• Clinical science

Neuroblastoma

Abstract

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.

Definition

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]

Epidemiology

  • Most common malignancy 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][6]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[3]

Classification

International Neuroblastoma Pathology Classification (INPC) system

  • Favorable histology
    • Poorly differentiated or differentiating neuroblastoma, with low or intermediate frequency of cell division, in patients ≤ 1.5 years
    • Differentiating neuroblastoma and neuroblastoma with low frequency of cell division, in patients 1.5–5 years
    • Ganglioneuroblastoma, intermixed, in patients of any age
    • Ganglioneuroma in patients of any age
  • Unfavorable histology
    • Undifferentiated tumors or those with high frequency of cell division in patients of any age
    • Poorly differentiated tumors or those with intermediate frequency of cell division in patients 1.5–5 years
    • Any grade of differentiation and any frequency of cell division in patients ≥ 5 years
    • Nodular ganglioneuroblastoma in patients of any age

Clinical features

General symptoms

Localized symptoms

Location Associated symptoms
  • Abdomen (in > 60% of cases)
  • Palpable, irregular abdominal mass that can cross the midline
  • Abdominal distension and pain
  • Hepatomegaly
  • Constipation
  • Neck
  • Bones
  • Skin
  • Subcutaneous nodules

Paraneoplastic syndromes

References:[7][8][5][9][10][11][12]

Stages

International Neuroblastoma Staging System (INSS)

Stage Definition
1
  • Localized tumor; complete gross excision ± microscopic residuals; negative ipsilateral lymph nodes
2A
2B
3
4
  • Any tumor with dissemination to distant lymph nodes or other organs (e.g., bone, liver, skin), with the exception of Stage 4S disease
4S

Diagnostics

Laboratory tests

Other procedures

  • Abdominal ultrasound
  • CT or MRI: to identify the primary site
    • Chest if radiograph shows evidence of disease
    • Head in patients presenting with orbital symptoms
    • Spine if compressive myelopathy is suspected
  • Scintigraphy
  • 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]{#2145]

Pathology

  • Homer Wright rosettes; : Halo-like clusters of cells surrounding a central pale area containing neuropil
  • Small round blue cells with hyperchromatic nuclei
  • Bombesin positive

References:[3]#3488][13][14]

Differential diagnoses

The differential diagnoses listed here are not exhaustive.

Treatment

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
    • All children with Stage 1 neuroblastoma
    • Children < 1 year with Stage 2A or 2B neuroblastoma
    • Children > 1 year with Stage 2A or 2B neuroblastoma and no MYCN amplification
    • Children with Stage 4S neuroblastoma (< 1 year by definition), favorable histology, a hyperdiploid tumor, and no MYCN amplification
  • Intermediate risk: generally children with intermediate and late-stage disease (Stages 3–4) and no MYCN amplification
    • Children < 1 year with Stage 3 neuroblastoma and no MYCN amplification
    • Children > 1 year with Stage 3 neuroblastoma, no MYCN amplification, and favorable histology
    • Children < 1 year with Stage 4 neuroblastoma and no MYCN amplification
    • Children with Stage 4S neuroblastoma (< 1 year by definition), unfavorable histology and/or a normal ploidy tumor, but no MYCN amplification
  • High risk: generally children with late-stage disease and/or MYCN amplification
    • Children > 1 year with Stage 2A or 2B neuroblastoma and MYCN amplification
    • All children with Stage 3 neuroblastoma and MYCN amplification
    • Children > 18 months with Stage 3 neuroblastoma and unfavorable histology
    • All children with Stage 4 disease and MYCN amplification
    • Children > 18 months with Stage 4 neuroblastoma
    • Children 12–18 months with Stage 4 neuroblastoma, MYCN amplification, unfavorable histology, and/or normal DNA ploidy
    • Children with Stage 4S neuroblastoma (< 1 year by definition) and 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
Treatment Low-Risk Neuroblastoma Intermediate-Risk Neuroblastoma High-Risk Neuroblastoma
Observation only X
Preoperative chemotherapy (e.g., doxorubicin, cyclophosphamide, etoposide, and a platinum drug) X X X
Surgery X X X
Postoperative chemotherapy X X
Radiation X X
GD2 antibody, dinutuximab, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 2 (IL-2), and cis-retinoic acid X
Other postoperative therapies (e.g., MIBG therapy) X

Spinal cord compression requires immediate surgical decompression or chemotherapy to shrink tumor tissue!
References:[15][16][17][18][19]

Prognosis

  • 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:[18][20]