A 3-year-old girl presents to the emergency department with decreased appetite, fatigue, and irritability for 1 month. She has periorbital ecchymoses (raccoon eyes) without a history of trauma (Figure 212-1). A CT scan is ordered to look for a neuroblastoma. The CT scan of her orbit shows bony erosions and periosteal reaction of her orbits. An MRI scan of her abdomen reveals a primary adrenal tumor. A biopsy is performed of the adrenal tumor confirming the diagnosis of neuroblastoma. She responds well to several courses of chemotherapy.

Neuroblastoma is a malignant embryonal childhood tumor of the sympathetic nervous system derived from primordial neural crest cells.

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  Neuroblastoma is the most common malignant extracranial solid tumor of childhood and accounts for 8 to 10 percent of childhood cancers in children under 15 year of age.¹

  
  
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  There are between 600 to 650 cases each year in the US.

  
  
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  Occurs in approximately 14/100,000 live births.

  
  
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  Occurs in approximately 0.8 to 1/100,000 children under age 15 per year.

  
  
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  It is the most common cancer of infancy (<12 months; 58/1,000,000 infants per year).

  
  
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  Median age at diagnosis is 17 to 22 months. Ninety percent of cases are diagnosed by 5 years of age. It is rare after the age of 10 years.¹

  
  
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  Accounts for approximately 15 percent of all pediatric cancer fatalities.

  
  
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  More common in Caucasians.

  
  
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  Occurs slightly more frequently in boys that girls (1.2:1).²

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  Neuroblastic tumors arise from the primitive sympathetic ganglion cells and include neuroblastomas, ganglioneuroblastomas, and gangliomas. They may arise anywhere along the sympathetic ganglia and in the adrenal medulla. The etiology of neuroblastoma in most cases remains unknown, but certain recurrent molecular abnormalities have been found including amplification of the oncogene MYCN in approximately 20 percent of tumors, deletion of 1p36 and 11q, and in patients under 18 months of age.³

  
  
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  Familial neuroblastoma accounts for 1 to 2 percent of all cases and demonstrates an autosomal dominant pattern of inheritance with incomplete penetrance. It is associated with an earlier presentation, and bilateral adrenal or multifocal disease. It has been linked to mutations in the Phox2B and ALK genes.⁴

  
  
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  Mutations in Phox2B mutations are also associated with Haddad’s syndrome, a rare congenital neurocristopathy that includes Hirschsprung disease, congenital central hypoventilation, and sympathetic ganglia tumors.

  
  
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  Neuroblastoma may be detected in utero on prenatal ultrasound and often regresses or differentiates without intervention.

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  Epidemiologic studies have failed to show identifiable environmental etiologic risk factors.¹

  
  
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  The consistent rates of neuroblastoma suggest a major role of genetic factors.⁴

Clinical presentation depends on the site of the primary tumor, the extent of disease as well as the presence of a paraneoplastic syndrome. Approximately 65 percent of patients have metastatic disease at the time of diagnosis.

Clinical Features

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  Children with adrenal primary tumors may present with an asymptomatic palpable abdominal mass along with constipation, hypertension due to renal artery compression, and early satiety.

  
  
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  Patients with neuroblastoma originating along the lower sympathetic chain may present with evidence of cord compression such as urinary incontinence and decreased lower extremity movement.

  
  
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  Patients with a thoracic primary tumor may present with superior vena cava syndrome, and those with a tumor originating in the superior cervical ganglion with Horner’s syndrome (Figure 212-2).

  
  
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  Evidence of metastatic disease depends on the location and may include periorbital ecchymoses (raccoon eyes; Figures 212-1 and 212-3) and bone pain with bone metastasis, hepatomegaly, and “blueberry muffin” spots. Extensive bone marrow involvement may result in signs and symptoms of anemia and thrombocytopenia (Figure 212-4).

  
  
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  Systemic symptoms include weight loss, irritability, and fever.

  
  
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  Patients may also present with hypertension as a result of catecholamine production by the tumor and diarrhea as result of vaso-intestinal peptide production by the tumor.

  
  
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  Opsoclonus/myoclonus is an autoimmune paraneoplastic syndrome associated with neuroblastoma. Opsoclonus is rapid, involuntary, multivectorial, unpredictable, and conjugate fast eye movements.

  
  
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  Infants under a year of age may present with wide spread metastatic disease including subcutaneous tumor nodules and extensive liver involvement but with limited bone marrow disease and a small primary tumor. This presentation is termed stage “4S” and does not include patients with bone or other metastatic lesions. These patients have a surprisingly good outcome despite extensive disease at diagnosis.