Brain Tumours in Children

Brain tumours in children are the commonest solid tumour of childhood in the US and England. Brain tumours have a better outcome compared with brain tumours in adults as children do not develop glioblastomas and metastases to the brain.

Despite this there is still a high morbidity and mortality due to late diagnosis, lack of clinical trials regarding best treatment and damage of normal brain tissue with current treatment regimens.

• Brain tumours affect 2.4 per 100,000 children in the USA. These figures are similar to those of acute lymphoblastic leukaemia.¹
  
  
• In the United Kingdom brain tumours occur in children between the ages of 0 - 9 affecting approximately 5 per 100,000 population.²
  
  
• Age does not appear to predict the tumour type although some types are more frequent at certain ages.

• The underlying cause of brain tumours is unknown. However, some tumours are more common with certain illnesses e.g. astrocytomas are seen with increased frequency in neurofibromatosis and haemangioblastomas are more prevalent in patients with von Hippel-Lindau syndrome. This suggests a genetic link and mutations in several genes including RB1 (retinoblastoma gene), NF1 (neurofibromatosis gene), NF2 and TSC1 (tuberous sclerosis gene) - which function as tumour suppressor genes have been proposed.³ However, most cases of brain tumours are sporadic.
• Previous cranial irradiation also increases the risk of brain tumours e.g. meningeal leukaemia.⁴ A Canadian study looked at the correlation between early infections and brain tumours in 272 children and found an increased proportion of this group had a positive history of infections e.g. use of antibiotics during gestation, removal of tonsils or adenoids.⁵ However, further observational based studies are required to draw any firm conclusions from this data.

Types of brain tumours

Localisation and frequency of childhood brain tumours¹

These can be divided in to generalised and localised symptoms.

Generalised symptoms

• Headaches - usually recurrent, frequent and gradually worsening⁶
• Headaches may be worse on waking indicating raised intracranial pressure
• Headaches are more common with infratentorial lesions
• Nausea and vomiting

Localised symptoms

• Seizures - the type depends on location e.g. frontal lobe seizures are associated with focal motor seizures.
• Focal neurological deficits - e.g. frontal lobe tumours are associated with personality change and occipital lobe tumours are associated with visual deficits.

Children under the age of 2 years have non-specific presentation with vomiting, lethargy, failure to thrive and irritability. They may develop macrocephaly, hyperreflexia and cranial nerve palsies.¹

Symptoms relating to type or location of brain tumour¹

• Chiasmal tumours - visual field defects and hydrocephalus
• Craniopharyngiomas - short stature, visual field defects, hormonal abnormalities and hydrocephalus
• Pineal tumours - impaired upgaze, impaired accommodation and hydrocephalus
• Infratentorial tumours

These include astrocytomas that tend to occur in the cerebellum or brain stem or medulloblastomas and ependyomas which are located in the fourth ventricle. Astrocytomas tend to be slow growing in comparison to medulloblastomas which grow rapidly (in about 3 months).

The presentation of infratentorial tumours relates to blockage of the CSF flow leading to hydrocephalus. Common signs and symptoms are:¹

• Morning headache
• Vomiting (may be the sole symptom of an ependyoma)
• Ataxic gait with unsteadiness
• Double vision
• Papilloedema
• Additionally brain stem tumours may present with facial or ocular muscle palsies and hemiparesis

• MRI is the preferred modality of imaging as it provides better images and there is no radiation involved. However, compared to CT scanning it takes longer and the child may need sedating as they are required to remain still for the entire procedure. Usually contrast is also given to detect areas of damage to the blood brain barrier and highlight the extent of oedema around the tumour.
• MRI will provide detailed information regarding the tumour size, location, extent, surrounding oedema and presence of hydrocephalus.
• Interestingly, CSF analysis can reveal increased levels of HCG and alpha fetoprotein in pineal tumours and raised serial polyamines in recurrence of medulloblastoma before radiological detectable recurrence.¹ However, practically CSF has little to add in the diagnosis of childhood brain tumours.

Staging plays a small role in brain tumours except medulloblastomas. The reason for this is that brain tumours in children rarely spread to lymph nodes and have a tendency not to metastasise.

Management involves three aspects:

• Surgical resection of the tumour
• Radiotherapy
• Chemotherapy

There are very few randomised controlled trials looking at the effectiveness of these various treatment modalities.

Surgical resection

• Surgical resection is very important and recent data suggest that complete total resection, especially of gliomas, should always be the aim and is associated with improved survival in children.⁷
• However, complete resection of the tumour is very rarely achievable as the margins of most tumours are indistinct. This means that during surgical resection it becomes difficult to determine whether abnormal or normal tissue is being resected. Resection also allows for a biopsy to be taken which in some types of brain tumour alters therapy.¹
• Biopsy may be performed beforehand and usually direct open biopsy is preferred at the time of surgery although, for basal ganglia and brain stem lesions stereotactic biopsies are taken. Preoperatively children may be given phenytoin to prevent seizures and corticosteroids to reduce brain oedema.
• Hydrocephalus is common postoperatively and therefore at the time of surgery an external ventricular drain or ventriculoperitoneal shunt is inserted which will be removed a few days later once the CSF clears.
• Very young children i.e. under the age of 2 years, require radical resection as radiotherapy is delayed until they are older as it will damage local normal tissue which is still developing. This is usually followed by chemotherapy.

Radiotherapy

• This is provided in low doses and to very localised areas to avoid damage to surrounding normal brain tissue. There are various techniques that can be employed e.g. gamma knife (used for slow growing lesions) and interstitial seeds which are implanted during surgery.¹

Chemotherapy

• There are various chemotherapy regimens in use and they usually involve vincristine. In the rare primary CNS lymphoma chemotherapy alone has been used with good outcomes.⁸
• In low grade gliomas if residual disease remains after excision then chemotherapy has been used. Newer chemotherapeutic regimens are being used including vincristine, etoposide, cyclophosphamide and 5-fluorouracil.⁹

Children have MRI scans every 6 months for the first two years and then annually (although this varies according to the centre and may become less frequent after the first few years).¹

• Intellectual decline - a recent study of 120 young patients with primary brain tumours showed a decline in sustained attention span and reaction times. This appeared to be caused by multiple factors including local tumour effects, surgery and radiotherapy.^10,1 More recently guidance on detecting and monitoring cognitive decline have been proposed.¹¹
• Growth hormone deficiency is common (thyroid hormone deficiency is less common).
• Neurological handicap may occur and be permanent.
• Increased risk of a second brain tumour 10 - 20 years down the line due to irradiation (e.g. develop meningioma or sarcoma) - risk is increased if the brain is irradiated at a very young age.^12,13
• Reduced bone mineral density of multifactorial origin.¹⁴
• Cavernomas presenting as haemorrhagic lesions are increasingly being associated with CNS irradiation.¹⁵

Resection of the tumour may resolve seizures and headaches. The surgical mortality is 1% for a paediatric craniotomy. The morbidity is higher and depends on the childs condition preoperatively. Figures such as, 5-10% for gliomas and 20-30% for basal ganglia gliomas have been reported.¹

In the United Kingdom childhood cancers are the main cause of death after accidents, and brain tumours account for 30% of these deaths.¹⁶ It is stated that more than 100 children die per year as a result of brain tumours.¹⁶

A recent meta analysis suggests that prenatal supplementation with multivitamins, including folic acid, is associated with a reduced incidence of brain tumours and leukaemia. However, this evidence still needs further validation.¹⁷