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.
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 :
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
Mature or maturing ganglion cells
Rare spindle nucleus, corresponding to Schwann cells
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:
Small uncommitted round cells
Neuroblasts with eccentric enlarged nucleus
Small eosinophilic nucleoli
Enlarged well-defined cytoplasm with Nissl substance
Immature ganglion cells
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
International Neuroblastoma Pathology Classification
(International Neuroblastoma Pathology Committee (INPC) classification)
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.
CD56 N-CAM: positive
Chromogranin A: positive
GD2 (only in frozen material): positive
CD117: positive (50%)*
*some authors associate to better prognosis
N-myc expression and amplification
Deletion of chromosome 1
Double minute chromosomes
Homogeneous staining regions
TrKA, TrKB and TrkC expression (receptor proteins)
Lack of fibrillary neuropil in the background
Lack of rosette formation
Neuroepithelial markers (NSE, CD56 N-CAM, synaptophysin and others): negative
More monotonous cellular population
Homogeneously prominent nucleoli
Cytokeratin: positive (dot)
Vimentin: positive (dot)
INI : negative
N-myc amplification (may be detected)
Desmoplastic small cell tumour
Desmin: positive (dot)
Most common in young adults.
Absence of fibrillary neuropil
Dual population of light and dark cells
CD99: positive (membranous pattern).
t (11:22) (q24; q12).
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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