Revisions of the International Criteria for Neuroblastoma

Diagnosis, Staging, and Response to Treatment

By Garrett M. Brodeur, Jon Pritchard, Frank Berthold, Niels L.T. Carlsen, Victoria Castel, Robert P. Castleberry,
Bruno De Bernardi, Audrey E. Evans, Marie Favrot, Fredrik Hedborg, Michio Kaneko, John Kemshead, Fritz Lampert,
Richard E.J. Lee, A. Thomas Look, Andrew D.J. Pearson, Thierry Philip, Borghild Roald, Tadashi Sawada,
Robert C. Seeger, Yoshiaki Tsuchida, and Paul A. Voute

Purpose and Methods: Based on preliminary expe-
rience, there was a need for modifications and clarifi-
cations in the International Neuroblastoma Staging Sys-
tem (INSS) and International Neuroblastoma Response
Criteria (INRC). In 1988, a proposal was made to establish
an internationally accepted staging system for neuro-
blastoma, as well as consistent criteria for confirming
the diagnosis and determining response to therapy
(Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A
meeting was held to review experience with the INSS
and INRC and to revise or clarify the language and intent
of the originally proposed criteria. Substantial changes
included a redefinition of the midline, restrictions on age
and bone marrow involvement for stage 45, and the
recommendation that meta-iodobenzylguanidine (MIBG)
scanning be implemented for evaluating the extent of
disease. Other modifications and clarifications of the
INSS and INRC are presented. In addition, the criteria
for the diagnosis of neuroblastoma were modified. Fi-
nally, proposals were made for the development of risk
groups that incorporate both clinical and biologic fea-
tures in the prediction of prognosis. The biologic features
that were deemed important to evaluate prospectively
included serum ferritin, neuron-specific enolase (NSE),
and lactic dehydrogenase (LDH); tumor histology; tumor-
cell DNA content; assessment of N-myc copy number;
assessment of lp deletion by cytogenetic or molecular
methods; and TRK-A expression.
Results and Conclusion: Modifications of the INSS and
INRC made at this conference are presented. In addition,
proposals are made for future modifications in these cri-
teria and for the development of International Neuro-
blastoma Risk Groups.
J Clin Oncol 11:1466-1477. © 1993 by American So-
ciety of Clinical Oncology.

From the Department (o Pediatrics, Washington University School

of Medicine, St Louis, MO; Department of Haematology and On-
cology,'. The Hospitals for Sick Children, London, England; Depart-
ment of(Pediatrics, University ofCologne, Koln, Germany-Department
of Pediatricsand Pediatric Surgery, GGK University Hospital, Co-
penhagen, Denmark, Unidad de Oncologia Pediatrica,Hospital In-
jantil La Fe, Valencia, Spain; Department of Pediatrics,Children s
Hospital of Birmingham and the University of Alabama at Bir-
mingham, Birmingham AL; Department of Pediatrics, Instituto
GianninaGaslini, Genova, Italy; Department of/Pediatrics, Children's
Hospital of Philadelphia,Philadelphia,PA; Department of Pediatrics,
Centre Leon Berard, Lyon, France; Department of Pediatrics,Uni-
versity Hospital,Uppsala, Sweden; Department of'PediatricSurgery.
University of' Tsukuba, Tsukuba, Japan, Imperial CancerResearch
Fund, Paediatricand Neuro-Oncology Group, Frenchay Hospital.
Bristol, England; Department #fPediatrics,Justus Liebig Universitat,
Giessen, Germany,-Department of Hematology Oncology, St Jude
Children 's Research Hospital,Memphis, TN; Department of Child
health, University of/Newcastle Upon Tyne, The Medical School
Framington Place, Newcastle, England; Institute of Pathology, Uni-
versity of Oslo, Oslo, Norway; Department of Pediatrics,Kyoto Pre-
fecitural University of Medicine, Kyoto, Japan; Department of Pedi-
atrics. Los Angeles Childrens Hospital, Los Angeles, CA; Department
of Pediatric Surgery, University of" Tokyo, Tokyo, Japan; and De-
partment olfPediatricOncology, Emma Kinder Ziekenhuis, Amster-
dam, the Netherlands.
Submitted November 23, 1992; acceptedApril 12, 1993.
The Second InternationalNeuroblastoma Staging System Confer-
ence was held in Berkeley. England, October 13-16, 1991. This meet-
ing was supported by' the William G. Forbeck Foundation (United
States) and by the Neuroblastoma Society (United Kingdom). Drs
Brodeur and Pritchardserved as cochairmen of the confJrence.
Presented at the 6th InternationalSymposium on Advances in
A VARIETY OF STAGING SYSTEMS'
3
or their
4
modifications -12 have been developed to classify the
extent of disease in neuroblastoma patients at the time of
diagnosis, and different criteria have been used to deter-
mine response to therapy. " Each system has its strengths,
but the differences have made it difficult to compare the
results of clinical trials and biologic studies performed by
different groups and in different countries. In 1986, a
meeting was held to establish international criteria for (1)
a diagnosis of neuroblastoma, (2) a common neuroblas-
toma staging system, and (3) definitions of response to
treatment. The outcome of this meeting and subsequent
deliberations were published in 1988.14 The staging system
is known as the International Neuroblastoma Staging
System (INSS), and the response criteria are called the
International Neuroblastoma Response Criteria (INRC).
Most groups and countries have begun to implement
the INSS and INRC in addition to, or instead of, the stag-
ing system and response criteria they previously used. In-
deed, both clinical and biologic reports have appeared
from many countries around the world using the inter-
Neuroblastoma Research, Philadelphia,PA, May 13-15, 1993.
Address reprint requests to Garrett M. Brodeur, MD, Division of
Oncology, Children's HospitalofPhiladelphia,34th and Civic Center
Blvd, Philadelphia,PA 19104-4399.
© 1993 by American Society of Clinical Oncology.
0732-183X/93/1108-0006$3.00/0

1466 Journalof Clinical Oncology, Vol 11, No 8 (August), 1993: pp 1466-1477

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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.
REVISIONS OF THE INSS AND INRC
national criteria.15- 29 However, some difficulties have been
encountered in the use of these criteria that have hindered
0
their full acceptance internationally. '"' Therefore, to re-
solve the difficulties, an international group of conferees
was convened, supported by the William G. Forbeck
Foundation of the United States and The Neuroblastoma
Society of the United Kingdom. A working group of about
20 individuals was assembled, with broad representation
from the major pediatric oncology cooperative groups in
the United States, Europe, and Japan. This working group
reviewed the experience with the INSS and INRC and
discussed modifications and clarifications of the language
and intent of the originally proposed criteria. Here we
report the recommendations of the conferees for modi-
fications of 1988 criteria for diagnosis, staging, and treat-
ment response. We also summarize proposals made for
the definitions of prognostic risk groups, incorporating
both clinical and biologic variables.
DIAGNOSIS
The recommended criteria for a diagnosis of neuro-
blastoma are listed in Table 1. In most cases, a tissue
diagnosis of neuroblastoma based on conventional stain-
ing (eg, hematoxylin and eosin) is not difficult, especially
if features suggestive of neuronal differentiation are pres-
ent. However, in some cases, neuroblastomas are char-
acterized by densely packed, small blue cells with little if
any differentiation, and electron microscopy may be nec-
essary to confirm this diagnosis. 30 In addition, we have
recommended the implementation of immunologic
methods (see later) to confirm the diagnosis of neuro-
blastoma of tumor tissue. Tumors with which neuro-
blastoma may be confused include Ewing's sarcoma,
peripheral neuroepithelioma (also called primitive
neuroectodermal tumor [PNET]), rhabdomyosarcoma,
and non-Hodgkin's lymphoma, as well as acute mega-
karyoblastic leukemia, so the clinical features and pattern
of staining must be typical of neuroblastoma and incon-
sistent with other possible diagnoses. 3 '
Involvement of MetastaticSites
The diagnosis of neuroblastoma may be based on bone
marrow involvement, as detected by bone marrow biopsy
or aspiration. Characteristic features of neuroblastoma in
a trephine biopsy have been described.34 The diagnosis of
neuroblastoma based on marrow aspirate requires that
characteristic clumps or syncytia of tumor cells be present,
in addition to significantly increased serum or urinary
catecholamines or metabolites. As noted previously, we
have recommended the use of immunologic methods to
confirm that clumps of tumor cells in the marrow are
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1467
Table 1. Diagnosis of Neuroblastoma
Established if:
(1) Unequivocal pathologic diagnosis* is made from tumor tissue by
light microscopy (with or without immunohistology, electron
microscopy, increased urine or serum catecholamines or
metabolitest );
OR
(2) Bone marrow aspirate or trephine biopsy contains unequivocal
tumor cells* leg, syncytia or immunocytologically positive clumps of
cells) and increased urine or serum catecholamines or metabolites.t
NOTE. See text also for clarifications.
*Ifhistology is equivocal, karyotypic abnormalities in tumor cells char-
acteristic of other tumors [eg, ti( 1;22)], then exclude a diagnosis of neu-
roblastoma, whereas genetic features characteristic of neuroblastoma (1 p
deletion, N-myc amplification) would support this diagnosis.
"tCatecholamines and metabolites include dopamine, HVA, and/or VMA;
levels must be > 3.0 SD above the mean per-milligram creatinine for age
to be considered increased, and at least 2 of these must be measured.
neuroblastoma cells.31 ,36 4 3 A variety of immunologic
reagents have been used to identify neuroblastoma
cells, including antibodies to neuron-specific enolase
(NSE),44"46 synaptophysin, 47 the ganglioside GD2,4 8 4, 9 the
neural cell adhesion molecule (NCAM),s,'5 ' neurofilament
proteins, 52 and chromogranin A (CGA). 53 In addition,
neural-associated antibodies to less well-characterized an-
tigens have been demonstrated to react with many neu-
roblastomas and not with normal marrow elements. It is
anticipated that an INSS subcommittee will recommend
a standardized set of widely available monoclonal anti-
bodies or other reagents that can be used for the assessment
of neuroblastoma involvement of marrow, as well as
lymph nodes, liver, or other sites of metastasis. Meanwhile,
the conferees recommend the use of commercially avail-
able antibodies against at least two of the following an-
tigens: NSE, synaptophysin, and CGA.
Genetic Analysis of Tumor Tissue
Cytogenetic and molecular genetic analyses of solid tu-
mors are being performed with increasing frequency. The
conferees thought that if tumor histology is ambiguous,
and characteristic features of another neoplasm are iden-
tified [such as t(l 1;22) in Ewing's sarcoma/PNET or
t(2; 13) in alveolar rhabdomyosarcoma], 54 58 this would
exclude a diagnosis of neuroblastoma. On the other hand,
genetic features characteristic of neuroblastoma (such as
lp deletion or N-myc amplification)"'9 6 would support
this diagnosis.
CatecholamineMetabolites
The conferees agreed that, in addition to the urinary
catecholamine metabolites homovanillic acid (HVA) and
vanillylmandelic acid (VMA), urine or serum dopamine
1468
should be included in the list of acceptable measurements
to document the adrenergic nature of the tumor. Some
thought that, in the case of undifferentiated tumors, do-
pamine might be a more sensitive measure of tumor bur-
den or activity. It was recommended that the cutoff for
increased levels of serum or urine catecholamines or their
metabolites be retained at 3.0 SD above the mean per-
milligram creatinine for age when making a diagnosis of
neuroblastoma in a patient. Using this value, approxi-
mately 92% of children with biopsy-proven neuroblastoma
will have increased catecholamines at diagnosis. However,
based on the experience with the urinary screening pro-
gram in Japan, 62 a cutoff of 2.5 SD may be more appro-
priate; a cutoff of 2.0 SD is not stringent enough and 3.0
SD may be too stringent for screening.
Needle Biopsies
Questions were raised about the use of true-cut core-
needle biopsy or fine-needle aspiration to make a diagnosis
of neuroblastoma. 24' 63-65 Core-needle biopsies would allow
some assessment of tissue architecture, as well as the pos-
sibility of obtaining sufficient tissue for biologic studies,
and so this technique should be acceptable in lieu of an
open biopsy or resection if the primary tumor is unre-
sectable and the patient is not a good candidate for surgery.
In addition, this approach could be used to obtain tumor
tissue for biologic studies in patients who have stage 4
neuroblastoma on the basis of substantial marrow in-
volvement and increased urinary catecholamine metab-
olites for age. Core-needle biopsy could be performed as
an open procedure or as a closed biopsy under ultrasound
guidance. 24 Fine-needle aspiration of the primary tumor
was deemed suboptimal because of the lack of any his-
tologic context for the tumor cells and the small amount
of tumor tissue obtained for essential (or optional) biologic
studies. However, this approach could be used to obtain
tissue for diagnosis if surgical biopsy was contraindicated
clinically, and if core-needle biopsies were not possible or
available.
UnacceptableDefinitions
There was a general consensus that a diagnosis of neu-
roblastoma based on a compatible radiographic appear-
ance of the primary tumor and increased urinary cate-
cholamine metabolites was not acceptable. For instance,
it has been documented that some patients with a gan-
glioneuroma have increased excretion of catecholamines
and their metabolites,66 and they can be visualized by
meta-iodobenzylguanidine (MIBG) scintigraphy.67 In ad-
dition, pheochromocytomas could be confused with
neuroblastomas6 8 if this definition were used. Finally,
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BRODEUR ET AL
PNETs, rhabdomyosarcomas, or other solid tumors could
have a compatible radiographic appearance and false-
positive urinary catecholamine metabolites. While in
practice such patients are uncommon, their inclusion
could bias clinical or laboratory studies.
RECOMMENDED TESTING
The tests recommended for assessment of extent of dis-
ease are listed in Table 2. One modification is that com-
puterized tomography (CT) or magnetic resonance im-
aging (MRI) (but not ultrasound) are recommended to
evaluate the abdomen. Most radiologists think that the
resolution of ultrasound is inferior to that of CT and MRI,
particularly for three-dimensional (3D) reconstruction of
the tumor to assess volume. It is recommended that 3D
measurements of the primary tumor and large metastases
be obtained by CT or MRI to determine response to treat-
ment (see following), but ultrasound may be a useful mo-
dality for interim assessments.
MIBG Scanning
One of the major changes since the original INSS pub-
lication is the recommendation that MIBG scanning be
undertaken, if it is available. Recent experience suggests
that MIBG scanning is particularly useful in distinguishing
residual active tumor from masses composed of scar tissue,
Table 2. Assessment of Extent of Disease
Tumor Site Recommended Tests
Primary tumor CT and/or MRI scan* with 3D measurements;
MIBG scan, if available.t
Metastastic sitest
Bone marrow Bilateral posterior iliac crest marrow aspirates
and trephine (core) bone marrow biopsies
required to exclude marrow involvement. A
single positive site documents marrow
involvement. Core biopsies must contain at
least 1 cm of marrow (excluding cartilage)
to be considered adequate.
Bone MIBG scan; WTc scan required if MIBG scan
negative or unavailable, and plain
radiographs of positive lesions are
recommended.
Lymph nodes Clinical examination (palpable nodes),
confirmed histologically. CT scan for
nonpalpable nodes (3D measurements).
Abdomen/liver CT and/or MRI scan* with 3D measurements.
Chest AP and lateral chest radiographs. CT/MRI
necessary if chest radiograph positive, or if
abdominal mass/nodes extend into chest.
NOTE. See text for clarifications.
Abbreviation: AP, anteroposterior.
*Ultrasound considered suboptimal for accurate 3D measurements.
tThe MIBG scan is applicable to all sites of disease.
REVISIONS OF THE INSS AND INRC
and it is more sensitive in detecting response of tumor
involving cortical bone. 69 Problems with MIBG scanning
have included (1) its lack of availability in some centers,
particularly in the United States and parts of Japan; (2)
the generally inferior quality of images compared with
technetium bone scans; and (3) the fact that not all pri-
mary tumors or metastases are MIBG-avid. However, in
experienced hands, MIBG scanning is a useful technique
for the detection of both primary and metastatic disease
and to follow response to treatment. Therefore, it is rec-
ommended that centers with ready access to this modality
of diagnostic imaging should use it routinely to evaluate
new patients with neuroblastoma and to monitor patients
whose tumors are MIBG-avid. Furthermore, it is rec-
ommended that oncologists and diagnostic radiologists at
institutions that lack the facility for MIBG scanning work
together to establish this technique at their institution.
Patients who have MIBG-negative tumors must use tech-
netium bone scans to evaluate cortical bone involvement.
Bone Marrow Assessment
The recommendation remains that two marrow aspi-
rates and two biopsies from the posterior iliac crests be
performed to rule out gross marrow involvement,7 "'7" but
only a single positive study is required to document mar-
row involvement. The criteria for an adequate biopsy now
stipulate that at least 1 cm of marrow (not cartilage or
bone cortex) be obtained. However, marrow biopsies may
not be feasible in infants younger than 3 to 6 months of
age. Recent experience suggests that, in the future, im-
munocytology of marrow aspirates, possibly combined
with MRI scans,'17 72 may obviate the need for marrow
biopsies.
Further studies will be required to investigate the im-
munologic assessment of bone marrow aspirates and
biopsies to determine the optimum reagents. Before this
approach can become the standard procedure to detect
and quantitate marrow involvement with neuroblastoma,
agreement will have to be reached on the monoclonal
antibodies or other reagents used. In addition, because it
may be possible to detect tumor cells in the marrow of
patients who would have stage 1, 2, or 3 by conventional
methods,7 criteria will have to be established by which
to consider a marrow positive when immunocytology is
implemented. Until then, patients with stages 1, 2, or 3
should not be upstaged to stage 4 (or 4S) because of de-
tection of tumor cells in the bone marrow based only on
immunocytology.
Lymph Node Assessment
There is some controversy over the clinical importance
of lymph node involvement in patients with neuroblas-
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1469
toma.74'7 5 Nodal involvement in the chest and abdomen
should be assessed by CT or MRI scans performed to
evaluate the primary tumor and metastatic disease. In-
volvement of inguinal, supraclavicular, and cervical nodes
may be assessed by physical examination as well. 3D
measurements of all enlarged nodes should be made to
determine response to treatment. At the time of surgery,
representative biopsies of regional ipsilateral nodes should
be performed. In cases with an abdominal primary, iden-
tifiable contralateral nodes should be sampled. Enlarged
nodes (> 2 cm) in the chest or abdomen should undergo
biopsy to document whether they are involved with neu-
roblastoma. If a biopsy cannot be performed, and if there
is no other reasonable explanation for their enlargement,
they should be assumed to be positive.
CorticalBone Involvement
A technetium bone scan generally is the most sensitive
conventional modality for the detection of cortical bone
involvement at the time of diagnosis.76 However, bone
scans in infants younger than 1 year of age may show so
much activity that it is difficult to detect small lesions.7 7
For this reason, it is recommended that skeletal surveys
be performed in this age group instead of, or in addition
to, bone scans.78 At all ages, plain radiographs should be
obtained of positive or suspicious lesions detected by bone
scan to document bony abnormalities and to rule out other
possible explanations for the abnormalities. The quality
of MIBG scans is improving, particularly if iodine 123 is
used instead of iodine 131 as the isotope, but there is
controversy as to whether MIBG scans are as sensitive as
technetium diphosphonate scans in detecting cortical bone
disease.79 '8" Therefore, a technetium bone scan should al-
ways be performed if the MIBG scan is negative, and it
may be useful even if the MIBG scan is positive.
Tumor Markers
A variety of serum or urinary markers have been used
to assist in the diagnosis of neuroblastoma and to follow
response to treatment. Some have been used to predict
outcome as well (see later). The conventional markers for
neuroblastoma are the urinary catecholamine metabolites
VMA and HVA,8 1but serum or urinary dopamine may
be a useful adjunct to these markers. 82' 83 Other serum
markers, such as ferritin, 8485 , lactic dehydrogenase
(LDH),86-88 NSE,8 9"92 GD2, 93 ' 94 and CGA,53,9 have been
used or suggested. However, only the catecholamines and
their metabolites are characteristic, sufficiently standard-
ized, and consistently increased to be useful and broadly
available. Serum ferritin and LDH may be useful prog-
nostic markers for neuroblastoma at diagnosis, but they
1470
lack sensitivity and specificity to monitor disease activity.
Serum NSE, GD2, and CGA are more specific, but they
are not as sensitive, and assays are not as widely available
at present. More data will be needed before these or other
markers can rival catecholamines for clinical monitoring.
STAGING
The INSS definitions are listed in Table 3. Gross re-
section of a localized tumor is associated with a favorable
outcome, regardless of microscopic residual disease or the
involvement of attached lymph nodes.7 ' 96 The definition
of stage I has been clarified to state that attached nodes
(adherent nodes in direct continuity with, and removed
with, the primary tumor) may be positive for tumor. Tu-
mors that cross the midline (or arise in the midline), but
are completely excised, are stage 1, assuming there is no
regional lymph node involvement or metastatic disease.
Resectability implies removal without a radical surgical
procedure (ie, without removing vital organs, compro-
mising major vessels, or disfiguring the patient). Most re-
sectable tumors are pseudoencapsulated, although they
may remain attached at the site of origin or invade the
spinal canal through neural foramina (see below).
The definitions for stages 2A and 2B have not changed
appreciably. The possibility of consolidating stages 2A and
2B was discussed, because those using the INSS14 have
not detected significant differences in the outcome of pa-
tients with stage 2A and 2B so far, especially for patients
younger than 1 year of age (R.P.C., V.C., T.P., unpub-
lished observations). Although stages 2A and 2B together
probably represent only 10% to 15% of the cases, there is
insufficient experience to recommend abandoning the
distinction between these two substages at this time.
Definition of the Midline and Midline Tumors
The most important change affecting the definition of
stage 3 was a redefinition of the midline. In the past, a
unilateral tumor may cross the absolute midline techni-
cally if it invades the spinal canal through neural foramina
or extends to the midline anterior to the spinal column.
However, such tumors are clinically different from a mas-
sive tumor, which infiltrates across the midline, encom-
passing major vessels and other vital structures. Therefore,
it was decided to consider the vertebral column as the
midline, and only tumors that extended by contiguous
invasion to or beyond the opposite side of the vertebral
bodies would be classified as stage 3. Although there will
still be ambiguous cases, they can be considered to have
stage 3 because they would be stage 3 unequivocally by
the old definition. A grossly resectable tumor arising in
the midline from pelvic ganglia or the organ of Zucker-
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BRODEUR ET AL
Table 3. INSS
Stage Definition
1 Localized tumor with complete gross excision, with or
without microscopic residual disease; representative
ipsilateral lymph nodes negative for tumor
microscopically (nodes attached to and removed with the
primary tumor may be positive).
2A Localized tumor with incomplete gross excision;
representative ipsilateral nonadherent lymph nodes
negative for tumor microscopically.
2B Localized tumor with or without complete gross excision,
with ipsilateral nonadherent lymph nodes positive for
tumor. Enlarged contralateral lymph nodes must be
negative microscopically.
3 Unresectable unilateral tumor infiltrating across the midline,*
with or without regional lymph node involvement; or
localized unilateral tumor with contralateral regional
lymph node involvement; or midline tumor with bilateral
extension by infiltration (unresectable) or by lymph node
involvement.
4 Any primary tumor with dissemination to distant lymph
nodes, bone, bone marrow, liver, skin and/or other
organs (except as defined for stage 4S).
4S Localized primary tumor (as defined for stage 1, 2A or 2B),
with dissemination limited to skin, liver, and/or bone
marrowt (limited to infants < 1 year of age).
NOTE. See text also for clarifications. Multifocal primary tumors leg,
bilateral adrenal primary tumors) should be staged according to the
greatest extent of disease, as defined above, and followed by a subscript
3
letter M leg, M).
*The midline is defined as the vertebral column. Tumors originating on
one side and crossing the midline must infiltrate to or beyond the opposite
side of the vertebral column.
tMarrow involvement in stage 4S should be minimal, ie, < 10% of total
nucleated cells identified as malignant on bone marrow biopsy or on mar-
row aspirate. More extensive marrow involvement would be considered
to be stage 4. The MIBG scan (if performed) should be negative in the
marrow.
kandl would be considered stage 1. A midline tumor that
extended beyond one side of the vertebral column and
was unresectable would be considered stage 2A. Ipsilateral
lymph node involvement would make it stage 2B, whereas
bilateral lymph node involvement would make it stage 3.
A midline primary tumor with bilateral infiltration that
was not resectable would be considered stage 3. A tumor
of any size with malignant ascites or peritoneal implants
would be stage 3 (but a thoracic tumor with malignant
pleural effusion unilaterally would be stage 2B).
Liver Involvement
Liver involvement in infants is often diffuse and may
not be apparent by diagnostic imaging or by inspection
of the liver at the time of surgery."9 In contrast, liver in-
volvement in older children is usually focal or nodular,
and is readily detected by diagnostic imaging or gross in-
REVISIONS OF THE INSS AND INRC
spection. Therefore, blind liver biopsy is required to rule
out liver involvement in infants (< 1 year of age) with
abdominal tumors, whereas liver biopsy in older patients
is required only if focal lesions are identified by diagnostic
imaging or by inspection at the time of surgery.
Marrow Involvement in Stage 4 Versus 4S
The definition of stage 4S has been clarified by quan-
titation of the extent of marrow involvement. The original
definition of stage IV-S included patients with primary
tumors that fit the definition of stage I or stage II by the
Evans staging system,2 '98 but with dissemination limited
to liver, skin, and bone marrow. Bone lesions were ex-
cluded, but the amount of marrow involvement was not
specified. It was not the intent of the originators of the
staging system to include patients with extensive marrow
involvement (A.E.E., personal communication, October
13-16, 1991), and all patients on whom the original con-
cept of stage IV-S was based had minimal marrow in-
volvement.2 98 In addition, a recent study that quantitated
marrow involvement7 3 found < 1% tumor cells in the
marrow of patients who were considered to have stage
IV-S by clinical criteria.
Therefore, an upper limit of 10% marrow involvement
is recommended, and most patients with bona fide stage
4S by INSS criteria will have < 1% tumor cells in the
marrow. Thus, infants with primary tumors that fit the
definition of stage 1 or stage 2 who have more than 10%
marrow involvement would be stage 4, and infants with
stage 3 primary tumors with any degree of marrow in-
volvement detected by conventional methods would be
considered stage 4. Admittedly, it may be difficult to pro-
vide an accurate quantitation of marrow involvement, as
neuroblastoma is frequently present in clumps. However,
almost all stage 4S patients will have s: 1% malignant
cells, and a best estimate of tumor involvement substan-
tially exceeding this should be considered stage 4.
Age Limitationfor Stage 4S
The issue of an age limitation on the definition of stage
4S was discussed, and it was generally agreed that the
favorable clinical behavior of patients with this stage was
associated with infants, defined as < 1 year of age. There
are few if any patients with stage 4S as currently defined
who are older than 1 year of age. Therefore, it was agreed
that this stage would be limited to infants (< 1 year of
age).
Multifocal Primary Tumors
The stage of patients with multifocal primary tumors
was not addressed in the original INSS.14 Because of the
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1471
potential genetic implications of this diagnosis, there
should be convincing evidence that such patients do, in-
deed, have multifocal primary tumors and not metastatic
disease. This may be relatively clear for patients with bi-
lateral adrenal primary tumors, but less clear for patients
with multiple thoracic masses, or with both abdominal
and thoracic disease. If there is serious doubt, the staging
should err on the side of under-diagnosing multifocal pri-
mary tumors. Those thought to have multiple primaries
should be staged according to the most advanced extent
of tumor, as defined previously, and stage should be fol-
lowed by a subscript letter M (eg, 3 M).
RESPONSE TO TREATMENT
Definitions of Response
The modified definitions of the INRC are listed in Table
4. Recognizing the difficulties in making accurate mea-
surements of tumor with an irregular shape, it is recom-
mended that the volume of the primary tumor and large
metastases be determined to the best approximation (Ta-
ble 2), and that the volume (rather than the product of
the two largest diameters) should be used to determine
response. A complete response (CR) indicates complete
disappearance of all primary and metastatic disease, and
the normalization of catecholamines and metabolites (if
they were increased at diagnosis). A very good partial re-
sponse (VGPR) indicates a 90% to 99% volume reduction
in the primary tumor, with clearing of all measurable
Table 4. INRC
Response Primary Tumor* Metastatic Sites*t
CR No tumor No tumor; catecholamines
normal.
VGPR Decreased by 90%-99% No tumor; catecholamines
normal; residual WTc bone
changes allowed.
PR Decreased by > 50% All measurable sites decreased
by > 50%. Bones and bone
marrow: number of positive
bone sites decreased by
> 50%; no more than 1
positive bone marrow site
allowed.t
MR No new lesions; > 50% reduction of any measurable lesion
(primary or metastases) with < 50%reduction in any
other; < 25% increase in any existing lesion.
NR No new lesions; < 50% reduction but < 25% increase in
any existing lesion.
PD Any new lesion; increase of any measurable lesion by
> 25%; previous negative marrow positive for tumor.
*Evaluation of primary and metastatic disease as outlined in Table 2.
tOne positive marrow aspirate or biopsy allowed for PR if this represents
a decrease from the number of positive sites at diagnosis.
1472
metastatic disease and normalization of catecholamines.
The only exception to this would be residual abnor-
malities on technetium bone scan attributable to in-
complete healing of the bone. The MIBG scan (if per-
formed) should be negative at all metastatic sites. A
partial response (PR) indicates a greater than 50% vol-
ume reduction of the primary tumor and a greater than
50% reduction of all measurable metastatic sites (but
not satisfying criteria for CR or VGPR). Residual pos-
itive marrow aspirate or biopsy (one site) is permitted
if this reflects a decrease from the number of sites of
involvement at the time of diagnosis (eg, two to four
sites positive initially). MIBG scans may allow residual
tumor to be distinguished, but if this is not available,
there should be no new bone lesions, and the preexisting
lesions should be improving.
The term mixed response (MR) is used to indicate a
greater than 50% response at one or more sites and a less
than 50% reduction at one or more other sites. This might
occur, for instance, if metastatic disease responded, but
the primary tumor size did not change. In such a case,
the histology of the tumor could have changed from neu-
roblastoma either to ganglioneuroma or to predominantly
scar tissue and necrosis. In this situation, a surgical pro-
cedure could convert such a patient status to PR, VGPR,
or even CR. Otherwise, such a category for a postsurgical
response is probably not meaningful. No response (NR)
indicates a less than 50% reduction of some or all mea-
surable lesions, but no increase of greater than 25% in
these lesions and no new lesions. Progressive disease (PD)
indicates a greater than 25% increase in any preexisting
lesion or any new lesion.
The determination of overall response is based on
the response of the primary tumor and all metastatic
sites. Thus, complete disappearance of all metastatic
disease, but only a PR at the primary site would rep-
resent a PR overall. However, if all residual tumor tissue
had become mature ganglioneuroma or was resectable,
the chemotherapy response would be a PR, but the re-
sponse to combined therapy would be a CR. Some
modifications have been made in the definitions of re-
sponse, but all six categories have been retained. In the
experience of some of the conferees, patients with a
VGPR had the same survival as patients with a CR,
whereas others found no difference between VGPR and
PR. Also, some felt that the MR and NR were indistin-
guishable, whereas others thought the MR category was
useful in the evaluation of phase I or II drugs. Therefore,
it was decided to accrue more experience with the six
INRC categories, with the probability of reducing the
number of four or five categories in the future.
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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.
BRODEUR ET AL
Timing ofResponse
Because of differences in protocols from one group or
country to another, it is difficult to mandate that all re-
sponses be determined at a specific time after diagnosis.
In practice, most protocols evaluate patients for response
after 3 to 4 months of intensive induction therapy, and
most tumors that are going to respond will do so by this
time. Therefore, it was recommended that responses be
quantitated at approximately 4 months from the initiation
of therapy, or as close to this time as possible, with an
interim evaluation at approximately 2 months. Tumors
that respond initially but grow back by 4 months would
be considered to have PD. Although it is expected that
any response would last for at least 4 to 6 weeks, a sus-
tained response without PD for a period of 4 months
should obviate the need for a reevaluation 4 weeks later.
A final point is that response should be determined at the
end of chemotherapy to determine the response to this
modality, but the final response to treatment should be
determined after delayed surgery (if indicated), because
chemotherapy may convert an unresectable tumor into a
resectable one, or it may lead to differentiation of a ma-
lignant mass into a benign tumor.
BIOLOGIC RISK GROUPS
A variety of biologic markers of prognosis have been
proposed to identify high-risk and low-risk patients. These
fall into three general categories: (1) serum and urinary
tumor markers, (2) tumor histology, and (3) genetic fea-
tures of the tumor. The tumor markers include the urinary
VMA-to-HVA ratio,99'100 serum ferritin,84,85 LDH,86 88
95
NSE, 89-91 GD2, 9 3' and CGA. The histology of neuro-
94
blastomas and related tumors have been classified ac-
cording to different schemes, based on the degree of dif-
ferentiation,l01-"°4 or the presence or absence of stroma,
mitoses, or karyorrhexis.l 0 5 ,106 The most popular scheme
was developed by Shimada et al,'os although a simpler
06
variation of this scheme was recently proposed.'
The genetic features of the tumor that have prognostic
significance include the karyotype or modal chromosome
number,10 7 - 0 9 the DNA index (DI) as determined by
flow cytometry, 04,110-1 5 the growth fraction (either the
percent in S-phase or S + G 2 /M) as determined by
flow cytometry,110,111,114,116,117 the N-myc copy num-
ber,60,61,83,113-115,118-120 and deletion of the short arm of
chromosome 1 (lp),12 -123 as well as expression of the N-
myc 16.124-127 and H-ras128 ,1 2 9 oncogenes, and expression
of the multidrug resistance gene.13 0 Another recent prog-
nostic marker with considerable promise is expression of
the primary component of the nerve growth receptor,
REVISIONS OF THE INSS AND INRC
known as TRK-A.' 3 1'-34 Indeed, virtually all of these ab-
normalities have been shown to have prognostic signifi-
cance as independent variables, at least in subsets of pa-
tients.
There have been studies that have used pairs of these
variables to refine the prediction of outcome based on age
and stage. One such study was a retrospective assessment
of serum ferritin and tumor histology (by the Shimada
classification) in a large group of patients over a 25-year
period.' 3 5 These two variables added significantly to age
and stage in predicting outcome. Patients with low ferritin
levels and favorable histology did well, whereas those with
high ferritin levels and unfavorable histology did poorly.
At least five studies have examined the DI and N-myc
copy number,1 13-115,136,137 and, in general, they found that
these variables add significantly to age and stage. Indeed,
in one study, age and stage no longer had prognostic sig-
nificance after the DI and N-myc copy number were con-
sidered.' 14 Patients with a hyperdiploid DI and a normal
N-myc copy number had a greater than 90% 3-year sur-
vival rate, those with near-diploid DI and normal N-mye
had an approximately 50% survival rate, and those with
N-myc amplification had a less than 10% survival
rate.' 14,115 Finally, recent studies document the combined
prognostic power of N-myc amplification as marker of
poor outcome and TRK-A as a marker of favorable out-
34
come.131-1
Several studies have assessed the prognostic significance
of multiple clinical variables in patients with neuroblas-
toma.138-140 However, none has assessed all of the afore-
mentioned clinical and biologic variables in a large group
of patients, so it is difficult to determine which are the
most powerful. It appears that selected serum factors (fer-
ritin, NSE, and LDH), tumor histology, and certain genetic
features (especially chromosome number or DI, N-myc
copy number, chromosome 1 deletion, and TRK-A
expression) are the most useful and widely accepted at
present. It was agreed that all of these studies would be
performed prospectively on as many patients as possible,
and any additional variables, or new variables that are
developed subsequently, would have to be compared with
these core variables. At the next consensus meeting,
planned for 1994, the INSS group would develop a set of
three to four risk groups-the International Neuroblas-
toma Risk Groups (INRGs)--that would include age,
stage, and the most informative combination of biologic
markers. The expectation is that the clinical/surgical stag-
ing system described here would remain essentially un-
changed, but that the INRG might change with time as
newer and more powerful prognostic markers were de-
veloped. Risk group categories would provide a uniform
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Copyright © 2021 American Society of Clinical Oncology. All rights reserved.
1473
method of stratifying patients in clinical trials to determine
the most appropriate type and intensity of therapy.
SUMMARY AND FUTURE DIRECTIONS
In summary, although no radical changes were made
in the definitions of the criteria for neuroblastoma diag-
nosis, INSS, and INRC, a number of important modifi-
cations and clarifications were agreed on. Recommen-
dations are made with regard to reagents to be used for
immunologic assessment of primary and metastatic tumor
(eg, antibodies against NSE, synaptophysin, and CGA).
Indeed, it would be optimal to have standardized reagents
for this purpose that would be available worldwide. The
redefinition of the midline described here should eliminate
some of the ambiguity that has resulted from dealing with
this landmark in the past. Stage 4S has been defined more
precisely in terms of the extent of marrow involvement
and the age of the patient. A special designation for mul-
tifocal primary tumors is proposed, and MIBG is rec-
ommended (if available) for the assessment of primary
and metastatic disease.
Plans for the future include a simplification of the INSS
and INRC from six to either four or five categories. It
seems likely that bilateral bone marrow aspiration with
immunocytology will replace bone marrow biopsies as
required tests to assess marrow involvement. However,
further investigation will be required to prove that this
approach will provide the same prognostic information.
Also, the foundation has been laid for the development
of INRGs based on serum and/or urinary tumor markers,
tumor histology, and genetic features of the tumor. This
approach should allow the identification of several distinct
categories of patient: (1) those whose tumor is likely to
regress spontaneously and require no therapy; (2) those
whose tumors are curable with treatment of limited in-
tensity; (3) those who may be curable only with intensive
treatment; and (4) those who have little chance of cure
even with very intensive chemo(radio)therapy and bone
marrow transplantation. Clearly, different approaches will
be necessary to offer the fourth group of patients a realistic
chance of cure.
Implicit in the move toward the inclusion of biologic
features to assess risk is the need to obtain tissue either
from the primary tumor or metastatic sites. In most
cases, the morbidity of a surgical procedure, especially
a limited open biopsy or a core-needle biopsy, is min-
imal when compared with the morbidity and mortality
associated with very intensive chemotherapy and mar-
row transplantation.1 4 1-145 In addition, important clin-
ical and biologic information (confirming the diagnosis,
determining resectability and nodal involvement, as-
1474
sessing biologic variables) can be obtained. Ultimately,
a better understanding of the genetic changes respon-
sible for malignant transformation and progression
should lead to the development of tumor-specific ther-
apy that is more effective and less toxic than current
modalities. Fundamentally new approaches are needed,
such as the induction of differentiation, the activation
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