This term includes all sympathetic nervous system tumours of neuroblastic origin. It comprises a wide spectrum of continuous morphological features, ranging from undifferentiated neuroblastoma to ganglioneuroma, depending on the proportion of neuroblastematous (NB) and ganglioneuromatous (GNR) components.

Clinical features

• It is the third most common extra cranial solid tumour of the paediatric age group.
• In 85% of the cases, it occurs in children under four years of age, and 50% under two years of age
• 65% of the cases present as an abdominal mass, with calcifications; although the adrenal is the most common site (50-80%), it can arise from any site containing sympathetic neural tissue
• Symptoms depend on its location: huge abdominal masses give rise to abdominal distension and respiratory symptoms; retroperitoneal masses can extend along the nerves and vertebral openings into the spine cord, resulting in pain and paralysis (Dumbbell)
• Nonspecific symptoms: fever, irritability, anorexia and malaise
• Para neoplastic syndromes may be related to other hormonal substances produced by the neuroblastoma or to an immune response (e.g. antibodies against the tumour) as a cause of myoclonus: opisthotonus, Horner syndrome or Ondine’s curse
• Metastases to regional lymph nodes, liver or bones at the time of diagnosis are common
• Metastases to the lungs are rare
• Catecholamine secretion: 24h urine specimens should be tested for homovanillic acid (HVA) and vanillylmandelic acid (VMA), before or soon after excision, for future follow-up and as an indicator of differentiation and survival.
• Familial incidence is reported
• Associations with Beckwith-Wiedemann Syndrome, Hirschsprung’s disease or neurofibromatosis, or as a complication of foetal hydantoin syndrome.

• Distinguishing between the different types of neuroblastoma and ganglioneuroblastoma (INPC-classification) is impossible by fine-needle cytology, since this depends on the architecture and on exhaustive sampling of the tumour
• Its appearance depends on whether the NB or the GNR component predominates.
  • neuroblastematous (NB) component :
    • Hypercellular smears
    • Undifferentiated loose, round, small cells
    • Undifferentiated neuroblasts have round to oval nucleus with granular salt-and-pepper chromatin and inconspicuous nucleoli
    • Background of fibrillary material
    • Mitoses are frequent
    • Necrosis may be abundant
  • ganglioneuromatous (GNR) component:
    • Feeling of hardness while puncturing
    • Hypocellular smears
    • Mature or maturing ganglion cells
    • Rare spindle nucleus, corresponding to Schwann cells
    • Collagen matrix
• Although these two components are essential for classifying neuroblastic tumours, the cytological appearance more frequently has an intermediate pattern:
  • Neuroblasts at varying degrees of maturation:
    • Undifferentiated neuroblasts
      • Small uncommitted round cells
    • Maturing neuroblasts
      • Neuroblasts with eccentric enlarged nucleus
      • Small eosinophilic nucleoli
      • Enlarged well-defined cytoplasm with Nissl substance
    • Immature ganglion cells
      • Frequent binucleation
      • Eccentric huge vacuolated nuclei with prominent eosinophilic nucleoli
      • Enlarged well-defined cytoplasm with Nissl substance
  • Variable amount of fibrillary neuropil (specific characteristic)
  • Homer-Wright rosettes (not a specific characteristic, but they occur at a higher frequency than in other small cell tumours)
  • Sparse Schwann cells
  • Variable numbers of mitoses and necrotic cells
  • Calcifications can be seen

[Table 1]

International Neuroblastoma Pathology Classification

(International Neuroblastoma Pathology Committee (INPC) classification)

*Original Shimada system (SR = stroma-rich; SP = stroma-poor; SD = stroma-dominant)

**INPC grade (FH = favourable histology; UH = unfavourable histology)

• *** GNBn:
  • Composite tumour with a favourable stroma-rich/stroma-dominant component and a nodular component of either a biologically favourable clone or an unfavourable clone, or both.
  • In a recent study on 70 patients with GNBn by Umehara et al (6), the clinical behaviour (FH/UH) was found to be connected with the grade of the most unfavourable component present in the tumour.
  • Large cell type phenotype – (large nuclei, clear chromatin, sharp nuclear membranes, and prominent nucleoli (7% of the cases); confers bad prognosis.

Immunocytochemistry

• CD56 N-CAM: positive
• NB84: positive
• NSE: positive
• Synaptophysin: positive
• Chromogranin A: positive
• Leu7: positive
• GD2 (only in frozen material): positive
• CD117: positive (50%)*
• Vimentin: negative
• CD99: negative
• Actin: negative
• Desmin: negative
• Cytokeratin: negative

*some authors associate to better prognosis

Genetic studies:

• N-myc expression and amplification
• Ploidy
• Deletion of chromosome 1
• 17q gains
• Double minute chromosomes
• Homogeneous staining regions
• TrKA, TrKB and TrkC expression (receptor proteins)

Differential diagnosis

• Lymphoma
  • Lymphoglandular bodies
  • Lack of fibrillary neuropil in the background
  • Lack of rosette formation
  • Neuroepithelial markers (NSE, CD56 N-CAM, synaptophysin and others): negative
  • CD45: positive
• Rhabdoid tumour
  • More monotonous cellular population
  • Vesicular chromatin
  • Homogeneously prominent nucleoli
  • Cytokeratin: positive (dot)
  • Vimentin: positive (dot)
  • INI : negative
• Alveolar rhabdomyosarcoma
  • Myogenin: positive
  • N-myc amplification (may be detected)
• Desmoplastic small cell tumour
  • Desmin: positive (dot)
  • Cytokeratin: positive
  • Vimentin: positive
  • t(11;22)(p13;q12)
• PNET
  • Most common in young adults.
  • Absence of fibrillary neuropil
  • Dual population of light and dark cells
  • Cytoplasm glycogen
  • CD99: positive (membranous pattern).
  • t (11:22) (q24; q12).

Main points

• Poor prognostic indicators: age over 1.5 years, 1p36,33 deletion, 14p deletion, N-myc amplification, diploid, low expression of TrKA (maturation factor), undifferentiated morphology, high MKI and CD44 positivity (correlates with N-myc amplification: the greater the number of copies of N-myc is, the worse the prognosis will be)
• Favourable prognostic indicators: age under one year, hyperdiploid/near-triploid, high levels of TrKA gene and no N-myc amplification
• Intermediate prognostic indicators: older patients, near diploid/tetraploid, low levels of TrKA gene, no N-myc amplification and no 1p deletion
• TrKB expression: generally expressed in advanced tumours
• Stage IVs (any localized tumour, with liver or bone marrow metastasis, but with no bone involvement); these cases are generally seen in infants and usually have a good prognosis
• Neuroblastoma in situ: incidental finding at autopsy in infants less than three months of age
• Extra-adrenal tumours are better differentiated and have better prognosis
• Low urinary VMA/HVA ratio is associated with poor outcome (sign of lack of differentiation)