Retinoblastoma

This is the commonest malignant tumour of the eye in children and accounts for 3% of all childhood cancers.¹ It is a tumour derived from the retinal precursor cells² and because these cells disappear within the first few years of life, the tumour rarely develops beyond early childhood.¹

• Occurs in about 1:20,000 live births.¹
• In children less than a year old, the UK incidence is 23.6 cases per million, dropping to 8.2 cases per million in the one to four year old age group and 0.6 cases per million between five and nine years old.³
• Higher incidence in some racial groups (highest in Navajo Indians).²

Genetics of retinoblastoma³

• Sporadic cases (~60%) - these account for the majority of cases and are caused by somatic mutations in a single retinal cell. In these patients, the tumour is unilateral.
• Hereditary cases (~40%) - there needs to be a homozygous gene defect in the retinoblastoma gene for the disease to occur.⁴ If an individual inherits one allele error and the other occurs through spontaneous somatic mutation, the homozygous state is achieved ('double hit' event). This is highly probable as the mutation rate for the gene is about 1:10,000,000 and there are 100,000,000 divisions needed to form the adult retina. Therefore it occurs frequently in affected families, even though it may skip a generation. These patients tend to have bilateral, multifocal tumours.

• Most present within the first 2 years of life. Bilateral tumours tend to present earlier (usually around 12 months, rarely after 3 years) and unilateral tumours a little later (around 16 months but rarely beyond 6 years).
• There is a positive family history in 8-12% of cases.
• The commonest presentation is with leukocoria (white pupillary reflex), followed by strabismus.
• Other modes of presentation may include unexplained ocular inflammation, secondary glaucoma, pseudohypopyon (an apparent fluid level of pus in the anterior chamber), buphthalmos (big eye), orbital or metastatic spread.

• Persistent hyperplastic primary vitreous - in utero, the globe is initially filled with a network of cytoplasmic 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 telangiectic 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) e.g. Norrie disease, Patau syndrome, Edward syndrome etc.
• Incontinentia pigmenti (Bloch-Sulzberger syndrome)⁵ - this X-linked dominant disease affects girls and is characterised by vesiculobullous dermatitis ± malformations of the teeth, bones and central nervous system. They may also develop a retinal detachment giving rise to a white pupillary reflex.
• Retinocytoma - a benign variant of retinoblastoma.
• Retinal astrocytoma - see retinal tumours.

Clinical examination is virtually diagnostic but further evaluation of the tumour is carried out with ultrasonography (assesses size and detects calcification), CT (assesses optic nerve or CNS involvement) and MRI (better image than CT and can differentiate from other mimicking conditions). Where the tumour is not confined to the globe, further investigations may be performed e.g. lumbar puncture or bone marrow aspiration.

Inherited retinoblastoma is associated with an increased risk of non-ocular cancers,³ particularly pinealoblastoma (= a trilateral tumour),¹ Ewing sarcoma, olfactory neuroblastoma and osteosarcoma.⁶

The treatment of retinoblastoma depends on the size and location of tumour(s), laterality of disease, whether the disease is hereditary, risk for metastasis or second tumour, systemic status and the age of the patient.

• Small tumours - transpupillary thermotherapy or cryotherapy.
• Medium-sized tumours - brachytherapy for tumours that are too big for thermotherapy or cryotherapy but where there is no seeding. Chemotherapy (with carboplatin, vincristine and etoposide ± cyclosporin) given in 3 week cycles over a 4 to 9 month period where there is seeding.
• Large tumours - chemotherapy is used to shrink the tumour in the first instance, to try and 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.
• Extraocular extension - enucleation followed by chemotherapy. Irradiation of the affected orbit may be required depending on the degree of spread.
• Metastatic disease - high dose chemotherapy.

Regular follow-up of the affected child is required. Their own children will need to be screened regularly until at least four years old.⁷ Families will also benefit from genetic counselling.

The overall mortality is 2 to 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 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 (e.g. sarcomas, breast, bladder, brain and lung) and may occur as late as 20 years on from original presentation.²