Neuroblastoma

Neuroblastomas are tumours of neuroblastic origin. Although they may occur anywhere along the sympathetic chain, the vast majority arise from the adrenal gland.

They represent the most common extracranial solid childhood malignancy and are the third commonest childhood tumour after leukaemia and brain malignancies. They account for ~15% of childhood cancer deaths.

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.

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

Clinical presentation

Typically with pain or a palpable mass and abdominal distension, although numerous other presentations may be encountered due to local mass effect.

Other accompanying syndromes include:

• HutchinsonHutchinson syndrome: bone metastases may present with pain or limping and irritability or proptosis with periorbital and cranial bumps ^2,7

• Pepper syndrome: hepatomegaly due to extensive liver metastasis

• blueberry muffin syndrome: multiple cutaneous lesions

• opsomyoclonus ⁵: rapid, involuntary conjugate fast eye movements

• proptosis and periorbital ecchymoses ("raccoon eyes"): orbital metastases

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. The majority of them demonstrate chromosome 1p deletion and N-myc amplification.

Macroscopically, they tend to be large grey-tan coloured 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, 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 disease (two-thirds of cases) is more prevalent than intrathoracic disease. 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%

Radiographic features

Plain radiograph

Appearances are non-specific, typically demonstrating an intrathoracic soft-tissue mass or an intra-abdominal mass displacing adjacent organs. 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.

Bone metastases are usually ill-defined and lucent (i.e. osteolytic), with periosteal reaction or metaphyseal lucency. Sclerotic bone metastases are uncommon ².

Ultrasound

Neuroblastoma on ultrasound demonstrates a heterogeneous mass with internal vascularity. Often there are areas of necrosis that appear as regions of low echogenicity. Calcification may or may not be evident on ultrasound 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 tumour morphology is often 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. The latter 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 intraspinal disease and bone marrow disease ².

• T1: heterogeneous and iso to hypointense

• T2

  • heterogeneous and hyperintense

  • cystic/necrotic areas very high intensity

  • signal voids may be evident

• T1 C+ (Gd): variable and heterogeneous enhancement

Nuclear medicine

Some compounds are used for diagnosis and staging:

• pentetreotide labelled to indium-111 (a somatostatin analogue)

  • not specific for neuroblastic tissue

• MIBG (metaiodobenzylguanidine labelled to iodine-123)

  • 95% of neuroblastomas secrete catecholamines, however, 10-30% of neuroblastomas are negative on MIBG

  • sensitivity: 88%

  • specificity: 99% (for sympathetic tissue) ²

  • does not distinguish between neuroblastoma, ganglioneuroblastoma, ganglioneuroma, carcinoid, and phaeochromocytoma

• FDG PET-CT

Surveillance for metastatic recurrence:

• Tc-99m MDP (technetium 99m-methyl diphosphonate)

  • 36% of primary tumours negative

  • mainly to evaluate bone metastases

  • also able to detect some lung and liver metastases ²

Staging and metastatic disease

For staging refer 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 hypoenhancing masses

• lung and pleura

  • discrete nodules

  • diffuse consolidation

  • pleural disease is uncommon

• brain and meninges

  • dural metastases can be diffuse or nodular

  • brain metastases are uncommon but variable in appearance

Treatment and prognosis

Treatment depends on the patient's 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 of surgery, chemotherapy +/- bone marrow transplantation is employed, unfortunately with poor overall results. In some cases, where tumours are very large, presurgical chemotherapy to attempt to downstage 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 diseases 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

• later age of onset: >18 months

• higher stage: particularly in the presence of metastasis

• N-Myc mutation

• chromosome 1p deletion

• unfavourable Shimada histology index

Better prognostic factors

• TRK-A expression

Differential diagnosis

For intrathoracic neuroblastoma consider:

• intrathoracic lymphoma

• inflammatory myofibroblastic tumours of the lungs

• extralobar pulmonary sequestration

• round pneumonia

• ganglioneuroma

• ganglioneuroblastoma

For intra-abdominal neuroblastoma consider:

• ganglioneuroma

• ganglioneuroblastoma

• rhabdomyosarcoma

• Wilms tumour