Embryonal Cns

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Advances in the Diagnosis, Molecular Genetics,and Treatment of Pediatric Embryonal CNS Tumors

TOBEY J. MACDONALD,a BRIAN R. ROOD,a MARIA R. SANTI,b GILBERT VEZINA,c

KIMBERLY BINGAMAN,d PHILIP H. COGEN,d ROGER J. PACKERe

Departments of aHematology/Oncology, bPathology, cRadiology, dNeurosurgery, and eNeurology,

Childrens Hospital National Medical Center, Washington, DC, USA

Key Words. Primitive neuroectodermal tumor Medulloblastoma Atypical teratoid/rhabdoid tumor Diagnosis Molecular genetics Treatment

ABSTRACT

Embryonal central nervous system (CNS) tumors

are the most common group of malignant brain tumors

in children. The diagnosis and classification of tumors

belonging to this family have been controversial; how-

ever, utilization of molecular genetics is helping to

refine traditional histopathologic and clinical classifica-

tion schemes. Currently, this group of tumors includes

medulloblastomas, supratentorial primitive neuroecto-

dermal tumors, atypical teratoid/rhabdoid tumors,

ependymoblastomas, and medulloepitheliomas. While

the survival of older children with nonmetastatic

medulloblastomas has improved considerably within

the past two decades, the outcomes for infants and for

those with metastatic medulloblastomas or other high-

risk embryonal CNS tumors remain poor. It is antici-

pated that the emerging field of molecular biology will

greatly aid in the future stratification and therapy for

pediatric patients with malignant embryonal tumors. In

this review, recent advances in the diagnosis, molecular

genetics, and treatment of the most common pediatric

embryonal CNS tumors are discussed. The Oncologist

2003;8:174-186

The Oncologist 2003;8:174-186 www.TheOncologist.com

Correspondence: Tobey J. MacDonald, M.D., Childrens Hospital National Medical Center, Department ofHematology/Oncology, 111 Michigan Avenue, NW, Washington, DC 20010, USA. Telephone: 202-884-2800; Fax: 202-884-5685; e-mail: [email protected] Received October 21, 2002; accepted for publication January 14, 2003. AlphaMedPress 1083-7159/2003/$12.00/0

INTRODUCTIONEmbryonal central nervous system (CNS) tumors com-

prise the most common group of childhood malignant brain

tumors (21%) [1]. The World Health Organization (WHO)

classification of tumors recognizes the following entities

within this group: medulloblastoma (MB), supratentorial

primitive neuroectodermal tumor (PNET), atypical teratoid/rhabdoid tumor (AT/RT), ependymoblastoma, and medul-

loepithelioma [2]. MBs, PNETs, and ependymoblastomas

share a histologically similar, undifferentiated morphology,

while medulloepitheliomas and AT/RTs have distinctly dif-

ferent histologies and appear to evolve by different genetic

TheOncologist

LEARNING OBJECTIVES

After completing this course, the reader will be able to:

1. Recognize the classification, clinical presentation, and diagnosis of embryonal CNS tumors.

2. Explain the important molecular genetic alterations identified in embryonal CNS tumors.

3. Describe the current management and novel treatment strategies for embryonal CNS tumors.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.comCMECME

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Unauthorized reproduction is prohibited.

For reprints contact: [email protected]


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pathways. The incidence of CNS embryonal tumors is con-

stant from infancy to 3 years of age (11.6 to 10.2 per mil-

lion) and then steadily declines thereafter [1]. MBs, PNETs,

and AT/RTs make up the majority of these tumors, the

remaining being rare, and thus are the focus of this review.

Controversy exists regarding the division between MBs and

PNETs, but emerging molecular, biologic, and clinical evi-

dence supports the separation of these tumors [3]. The inci-

dence and classification of the more recently described

entity, AT/RT, is also evolving due in large part to the

expanded use of diagnostic molecular genetics. Historically,

AT/RTs have been confused with MBs or PNETs.

Treatment of these tumors has traditionally relied on

surgery and radiation therapy (RT). More recently, chemother-

apy has been utilized to improve outcome and/or delay or

reduce the dose of RT in an attempt to lessen its neurotoxic

effects. While the survival of older children with nonmetasta-

tic MBs has improved considerably within the past two

decades, the outcomes for infants and for those with metasta-

tic MBs or other high-risk embryonal CNS tumors remain

poor. It is hoped that the field of molecular biology will aid in

the development of novel therapeutics that target specific char-

acteristics of individual tumors, while minimizing toxicity to

normal organ systems. This review discusses important

advances in the diagnosis, molecular genetics, and treatment of

the most common pediatric embryonal CNS tumors.

MEDULLOBLASTOMAS AND PRIMITIVE

NEUROECTODERMAL TUMORSMedulloblastomas account for 40% of all posterior

fossa tumors and 15%-20% of all childhood brain tumors.

The peak incidence occurs between 3 and 4 years of age,

with a male predilection of 1.5- to two-fold [1]. PNETs con-

stitute 2% of all childhood brain tumors and are most often

located in the cerebrum, suprasellar, or pineal region of chil-

dren in their first decade of life [2]. Metastatic disease at

diagnosis occurs in 11%-43% of MB/PNET cases and is one

of the most important clinical predictors of outcome [4].

Extraneural spread of MBs/PNETs is an uncommon event,

with bone, bone marrow, lymph nodes, liver, and lung

involvement occurring in decreasing order of frequency.

Clinical Presentation

Medulloblastomas arise from the cerebellum, typically

growing into the fourth ventricle. Patients often present with

hydrocephaly and raised intracranial pressure (ICP) symp-

toms, such as headache, lethargy, and morning vomiting.

Infants in whom the cranial sutures have not fused can pre-

sent with increasing head circumferences. Cerebellar inva-

sion results in ataxia and dysmetria. Patients with PNETs

present with symptoms dependent upon tumor location.

Paresis and seizures can occur with tumors of the cerebral

cortex, raised ICP symptoms occur with tumors that obstruct

cerebrospinal fluid (CSF) flow, and endocrinopathies or

visual deficits may result from suprasellar tumors.

Neuropathologic Diagnosis

The classic histologic appearance of an MB is that of

densely packed cells with hyperchromatic nuclei, indis-

cernible cytoplasms, and numerous mitoses (Fig. 1A). Homer

Wright rosettes and neuroblastic differentiation are observed

in a minority of cases (Fig. 1B). These tumors may be

strongly immunoreactive for vimentin and at least focally for

synaptophysin [5]. Although classic MB is the most common

form, the WHO classification of CNS tumors describes three

additional subtypes of MB [2] (Table 1). These subtypes

include large cell, occurring in approximately 4% of cases,

desmoplastic (Fig. 1C and D), and the rare MB variant char-

acterized by extensive nodularity and advanced neuronal dif-

ferentiation, also known as cerebellar neuroblastoma [2, 6].

PNETs are histologically similar to classic MBs [2, 7].

Nuclear polymorphism, brisk mitotic activity, and necrosis

may be present. Rarely, Homer Wright or Flexner-

Wintersteiner rosettes are seen. Fields of neuronal cells, glial

cells, ependymal canals, and striated muscle or melanin-

bearing cells may be identified, confirming divergent differ-

entiation along neuronal, astrocytic, ependymal, muscular,

or melanocytic lines, respectively [8].

Molecular Genetics and NeurobiologyMolecular biology has augmented traditional histo-

pathologic and clinical classification schemes by providing

further insight into the biological diversity of MBs/PNETs.

This emerging field is expected to have a great impact on

the diagnosis, classification, and prognosis of MBs/PNETs

as well as aid in the rational development of innovative

molecularly targeted therapies. A summary of the most com-

mon molecular genetic alterations recognized in MBs/PNETs

is shown in Table 2.

Expression of the neurotrophin-3 receptor trkCwas the

first molecular alteration in MBs to be correlated with out-

come [9]. Neurotrophin receptors regulate cell differentia-

tion, growth, and apoptosis in the developing cerebellum.

TrkC activation in MB cells induces apoptosis by initiating

c-jun and c-fos early gene expression [10]. trkCexpression

has been found in up to 48% of MB cases [9, 11]. High trkC

expression is the single most powerful independent predic-

tor of favorable outcome, with 5-year survival rates as high

as 89%, compared with 46% for those patients with low

trkCexpression levels [9, 11].

High expression of the erbB-2 (c-erbB-2) oncogene

product, HER2, a member of the epidermal growth factor

175 Pediatric Embryonal CNS Tumors


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receptor family, correlates with

poor outcome in MB patients.

HER2 expression has been found

in 84% of MB cases, and in those

patients with more than 50% posi-tive tumor cells, the 10-year sur-

vival rate was 10%, compared with

48% for all others [12]. Low

expression level of the MYCC

(C-myc) oncogene is predictive of

greater survival in MB patients

[13]. MYCC expression has been

detected in 42% of MB cases. A

recent study showed that MYCC

amplification occurs in only 5% of

MB cases; however, all patientswith this amplification died of

aggressive disease within 7 months

of diagnosis [14].

The nevoid basal cell carci-

noma syndrome (NBCCS, Gorlins

syndrome) is an autosomal domi-

nant disease resulting from mutations of the PTCHgene on

chromosome 9q22.3. This mutation leads to the develop-

ment of MB in about 4% of affected patients. Similarly,

NBCCS is responsible for 1%-2% of all MBs. Studies have

shown PTCH mutations in about 10% of sporadic MB

cases, particularly in desmoplastic MBs [15]. PTCH

MacDonald, Rood, Santi et al. 176

Figure 1. Histologic features of medul-

loblastomas. Undifferentiated, classic

medulloblastoma (A) is characterized

by patternless sheets of small round

hyperchromatic cells. Homer Wright

rosettes (B), the histologic expression

of neuroblastic differentiation, are

seen in a minority of cases. In desmo-plastic lesions, the tumor cells are

compressed into slender columns (C)

or are organized in nodular zones

(arrow) (D). (Hematoxylin-eosin stain,

200magnification).

Table 1. Histopathologic subtypes of medulloblastomas by WHO classification of CNS tumors

Medulloblastoma subtype Histologic characteristics IHC+

Classic [2, 5] High cell density, numerous mitoses, hyperchromatic nuclei, scant cytoplasm Vm, Sn

Extensive nodularity and Nodules with uniform cells resembling neurocytes of neurocytoma; rare variant NSE, Sn, Nfneuronal differentiation [2, 6]

Desmoplastic [2] Reticulin-free nodules (pale islands) with uniform cells of low mitotic rate, NSE, Sn, Nfsurrounded by reticulin and mitotically active, hyperchromatic irregular cells

Large cell [2] Sheets and lobules of round cells with pleiomorphic nuclei, prominent nucleoli, Vm, Snabundant cytoplasm, high mitoses, apoptosis and necrosis; background anaplasiamay be observed.

Abbreviations: IHC+ = positive immunoreactivity; Vm = vimentin; Sn = synaptophysin; NSE = neuron-specific enolase; Nf = neurofilaments.


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encodes a membrane receptor important for cell growth in

the developing cerebellum. Experimental models have

shown that loss of p53 accelerates the development of MBs

in mice heterozygous for PTCH[16], indicating that PTCH

acts as a tumor suppressor gene. Sonic hedgehog (SHH),

a major ligand for the PTCH receptor, is considered a

putative oncogene.

Loss of genetic material from the short arm of chromo-some 17 (17p) is the most common cytogenetic abnormality

in MBs, occurring in 35%-50% of cases [17]. Among the

genes localized to the common breakpoint at 17p13.3,HIC-

1 is the leading tumor suppressor gene candidate inactivated

by 17p deletion. HIC-1 encodes for a zinc finger transcrip-

tional repressor whose expression is upregulated by p53 and

is silenced by hypermethylation. Hypermethylation of the

HIC-1 gene is a frequent event in MB that predicts for a poor

outcome [18]. Other frequent cytogenetic abnormalities

include deletions of regions on chromosomes 10q and 11 as

well as rearrangements of chromosomes 3, 14, 10, 6, 13, 18,

and 22 [19, 20].

Despite similar histological appearances, many of the

molecular genetic aberrations found in MBs are absent in

PNETs. For example, loss of genetic material from chromo-

some 17p is not found in PNETs [21]. Patterns of aberrant

methylation in the region of the 17p breakpoint cluster of

MBs are also absent [22]. Recent microarray studies have

revealed that MBs and PNETs could be separated based on

their specific patterns of gene expression [3]. Furthermore,

this work illustrated that the sporadic form of desmoplastic

MB is molecularly similar to that of MB associated with

NBCCS, yet distinct from classic MB, predominantly due todifferential expression of the PTCH/SHH genes. Most

importantly, the clinical outcomes of children with MBs

were best predicted by the gene expression profile of the

individuals tumor.

Using similar methodology, another study compared

gene expression profiles of metastatic (M+) and non-

metastatic (M0) MBs. This analysis discovered that the

platelet-derived growth factor receptor alpha (PDGFR-)

and theRas/mitogen-activated protein (MAP) kinase path-

way genes were significantly upregulated in M+ tumors

[23]. This finding suggests that the PDGFR- and

Ras/MAP kinase signal transduction pathways may be

rational therapeutic targets for M+ disease.

Neuroradiographic Findings

The imaging features of MBs/PNETs are fairly homoge-

neous throughout the CNS. On T1-weighted images, the solid

components generally have low signals and strong contrastenhancements. On T2-weighted images, the solid component

signals are intermediate between gray and white matter; on

fast fluid-attenuated inversion recovery (FLAIR) images, the

signals are isointense to gray matter. In contrast, most other

CNS tumors tend to have T2-weighted and FLAIR signal that

are greater than gray matter [24]. MBs typically arise in the

cerebellar vermis and roof of the fourth ventricle, growing for-

ward into the fourth ventricle, which is displaced anteriorly

(Fig. 2A and 2B). Invasion of the dorsal brain stem or exten-

sion into the medial cerebellar hemisphere may occur. MBs

are typically 3-5 cm in maximal diameter. In older children

and adolescents, MBs have a tendency to present either in the

lateral cerebellar hemisphere or near the cerebellopontine

angle cistern [24]. Atypical imaging features include an exten-

sive or complete lack of enhancement in up to 25% of lesions,

cystic or large necrotic areas, and hemorrhage. On computer-

ized tomography (CT) scans, MBs have a hyperdense appear-

ance compared with the cerebellum, and calcifications are

seen in approximately 10% of cases [25].

PNETs replicate the appearance of MBs (Fig. 3A-3C).

However, these lesions are generally larger and more com-

monly display large cystic/necrotic areas. They are typically

well defined rather than infiltrative, most often located in thefrontoparietal region, and can arise either cortically or in the

deep periventricular white matter. Calcifications and hemor-

rhage are more common, especially within the larger cystic

or necrotic foci. These characteristics result in more hetero-

geneous magnetic resonance imaging (MRI) features,

including areas of high T1-weighted signal (hemorrhage)

and a mixed low and high T2-weighted signal (high cellu-

larity and cystic, necrotic, and/or hemorrhagic changes)

[26]. Peritumoral edema is common, though often minimal

given the large size of these tumors [27].


Table 2. Common molecular alterations detected in MB and PNET

Molecular alteration Detected rate Clinical association

trkC[2, 3, 9-11] 48% of MB cases Low expression unfavorable outcome

erbB-2 (HER2) [12] 84% of MB cases High expression unfavorable outcome

MYCC[13, 14] 42% of MB/PNET cases High expression unfavorable outcome

PTCH[2, 3, 15, 16] 8%-10% of MB cases Mutation development of sporadic and nonsporadic desmoplastic MB

17p [2, 17-22] 35%-50% of MB cases Deletion unknown significance; putative tumor suppressor gene locus


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nodules or carpet-like coverings of the meningeal sur-

faces of the brain and spinal cord. However, nonenhanc-

ing metastatic disease can also be present, especially when

the primary tumor does not enhance. The nonenhancing

deposits are often only identified on T2-weighted images

as areas of distortion of the subarachnoid spaces and can

also be seen as areas of abnormal signal on FLAIR or

diffusion images.

Diffusion-weighted imaging, which reflects Brownian

diffusion of water molecules, reveals abnormal restriction

of water movement in most MBs/PNETs. In contrast to

most CNS tumors, MBs/PNETs are hyperintense on diffu-

sion-weighted images. The restricted diffusion character-

istics likely reflect the high cellularity and dense packing

of MBs/PNETs [26]. The MR spectroscopy (MRS) signa-

tures of MBs/PNETs reflect that of malignant tumors and

are not as specific as the imaging features on conventional

and diffusion images. In general, choline levels are

markedly increased, N-acetyl aspartate (NAA) is either

markedly decreased or absent, and lactate/lipid moieties

can be identified. Choline is a cellular membrane marker;

its increase reflects increased membrane turnover within

the tumor. NAA is a neuronal marker; its diminution or

absence confirms the lack of neuronal differentiation of

MBs/PNETs. Lactate is a product of anaerobic glycolysis

and indicates the presence of necrosis or nonaerobic

cellular metabolism.

Therapeutic Considerations

Clinical Prognostic Factors

Treatment groups for MB are designated high risk and

average risk based upon the criteria of age greater than or

less than 3 years, residual tumor greater than or less than

1.5 cm2, and the presence or absence of metastatic disease

on neuroimaging or CSF sampling [4, 24]. Age younger

than 3 years is predictive of poor outcome. One explanation

for this is that younger children more commonly present

with metastatic disease [28]; however, they are also less

likely to be treated with conventional doses of RT [29] and

are more likely to have subtotal tumor resection [30].

Extent of resection correlated with better survival for

patients without metastatic disease in the Childrens Cancer

Group (CCG) study 921 [31]. Metastatic disease at diagno-

sis has been repeatedly correlated with poor survival, the

exception being M1 disease, defined as only CSF cytology

positive for MB cells [4, 32]. PNETs are considered high

risk regardless of the patients age, extent of resection, or

the presence or absence of metastatic disease at diagnosis,

and as such, are treated in a similar fashion as high-risk

MBs as outlined below.

Surgery

Most MBs are located in the midline of the fourth ven-

tricle and/or cerebellar vermis, with associated important

hydrocephalus. If the child presents in extremis from his or

her hydrocephalus, an emergency ventriculostomy should

be performed through a frontal burr hole, often at the bed-

side using conscious sedation. The CSF may then be sam-

pled for tumor cells as well as drained to a level sufficient to

relieve the acute symptoms. If the child is not obtunded and

responds to intravenous corticosteriods alone, a burr hole

can be placed in the occipital skull at the time of the tumor

resection and an external ventricular drain placed [33]. In

the rare instances where hydrocephalus is not initially pre-

sent, a burr hole should usually be placed anyway at the time

of tumor resection to allow bedside ventriculostomy should

postoperative swelling result in CSF obstruction. The child

is usually operated upon in the prone position: we favor the

use of a craniectomy rather than replacing the bone flap, for

these highly malignant tumors often produce considerable

posterior fossa edema postoperatively. It may be necessary

to remove the posterior arch of the first cervical vertebra to

gain access below the cerebellar tonsils.

Using the operating microscope, the cerebellar tonsils

should be carefully separated following the dural opening,

and the floor of the fourth ventricle can be identified and

protected with a cottonoid pledgett. The majority of these

tumors arise from this region, and their attachment may be

identified. The bulk of the tumor can then be resected by

splitting the vermis and retracting the cerebellar hemi-spheres. Useful surgical adjuncts include the Cavitron ultra-

sonic aspirator. Care must be taken to avoid undue

dissection of the roof of the third ventricle, which results in

ocular pareses, but the tumor must be fully resected from

this location to remove the inferior third ventricular obstruc-

tion that is almost always present. Dissection at the junction

of the cerebellar peduncles and brainstem may be the origin

of the phenomenon of postoperative mutism [34]. In gen-

eral, an attempt should be made to remove the entire tumor

[35]. This may not be possible when there is encasement of

the posterior inferior cerebellar artery or extensive involve-

ment of the brainstem. However, it is sometimes possible

that residual tumor detected on the postoperative MRI scan

can be safely resected, and under these circumstances, a sec-

ond operation should be attempted to achieve a complete

resection in patients with nonmetastatic disease. If there is

already leptomeningeal dissemination seen at the time of the

resection, then no attempt should be made to route out every

last cell of the primary mass. Common postoperative

deficits in addition to mutism include ataxia, hemiparesis,

and sixth nerve palsy, which generally resolve over time

[36]. Approximately 60%-75% of children in whom a total



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or near-total resection of the mass is achieved will not

require permanent CSF diversion. The remainder of these

children should undergo placement of a ventricular shunt

generally at day 5-7 postoperatively, when the CSF has

cleared from blood and debris, and it is clear that a

permanent implant will be required.

Medulloblastomas that present in the cerebellopontine

angle, once classified as reticulum cell sarcomas (primarily

now known as the desmoplastic variant), should be

approached through a laterally placed incision and craniec-

tomy. These tumors are generally completely resectable, as

they do not involve the fourth ventricle, and often present

with hydrocephalus. This is also a common location for

AT/RTs, although this latter type tends to envelop the cra-

nial nerves, arteries, and brainstem, making their resection

more problematic. Supratentorial PNETs should be

approached through a craniotomy placed in relation to their

site of origin. These tumors are most often extremely largeand vascular. An attempt should be made to resect the

entire primary mass, unless there is widespread lep-

tomeningeal disease. The use of intraoperative neuronavi-

gation (frameless stereotactic guidance) can be quite

helpful in the resection of these tumors.

Radiation and Chemotherapy

The cornerstone of MB/PNET treatment has been RT of

the primary tumor site. However, given the propensity of

MBs/PNETs to spread, the addition of craniospinal radio-

therapy (csRT) for prophylactic treatment of metastasis hasbeen necessary to maximize survival [37]. Unfortunately,

the neurocognitive and endocrine effects resulting from irra-

diation of the developing neuraxis have presented a high

price for this protection. In an attempt to lessen RT-induced

neurotoxicity, clinical trials utilizing adjuvant chemotherapy

have been explored.

Medulloblastomas respond to a range of alkylator and

platinum-based drugs. A CCG study of patients with aver-

age-risk MBs reduced the csRT dose from the standard

3,600 cGy to 2,340 cGy (total boost 5,580 cGy) and added

adjuvant chemotherapy consisting of vincristine, cisplatin,

and lomustine (CCNU). Progression-free survival was 86%

at 3 years and 79% at 5 years [38]. These rates compared

favorably with historical controls. A CCG trial using an

identical RT dose followed by a randomization between the

chemotherapy described above and one substituting

cyclophosphamide for the CCNU was recently completed.

These data are awaited to confirm the promising results for

reduced-dose csRT in this group of patients.

Despite this reduction in csRT, neurocognitive deficits

were still noted. Patients who underwent longitudinal intel-

ligence testing demonstrated an estimated rate of change

from baseline of -4.3 Full Scale Intelligence Quotient points

per year, -4.2 Verbal IQ points per year, and -4.0 Nonverbal

IQ points per year (p < 0.001 for all three outcomes).

Females, children aged less than 7 years, and those with

higher baseline IQs were at greatest risk [39].

Doses of 3,600 cGy csRT with total tumor boost to

5,400 cGy have been used to treat high-risk MBs and

PNETs in neurodevelopmentally appropriate patients.

However, when used as the sole postoperative treatment,

results were dismal. Yet objective responses to chemother-

apy were observed in up to 50% of patients. Postoperative

chemoradiotherapy for non-pineal PNETs have produced 5-

year survivals in approximately one-third of patients, with

children less than 2 years faring more poorly [30]. Although

infants with pineal PNETs did poorly, older patients with

this type of tumor in this location appeared to have a better

prognosis [30].

In very young children, for whom the long-term neu-rocognitive sequelae of RT are unacceptable, high-dose

chemotherapy (HDCT) and autologous stem cell (ACS) sup-

port have been used in an attempt to delay or obviate the need

for RT. In a study of 23 relapsed MB patients who received

HDCT consisting of carboplatin, thiotepa, and etoposide

with autologous stem cell (ASC) rescue, 3-year event-free

survival (EFS) and overall survival (OS) rates were 34% and

46%, respectively [40]. Trials of HDCT and ASC as front-

line therapy are ongoing in patients less than 3 years of age

with MBs/PNETs and as therapy following csRT for older

children with high-risk MBs or PNETs.

ATYPICAL TERATOID/RHABDOID TUMORS

Atypical teratoid/rhabdoid tumors, first described by

Rorke et al. in 1987, are considered by some as a subtype

of PNET [41-44]. With the wider utilization of immunohis-

tochemistry and new molecular genetic probes, AT/RTs

have been increasingly diagnosed, especially in infants and

very young children [42, 44]. AT/RTs also have been diag-

nosed in older children and young adults [45-48]. The exact

incidence of this tumor is unknown, but it has been sug-

gested that approximately 10%-15% of children less than 3

years of age thought to have MBs or other forms of PNETs,

actually had AT/RTs [45-48]. Others have reported that the

ratio of AT/RTs to other more common PNETs is as low as

1:4 among children less than 3 years of age [49].

Clinical Presentation

AT/RTs present in a similar fashion to other PNETs and

can arise throughout the nervous system. Approximately

one-half of patients will have tumors originating in the pos-

terior fossa, with a possible predilection for the cerebello-

pontine angle [42, 47]. Supratentorial AT/RTs tend to be



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extremely large at the time of diagnosis and may have cys-

tic/necrotic components [42-48]. The tumors can be intra-

or extra-axial and often invade adjacent structures. The

incidence of leptomeningeal dissemination at the time of

diagnosis has not been firmly established. Early review

suggested that as much as 30%-40% of patients had lep-

tomeningeal dissemination, although in more recent studies

the incidence of dissemination was noted to be closer to

15% [42-48].

Neuropathologic Diagnosis

AT/RTs are malignant embryonal tumors composed of

rhabdoid cells usually with additional, variable components

of primitive neuroectodermal, mesenchymal, and epithelial

cells [42, 44, 50]. The typical rhabdoid cell is medium sized,

round to oval, with distinct borders, an eccentric nucleus, and

commonly a prominent nucleolus (Fig. 4). The cytoplasm

has a fine granular character or may contain a poorly defined

pink body resembling an inclusion. Variable elements

from small cells with tapering cytoplasmic tails to large

bizarre cells may be identified. The primitive neuroectoder-

mal component may consist of sheets of small round blue

cells or may display Homer Wright or Flexner-Wintersteiner

rosettes. The mesenchymal component appears as loose

arrangements of small spindle cells or tightly arranged in a

fascicular pattern resembling sarcoma. Epithelial differentia-

tion is uncommon, and if present, is confined to few gland-

like spaces. Mitoses are abundant, and field necrosis is

common. The immunophenotype is broad, as the large rhab-doid cells display a range of immunoreactivity with clusters

of cells almost always positive for epithelial membrane anti-

gen and vimentin. Also frequent is reactivity for glial fibril-

lary acidic protein and cytokeratin, and less frequent is

reactivity for smooth muscle actin and neurofilament protein.

The rhabdoid cells are negative for desmin and any of the

markers for germ cell tumors [42, 44].

Molecular Genetics and Neurobiology

Molecular genetic analysis has aided greatly in the diag-

nosis and understanding of AT/RTs. The vast majority of

AT/RTs demonstrate monosomy 22 or deletions of chromo-

some band 22q11 [51, 52]. Other CNS tumors may demon-

strate chromosome 22 abnormalities, and this abnormality

alone is not sufficient for diagnosis. MBs and other PNETs

may show a deletion of chromosome 22, but can be distin-

guished from AT/RTs by the presence of associated chromo-

some abnormalities. Eighty-five percent or more of AT/RTs

show alterations of the hSNF5/INI1 gene [52-54]. The direct

function of this gene in tumor development is unknown, but

homozygous inactivation of the hSNF5/INI1 gene likely

results in altered transcriptional regulation of downstream

targets by the chromatin remodeling complex (SWI/SNF).

The mutations in this gene are predominantly point muta-

tions that result in the coding of a novel stop codon, which

predicts premature truncation of the protein [53-55].


Figure 4. Histologic features of an AT/RT. The cells have large

nuclei with prominent nucleoli (arrowhead), and some cells pos-

sess abundant eosinophilic cytoplasm (arrow) (A). Vimentin reac-

tivity (B) is universal, and positive staining for epithelial

membrane antigen (C) is common in groups of cells (arrow).

(Hematoxylin-eosin, vimentin, and epithelial membrane antigen

stains, 400magnification).


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Neuroradiographic Findings

The CT findings of AT/RTs are relatively characteris-

tic, but not diagnostic. These tumors are usually hyperdense

and enhance intensely [42]. Calcifications may occur but

are not common, while cysts are more common in the

supratentorial lesions. On MRI imaging (Fig. 5), the T1 sig-

nal of the solid portion of the tumor is typically isointense;

there are frequent T1 hyperintense foci (secondary to intra-

tumoral hemorrhage) and hypointense foci (secondary to

cystic/necrotic change). AT/RTs commonly display intense

contrast enhancement. The T2 appearance is heterogeneic.

The MRS appearance of an AT/RT is similar to that of a

PNET, with marked elevation of choline and low or absentNAA and creatine; lipids and lactate peaks can often be

identified.

Therapeutic Considerations

To date, the therapy for AT/RTs has been suboptimal.

Information about response to therapy and outcome has

been primarily gathered from retrospective reviews of a

handful of patients [42-48]. An AT/RT registry has added

some useful information [47]. The role of surgery for

AT/RTs is unsettled [56]. Although initial reports suggested

that, because of the age of the patients, the large extent ofthe tumors, and their tendency to be more laterally placed

in the cerebellopontine angle, total or near-total resection

was quite uncommon. In the AT/RT registry, six of the

eight patients who survived for greater than 18 months had

undergone total resection.

Given the young age of the patients, chemotherapy has

been the primary modality of treatment after radiation ther-

apy [56]. Even after aggressive surgery and chemotherapy,

overall survival rates for children, especially those less than

2 years of age, have been extremely poor, with less than 20%

of patients surviving less than 12 months from diagnosis. A

variety of different chemotherapeutic agents have been uti-

lized, but no one agent or combination of agents has been

shown to be most effective. The majority of children have

been treated with chemotherapeutic regimens developed for

infantile brain tumors that have included drugs such as

cyclophosphamide, cisplatin, etoposide, and vincristine. The

use of myeloablative doses of chemotherapy, supported

either by autologous bone marrow transplant or peripheral

stem cell rescue, has not been shown to increase survival.

Because of the histological appearance of these tumors,

another approach has been to utilize sarcoma chemotherapy


Figure 5. Atypical teratoid/rhabdoid tumor in the right cerebello-

pontine angle. Axial T2-weighted (A), postcontrast axial (B), and

sagittal (C) T1-weighted images demonstrate a heterogeneous mass

(A) with central enhancement and dural extension (B, C).


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regimens [56]. In general, these regimens have shown a

slightly higher overall response rate; however, the majority

of patients treated with such regimens have been somewhat

older. In general, the results of chemotherapeutic studies

suggest that a variety of chemotherapeutic regimens may

result in tumor stabilization and, for fewer patients, objective

tumor shrinkages. The benefit of chemotherapy has not been

durable for most patients. Because of the age of patients,

radiotherapy has been less widely employed in children with

AT/RTs [42-48, 56]. Most of the children reported to the

AT/RT tumor registry that survived for greater than 18

months received at least local RT [47, 56]. However, conclu-

sions are difficult to draw, since many of those patients were

older at the time of diagnosis.

In summary, therapeutic approaches have been subopti-

mal, with the majority of patients developing progressive dis-

ease within 12 months of diagnosis and dying soon after. As

the prognosis of children with AT/RTs seems to differ from

those with MBs/PNETs, investigators have suggested that

AT/RTs be removed from present infant brain tumor proto-

cols and entered on protocols designed specifically for

AT/RTs [56]. There is sentiment to use high-dose chemother-

apy for a shorter period of time and institute at least local

radiotherapy earlier for patients with localized disease at the

time of diagnosis. The optimal induction therapy is not clear

from available data and there is no treatment that has shown

significant efficacy for children with disseminated disease at

the time of diagnosis.

NOVEL THERAPEUTIC STRATEGIES FOR EMBRYONAL

CNS TUMORS

The development of therapies with acceptable toxicities

that can adequately penetrate the CNS yet remain relatively

unsusceptible to the emergence of tumor resistance is criti-

cal to improving the outcome of pediatric embryonal CNS

tumors. Treatment strategies can be broadly separated into

two categories: methods that increase the total dose of

drug/radiation delivered to the focal sites of CNS disease

and novel therapeutics that exploit the specific biological

characteristics of the tumor. Clinical strategies that are

currently active are summarized in Table 3.

High-dose systemic chemotherapy, with ASC or periph-

eral blood stem cell (PBSC) support, is being evaluated in

children with CNS tumors. The aim of HDCT is to increase

the tumors exposure to cytotoxic agents by overcoming the

limited permeability of the blood-brain barrier (BBB).

Classic alkylating agents, which generally have nonoverlap-

ping hematological toxicities, show little cross-resistance,

and maintain steep and linear dose-response curves, have

been predominantly investigated by this approach. Because

of its lipid solubility, thiotepa has been commonly used.

Initial results with thiotepa and busulfan in 20 children with

relapsed malignant tumors showed five partial responses

(4/8 MB/PNET) for an overall response rate of 26% [57].

A more recent CCG study using carboplatin, thiotepa, and

etoposide followed by ASC support for 23 patients with

recurrent MBs reported a 3-year EFS rate of 34% and an OS

rate of 46% [40]. A subsequent study evaluated this regimen

in 62 patients with newly diagnosed malignant brain tumors.

The EFS and OS rates at 3 years were 25% and 40%, respec-

tively [58]. The most impressive responses were again noted

in MB/PNET patients. Despite these promising responses,

the toxicity associated with these regimens has been exces-

sively high (5%-15% death rate). In an effort to reduce toxi-

city, more recent investigations have used multiple cycles ofsomewhat lower doses of chemotherapy followed by PBSC

support. This has decreased transplant-related complications;

however, the data relating to efficacy from ongoing trials are

still premature.

Administration of intrathecal (IT) chemotherapy or coad-

ministration of systemic chemotherapy with biologic agents

that disrupt BBB permeability are alternative methods to


Table 3. Active clinical trials utilizing novel therapeutic strategies for embryonal CNS tumors

Novel treatment strategy Desired effect Active clinical trials (agent)HDCT and ASC support Penetrate BBB, CNS drug level COG-99702, high-risk patients, closed; COG-99703, infant patients;

POG-9430, recurrent disease

IT chemotherapy Prevent or treat LM disease PBTC-001 (mafosfamide); PBTC-005 (busulfan); COG-P9962 (topotecan)

Radiosensitization RT cytotoxicity COG-99701 (carboplatin/RT)

BBB disruption CNS drug level COG-09716 (carboplatin/lobradimil)

Biologic therapy Target essent ial tumor bioactivity PBTC-002 (VEGFR TKI), closed; PBTC-003 (FTI)

Focal RT RT neurotoxicity PBTC-001 (3-D conformal RT)

Abbreviations: ASC = autologous stem cell; COG = Childrens Oncology Group; FTI = farnesyl transferase inhibitor; HDCT = high-dose chemotherapy;LM = leptomeningeal; PBTC = Pediatric Brain Tumor Consortium; POG = Pediatric Oncology Group; VEGFR TKI = vascular endothelial growth factorreceptor tyrosine kinase inhibitor.


11/13

increase CNS drug penetration and control leptomeningeal

disease. The former method had been limited by the lack of

available active agents that can be given by IT administration.

The availability of topotecan and mafosfamide, a preactivated

derivative of cyclophosphamide, has led to renewed interest in

regional therapy. A European trial with IT mafosfamide (20

mg) and systemic chemotherapy for disseminated pediatric

brain tumors demonstrated complete responses in eight of nine

evaluable patients and, at a median follow-up of 21 months, 11

of 16 patients remained in complete or partial remission [59].

For the latter method, bradykinin agonists, such as lobradimil,

which cause vasodilatation and leakiness of the BBB, have

been utilized. This agent has been used in conjunction with

systemic carboplatin for refractory CNS tumors.

Poorly oxygenated cells comprise a significant portion of

the total tumor mass and are nearly three times less sensitive

than well-oxygenated cells to the effects of RT. Investigations

have thus focused on particles that are less dependent on oxy-gen for their effect, such as neutrons, or agents that enhance

the effect of radiation-induced free radicals, such as platinum

agents and halogenated pyrimidines. Topotecan and pacli-

taxel, members of the camptothecin and taxane classes of

chemotherapeutic agents, respectively, are under investiga-

tion for their effects as radiosensitizers. Pediatric trials are

also investigating gadolinium-texaphyrin, a porphyrin com-

pound that produces long-lived free radicals, conjugated to

gadolinium [60]. This conjugate forms a tumor-selective

radiosensitizer that can be visualized by MRI.

The delivery and transfer of foreign genes into tumorcells, a process known as gene therapy, has broad implica-

tions for the treatment of neoplastic diseases. The postmitotic

environment of the CNS may provide an advantage over other

tissues in that it allows for the specific uptake of foreign

genetic material into the genome of the rapidly dividing

tumor. To date, one study has been completed and reported in

pediatric CNS tumors. In this phase I study, 12 patients with

recurrent malignant supratentorial tumors were multiply

injected in the rim of the resection cavity with murine vector-

producing cells shedding the retroviral vector containing the

herpes simplex virus-1 thymidine kinase gene, and then

treated with cytotoxic ganciclovir [61]. The procedure was

well tolerated and future trials are planned.

The advent of STI571 (imatinib mesylate), an inhibitor

of the bcr-abl fusion protein found in Philadelphia-chromo-

some-positive leukemias, ushered in a new paradigm for

cancer treatment based upon the identification of molecular

targets [62]. Following this model, investigation is under

way to find molecular targets in MBs/PNETs. A number of

promising compounds are just entering phase I clinical trials

in pediatric patients, including tyrosine kinase inhibitors that

impede growth factor signaling and farnesyl transferase

inhibitors that block Ras activation.

It is unclear whether chemotherapy alone can induce

durable responses in a significant proportion of patients.

Three-dimensional (3-D) conformal RT is a technique that

attempts to minimize neurotoxicity by integrating many

beams, precisely directing RT to the desired site while leav-

ing untargeted areas minimally exposed. The achievement of

this goal depends upon precise localization of the tumor and

normal critical structures by integrating CT or MRI withreproducible positioning of the patient. Intensity-modulated

radiation therapy (IMRT) is a new conformal technique that

makes use of 3-D-based treatment planning and nonuniform

radiation beams. The beams are of greatest intensity within

the tumor, sparing nearby critical structures. The high-dose

treatment volume can then be made to conform to an irreg-

ular target. When compared with conventional RT, IMRT

delivered 68% of the dose to the auditory apparatus (mean

dose, 36.7 versus 54.2 Gy), while the overall incidence of

ototoxicity was lower in the IMRT group [63].

SUMMARY

The current treatment of pediatric embryonal CNS

tumors continues to be very challenging and too frequently

results in significant long-term sequelae in survivors. This

is especially true for very young children, the most com-

mon age group diagnosed with these tumors, in which the

effects of chemoradiotherapy on the developing neuraxis

are greatest. Innovative delivery and decreased neurotoxic-

ity of chemoradiotherapy are major directives for future

clinical trials. It is also anticipated that the expanded use of

molecular genetics will help to better stratify patients, tailor

individual therapy, and aid in the development of targeted

therapeutics.


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