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Neuroblastoma Treatment (PDQ®)–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 the United States.[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.

Neuroblastoma Screening (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.
Germline mutations. 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 MYCN amplification, ALK is co-amplified (ALK is near MYCN on chromosome 2), which may also result in ALK activation. ALK is a tyrosine kinase receptor (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] Germline aberrations of PHOX2B have 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. The following syndromes primarily involve genes in the canonical RAS pathway:
  • Costello syndrome.[21]
  • Noonan syndrome.[22]
  • Neurofibromatosis type 1.[23]
In addition, neuroblastoma has been described in patients with the following syndromes:
  • Li-Fraumeni syndrome.
  • Hereditary pheochromocytoma/paraganglioma syndromes.[24]
  • ROHHAD syndrome (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysfunction).[25]
  • 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]

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 highly penetrant, heritable ALK or PHOX2B (NPARM) mutations (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.
  • Individuals 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.[28] Patients with Li-Fraumeni syndrome should not undergo chest x-rays.[24]
About 5% of children with Beckwith-Wiedemann syndrome have the molecular etiology of mutations causing decreased activity of CDKN1C. A review of all large studies of genetically subtyped Beckwith-Wiedemann syndrome found 70 children with the CDKN1C mutation, 4.6% of whom developed neuroblastoma; there were no cases of Wilms tumor or hepatoblastoma. There is little experience with screening these children for neuroblastoma, so there are no generally accepted guidelines, although the authors of the study suggest screening with urinary VMA/HVA every 4 to 6 months. Other genetic subtypes of Beckwith-Wiedemann syndrome have a prevalence of neuroblastoma of less than 1%, and no neuroblastic tumors were found among 123 children with the genotype gain of methylation at imprinting control region 1.[29]

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]

Genomic and Biologic Features of Neuroblastoma

Molecular 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.
  • Low-risk or intermediate-risk neuroblastoma patients. Patients classified as low-risk or intermediate-risk have a favorable prognosis, with survival rates exceeding 95%. 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.[30,31]
  • High-risk neuroblastoma patients. The prognosis is more guarded for patients with high-risk neuroblastoma, with less than a 50% long-term survival rate. 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 are usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[30-36] 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).[37]
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 neuroblastoma tumors.[32-36] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of segmental chromosome aberrations) correlated with the following:[32-36][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%.[38]
In a study of children older than 12 months who had 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.[36]
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[30,31]
MYCN gene amplification
MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[39] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[40]
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.[30,31] Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors.[41] 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.[32]
In a Children’s Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma, the following results were reported:[42]
  • 79% of patients 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 of unfavorable features 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.
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, 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 MYCN amplification.[43,44]
In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (<18 months: HR, 19.6; ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis karrhyohexis index, and low ferritin.[45][Level of evidence: 3iiiA]
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.[46-52] 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 GeneticsExit Disclaimer (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.[51]
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 and the following results were observed:[51]
  • 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.
  • ALK mutations 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.
  • 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 ALK activation.
In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK mutations.[53]
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).[51]
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,[54] while a second study evaluated 16 paired diagnostic and relapsed specimens.[55] 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.[56]
  • 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.[54]
    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 mutations 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.[55]
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.[57] 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.[46,47,58] 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 MYCN amplifications and ATRX mutations.[46,47] 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,[59] 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,[48] and is associated with telomere lengthening by a different mechanism, termed alternative lengthening of telomeres.[48,58]
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.[60] 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.[60]
  • 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.[61]
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.[62,63] 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.[64][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.

Clinical Presentation

The most frequent signs and symptoms of neuroblastoma are caused by tumor mass and metastases and include the following:
  • Abdominal mass: This is the most common presentation of neuroblastoma.
  • 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.[65] Vasoactive intestinal peptide secretion may also occur with chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[66]
  • 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.[67]
  • 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.[68]

Opsoclonus/myoclonus syndrome

Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, occur rarely in children with neuroblastoma.[69] Of young children presenting with opsoclonus/myoclonus syndrome, about one-half are found to have neuroblastoma.[70,71] The incidence in the United Kingdom is estimated at 0.18 cases of opsoclonus/myoclonus per 1 million children per year and the average age at diagnosis is 1.5 to 2 years.[72]
The usual presentation is the onset of progressive neurologic dysfunction over a few days before a neuroblastoma is discovered, but, occasionally, neurologic symptoms arise long after removal of the primary tumor.[70,73,74] Neuroblastoma patients who present with opsoclonus/myoclonus syndrome often have neuroblastoma with favorable biological features and have excellent survival rates, although tumor-related deaths have been reported.[70]
Genomic copy number profiles were analyzed in 44 cases of neuroblastoma associated with opsoclonus/myoclonus syndrome. Because there were no tumor relapses or disease-related deaths, the overall genomic profile was not of prognostic significance.[75]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully characterized.[70] The primary tumor is typically diffusely infiltrated with lymphocytes.[76] Cerebrospinal fluid shows increased number of B cells, and oligoclonal immunoglobulin bands are often seen. Steroid-responsive elevations of B-cell–related cytokines are also often seen.[77]
Some patients may rapidly respond neurologically to immune interventions or simply to removal of the neuroblastoma, but in many cases, improvement may be slow and partial. The improvement in acutely presenting motor deficits and ataxia seen with immunological therapy is not clearly associated with improvement in long-term neuropsychological disability, which primarily consists of cognitive and behavioral deficits. The long-term benefits of rapid improvement resulting from treatment, whether of symptoms or of the underlying neuroblastoma, are unclear, but rapid improvement appears to be worthwhile.[74,78]
Treatment with adrenocorticotropic hormones or corticosteroids can be effective for acute symptoms, but some patients do not respond to corticosteroids.[73,79] Other therapy with various immunomodulatory drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in select cases.[73,80-83] Combination immunosuppressive therapy has been explored, with improved short-term results.[84] The short-term neurologic outcomes may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[69]
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).[85] Patients with newly diagnosed neuroblastoma and opsoclonus/myoclonus ataxia syndrome who were younger than 8 years were randomly assigned to receive either intravenous immunoglobulin (IVIG) or no IVIG in addition to prednisone and risk-adapted treatment of the tumor. Of the 53 patients who participated, 21 of 26 patients (81%) in the IVIG group had an opsoclonus/myoclonus ataxia syndrome response over a period of weeks to months, 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.[85] 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.[86,87] MIBG scanning is also critical to assess response to therapy.[87] 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.[88] (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.[89] 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.[90] 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.[91] 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.[90]
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).[92]
  2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) and increased levels of urinary catecholamine metabolites.[92]

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.[93] 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.[94] (Refer to Table 1 for more information.) Similarly, the COG ANBL0531 (NCT00499616) study found equivalent outcomes for many subsets of intermediate-risk children who were treated with substantially reduced chemotherapy, when compared with the earlier COG-A3961 (NCT00003093) study.[95]

Age at diagnosis

Infants and children
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:[93]
  • 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:
  • In the COG ANBL0531 (NCT00499616) study for intermediate-risk patients with neuroblastoma, treatment was assigned using a biology-based and response-based algorithm, which included allelic status of 1p36 and 11q23. Patients with MYCN-amplified tumors were excluded.[95]
    • EFS was statistically significantly better for infants with stage 4 disease with favorable tumor biology (n = 61) (3-year EFS rate, 86.9%; 95% CI, 78.3%–95.4%) compared with those with confirmed unfavorable tumor biology (n = 47) (3-year EFS rate, 66.8%; 95% CI, 53.1%–80.6%; P = .02).
    • OS for infants with stage 4 disease and favorable tumor biology showed a trend toward OS advantage (3-year OS rate: 95.0%; 95% CI, 89.5%–100% vs. 86.7%; 95% CI, 76.6%–96.7%; P = .08).
    • Among the group 4 infants (n = 24) with stage 4 disease with confirmed diploid or unfavorable histology tumors, with or without 1p36/11q23 loss of heterozygosity, the 3-year EFS rate estimate was 63.9% (95% CI, 43.8%–84.0%), and the 3-year OS rate estimate was 77.3% (95% CI, 59.2%–95.3%).
    • For infants with stage 4 hyperdiploid favorable histology tumors assigned to group 4 because of 1p36/11q23 loss of heterozygosity or unknown allelic status (n = 32), the 3-year EFS and OS rate estimates were 68.6% (95% CI, 52.2%–85.1%) and 93.8% (95% CI, 85.2%–100%), respectively.
    • The EFS and OS rate estimates for the eight toddlers (aged 12–18 months) with stage 4 hyperdiploid favorable histology tumors were 62.5% (95% CI, 28.9%–96.1%) and 100%, respectively.
    • Patients with favorable biology and localized disease had a 100% survival rate.
  • 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.[96]
  • In the COG intermediate-risk study A3961 (NCT00003093) that included only MYCN nonamplified 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%).[97]
  • 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%.[98]
Adolescents and young adults
Adolescents and adults rarely develop neuroblastoma, accounting for less than 5% of all cases. When neuroblastoma occurs in this age range, it shows a more indolent clinical course than does neuroblastoma in younger patients, and it shows de novo chemotherapy resistance.[48] Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or in adults, regardless of stage or site.
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.[36,37,99] In adolescents, approximately 40% of the tumors will have loss-of-function mutations in ATRX, compared with less than 20% in younger children and 0% in infants younger than 1 year.[48]
The 5-year OS rate for adolescent and young adult patients (aged 15–39 years) is 38%.[100][Level of evidence: 3iA] 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%.[101] Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[68,102] 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.[101,102]
Adults
The biology of adult-onset neuroblastoma appears to differ from the biology of pediatric or adolescent neuroblastoma based on a single-institution series of 44 patients (aged 18–71 years). Genetic abnormalities in adult patients included somatic ATRX (58%) and ALK mutations (42%) but no MYCN amplification. Germline testing was performed in four patients, two of whom had aberrations (one patient with a BRCA1 mutation, the other patient with TP53 and NF1 mutations). In the 11 patients with locoregional disease, 10-year progression-free survival (PFS) was 35%, and OS was 61%. Among 33 adults with stage 4 neuroblastoma, 7 (21%) patients achieved a complete response (CR) after induction chemotherapy and/or surgery. In patients with stage 4 disease at diagnosis, the 5-year PFS was 10% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years; 10-year OS was 19%. CR after induction was the only prognostic factor for PFS and OS. Anti-GD2 immunotherapy (m3F8 or hu3F8) was well tolerated in adults.[103]

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 4 of 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.[104,105]
  • 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.[106]
High mitosis/karyorrhexis index and undifferentiated tumor cells are considered prognostically unfavorable histologic characteristics, but the prognostic value is age dependent.[107,108]
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%.[96]

Biological features

(Refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information.)

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:[109]
  • Adrenal tumors. 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. 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 (HR, 0.79; 95% 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).
Using the Therapeutically Applicable Research to Generate Effect Treatments (TARGET) and genome-wide association study datasets, a study compared the genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118). Neuroblastomas arising in the adrenal gland were more likely to harbor structural DNA aberrations such as MYCN amplification, whereas thoracic tumors showed defects in mitotic checkpoints resulting in hyperdiploidy. Thoracic tumors were more likely to harbor gain-of-function ALK aberrations than were adrenal tumors among all cases (OR, 1.89; P = .04), and among cases without MYCN amplification (OR, 2.86; P = .003). Because 16% of thoracic tumors harbor ALK mutations, routine sequencing for these mutations in this setting should be considered.[53]
In the TARGET cohort, 70% of patients with adrenal primary tumors and 51% of patients with thoracic primary tumors were stage 4; in the genome-wide association study without MYCN amplification, 43% of patients with adrenal primary tumors and 17% of patients with thoracic primary tumors were stage 4. By multivariate analysis, adrenal site was an independent predictor of worse outcome in the genome-wide association study cohort but not in the TARGET cohort after adjusting for MYCN amplification status, disease stage, and age of at least 18 months. Adrenal neuroblastoma was not an independent predictor of worse EFS by similar multivariable analysis for either the genome-wide association study or TARGET cohorts.[53]
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 neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[110] Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.

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.[92] The INSS predicted outcome on the basis of stage at diagnosis, although important interactions with biological variables were also found.[2-4,7,41,42,92,96,97] 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.[30,111] 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.

Response to treatment

Response to treatment has been associated with outcome. In patients with intermediate-risk disease who had a poor response to initial therapy in the COG ANBL0531 (NCT00499616) study, 6 of 20 patients subsequently developed progressive or recurrent disease, and one patient died.[95] 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.[112-114] 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 a worse outcome for high-risk patients with MYCN-amplified disease.[115,116]
Treatment-associated decrease in mitosis and increase in histologic differentiation of the primary tumor are also prognostic of response.[117]
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.[118]

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.[119] (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:[120]
  • 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,[121,122] the expression of the H-Ras protein,[123] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[124]
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.[125-127]
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.[90]
    • 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.[91] 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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