Epidemiology

• Occurs in about 1:20,000 live births.^[1]
• Between 40-50 cases are diagnosed each year in the UK.
• Although it is essentially a disease of childhood, there have been a few cases of retinoblastoma in early adulthood reported in the literature.^[2] A retrospective review of these suggests that these may actually be lesions arising from pre-existing retinocytomas.
• There is no gender or race predisposition.

Genetics of retinoblastoma

Retinoblastoma may be sporadic or inherited. The retinoblastoma (Rb) gene (RB1 gene) is found on chromosome 13 and there are two copies of it.

How does retinoblastoma develop?
In the first few years of life the retina grows very quickly. At this fast pace, mutations are more likely to occur as our genes are copied. As a result of these mutations a retinoblastoma can occur. This can happen in either of two different ways:

One possibility is that a child inherits one altered copy of the Rb1 gene from a parent. If the normal copy of the gene does not become mutated in a retinal cell, no retinoblastoma will develop. If a mutation occurs to the normal copy, a retinoblastoma can develop. This is the heritable form of Rb. About 90% of people who inherit a mutated Rb1 gene from a parent will develop Rb. Most will have bilateral disease, a few will have multifocal disease (more than one tumour in an eye), and a few will have unilateral disease (one eye affected) with only one tumour. About 10% will not develop a tumour at all. In heritable Rb all the cells in the body, including the blood cells, will contain the altered copy.

Another possibility is the child inherits one normal copy of the Rb gene from each parent and copying mistakes then affect both copies of the gene in one cell of the retina. Again, as a result of these alterations a retinoblastoma can develop. In these circumstances the child will develop the non-heritable type of Rb, and there will be one tumour in one eye.

Presentation^[3]

There are several signs (below) which could indicate retinoblastoma but it is important to remember that a child with retinoblastoma may appear systemically well. The initial signs are confined to the eye.  If any child presents with one of the following, a red reflex test must be performed with a direct ophthalmoscope.  All suspected cases or cases where retinoblastoma cannot be ruled out by the test must be referred urgently to a local ophthalmology department.

How to do a red reflex test (provided by CHECT UK):

• Leukocoria - (intermittent) white pupillary reflex noticed in dim lighting or a photo.
• Strabismus - squint (retinoblastoma must be ruled for all cases of squint in babies and children, using a red reflex test).
• A change in the colour of the iris or part of the iris.
• Inflammation, redness or increased pressure in or around the eye without an infection.
• An absence of red reflex when doing a red reflex test.
• Deterioration of vision in one or both eyes or poor vision from birth.
• Wandering eyes (nystagmus).
• Parental history of retinoblastoma - the condition is heritable so children of an affected parent with retinoblastoma must be screened from birth.
• Parental concern over vision or eye appearance.

Main differential diagnoses^[1][2]

There is a long list of differential diagnoses. This includes:

• Diseases presenting with leukocoria (such as congenital cataract)
• Diseases presenting as an endophytic tumour (such as retinal hamartomas)
• Diseases presenting with an exophytic tumour (such as choroiditis)

Below is a list of some of the more commonly considered differentials:

• Persistent hyperplastic primary vitreous - in utero, the globe is initially filled with a network of vascularised processes (the primary vitreous) which is then pushed out of the way by a gel (the definitive vitreous) produced by retinal cells.
• Coats' disease - a unilateral formation of telangiectatic retinal blood vessels that is associated with a yellow exudate and retinal detachment.
• Retinopathy of prematurity - if this is advanced, there may be retinal detachment resulting in leukocoria.
• Toxocariasis - this may be associated with endophthalmitis which gives rise to membrane formation resulting in a white pupil.
• Retinal dysplasia - this may be an isolated finding (unilateral cases) or associated with systemic disease (bilateral cases) - eg, Norrie's disease, Patau's syndrome, Edwards' syndrome, etc.
• Incontinentia pigmenti (Bloch-Sulzberger disease)^[4] - this X-linked dominant disease affects girls and is characterised by vesiculobullous dermatitis ± malformations of the teeth, bones and central nervous system (CNS). They may also develop a retinal detachment, giving rise to a white pupillary reflex.
• Retinoma - a benign variant of retinoblastoma.
• Retinal astrocytoma - see separate article Retinal Tumours.

Investigations

If an infant or child presents with a sign or indication of retinoblastoma a red reflex test must be performed.

When retinoblastoma is suspected or if the test shows anything unusual, urgent referral needs to be made to a local ophthalmology department, stating the cause for concern.  If the local ophthalmology department identifies or suspects retinoblastoma an urgent referral is made to one of two retinoblastoma hospitals in the UK - Birmingham Children’s Hospital or the Royal London Hospital - for diagnosis and treatment.

The speed of referral is vitally important, as a swift referral can reduce the long-term impact of the disease and treatment on the baby or child.

Staging

The International Classification for Intraocular Retinoblastoma (ICIRB) is used.^[5] This was introduced in 2003 and has assisted communication between departments and prediction of clinical outcomes for diuffering treatment modalities. 

Associated diseases

Heritable retinoblastoma is associated with an increased risk of non-ocular cancers, particularly pinealoblastoma (= a trilateral tumour),^[1] Ewing's sarcoma, olfactory neuroblastoma and osteosarcoma.^[6]

Management^[1]

Further referral to specialist centres can than be made by the ophthalmology team. These centres are the Royal London Hospital and Birmingham Children's Hospital in the UK. The exact treatment will be customised to each child.

The treatment of retinoblastoma depends on the size and location of tumour(s), laterality of disease, whether the disease is heritable, risk for metastasis or second tumour, systemic status and the age of the patient. The sorts of approaches that might be used include:

• Small tumours - transpupillary thermotherapy or cryotherapy.
• Medium-sized tumours - cryotherapy where there is no seeding. Chemotherapy (typically - a 3-drug chemo-reduction^[7] using various combinations of carboplatin, vincristine and etoposide ± ciclosporin) is given in 3-week cycles over a 4- to 9-month period where there is seeding. Transpupillary therapy and plaque radiotherapy have been used for local treatment also.
• Large tumours - chemotherapy is used to shrink the tumour in the first instance, to try to facilitate cryotherapy or thermotherapy. However, if this fails or if there is a normal fellow eye that would suffer from treatment to the affected eye, enucleation is used (removal of the globe).
• Extraocular extension - enucleation followed by chemotherapy. Exenteration is radical surgery which involves removal of the orbital content as well as surrounding tissues. This is rarely performed in developed nations.
• Metastatic disease - high-dose chemotherapy.
• Intrarterial melphalan is used to treat relapses in the UK.

Work is being done to improve drug delivery systems to minimise the harmful side-effects of chemotherapy. There is also a lot of research into molecular targeting therapy which is emerging as a potential strategy to individualise therapy but this is still in a developmental stage.^[7]

Regular follow-up of the affected child is required. The age limits for follow-up will depend on the case and the specialist centre, as practice varies. Other children in the family may need to be screened regularly until they are between 3.5 and 5 years old.^[8] The need for screening will depend on what type of retinoblastoma the family member had and also the family member's genetic status, if known. Families will also benefit from genetic counselling. It is worth noting that siblings of an affected child with a negative family history have a small risk of disease, as some (<5%) carrier parents are unaffected due to germline mosaicism.^[9]

Prognosis

Untreated, the tumours invade locally and then metastasise, causing death within two years.^[10] Very occasionally, the tumour may spontaneously stop growing. However, in developed nations, the overall mortality is 2-5% and depends on the size and location of the tumour, the degree of spread and the degree of cellular differentiation (highly undifferentiated tumours carry a poor prognosis).^[1] Older age of the child, CNS spread along the optic nerve, spread to the orbit or distant metastases as well as a trilateral tumour are all associated with early death.

Later death usually occurs in the context of second tumours (eg, sarcomas, breast, bladder, brain and lung). This risk is increased with radiation exposure.^[10] The cumulative incidence of such tumours is approximately 1% a year^[9] and they may occur as late as 20 years on from original presentation.^[3]