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. PACKER
e
Departments of
a
Hematology/Oncology,
b
Pathology,
c
Radiology,
d
Neurosurgery, and
e
Neurology,
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 of
Hematology/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. AlphaMed
Press 1083-7159/2003/$12.00/0
INTRODUCTION
Embryonal 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
The
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LEARNING OBJECTIVES
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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.
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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 TUMORS
Medulloblastomas 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 Neurobiology
Molecular 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 trkC was 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]. trkC expression
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
trkC expression 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
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 patients
with 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 PTCH gene 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,
200 magnification).
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, Nf
neuronal differentiation [2, 6]
Desmoplastic [2] Reticulin-free nodules (pale islands) with uniform cells of low mitotic rate, NSE, Sn, Nf
surrounded by reticulin and mitotically active, hyperchromatic irregular cells
Large cell [2] Sheets and lobules of round cells with pleiomorphic nuclei, prominent nucleoli, Vm, Sn
abundant cytoplasm, high mitoses, apoptosis and necrosis; background anaplasia
may be observed.
Abbreviations: IHC
+
= positive immunoreactivity; Vm = vimentin; Sn = synaptophysin; NSE = neuron-specific enolase; Nf = neurofilaments.
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 to
differential 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 the Ras/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 contrast
enhancements. 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 the
frontoparietal 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].
177 Pediatric Embryonal CNS Tumors
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
At the time of diagnosis, meticulous imaging of the
entire CNS is required for all MB/PNET patients, as these
tumors have a propensity to spread throughout the sub-
arachnoid spaces. In general, metastatic deposits are iden-
tified on gadolinium T1-weighted images as enhancing
MacDonald, Rood, Santi et al. 178
Figure 2. Medulloblastoma with extensive subarachnoid metastatic
dissemination. Axial T2-weighted (A) and postcontrast sagittal T1-
weighted (B) images show a mass filling the fourth ventricle. The
ventral brainstem is coated with enhancing tumor (B).
Figure 3. Supratentorial PNET. Axial T2-weighted (A), postcontrast
axial (B), and sagittal (C) T1-weighted images reveal a large mass in
the left temporal lobe and the subfrontal region. Necrosis is seen on
the contrast image (B, C) as serpiginous nonenhancing regions
within the tumor. A metastatic nodule is present behind the vermis of
the cerebellum.
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 cm
2
, 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
179 Pediatric Embryonal CNS Tumors
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 large
and 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 has
been 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
MacDonald, Rood, Santi et al. 180
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].
181 Pediatric Embryonal CNS Tumors
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, 400 magnification).
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 absent
NAA 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 of
the 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
MacDonald, Rood, Santi et al. 182
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).
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 of
somewhat 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
183 Pediatric Embryonal CNS Tumors
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 essential 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 factor
receptor tyrosine kinase inhibitor.
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 tumor
cells, 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 with
reproducible 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.
MacDonald, Rood, Santi et al. 184
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