Retinoblastoma

This is the most common 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 Over the past four decades, the management of this disease has evolved tremendously, changing the outlook from a deadly childhood cancer to a largely curable disease.³

• Occurs in about 1:20,000 live births.¹
• The cumulative incidence at 11 years old is 0.44 per million births in the UK.⁴
• Although it is essentially a disease of childhood, there have been a few cases of retinoblastoma in early adulthood reported in the literature.⁵ 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 is caused by a loss of function of the Rb tumour suppressor gene (Ch13q14).⁶

• Sporadic cases (~90%) - 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 (~10%) - there needs to be a homozygous gene defect in the retinoblastoma gene for the disease to occur.⁷ 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 two years of life. Bilateral tumours tend to present earlier (usually around 12 months, rarely after three years) and unilateral tumours a little later (around 16 months but rarely beyond six years).
• There is a positive family history in 8-12% of cases.
• The most common presentation, occurring in 55% of patients, is with leukocoria (white pupillary reflex), followed by strabismus (25% of patients).⁴
• Other modes of presentation may include unexplained ocular inflammation, spontaneous hyphaema, secondary glaucoma, pseudohypopyon (an apparent fluid level of pus in the anterior chamber), buphthalmos (big eye), orbital or metastatic spread. Extraocular, fungating tumours associated with extraocular extension are rare in developed countries.⁴

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 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 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), e.g. Norrie's disease, Patau's syndrome, Edwards' syndrome, etc.
• Incontinentia pigmenti (Bloch-Sulzberger disease)⁸ - 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.
• Retinocytoma - a benign variant of retinoblastoma.
• Retinal astrocytoma - see separate article Retinal Tumours.

Clinical examination is virtually diagnostic (infants typically require an examination under general anaesthesia)⁴ but further evaluation of the tumour is carried out with ultrasonography (assesses size and detects calcification), CT scan (assesses optic nerve or CNS involvement) and MRI scan (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. Immunohistopathology and DNA testing of blood or tumour cells helps determine germline mutations⁴ and can aid in genetic counselling.⁵

Further investigation will aim to determine the presence and extent of any tumour spread. This could include more extensive distal imaging of distal sites, blood testing (liver and renal function), lumbar puncture and bone marrow aspiration/biopsy.

The Reese-Ellsworth classification of retinoblastoma is based on the size, number and location of tumour lesions within the eye as well as the presence or otherwise of any vitreous seeding. Tumours are categorised from Group I (associated with the best outcome) to Group V (with the worst prognosis). Treatment is guided by this classification system³ which is still being developed and refined.

Inherited retinoblastoma is associated with an increased risk of non-ocular cancers, particularly pinealoblastoma (= a trilateral tumour),¹ Ewing's sarcoma, olfactory neuroblastoma and osteosarcoma.⁹

• 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 (typically - a 3-drug chemoreduction³ 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.
• 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. Irradiation of the affected orbit may be required depending on the degree of spread. 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.

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.³

Regular follow-up of the affected child is required. This is at the specialist centre until seven years of age and then yearly by the local ophthalmology team thereafter. Their own children will need to be screened regularly until at least four years old.¹⁰ 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.⁴

There is a risk of complications in all treatment modalities but noted ocular complications of radiotherapy include:⁶

• Cataract formation
• Orbital growth abnormalities
• Radiation retinopathy
• Secondary malignancies

Untreated, the tumours invade locally and then metastasise, causing death within two years.⁶ 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 (e.g. sarcomas, breast, bladder, brain and lung). This risk is increased with radiation exposure.⁶ The cumulative incidence of such tumours is approximately 1% a year⁴ and they may occur as late as 20 years on from original presentation.²

1. Kanski J. Clinical Ophthalmology: A Systematic Approach (5th Ed) Butterworth Heinemann (2003).
2. Willshaw H, Scotcher S, Beatty S: A Handbook of Paediatric Ophthalmology, 2000. HEWillshaw.
3. Lin P, O'Brien JM; Frontiers in the management of retinoblastoma. Am J Ophthalmol. 2009 Aug;148(2):192-8. Epub 2009 May 24. [abstract]
4. Jackson TL. Moorfields Manual of Ophthalmology, Mosby (2008).
5. Isidoro MA, Roque MR; Retinoblastoma. eMedicine (January 2009).
6. Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology, OUP (2008).
7. OMIM; Retinoblastoma (RB1). Online Mendelian Inheritance in Man. Last updated February 2009.
8. OMIM; Familial incontinentia pigmenti (IP). Online Mendelian inheritance in Man. Last updated August 2008.
9. Cope JU, Tsokos M, Miller RW; Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms. Med Pediatr Oncol 2001;36(2): 290-4. [abstract]
10. Moll AC, Imhofa SM, Schouten-Van Meeterenb AYN et al; At what age could screening for familial retinoblastoma be stopped? A register based study 1945-98. Br J Ophthalmol 2000;84:1170-1172.

• Childhood Eye Cancer Trust; Patient and family information about retinoblastoma.
• Contact a Family; Retinblastoma page.
• Maki JL, Marr BP, Abramson DH; Diagnosis of retinoblastoma: how good are referring physicians? Ophthalmic Genet. 2009 Dec;30(4):199-205. [abstract]