Pe d i a t r i c I m a g i n g P i c t o r i a l E s s ay

DAmbrosio et al.
Metastatic CNS Neuroblastoma

Pediatric Imaging
Pictorial Essay
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FOCUS ON:

Imaging of Metastatic CNS

Neuroblastoma
Nicholas DAmbrosio1 OBJECTIVE. Although neuroblastoma is a common childhood malignancy, which fre-
John K. Lyo quently metastasizes, involvement of the CNS is rarely reported in the literature. However,
Robert J. Young over the past several years, we have encountered an increasing number of cases of metastatic
Sophia S. Haque neuroblastoma to the CNS. This metastatic potential and changing metastatic pattern may, in
Sasan Karimi part, be due to advances in medical treatment, leading to prolonged survival. This article will
review the common and uncommon manifestations of metastatic neuroblastoma with an em-
DAmbrosio N, Lyo JK, Young RJ, Haque SS, phasis on the skull, dura, brain, ventricles, and leptomeninges.
Karimi S CONCLUSION. Neuroblastoma has diverse manifestations including masquerading as
primary neurologic disease. This disease must be considered in a child with any unexplained
neurologic disorder. Realizing that neuroblastoma may represent the cause of neurologic dis-
ease in a child will lead to earlier diagnosis.

Keywords: CNS metastases, dural metastases,
neuroblastoma, pediatric neuroradiology, skull
metastases
DOI:10.2214/AJR.09.3203
Received June 17, 2009; accepted after revision
October 25, 2009.
1
All authors: Department of Radiology, Memorial
Sloan-Kettering Cancer Center, 1275 York, Ave.,
New York, NY 10065. Address correspondence to
N. DAmbrosio (dambrosn@hotmail.com).
AJR 2010; 194:12231229
0361803X/10/19451223
American Roentgen Ray Society
N
euroblastoma is the third most
common malignancy in children
after leukemia and primary CNS
brain tumors. It accounts for 10
15% of childhood malignancies. The prima-
ry tumor commonly arises in the adrenal
gland or along the sympathetic chain, usual-
ly in the abdomen. The recognition of neuro-
blastoma may be difficult because of its many
different manifestationshence, the term,
the great imitator.
Metastases are present in up to 70% of pa-
tients with neuroblastoma at the time of di-
agnosis [1]. Secondary craniocerebral neu-
roblastoma manifests most often as osseous
metastases involving the calvaria, orbit, or
skull base [2]. Metastatic CNS neuroblas-
toma may also occur anywhere in the CNS
as a parenchymal, intraventricular, or spinal
cord mass.
Materials and Methods
Study Group
We retrospectively reviewed neuroimaging ex-
aminations of 90 neuroblastoma patients whose
cases were presented at neurooncology tumor
board rounds over the previous 3 years at Memo-
rial Sloan-Kettering Cancer Center (MSKCC).
This series of patients does not represent the en-
tire population of neuroblastoma patients treated
at our institution, but represents a selected sub-
set of patients with CNS manifestations. Most of
these patients had primary or metastatic neuro-
blastoma confined to the spinal cord and paraspi-
nal regions. These particular manifestations of the
disease will not be emphasized in this review. In-
stead, this article will focus on the unusual mani-
festations of metastatic neuroblastoma involving
the brain, skull, dura, and leptomeninges.
Metastatic CNS Neuroblastoma
SkullMetastatic involvement of the skull has
been found in up to 25% of patients with neuro-
blastoma. Neuroblastoma is the most common
malignant metastasis to the skull in children [3].
These calvarial lesions often extend to produce
epidural deposits.
Metastatic involvement of the skull produces sev-
eral possible radiographic findings: thickened bone,
the so-called hair-on-end periosteal reaction, lyt-
ic defects, and separation of sutures. The differen-
tial diagnosis of multiple lytic skull lesions in a child
includes Langerhans cell histiocytosis, leukemia,
lymphoma, and sarcoma metastases [2, 4].
The sutural separation secondary to direct in-
volvement of neuroblastoma is different from that
found with generalized increased intracranial pres-
sure. In neuroblastoma, the sutural separation is not
uniform and the margins of the sutures are some-
what indistinct [3, 5] (Fig. 1). Extension of epidural
deposits along the sutures produces erosion of the
suture that then results in split sutures [4].
The hair-on-end appearance is a periosteal re-
sponse to tumor cells extending from a calvarial

AJR:194, May 2010 1223


metastasis (Fig. 2). The inner aspect of the perios-
teum is particularly resistant to penetration by tu-
mor cells so the tumor, as it breaks out of the bone,
lifts the periosteum, thereby producing plaquelike
epidural deposits of tumor [2]. Skull metastases
are often very subtle. Scalp lesions are a com-
mon accompaniment of calvarial metastases [4,
Downloaded from www.ajronline.org by 36.79.137.44 on 01/04/17 from IP address 36.79.137.44. Copyright ARRS. For personal use only; all rights reserved
6] (Fig. 3).
DuraMetastatic neuroblastoma has a predi-
lection to metastasize to the dura (Fig. 4). Dural
metastases tend to favor the external surface of the
dura, spreading diffusely over both the convexi-
ties and base of the skull. The dura acts as a bar-
rier to direct invasion, so involvement of the brain
parenchyma is rarely seen [1]. Dural metastases
are almost always associated with osseous metas-
tases and can be hemorrhagic. Dural metastases
may respond favorably to treatment (Fig. 5).
Neuroblastoma commonly metastasizes to the
base of the skull and orbits late in the disease. Both
Langerhans cell histiocytosis and metastatic neu-
roblastoma characteristically involve the postero-
lateral part of the orbit where the frontal bone and
greater wing of the sphenoid meet [7] (Fig. 6).
Parenchymal metastasesDespite the high
frequency of dissemination to the bone marrow,
metastatic spread to the CNS, including involve-
ment of either brain parenchyma or leptomenin-
ges, has been rare. Like primary CNS neuroblas-
toma, which is even rarer, metastases are often
hemorrhagic (Fig. 7). Supratentorial lesions are
more common than infratentorial lesions [8]. CNS
involvement can be clinically occult and carries
with it a poor prognosis.
Histologically, secondary forms of cerebral
neuroblastoma are similar. They are highly cel-
lular tumors. Grossly, they appear lobulated and
well defined but frequently show cystic degenera-
tion and blood staining of cysts and occasionally
show extensive hemorrhages (Fig. 8). Hemorrhage
is uncommon in most other childhood cerebral
neoplasms [2, 4].
Neuroblastoma should be considered in the
differential diagnosis of a child with an intracra-
nial mass. Some helpful distinguishing features,
including frequent hemorrhage and calcification,
have been reported.
Oligodendroglioma, astrocytoma, ependymo-
ma, and other primitive neuroectodermal tumors
must be included in the differential diagnosis [9].
Most CNS metastases are detected at the time
of recurrence rather than diagnosis. The CNS is
the sole site of recurrence in 64% of neuroblas-
toma patients. As the survival of children with
metastatic neuroblastoma improves with recent
advances in treatment, CNS involvement is being
detected more frequently. The CNS can be a sanc-
tuary site for cancer cells because the bloodbrain
1224 AJR:194, May 2010
DAmbrosio et al.
barrier impedes penetration of most chemothera-
peutic agents [1012].
The MSKCC experience has confirmed the low
but increasing incidence of CNS neuroblastoma as
a complication of stage IV metastatic disease (Fig.
9). Although the overall incidence rate for newly
diagnosed patients is approximately 6.3%, among
those who have recently been treated with inten-
sive chemotherapy and immunotherapy, the inci-
dence rate is 10% [13].
New regimens for the treatment of neuroblas-
toma have been developed including bone marrow
transplantation and intensive chemotherapy and
radiation, which may be changing the metastatic
pattern of neuroblastoma. It is also possible that
intensive chemotherapy leads to further genetic
evolution of the tumors, with a change in meta-
static potential [8].
Intraventricular and leptomeningeal metasta
sesAn intraventricular location of metastasis ap-
pears to be exceptional: It was observed at diagnosis
in only one patient in our series (Fig. 10) and has
not been reported previously to our knowledge.
Leptomeningeal metastasis is rare except in
widely disseminated disease. In children, most
leptomeningeal metastases are associated with
medulloblastoma, ependymoma, and pineal gland
tumors. Leptomeningeal metastases are very sen-
sitive to radiation therapy [14]. The pathogenet-
ic process leading to leptomeningeal involvement
by extracranial neuroblastoma is uncertain. Neu-
roblastoma develops in the embryo from the neu-
ral crest, an ectodermal tissue with pluripotential
differentiating capability. Investigators have pos-
tulated that leptomeningeal tissues, also derived
from ectoderm, provide the appropriate soil to
support metastasizing neuroectodermal tumors,
such as neuroblastoma [15] (Fig. 11).
In one exceptional case in our series, progres-
sive leptomeningeal metastases were detected in
a 3-year-old girl over several months, with subse-
quent development of hemorrhagic transformation
(Fig. 12). To our knowledge, this is the first case of
hemorrhagic leptomeningeal metastases reported
in the literature.
Discussion
CNS involvement in patients with neuro-
blastoma can be clinically occult and is asso-
ciated with a poor prognosis. Early detection
and aggressive treatment of this complication
may allow some patients to live longer than
they would have otherwise. MRI and CT are
the techniques of choice in the assessment
of CNS relapse in children with primary ex-
tracerebral neuroblastoma. Metaiodobenzyl-
guanidine scanning is not a reliable predictor
of CNS disease [10].
Secondary craniocerebral neuroblastoma
manifests most often as osseous metastases
involving the calvaria, orbit, or skull base.
Metastatic involvement of the skull has been
found in up to 25% of cases of neuroblasto-
ma. The reported frequency of CNS metasta-
ses (i.e., parenchymal or leptomeningeal) in
disseminated neuroblastoma is 216%.
The 3-year reported risk of CNS metasta-
ses in children with stage IV neuroblastoma
is 8%. Most CNS metastases are detected at
the time of recurrence rather than diagnosis.
CNS metastases are usually from tumor in-
filtration of the mesoderm (dura) and neural
crest (leptomeninges) [16]. Direct involve-
ment of the brain parenchyma and of the pia
arachnoid and subarachnoid membranes af-
ter relapse of classic childhood neuroblasto-
ma is a serious complication that must be rec-
ognized and treated early to provide the best
opportunity for a favorable outcome [17].
We have assembled representative cas-
es that illustrate many aspects of metastat-
ic neuroblastoma affecting the CNS. Neu-
roblastoma should be considered in the
differential diagnosis of a child with an in-
tracranial mass. Some helpful distinguishing
features, including frequent hemorrhage and
calcification, have been reported.
Neuroblastoma has diverse manifestations
including masquerading as primary neuro-
logic disease. This disease must be consid-
ered in a child with any unexplained neuro-
logic disorder. Realizing that neuroblastoma
may represent the cause of neurologic dis-
ease in a child will lead to earlier diagnosis.
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Fig. 11-year-old boy with metastatic neuroblastoma. Axial CT image shows Fig. 29-year-old girl with metastatic neuroblastoma. Axial CT image shows
large lytic defect, resulting in separation of lambdoid suture, and indistinctness of periosteal response to tumor cells extending from calvarial metastases (arrow),
sutures (arrows). resulting in characteristic hair-on-end appearance, which is often subtle.

Fig. 37-year-old boy with metastatic
neuroblastoma. Axial CT image shows scalp soft-
tissue mass in occipital region (arrow). Erosive lytic
changes were identified in subjacent occipital bone
(not shown).
Fig. 44-year-old asymptomatic boy with metastatic
neuroblastoma. Coronal contrast-enhanced T1
image obtained as part of routine surveillance
shows expansile right frontal epidural mass (arrow)
compatible with metastasis.

AJR:194, May 2010 1225

 DAmbrosio et al. Fig. 51-year-old girl with metastatic neuroblastoma.
A, Axial contrast-enhanced CT image shows
enhancing bilateral dural metastases (arrows).
B, Axial contrast-enhanced CT image 6 months
after patient had undergone therapy shows interval
resolution of dura-based metastases.
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A B

Fig. 63-year-old girl with stage IV neuroblastoma

who presented with visual disturbances.
A, Contrast-enhanced CT scan shows large epidural
mass (arrow) projecting into suprasellar cistern.
B, Image obtained using bone windows shows
underlying osseous metastasis (arrow),
characteristically involving area where lateral orbital
wall meets greater wing of sphenoid bone.

A B

A B C
Fig. 76-year-old girl who presented with left-sided weakness and headaches.
A and B, Unenhanced (A) and contrast-enhanced (B) T1-weighted images show complex, hemorrhagic right parietal lobe mass, with enhancing solid component (arrow, B).
C, T2-weighted image shows mild vasogenic edema (arrow) surrounding mass.

1226 AJR:194, May 2010

 Metastatic CNS Neuroblastoma
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A B C
Fig. 84-year-old girl with rapidly progressive neuroblastoma seen over course of 2 months.
A, Initial CT scan obtained during staging is unremarkable.
B, Unenhanced CT scan obtained 2 months after A shows acute right frontoparietal lobe hematoma, with surrounding vasogenic edema.
C, Contrast-enhanced CT scan obtained at same time as B better defines underlying peripherally enhancing lesion (arrow), which was metastatic neuroblastoma, biopsy-
proven.

Fig. 9A and B, 4-year-old boy with stage IV

neuroblastoma who presented with hemorrhagic left
frontal lobe lesion marked by fluidfluid level (arrows)
and peripheral rim of enhancement.
A B

AJR:194, May 2010 1227

 DAmbrosio et al.

Fig. 1010-year-old girl with metastatic

neuroblastoma.
A, Initial contrast-enhanced MR image shows tiny
enhancing intraventricular lesion (arrow) within left
lateral ventricle suspicious for metastasis.
B, MR image obtained after patient had undergone
3 months of therapy shows lesion (arrow) is more
conspicuous and has nearly doubled in size.
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A B

Fig. 116-year-old girl with metastatic

neuroblastoma. Axial (left) and sagittal (right)
contrast-enhanced T1-weighted images show diffuse
leptomeningeal enhancement, particularly involving
posterior fossa and brainstem, compatible with
leptomeningeal metastases.

A B C
Fig. 123-year-old girl with neuroblastoma and leptomeningeal metastases.
A, Initial contrast-enhanced T1-weighted image shows diffuse leptomeningeal enhancement (arrow).
B, Contrast-enhanced T1 image obtained 2 months after A shows leptomeningeal enhancement has progressed over 2-month period. Progression of nodular
leptomeningeal metastases (arrows) is also apparent. Two weeks after this image was obtained, patient presented with acute left-sided weakness.
C, Contrast-enhanced T1 image shows marked interval progression of leptomeningeal enhancement (arrows) with apparent parenchymal invasion and surrounding
vasogenic edema.
(Fig. 12 continues on next page)

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 Metastatic CNS Neuroblastoma
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D E
Fig. 12 (continued)3-year-old girl with neuroblastoma and leptomeningeal metastases.
D and E, Axial gradient-echo image (D) and unenhanced CT image (E) obtained shortly after B and C show hemorrhagic transformation of leptomeningeal metastases.

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