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Neuroblastoma Treatment (PDQ®)

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General Information About Neuroblastoma

Incidence
Anatomy
Risk Factors
Biologic and Molecular Features
        Biological subtypes
        Molecular features
Neuroblastoma Screening
Clinical Presentation
        Opsoclonus/myoclonus syndrome
Diagnosis
Prognostic Factors
        Age at diagnosis
        Site of primary tumor
        Tumor histology
        Regional lymph node involvement
        Response to treatment
        Biological features
Spontaneous Regression of Neuroblastoma

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer are usually referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life:

  • Primary care physician.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.

(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] Childhood and adolescent cancer survivors require close follow-up since 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

Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[5,6] 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.[7]

While there is no racial variation in incidence, there are racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcome.[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]

Anatomy

Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present.

Risk Factors

Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked to neuroblastoma.

Germline deletion at the 1p36 or 11q14-23 locus is associated with neuroblastoma, and the same deletions are found somatically in sporadic neuroblastomas.[13,14]

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 neuroblastomas. The primary cause of familial neuroblastoma is a germline mutation in the ALK gene.[15] Familial neuroblastoma is rarely associated with congenital central hypoventilation syndrome (Ondine’s curse), which is caused by a germline mutation of the PHOX2B gene.[16]

Biologic and Molecular Features

Biological subtypes

On the basis of biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, neuroblastic tumors have been categorized into the following three biological types:

  • Type 1: Characterized by gains and losses of whole chromosomes. It expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.[17,18]

  • Type 2A: Characterized by copy number alterations in portions of chromosomes. Type 2A expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy of chromosome 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable.[17,18]

  • Type 2B: Generally has the MYCN gene amplified and has a gain of chromosome 17q, loss of chromosome 1p, and expression of the TrkB neurotrophin receptor and its ligand.[17,18]

These specific genetic changes may be combined with traditional clinical factors such as patient age and tumor stage to refine neuroblastoma risk classes.

Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental chromosome changes in gene copy number compared with children whose tumors show MYCN amplification.[19,20] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.[21]

Molecular features

Approximately 6% to 10% of sporadic neuroblastomas carry somatic ALK-activating mutations, and an additional 3% to 4% have a high frequency of ALK gene amplification. The mutations result in constitutive phosphorylation of ALK, leading to dysregulation of cell signaling and uncontrolled proliferation of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification.[22]

Genome-wide association studies in children with neuroblastoma have found common single-nucleotide polymorphisms (SNPs) associated with a modest susceptibility to develop high-risk neuroblastoma.[23,24] Other SNPs are associated with susceptibility to develop low-risk neuroblastoma.[24] SNPs associated with race predict a higher incidence of neuroblastoma and worse outcome.[25]

Large genomic studies have found few recurrent gene mutations in patients with neuroblastoma, including ALK (9.2%), PTPN11 (2.9%), ATRX (2.5%; 7.1% focal deletions), MYCN (1.7%), and NRAS (0.8%).[19,21,26,27] ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with older age at diagnosis in adolescents and young adults with metastatic neuroblastoma.[28] It is unclear whether an ATRX mutation is an independent prognostic risk factor.

Neuroblastoma Screening

Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[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 due to spontaneous regression of the tumors.

  2. Another study of infants screened at the age of 1 year shows similar results.[12]

Clinical Presentation

The most common presentation of neuroblastoma is an abdominal mass. The most frequent signs and symptoms of neuroblastoma are due to 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: Because they originate in paraspinal ganglia, neuroblastomas 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 due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[29] Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[30]

  • Presence of Horner syndrome: 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.[31]

  • Subcutaneous skin nodules: Neuroblastoma subcutaneous metastasis often has bluish discoloration in the overlying skin and usually is 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.[32]

Opsoclonus/myoclonus syndrome

Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, are rare in children with neuroblastoma.[33] Opsoclonus/myoclonus syndrome is frequently 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.[34-36]

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.[34]

The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[34,37] The primary tumor is typically diffusely infiltrated with lymphocytes.[38]

Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment is thought to be effective, but some patients do not respond to corticosteroids.[35,37] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[35,39-41] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[33,39]

Diagnosis

Diagnostic evaluation of neuroblastoma includes the following:

  • Metaiodobenzylguanidine (mIBG) scan.[42,43]

  • Imaging of the primary tumor mass: This 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.

  • Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per mg 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, 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 11q and 1p loss of heterozygosity. 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 and 1p/11q loss of heterozygosity may be successfully performed on involved bone marrow if there is at least 30% to 40% tumor involvement.

    In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[44] 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. Biopsy was not required for infants entered into a COG study of expectant observation of small adrenal masses in neonates, and 81% avoided undergoing any surgery at all.[45] In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects of the delay.[46]

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, electron microscopy, or increased levels of serum catecholamines [dopamine and norepinephrine] or urinary catecholamine metabolites [VMA or HVA]).[47]

  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 serum catecholamines or urinary catecholamine metabolites.[47]

Prognostic Factors

Between 1975 and 2002, the 5-year survival rate for neuroblastoma in the United States has remained stable at approximately 87% for children younger than 1 year and has increased from 37% to 65% in children aged 1 to 14 years.[1] The 5-year overall survival (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;[48] however, this single number can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular Classification of Neuroblastic Tumors section of this summary for more information.) Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis.

The prognosis for patients with neuroblastoma is related to the following:[49-52]

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. The 5-year survival stratified by age is as follows:[48]

  • 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.[53] The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features.[54] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy.

Survival of patients with International Neuroblastoma Staging System (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 disease-free survival rate of 50%–80%),[55,56] with outcome particularly dependent on MYCN amplification and tumor cell ploidy. Hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure.[57,58] Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk and have a 3-year event-free survival (EFS) of 81% and OS of 93%.[7,59-62]

Adolescents and young adults

Neuroblastoma has a worse long-term prognosis in an adolescent older than 12 years or in an adult compared with a child, regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[32,63,64] Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[63,64]

Site of primary tumor

Site of primary tumor is not an independent prognostic factor. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[65] Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.

Tumor histology

Neuroblastoma tumor histology has a significant impact on prognosis and risk group assignment (refer to the Cellular Classification of Neuroblastic Tumors section and Table 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 amplification, determine prognosis.[66,67]

  • 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.[54]

Histologic characteristics considered prognostically unfavorable include the following:

  • Mitosis.
  • Karyorrhexis.

A COG study of children with stage 1 and stage 2 neuroblastoma without MYCN amplification and 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%.[68] Similar results were found in a European study.[69-71]

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.

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.[72-74] The degree of tumor volume reduction predicts response in high-risk patients, as does a decrease in mitosis and an increase in histologic differentiation.[75,76] Similarly, the persistence of mIBG-avid tumor after completion of induction therapy predicts a poor prognosis.[77]

Biological features

A number of biologic variables have been studied in children with this tumor:[78]

  • Biological subtype: These biological types are not used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2A and 2B have poor prognoses. (Refer to the Biological subtypes subsection of this summary for more information on subtypes 1, 2A, and 2B.)

  • MYCN amplification: MYCN amplification (defined as greater than 10 copies per diploid genome) is detected in 16% to 25% of tumors.[79] In stage 2, 3, 4, and 4S patients, 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. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, but also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis.[80] Within the localized MYCN-amplified cohort, ploidy status may further predict outcome.[81]

    The degree of expression of the MYCN gene in the tumor does not predict prognosis.[82] However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence.[83]

  • Segmental chromosome changes: Segmental chromosome number changes predict recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification. Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with advanced age at diagnosis, advanced stage of disease, higher risk of relapse, and a poorer outcome, whether or not MYCN amplification was considered.[19,21,26,84]

  • Whole chromosome changes: Whole chromosome copy number changes do not predict recurrence and are associated with hyperdiploidy.

Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[85,86] urinary VMA, HVA, and their ratio;[87] MRP1;[88] GABAergic receptor profile;[89] dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.[78] These factors are currently not in use for stratification on clinical trials.

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.[90] (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:[91]

  • 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,[92,93] the expression of Ha-ras,[94] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[95]

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.[96-98]

Evidence (observation):

  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.[45]
    • Eighty-one percent were spared surgery and all were alive at 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 nearly one-half of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification.[46]
    • All were observed after biopsy and partial or no resection.

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