Neuroblastoma

Diagnosis

Indications for Testing

• Abdominal swelling
• Mass identified with imaging
• Presence of an associated syndrome

Laboratory Testing

• Initial testing – VMA and HVA urine tests
  • 24-hour urine collection is not necessary (National Cancer Institute [NCI] PDQ, 2017)
  • VMA/creatinine and HVA/creatinine ratios may be used
• Genetic mutation testing for familial neuroblastoma (NCI PDQ, 2017)
  • 1-2% of patients with neuroblastoma have a family history of neuroblastoma
  • Germline mutations have been associated with an increased risk of developing neuroblastomas, including
    • ALK – approximately 75% of familial neuroblastoma caused by germline mutations in the ALK gene
    • PHOX2B – usually in combination with central hypoventilation syndrome or Hirschsprung disease
    • Deletion at 1p36 or 11q14-23 – both germline and somatic changes associated with neuroblastoma
  • Single nucleotide polymorphisms (SNPs) identified in several genes have been associated with variable risk of developing neuroblastomas
    • SNPs associated with susceptibility to high-risk neuroblastomas include
      • BARD1
      • LMO1
      • LIN28B
      • HACE1
      • CASC15/NBAT-1
  • Other SNPs have been linked to low-risk neuroblastomas

Histopathology

• Diagnosis and prognosis is based on evaluation of a surgical specimen; however, in infants who present with tumor at or before 6 months, biopsy may be postponed until up to 18 months of age
• Bone marrow aspiration and biopsy – required for staging of disease
• Protocol for examination of neuroblastoma specimens (College of American Pathologists [CAP], 2016)

Imaging Studies

• Computed tomography (CT) or magnetic resonance imaging (MRI) – chest, abdomen, and pelvis
• Metaiodobenzylguanidine (MIBG) scintigraphy – if CT scan is not revealing
• Technetium bone scan – if bone disease is suspected and MIBG scan is negative

Prognosis

• Markers for high-risk neuroblastoma (NCI PDQ, 2017)
  • MYCN (N-MYC) – amplification associated with advanced stage disease, rapid tumor progression, and poor prognosis
  • Ploidy status
    • Hyperdiploid and near triploid – low risk
    • Near diploid and near tetraploid – high risk or intermediate risk

Differential Diagnosis

• Renal tumors
• Rhabdomyosarcoma
• Germ cell tumors
• Hepatoblastoma
• Ewing sarcoma/desmoplastic small round cell tumor
• Non-Hodgkin lymphoma (especially Burkitt lymphoma)
• Primary neuroendocrine tumor

Screening

• VMA and HVA urinary screening – not recommended for general population
• Obstetrical ultrasound screening – detects prenatal neuroblastoma

Background

Epidemiology

• Incidence – 10.5/million children <15 years worldwide
• Age – <5 years; median is 2 years
• Sex – M<F (1:2.1)
• Occurrence – mostly sporadic; 1-2% are familial

Pathophysiology

• Malignant tumor from undifferentiated or poorly differentiated neuroectodermal cells of the neural crest
  • Some infants born with tumors
• Abdominal tumors in ~65% of cases, 40% of which are adrenal
• About 50% of cases have aggressive, fast-growing tumors
  • May spread to lymph nodes and other organs before symptoms are evident

Clinical Presentation

• Symptoms determined by tumor location and stage
  • Abdominal site
    • Most common
    • Symptoms can include abdominal pain, distension, swelling, and bowel obstruction
    • Local compression of renal vasculature may cause hypertension
  • Metastatic tumors
    • Frequently associated with crying and irritability, fever, bone pain, weight loss
    • Initially may be asymptomatic (~50% of patients)
    • Orbital metastases – periorbital ecchymoses (“raccoon eyes”) and proptosis
    • May be confused with trauma
    • Paraspinal disease – paresis and cord compression
    • Cervical, apical thoracic disease
  • Localized tumors often asymptomatic
• Syndromes associated with neuroblastoma
  • Horner syndrome
    • Ptosis, miosis, anhidrosis (associated with thoracic or cervical [neck] primary tumor)
  • Hutchinson syndrome
    • Limping and irritability associated with bone pain and bone marrow metastases
  • Neurocristopathy syndromes
    • Congenital neuroblastoma associated with other neural crest disorders
    • Congenital central hypoventilation syndrome (also called Ondine curse)
    • Hirschsprung disease – congenital megacolon
    • Opsoclonus-myoclonus syndrome (also called dancing eyes-dancing feet syndrome, Kinsbourne syndrome, myoclonic encephalopathy of infants)
      • Involuntary eye fluttering
      • Muscle jerking
      • Ataxia
  • Pepper syndrome
    • Massive metastatic disease in infants <1 year involving skin, liver, bone marrow
  • Verner-Morrison syndrome
    • Vasoactive intestinal polypeptide secretion causing refractory diarrhea, hypokalemia, hypovolemia, failure to thrive