Neuroblastoma NOS

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.

 

Fig 43a - Neuroblastoma NOS - Neuroblastoma poorly differentiated- Smears consisting mainly of neuroblastematous component. Small round cells with very high nuclear-cytoplasmic ratio, granular “salt and pepper” chromatin and inconspicuous nucleoli in fine fibrillary background. Absence of neuroblastic differentiation (H&E)
Fig 43b- Neuroblastoma- Large cell type- Smears consisting mainly of cohesive cellular groups of large cells with large nuclei, sharp nuclear membranes, and prominent nucleoli
Fig 44 - Neuroblastoma NOS – Calcifications can be seen and are frequent in neuroblastoma (H&E)
Fig 45 - Neuroblastoma NOS – Neuroblastoma poorly differentiated -Poorly differentiated neuroblasts. Homer-Wright rosette as well and fibrillary background (H&E)
Fig 46 - Neuroblastoma NOS –Well differentiated neuroblastoma- Neuroblasts, multinucleated immature ganglion cell and single spindle shaped Schwann cells (bottom right) (Giemsa)
Fig 47 - Neuroblastoma NOS – Neuroblasts in varying degrees of maturation. (remark anysokariosis) (H&E)
Fig 48a - Neuroblastoma NOS –Small uncommitted round cells together with an immature ganglion cell. These cells are frequently multinucleated with round nuclei, prominent nucleoli and abundant granular cytoplasm (H&E)
Fig 48b - Neuroblastoma NOS –Small uncommitted round cells together with an immature ganglion cell. These cells are frequently multinucleated with round nuclei, prominent nucleoli and abundant granular cytoplasm (H&E)
Fig 49 - Neuroblastoma NOS – Aspirate of a ganglioneuroblastoma - neuroblasts in different stages of maturation. Predominance of multinucleated ganglion cells (H&E)

 

 

  • 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)
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