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

FOCUS ON:

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Pediatric Imaging
Pictorial Essay

Nicholas DAmbrosio1
John K. Lyo
Robert J. Young
Sophia S. Haque
Sasan Karimi
DAmbrosio N, Lyo JK, Young RJ, Haque SS,
Karimi S

Imaging of Metastatic CNS

Neuroblastoma
OBJECTIVE. Although neuroblastoma is a common childhood malignancy, which frequently metastasizes, involvement of the CNS is rarely reported in the literature. However,
over the past several years, we have encountered an increasing number of cases of metastatic
neuroblastoma to the CNS. This metastatic potential and changing metastatic pattern may, in
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 emphasis on the skull, dura, brain, ventricles, and leptomeninges.
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 disease 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

AJR:194, May 2010

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 primary tumor commonly arises in the adrenal
gland or along the sympathetic chain, usually in the abdomen. The recognition of neuroblastoma may be difficult because of its many
different manifestationshence, the term,
the great imitator.
Metastases are present in up to 70% of patients with neuroblastoma at the time of diagnosis [1]. Secondary craniocerebral neuroblastoma manifests most often as osseous
metastases involving the calvaria, orbit, or
skull base [2]. Metastatic CNS neuroblastoma may also occur anywhere in the CNS
as a parenchymal, intraventricular, or spinal
cord mass.
Materials and Methods
Study Group
We retrospectively reviewed neuroimaging examinations of 90 neuroblastoma patients whose
cases were presented at neurooncology tumor
board rounds over the previous 3 years at Memorial Sloan-Kettering Cancer Center (MSKCC).
This series of patients does not represent the entire population of neuroblastoma patients treated
at our institution, but represents a selected subset of patients with CNS manifestations. Most of

these patients had primary or metastatic neuroblastoma confined to the spinal cord and paraspinal regions. These particular manifestations of the
disease will not be emphasized in this review. Instead, this article will focus on the unusual manifestations 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 neuroblastoma. 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 several possible radiographic findings: thickened bone,
the so-called hair-on-end periosteal reaction, lytic defects, and separation of sutures. The differential 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 involvement of neuroblastoma is different from that
found with generalized increased intracranial pressure. In neuroblastoma, the sutural separation is not
uniform and the margins of the sutures are somewhat 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 response to tumor cells extending from a calvarial

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DAmbrosio et al.
metastasis (Fig. 2). The inner aspect of the periosteum is particularly resistant to penetration by tumor 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 common accompaniment of calvarial metastases [4,
6] (Fig. 3).
DuraMetastatic neuroblastoma has a predilection to metastasize to the dura (Fig. 4). Dural
metastases tend to favor the external surface of the
dura, spreading diffusely over both the convexities and base of the skull. The dura acts as a barrier to direct invasion, so involvement of the brain
parenchyma is rarely seen [1]. Dural metastases
are almost always associated with osseous metastases 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 neuroblastoma characteristically involve the posterolateral 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 involvement of either brain parenchyma or leptomeninges, has been rare. Like primary CNS neuroblastoma, 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 cellular tumors. Grossly, they appear lobulated and
well defined but frequently show cystic degeneration 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 intracranial mass. Some helpful distinguishing features,
including frequent hemorrhage and calcification,
have been reported.
Oligodendroglioma, astrocytoma, ependymoma, 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 neuroblastoma 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 sanctuary site for cancer cells because the bloodbrain

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barrier impedes penetration of most chemotherapeutic 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 intensive chemotherapy and immunotherapy, the incidence rate is 10% [13].
New regimens for the treatment of neuroblastoma 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 metastatic potential [8].
Intraventricular and leptomeningeal metasta
sesAn intraventricular location of metastasis appears 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 sensitive to radiation therapy [14]. The pathogenetic process leading to leptomeningeal involvement
by extracranial neuroblastoma is uncertain. Neuroblastoma develops in the embryo from the neural crest, an ectodermal tissue with pluripotential
differentiating capability. Investigators have postulated 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, progressive leptomeningeal metastases were detected in
a 3-year-old girl over several months, with subsequent 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 neuroblastoma can be clinically occult and is associated 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 extracerebral neuroblastoma. Metaiodobenzylguanidine 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 neuroblastoma. The reported frequency of CNS metastases (i.e., parenchymal or leptomeningeal) in
disseminated neuroblastoma is 216%.
The 3-year reported risk of CNS metastases 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 infiltration of the mesoderm (dura) and neural
crest (leptomeninges) [16]. Direct involvement of the brain parenchyma and of the pia
arachnoid and subarachnoid membranes after relapse of classic childhood neuroblastoma is a serious complication that must be recognized and treated early to provide the best
opportunity for a favorable outcome [17].
We have assembled representative cases that illustrate many aspects of metastatic neuroblastoma affecting the CNS. Neuroblastoma should be considered in the
differential diagnosis of a child with an intracranial mass. Some helpful distinguishing
features, including frequent hemorrhage and
calcification, have been reported.
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 disease in a child will lead to earlier diagnosis.
References
1. Chirathivat S, Post MJ. CT demonstration of dural
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2. Zimmerman RA, Bilaniuk L. CT of primary and
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1980; 135:12391242
3. Healy JF, Bishop J, Rosenkrantz H. Cranial computed tomography in the detection of dural, orbital, and skull involvement in metastatic neuroblastoma. J Comput Tomogr 1981; 5:319323
4. Latchaw RE, LHeureux PR, Young G, Priest JR.
Neuroblastoma presenting as central nervous system disease. AJNR 1982; 3:623630
5. Pascual-Castroviejo I, Lopez-Martin V, RodriguezCosta T, Pascual-Pascual JI. Radiological and anatomical aspects of the cranial metastases of neuroblastomas. Neuroradiology 1975; 9:3338
6. Devkota J, El Gammal T, Brooks BS, Dannawi H.
Role of computed tomography in the evaluation of
therapy in case of cranial metastatic neuroblastoma.

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Metastatic CNS Neuroblastoma

J Comput Assist Tomogr 1981; 5:654659
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Karimi S. Craniofacial and intracranial manifestations of Langerhans cell histiocytosis: report of
findings in 100 patients. AJR 2008; 191:589597
8. Matthay K, Brisse H, Couanet D, et al. Central
nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 2003; 98:155165
9. Polat P, Kantarci M, Eren S, Suma S. Primary cerebral neuroblastoma. JBR-BTR 2005; 88:148
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10. Porto L, Keislich M, Yan B, Schwabe D, Zanella

F, Lanfermann H. Isolated CNS relapse in neuroblastoma. Neuropediatrics 2005; 36:112116

11. Egelhoff JC, Zalles C. Unusual CNS presentation
of neuroblastoma. Pediatr Radiol 1996; 26:5154
12. Gallet BL, Egelhoff JC. Unusual CNS and orbital
metastases of neuroblastoma. Pediatr Radiol
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13. Kramer K, Kushner B, Heller G, Cheung N. Neuroblastoma metastatic to the CNS: the Memorial
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14. Shaw DW, Weinberger E, Brewer DK. Leptomeningeal metastasis from primary extracerebral

Fig. 11-year-old boy with metastatic neuroblastoma. Axial CT image shows

large lytic defect, resulting in separation of lambdoid suture, and indistinctness of
sutures (arrows).

Fig. 37-year-old boy with metastatic

neuroblastoma. Axial CT image shows scalp softtissue mass in occipital region (arrow). Erosive lytic
changes were identified in subjacent occipital bone
(not shown).

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neuroblastoma: CT demonstration. AJNR 1990;

11: 804
15. Palasis S, Egelhoff JC, Morris JD, Koch BL, Ball
BS. CNS Relapse of treated stage IV neuroblastoma. Pediatr Radiol 1998; 28:990994
16. Blatt J, Fitz C, Mirro J Jr. Recognition of central
nervous system metastases in children with metastatic extracranial neuroblastoma. Pediatr Hema
tol Oncol 1997; 14:233241
17. Kellie SJ, Hayes FA, Bowman L, et al. Primary
extracranial neuroblastoma with CNS metastases
characterization by clinicopathologic findings
and neuroimaging. Cancer 1991; 68:19992006

Fig. 29-year-old girl with metastatic neuroblastoma. Axial CT image shows

periosteal response to tumor cells extending from calvarial metastases (arrow),
resulting in characteristic hair-on-end appearance, which is often subtle.

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.

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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.

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.

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.

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Metastatic CNS Neuroblastoma

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, biopsyproven.

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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.

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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.

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.

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

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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