Neuroblastoma

Neuroblastoma is an aggressive tumour typically arising from adrenal glands in young children, characterised by small, round, blue cells, and the presence of Homer-Wright pseudorosettes.

Description

Neuroblastoma is a type of cancer that develops from immature nerve cells found in several areas of the body. It most commonly arises in and around the adrenal glands, which have similar origins to nerve cells and sit atop the kidneys. However, neuroblastoma can also develop in nerve tissue along the spine, chest, abdomen or pelvis. It is the most common cancer in infants and makes up a large proportion of all cancers in children. Low-risk and infant neuroblastomas can undergo spontaneous regression without any treatment.

Pathogenesis

Neuroblastoma originates from the neural crest cells, which are primordial cells that contribute to the development of the peripheral nervous system and adrenal medulla. While the exact cause is unknown, it is believed to occur due to genetic mutations, some of which may be inherited. Alterations in the ALK and PHOX2B genes are often associated with neuroblastoma, but additional factors are likely involved in its development.

Epidemiology, Risk Factors and Associations

• Neuroblastoma accounts for about 6% of all types of cancer in children.
• It is most commonly diagnosed in children aged 5 or younger, though it may rarely occur in older children or adults.
• A small number of neuroblastomas are inherited from a parent (familial neuroblastoma), but most cases are not (sporadic neuroblastoma).
• Familial cases are often associated with mutations in the ALK or PHOX2B gene.

Clinical Features

• Symptoms vary depending on the location of the tumour.
• Common signs and symptoms include a lump or swelling in the abdomen (often found during routine physical examination), fatigue, loss of appetite, and fever.
• If the disease is widespread, symptoms might include bone pain, unsteady gait, inability to move certain body parts, and high blood pressure.
• Opsoclonus myoclonus syndrome – a condition causing abnormal eye movements and muscle twitching, can be associated with neuroblastoma.
• Raccoon eyes – periorbital lesions
• Blueberry muffin lesions – skin metastases

Pathological Features

Histopathological

• Solid or multinodular mass, deep red with small cysts and foci of necrosis and calcification
• The tumours are typically composed of small, round, blue cells.
• Presence of Homer-Wright rosettes are a classic (but not exclusive) feature

Biochemical

• Many children with neuroblastoma have elevated levels of catecholamines or their metabolites in the blood or urine, reflecting the origin of this cancer from adrenal cells that produce these hormones.

Radiological Features

CT

• Typically heterogeneous due to necrosis, haemorrhage and calcification. Calcifications are seen in 85-90% of cases.
• The mass often encases vessels and may cause mass effect on adjacent organs.
• It can invade local structures and can extend across the midline, unlike Wilms’ tumour, which is usually confined to one side of the abdomen.
• Metastatic disease can be identified, with common sites being the liver, bone, lymph nodes, and less commonly, lung.
• Prenatally, it is often associated with hydrops. It can also metastasise to the placenta.

MRI

• Dumbell morphology suggests intraspinal extension of the tumour (occurs in 10-20% of cases)
• T1: Tumour is typically iso- to hypointense compared to the liver
• T2: Usually hyperintense.
• T1: Heterogeneous enhancement.

NM

• MIBG scan: MIBG is taken up by neuroblastoma cells.  90% of tumours demonstrate uptake.
• PET scan: Increased FDG uptake.
• Bone scan: Bone scintigraphy can be used to detect osseous metastases, which are common in neuroblastoma. The classic pattern of spread in neuroblastoma is called pepper-salt appearance due to a mix of sclerotic (salt) and lytic (pepper) lesions.

US

• Usually appears as a solid, heterogeneously hypoechoic mass.
• Calcifications, seen in around 20% of cases, may produce acoustic shadowing.
• Internal vascularity may be demonstrated with Doppler interrogation.
• The lesion often displaces adjacent structures.

Grading & Staging

The International Neuroblastoma Staging System (INSS) is a standardised system used to stage neuroblastoma, which takes into account both the extent of the primary tumour and the presence of metastasis, determined through clinical, radiological, and surgical assessments.

INSS Staging for Neuroblastoma

Stage	Description	Surgical Criteria	Lymph Node Involvement
Stage 1	Localised tumour confined to the area of origin.	Complete gross excision, with or without microscopic residual disease.	Negative ipsilateral lymph nodes (nodes immediately adjacent to the primary tumour may be positive).
Stage 2A	Unilateral tumour with incomplete gross excision.	Incomplete gross excision.	Negative ipsilateral lymph nodes (nodes immediately adjacent to the primary tumour may be positive).
Stage 2B	Unilateral tumour with or without complete gross excision.	Complete or incomplete gross excision.	Positive ipsilateral non-adherent lymph nodes; negative contralateral lymph nodes.
Stage 3	Unilateral tumour with or without complete gross excision.	–	Positive or negative ipsilateral and contralateral lymph nodes.
Stage 4	Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs (except as defined for stage 4S).	–	–
Stage 4S (Special Neuroblastoma) Applies only to infants younger than 1 year old.	Localised primary tumour (as defined for stage 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow.	–	–

Key Points

• Localised Disease (Stages 1, 2A, 2B): Generally associated with a better prognosis and are often amenable to surgical resection with or without adjunct therapy.
• Midline Involvement (Stage 3): Tumour crosses the midline, indicative of more extensive disease and often requiring multimodal therapy.
• Metastatic Disease (Stage 4): Indicates advanced disease with distant metastasis, necessitating comprehensive treatment approaches including chemotherapy, radiation, surgery, and possibly stem cell transplant.
• Special Case (Stage 4S): Unique to infants, characterised by specific patterns of metastasis and a better prognosis compared to other stage 4 neuroblastomas.

Differential Diagnosis

Neuroblastoma must be differentiated from other conditions that present similarly in paediatric patients, particularly those that form in the adrenal gland or along the sympathetic chain. Key differentials include:

• Wilms Tumour: Typically presents as a large, asymptomatic abdominal mass in older children (average age 3-4 years). Unlike neuroblastoma, it is of renal origin, and does not cause the symptoms associated with catecholamine release.
• Ganglioneuroma: A benign neoplasm composed primarily of mature ganglion cells and neurites. It is often silent until it becomes large and compresses surrounding structures.
• Pheochromocytoma: Although rare in children, it can present with hypertension due to catecholamine secretion, similar to neuroblastoma. However, pheochromocytoma predominantly affects adults.
• Rhabdomyosarcoma: A malignant tumour of striated muscle, it is the most common soft tissue sarcoma in children. However, it typically affects the head, neck, and genitourinary system.
• Ewing’s Sarcoma/Primitive Neuroectodermal Tumour (PNET): A small, round blue cell tumour, typically affecting the long bones and pelvis in older children and adolescents.

Management

Neuroblastoma management involves a multi-disciplinary team, and treatment is guided by the stage and risk group of the disease. Referral to a paediatric oncologist is crucial for coordinating care.

• Low-risk and infant neuroblastomas often undergo spontaneous regression without any treatment.
• Surgery is otherwise usually the first step to remove as much of the tumour as possible.
• Chemotherapy is typically used to shrink any remaining tumour or to treat neuroblastoma that has spread to other parts of the body.
• Radiation therapy may be used for tumours that are not fully removed by surgery, or for neuroblastoma that has spread.
• High-dose chemotherapy and stem cell transplant may be used in cases of high-risk neuroblastoma.
• Retinoic acid is often given after high-dose chemotherapy and stem cell transplant to help differentiate any remaining neuroblastoma cells.
• Immunotherapy is a newer type of treatment that helps the body’s immune system fight the cancer.