Neuroblastoma Treatment (PDQ®)–Health Professional Version
- General Information About Neuroblastoma
- Cellular Classification of Neuroblastic Tumors
- Stage Information for Neuroblastoma
- Treatment Option Overview for Neuroblastoma
- Treatment of Low-Risk Neuroblastoma
- Treatment of Intermediate-Risk Neuroblastoma
- Treatment of High-Risk Neuroblastoma
- Treatment of Stage 4S Neuroblastoma
- Recurrent Neuroblastoma
- Changes to this Summary (08/19/2016)
- About This PDQ Summary
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General Information About Neuroblastoma
Dramatic improvements in survival have been achieved for children and adolescents with cancer. 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. 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% are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months. 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 that in white children. 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 incidence of neuroblastoma.
Neuroblastoma originates in the adrenal medulla and paraspinal or periaortic regions where sympathetic nervous system tissue is present.
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 have multifocal primary neuroblastoma (about 20%).
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 a germline mutation in the ALK (anaplastic lymphoma kinase) gene. Somatic mutation in ALK is also seen in sporadic neuroblastoma. ALK is a tyrosine kinase receptor mutated in some lymphomas (refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information).
- 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. 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. Aberration of PHOX2B has not been seen in patients with sporadic neuroblastoma without associated Ondine curse or Hirschsprung disease.
- Germline 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 sporadic neuroblastoma.[17,18]
Sporadic neuroblastoma may also show a germline contribution, either with modest effect sizes for common polymorphic alleles or with greater effect sizes for rare pathogenic variants. As an example of the latter, rare germline variants of BARD1 have been identified in children with high-risk neuroblastoma.
Genome-wide association studies have identified several common genomic variables (single nucleotide polymorphisms [SNPs]) with modest effect size that are associated with neuroblastoma. A subset of these SNPs is associated with susceptibility to high-risk neuroblastoma, including variants related to the following:
Other SNPs are associated with susceptibility to low-risk neuroblastoma. One example that illustrates a mechanism by which SNPs may contribute to neuroblastoma risk is the polymorphism in the first intron of the oncogene LMO1 that forms a GATA transcription factor–binding site in an enhancer.[21,26] This risk allele is associated with high expression of LMO1 in aggressive neuroblastoma. LMO1 protein is necessary for growth of neuroblastoma in vitro and enhances growth of neuroblastoma cell lines with low LMO1expression.
Genomic and Biologic Features of Neuroblastoma
Neuroblastoma can be subdivided into a biologically defined subset that has a very favorable prognosis (i.e., low-risk neuroblastoma) and another group that has a guarded prognosis (i.e., high-risk neuroblastoma). While neuroblastoma in infants with tumors that have favorable biology is highly curable, only 50% of children with high-risk neuroblastoma are alive at 5 years from diagnosis, at best.
Low-risk neuroblastoma is usually found in children younger than 18 months with limited extent of disease; the tumor has changes, usually increases, in the number of whole chromosomes in the neuroblastoma cell. Low-risk tumors are hyperdiploid when examined by flow cytometry.[27,28] In contrast, high-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and usually has segmental chromosome abnormalities. They are near diploid or near tetraploid by flow cytometric measurement.[27-33] High-risk tumors also show exonic mutations (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack mutations in genes that are recurrently mutated. Compared with adult cancers, neuroblastomas show a low number of mutations per genome that affect protein sequence (10–20 per genome).
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
- Segmental chromosomal aberrations, including MYCN gene amplification.
- 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 (including MYCN gene amplification)
Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p (and MYCN amplification), are best detected by comparative genomic hybridization and are seen in almost all high-risk and/or stage 4 neuroblastomas.[29-33] Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with the following, whether or not MYCN amplification was considered:
- Advanced age at diagnosis.
- Advanced stage of disease.
- Higher risk of relapse.
- Poorer outcome.[29-33][Level of evidence: 3iiD]
In a study of unresectable primary neuroblastomas without metastases in children older than 12 months, 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 in children with segmental chromosomal aberrations versus children without segmental chromosomal aberrations (67% vs. 100%), regardless of the histologic prognosis.
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[27,28]
MYCN amplification (defined as more than 10 copies per diploid genome) is one of the most common segmental chromosomal aberrations, detected in 16% to 25% of tumors. For high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification. 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.[27,28] Within the localized MYCN-amplified cohort, ploidy status may further predict outcome. However, patients with hyperdiploid tumors with any segmental chromosomal aberrations do relatively poorly.
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 gain of 17q were the only poor prognostic features not associated withMYCN amplification. However, segmental chromosomal aberrations at 11q are almost mutually exclusive of MYCN amplification.
Exonic mutations in neuroblastoma
Multiple reports have documented that a minority of high-risk neuroblastomas have a small number of low-incidence, 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 mutation include ATRX, PTPN11, ARID1A, and ARID1B.[37-43] As shown in Figure 2, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.
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 mutations are also found as oncogenic drivers in neuroblastoma.
The presence of an ALK mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. ALK mutation was examined in 1,596 diagnostic neuroblastoma samples. 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 withoutMYCN 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.
Small-molecule ALK kinase inhibitors such as crizotinib are being developed and tested in patients with recurrent and refractory neuroblastoma. (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 neuroblastomas to define somatic genetic alterations associated with relapse, while a second study evaluated 16 paired diagnostic and relapsed specimens. Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis.
- The first study found increased incidence of mutations in genes associated with RAS-MAPK signaling at relapse than at diagnosis, with 15 of 23 relapse samples containing somatic mutations in genes involved in this pathway and each mutation consistent with pathway activation.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.
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 neuroblastomas have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified for high-risk neuroblastoma.[37,38,46] 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.[37,38] 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, which is associated with approximately 40% to 50% of high-risk neuroblastomas.
- The ATRX mutation or deletion is found in 10% to 20% of high-risk neuroblastomas, almost exclusively in older children, and is associated with telomere lengthening by a different mechanism, termed alternative lengthening of telomeres.[39,46]
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on 357 undifferentiated/poorly differentiated neuroblastomas has demonstrated that elevated MYC/MYCN protein expression is prognostically significant. Sixty-eight tumors highly expressed MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors expressed MYC highly and were mutually exclusive of high MYCN expression. Segmental chromosomal aberrations were not examined in this study, except for MYCN amplification.
- Patients with favorable-histology (FH) 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.
- Further, when high expression of MYC and MYCN proteins were analyzed with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.
Most neuroblastomas with MYCN amplification in the International Neuroblastoma Pathology Classification system have unfavorable histology, but about 7% have FH. Of those with MYCN amplification and FH, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those that express MYCN. Segmental chromosomal aberration at 11q is almost mutually exclusive of MYCNamplification.
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.
Current data do not support neuroblastoma screening. 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):
- 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.
- Another study of infants screened at the age of 1 year shows similar results.
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 due to 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. Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.
- 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.
- Subcutaneous skin nodules: Neuroblastoma subcutaneous metastases often have bluish discoloration of the overlying skin and is usually seen only in infants.
The clinical characteristics of neuroblastoma in adolescents are similar to those observed 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.
Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, occur rarely in children with neuroblastoma. Opsoclonus/myoclonus syndrome can be 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 tumor.[56-58]
Patients who present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[56,59] The primary tumor is typically diffusely infiltrated with lymphocytes.
Some patients may respond neurologically to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment can be effective, but some patients do not respond to corticosteroids.[57,59] Other therapy with various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[57,61-63] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[55,61]
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 may also be used.[64,65]
- Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per milligram of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If elevated, these markers can be used to determine the persistence of disease.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 Children’s Oncology Group (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 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.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.In rare cases, neuroblastoma may be discovered prenatally by fetal ultrasonography. Management recommendations are evolving with regard to 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 in neonates, biopsy was not required for infants; 81% of patients avoided undergoing any surgery at all. 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.
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:
- An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology or electron microscopy).
- 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.
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. The 5-year OS for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005. This single statistic can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma 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 those diagnosed from 1990 to 1999. (Refer to Table 1 for more information.)
- Age at diagnosis.
- Site of primary tumor.
- Tumor histology.
- Regional lymph node involvement (in children older than 1 year; however, this is controversial).
- Response to treatment.
- Biological features. (Refer to the Genomic and Biologic Features of Neuroblastomasection of this summary for more information.)
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.)
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:
- Age younger than 1 year – 90%.
- Age 1 to 4 years – 68%.
- Age 5 to 9 years – 52%.
- Age 10 to 14 years – 66%.
Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival (DFS). The prognosis for fetal and neonatal neuroblastoma is similar to that for older infants with neuroblastoma and similar biological features. Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy.
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 International Neuroblastoma Staging System (INSS) stage 1 or 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.
- In the COG intermediate-risk study A3961 (NCT00003093) that included only MYCN non-amplified 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%).
In North American clinical trials reported in the 1990s, infants aged 1 year and younger had a cure rate higher than 80%, while older children had a cure rate of 50% to 70% with then-current, relatively intensive therapy.[80-83]
Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 18 months at diagnosis have a good chance of long-term survival (i.e., a 5-year DFS rate of 50%–80%),[84,85] with outcome particularly dependent on MYCN status, tumor cell ploidy, and the pattern of chromosomal aberrations (numerical chromosomal aberrations and segmental chromosomal aberrations). Hyperdiploidy and numerical chromosomal aberrations confer a favorable prognosis while diploidy and segmental chromosomal aberrations are associated with early treatment failure.[81,86] Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not haveMYCN gene amplification are categorized as intermediate risk and have a 3-year EFS of 81% and OS of 93%.[6,79,87-89] Infants younger than 12 months with INSS stage 4 disease andMYCN amplification are categorized as high risk and have a 3-year EFS of 10%.
Adolescents and young adults
Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or adults, 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.[19,33,90]
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 and OS rate is 5%. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[54,92,93] 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.[91-93]
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:
- 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 (HR, 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).
Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.
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 withoutMYCN 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.[96,97]
- 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.
High mitosis/karyorrhexis index is considered a prognostically unfavorable histologic characteristic, but its prognostic ability is age dependent.[98,99]
In a COG study (P9641 [NCT00003119]), 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%.
Regional lymph node involvement
According to the INSS, the presence of cancer in the regional lymph nodes on the same side of the body as the primary tumor has no effect on prognosis. However, when lymph nodes with metastatic neuroblastoma cross the midline and are on the opposite sides of the body from the primary tumor, the patient is upstaged (refer to the Stage Information for Neuroblastoma section of this summary for more information), and a poorer prognosis is conferred. In the COG P9641 (NCT00003119) low-risk study, stage 2b patients (those with tumor-containing lymph nodes on the same side of the body cavity as the tumor, but not on the opposite side of the cavity), but not stage 1 or 2a patients, had a poorer outcome with unfavorable histology (86% ± 5% vs. 99% ± 1%). The poorer outcome was predominantly in patients older than 18 months.
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.[100-102] Similarly, the persistence of mIBG-avid tumor measured as Curie score (refer to the Curie score and SIOPEN score section of this summary for more information about Curie scoring) in two or more sites after completion of induction therapy predicts a poor prognosis. A decrease in mitosis and an increase in histologic differentiation of the primary tumor are also prognostic.
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 surgical removal of the primary tumor, radiation to the tumor bed, and, in most cases, antiGD2 antibody–enhanced immunotherapy. Primary tumor response was measured 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 were predictive of outcome.
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. (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:
- 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,[108,109] the expression of Ha-ras, and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[112-114]
Evidence (observation [spontaneous regression]):
- 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.
- Eighty-one percent were spared surgery, and all were alive after 2 years of follow-up (refer to the Surgery subsection of this summary for more information).
- 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. In some cases, regression did not occur until more than 1 year after diagnosis.
- 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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