Neuroblastoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Neuroblastoma Treatment (PDQ®)–Health Professional Version

Stage Information for Neuroblastoma

Staging Evaluation

Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. A thorough evaluation for metastatic disease is performed before therapy initiation. The studies described below are typically performed.[1]

Metaiodobenzylguanidine (MIBG) scan

The extent of metastatic disease is assessed by MIBG scan, which is applicable to all sites of disease, including soft tissue, bone marrow, and cortical bone. Approximately 90% of neuroblastomas will be MIBG avid. The MIBG scan has a sensitivity and specificity of 90% to 99%, and MIBG avidity is equally distributed between primary and metastatic sites.[2] Although iodine I 123 (123I) has a shorter half-life, it is preferred over 131I because of its lower radiation dose, better quality images, reduced thyroid toxicity, and lower cost.

Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to positron emission tomography–computed tomography (PET-CT) in one prospective comparison.[3] In a retrospective review of 132 children with neuroblastoma, technetium Tc 99m-methylene diphosphonate (99mTc-MDP) bone scintigraphy failed to identify unique sites of metastatic disease that would change the disease stage or clinical management determined using 123I-MIBG or PET scanning. It was concluded that bone scans can be omitted in most cases.[4]

Baseline MIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.[5] A retrospective analysis of paired 123I-MIBG and PET scans in 60 patients with newly diagnosed neuroblastoma demonstrated that for International Neuroblastoma Staging System (INSS) stage 1 and stage 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123I-MIBG imaging was superior for the detection of bone marrow and bony metastases.[6]

Curie and SIOPEN scoring methods

Multiple groups have investigated a semiquantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) methods.

Curie scoring method: The Curie score is a semiquantitative scoring system developed to predict the extent and severity of MIBG-avid disease. The use of the Curie scoring system was assessed as a prognostic marker for response and survival with MIBG-avid, stage 4, newly diagnosed, high-risk neuroblastoma (N = 280), treated on the Children’s Oncology Group (COG) protocol COG-A3973 (NCT00004188). For patients with MYCN-nonamplified neuroblastoma, a postinduction chemotherapy Curie score greater than 2 was associated with a higher risk of an event, independent of other known neuroblastoma clinical and biological factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade.[7] For patients with MYCN-amplified tumors, a postinduction Curie score greater than 0 was associated with worse outcomes.
The prognostic significance of postinduction Curie scores has been validated in an independent cohort of patients.[8] A retrospective study of Curie scoring of 123I-MIBG scans obtained from high-risk patients who had been prospectively enrolled in the SIOPEN/HR-NBL1 (NCT00030719) trial was performed. Scans of ten anatomic regions were evaluated, with each region being scored 0 to 3 on the basis of disease extent, and a cumulative Curie score generated. The optimal prognostic cut point for Curie score at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by Curie score noted (5-year event-free survival [EFS] rate, 43.0% ± 5.7% [Curie score ≤12] vs. 21.4% ± 3.6% [Curie score >12], P < .0001). The optimal Curie score cut point after induction chemotherapy was 2 in SIOPEN/HR-NBL1, with a postinduction Curie score of greater than 2 being associated with an inferior outcome (5-year EFS rate, 39.2% ± 4.7% [Curie score ≤2] vs. 16.4% ± 4.2% [Curie score >2], P < .0001). The postinduction Curie score maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number.[8]
SIOPEN scoring method: SIOPEN independently developed an MIBG scan scoring system that, compared with the Curie scoring system, divided the body into 12 segments, rather than 10 segments, and assigned six degrees, rather than four degrees, of MIBG uptake in each segment.[9] Subsequently, the SIOPEN scoring system was independently validated using data from a second large clinical trial.[10]

The German Pediatric Oncology Group compared the prognostic value of the Curie and SIOPEN scoring methods in a retrospective study of 58 patients with stage 4 neuroblastoma who were older than 1 year. They demonstrated very similar results. At diagnosis, a Curie score of 2 or lower and a SIOPEN score of 4 or lower (best cutoff) at diagnosis correlated with significantly better EFS and overall survival (OS) rates, compared with higher scores. After four cycles of induction chemotherapy, patients with a complete response by SIOPEN and Curie scoring had a better outcome than did patients with residual uptake in metastases; however, subsequent resolution of MIBG-positive metastases occurring between the fourth and sixth cycles of chemotherapy did not affect prognosis.[11]

The cited clinical trials did not include postinduction-phase assessments of Curie or SIOPEN scores after transplant and immunotherapy, and cutoffs and outcomes associated with those assessments may differ from the preinduction and postinduction scores.

Positron emission tomography (PET) scan

Fluorine F 18-fludeoxyglucose PET scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.[6]

Other staging tests and procedures

Other tests and procedures used to stage neuroblastoma include the following:

Bone marrow aspiration and biopsy: Bone marrow is assessed by bilateral iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Many COG studies require two core biopsies and two aspirates. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.[12]
Lymph node assessment: Palpable lymph nodes are clinically examined and histologically confirmed if INSS staging is used to evaluate extent of disease.[1] CT, magnetic resonance imaging (MRI), or both are used to assess lymph nodes in regions that are not readily identified by physical examination. The International Neuroblastoma Risk Group (INRG) staging system does not require lymph node assessment, although lymph node masses can affect image-defined risk factors (IDRFs) (refer to the lists of IDRFs [original IDRFs and COG IDRFs]).
CT and MRI scan:
- Three-dimensional (3-D) imaging of the primary tumor and potential lymph node drainage sites is done using CT scans and/or MRI scans of the chest, abdomen, and pelvis. Ultrasonography is generally considered suboptimal for accurate 3-D measurements.
- Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is part of the staging evaluation.
- A brain/orbit CT and/or MRI is performed if clinically indicated by examination and/or uptake on MIBG scan.

Lumbar puncture is avoided because central nervous system (CNS) metastasis at diagnosis is rare,[13] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[14]

International Neuroblastoma Staging Systems

International Neuroblastoma Staging System (INSS)

The INSS combines certain features from each of the previously used Evans and Pediatric Oncology Group staging systems [1,15] and is described in Table 3. This system represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a surgical staging system that was developed in 1988 and is used to assess the extent of resection in staging patients. This led to some variability in stage assignments in different countries because of regional differences in surgical strategy and, potentially, because of limited access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies.[1,15-17]

Table 3. The International Neuroblastoma Staging System (INSS)

Stage/Prognostic Group	Description
MIBG = metaiodobenzylguanidine.
Stage 1	Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).
Stage 2A	Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Stage 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.
Stage 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. 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.
Stage 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.
Stage 4S	Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by definition limited to infants younger than 12 months).[18] Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the MIBG scan, if performed, should be negative for disease in the bone marrow.

The COG Neuroblastoma Risk Grouping that incorporates INSS is described in Table 6 found in the Treatment Option Overview for Neuroblastoma section of this summary.

A study from the INRG database identified 146 patients with distant metastases limited to lymph nodes, termed stage 4N, who tended to have favorable-biology disease and a good outcome (5-year OS, 85%), which suggests that less-intensive therapy might be considered.[19]

International Neuroblastoma Risk Group Staging System (INRGSS)

The final use of the INSS by the COG was for the intermediate-risk ANBL0531 (NCT00499616) study, which was closed in 2014. Subsequent studies have used the INRGSS. The INRGSS is a preoperative staging system that was developed specifically for the INRG classification system (refer to Table 4). This staging system has replaced the INSS in active COG and SIOPEN clinical trials. The extent of disease is determined by the presence or absence of IDRFs and/or metastatic tumor at the time of diagnosis, before any treatment or surgery. IDRFs are surgical risk factors, detected by imaging, which could potentially make total tumor excision risky or difficult at the time of diagnosis and increase the risk of surgical complications.

Table 4. International Neuroblastoma Risk Group Staging Systema

Stage	Description
IDRFs = image-defined risk factors; INSS = International Neuroblastoma Staging System.
aAdapted from Monclair et al.[20]; [21]
L1	Localized tumor not involving vital structures as defined by the list of IDRFsa and confined to one body compartment.
L2	Locoregional tumor with presence of one or more IDRFs.a
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. The primary tumor can be INSS stage 1, 2, or 3.

IDRFs, as defined in the original literature, include the following:[20]

Ipsilateral tumor extension within two body compartments: neck and chest; chest and abdomen; abdomen and pelvis.
Infiltration of adjacent organs/structures: pericardium, diaphragm, kidney, liver, duodenopancreatic block, mesentery.
Encasement of major vessels by tumor: vertebral artery, internal jugular vein, subclavian vessels, carotid artery, aorta, vena cava, major thoracic vessels, branches of the superior mesenteric artery at its root and the coeliac axis, iliac vessels.
Compression of trachea or central bronchi.
Encasement of brachial plexus.
Infiltration of portohepatic or hepatoduodenal ligament.
Infiltration of the costovertebral junction between T9 and T12.
Tumor crossing the sciatic notch.
Tumor invading renal pedicle.
Extension of tumor to base of skull.
Intraspinal tumor extension such that more than one-third of the spinal canal is invaded, leptomeningeal space is obliterated, or spinal cord MRI signal is abnormal.

COG IDRFs, using an anatomic localization approach, include the following:[21,22]

Neck/cervicothoracic junction: Tumor encasing brachial plexus roots; tumor encasing subclavian vessels and/or vertebral 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 costovertebral junction between T9 and T12; significant pleural effusion with or without presence of malignant cells.
Thoracoabdominal: Tumor encasing the aorta and/or vena cava.
Abdomen/pelvis: Tumor infiltrating the porta hepatis; tumor infiltrating the branches of the superior mesenteric 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; ascites with or without presence of malignant cells.
Dumbbell tumors with symptoms of spinal cord compression.
Any localization involvement/infiltration of adjacent organs/structures: Pericardium, diaphragm, kidney, liver, duodenopancreatic block, mesentery, and others.

Assessment of surgical resectability should include IDRFs. The more IDRFs present, the higher the morbidity of the operation and the lower the chance of complete resection.

Neoadjuvant chemotherapy is not always effective in eliminating IDRFs, as seen in a retrospective study in the European Unresectable Neuroblastoma trial from 2001 to 2006 that examined data from 143 patients with INSS stage 3 neuroblastoma who were older than 1 year without MYCN amplification. All patients had surgical risk factors that deemed the tumors unresectable. In a centrally reviewed subset, unfavorable histology by International Neuroblastoma Pathology Classification was found in 53% of patients. At diagnosis, 228 IDRFs were identified.[22]; [23][Level of evidence: 3iiA]

After four cycles of chemotherapy with carboplatin/etoposide alternating with vincristine/cyclophosphamide/doxorubicin, only 32.2% of patients demonstrated resolution of the IDRFs, 49% of patients showed no change in IDRFs, and 18.8% of patients developed new IDRFs.
Complete resection was possible in 71.2% of patients in whom the IDRFs were reduced or disappeared. Complete or near complete resection was achieved in 84% of patients (37 of 44) whose IDRFs decreased or disappeared. Complete or near complete resection was achieved in 70% of patients (39 of 56) who had stable IDRFs and in 52% of patients (13 of 25) who had new IDRFs appear.
No significant differences were observed in EFS or OS on the basis of the response of the IDRF to chemotherapy and surgical outcomes. There was no association between type of IDRF before surgery and extent of resection.
When the tumor was wrapped around the superior mesenteric artery and/or celiac axis, disease-free survival (DFS) and OS were impacted (perhaps because of the difficulty in achieving a complete resection in these areas).
Prolonged chemotherapy with more than five courses did not aid in the reduction of IDRFs and was associated with a lower DFS and OS.

The INRGSS has incorporated this staging system into a risk grouping system using multiple other parameters at diagnosis.[24] (Refer to Table 6 in the Treatment Option Overview for Neuroblastoma section of this summary for more information.)

The INRGSS simplifies stages into L1, L2, M, or MS (refer to Table 4 and the lists of IDRFs [original IDRFs and COG IDRFs] for more information). Localized tumors are classified as stage L1 or L2 disease on the basis of whether one or more of the 20 IDRFs are present.[20] For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. The INRG collaboration has also defined techniques for detecting and quantifying neuroblastoma in bone marrow, both at diagnosis and after treatment. Quantification of bone marrow metastatic disease may result in more accurate assessment of response to treatment, but has not yet been applied to any clinical trials.[25]

The decision by the INRG Task Force to replace the category of 4S disease with that of the new MS definition was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including those aged 12 to 18 months, had favorable outcomes.[18,20] A subsequent study of the actual INRG data found that a number of biological characteristics predicted poor outcome of MS patients (aged 12 to 18 months), and that only those infants with favorable biology had long-term outcomes similar to those with the traditional 4S diagnosis.[18]

By combining the INRGSS, preoperative image-defined IDRFs, and biological factors, each patient is assigned a risk stage that predicts outcome and dictates the appropriate treatment approach. The validity of the INRGSS was explored in the following retrospective studies of localized neuroblastoma with previously defined INSS stage without MYCN amplification:

In the first study, using data from a SIOPEN trial, L2 tumors were found in INSS stage 1 (21%), stage 2 (45%), and stage 3 (94%) patients. The INRGSS had predictive value for outcomes, with stage L1 having a 5-year EFS of 90% and OS of 96%, versus 79% EFS and 89% OS for L2.[20]
In the second study, using data from the European multicenter study LNESG1, a trial of primary surgery followed by observation performed between 1995 and 1999, 291 children had L1 tumors and all underwent primary surgery. Of the L2 patients, 118 had primary surgery and 125 had no surgery (106 of the latter group received neoadjuvant chemotherapy).[26]
- Five-year EFS and OS rates were 92% and 98% for the L1 group, 86% and 95% for the L2 with primary surgery group, and 73% and 83% for the L2 without primary surgery group.
- It should be noted that many children with L2 tumors underwent primary surgery and had an outcome significantly superior to that of children who underwent biopsy only as the initial operative procedure (5-year OS rate of 93% vs. 83%). The L2 tumors that underwent primary resection may have been selected for less-risky resectability. However, these children also had a 17% rate of operative complications (vs. 5% in L1 resections).
- In patients who underwent primary surgery, those with operative complications had a lower OS (92% vs. 97%, P = .05), but this effect on outcome was statistically significant only in patients with L1 tumors.
- For L2 patients, the operative complications were not statistically related to the IDRFs.[26]

Most international protocols have begun to incorporate the collection and use of IDRFs in risk stratification and assignment of therapy.[27,28] The COG has been collecting and evaluating INRGSS data since 2006. A COG trial that opened in 2014 uses the INRGSS along with input from the surgeon to determine therapy for subsets of patients not at high risk, including those with L1, L2, and MS disease (ANBL1232 [NCT02176967]). Note that the INSS allows patients up to age 12 months to be classified as stage 4S, while the INRGSS allows patients up to age 18 months to be staged as MS. The primary tumor in INSS stage 4S must be INSS stage 1 or 2, while the primary tumor in MS can be INSS stage 3. In August 2018, a COG study for subsets of high-risk patients was opened (ANBL1531 [NCT03126916]). Eligible patients include those with stage M disease older than 547 days, stage M patients younger than 547 days with MYCN amplification, and patients of any age with stage L2 or MS disease with MYCN amplification. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.

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