Brain Tumor Pathol (2012) 29:107112

DOI 10.1007/s10014-011-0071-z

CASE REPORT

A huge intraventricular congenital anaplastic astrocytoma: case

report with histopathological and genetic consideration
Shinji Yamashita Shinitsu Ryu Shiro Miyata Syunrou Uchinokura Kiyotaka Yokogami
Hisao Uehara Sayaka Moriguchi Takashi Iwakiri Kousuke Marutsuka Makoto Ikenoue
Daisuke Sawa Naoshi Yamada Yuki Kodama Hideo Takeshima

Received: 19 October 2011 / Accepted: 23 October 2011 / Published online: 3 December 2011
The Japan Society of Brain Tumor Pathology 2011

Abstract Congenital malignant gliomas are rare brain

tumors about which few reports have been published. We
present the clinical course and genetic alterations in an infant
with a congenital malignant glioma detected incidentally by
ultrasonography at 36 weeks. The tumor occupied the right
temporoparietal region, extended to the posterior fossa, and
significantly compressed surrounding structures. The female
infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally
resected by two-stage surgery; pathological diagnosis was
anaplastic astrocytoma. Immunohistochemical staining was
positive for p53 and negative for epidermal growth factor
receptor. There was no O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, no 1p/19q
loss of heterozygosity, and no isocitrate dehydrogenase 1
(IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery.

S. Yamashita (&)
S. Ryu
S. Miyata
S. Uchinokura

K. Yokogami
H. Uehara
H. Takeshima
Division of Neurosurgery, Department of Clinical Neuroscience,
Faculty of Medicine, versity of Miyazaki, 5200 Kihara,
Kiyotake, Miyazaki 889-1692, Japan
e-mail: shinjiy@fc.miyazaki-u.ac.jp
S. Moriguchi
T. Iwakiri
K. Marutsuka
Department of Pathology, Faculty of Medicine,
University of Miyazaki, Miyazaki, Japan
M. Ikenoue
D. Sawa
Division of Pediatrics, Department of Reproductive and
Development Medicine, Faculty of Medicine,
University of Miyazaki, Miyazaki, Japan
N. Yamada
Y. Kodama
Perinatal Center, Faculty of Medicine, University of Miyazaki,
Miyazaki, Japan

Keywords Congenital malignant glioma
Anaplastic

astrocytoma
Genetic analysis
IDH1
MGMT

Introduction
Congenital brain tumors are rare; their incidence is
1.13.6 per 100,000 newborns [1, 2]. These neoplasms
account for 0.34% of central nervous system (CNS)
tumors in children [3, 4]. Different definitions have been
proposed for the term congenital. Three categories of
intracranial tumors in newborns have been proposed:
definitely congenital (present at birth), probably congenital (detected within the first week of life), and possibly
congenital (detected within the first few months of life)
[5]. Histologically, these tumors tend to be teratomas
(usually with immature elements), astrocytomas, choroid
plexus papillomas, craniopharyngiomas, primitive neuroectodermal tumors (PNETs), or atypical teratoid/rhabdoid
tumors (AT/RTs). The most frequent location of this
tumor is the supratentorial compartment rather than the
posterior fossa [68].
We present a rare case of a definitely congenital
anaplastic astrocytoma and analysis of its genetic alterations. Although there are some reports on genetic alterations in these tumors, none address the methylation
status of O6-methylguanine-DNA methyltransferase
(MGMT), 1p/19q loss of heterozygosity (LOH), or isocitrate dehydrogenase 1 (IDH1) mutations, factors that
are usually examined in genetic analyses of adult gliomas. Analysis of these factors may be helpful for
developing a treatment strategy and assessing the prognosis of patients with congenital malignant gliomas. We
report the genetic alternations and clinical course of a
patient with this rare tumor.

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Clinical summary
The mother, a 33-year-old gravida 2, para 2 woman,
underwent routine fetal ultrasonography (US) examination
at 36 weeks and 2 days of pregnancy that revealed fetal
macrocephaly and a huge mass in the right cerebral
hemisphere. The intracranial mass was confirmed by fetal
magnetic resonance imaging (MRI) study (Fig. 1). A 3.33kg girl was delivered vaginally at term (39 weeks of gestation). Her Apgar scores were 6 and 9 at 1 and 5 min
postdelivery, her head circumference was 37.5 cm, and the
anterior fontanel exhibited a slight bulge. Physical and
neurological examinations returned normal results without
macrocrania, tense fontanel, or sucking difficulties.
MRI performed after birth revealed a huge intraventricular mass occupying the right temporoparietal region; it
extended to the posterior fossa and resulted in midline shift
and brainstem compression. The mass was slightly hyperintense on T1-weighted images, hypointense on T2-weighted
images, and heterogeneously enhanced by gadolinium
diethylenetriamine pentaacetic acid (Gd-DTPA) (Fig. 2).
Computed tomography (CT) revealed no hemorrhage
or calcification. CT venography (CTV) showed that the
internal cerebral vein, vein of Galen, and basal vein of
Rosenthal were enlarged in this tumor (Fig. 3).
The tumor was subtotally resected via right temporoparietal craniotomy by two-stage surgical intervention. At
initial operation, we first coagulated main feeders, such as
anterior choroidal artery and posterior choroidal artery.
Nevertheless, due to significant blood loss, we were able to
perform only partial tumor resection at the first operation.

Fig. 1 Fetal magnetic resonance image (MRI) obtained at 37 weeks

of gestation. Axial T2-weighted image demonstrates a huge, lowintensity mass occupying the right cerebral hemisphere and encasing
enlarged vessels

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Brain Tumor Pathol (2012) 29:107112

The residual tumor with large necrotic component was

subtotally resected 3 weeks later. It was grayish and had a
strong bleeding tendency. As the tumor border was not
clearly demarcated we had to leave a small piece of the
tumor surrounding the brainstem. We subsequently delivered three cycles of chemotherapy consisting of 500 mg/m2
carboplatin for 1 day and 80 mg/m2 etoposide for 3 days.
During chemotherapy, the infant developed anemia and
leukopenia due to bone marrow suppression; this was
addressed by transfusing concentrated erythrocytes. MRI
and methionine positron emission tomography/computed
tomography (PET/CT) images acquired after chemotherapy
revealed that the residual mass at the dorsal portion of the
brainstem was not enlarged; there was no recurrence of the
lesion (Fig. 4). The patient was alive and doing well
12 months after surgery.

Pathological findings and results of genetic analysis

Tumor samples were obtained during the surgical procedures, formalin fixed, and paraffin embedded for histological studies, or quick-frozen in liquid nitrogen and kept
at -80C for genetic studies. Serial sections (5 lm) were
stained routinely with hematoxylin and eosin or used for
immunohistochemical studies. The latter were stained
using avidinbiotin immunoperoxidase methods after
microwave heat-induced antigen retrieval. The antibodies
were glial fibrillary acidic protein (prediluted; Dako Cytomation, Glostrup, Denmark), p53 (dilution 1:400; Dako),
epidermal growth factor receptor [EGFR (dilution 1:50;
Zymed Laboratories, South San Francisco, CA, USA)], and
MIB-1 (dilution 1:50; Dako). The DNA methylation pattern of the MGMT gene promoter was determined with
methylation-specific polymerase chain reaction (PCR).
Genomic DNA was isolated from frozen surgical specimens with the Qiagen kit (Qiagen, Valencia, CA, USA).
Tumor DNA was treated with sodium bisulfite using the
CpG genome DNA modification kit (Qiagen). IDH1
alteration of the mutational hotspot codon R132 was
assessed by directional sequencing of PCR-amplified
fragments on an ABI 310 PRISM DNA sequencer (Applied
Biosystems, Foster City, CA, USA), with the Big DyeTM
terminator cycle sequencing kit (Applied Biosystems).
Chromosomal alterations of 1p and 19q were analyzed
using fluorescent in situ hybridation (FISH) (Mitsubishi
Chemical Medience Corp., Tokyo). Four probes mapping
1p36, 1q25, 19p13, and 19q13 were selected. Histopathological examination confirmed the diffuse proliferation
of atypical glial cells with pleomorphic nuclei associated
with marked hemorrhage in this tumor. Cellularity was
moderate, and there were occasional mitoses (Fig. 5a, b).
Neither geographic necrosis nor glomeruloid vascular

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109

Fig. 2 Magnetic resonance

images (MRI) obtained after
birth. A huge, slightly
hyperintense, mass is seen on
the T1-weighted image (a); it is
hypointense on T2-weighted
images (b), and heterogeneously
enhanced by gadolinium
gadolinium diethylenetriamine
pentaacetic acid Gd-DTPA)
(c, d). The tumor was located
mainly intraventricularly in the
right cerebral hemisphere. It
extended to the opposite side
and the infratentorial region,
resulting in severe compression
of the brain stem and in
hydrocephalus

Fig. 3 Computed tomography

(CT) and computed tomography
venography (CTV) images
obtained after birth. The tumor
was a hyperdense mass on the
CT scan; no hemorrhage or
calcification was observed. CTV
revealed an enlarged internal
cerebral vein (ICV), vein of
Galen, and basal vein of
Rosenthal

proliferation was observed. Immunohistochemically; tumor

cells were diffusely positive for glial fibrillary acidic protein (GFAP) (Fig. 5c). The MIB-1 labeling index was 19%
(Fig. 5d). Based on these findings, the tumor was diagnosed as an anaplastic astrocytoma.
Results of genetic analyses of the tumor (congenital) and
of three high-grade pediatric gliomas and an adult glioma
treated at our institution are shown in Table 1. In this case,
we observed no MGMT gene promoter methylation and no

1p/19q LOH or IDH1 mutation. Immunohistochemical

staining was positive for p53 but negative for EGFR
(Fig. 5e, f). The three pediatric tumors encountered earlier
at our institution showed no IDH1 mutation; they were
positive for p53 and negative of EGFR protein expression,
which was common in pediatric high-grade gliomas
reported previously [913]. Genetic alterations were similar to those observed in the patient with congenital anaplastic astrocytoma in this report.

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Brain Tumor Pathol (2012) 29:107112

Fig. 4 Magnetic resonance

imaging (MRI) and methionine
positron emission tomography/
computed tomography (PET/
CT) images obtained after
chemotherapy. Most of the
enhanced region, excepting the
dorsal portion of the brainstem,
has disappeared. The axial PET/
CT fusion image shows slightly
increased methionine uptake at
this portion [measured
maximum standardized uptake
value (SUVmax) = 1.02]. This
lesion was considered to be the
residual tumor, but had a
biologically inactive nature

Discussion
As congenital malignant gliomas are very rare, no standard
treatment has been developed. Malano et al. [14] reviewed
67 cases and showed that the combination of grosstotal
resection and adjuvant chemotherapy extended the survival
duration. However, this treatment cannot be delivered to
neonates because the amount of circulating blood is small
and even a small blood loss may induce hemodynamic
instability. In addition, neonates are at risk for myelosuppression and infection due to the toxicity of chemotherapy.
We successfully treated our patient by two-stage surgical
intervention followed by chemotherapy; to date, she has
not suffered tumor recurrence. Before surgery, we established an infusion route for blood transfusion and were
prepared to stop operating if the situation warranted discontinuation. Our chemotherapy protocol delivered carboplatin and etoposide; we found these agents effective and
safe for treating this tumor.
Genetic alterations involved in congenital malignant gliomas remain unknown. Our case was immunopositive for
p53 and negative for EGFR. According to Brat et al. [15],
congenital glioblastoma multiforme (GBM) overexpressed
p53 and minimally expressed EGFR. The authors found no

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EGFR amplifications, 9p21 deletions, or TP53 or PTEN

mutations, which are genetic alterations common in adult
GBM. As the p53 overexpression is frequently observed in
pediatric GBM, the authors speculated that p53 dysregulation
plays an important role in tumorigenesis. Others also reported a positive correlation between overexpression of p53 and
a poor prognosis in children with GBM; no such relationship
has been documented in congenital GBM [15, 16].
IDH1 mutations have not been demonstrated previously
in congenital malignant glioma. In our case, there was no
IDH1 mutation. These mutations were very rare in pediatric cases and were helpful in differentiating between
pediatric- and adult secondary GBM [9, 10, 17]. Of three
cases previously encountered at our institution, none
manifested this mutation. MGMT methylation has not been
reported in congenital malignant glioma, although MGMT
gene promoter methylation was observed in 4050% of
pediatric- and 4047% of adult GBM [18, 19]. According
to Donson et al. [19], MGMT promoter methylation was
correlated with prolonged survival in children treated with
temozolomide (TMZ) and radiotherapy and also with the
overall survival of pediatric patients, regardless of treatment. None of the pediatric patients encountered at our
institution manifested methylation.

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111

Fig. 5 Micrographs of
histological findings
(hematoxylin and eosin
staining) and of
immunohistochemical staining
of tumor specimens. Note the
diffuse proliferation of atypical
glial cells and hemorrhage.
There was neither geographic
necrosis nor glomeruloid
vascular proliferation (a).
Tumor cells showed a moderate
degree of polymorphism.
Mitoses were occasionally
found (b). Tumor cells were
positive for glial fibrillary acidic
protein (GFAP) (c). The MIB-1
labeling index was
approximately 19% (d). Tumor
cells were positive for p53 but
negative for epidermal growth
factor receptor (EGFR) (e, f).
a 9100; b, c 9400; d 9200; e,
f 9400

Table 1 Summary of genetic

alterations of gliomas in our
institution

Classification

Histology

Age

Sex

MGMT
methylation

1p
LOH

19q
LOH

IDH1
mutation

p53

EGFR

Pediatric

AA anaplastic astrocytoma,
GBM glioblastoma, F female,
M male, - negative, ? positive,
NE not examined, MGMT O6methylguanine-DNA
methyltransferase, LOH loss of
heterozygosity, IDH1 isocitrate
dehydrogenase 1

Congenital (this
case)

AA

Pediatric 2

AA

Pediatric 3

AA

NE

Pediatric 4
Adult

GBM

10

Grade II/III (26 cases) (%)

68

50

41

54

70

54

Grade IV (27 cases) (%)

41

19

22

82

68

In our search of the literature we found no report of 1p/

19q LOH in congenital malignant glioma. The combined
loss of 1p and 19q is an established molecular signature of
oligodendrogliomas and oligoastrocytomas; it is associated
with chemosensitivity and a better prognosis [2022]. In
adult GBM, the combined loss of 1p and 19q is uncommon

(020%) and its clinical significance remains to be established [23, 24]. Pollac et al. [25] reported 1p LOH in
29.9%, 19q LOH in 28%, and combined 1p and 19q LOH
in 13.1% of pediatric cases; they found no favorable
association of LOH of 1p or 19q, singly or in combination,
with survival. We did not observe 1p and/or 19q LOH in

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Brain Tumor Pathol (2012) 29:107112

the four pediatric cases seen at our hospital. As this genetic

alteration may be affected by tumor pathology, its relationship with the clinical course deserves study.
The patterns of genetic alterations in high-grade gliomas
appear to be different in pediatric and adult patients. Paugh
et al. [9] reported the focal amplification of platelet-derived
growth factor receptor alpha, a frequent gain of chromosome 1q, and the absence of IDH1 hotspot mutations as
characteristic events in pediatric high-grade gliomas. How
are genetic alterations different in pediatric- and congenital
gliomas? None of 11 high-grade gliomas in infants reported by Paugh et al. [9] manifested a chromosome 1q gain, a
finding significantly different from that made in older
children; the prognosis of the infants was better than of the
older children. We used reverse transcriptase polymerase
chain reaction (RT-PCR) to study RNA expression of the
MDM4 gene that was mapped on chromosome 1q, which
we found in our infant with congenital glioma but not in the
other three children. Although RNA overexpression of
MDM4 may not be directly reflective of a chromosome 1q
gain, our finding suggests that the genetic background is
different between patients with congenital glioma and older
children with this tumor.
Acknowledgments
assistance.

We thank Ms. Mai Fujita for technical

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