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566
PEDIATRIC IMAGING
Updates in Diagnosis, Management,
and Treatment of Neuroblastoma1
Caroline C. Swift, MD
Meryle J. Eklund, MD
Jacqueline M. Kraveka, DO
Adina L. Alazraki, MD
Abbreviations: FDG = fluorine 18 fluorodeoxy-
glucose, IDRF = image-defined risk factor,
INRGSS = International Neuroblastoma Risk
Group Staging System, INSS = International
Neuroblastoma Staging System, MIBG =
metaiodobenzylguanidine
RadioGraphics 2018; 38:566–580
https://doi.org/10.1148/rg.2018170132
Content Codes:
1
From the Department of Radiology and Ra-
diological Science (C.C.S., M.J.E.) and Depart-
ment of Pediatrics (J.M.K.), Medical University
of South Carolina, 96 Jonathan Lucas St, MSC
323, Suite 210, Charleston, SC 29425; and De-
partment of Radiology and Imaging Sciences,
Emory University, Atlanta, Ga (A.L.A.). Pre-
sented as an education exhibit at the 2016 RSNA
Annual Meeting. Received May 11, 2017; revi-
sion requested August 25 and received Septem-
ber 22; accepted September 28. For this journal-
based SA-CME activity, the authors, editor, and
reviewers have disclosed no relevant relation-
ships. Address correspondence to C.C.S. (e-
mail: carriecusack2014@gmail.com).
©
RSNA, 2018
SA-CME LEARNING OBJECTIVES
After completing this journal-based SA-CME
activity, participants will be able to:
■■Recognize the role of different imaging
modalities in the detection, diagnosis,
treatment, and surveillance of neuroblas-
toma.
■■Listfactors associated with prognosis
and risk stratification in patients diag-
nosed with neuroblastoma.
■■Describe the INRGSS staging system
for neuroblastoma and recognize image-
defined risk factors.
See www.rsna.org/education/search/RG.
Neuroblastoma is an embryonic tumor of the peripheral sympathet-
ic nervous system. It is the most common extracranial solid tumor
of childhood and accounts for up to 15% of all pediatric cancer
fatalities. The manifestation of neuroblastoma is variable depend-
ing on the location of the tumor and on the presence or absence of
paraneoplastic syndromes. The prognosis of neuroblastoma is also
highly variable, ranging from spontaneous regression to widespread
metastatic disease that is unresponsive to treatment. The age of
the patient, stage of disease, histopathologic results, and multiple
biologic factors contribute to the presurgical and pretreatment
risk stratification of a patient with neuroblastoma. Multimodality
anatomic imaging with ultrasonography, computed tomography,
and magnetic resonance imaging, as well as functional or metabolic
nuclear imaging, are essential to determining the risk status of a
patient with neuroblastoma. Patients at low risk of metastasis or
death receive minimal intervention and those at high risk receive
multimodality treatment. New immunotherapeutic techniques and
nuclear medicine–targeted therapies have emerged and are demon-
strating promising response rates for patients at high risk. This ar-
ticle reviews updates in the diagnosis, management, and treatment
of neuroblastoma that have evolved over the past 2 decades, includ-
ing emphasis on presurgical risk stratification, genetic evaluation
of tumors, and the use of modern, high-quality, advanced imaging
modalities.
©
RSNA, 2018 • radiographics.rsna.org
Introduction
Neuroblastoma is a complex heterogeneous disease that arises from
the embryonic cells that form the primitive neural crest, with a natu-
ral history ranging from a benign course to a terminal illness. In re-
cent years, new imaging and molecular genetic techniques have been
used to stratify patients according to risk of metastasis or death and
to optimize treatment. In this article, we discuss the epidemiology
and pathogenesis of neuroblastoma, with focus on modern practices
in diagnosis, imaging, staging, and treatment of the disease.
Epidemiology
Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma com-
prise a spectrum of tumors that arise from primitive sympathetic
ganglion cells (neural crest cells). Overall, approximately 46% of
neuroblastomas arise from the adrenal gland, 18% arise from an
extra-adrenal abdominal location, 14% arise from the posterior me-
diastinum or thorax, and the remainder arise from the neck, pelvis,
RG  •  Volume 38  Number 2 Swift et al  567

TEACHING POINTS
■■ Clinical symptoms are diverse and vary depending on the an-
atomic location of the tumor. The majority of tumors (65%)
occur in the abdomen, most of which arise from the adrenal
gland.
■■ Genetic analysis of the tumor is an important component
of risk stratification and determining the prognostic effect of
neuroblastoma. Molecular classification of tumors is now rou-
tine due to the influence of genetic variations on outcome.
■■ The INRGSS was published in 2008 as a new way to stratify
patients before surgical intervention. This system is now used
in parallel with the older INSS. There are several key differenc-
es between the INRGSS and the INSS. First, whereas the INSS
was intended for postsurgical staging, the INRGSS places an
emphasis on pretreatment risk stratification based on clinical
criteria and IDRFs.
■■ Combining the INSS/INRGSS stage with the age at diagnosis,
the histologic results, and the biology and genetics of the tu-
mor allows patients to be placed into a low-, intermediate- or
high-risk group.
■■ US is often the first modality used to identify neuroblastic tu-
mors. CT or MR imaging is then used to further character-
ize masses and evaluate for IDRFs. MIBG scintigraphy is now
required for staging and to determine eligibility for potential
MIBG therapy. In addition, nuclear medicine imaging, bone
scanning, FDG PET /CT, whole-body MR imaging, and radi-
ography may be used as adjuncts in evaluation of metastatic
disease. Figure 1.  Anatomic illustration shows the distribution of the
sympathetic ganglia extending from the neck to the pelvis,
including the adrenal medulla (sympathetic tissue shown in
blue). (Reprinted, with permission, from reference 2.)

and other locations (1) (Fig 1). Neuroblastoma

represents approximately 97% of all neuroblastic
tumors and is the third most common childhood
cancer (3,4). It is the most common extracra-
nial solid tumor of childhood (4,5). Because
of the aggressive nature and high likelihood of
metastatic disease at diagnosis, neuroblastoma
accounts for nearly 15% of all pediatric cancer
fatalities (6,7).
Neuroblastoma is the most commonly diag-
nosed cancer in infancy, and 41% of patients
with neuroblastoma receive the diagnosis within
the first 3 months of life (4). The median age
at diagnosis is 19 months (8). The prognosis of
neuroblastoma varies with age. Children who are
less than 1 year old at diagnosis of neuroblastoma
have a significantly higher 5-year survival rate
compared with those who receive the diagnosis
at greater than 1 year of age (4,8).There are also
racial and ethnic disparities in risk and survival in
children with neuroblastoma. Analysis of 3539 pa-
tients enrolled in the Children’s Oncology Group
neuroblastoma biology study demonstrated that
black and Native American patients had a higher
prevalence of high-risk disease, which was thought
to be due to genetic differences (8).
Neuroblastomas can arise anywhere through-
out the sympathetic nervous system. Clinical
symptoms are diverse and vary depending on the
anatomic location of the tumor. The majority of
tumors (65%) occur in the abdomen, most of
which arise from the adrenal gland (Fig 2) (6,7).
Abdominal masses often manifest with constipa-
tion and abdominal distention that may be painful.
Sometimes a palpable mass is found at routine
physical examination (Fig 3). In other cases, com-
pression of renal vessels can lead to hypertension.
Some thoracic neuroblastomas can manifest with
scoliosis or compression of the airway. If the tumor
arises from the paravertebral sympathetic ganglia,
it can invade the spinal canal and cause compres-
sion, leading to pain, motor sensory deficits, or
Horner syndrome (Fig 4) (7,10). Common sites
of metastasis include regional lymph nodes, bone
marrow and cortex, and the liver (1). Infrequently,
orbital metastasis can cause a “raccoon eyes”
appearance and proptosis (Fig 5) (10,11). This is
due to obstruction of ophthalmic and facial veins
by metastatic tumor but could be misdiagnosed as
nonaccidental trauma or coagulopathy. Most cases
of disease recurrence occur in the bone marrow,
cortex, or central nervous system (11).
Occasionally, the diagnosis is suspected on the
basis of a bioactive molecular phenomenon in the
form of a paraneoplastic syndrome. In 2%–3%
of patients with neuroblastoma, opsoclonus-
myoclonus syndrome occurs (12). This is believed
to be an immune-mediated response that causes
568  March-April 2018 radiographics.rsna.org

Figure 2.  High-risk neuroblastoma in

a 10-year-old girl. Coronal computed
tomographic (CT) image shows a large
heterogeneously enhancing mass. The
primary mass is centered in the right ad-
renal gland (arrowheads). The left adrenal
gland (circle) is normal.

Figure 3.  Stage IV intermediate-risk neuroblastoma in a 5-month-old girl with hepatomegaly at

physical examination. (a) Transverse ultrasonographic (US) view of the liver shows numerous hepatic
masses replacing the normal hepatic tissue (arrowheads). (b) Subsequently acquired coronal CT
image of the abdomen and pelvis with oral and intravenous contrast material shows innumerable
hypoattenuating and heterogeneously enhancing metastatic lesions throughout the liver. The liver
is markedly enlarged.

Figure 4.  Biopsy-proven neuroblastoma in a 16-month-old girl with new-onset lower extremity weak-
ness and inability to walk. Coronal (a) and axial (b) T2-weighted magnetic resonance (MR) images of
the thoracic spine reveal a right lower thoracic paraspinal mass with extension through multiple neural
foramina, invasion of the spinal canal (arrowheads), and compression of the spinal canal (arrow in b).
RG  •  Volume 38  Number 2 Swift et al  569

Figure 5.  Neuroblastoma in a 22-month-old girl who presented with left-sided proptosis, facial swell-
ing, and bruising. (a) Axial CT image of the face (bone window) shows an osseous lesion centered in the
left lateral orbital wall (circle) with an extraosseous component exhibiting mass effect on the intraconal
structures. (b) Axial postcontrast T1-weighted MR image reveals infiltration of the intraorbital extraconal
space with associated mass effect and proptosis (arrowheads). There is extensive associated erosion of the
pterygoid plates and invasion of the posterior paranasal sinuses. (c) Coronal CT image of the face (bone
window) shows extensive tumor involvement of the skull base (arrowheads), with an additional lesion in
the left mandibular ramus (circle).

Another paraneoplastic syndrome seen with

neuroblastoma is associated with the secretion
of vasoactive intestinal peptide. This is a less
common phenomenon in which autonomous
secretion of vasoactive intestinal peptide by the
tumor causes profuse diarrhea and electrolyte
abnormalities. This can be diagnosed by mea-
suring serum vasoactive intestinal peptide levels.
Symptoms usually subside after removal of the
tumor (16).

dancing eye movement, rhythmic jerking of the
limbs and trunk, and ataxia. Affected children have
a high level of antibodies that react with central
nervous system antigens (13). Tumors tend to be
small at diagnosis, likely owing to the early clinical
presentation, and these patients are often good
candidates for surgical resection (Fig 6). Unfor-
tunately, removal of the tumor does not always
improve neurologic symptoms. Immunotherapy
with intravenous immunoglobulin has been shown
to improve neurologic symptoms in up to 83% of
patients during initial treatment; however, relapse
is common (14). Up to 69% of patients with
opsoclonus-myoclonus have residual behavioral
abnormalities or psychomotor impairment after
treatment, even if no evidence of active tumor can
be detected at imaging or chemical analysis (15).
Pathogenesis
Genetic analysis of the tumor is an important
component of risk stratification and determining
the prognostic effect of neuroblastoma. Molecu-
lar classification of tumors is now routine due to
the influence of genetic variations on outcome.
MYCN gene amplification and ploidy have been
linked with neuroblastoma prognosis for more
than 2 decades, and many more genetic abnor-
malities have been identified.
MYCN amplification occurs in approximately
20% of primary tumors and is associated with
advanced stage and poor outcome. The detection
of MYCN gene amplification can be performed
with fluorescence in-situ hybridization (17). Al-
though infants with neuroblastoma usually have
a favorable prognosis, MYCN amplification has
been shown to have significantly worse event-
free and overall survival rates in both infants and
young children. It is associated with advanced-
stage disease, rapid tumor progression, and a
poorer prognosis (18,19).
570  March-April 2018 radiographics.rsna.org
Tumor cell DNA content is also implicated
in the pathogenesis of neuroblastoma. DNA
content is measured and given a DNA index to
compare the DNA content of the tumor cells to
that of normal cells. Normal cells have a DNA
index of 1. Neuroblastomas with a higher DNA
content (DNA index > 1, hyperdiploid) are as-
sociated with lower tumor stage and improved
outcomes in children younger than 18 months.
In these younger patients, this increased DNA
content is likely caused by defects in mitosis
that lead to whole-chromosome gains, with no
segmental aberration. In older patients, however,
hyperploidy is often seen because of segmental
chromosomal aberrations and is not as impor-
tant for prognosis (20,21).
Chromosomal deletions are found in up to
50% of neuroblastomas. Segmental chromosomal
aberrations associated with poor outcome include
deletion of 1p36, unbalanced gain of 17q, and
deletion of 11q (22,23). Unlike in adult tumors,
somatic mutations are not common in the tumors
of children. More frequently mutated genes in
neuroblastomas include anaplastic lymphoma
kinase (ALK), protein tyrosine phosphatase
nonreceptor type 11 (PTPN11), α-thalassemia
X-linked intellectual disability (ATRX), MYCN,
and NRAS oncogenes (24).
The majority of neuroblastomas are sporadic,
with patients in whom they occur having no
genetically inherited predisposition or additional
congenital abnormality. Approximately 1% of
cases are familial (17). Mutations in the ALK,
PHOX2B, and KIF1B genes have been identified
in patients with genetically inherited cases. Acti-
vating mutations in the tyrosine kinase domain
of the ALK oncogene account for most cases of
hereditary neuroblastoma (25). ALK mutations
and amplification occur in approximately 15%
of primary neuroblastoma tumors (26). Muta-
tions in the tyrosine kinase region of this gene
are involved in tumor development, and ALK
inhibitors may be a therapeutic intervention in
the future (27,28). Children with either sporadic
or familial neuroblastoma in conjunction with
congenital central hypoventilation syndrome,
Hirschsprung disease, or both usually have loss-
of-function mutations in the homeobox gene
PHOX2B (18). Numerous other genetic abnor-
malities have been implicated in patients with
neuroblastoma.
Diagnosis
Diagnosis of neuroblastoma is made on the basis
of histologic confirmation combined with chemi-
cal profiling and imaging characteristics. Histo-
logic confirmation is usually performed by acquir-
ing an incisional biopsy of the primary tumor. For
Figure 6.  Neuroblastoma in a 27-month-old girl with
worsening ataxia, tremulousness, myoclonus, and weight
loss. Axial CT image of the abdomen shows a 2.3-cm soft-tis-
sue mass between the right kidney and aorta (arrowheads).
tumors that appear to be localized, the incisional
biopsy may also include a sampling of nonadher-
ent ipsilateral and contralateral lymph nodes. Bone
marrow aspiration of two separate sites is neces-
sary to evaluate fully the extent of disease.
Histologically, neuroblastoma falls into a cate-
gory of malignant small round cell tumors. These
tumors demonstrate small, round, relatively
undifferentiated cells. They are sometimes called
“blue” because they have large hyperchromatic
nuclei and a thin rim of cytoplasm. Other malig-
nancies that fall into this category include Ewing
sarcoma, rhabdomyosarcoma, non-Hodgkin
lymphoma, retinoblastoma, nephroblastoma, and
hepatoblastoma. These malignant small round
cell tumors can be difficult to diagnose when they
are poorly differentiated. In neuroblastoma, small
clusters of cells may be separated by a fibril-
lar matrix forming pseudorosettes (sometimes
called Homer-Wright rosettes) (29). Immuno-
histochemical stains for biologic markers such
as neuron-specific enolase, S-100 protein, and
chromogranin can be used to aid in the histologic
diagnosis of neuroblastoma (29).
The International Neuroblastoma Pathology
Committee (30) modified the previously used Shi-
mada system as a prognostic classification system
based on the morphologic features of neuroblas-
toma in 1999. Evaluation includes comment on
the amount of Schwannian stroma, the degree of
nodularity, the degree of neuroblastic differentia-
tion, the mitosis-karyorrhexis index, and a note on
the presence or absence of calcifications, among
other descriptors. Two prognostic subgroups are
possible: favorable and unfavorable histologic
results. A favorable histologic result is assigned
to children younger than 1.5 years with a low or
intermediate mitosis-karyorrhexis index and a
differentiating or partially differentiating tumor or
RG  •  Volume 38  Number 2 Swift et al  571
Figure 7.  Sagittal US image in a 14-month-old girl with
opsoclonus-myoclonus syndrome shows a left pararenal
mass (arrowheads) with punctate calcifications.
to children 1.5–5 years of age with a low mitosis-
karyorrhexis index and a differentiating tumor.
Results of genetic and molecular classifications
can then be included in an integrated prognostic
evaluation (30).
Since neuroblastoma is derived from neural
crest cells, it often expresses the enzymes required
for catecholamine metabolism. Degradation of
norepinephrine, epinephrine, and dopamine by
these enzymes leads to the final end products,
vanillylmandelic acid and homovanillic acid.
Detection of elevated serum and urine levels of
vanillylmandelic acid and homovanillic acid can
provide chemical evidence of disease. Although
not specific for neuroblastoma, high vanillylman-
delic acid and homovanillic acid levels are present
in approximately 75% of patients with neuroblas-
toma (31). If pathologic examination is unequivo-
cal for neuroblastoma, or tumor cells are detected
in bone marrow, and there are elevated urinary
vanillylmandelic acid and homovanillic acid levels,
then a diagnosis can be made (32).
Imaging of Neuroblastoma
Evaluation with US
US is usually the first examination performed
when an abdominal mass is suspected in a child.
At US, neuroblastoma appears as a solid het-
erogeneous mass that demonstrates calcification
30%–90% of the time (Fig 7) (1,33,34). If the
mass arises from the adrenal gland, there may
be inferior displacement of the adjacent kidney.
Doppler evaluation can be performed in cases
of suspected neuroblastoma to interrogate the
regional vasculature. Neuroblastomas tend to
encase the surrounding vessels or displace them
rather than infiltrate them (33,35,36). A search
for regional lymphadenopathy also can be per-
formed during US evaluation. US is typically fol-
lowed by CT or MR imaging to further evaluate
the extent of disease and assist in staging.
The growing use of US during pregnancy is
leading to an increasing number of prenatally
diagnosed (congenital) neuroblastomas (Fig 8)
(37–39). Congenital neuroblastoma should be
considered in addition to adrenal hemorrhage
and pulmonary sequestration when a solid or
cystic adrenal mass is detected at prenatal imag-
ing. Associated vascular flow and calcifications
are common. More than 90% of congenital
neuroblastomas arise from the adrenal gland
compared with only 35% of postnatal cases
(39,40). Most of these antenatal cases have
favorable staging and histopathologic features,
with spontaneous regression in the 1st year of
life. Results of prior large-scale prospective stud-
ies have shown that screening for neuroblastoma
in infancy does not reduce mortality, further
supporting the notion that neuroblastoma in
very young patients is a distinct disease that fol-
lows a different course than that in patients who
are older at diagnosis (41–44).
CT and MR Imaging
There is no clear answer as to whether CT or
MR imaging is superior for detection and evalu-
ation of neuroblastoma. CT is rapidly performed
and widely available, with superior detection of
calcifications. MR imaging is better for evaluat-
ing spinal involvement and does not involve use
of ionizing radiation. Often, both CT and MR
imaging are performed at the initial evaluation,
especially if the tumor is paraspinal. CT and MR
imaging both demonstrate a heterogeneously en-
hancing solid mass that crosses the midline and
encases or displaces vessels. Both modalities can
also demonstrate metastasis to the liver, lymph
nodes, bone, and skin (35,36).
Whole-body MR imaging can be a helpful
diagnostic tool for imaging neuroblastomas in
certain contexts. The entire body, from the ver-
tex to the toes, is imaged in one or more planes,
usually with multiple sequences (Fig 9). This
method is radiation free and allows a complete
workup for disease staging in a single session of
sedation or anesthesia. For evaluation of all solid
tumors in children, whole-body MR imaging
has consistently shown sensitivity comparable to
or greater than that of skeletal scintigraphy with
technetium 99m (99mTc) diphosphonates for
detecting skeletal metastases to bone (45). When
evaluating neuroblastoma, authors of previous
studies showed that MR imaging demonstrates
higher sensitivity than that with MIBG, whereas
MIBG scintigraphy demonstrates higher speci-
ficity (46,47). MR imaging also demonstrates
superior sensitivity to that with CT alone. The
increased sensitivity of MR imaging is due to
superior detection of osseous metastases (48).
572  March-April 2018 radiographics.rsna.org

Figure 8.  Congenital neuroblastoma in a female neonate with a history of an adrenal mass at prenatal imaging.
(a) US image at 23 days of life shows a 3.5-cm heterogeneous left adrenal mass with mild vascularity (arrowheads).
(b) Coronal single photon emission computed tomography (SPECT)/CT image from a metaiodobenzylguanidine
(MIBG) scan performed at 1 month after birth shows uptake in the mass (arrow), compatible with congenital neu-
roblastoma. (c) On a US image after 2 months, the mass is smaller (arrowheads). (d) US image 4.5 months later
shows no evidence of a residual mass. The patient was observed only and did not undergo antineoplastic therapy.

However, the specificity of whole-body MR mas in children. As an analog of norepinephrine,

imaging remains low, because it is difficult to
distinguish treated from active disease. MIBG
and fluorine 18 (18F) fluorodeoxyglucose (FDG)
positron emission tomography (PET)/CT are
more helpful in determining tumor viability (Fig
10). Owing to the increased number of se-
quences and length of imaging required, whole-
body MR imaging is less likely to be used for
staging and more likely to be used for surveil-
lance and for evaluation of osseous metastatic
disease that may be less conspicuous at CT.
Nuclear Medicine
Iodine 123 (123I) and 131 (131I)–labeled MIBG
are functional agents ideal for use in imaging of
neuroendocrine tumors, primarily neuroblasto-
MIBG is taken up by norepinephrine transporters.
This is demonstrated in up to 90% of neuroblas-
tomas (49). Although 123I MIBG is now the agent
of choice for diagnostic imaging, there are some
centers that still use 131I MIBG because of avail-
ability and/or decreased cost. In a study by Yanik
et al (50), in approximately 27% of their centrally
reviewed examinations, 131I was used instead of
123
I. They did not report any notable difference in
the mean Curie score based on isotope type. The
addition of SPECT and SPECT/CT improves the
accuracy of identification of specific sites of uptake
(Fig 11) (49). The high specificity and improved
accuracy of localization make MIBG imaging
the test of choice for identification of metastatic
disease. Imaging is qualitative, with any uptake be-
RG  •  Volume 38  Number 2 Swift et al  573
Figure 9.  Newly diagnosed neuroblas-
toma in a 3-year-old boy. Coronal T2-
weighted short inversion time inversion-
recovery whole-body MR image shows a
large soft-tissue mass in the left superior
mediastinum (*) and osseous metasta-
ses to the proximal humeri, right femur,
and right tibia (arrowheads). Left cervi-
cal lymphadenopathy is also partially
included.
yond the physiologic distribution of the radiotracer
considered as disease involvement (51).
Interpretation of MIBG avidity is performed
by means of semiquantitative scoring of skeletal
segments. The modified Curie score and the In-
ternational Society of Pediatric Oncology Europe
Neuroblastoma (SIOPEN) score are the two
most commonly used systems. In North America
and at Children’s Oncology Group institutions,
staging of the MIBG scan results is performed
by using the modified Curie score (Fig 12). This
score carries with it prognostic significance in
patients with high-risk neuroblastoma.
The body is divided into nine skeletal seg-
ments with an additional segment for soft-tissue
involvement. Each segment is assigned a score of
0–3 depending on the extent of disease involve-
ment: (a) If there is no disease involvement, the
segment is given a score of 0. (b) If there is a
single site of disease, the segment is given a score
of 1. (c) If there are two or more sites of disease
but less than 50% involvement of the segment,
it is given a score of 2. (d) If more than 50% of
the segment has disease involvement, it is given a
score of 3. (e) The maximum score is 30.
Assessment of MIBG avidity at follow-up
may be a useful surrogate marker for evaluat-
ing response to therapy over time. In a study by
Yanik et al (50) conducted through the Chil-
dren’s Oncology Group, children with stage
4 high-risk neuroblastoma were evaluated. A
Curie score of greater than or equal to 2 at the
end of induction was associated with an inferior
outcome to those with Curie scores less than 2.
The event-free survival rate was approximately
15% for patients who had more than minimal
residual disease compared with 46% for those
who had an absolute Curie score of less than 2.
Furthermore, they showed that the presence of
more than minimal residual disease was more
predictive than the percentage of response from
diagnosis to end induction (50,51).
Indium 111 (111In) pentetreotide has been
shown to be taken up by somatostatin receptor–
positive neuroblastomas. With preferential affinity
for somatostatin type-2 receptors, it was shown
in studies in the 1990s to have a complementary
role to that of 123I MIBG. However, the high
specificity of MIBG outmatched the added value
of pentetreotide in these patients. Furthermore,
the imaging protocol and radiation exposure of
111
In required patients to be imaged at 48–72
hours, whereas MIBG imaging typically is com-
pleted at 24 hours. In MIBG-nonavid neuroblas-
tomas, the addition of another metabolic imaging
study may be more pertinent (52).
When neuroblastoma tumors are not MIBG
avid, or when MIBG imaging and anatomic
imaging do not correlate, FDG PET/CT is a
useful diagnostic tool (Fig 13). Although MIBG
is thought to be more sensitive for detection of
individual lesions in patients with relapse of neu-
roblastoma, FDG PET/CT, and even FDG PET/
MR imaging, can have a complementary role,
particularly in soft-tissue lesions. The complete
FDG response does not always correlate with the
MIBG response (47).
Newer agents for use in PET/CT that have
higher image resolution than agents imaged
with gamma cameras (even with the addition of
SPECT/CT) are gaining interest in the community
574  March-April 2018 radiographics.rsna.org

Figure 10.  Neuroblastoma refractory to treatment with unfavorable histologic features in a 3.5-year-old boy. (a) Whole-body MIBG
maximum intensity projection image shows several sites of osseous metastatic disease (arrowheads). (b, c) Whole-body MR images
show multifocal osseous lesions with sagittal T1-weighted (b) and coronal short inversion time inversion-recovery (c) sequences (ar-
rowheads). (d, e) FDG PET/CT (d) and PET maximum intensity projection (e) images confirm active disease at some metastatic sites
(arrowheads), while others had no FDG avidity, indicating treated disease.

of physicians who study and treat neuroblasto-

mas. Gallium 68 (68Ga)-[tetraxetan-D-Phe1,
Tyr3]-octreotate (68Ga DOTATATE) and
68
Ga-[tetraxetan-D-Phe1, Tyr3]-octreotide (68Ga
DOTATOC) are somatostatin analogs suited for
use with PET/CT. A third somatostatin receptor
analog specific to somatostatin receptor 3 (68Ga
DOTANOC) has also been studied but has not
been as widely investigated in neuroblastomas,
which more commonly express somatostatin
receptor 2. As recently as late 2016, 68Ga DOT-
ATATE received U.S. Food and Drug Admin-
istration approval and is now commercially
available for detection of somatostatin receptor–
positive neuroendocrine tumors. The advantage
of this agent over 111In pentetreotide is twofold:
not only do the images show higher resolution
with clearer definition than those with111In pen-
tetreotide or 123I MIBG, but the imaging protocol
allows injection and imaging during the same
single-day visit (53–57).
Figure 11.  Newly diagnosed neuroblastoma in a 4-year-old
99m
Tc bone scans are an additional tool in the girl. (a) Anterior whole-body planar image from a 24-hour
diagnosis and staging of neuroblastoma. A bone 123
I MIBG study shows increased radiotracer uptake in a left
scan is performed if the primary tumor is not adrenal mass (*) as well as diffuse osseous metastatic disease
MIBG avid or if the tumor has been excised. In (arrowheads). (b) SPECT/CT image shows superior anatomic
detail for characterization of sites of tumor involvement (*,
some instances, where MIBG may not be readily arrowheads). Physiologic activity is present within the salivary
available, a bone scan is still routinely used. Iso- glands, oropharynx, liver, heart, and urinary bladder.
lated bone uptake of 99mTc should be confirmed
with another imaging modality or biopsy.
RG  •  Volume 38  Number 2 Swift et al  575

Figure 12.  The Curie score provides prognostic information in evaluation of patients with neuroblas-
toma based on the number of involved segments and extent of disease on MIBG images. (a) Anatomic
drawing shows regions used to determine the Curie score. (b) Anterior whole-body planar image from
a 24-hour 123I MIBG study in a 14-month-old girl with opsoclonus-myoclonus syndrome shows isolated
uptake in a left paraspinal mass (arrowhead), compatible with a Curie score of 1. (c) Anterior whole-body
planar image from a 24-hour 123I MIBG study in a 22-month-old girl with newly diagnosed neuroblas-
toma shows extensive abnormal uptake (arrowheads), including the right frontal calvaria, sphenoid bone,
left mandible, bilateral proximal femora, distal left femur, and abdominal and pelvic soft tissue. The Curie
score was 12.

Figure 13. MIBG-nonavid neuroblas-

toma. (a) Anterior whole-body planar
image from a 24-hour 123I MIBG study
shows no abnormal foci of MIBG uptake.
(b) Image from subsequent 99mTc bone
scan shows physiologic uptake with sub-
tle findings of diffusely increased metaph-
yseal uptake (arrowheads), most notice-
able in the proximal femora and humeri.
This pattern can be difficult to recognize.
(c) FDG PET/CT image reveals abnormally
increased metabolic activity within a large
left retroperitoneal mass (*) and exten-
sive liver metastases (arrowheads), and a
metastatic focus within the left lamina of
the T4 vertebral body (arrow), compatible
with viable tumor.
576  March-April 2018 radiographics.rsna.org
Staging
The International Neuroblastoma Risk Group
Staging System (INRGSS) was published in
2008 as a new way to stratify patients before
surgical intervention (58). This system is now
used in parallel with the older International
Neuroblastoma Staging System (INSS). There
are several key differences between the INRGSS
and the INSS. First, whereas the INSS was
intended for postsurgical staging, the INRGSS
emphasizes pretreatment risk stratification based
on clinical criteria and image-defined risk fac-
tors (IDRFs) (Table 1, Fig 14). These IDRFs
are focused on evaluation of tumor extent to
nearby vessels and adjacent structures. Brisse
et al (59) further clarified the terminology to
describe a primary tumor in the INRGSS:
(a) “Encasement” of a vessel means that more
than 50% of the vessel circumference is in con-
tact with the tumor, (b) “contact” means that
less than 50% of the vessel’s circumference is
in contact with the tumor, and (c) “flattened”
is used to describe a vessel that has a reduced
diameter with a partially visible lumen. Of
these, only encasement constitutes an IDRF.
Infiltration is used to describe a tumor that has
no well-defined layer (usually fat) between the
tumor and a neighboring structure, and also
represents an IDRF. CT and/or MR imaging
of the primary tumor is required to determine
IDRFs, and MIBG imaging is mandatory in this
new system. If one unequivocal MIBG-positive
lesion is shown at a distant site, that is consid-
ered metastatic disease. If one positive lesion is
found at a distant site at MIBG imaging, it is
considered metastatic disease (60).
With the addition of the IDRFs, several other
modifications have been made to the INSS. Now,
local-regional disease is divided into two instead
of three stages, with no importance given to tu-
mor extension across the midline. Lymph nodes
are now classified as regional or nonregional
rather than ipsilateral, contralateral, or distant.
Also, stage MS, which includes metastatic disease
confined to the liver, marrow, and/or skin only,
has an upper age limit of 18 months. The previ-
ous corresponding stage of 4S disease had an
upper age limit of 12 months (Table 2) (60).
Treatment
In North America, most patients are treated
under protocols designed by the National Cancer
Institute–funded cooperative group, the Children’s
Oncology Group. To determine the appropriate
treatment strategy, the Children’s Oncology Group
risk group stratification has been developed from
more than 20 years of clinical trials. Combining
the INSS/INRGSS stage with the age at diagnosis,
Table 1: IDRFs in Neuroblastoma
Ipsilateral tumor extension within two body com-
partments
  Neck-chest, chest-abdomen, abdomen-pelvis
Neck
  Tumor encasing carotid and/or vertebral body
and/or internal jugular vein
  Tumor extending to base of skull
  Tumor compressing the trachea
Cervicothoracic junction
  Tumor encasing brachial plexus roots
  Tumor encasing subclavian vessels and/or verte-
bral and/or carotid artery
  Tumor compressing the trachea
Thorax
  Tumor encasing the aorta and/or major branches
  Tumor compressing the trachea and/or principal
bronchi
  Lower mediastinal tumor, infiltrating the costo-
vertebral junction between T9 and T12
Thoracoabdominal tumor encasing the aorta and/
or vena cava
Abdomen and/or pelvis
  Tumor infiltrating the porta hepatis and/or the
hepatoduodenal ligament
  Tumor encasing branches of the superior mesen-
teric artery at the mesenteric root
  Tumor encasing the origin of the celiac axis and/
or of the superior mesenteric artery
  Tumor invading one or both renal pedicles
  Tumor encasing the aorta and/or vena cava
  Tumor encasing the iliac vessels
  Pelvic tumor crossing the sciatic notch
Intraspinal tumor extension whatever the location
provided that more than one-third of the spinal
canal in the axial plane is invaded, and/or the
perimedullary leptomeningeal spaces are not
visible, and/or the spinal cord signal intensity is
abnormal
Infiltration of adjacent organs and structures:
pericardium, diaphragm, kidney, liver, duodeno-
pancreatic block, and mesentery
Conditions to be recorded, but not considered
IDRFs
  Multifocal primary tumors
  Pleural effusion, with or without malignant cells
  Ascites, with or without malignant cells
Note.—Reprinted, with permission, from refer-
ence 58.
the histologic results, and the biology and genet-
ics of the tumor allows the patient to be placed
into a low-, intermediate-, or high-risk group. The
intensity and duration of treatment are then de-
termined. The most important imaging factors for
determining induction and consolidation therapy
include the presence or absence of localized disease
RG  •  Volume 38  Number 2 Swift et al  577

Figure 14.  Examples of IDRFs in neuroblastomas. (a) Coronal T2-weighted MR image shows tumor extending to
the skull base (arrowheads) and encasing the left carotid artery (arrow), both IDRFs, in the same patient as in Figure 5.
(b) Axial T2-weighted MR image reveals tumor encasement (arrowheads) of the thoracic aorta (white *). There is a
small right pleural effusion (black *), which should be recorded but does not qualify as an IDRF. (c) Axial contrast-
enhanced chest CT image in a child with newly diagnosed neuroblastoma shows tumor encasing and compressing the
main bronchi (arrowheads), an IDRF. (d) Axial CT image of the abdomen with intravenous and oral contrast material
shows tumor encasement (arrowheads) of the superior mesenteric artery (arrows). * = aorta. (e, f) Axial (e) and coro-
nal (f) CT images of the abdomen with intravenous contrast material show a large heterogeneous mass in the right
upper quadrant that encases the right renal artery (arrows), inferior vena cava (∗), and aorta (arrowhead in e) and also
infiltrates the liver (arrowheads in f), which are all IDRFs in the INRGSS.
578  March-April 2018 radiographics.rsna.org
Table 2: INRGSS Stages
Stage
L1 Localized tumor not involving vital structures as defined by the list of IDRFs and confined to one body
compartment
L2 Local-regional tumor with presence of one or more IDRFs
M Distant metastatic disease (except stage MS)
MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or
bone marrow
Note.—Patients with multifocal primary tumors should be staged according to the greatest extent of disease.
Reprinted, with permission, from reference 58.
at the original tumor site, confined unilateral dis-
ease, contralateral disease, and metastatic disease.
IDRFs have an increasingly important role in
determining a treatment approach.
Once a diagnosis of neuroblastoma is estab-
lished, there are various surgical approaches
according to risk classification and Children’s
Oncology Group guidelines. Surgical removal of
the tumor may be all that is necessary for children
with low-risk disease that is localized. Authors of
recent studies (61–63) in North America and Eu-
rope suggest that complete surgical resection is of-
ten not necessary for low- to intermediate-risk tu-
mors. Patients with intermediate-risk tumors may
receive chemotherapy to shrink the tumor before
surgical removal. In patients at higher risk, surgery
may be performed to remove as much tumor as
possible after the induction of chemotherapy.
If there is a congenital neuroblastoma, observa-
tion may be the most appropriate management
(39,62). For other low-risk tumors, surgery is the
mainstay of treatment. Chemotherapy is added for
tumors that cannot be resected or for tumors that
may cause spinal cord compression or respiratory
compromise from hepatic involvement. Patients at
intermediate risk usually receive chemotherapy in
combination with surgical resection when possible.
Radiation therapy is rarely indicated for patients
at intermediate risk but should be considered for
those with tumor progression or life-threatening
complications from chemotherapy. Outcomes for
patients at low risk (event-free survival, >95%)
and intermediate risk (event-free survival, 80%–
95%) are excellent (64).
For patients at high risk, an aggressive multi-
modality approach is used, including neoadjuvant
chemotherapy, surgical resection, adjuvant high-
dose chemotherapy with hematopoietic stem cell
rescue, and radiation therapy (65). Maintenance
therapy is directed at eradication of residual dis-
ease. Anti-GD2 immunotherapy with dinutuximab
is the standard of care (66). Historically, event-free
survival for patients at high risk was less than 50%.
The addition of anti-GD2 immunotherapy with
Description
dinutuximab improved 2-year event-free survival
to 66% (66). Now, emerging therapy of 131I MIBG
imaging followed by autologous stem cell rescue
has shown promising response rates.
MIBG labeled with 131I allows for targeted
therapy of neuroblastoma. 131I MIBG therapy is a
new and emerging technique. Patients tolerate it
better than they do many other treatments, largely
because it does not cause adverse effects such as
nausea and pain, and it has been shown to provide
palliative relief of pain from metastatic bone dis-
ease in patients with other neuroendocrine tumors
(67). Clinical trials are underway to investigate its
use as a primary and adjunctive therapy. Stud-
ies have shown response rates of up to 66% in
patients newly diagnosed with high-risk disease
(68). Response rates of 37% have been demon-
strated in cases of relapsed neuroblastoma (69).
Potential adverse effects of therapeutic 131I MIBG
include myelosuppression, transient hypertension,
and thyroid disorders (51). In addition, on the
basis of the avidity of this agent for neuroblastoma,
as with MIBG, an agent currently in clinical trials
for therapy for refractory neuroblastoma, lutetium
177-DO­TATATE, that shows promise in select
patients has been developed (70).
Conclusion
Neuroblastoma is a heterogeneous disease with a
broad range of clinical presentations. The prog-
nosis varies depending on the age of the patient
and the histologic and biologic characteristics of
the tumor. US is often the first modality used to
identify neuroblastic tumors. CT or MR imaging
is then used to further characterize masses and
evaluate for IDRFs. MIBG scintigraphy is now
required for staging and to determine eligibil-
ity for potential MIBG therapy. In addition,
nuclear medicine imaging, bone scanning, FDG
PET/CT, whole-body MR imaging, and radi-
ography may be used as adjuncts in evaluation
of metastatic disease. The INRGSS emphasizes
pretreatment image-defined risk classifications.
New immunotherapy techniques and 131I MIBG
RG  •  Volume 38  Number 2 Swift et al  579
targeted therapy have shown promising results
in high-risk patients. Although our understand-
ing of neuroblastoma will continue to evolve, it is
important for radiologists to understand the most
updated guidelines to optimize disease evaluation
and treatment course.
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TM