Neuroblastoma

Neuroblastoma is a tumour of neuroblastic origin and is the most common extracranial solid childhood malignancies, and the third commonest childhood tumor after leukemia and brain malignancies. It accounts for ~15% of childhood cancer deaths ².

Epidemiology

The tumours typically occur in infants and very young children (mean age of presentation being ≈22 months) with 95% of cases diagnosed before the age of 10 years. Occasionally, they may be identified antenatally or immediately at birth (see congenital neuroblastoma) ².

Clinical presentation

Clinical presentation is typically with pain or a palpable mass and abdominal distension, although numerous other presentations are encountered due to local mass effect.

Other accompanying syndromes include:

• Hutchinson syndrome: bony metastases may present with skeletal pain or a palpable lump or limping and irritability due to skeletal metastases ²
• Pepper syndrome: hepatomegaly due to extensive liver metastasis
• blueberry muffin syndrome: multiple cutaneous lesions
• opsomyoclonus ⁵: rapid, involuntary conjugate fast eye movements 

Pathology

The tumours arise from the primitive neuroectodermal cells or neural crest cells (adrenal medulla precursor). The histology is similar to small round blue cell tumours ³. Majority of them demonstrate chromosome 1p deletion and  N-myc amplification. Macroscopically

Macroscopically, they tend to be large grey tan colour, soft lesions with or without fibrous pseudocapsule hence some are well defined and some are infiltrative. Areas of necrosis, haemorrhage, and particularly calcification are very common. Microscopically

Microscopically, they form Homer Wright rosettes ³. Most of them secrete catecholamines: vanillylmandelic acid (VMA) and homovanillic acid (HVA) ^2​.

Location

Neuroblastomas arise from the sympathetic nervous system ^2-3:

Intra abdominal occurrence is commoner than intra thoracic and comprise of almost two third of cases. Specific sites include:

• adrenal glands: most common site of origin, 35%
• retroperitoneum: 30-35%
  • organ of Zuckerkandl
  • coeliac axis
  • paravertebral sympathetic chain
• posterior mediastinum: 20%
• neck: 1-5%
• pelvis: 2-3%

Associations

The vast majority of neuroblastomas are sporadic, however in rare instances they may be associated with ^1-4:

• Beckwith-Wiedemann syndrome
• central failure of ventilation
• DiGeorge syndrome
• Hirschsprung disease
• Neurofibromatosis type 1 (von Recklinghausen disease)

Radiographic features

Plain film

Appearances are non-specific, typically demonstrating an intrathoracic or intrabdominal a soft-tissue mass. Pressure on adjacent bones may cause remodelling of ribs, vertebral bodies or pedicle thinning. Up to 30% may have evidence of calcification on the plain film.

Skeletal metastases are usually ill-defined and lucent, with periosteal reaction or metaphyseal lucency. Sclerotic metastases are uncommon ².

Ultrasound

Neuroblastoma on ultrasound demonstrates a heterogeneous mass with internal vascularity. Often there are areas of necrosis which appear as regions low echogenicity. Calcification may or may not be evident on ultrasound ².

Nuclear medicine

A number of compounds are used for diagnosis and staging:

• pentetreotide labeled to Indium-In¹¹¹ (somatostatin analog)
  • not specific for neuroblastic tissue
• MIBG (metaiodobenzylguanidine labeled to Iodine-¹²³)
  • 95% of neuroblastomas secrete catecholamines, however
  • 30, 30% of neuroblastomas are negative on MIBG
  • sensitivity: 88%
  • specificity: 99% (for sympathetic tissue) ²
  • does not distinguish between neuroblastoma, glanglioneuroblastoma, ganglioneuroma, carcinoid, and pheochromocytoma

Surveillance for metastatic recurrence

• Tc-⁹⁹m MDP
  • 36% of primary tumours negative
  • mainly to evaluate skeletal metastases
  • also able to detect some lung and liver metastases ²

CT

On CT, the tumour typically is heterogeneous with calcifications seen in 80-90% of cases ². Areas of necrosis are of low attenuation.

The morphology of is often most helpful, with the mass seen insinuating itself beneath the aorta and lifting it off the vertebral column. It tends to encase vessels and may lead to compression. Adjacent organs are usually displaced, although in more aggressive tumours direct invasion of the psoas muscle or kidney can be seen. In the latter it can make distinguishing neuroblastoma from Wilms tumour difficult (see neuroblastoma vs Wilms tumour).

Lymph node enlargement is often present.

MRI

MRI is superior to all other modalities in assessing the organ of origin, intracranial or intra-spinal disease and bone marrow disease ².

• T1: heterogeneous and iso to hypointense
• C+ (Gd): variable and heterogeneous enhancement
• T2
  • heterogeneous and hyper intense
  • cystic/necrotic areas very high intensity
  • signal voids may be evident

Staging and metastatic disease

For staging refers to: neuroblastoma staging

Metastatic disease is common and has a variety of patterns:

• bone
  • most common 
• liver
  • diffuse infiltration (more common in stage 4S)
  • focal hypo-enhancing masses
• lung and pleura
  • discrete nodules
  • diffuse consolidation
  • pleural disease is uncommon
• brain and meninges
  • dural metastases can be diffuse of nodular
  • brain metastases are uncommon but variable in appearance

Treatment and prognosis

Treatment depends on the patients stage. Localised tumours considered to be 'low-risk' are surgically excised and patients tend to do very well (see below). In 'high-risk' tumours, a combination or surgery, chemotherapy +/- bone marrow transplantation is employed, unfortunately with poor overall results. In some cases, where tumours are very large, pre-surgical chemotherapy to attempt to down-stage the tumour may be administered ².

Patients with stage 1, 2 or 4S have a better prognosis. Unfortunately 40-60% of patients present with stage 3 or 4 disease ⁴. For advanced disease, the age of the child is most important ³.

• stage 1, 2 or 4S: 75-90% 3 year survival
• stage 3
  • <1 year of age:  80-90% 1 year event free survival
  • >1 year of age:  50% 3 year survival
• stage 4
  • <1 year of age: 60-75% 1 year event free survival
  • >1 year of age: 15% 3 year survival

Poor prognostic factors

• N-Myc mutation
• chromosome 1p deletion
• unfavourable Shimada histology index
• later age of onset

Better prognostic factors

• TRK-A expression

Differential diagnosis

For an intra-thoracic neuroblastoma consider:

• intrathoracic lymphoma
• extra lobar pulmonary sequestration
• round pneumonia
• ganglioneuroma
• ganglioneuroblastoma

For an intra-abdominal neuroblastoma consider:

• ganglioneuroma
• ganglioneuroblastoma
• rhabdomyosarcoma
• Wilms tumour

See also

• paediatric mediastinal masses