagnosis (Harris et al., 2011); the presence of calcification or fat in the lesion suggests a germ cell tumor, homogeneous and intense uptake of contrast suggests a germinoma or a pinealoblastoma, a cystic aspect suggests a mixed germ cell tumor, and the presence of a second suprasellar lesion suggests a bilocated germ cell tumor. The metastatic workup should always include a spinal MRI, and a lumbar puncture should be performed once the hydrocephalus has been treated, to check for the presence of malignant cells in the cerebrospinal fluid (CSF). Peripheral blood and CSF should be analyzed for germinal tumor marker levels: alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and beta-hCG. A discrete rise in beta-hCG levels could signify a germinoma, but in general raised tumor marker levels are indicative of a mixed germ cell tumor. If the tumor markers are negative, a surgical or stereotaxic biopsy is necessary.

PINEALOBLASTOMA Pinealoblastomas are PNET located in the pineal region. Some 3% of retinoblastomas are associated with a pinealoblastoma (trilateral presentation). The tumoral cells express neuronal markers (synaptophysin and chromogranin) and have a markedly raised proliferation index. Metastatic dissemination at presentation via the CSF is common and these tumors require the same diagnostic workup as a medulloblastoma. These tumors are less chemosensitive than medulloblastomas, but with the

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use of multimodality treatment programs, which include chemotherapy, surgery, and craniospinal radiotherapy, nearly one half of all patients are cured (Reddy et al., 2000). Recent studies have shown that the use of highdose chemotherapy to replace the craniospinal irradiation can result in better outcomes (Dufour et al., 2008, 2012; Fangusaro et al., 2008; Fouyssac et al., 2010).

MALIGNANT GERM CELL TUMORS The diagnosis is based on either elevated tumor markers or, in the absence of these markers, a stereotactic biopsy. Once the diagnosis has been confirmed, the first part of the treatment program consists of chemotherapy based on platinum salts, followed by resection of the inevitable tumoral residue and completed by focal or locoregional irradiation to include the ventricles. Highdose chemotherapy has been used either to avoid radiotherapy completely (Balmaceda et al., 1996) or to treat relapsed disease (Modak et al., 2004). Craniospinal irradiation is used only for metastatic or relapsed disease. Current survival rates for localized germinomas are in the region of 90%, and 80% for metastatic disease (Echevarrı´a et al., 2008). Secreting germ cell tumors do less well, with progression-free survival of 50–60%, with tumors with high tumor marker levels doing worst (Kim et al., 2008).

PINEAL PARENCHYMAL TUMORS The most common pineal gland lesions are cystic. They are generally discovered incidentally, as they do not cause hydrocephalus. Usually they are well limited, rarely multiloculated, and have no contrast uptake. The cysts may have a protein content higher than CSF, which is also sometimes slightly blood stained. Pineal parenchymal tumors and pinealocytomas are rare grade II tumors that can present in adults or children (Fe`vre-Montange et al., 2008). They have a pleomorphic appearance and demonstrate extensive neuronal differentiation. Relapse is rare, even when the resection was incomplete. Papillary tumors of the pineal region are a recently described entity, characterized by perivascular rosettes, with positive staining for neuron-specific enolase (NSE), cytokeratin 18, vimentin, S100, and microtubule-associated protein 2 (MAP2) (Fe`vre-Montange et al., 2006). They have a very poor prognosis, with 75% of patients relapsing within 5 years, which includes those treated with radiotherapy.

Suprasellar tumors These tumors usually present with a triad of symptoms: visual problems (a decrease in visual acuity, hemianopia), endocrinological problems (diabetes insipidus, weight gain), and intracranial hypertension. The histology

of the tumors in order of frequency is: hypothalamochiasmatic gliomas, craniopharyngiomas, malignant germ cell tumors, hypothalamic hamartomas, and pituitary adenomas. Histological diagnosis tends to vary with age. All children with a suprasellar tumor require an ophthalmological and endocrinological evaluation.

HYPOTHALAMO-CHIASMATIC GLIOMAS Epidemiology Hypothalamo-chiasmatic gliomas can be separated into hypothalamic gliomas and optic pathway gliomas (OPG); they represent 4–6% of all pediatric brain tumors. They are mostly diagnosed before the age of 10 years, which is younger than low-grade gliomas located in other areas. Just under 50% of cases arise in the context of NF1. Between 1% and 5% of all patients with NF1 develop an OPG. The relative risk for an individual with NF1 of developing an OPG is 50 times that in the normal population. Clinical symptoms and diagnosis Clinical features at presentation depend on the age of the patients, but generally visual problems are the first to develop. They usually present with nystagmus first, due to visual difficulties in infants or indeed impaired vision in older children. If the intraorbital component of the optic nerve is involved they can present with an exophthalmos. The tumor sometimes reveals itself following the development of secondary precocious puberty. Infants with hypothalamo-chiasmatic gliomas may develop diencephalic cachexia or Russel syndrome (severe emaciation despite normal caloric intake). Specially adapted nutritional care is required in addition to treatment of the tumor. OPG may develop anywhere along the visual pathway from the optic nerve to the occipital cortex, including the chiasma, the optic radiation, and the geniculate body. These tumors may involve the hypothalamus. In addition hypothalamic and third ventricle tumors can extend anteroinferiorly to compress or infiltrate the optic pathways. The distinction between these two types of tumor is not always easy, but it is extremely important to do so in order to guide treatment (including whether to perform surgery or not). The classical classification system described by Dodge (Dodge et al., 1958) is still in use: type 1 is limited to the optic nerve; type 2 extends to and involves, but does not extend beyond, the chiasma; and type 3 extends from the chiasma to the optic radiation or the hypothalamus (Fig. 99.10). More recently, an English group proposed a classification system based on the degree of visual impairment (Taylor et al., 2008). Involvement of the visual pathway beyond the chiasma results in worse visual outcome. There are also exophytic forms of the disease that have

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is associated with an increased risk of relapse (Bartels et al., 2006). The association of gliomas and NF1, where there is an activation of the ras pathway and a duplication of BRAF, a ras analog (Pfister et al., 2008), highlights the importance of this pathway in the development of pilocytic astrocytomas. Treatment

Fig. 99.10. Different aspects of optic pathway tumors. Isolated optic nerve enlargement causing unilateral proptosis and limitation of ocular movement corresponding to Dodge stage 1 (upper left panel). Bilateral optic enlargement in a child with neurofibromatosis type 1 (upper right panel). Chiasmatic tumor corresponding to Dodge stage 2 (lower left panel). Huge hypothalamo-chiasmatic glioma in a infant with diencephalic cachexia corresponding to Dodge stage 3 (lower right panel).

intense, homogeneous contrast uptake, and others that are more infiltrating and are seen simply to result in an increase in size of the chiasma and the optic nerves. The latter type is more frequent in patients with NF1 (Grill et al., 2000). Leptomeningeal metastases may develop even in the absence of a malignant primary tumor (Gajjar et al., 1995). Histopathology and biology These tumors are not always biopsied, such as in the context of NF1 or typical imaging. Histologically they are generally pilocytic astrocytomas and nearly always a low-grade glioma. The rate at which these tumors grow varies greatly, and is most significant in younger patients (Laithier et al., 2003; Tabori et al., 2006a; De Haas et al., 2009). One of the proposed mechanisms behind the decrease in growth with age is the progressive shortening of telomeres, a normal phenomenon linked to cellular aging. Generally tumors maintain telomere length despite ongoing cellular division. This trait does not exist in low-grade pediatric gliomas (Tabori et al., 2006a). A more aggressive form, monomorphic pilomyxoid astrocytoma, has been described. This tumor is generally found in younger children and usually is found at the level of the optic nerves (Tihan et al., 1999). It appears to have a worse prognosis when compared with other pilocytic astrocytomas (Komotar et al., 2004). Very few immunohistochemical markers have been found that can predict clinical progress, apart from the proliferation index marker MIB-1 (Bowers et al., 2003). It appears that active angiogenesis

The therapeutic program for these tumors has changed dramatically since the discovery in the early 1990s that they are extremely chemosensitive. The first problem to be dealt with is when to initiate treatment. This is because in a significant proportion of NF1 patients with a low-grade glioma the tumor does not progress (Grill et al., 2000; Mikaeloff et al., 2002). In general treatment is initiated only if the tumor is clearly progressing or if there is a rapid deterioration in vision from the time of presentation. Rapid evolution usually affects only younger children, who are more likely to present with very large tumors at diagnosis. Surgery is usually avoided, except where there is symptomatic hydrocephalus or in the case of an atypical presentation with no history of NF1. In these cases, either the tumor is biopsied for diagnosis and/or the CSF blockage is relieved by performing a bypass procedure (ventriculoperitoneal shunt or ventriculocisternostomy) or the tumor is de-bulked. The next step after the surgical procedure is to commence chemotherapy. This results in a decrease in tumor volume in about 50% of patients. Only 10% of tumors will progress while receiving chemotherapy. Various different drug combinations are effective, but the most frequently used is the combination of vincristine with carboplatin (Packer et al., 1997). Despite these promising figures, in excess of 50% of all patients will progress in the months and years after stopping treatment (De Haas et al., 2009). Further treatment is usually offered in an attempt to delay radiotherapy as long as possible, but this is associated with an increased risk of serious complications which may be endocrinological (Cappelli et al., 1998), cognitive (Fouladi et al., 2003b; Lacaze et al., 2003), or vascular (Grill et al., 1999). The complication of moyamoya disease, which may be radiotherapy-induced or spontaneous, can be treated by neurosurgical intervention (Sainte-Rose et al., 2006). It appears that tumoral progression decreases with age, and as a result the main focus of treatment is to try to minimize disease progression and the subsequent symptoms, through the use of the least aggressive treatments possible for as long as possible. As a result radiotherapy is used less and less. Prognosis and quality of life Apart from NF1, which appears to be associated with a slightly decreased risk of disease progression (Laithier

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et al., 2003), there is very little information available in relation to clinical prognostic factors apart from age (Opocher et al., 2006). Studies have demonstrated that OPG in children under 1 year of age tends to be more aggressive (Laithier et al., 2003; Gnekow et al., 2004). Radiological response to chemotherapy has also been shown to be a positive prognostic factor (Packer et al., 1997; Laithier et al., 2003). OPG are rarely life-threatening at diagnosis, except in the case of a very large tumor in a young child, or in patients who relapse. The risk of death rises to approximately 25% with disease relapse (De Haas et al., 2009). In contrast, the outlook for vision preservation is guarded with 50% of patients being declared visually impaired – that is a visual acuity of 6/3 (20/10) in the best eye, despite treatment. Patients with NF1 are particularly at risk of visual impairment (Dalla Via et al., 2007). In terms of cognitive performance, patients treated with chemotherapy alone maintain their premorbid level of function, in contrast to those who received radiotherapy (Lacaze et al., 2003; Fouladi et al., 2003b). It is clear, however, that patients with NF1 do develop cognitive problems, even if treated only with chemotherapy, which is most likely related to the NF1.

MALIGNANT GERM CELL TUMORS Frequently these tumors present with diabetes insipidus, which may have been present for months before diagnosis. A pituitary stalk larger than that of the basilar artery may be the only sign of the tumor. If the tumor marker levels in the CSF are negative, then a biopsy (open surgical or stereotactic) must be performed to make the diagnosis. Nonsecreting germ cell tumors are more frequently found in the suprasellar region than the pineal region. Management of suprasellar germ cell tumors is identical to that of pineal region germ cell tumors. The child’s parents should be informed of the risk to the hypothalamus when performing surgery.

CRANIOPHARYNGIOMA Craniopharyngiomas are among the most frequent suprasellar tumors, second to optic pathway gliomas in frequency. The initial symptoms are usually quite innocuous, but at the time of diagnosis the majority of patients have developed significant neurological (headaches, visual impairment, visual deficits) and endocrinological (growth retardation, delay of puberty, excessive weight gain) symptoms. There are two schools of thought in relation to how these tumors originate: they develop either in embryonic rests in Rathke’s pouch or the craniopharyngial canal, or from metaplasia of squamous epithelial cell rests of the stomadeum that participate in forming the buccal mucosa. The neuroradiological

diagnosis is based on identifying the three classical components of craniopharyngiomas (cystic, solid, and calcified tissue) and the sellar or suprasellar location of the lesion. It is confirmed histologically after surgery. The standard therapeutic approach is radical surgery if the hypothalamus is not involved and subtotal resection followed by conformational irradiation if radical surgery is not possible (Puget et al., 2007b). Endocrine deficits are generally complete and permanent and require specialist follow-up as endocrine dysregulation is an important cause of death in these patients. Overall survival at 5 years is more than 80%, but there is often a severe level of morbidity associated with the diagnosis and its subsequent treatment, particularly hypothalamic problems: nutritional difficulties such as bulimia, difficult behavior frequently involving excessive aggression, sleep problems such as narcolepsy, and neuropsychological deficits involving primarily memory and higher reasoning (Garnett et al., 2007).

INTRAVENTRICULAR TUMORS Choroid plexus tumors These are rare tumors accounting for only 3% of pediatric brain tumors. They develop from the epithelium of the intraventricular plexus with a preference for the lateral ventricles (75% of cases). Half of these tumors arise in children younger than 2 years of age. There are three histological subtypes: papillomas, atypical papillomas (atypical nuclear cytoplasm and a proliferation index of more than 10%), and carcinomas (Jeibmann et al., 2006). Papillomas, which have numerous cytogenetic anomalies, are at risk of undergoing malignant transformation (Grill et al., 2002; Jeibmann et al., 2007). Biologically, an amplification of PDGF receptors is frequently identified and this could represent a novel therapeutic target (Nupponen et al., 2008). The main differential diagnosis to exclude is that of an atypical teratoid rhabdoid tumor (ATRT) (Wyatt-Ashmead et al., 2001). The loss of nuclear expression of the tumor suppressor gene INI1 should always be looked for immunohistochemically (see below). The diagnosis of a choroid plexus carcinoma should result in the search for a malignant tumor predisposition syndrome in the affected patient such as the germline mutation of p53 (Krutilkova et al., 2005) or a germline mutation of INI1 (Se´venet et al., 1999). The clinical features at diagnosis are usually those of intracranial hypertension, which are due to the size of the tumor and/or hydrocephalus. Hydrocephalus may arise for several reasons: either a hypersecretion of CSF by the tumor, decreased resorption of the CSF due to blockage of the drainage system or due to arachnoid villosity caused by increased protein in the CSF.

CENTRAL NERVOUS SYSTEM TUMORS Infants usually present with increased head circumference. At diagnosis, the tumors are usually massive with intense contrast uptake which seems to reshape the dilated ventricle. Contralateral ventricular dilatation is radiologically a strong argument in favor of a choroid plexus originating tumor. Angiography may be useful, particularly if preoperative embolization is being considered. Treatment depends primarily on surgery for these tumors. Resection of these tumors is highly complex, with a high risk of hemorrhage and therefore a perioperative mortality rate of approximately 10%. Management of the hydrocephalus is also complex due to its multifactorial etiology. The complete resection of the tumor is sometimes insufficient on its own to treat the hydrocephalus due to the procedure frequently resulting in a subdural effusion/hematoma, and requires a subdural–peritoneal shunt (Pencalet et al., 1998). The treatment of carcinomas involves prolonged adjuvant chemotherapy in addition to surgery, which results in progression-free survival in 50% of cases (Berger et al., 1998; Wrede et al., 2007). The place of radiotherapy is debatable, but it seems to improve outcome in incompletely resected disease and is better tolerated in older children (Wolff et al., 1999).

Other tumors These consist of more commonly seen lesions in intraventicular locations, for example ependymomas and meningiomas or rare tumors that arise only in the ventricles, for example neurocytomas or chordoid gliomas.

INTRACRANIAL EXTRACEREBRAL (NEURAL) TUMORS Atypical teratoid rhabdoid tumor DEFINITION AND EPIDEMIOLOGY Atypical teratoid rhabdoid tumors (ATRT) are rare, extracerebral, extremely aggressive tumors. Even though the initial reports of this tumor presented them as being renal tumors, the intracranial form of the disease is more common. Bifocal disease, with renal and intracranial locations, has been described and is usually due to a constitutional mutation. There is not much difference in biology, prognosis, and treatment options between the intracranial and extracranial forms (Bourdeaut et al., 2008). These tumors nearly always present in children younger than 3 years of age, but can develop at any age, adults included. They are defined by a mutation that results in a loss of nuclear expression of the tumor gene suppressor INI1, which is involved in chromatin organization and cell cycle control (Versteege et al., 1998). It has a complex phenotype which

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is characterized by mesenchymal, epithelial, neuroectodermal, and even sometimes glial tissue associated with rhabdoid-like cells. In some cases, the immunohistochemical appearance is atypical, and in others there is no loss of INI1 expression (Bourdeaut et al., 2007). Recently a novel immunohistochemical marker was described by an American team (Birks et al., 2010). Familial forms have also been described, which have a germline mutation of INI1, and genetic analysis suggests that penetrance is incomplete (Se´venet et al., 1999).

IMAGING ATRT are usually extraaxial tumors that invade the cerebral parenchyma from the outside. They are frequently attached to the meninges. They can mold cerebral structures. Some 50% of the time they arise in the posterior fossa, most commonly at the level of the cerebellopontine angle. They are very cellular and very vascular. As a consequence they appear to be hyperdense with CT, isodense compared to the cortex, and there is intense contrast uptake. The diagnostic workup should include a thorough examination of the entire craniospinal axis, as they have a propensity for leptomeningeal spread and/or to be bifocal. Abdominal (especially renal) synchronous tumors have to be searched for, especially in young children where germline INI1 mutations are frequent, and in this case multiple tumors may be present.

TREATMENT The only chance of cure for these patients lies with complete resection of the tumor. This may be done as one procedure or as an initial intervention, followed by cytoreductive chemotherapy, completed by followup surgery once the tumor has sufficiently decreased in size. Various different combinations of conventional chemotherapy have proven effective in treating ATRT; however, these tumors quickly develop resistance, particularly if there is a delay between chemotherapy courses (Chi et al., 2009). Intrathecal chemotherapy is indicated given the frequency of CSF/meningeal dissemination. Radiotherapy is extremely effective, but given the very young age of these children and the often extensive nature of these tumors, is not always feasible. In these cases, high-dose chemotherapy may be proposed.

PROGNOSIS Outlook is poor, with less than 20% of children cured, especially in the case of metastatic disease (Reinhard et al., 2008). Exceptions to this rule are older children

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who can be treated with craniospinal irradiation (Hilden et al., 2004; Tekautz et al., 2005).

Meningiomas These tumors are much rarer in children than in adults. They account for less than 5% of CNS tumors in children less than 15 years of age. They can present at any age in children, but are frequent during adolescence. They are the most common radiotherapy-induced CNS tumors. Pediatric meningiomas differ from the adult type in that they have a male predominance, they arise in atypical locations such as intraventricular sites, they have an increased frequency of atypical and malignant (30%) forms, they relapse more frequently, and they are associated with neurofibromatosis type 2 (NF2). As a result, NF2 should be out ruled systematically in these patients, particularly midline meningiomas (Rushing et al., 2005). The most common symptoms at presentation are seizures (a third of cases), headaches, and motor problems, most notably when walking. In general they are supratentorial in two-thirds of cases, infratentorial in a third of cases, intraventricular in 1 in 10 cases, and spinal in 1 in 10 cases. There is an intense uptake of contrast on MRI, and sometimes vasogenic, peritumoral edema is present. Biologically, one frequently detects the loss of the NF2 gene in pediatric meningiomas (Begnami et al., 2007). The gold standard treatment is complete resection, with the addition of conformal irradiation or proton therapy in atypical cases or where there has been an incomplete resection. The outlook for children is as good as that of adults (>90% progression-free survival), except for patients with NF2 or those with multiple meningiomas, neurinomas, or spinal ependymomas.

Neurinomas or schwannomas These represent less than 10% of intracranial tumors and 20–30% of intraspinal tumors. They may develop spontaneously or in the context of neurofibromatosis; either NF2 where they usually develop at the level of the cranial nerve VIII (acoustic), or NF1 where they tend to arise at the level of spinal nerve roots. Treatment is surgical, with radiotherapy being reserved for relapsed or inoperable tumors. Vestibular tumors treated with radiosurgery (gamma-knife irradiation) have the same outcome in terms of hearing compared with conventional surgery (Slattery et al., 2007).

Sarcomas Sarcomas may develop from the meninges or the base of the skull. They often evolve rapidly, presenting with progressive motor deficits and intracranial hypertension. Skull base and vertebral lesions are generally either

chondrosarcomas or Ewing sarcomas. Sarcomas arising from the meninges tend to be either vascular-type tumors (hemangiopericytomas), undifferentiated sarcomas, or meningeal chondrosarcomas. Apart from surgery, which is frequently inadequate and often extremely complicated, irradiation by gamma-knife or protons can improve local control by delivering higher doses while limiting toxicity to organs at risk (Habrand et al., 2008). Chemotherapy can play an important role in certain tumors depending on the histology, such as Ewing sarcomas and meningeal sarcomas.

Chordomas Chordomas arise from embryonic notochord residual tissue, most commonly at the level of the clivus and the first cervical vertebra. They can present insidiously, often with cranial nerve palsies, notably the mixed nerves, and tend to evolve slowly. Younger children tend to have more aggressive tumors, often with atypical histology. They are easily identified on T2-weighted imaging. Histological analysis of the tumors demonstrates the typical physaliform cells that are particular to this disease and that, in contrast to other skull base tumors, express epithelial markers. Treatment consists of surgery, if necessary in two stages, followed by irradiation with protons (Habrand et al., 2008). In younger children, chemotherapy may increase the resectability of the tumor, thereby decreasing the radiotherapy volume. Radiotherapy is necessary to prevent metastatic spread.

Pituitary adenomas Pituitary adenomas are less common in children compared to adults and when they do develop it is nearly always in adolescents. They represent 2% of all pediatric brain tumors. Patients present with visual and endocrine problems. Treatment consists of surgery (usually trans-sphenoidal) and certain cases may warrant chemotherapy (such as secreting germ cell tumors). Radiotherapy is being used less and less in treatment programs (Jane, 2008).

INTRACRANIAL LOCATIONS OF HEMATOPOIETIC TUMORS Only primary primitive cerebral lymphomas (exceptionally rare apart from in immunocompromised patients) and cerebral involvement in Langerhan’s cell histiocytosis (LCH) will be discussed here. LCH lesions may be degenerative or tumoral (3–4% of LCH cases) (GuyotGoubin et al., 2008). Cerebral LCH lesions are rarely the cause of presentation, which is usually as a systemic illness. It is necessary to search for cutaneous and bony lesions. The most frequent intracranial location is the posterior pituitary gland, which results in diabetes

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insipidus. After germ cell tumors, LCH is the most common cause of a pituitary mass and diabetes insipidus caused by a tumor. Apart from tumoral lesions, LCH can also present with degenerative lesions, which tend to be asymptomatic from a neurological point of view, but not always from a cognitive point of view, due to their tendency to be situated in the dentate nuclei and white matter of the posterior fossa (90% of cases). They are easily visible on T2-weighted imaging. They are sometimes associated with cortical atrophy (MartinDuverneuil et al., 2006). Retinoic acid seems to be able to slow the progression of these lesions (Idbaih et al., 2004). Histological analysis can confirm the diagnosis, with positive immunohistochemistry staining of CD1a. It may be difficult to differentiate between LCH and a germinoma, as germinomas may have an inflammatory component with very rare germ cell. Intracranial granulomas are treated with vinblastine and corticosteroids if complete resection is not possible. A large pituitary stalk with isolated diabetes insipidus is not in itself sufficient to initiate antineoplastic treatment.

2005b). These treatments often produce a significant improvement in the level of neurological functioning (Doireau et al., 1998). Radiotherapy carries with it a significant risk of aggravating orthopedic problems and is thus much less frequently utilized apart from in the case of a malignant tumor.

INTRASPINAL TUMORS

Cauda equina tumors

Intramedullary tumors

The tumors that arise in this location are either myxopapillary ependymomas or neurinomas. They present with signs of cauda equine compression that are slowly progressive and affect the lumbosacral area. They may present initially with a waddling gait. Ependymomas in this location can metastasize and the risk of doing so may persist for years: 35% in the series by Kestle (Fassett et al., 2005).

Spinal cord tumors represent 40% of all intraspinal tumors. Most of them are glial tumors. Of these the most common are: fibrillary or pilocytic astrocytomas, gangliogliomas, and ependymomas. Malignant forms are extremely rare. Good outcomes in terms of maintaining neurological functions and survival are dependent on early diagnosis. This is made difficult by their often insidious presentation, with slowly worsening lower or upper back pain, a slowly evolving scoliosis, discrete difficulties walking, and problems urinating. The main prognostic factor is the delay between the onset of symptoms and the diagnosis; an interval of more than 2 months is associated with a better outcome (Bouffet et al., 1998). A rare type of presentation is that of hydrocephalus, which probably arises due to the dissemination of occult metastases (Cinalli et al., 1995). These tumors display contrast uptake, except for certain fibrillary astrocytomas with MRI. A cystic appearance is suggestive of an astrocytoma. Spinal cord edema is suggestive of a malignant lesion. Surgery is the treatment of choice, and even a subtotal resection may result in prolonged survival. The preoperative level of neurological fuctioning is the main prognostic factor for postoperative sequelae (McGirt et al., 2008a). Orthopedic sequelae are much less frequent when a laminotomy is performed compared to a laminectomy (McGirt et al., 2008b). For patients who relapse after an incomplete resection, oncological treatments may be effective, most notably chemotherapy (Doireau et al., 1998; Townsend et al., 2004; Grill et al.,

Extramedullary spinal cord tumors Epidural tumors generally present with compression symptoms, with a sensation and pain level as well as motor and sphincter problems. The most frequent type of tumors seen are the “dumbbell” neuroblastomas, socalled due to their dumbbell appearance of a mass either side of the vertebral body. The other types of epidural tumor encountered are Ewing sarcomas arising from a vertebral body. Urgent surgical decompression is usually advocated only where there are acutely progressive signs of paraplegia with sphincter problems. Otherwise, chemotherapy is commenced rapidly with high-dose corticosteroids, with the aim of limiting orthopedic sequelae.

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