Neuroblastoma

Neuroblastoma is a malignant neuroendocrine tumor of the sympathetic nervous system that originates from neural crest cells. It is the most common extracranial solid malignancy in children and the most common malignancy found in infants. Given its origin, neuroblastoma can occur in any aggregation of sympathetic nervous tissue, including the adrenal glands, the sympathetic chain, and the paraganglia (e.g., the carotid body). The clinical presentation is mainly determined by the site of the primary tumor, if it secretes catecholamines, and whether it has metastasized. In most cases, neuroblastomas stem from the adrenal glands within the abdominal cavity and present as a palpable abdominal mass that can cross the midline. Urine tests for catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) play an important role in diagnosis. Treatment is determined mainly by patient age at the time of diagnosis, clinical stage, and possible amplification of the MYCN oncogene. The prognosis depends on disease progression and is very good in early stages. Spontaneous remission may occur even in cases of metastatic disease.

Neuroblastoma is a malignant, embryonal neuroendocrine neoplasm of the sympathetic nervous system that originates from neural crest cells; , potentially secretes catecholamines; , and is usually found in the adrenal glands or sympathetic ganglia.
References:^[1]

• Most common malignancy of the adrenal medulla in infants and third most common childhood cancer overall following leukemia and brain tumors
• Mean age at diagnosis: 1–2 years
• The majority of children have progressed to advanced-stage disease by the time of diagnosis.

References:^[2][3][4][5]

Epidemiological data refers to the US, unless otherwise specified.

• Cause: unclear
• Genetic associations: chromosomal abnormalities, especially deletions (found in ∼ 50% of neuroblastomas)
  • Deletions of 1p; , 11q, and 14q chromosomal regions ^[3]
  • Amplification and overexpression of oncogene MYCN (N-myc) ^[6]
• Risk factors
  • Maternal: gestational diabetes, opiates, folate deficiency
  • Congenital syndromes: Turner syndrome, neurofibromatosis, Hirschsprung's disease, Beckwith-Wiedemann syndrome
  • Familial

References:^[3]

General symptoms

• Failure to thrive or weight loss
• Fever
• Nausea, vomiting, loss of appetite
• Hypertension

Localized symptoms

Paraneoplastic syndromes

• Chronic diarrhea → electrolyte imbalances
• Opsoclonus-myoclonus-ataxia; : a paraneoplastic syndrome of unclear etiology characterized by rapid and multi-directional eye movements, rhythmic jerks of the limbs, and ataxia (dancing eyes dancing feet syndrome)
• Possibly hypertension, tachycardia, palpitations, sweating, flushing; (hypertension is more commonly seen in pheochromocytoma)

References:^{[7][8][9][10][11][12]}

Laboratory tests

• Urine
  • ↑ Catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in 24-hour urine
  • Urinalysis
• Blood
  • ↑ Catecholamine metabolites (HVA/VMA)
  • ↑ Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE)
  • CBC with differential
  • Serum chemistry profile
  • Liver and kidney function tests

Other procedures

• Imaging: to identify the primary site
  • Abdominal ultrasound
  • CT or MRI (depending on the presumable site of the lesion)
• Scintigraphy
  • MIBG scan: Uptake scan of metaiodobenzylguanidine (MIBG) combined with a radioactive iodine tracer.
  • In MIBG non-avid tumors: technetium bone scan and plain radiographs
• Biopsy
  • Image-guided needle aspiration of the tumor or biopsy at the time of surgical tumor resection
    • Evaluation for MYCN gene amplification
    • Evaluation for DNA ploidy
  • Bilateral bone marrow biopsy of iliac crests

References:^[7]

• Homer Wright rosettes: Halo-like clusters of neuroblast cells surrounding a central pale area containing neuropil (associated with tumors of neuronal origin such as neuroblastoma, medulloblastoma, primitive neuroectodermal tumors, and pineoblastoma)
• Small round blue cells with hyperchromatic nuclei
• Bombesin and NSE positive

References:^[3][14][15]

• Differential diagnosis of nephroblastoma
• Pheochromocytoma
• Lymphoma
• Sarcomas
• Osteomyelitis or transient synovitis

The differential diagnoses listed here are not exhaustive.

Neuroblastoma patients are treated based on their risk category (low, intermediate, or high), which is based on the stage of their neuroblastoma (extent of disease), age at diagnosis, and the presence/absence of MYCN amplification.

• Low risk: generally children with early-stage disease (Stages 1–2) and no MYCN amplification
• Intermediate risk: generally children with intermediate and late-stage disease (Stages 3–4) and no MYCN amplification
• High risk: generally children with late-stage disease and/or MYCN amplification
• Stage 4S (an exception): disseminated disease in infants (< 12 months)
  • Better prognosis than other stage 4 neuroblastoma and spontaneous regression is very common
  • Children with Stage 4S belong to the low-risk or intermediate-risk groups unless they have a MYCN amplification, in which case they are high-risk patients

Spinal cord compression requires immediate surgical decompression or chemotherapy to shrink tumor tissue!

References:^{[16][17][18][19][20]}

• Prognosis depends on the risk group. Important factors include:
  • Age
  • Children with MYCN amplification are classified as high risk
  • Histopathology, disease dissemination and biochemical markers

References:^[19][21]