Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an incidence of about 650 cases per year in the U.S., and 100 cases per year in the UK. Nearly half of neuroblastoma cases occur in children younger than two years. It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system (SNS). It most frequently originates in one of the adrenal glands, but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.

Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance. It is a disease exhibiting extreme heterogeneity, and is stratified into three risk categories: low, intermediate, and high risk. Low-risk disease is most common in infants and good outcomes are common with observation only or surgery, whereas high-risk disease is difficult to treat successfully even with the most intensive multi-modal therapies available.

Signs and symptoms

The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:[8]

  • In the abdomen, a tumor may cause a swollen belly and constipation.
  • A tumor in the chest may cause breathing problems.
  • A tumor pressing on the spinal cord may cause weakness and thus an inability to stand, crawl, or walk.
  • Bone lesions in the legs and hips may cause pain and limping.
  • A tumor in the bones around the eyes or orbits may cause distinct bruising and swelling.
  • Infiltration of the bone marrow may cause pallor from anemia.

Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.[9]

The most common location for neuroblastoma to originate (i.e., the primary tumor) is in the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.[10]

Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner’s syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome[11] and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).

The “International Neuroblastoma Staging System” (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:[29][30][31]

  • Stage 1: Localized tumor confined to the area of origin.

  • Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.

  • Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.

  • Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.

  • Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.

  • Stage 4S: ‹ Age 1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).

Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12–18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12–18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.[32]

The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):

  • Stage L1: Localized disease without image-defined risk factors.

  • Stage L2: Localized disease with image-defined risk factors.

  • Stage M: Metastatic disease.

  • Stage MS: Metastatic disease “special” where MS is equivalent to stage 4S.

The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.


Urine catecholamine level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s.[34][35] Japan began screening six-month-olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.[36][37][38]


When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy[39] with anti-GD2 monoclonal antibody therapy).

Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity.[40] These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogeneamplification (N-myc regulates microRNAs[41]), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk.[42] (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)[43]

The therapies for these different risk categories are very different.

  • Low-risk disease can frequently be observed without any treatment at all or cured with surgery alone.[44]

  • Intermediate-risk disease is treated with surgery and chemotherapy.[45]

  • High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / hematopoietic stem cell transplantation,[46] biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane)[47] and antibody therapy usually administered with the cytokines GM-CSF and IL-2.[48]

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70–90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time.[49] The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children’s Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to received ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.[50]

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.


Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory.[51][52] Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.[53]

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease.[54][55] An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.[56][57][58]
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