jueves, 7 de marzo de 2019

Neuroblastoma Treatment (PDQ®) 1/2 —Health Professional Version - National Cancer Institute

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



National Cancer Institute



Neuroblastoma Treatment (PDQ®)–Health Professional Version

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General Information About Neuroblastoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1-3] For neuroblastoma, the 5-year survival rate increased over the same time, from 86% to 95% for children younger than 1 year and from 34% to 68% for children aged 1 to 14 years.[2] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence and Epidemiology

Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[4,5] The prevalence is about 1 case per 7,000 live births; the incidence is about 10.54 cases per 1 million per year in children younger than 15 years. About 37% of patients are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months.[6] The data on age at diagnosis show that this is a disease of infancy, with the highest rate of diagnosis in the first month of life.[4-6]
The incidence of neuroblastoma in black children is slightly lower than the incidence in white children.[7] However, there are also racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcomes.[8,9]
Population-based studies of screening for infants with neuroblastoma have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.[10-12]
Epidemiologic studies have shown that environmental or other exposures have not been unequivocally associated with increased or decreased incidences of neuroblastoma.[13]

Anatomy

Neuroblastoma originates in the adrenal medulla and paraspinal or periaortic regions where sympathetic nervous system tissue is present (refer to Figure 1).
ENLARGEDrawing shows parts of the body where neuroblastoma may be found, including the paraspinal nerve tissue and the adrenal glands. Also shown are the spine and right and left kidney.
Figure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.

Genetic Predisposition and Familial Neuroblastoma

Studies analyzing constitutional DNA in rare cohorts of familial neuroblastoma patients have provided insight into the complex genetic basis for tumor initiation. About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma. These children are, on average, younger (9 months at diagnosis) and about 20% have multifocal primary neuroblastoma.
Several germline mutations have been associated with a genetic predisposition to neuroblastoma, including the following:
  • ALK gene mutation. The primary cause of familial neuroblastoma (about 75% of familial cases) is aberrant activation of the germline ALK signaling pathway resulting from point mutations in the tyrosine kinase domain of the ALK gene.[14] Somatic activating point mutations in ALK are also seen in about 9% of sporadic neuroblastoma cases. In addition, in a small proportion of neuroblastoma cases with MYCNamplification, ALK is co-amplified (ALK is near MYCN on chromosome 2), which may also result in ALK activation. ALK is a tyrosine kinase receptor; it is activated by translocations in some lymphomas, non-small cell lung cancer, and inflammatory myofibroblastic tumors (refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information about ALK mutations).
  • PHOX2B gene mutation. Rarely, familial neuroblastoma may be associated with congenital central hypoventilation syndrome (Ondine curse), which is caused by a germline mutation of the PHOX2B gene.[15] Most PHOX2B mutations causing Ondine curse or Hirschsprung disease are polyalanine repeats and are not associated with familial neuroblastoma. However, germline loss-of-function PHOX2B mutations have been identified in rare patients with sporadic neuroblastoma and Ondine curse and/or Hirschsprung disease.[16] Aberration of PHOX2B has not been seen in patients with sporadic neuroblastoma without associated Ondine curse or Hirschsprung disease. Additionally, somatic PHOX2B mutations occur in about 2% of sporadic cases of neuroblastoma.[17,18]
  • Deletion at the 1p36 or 11q14-23 locus. In case studies, germline deletion at the 1p36 or 11q14-23 locus has been associated with familial neuroblastoma, and the same deletions are found somatically in some sporadic neuroblastoma cases.[19,20]
Other cancer predisposition syndromes. Children with gene aberrations associated with other cancer predisposition syndromes can be at increased risk of developing neuroblastoma and other malignancies. These syndromes primarily involve genes in the canonical RAS pathway, including Costello syndrome,[21] Noonan syndrome,[22] and neurofibromatosis type 1.[23] In addition, neuroblastoma has been described in patients with Li-Fraumeni syndrome, hereditary pheochromocytoma/paraganglioma syndromes,[24] ROHHAD syndrome (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysfunction),[25] and Beckwith–Wiedemann syndrome.[26]
Sporadic neuroblastoma may also have an increased incidence resulting from less potent germline predispositions. Genome-wide association studies have identified several common genomic variables (single nucleotide polymorphisms [SNPs]) with modest effect size that are associated with increased risks of developing neuroblastoma. Most of these genomic risk variables are significantly associated with distinct neuroblastoma phenotypes (i.e., high-risk vs. low-risk disease).[27]

Genomic and Biologic Features of Neuroblastoma

Children with neuroblastoma can be subdivided into subsets with different predicted risks of relapse on the basis of clinical factors and biological markers at the time of diagnosis. Patients classified as low-risk or intermediate-risk have a favorable prognosis, with survival rates exceeding 95%. In contrast, the prognosis is more guarded for patients with high-risk neuroblastoma, with less than a 50% long-term survival rate.
Low-risk and intermediate-risk neuroblastoma usually occur in children younger than 18 months. These tumors commonly have gains of whole chromosomes and are hyperdiploid when examined by flow cytometry.[28,29]
In contrast, high-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and segmental chromosome abnormalities (gains or losses) and/or MYCN gene amplification is usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[28-34] High-risk tumors may rarely harbor exonic mutations, (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack such gene mutations. Compared with adult cancers, neuroblastoma tumors show a low number of mutations per genome that affect protein sequence (10–20 per genome).[35]
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
  • Segmental chromosomal aberrations.
  • MYCN gene amplifications.
  • Low rates of exonic mutations, with activating mutations in ALK being the most common recurring alteration.
  • Genomic alterations that promote telomere lengthening.
Segmental chromosomal aberrations
Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p are best detected by comparative genomic hybridization and are seen in most high-risk and/or stage 4 neuroblastomas.[30-34] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of segmental chromosome aberrations) correlated with the following:[30-34][Level of evidence: 3iiD]
  • Advanced age at diagnosis.
  • Advanced stage of disease.
  • Higher risk of relapse.
  • Poorer outcome.
An international collaboration studied 556 patients with high-risk neuroblastoma and identified two types of segmental copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%; amplifications of regions not encompassing the MYCN locus, in addition to MYCN amplification, were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[36]
In a study of children older than 12 months who have unresectable primary neuroblastomas without metastases, segmental chromosomal aberrations were found in most, and older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on event-free survival (EFS) but not on overall survival (OS). However, in children older than 18 months, there was a significant difference in OS between children with segmental chromosomal aberrations (67%) and children without segmental chromosomal aberrations (100%), regardless of tumor histology.[34]
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[28,29]
MYCN gene amplification
MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[37] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[38] In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis, in both time to tumor progression and OS, in almost all multivariate regression analyses of prognostic factors.[28,29] Within the localized tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors.[39] However, patients with hyperdiploid tumors with MYCN amplification or any segmental chromosomal aberrations do relatively poorly compared with patients with hyperdiploid tumors without MYCN amplification.[30]
In a Children’s Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma, 79% had MYCN–wild-type tumors, 3% had tumors with MYCN gain (defined as a twofold to fourfold increase in signal by fluorescence in situ hybridization), and 18% had MYCN-amplified tumors. When individual clinical/biological features were examined, the percentage of patients with unfavorable features was lowest in the MYCN–wild-type category, intermediate in the MYCN-gain category, and highest in the MYCN-amplified category (P < .0001), except for the tumors with 11q aberration, for which the highest rates were in the MYCN-gain category. Patients with non–stage 4 disease and patients with non–high-risk disease and MYCN gain had a significantly increased risk of death than did patients with MYCN–wild-type tumors.[40]
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 International Neuroblastoma Risk Group patients, pooled segmental chromosomal aberrations and gains of 17q were poor prognostic features even when not associated with MYCN amplification. However, another poor prognostic feature, segmental chromosomal aberrations at 11q, are almost entirely mutually exclusive of diffuse MYCN amplification.[41,42]
Exonic mutations in neuroblastoma
Multiple reports have documented that a minority of high-risk neuroblastomas have a low incidence of recurrently mutated genes. The most commonly mutated gene is ALK, which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutations include ATRX, PTPN11, ARID1A, and ARID1B.[43-49] As shown in Figure 2, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.
ENLARGEChart showing the landscape of genetic variation in neuroblastoma.
Figure 2. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were sex (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).
ALK, the exonic mutation found most commonly in neuroblastoma, is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic mutations are also found as oncogenic drivers in neuroblastoma.[48]
The presence of an ALK mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. ALK mutations were examined in 1,596 diagnostic neuroblastoma samples.[48] ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in patients with high-risk and intermediate-risk neuroblastoma. ALKmutations were found in 10.9% of MYCN-amplified tumors versus 7.2% of those without MYCN amplification. ALK mutations occurred at the highest frequency (11%) in patients older than 10 years.[48] The frequency of ALK aberrations was 14% in the high-risk neuroblastoma group, 6% in the intermediate-risk neuroblastoma group, and 8% in the low-risk neuroblastoma group. The high-risk group included tumors with ALK aberrations, consisting of ALK co-amplification with MYCN amplification, which may also result in ALKactivation.
Small-molecule ALK kinase inhibitors such as crizotinib (added to conventional therapy) are being tested in patients with newly diagnosed high-risk neuroblastoma and activated ALK(COG ANBL1531).[48] (Refer to the Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma section in the PDQ summary on Neuroblastoma Treatment for more information about crizotinib clinical trials.)
Genomic evolution of exonic mutations
There are limited data regarding the genomic evolution of exonic mutations from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[50] while a second study evaluated 16 paired diagnostic and relapsed specimens.[51] Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis; this has been confirmed in a study of neuroblastoma tumor samples sent for next-generation sequencing.[52]
  • In the first study, an increased incidence of mutations in genes associated with RAS-MAPK signaling were found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic mutations in genes involved in this pathway and each mutation was consistent with pathway activation.[50]
    In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 relapse samples (78%). Aberrations were found in ALK (n = 10), NF1(n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutation presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
  • In the second study, ALK mutations were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[51]
In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK mutational hot spots, which revealed 4.8% clonal mutations and an additional 5% subclonal mutations, suggesting that subclonal ALK gene mutations are common.[53] Thus, deep sequencing can reveal the presence of mutations in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.
Genomic alterations promoting telomere lengthening
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, resulting eventually in the lack of a cell’s ability to replicate. Low-risk neuroblastoma tumors have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[43,44,54] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:
  • Chromosomal rearrangements involving a chromosomal region at 5p15.33 proximal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCNamplifications and ATRX mutations.[43,44] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements.
  • Another mechanism promoting TERT overexpression is MYCN amplification,[55] which is associated with approximately 40% to 50% of high-risk neuroblastoma cases.
  • The ATRX mutation or deletion is found in 10% to 20% of high-risk neuroblastoma tumors, almost exclusively in older children,[45] and is associated with telomere lengthening by a different mechanism, termed alternative lengthening of telomeres.[45,54]
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[56] Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression; in the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. Segmental chromosomal aberrations were not examined in this study.[56]
  • Patients with favorable-histology tumors without high MYC/MYCN expression had favorable survival (3-year EFS, 89.7% ± 5.5%; 3-year OS, 97% ± 3.2%).
  • Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% (± 13.6%) and a 3-year OS rate of 83.5% (± 9.4%).
  • Three-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% (± 11.5%), 46.2% (± 12%), and 43.4% (± 23.1%), respectively, and OS rates were 65.8% (± 11.1%), 63.2% (± 12.1%), and 63.5% (± 19.2%), respectively.
  • Additionally, when high expression of MYC and MYCN proteins underwent multivariate analysis with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.
Neurotrophin receptor kinases
Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.[57]
Immune system inhibition
Anti-GD2 antibodies, along with modulation of the immune system to enhance the antibody's antineuroblastoma activity, are often used to help treat neuroblastoma. The clinical effectiveness of one such antibody led to U.S. Food and Drug Administration approval of dinutuximab. The patient response to immunotherapy may, in part, be caused by variation in immune function among patients. One anti-GD2 antibody, termed 3F8, used for treating neuroblastoma exclusively at one institution, utilizes natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor (KIR) subtypes.[58,59] This finding was confirmed and expanded by an analysis of outcomes for patients treated on the national randomized COG-ANBL0032 (NCT00026312) study with the anti-GD2 antibody dinutuximab combined with granulocyte-macrophage colony-stimulating factor and interleukin-2. The study found that certain KIR/KIR-ligand genotypes were associated with better outcomes for patients who were treated with immunotherapy.[60][Level of evidence: 1A] The presence of inhibitory KIR/KIR ligands was associated with a decreased effect of immunotherapy. Thus, the patient's immune system genes help determine response to immunotherapy for neuroblastoma. Additional studies are needed to determine whether this immune system genotyping can guide patient selection for certain immunotherapies.

Neuroblastoma Predisposition and Surveillance

Screening recommendations from the American Association for Cancer Research (AACR) emerged from the 2016 Childhood Cancer Predisposition Workshop. The AACR recommends that the following individuals undergo biochemical and radiographic surveillance for early detection of tumors in the first 10 years of life:[24]
  • Individuals with a highly penetrant, heritable ALK or PHOX2B (NPARM) mutation (45%–50% risk of developing one or more tumors).
  • Individuals with Li-Fraumeni syndrome and germline TP53-R337H mutations.
  • Individuals with Beckwith-Wiedemann syndrome and germline CDKN1C mutations.
  • Individuals with Costello syndrome and HRAS mutations.
  • Patients with neuroblastoma and a strong family history of neuroblastoma or clearly bilateral/multifocal neuroblastoma.
Surveillance consists of the following:[24]
  • Abdominal ultrasonography.
  • Quantitative, normalized assessment of urinary catecholamines, such as urine vanillylmandelic acid (VMA) and homovanillic acid (HVA), by gas chromatography and mass spectroscopy (can be a random urine collection normalized for urine creatinine).
  • Chest x-ray.
Surveillance begins at birth or at diagnosis of neuroblastoma predisposition and continues every 3 months until age 6 years and then continues every 6 months until age 10 years. Patients with Costello syndrome may have elevated urinary catecholamines in the absence of a catecholamine-secreting tumor, so only very high levels or significantly rising levels should prompt further investigation beyond the ultrasonography and chest x-ray.[61] Patients with Li-Fraumeni syndrome should not undergo chest x-rays.[24]

Neuroblastoma Screening (General Population)

Current data do not support neuroblastoma screening in the general public. Screening at the ages of 3 weeks, 6 months, or 1 year did not lead to reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce overall mortality from neuroblastoma.[11,12] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary on Neuroblastoma Screening for more information.)
Evidence (against neuroblastoma screening):
  1. A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [10,11] that would never have been detected clinically, apparently because of spontaneous regression of the tumors.
  2. Another study of infants screened at the age of 1 year showed similar results.[12]

Clinical Presentation

The most common presentation of neuroblastoma is an abdominal mass. The most frequent signs and symptoms of neuroblastoma are caused by tumor mass and metastases. They include the following:
  • Proptosis and periorbital ecchymosis: Common in high-risk patients and arise from retrobulbar metastasis.
  • Abdominal distention: May occur with respiratory compromise in infants because of massive liver metastases.
  • Bone pain: Occurs in association with metastatic disease.
  • Pancytopenia: May result from extensive bone marrow metastasis.
  • Fever, hypertension, and anemia : Occasionally found in patients without metastasis.
  • Paralysis: Neuroblastoma originating in paraspinal ganglia may invade through neural foramina and compress the spinal cord extradurally. Immediate treatment is given for symptomatic spinal cord compression. (Refer to the Treatment of Spinal Cord Compression section of this summary for more information.)
  • Watery diarrhea: On rare occasions, children may have severe, watery diarrhea caused by the secretion of vasoactive intestinal peptide by the tumor, or they may have protein-losing enteropathy with intestinal lymphangiectasia.[62] Vasoactive intestinal peptide secretion may also occur with chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[63]
  • Presence of Horner syndrome: Horner syndrome is characterized by miosis, ptosis, and anhidrosis. It may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without other apparent cause are also examined for neuroblastoma and other tumors.[64]
  • Subcutaneous skin nodules: Subcutaneous metastases of neuroblastoma often have bluish discoloration of the overlying skin and is usually seen only in infants.
The clinical presentation of neuroblastoma in adolescents is similar to the clinical presentation in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.[65]

Opsoclonus/myoclonus syndrome

Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, occur rarely in children with neuroblastoma.[66] The incidence in the United Kingdom is estimated at 0.18 cases per 1 million children per year and the average age at diagnosis is 1.5 to 2 years.[67] Opsoclonus/myoclonus syndrome is often associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the primary tumor.[68-70] Of young children presenting with opsoclonus/myoclonus, about one-half are found to have neuroblastoma.[68,71]
Neuroblastoma patients who present with opsoclonus/myoclonus syndrome often have neuroblastoma with favorable biological features and are likely to survive, although tumor-related deaths have been reported.[68]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully characterized.[68] The primary tumor is typically diffusely infiltrated with lymphocytes.[72]
Some patients may acutely respond neurologically to immune interventions or removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary.
The short-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[66] Adrenocorticotropic hormone or corticosteroid treatment can be effective, but some patients do not respond to corticosteroids.[69,73] Other therapy with various immunomodulatory drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in select cases.[69,74-77] Combination immunosuppressive therapy has been explored, with improved short-term results.[78]
The first randomized, open-label, phase III study of patients with opsoclonus-myoclonus ataxia syndrome has been completed by the Children’s Oncology Group (COG). Patients with newly diagnosed neuroblastoma and opsoclonus-myoclonus ataxia syndrome who were younger than 8 years were randomly assigned to receive intravenous immunoglobulin (IVIG) or no IVIG in addition to prednisone and risk-adapted treatment. Of the 53 patients who participated, 21 of 26 patients (81%) in the IVIG group had an opsoclonus-myoclonus ataxia syndrome response, compared with 11 of 27 patients (41%) in the non-IVIG group (odds ratio [OR], 6.1; P = .0029). This study demonstrates that short-term neurologic response is improved in patients treated with chemotherapy, corticosteroids, and immunoglobulin, compared with patients treated with chemotherapy and corticosteroid without immunoglobulin.[79] Additional follow-up is needed to assess long-term neurodevelopment and learning problems in this population.

Diagnosis

Diagnostic evaluation of neuroblastoma includes the following:
  • Tumor imaging: Imaging of the primary tumor mass is generally accomplished by computed tomography or magnetic resonance imaging (MRI) with contrast. Paraspinal tumors that might threaten spinal cord compression are imaged using MRI. Metaiodobenzylguanidine (MIBG) scanning is a critical part of the standard diagnostic evaluation of neuroblastoma, for both the primary tumor and sites of metastases.[80,81] MIBG scanning is also critical to assess response to therapy.[81] About 90% of neuroblastoma cases are MIBG avid; fluorine F 18-fludeoxyglucose positron emission tomography (PET) scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.[82] (Refer to the Stage Information for Neuroblastoma section of this summary for more information about imaging of neuroblastoma.)
  • Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites VMA and HVA per milligram of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If they remain elevated, these markers can be used to suggest the persistence of disease.
    In contrast to urine, serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
  • Biopsy: Tumor tissue is often needed to obtain all the biological data required for risk-group assignment and subsequent treatment stratification in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC). In the risk/treatment group assignment schema for COG studies, INPC has been used to determine treatment for patients with International Neuroblastoma Staging System (INSS) stage 3 disease, patients with stage 4S disease, and patients aged 18 months or younger with stage 4 disease. Additionally, a significant number of tumor cells are needed to determine MYCN copy number, DNA index, and the presence of segmental chromosomal aberrations. Tissue from several core biopsies, or approximately 1 cm3 of tissue from an open biopsy, is needed for adequate biologic staging.
    For patients older than 18 months with stage 4 disease, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites may be adequate for diagnosis and assigning risk/treatment group; however, INPC cannot be determined from tumor metastatic to bone marrow. Testing for MYCN amplification may be successfully performed on involved bone marrow if there is at least 30% tumor involvement. However, every attempt should be made to obtain an adequate biopsy from the primary tumor.
    Diagnosis of fetal/neonatal neuroblastoma. In rare cases, neuroblastoma may be discovered prenatally by fetal ultrasonography.[83] Management recommendations are evolving regarding the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. In a COG study of expectant observation of small adrenal masses of 3.1 cm or less in neonates, biopsy was not required for infants; 81% of patients avoided undergoing any surgery at all.[84] In a German clinical trial, 25 infants aged 3 months and younger with presumed localized neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects from the delay.[85] Therefore, prenatally identified adrenal masses approximately 3.1 cm or less can be safely observed if no metastatic disease is identified and there is no involvement of large vessels or organs.[84]
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated morphologically, via conventional light microscopy with hematoxylin and eosin staining alone, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. In such cases, immunohistochemical and cytogenetic analysis may be needed to diagnose a specific small round blue cell tumor.
The minimum criterion for a diagnosis of neuroblastoma, as established by international agreement, is that diagnosis must be based on one of the following:
  1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology or electron microscopy).[86]
  2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) andincreased levels of urinary catecholamine metabolites.[86]

Prognostic Factors

The prognosis for patients with neuroblastoma is related to the following:
Some of these prognostic factors have been combined to create risk groups to help define treatment. (Refer to the International Neuroblastoma Risk Group Staging System section and the Children’s Oncology Group Neuroblastoma Risk Grouping section of this summary for more information.)

Treatment era

Between 1975 and 2010, the 5-year survival rate for neuroblastoma in the United States increased from 86% to 95% for children younger than 1 year and increased from 34% to 68% for children aged 1 to 14 years.[2] The 5-year overall survival (OS) for all infants and children with neuroblastoma increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005.[87] This single statistic can be misleading because of the extremely heterogeneous prognosis based on the patient's age, stage, and biology. However, studies demonstrate a significant improvement in survival for high-risk patients diagnosed and treated between 2000 and 2010 compared with patients diagnosed from 1990 to 1999.[88] (Refer to Table 1 for more information.)

Age at diagnosis

The effect of age at diagnosis on 5-year survival is profound. According to the 1975 to 2006 U.S. Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival stratified by age is as follows:[87]
  • Age younger than 1 year: 90%.
  • Age 1 to 4 years: 68%.
  • Age 5 to 9 years: 52%.
  • Age 10 to 14 years: 66%.
The effect of patient age on prognosis is strongly influenced by clinical and pathobiological factors, as evidenced by the following:
  • Since 2000, nonrandomized studies of low-risk and intermediate-risk patients have demonstrated that patient age has no effect on outcome of INSS stage 1 or stage 2A disease. However, stage 2B patients younger than 18 months had a 5-year OS of 99% (± 1%) versus 90% (± 4%) for children aged 18 months and older.[89]
  • In the COG intermediate-risk study A3961 (NCT00003093) that included only MYCNnonamplified tumors, infants with INSS stage 3 tumors were compared with children with INSS stage 3 favorable-histology tumors. When INSS stage 3 infants with any histology were compared with stage 3 children with favorable histology, only EFS rates, not OS rates, were significantly different (3-year EFS, 95% ± 2 % vs. 87% ± 3 %; OS, 98% ± 1% vs. 99% ± 1%).[90]
Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk and have a 3-year EFS of 81% and an OS of 93%.[6,90-93] Infants younger than 12 months with INSS stage 4 disease and MYCN amplification are categorized as high risk and have a 3-year EFS of 10%.[91]
Adolescents and young adults
Adolescents older than 10 years or adults with neuroblastoma have a worse long-term prognosis, regardless of stage or site. The disease is more indolent in older patients than in children.
Although adolescent and young adult patients have infrequent MYCN amplification (9% in patients aged 10–21 years), older children with advanced disease have a poor rate of survival. Tumors from the adolescent and young adult population commonly have segmental chromosomal aberrations, and ALK and ATRX mutations are much more frequent.[34,35,94]
The 5-year EFS rate is 32% for patients between the ages of 10 years and 21 years, and the OS rate is 46%; for stage 4 disease, the 10-year EFS rate is 3%, and the OS rate is 5%.[95] Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[65,96] Other modalities, such as local radiation therapy, autologous stem cell transplant, and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[95,96]

Stage of disease

Several imaged-based and surgery-based systems were used for assigning disease stage before the 1990s. In an effort to facilitate comparison of results obtained throughout the world, a surgical pathologic staging system, termed the International Neuroblastoma Staging System (INSS), was developed.[86] However, because surgical approaches differ from one institution to another, INSS stage for patients with locoregional disease may also vary considerably. More recently, to define extent of disease at diagnosis in a uniform manner, a presurgical International Neuroblastoma Risk Group staging system (INRGSS) was developed for the International Neuroblastoma Risk Group Classification System.[28,97] The INRGSS is currently used in North American and European cooperative group studies. Unlike the INSS, the INRGSS stage is not affected by locoregional lymph node involvement.

Site of primary tumor

Clinical and biological features of neuroblastoma differ by primary tumor site. In a study of data on 8,389 patients entered in clinical trials and compiled by the International Risk Group Project, the following results were observed, confirming much smaller, previous studies with less complete clinical and biological data:[98]
  • Adrenal primary tumors were more likely than tumors originating in other sites to be associated with unfavorable prognostic features, including MYCN amplification, even after researchers controlled for age, stage, and histologic grade. Adrenal neuroblastomas were also associated with a higher incidence of stage 4 tumors, segmental chromosomal aberrations, diploidy, unfavorable INPC histology, age younger than 18 months, and elevated levels of lactate dehydrogenase (LDH) and ferritin. The relative risk of MYCN amplification compared with adrenal tumors was 0.7 in abdominal nonadrenal tumors and about 0.1 in nonabdominal paraspinal tumors.
  • Thoracic tumors were compared with nonthoracic tumors; after researchers controlled for age, stage, and histologic grade, results showed thoracic tumor patients had fewer deaths and recurrences (hazard ratio, 0.79; 95% confidence interval [CI], 0.67–0.92) and thoracic tumors had a lower incidence of MYCN amplification (adjusted OR, 0.20; 95% CI, 0.11–0.39).
It is not clear whether the effect of primary neuroblastoma tumor site on prognosis is entirely dependent on the differences in tumor biology associated with tumor site.
Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[99] Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.

Tumor histology

Neuroblastoma tumor histology has a significant impact on prognosis and risk group assignment (refer to the Cellular Classification of Neuroblastic Tumors section and Table 4of this summary for more information).
Histologic characteristics considered prognostically favorable include the following:
  • Cellular differentiation/maturation. Higher degrees of neuroblastic maturation confer improved prognosis for stage 4 patients with segmental chromosome changes without MYCN amplification. Neuroblastoma tumors containing many differentiating cells, termed ganglioneuroblastoma, can have diffuse differentiation conferring a very favorable prognosis or can have nodules of undifferentiated cells whose histology, along with MYCN status, determine prognosis.[100,101]
  • Schwannian stroma.
  • Cystic neuroblastoma. About 25% of reported neuroblastomas diagnosed in the fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorable biology.[102]
High mitosis/karyorrhexis index and undifferentiated tumor cells are considered prognostically unfavorable histologic characteristics, but the prognostic value is age dependent.[103,104]
In a COG study (P9641 [NCT00003119]) investigating the effect of histology, among other factors, on outcome, 87% of 915 children with stage 1 and stage 2 neuroblastoma without MYCN amplification were treated with initial surgery and observation. Patients (13%) who had or were at risk of developing symptomatic disease, or who had less than 50% tumor resection at diagnosis, or who had unresectable progressive disease after surgery alone, were treated with chemotherapy and surgery. Those with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%.[89]

Response to treatment

Response to treatment has been associated with outcome. In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy, for example, is associated with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques.[105-107] Similarly, the persistence of MIBG-avid tumor measured as Curie score greater than 2 (refer to the Curie score and SIOPEN score section of this summary for more information about Curie scoring) after completion of induction therapy predicts a poor prognosis for patients with MYCN-nonamplified high-risk tumors. A Curie score greater than 0 after induction therapy is associated with worse outcome for high-risk patients with MYCN-amplified disease.[108,109]
Treatment-associated decrease in mitosis and increase in histologic differentiation of the primary tumor are also prognostic of response.[110]
The accuracy of prognostication based on decrease in primary tumor size is less clear. In a study conducted by seven large international centers, 229 high-risk patients were treated in a variety of ways, including chemotherapy, surgical removal of the primary tumor, radiation to the tumor bed, high-dose myeloablative therapy plus stem cell transplant, and, in most cases, isotretinoin and anti-GD2 antibody immunotherapy enhanced by cytokines. Primary tumor response was measured after induction chemotherapy in three ways: as 30% or greater reduction in the longest dimension, 50% or greater reduction in tumor volume, or 65% or greater reduction in tumor volume (calculated from three tumor dimensions, a conventional radiologic technique). The measurements were performed at diagnosis and after induction chemotherapy before primary tumor resection. None of the methods of measuring primary tumor response at end of induction chemotherapy were predictive of survival.[111]

Spontaneous Regression of Neuroblastoma

The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the 4S pattern of metastatic spread.[112] (Refer to the Stage Information for Neuroblastoma section of this summary for more information.)
Spontaneous regression generally occurs only in tumors with the following features:[113]
  • Near triploid number of chromosomes.
  • No MYCN amplification.
  • No loss of chromosome 1p.
Additional features associated with spontaneous regression include the lack of telomerase expression,[114,115] the expression of the H-Ras protein,[116] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[117]
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasonography often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[118-120]
Evidence (observation [spontaneous regression]):
  1. In a COG study, 83 highly selected infants younger than 6 months with stage 1 small adrenal masses, as defined by imaging studies, were observed without biopsy. Surgical intervention was reserved for those with growth or progression of the mass or increasing concentrations of urinary catecholamine metabolites.[84]
    • Eighty-one percent of patients were spared surgery, and all were alive after 2 years of follow-up (refer to the Surgery subsection of this summary for more information).
  2. In a German clinical trial, spontaneous regression and/or lack of progression occurred in 44 of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification. All were observed after biopsy and partial or no resection.[85] In some cases, regression did not occur until more than 1 year after diagnosis.
  3. In neuroblastoma screening trials in Quebec and Germany, the incidence of neuroblastoma was twice that reported without screening, suggesting that many neuroblastomas are never noted and spontaneously regress.[10-12]
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  89. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
  90. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
  91. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED Abstract]
  92. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005. [PUBMED Abstract]
  93. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005. [PUBMED Abstract]
  94. Mazzocco K, Defferrari R, Sementa AR, et al.: Genetic abnormalities in adolescents and young adults with neuroblastoma: A report from the Italian Neuroblastoma group. Pediatr Blood Cancer 62 (10): 1725-32, 2015. [PUBMED Abstract]
  95. Mossé YP, Deyell RJ, Berthold F, et al.: Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer 61 (4): 627-35, 2014. [PUBMED Abstract]
  96. Kushner BH, Kramer K, LaQuaglia MP, et al.: Neuroblastoma in adolescents and adults: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 41 (6): 508-15, 2003. [PUBMED Abstract]
  97. Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009. [PUBMED Abstract]
  98. Vo KT, Matthay KK, Neuhaus J, et al.: Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol 32 (28): 3169-76, 2014. [PUBMED Abstract]
  99. Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgical aspects. Cancer 88 (8): 1955-63, 2000. [PUBMED Abstract]
  100. Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma. J Pediatr Surg 35 (1): 92-5, 2000. [PUBMED Abstract]
  101. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]
  102. Isaacs H Jr: Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol 26 (4): 177-84, 2007 Jul-Aug. [PUBMED Abstract]
  103. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002. [PUBMED Abstract]
  104. Teshiba R, Kawano S, Wang LL, et al.: Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children's Oncology Group. Pediatr Dev Pathol 17 (6): 441-9, 2014 Nov-Dec. [PUBMED Abstract]
  105. Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J Clin Oncol 19 (6): 1795-801, 2001. [PUBMED Abstract]
  106. Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 18 (24): 4067-76, 2000. [PUBMED Abstract]
  107. Bochennek K, Esser R, Lehrnbecher T, et al.: Impact of minimal residual disease detection prior to autologous stem cell transplantation for post-transplant outcome in high risk neuroblastoma. Klin Padiatr 224 (3): 139-42, 2012. [PUBMED Abstract]
  108. Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. J Nucl Med 54 (4): 541-8, 2013. [PUBMED Abstract]
  109. Yanik GA, Parisi MT, Naranjo A, et al.: Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1. J Nucl Med 59 (3): 502-508, 2018. [PUBMED Abstract]
  110. George RE, Perez-Atayde AR, Yao X, et al.: Tumor histology during induction therapy in patients with high-risk neuroblastoma. Pediatr Blood Cancer 59 (3): 506-10, 2012. [PUBMED Abstract]
  111. Bagatell R, McHugh K, Naranjo A, et al.: Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34 (7): 740-6, 2016. [PUBMED Abstract]
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  113. Ambros PF, Brodeur GM: Concept of tumorigenesis and regression. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 21-32.
  114. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995. [PUBMED Abstract]
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  116. Kitanaka C, Kato K, Ijiri R, et al.: Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J Natl Cancer Inst 94 (5): 358-68, 2002. [PUBMED Abstract]
  117. Brodeur GM, Minturn JE, Ho R, et al.: Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15 (10): 3244-50, 2009. [PUBMED Abstract]
  118. Yamamoto K, Ohta S, Ito E, et al.: Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol 20 (5): 1209-14, 2002. [PUBMED Abstract]
  119. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment. Pediatr Surg Int 20 (1): 27-32, 2004. [PUBMED Abstract]
  120. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED Abstract]

Cellular Classification of Neuroblastic Tumors

Neuroblastomas are classified as one of the small round blue cell tumors of childhood. They are a heterogenous group of tumors composed of cellular aggregates with different degrees of differentiation, from mature ganglioneuromas to less mature ganglioneuroblastomas to immature neuroblastomas, reflecting the varying malignant potential of these tumors.[1]
There are two cellular classification systems for neuroblastoma:

International Neuroblastoma Pathology Classification (INPC) System

The INPC system involves evaluation of tumor specimens obtained before therapy for the following morphologic features:[2-6]
  • Amount of Schwannian stroma.
  • Degree of neuroblastic maturation.
  • Mitosis-karyorrhexis index of the neuroblastic cells.
Favorable and unfavorable prognoses are defined on the basis of these histologic parameters and patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies (refer to Table 1).[2-4,6]
In the future, the INPC system is likely to be replaced by a system that does not include patient age as a part of cellular classification.
Table 1. Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification (Shimada System)a
International Neuroblastoma Pathology ClassificationOriginal Shimada ClassificationPrognostic Group
MKI = mitosis-karyorrhexis index.
aReprinted with permission. Copyright © 1999 American Cancer Society. All rights reserved.[2] Hiroyuki Shimada, Inge M. Ambros, Louis P. Dehner, Jun-ichi Hata, Vijay V. Joshi, Borghild Roald, Daniel O. Stram, Robert B. Gerbing, John N. Lukens, Katherine K. Matthay, Robert P. Castleberry, The International Neuroblastoma Pathology Classification (the Shimada System), Cancer, volume 86, issue 2, pages 364–72.
bSubtypes of neuroblastoma are described in detail elsewhere.[7]
cRare subtype, especially diagnosed in this age group. Further investigation and analysis required.
dPrognostic grouping for these tumor categories is not related to patient age.
Neuroblastoma:(Schwannian stroma-poor)bStroma-poor 
 Favorable:FavorableFavorable
 <1.5 yPoorly differentiated or differentiating & low or intermediate MKI tumor  
 1.5–5 yDifferentiating & low MKI tumor  
 Unfavorable:UnfavorableUnfavorable
 <1.5 ya) undifferentiated tumorc  
b) high MKI tumor
 1.5–5 ya) undifferentiated or poorly differentiated tumor  
b) intermediate or high MKI tumor
 ≥5 yAll tumors  
Ganglioneuroblastoma, intermixed(Schwannian stroma-rich)Stroma-rich Intermixed (favorable)Favorabled
Ganglioneuroma:(Schwannian stroma-dominant)  
 Maturing Well differentiated (favorable)Favorabled
 Mature Ganglioneuroma 
Ganglioneuroblastoma, nodular(composite Schwannian stroma-rich/stroma-dominate and stroma-poor)Stroma-rich nodular (unfavorable)Unfavorabled
Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of neuroblastoma tumors with MYCNamplification and favorable histology, most do not express MYCN, despite the gene being amplified, and these patients have a more favorable prognosis than do patients whose tumors do express MYCN.[8]

International Neuroblastoma Risk Group (INRG) Classification System

The INRG used a survival-tree analysis to compare 35 prognostic factors in more than 8,800 patients with neuroblastoma from a variety of clinical trials. The following INPC (Shimada system) histologic factors were included in the analysis:[9,10]
  • Diagnostic category.
  • Grade of differentiation.
  • Mitosis-karyorrhexis index.
Because patient age is used in all risk stratification systems, a cellular classification system that did not employ patient age was desirable, and underlying histologic criteria, rather than INPC or Shimada Classification, was used in the final decision tree. Histologic findings discriminated prognostic groups most clearly in two subsets of patients, as shown in Table 2.
Table 2. Histologic Discrimination of International Neuroblastoma Risk Group Subsets of Neuroblastoma Patientsa
INSS Stage/Histologic SubtypeNumber of CasesEFS (%)OS (%)
EFS = event-free survival; GN = ganglioneuroma; GNB = ganglioneuroblastoma; INSS = International Neuroblastoma Staging System; NB = neuroblastoma; OS = overall survival.
aAdapted from Cohn et al.[9]
INSS stage 1, 2, 3, 4S5,13183 ± 191 ± 1
 GN, maturing16297 ± 298 ± 2
GNB, intermixed
NB4,97083 ± 190 ± 1
GNB, nodular
INSS stage 2, 3; age >547 d26069 ± 381 ± 2
 11q normal and differentiating1680 ± 16100
11q aberration or undifferentiated4961 ± 1173 ± 11
The INRG histologic subsets are incorporated into the INRG Risk Classification Schema. (Refer to Table 6 in the Treatment Option Overview for Neuroblastoma section of this summary for more information.)
References
  1. Joshi VV, Silverman JF: Pathology of neuroblastic tumors. Semin Diagn Pathol 11 (2): 107-17, 1994. [PUBMED Abstract]
  2. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999. [PUBMED Abstract]
  3. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (9): 2451-61, 2001. [PUBMED Abstract]
  4. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]
  5. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]
  6. Teshiba R, Kawano S, Wang LL, et al.: Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children's Oncology Group. Pediatr Dev Pathol 17 (6): 441-9, 2014 Nov-Dec. [PUBMED Abstract]
  7. Shimada H, Ambros IM, Dehner LP, et al.: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 86 (2): 349-63, 1999. [PUBMED Abstract]
  8. Suganuma R, Wang LL, Sano H, et al.: Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children's Oncology Group and the International Neuroblastoma Pathology Committee. Pediatr Blood Cancer 60 (3): 363-70, 2013. [PUBMED Abstract]
  9. Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009. [PUBMED Abstract]
  10. Okamatsu C, London WB, Naranjo A, et al.: Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG. Pediatr Blood Cancer 53 (4): 563-9, 2009. [PUBMED Abstract]

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. Fluorine F 18-fludeoxyglucose positron emission tomography (PET) scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.[3]
Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to PET–computed tomography (PET-CT) in one prospective comparison.[4] 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.[5] Baseline MIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.[6] 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.[3]
Curie score and SIOPEN score
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 score: 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], 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, 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 score: 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]

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).
  • 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 (POG) staging systems [1,15] and is described in Table 3. This 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 GroupDescription
MIBG = metaiodobenzylguanidine.
Stage 1Localized 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 2ALocalized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Stage 2BLocalized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
Stage 3Unresectable 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 4Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.
Stage 4SLocalized 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 6found 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 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
StageDescription
IDRFs = image-defined risk factors; INSS = International Neuroblastoma Staging System.
aAdapted from Monclair et al.[20]; [21]
L1Localized tumor not involving vital structures as defined by the list of IDRFsa and confined to one body compartment.
L2Locoregional tumor with presence of one or more IDRFs.a
MDistant metastatic disease (except stage MS).
MSMetastatic 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, duodeno-pancreatic 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 porto-hepatic or hepato-duodenal ligament.
  • Infiltration of the costo-vertebral 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.
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. However, neoadjuvant chemotherapy is not always effective in eliminating IDRFs. A retrospective study of IDRFs in the European Unresectable Neuroblastoma trial from 2001 to 2006 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. 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.[22]; [23][Level of evidence: 3iiA]
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 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]
By combining the INRGSS, preoperative imaging, 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 two 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 was 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 of 93% vs. 83%).[26] 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 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.
References
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  2. Howman-Giles R, Shaw PJ, Uren RF, et al.: Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med 37 (4): 286-302, 2007. [PUBMED Abstract]
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  4. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011. [PUBMED Abstract]
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  8. Yanik GA, Parisi MT, Naranjo A, et al.: Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1. J Nucl Med 59 (3): 502-508, 2018. [PUBMED Abstract]
  9. Lewington V, Lambert B, Poetschger U, et al.: 123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel. Eur J Nucl Med Mol Imaging 44 (2): 234-241, 2017. [PUBMED Abstract]
  10. Ladenstein R, Lambert B, Pötschger U, et al.: Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging 45 (2): 292-305, 2018. [PUBMED Abstract]
  11. Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013. [PUBMED Abstract]
  12. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005. [PUBMED Abstract]
  13. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun. [PUBMED Abstract]
  14. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001. [PUBMED Abstract]
  15. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]
  16. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J Clin Oncol 12 (11): 2378-81, 1994. [PUBMED Abstract]
  17. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002. [PUBMED Abstract]
  18. Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011. [PUBMED Abstract]
  19. Morgenstern DA, London WB, Stephens D, et al.: Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predicts outcome in patients with stage 4 disease: A study from the International Neuroblastoma Risk Group Database. J Clin Oncol 32 (12): 1228-35, 2014. [PUBMED Abstract]
  20. Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009. [PUBMED Abstract]
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  23. Avanzini S, Pio L, Erminio G, et al.: Image-defined risk factors in unresectable neuroblastoma: SIOPEN study on incidence, chemotherapy-induced variation, and impact on surgical outcomes. Pediatr Blood Cancer 64 (11): , 2017. [PUBMED Abstract]
  24. Pinto NR, Applebaum MA, Volchenboum SL, et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 33 (27): 3008-17, 2015. [PUBMED Abstract]
  25. Burchill SA, Beiske K, Shimada H, et al.: Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer 123 (7): 1095-1105, 2017. [PUBMED Abstract]
  26. Monclair T, Mosseri V, Cecchetto G, et al.: Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group. Pediatr Blood Cancer 62 (9): 1536-42, 2015. [PUBMED Abstract]
  27. Cecchetto G, Mosseri V, De Bernardi B, et al.: Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23 (33): 8483-9, 2005. [PUBMED Abstract]
  28. Simon T, Hero B, Benz-Bohm G, et al.: Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer 50 (5): 965-9, 2008. [PUBMED Abstract]

Treatment Option Overview for Neuroblastoma

Most children with neuroblastoma in North America have been treated according to the Children’s Oncology Group (COG) risk-group assignment, even if they were not enrolled in a COG study. In the ongoing COG studies, the International Neuroblastoma Risk Group (INRG) risk grouping is used to assign treatment. Because the older system is still being used by some physicians to plan treatment, the treatments described in this summary are based on both the INRG risk grouping using the International Neuroblastoma Risk Group Staging System (INRGSS) and the 2007 COG risk stratification system that uses the International Neuroblastoma Staging System (INSS), as described in the COG biology study ANBL00B1 (NCT00904241). The COG is in the process of revising the COG risk stratification schema and the next version will be based on the INRGSS.
In the previous COG risk system, each child was assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 7, 10, and 13 for more information) on the basis of the following factors:[1-6]
  • INSS stage.
  • Age.
  • International Neuroblastoma Pathologic Classification (INPC).
  • Ploidy.
  • Amplification of the MYCN oncogene within tumor tissue.[1-6]
Other biological factors that influenced treatment selection in previous COG studies included unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.[7,8] However, in 2012, the COG Neuroblastoma Committee defined favorable genomics, for purposes of risk assignment, as hyperdiploid neuroblastoma cells without segmental copy number aberrations, including no loss of copy number at 1p, 3p, 4p, or 11q and no gain of copy number at 1q, 2p, or 17q. This does not correspond to the INRGSS, which only includes 11q abnormalities; however, the criteria may change in future versions.
Generally, treatment is based on whether the tumor is classified as low, intermediate, or high risk, as follows:
  • For patients with low-risk tumors, the approach is either observation or resection, with chemotherapy restricted to symptomatic patients with low-risk biology. Five-year overall survival (OS) was 97% in a large COG study.[9] The ongoing COG study is looking at the reduction of therapy in a limited subset of patients with low-risk tumors.
  • For patients with intermediate-risk tumors, chemotherapy is often given before definitive resection, and the number of chemotherapy cycles is based on clinical and tumor biological risk factors and response to therapy. In recent studies, select patients have been observed without undergoing chemotherapy or attempted resection. The 3-year OS rate for intermediate-risk patients was about 96% in a large COG study;[10] thus, the current focus of ongoing studies is to decrease the intensity of chemotherapy in a limited subset of intermediate-risk children to further diminish side effects.
  • For high-risk patients, treatment has intensified to include chemotherapy, surgery, radiation therapy, myeloablative therapy and stem cell transplant (SCT), isotretinoin, and immunotherapy, resulting in survival rates of about 50%. Statistically significant improvement in survival was observed in a randomized phase III COG study (ANBL0532 [NCT00567567]) with tandem cycles of myeloablative therapy with SCT compared with a single cycle of myeloablative therapy and SCT among patients, all of whom received immunotherapy.[11]
Table 5 describes the treatment options for low-risk, intermediate-risk, high-risk, stage 4S, and recurrent neuroblastoma by INSS-based risk group.
Table 5. Treatment Options for Neuroblastoma
COG Risk-Group AssignmentTreatment Options
COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-MIBG = iodine I 131-metaiodobenzylguanidine; SCT = stem cell transplant.
Low-Risk NeuroblastomaSurgery followed by observation.
Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
Observation without biopsy(for perinatal neuroblastoma with small adrenal tumors).
Radiation therapy (only for emergency therapy).
Intermediate-Risk NeuroblastomaChemotherapy with or without surgery.
Surgery and observation (in infants).
Radiation therapy (only for emergency therapy).
High-Risk NeuroblastomaA regimen of chemotherapy, surgery, tandem cycles of myeloablative therapy and SCT, radiation therapy, and dinutuximab, with interleukin-2/GM-CSF and isotretinoin.
Stage 4S/MS NeuroblastomaObservation with supportive care (for asymptomatic patients with favorable tumor biology).
Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).
Recurrent NeuroblastomaLocoregional recurrence in patients initially classified as low riskSurgery followed by observation or chemotherapy.
Chemotherapy that may be followed by surgery.
Metastatic recurrence in patients initially classified as low riskObservation (if metastatic disease is in a 4S pattern in an infant).
Chemotherapy.
Surgery followed by chemotherapy.
High-risk therapy.
Locoregional recurrence in patients initially classified as intermediate riskSurgery (complete resection).
Surgery (incomplete resection) followed by chemotherapy.
Metastatic recurrence in patients initially classified as intermediate riskHigh-risk therapy.
Recurrence in patients initially classified as high riskChemotherapy combined with immunotherapy.
131I-MIBG alone, in combination with other therapy, or followed by stem cell rescue.
ALK inhibitors.
Chemotherapy.
Novel therapeutic approaches.
Recurrence in the central nervous systemSurgery and radiation therapy.
Novel therapeutic approaches.

Children’s Oncology Group (COG) Neuroblastoma Risk Grouping

The treatment sections of this summary are organized to correspond with the COG risk-based treatment plan that assigned all patients to a low-, intermediate-, or high-risk group. The COG risk-based treatment plan is no longer in use for ongoing COG studies, which are based on the INRG risk grouping. This risk-based schema was based on the following factors:
  • Patient age at diagnosis.
  • Certain biological characteristics of the tumor, which included MYCN status and genomic segmental aberrations, INPC histopathology classification, and tumor DNA index.
  • Stage of the tumor as defined by the INSS.
Table 7 (in the Treatment of Low-Risk Neuroblastoma section), Table 10 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 13 (in the Treatment of High-Risk Neuroblastoma section) describe the risk-group assignment criteria used to assign treatment in the low-risk COG-P9641 trial, the intermediate-risk COG-A3961 and ANBL0531 (NCT00499616) trials, and the high-risk COG-A3973 and ANBL0532 (NCT00567567) studies.
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 patients with INSS stage 1 and stage 2 neuroblastoma pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%).[12] The overall EFS and OS for infants with stage 4 and 4S disease and MYCN amplification was only 30% at 2 to 5 years after treatment in a European study.[13] The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.[4]

International Neuroblastoma Risk Grouping

The INRG classification schema assigns neuroblastoma patients to one of 16 pretreatment risk groups on the basis of INRG stage, age, histologic category, grade of tumor differentiation, MYCN amplification, 11q aberration (the only segmental chromosomal aberration studied), and ploidy. Four levels of risk were defined according to outcomes among 8,800 patients with high-quality data, as they had been entered in clinical trials (refer to Table 6). In the overall risk grouping, histology is an important risk determinant for all stage L1 and L2 tumors, and grade of differentiation discriminates among neuroblastomas and nodular ganglioneuroblastomas in patients older than 18 months. The goals of the INRG are to develop shared data from the patients in clinical trials and to define risk groups for future trials.[14]
Table 6. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schemaa
ENLARGE
INRG StageHistologic CategoryGrade of Tumor DifferentiationMYCN11q AberrationPloidyPretreatment Risk Group
GN = ganglioneuroma; GNB = ganglioneuroblastoma; NA = not amplified.
aReprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved. Pinto N et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma, J Clin Oncol 33 (27), 2015: 3008–3017.[15]
L1/L2GN maturing, GNB intermixed    A (very low)
L1Any, except GN maturing or GNB intermixed NA  B (very low)
Amplified  K (high)
L2 
 Age <18 moAny, except GN maturing or GNB intermixed NANo D (low)
Yes G (intermediate)
 Age ≥18 moGNB nodular neuroblastomaDifferentiatingNANo E (low)
Yes H (intermediate)
Poorly differentiated or undifferentiatedNA  H (intermediate)
Amplified  N (high)
M 
 Age <18 mo  NA HyperdiploidF (low)
 Age <12 mo  NA DiploidI (intermediate)
 Age 12 to <18 mo  NA DiploidJ (intermediate)
 Age <18 mo  Amplified  O (high)
 Age ≥18 mo     P (high)
MS 
 Age <18 mo  NANo C (very low)
Yes Q (high)
Amplified  R (high)
Controversy exists regarding the current COG risk grouping system, the INRG Risk Grouping Schema, and the treatment of certain small subsets of patients.[16-18] Risk group definitions of very low-, low-, intermediate-, and high-risk subsets and the recommended treatments are expected to evolve as new biomarkers are identified and additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single-copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both Pediatric Oncology Group and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.[19-21] Future versions of the INRG are expected to contain more tumor genomic criteria to help assign risk.[15]

Revised International Neuroblastoma Response Criteria (INRC)

In COG clinical trials, before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met.[22-24] The revised INRC depend on the use of three-dimensional (3-D) imaging combined with metaiodobenzylguanidine (MIBG) scanning for primary tumor, bone, and lymph node or soft tissue metastases. Positron emission tomography (PET) scans are used instead of MIBG in the 10% of patients with MIBG non-avid tumors; technetium Tc 99m (99mTc) bone scans are no longer used, because a retrospective study of 132 patients who received both MIBG and 99mTc scans showed no staging benefit.[25]
Overall response in the revised INRC integrates tumor response of the primary tumor, bone marrow, and soft tissue and bone metastases. Primary and metastatic soft tissue sites are assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine I 123 (123I)-MIBG scans or fluorine F 18-fludeoxyglucose (18F-FDG) PET scans if the tumor is MIBG non-avid. Bone marrow is assessed by histology, immunohistochemistry and cytology, or immunocytology with the help of immunorecognition tools. Bone marrow with less than 5% tumor involvement is classified as minimal disease. Urinary catecholamine levels are not included in response assessment.[24]
The overall INRC response criteria are defined as follows:[22,23]
  • Complete Response: No evidence of disease, including resolution of MIBG uptake (or PET scan positivity in MIBG non-avid disease) in any location of soft tissue or bone, with less than 10 mm remaining on 3-D imaging of primary tumor; target lymph nodes less than 10 mm in short dimension; and no histologic tumor in two bone marrow biopsies and two bone marrow aspirates.
  • Partial Response: 30% or more decrease in longest diameter of primary site and no new lesions and MIBG (or 18F-FDG PET) stable or improved and at least a 50% reduction in absolute MIBG bone score or a 50% or greater reduction in number of 18F-FDG PET-avid bone lesions.
  • Minor Response: Partial response or complete response of at least one component of disease, but at least one other component with stable disease and no component with progressive disease.
  • Progressive Disease: Any new lesion; increase in longest diameter in any measurable lesion by 20% and increase of at least 5 mm in longest diameter; previous negative bone marrow now positive for tumor; any new soft tissue lesion that is MIBG (or 18F-FDG PET) avid or positive by biopsy; a new avid bone site; or increase in relative MIBG score of 1.25% or greater.
  • Stable Disease: Neither sufficient shrinkage for partial response nor sufficient increase for progressive disease and may have greater than 5% tumor infiltration as defined in minimal disease.
Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (involvement of skin, liver, and/or bone marrow, the latter less than 10% involved), these patients are not classified as having progressive/metastatic disease, which would typically be a criterion for removal from protocol therapy. Instead, these patients are managed as stage 4S patients.
Controversy exists regarding the necessity of measuring the primary tumor response in all three dimensions or whether the single longest dimension, as in RECIST tumor response determination, is equally useful.[26] The latter has been adopted for use in the INRC.

Surgery

In patients without metastatic disease, the standard of care is to perform an initial surgery, on the basis of the stage and the risk group, to accomplish the following:
  • Obtain tissue for diagnosis.
  • Resect as much of the primary tumor as is safely possible. This is most appropriate for low-risk (excluding prenatally diagnosed infants) and intermediate-risk disease.
  • Accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor. This is most appropriate for non–high-risk patients undergoing resection at the time of diagnosis. Lymph node involvement alone is not used to discriminate between L1 and L2 disease.
In patients with L1 tumors (defined as having no image-defined surgical risk factors), the tumors are resectable and resection is less likely to result in surgical complications. L2 tumors, which have at least one image-defined surgical risk factor, are treated with chemotherapy when deemed too risky to attempt resection, followed by surgery when the tumors have responded. Recent German studies of selected groups of patients have biopsied tissue and observed infants with both L1 and L2 tumors without MYCNamplification, avoiding additional surgery and chemotherapy in most patients.[27]
The COG reported that expectant observation in infants younger than 6 months with small (L1) adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.[28] According to the surgical guidelines described in the intermediate-risk neuroblastoma clinical trial (ANBL0531 [NCT00499616]), the primary tumor is not routinely resected in patients with 4S neuroblastoma.
Whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy in stage 4 patients older than 18 months remains controversial.[29-34] A meta-analysis of stage 3 versus stage 4 neuroblastoma patients, at all ages combined, found an advantage for gross-total resection (>90%) over subtotal resection in stage 3 neuroblastoma only, not stage 4.[35] Also, a small study suggested that after neoadjuvant chemotherapy, completeness of resection was affected by the number of image-defined risk factors remaining.[36] When an experienced surgeon performed the procedure, a 90% or greater resection of the primary tumor in stage 4 neuroblastoma resulted in a higher local control rate, but did not have a statistically significant impact on OS. This practice remains controversial.[37]

Radiation Therapy

In the completed COG treatment plan, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:
  • Infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy.
  • Symptomatic spinal cord compression that has not responded to initial chemotherapy and/or surgical decompression.

Treatment of Spinal Cord Compression

Spinal cord compression is considered a medical emergency. Patients receive immediate treatment because neurologic recovery is more likely when symptoms are present for a relatively short time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.
The completed COG low-risk and intermediate-risk neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in low-risk or intermediate-risk patients.[38-40] In a single study in this setting looking at the effect of glucocorticoids on neurological outcome, it was associated with improved early symptom relief. However, glucocorticoids did not prevent late residual impairment.[40]
Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy.[38-40] It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion, but there is no evidence that functional neurologic deficit is improved with laminoplasty.[41]
The burden of long-term health problems in survivors of neuroblastoma with intraspinal extension is high. In a systematic review of 28 studies of treatment and outcome of patients with intraspinal extension, the severity of the symptoms at diagnosis and the treatment modalities were most associated with the presence of long-term health problems. In particular, the severity of neurological motor deficit was most likely to predict neurological outcome.[42] The severity of motor deficit at diagnosis is associated with spinal deformity and sphincter dysfunction at the end of follow-up, while sphincter dysfunction at diagnosis was correlated with long-term sphincter problems.[43] This supports the initiation of treatment before symptoms have deteriorated to complete loss of neurological function.
In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae, which were severe in about one-half of patients.[44]

Surveillance During and After Treatment

Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, which includes urinary vanillylmandelic acid and homovanillic acid testing, one of the most reliable imaging tests to detect disease progression or recurrence is the 123I-MIBG scan.[45,46] Cross-sectional imaging with computed tomography scans is controversial because of the amount of radiation received and the low proportion of relapses detected with this modality.[47]
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