Retinoblastoma

What is retinoblastoma?

Retinoblastoma (Rb) is an embryonal tumour of the retina and is the most common malignancy of the eye in children. Onset generally occurs between the third month of pregnancy and 5 years of age.¹

Around 40% of retinoblastoma cases are caused by a hereditary mutation on chromosome 13, called the retinoblastoma 1 (Rb1) gene. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of Rb1.

How common is retinoblastoma? (Epidemiology)^{1 2}

• The incidence of retinoblastoma is constant worldwide at 1 in every 16,000 live births.³

• There is no ethnic variation in incidence.⁴

• About 40% of cases are diagnosed in the first year of life. Incidence rates drop to a very low rate after 5 years of age.

• About 60% of all cases are unilateral.

• Around 40% of all cases are heritable.

• Around 4% of patients with the heritable type also have malignant midline neuroectodermal tumours, usually pinealoblastoma. This is called trilateral retinoblastoma.⁵

Genetics of retinoblastoma^{6 7 8}

• Mutations in both alleles of the Rb1 gene are needed for retinoblastoma to develop.

• Hereditary retinoblastoma is caused by a heterozygous germline mutation on one allele AND a somatic mutation on the other allele of the Rb1 gene on chromosome 13q14.

• The expression of the mutation is variable.

• Patients who carry the heritable mutation have a 90% chance of developing retinoblastoma and a 50% chance of passing the gene to their children

• 10% of patients who carry the heritable mutation do not develop retinoblastoma.

• The germline mutation may be inherited from an affected parent (25% of cases) or may have occurred de novo in a parental germ cell or in utero (75% of cases).

• The term 'germline mutation' means that the genetic abnormality is present in all cells of the body, whereas 'non-germline (somatic) mutations' mean that only the tissue of concern harbours the mutation (ie the individual has genetic mosaicism):

  • Bilateral and familial retinoblastomas have germline mutations and are heritable.

  • Unilateral sporadic retinoblastoma is usually not heritable, because in most patients with sporadic unilateral retinoblastoma, both of the necessary gene mutations occur in somatic cells of one eye only and are therefore not passed to offspring.

Heritable retinoblastoma

• Heritable Rb is inherited as an autosomal dominant susceptibility for Rb. Average age at diagnosis is 12 months.

• Patients with bilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.

• The risk of other cancers, particularly sarcoma, in these patients is increased.

Non-heritable retinoblastoma

• About 60% of patients with Rb have the non-heritable form of the disease with normal life expectancy if the eye cancer is cured.

• In this type, the average age at diagnosis is about 24 months and the eye tumour is unilateral.

• The risk of other cancers in these patients is not increased.

Retinoblastoma symptoms (presentation)^{1 9}

Most children are diagnosed before the age of 5 years:

• In the UK, bilateral cases usually present within the first year with the average age at diagnosis being 9 months.

• Diagnosis of unilateral cases peaks between 24 and 30 months.

• Patients with heritable disease present at a younger age, usually by 12 months.

The most common first signs of retinoblastoma are leukocoria, a white reflex visible through the pupil, and strabismus.

A later sign is proptosis, where the tumour causes the eye to bulge from the orbit. Retinoblastoma can affect one or both eyes, and sometimes also the pineal, parasellar or suprasellar regions (trilateral retinoblastoma).

Other less common and less specific signs and symptoms are deterioration of vision, a red and irritated eye, faltering growth or delayed development.

Advanced intraocular tumours present with pain, glaucoma, or buphthalmos. As the tumour progresses, patients may present with orbital or metastatic disease. Metastases occur most commonly in the CNS, bones, bone marrow and liver.

If any child presents with one of the following, a red reflex test (bulleted text provided by the Childhood Eye Cancer Trust¹⁰ ) must be performed with a direct ophthalmoscope:

• Leukocoria - (intermittent) white pupillary reflex noticed in dim lighting or a photo.

• Strabismus - squint (Rb must be ruled out for all cases of squint in babies and children, using a red reflex test).

• An apparent 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 on testing.

• Deterioration of vision in one or both eyes (or poor vision from birth).

• Nystagmus.

• Parental history of Rb - children of an affected parent who has Rb should be screened from birth.

• Parental concern over vision or eye appearance.

• A white eye reflection is not always a positive indication and can be caused by light being reflected badly or by other conditions such as Coats' disease (see 'Differential diagnosis', below).

• Asymmetrical red eye in photographs may also be a sign of Rb.

• Rb presents with advanced disease in developing countries and eye enlargement is a common finding. Depending on the position of the tumours, they may be visible during a simple eye examination, using an ophthalmoscope to look through the pupil.

Differential diagnoses

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.¹²

• 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) - this X-linked dominant disease affects girls and is characterised by vesiculobullous dermatitis ± malformations of the teeth, bones and CNS.¹³ They may also develop a retinal detachment, giving rise to a white pupillary reflex.

• Retinal astrocytoma - see separate Retinal Tumours article.

Referral¹⁴

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

• In a child with a white pupillary reflex (leukocoria) noted by the parents, identified in photographs or found on examination, an urgent referral should be made. The primary healthcare professional should pay careful attention to the report by a parent of noticing an odd appearance in their child's eye.

• A child with a new squint or change in visual acuity should be referred. If cancer is suspected, referral should be urgent; otherwise (ie if normal fundi have been clearly visualised), referral can be non-urgent.

• A family history of retinoblastoma should alert to the possibility of retinoblastoma in a child presenting with visual problems.

• Offspring of a parent who has had retinoblastoma, or siblings of an affected child, should undergo screening soon after birth.

• 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.

• Speed of referral is vitally important, as early diagnosis and intervention are critical to successful treatment.

• Genetic testing identifies children with heritable retinoblastoma. These children have a genetic predisposition for second malignancies - eg, osteosarcoma.¹⁵

Diagnosis and evaluation³

Clinical diagnosis of retinoblastoma is based on the clinical features of the tumours visible in the eye with dilation of the pupil.

Calcification is often visible to the naked eye with fundoscopy, and can also be detected by ultrasound or MRI.

Biopsy of retinoblastoma is not recommended, as it can induce seeding and extraocular spread along the needle tract.

Evaluation for the presence of metastatic disease also needs to be considered in patients with extraocular extension suspected by imaging, or with high-risk pathology in the enucleated eye (ie massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). Patients presenting with these features in the enucleated eye are at high risk of developing metastases. Bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture are therefore performed.

Genetic counseling is recommended for all patients with retinoblastoma. Blood and tumour samples can be tested for mutation in the Rb1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. Genetic counselling is not always straightforward, as around 10% of children with retinoblastoma have somatic genetic mosaicism.

Staging¹⁶

The International Classification for Intraocular Retinoblastoma is often used. It divides intraocular Rbs into five groups based on the chances that the eye can be saved using current treatment options:¹⁷

• Group A: 3 mm or less in basal diameter or thickness.

• Group B: more than 3 mm in basal diameter or thickness, or tumour location 3 mm or less from foveola, 1.5 mm or less from optic disc, tumour-associated subretinal fluid 3 mm or less from tumour margin.

• Group C: subretinal seeds 3 mm or less from tumour, vitreous seeds 3 mm or less from tumour, subretinal and vitreous seeds 3 mm or less from tumour.

• Group D: subretinal seeds more than 3 mm from tumour, vitreous seeds more than 3 mm from tumour, subretinal and vitreous seeds more than 3 mm from tumour.

• Group E: occupying more than 50% of the globe, or neovascular glaucoma, opaque media from haemorrhage in subretinal space, vitreous or anterior chamber invasion of postlaminar optic nerve, choroid (more than 2 mm), sclera, orbit, anterior chamber.

Trilateral Rb typically develops between the ages of 20 and 36 months and has a poor prognosis, accounting for around half of mortality in the first ten years after diagnosis.^{5 18}

Associated diseases

• Hereditary retinoblastoma is associated with an increased risk of non-ocular cancers, particularly Ewing's sarcoma, olfactory neuroblastoma and osteosarcoma.¹⁹

• There is a significant increased risk of soft tissue and bone sarcomas which persists for decades after the retinoblastoma diagnosis.²⁰

Retinoblastoma treatment and management²¹

If retinoblastoma is suspected, urgent local ophthalmology referral is needed. Further referral to specialist centres is made by the ophthalmology team. In the UK, these centres are the Royal London Hospital and Birmingham Children's Hospital.

Treatment depends upon laterality and the extent of tumour. Management aims at minimising systemic exposure to drugs, optimising ocular drug delivery and preserving useful vision. Current treatment modalities include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, intracameral chemotherapy, consolidation therapies (cryotherapy and transpupillary thermotherapy), radiation-based therapies (external beam radiotherapy and plaque radiotherapy), and enucleation.¹⁶

Follow-up

• Regular follow-up is required. The age limits for follow-up depend on the case and the specialist centre.

• Other children in the family may need to be screened regularly until they are between 3.5 and 5 years old. Siblings of an affected child with a negative family history have a small risk of disease, as some carrier parents are unaffected due to germline mosaicism.

• Screening with MRI is recommended every six months for five years for those suspected of having heritable disease.

• Children known to have an Rb1 germline pathogenic variant should have:

  • Eye examination every three to four weeks until the age of 6 months, then less frequently until the age of 3 years.

  • Clinical examinations every three to six months until the age of 7 years and eventually biennially for life.

• Children who have unilateral disease without an identified heterozygous germline Rb1 pathogenic variant could have undiagnosed low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound.

• Individuals with retinomas are followed with retinal examinations and imaging every one to two years.

• Physicians and parents should be vigilant for sarcoma and should promptly evaluate complaints of bone pain or lumps; effective screening protocols have not yet been developed.

• Approximately 5-10% of children with heritable Rb develop pineal gland cysts detected by MRI; these cyst abnormalities must be distinguished from the pineoblastoma that typically defines trilateral Rb.

Prognosis¹

Early outcomes

Invasion of the optic nerve is the most significant prognostic factor. Delayed treatment increases the risk of optic nerve invasion.²²

• In high-income countries, retinoblastoma is considered a curable cancer with a near 100% disease-free survival rate. However, the prognosis in low-and-middle-income countries (where more than 80% of global cases occur) is often poor.¹⁶

• Extraocular retinoblastoma is very rare in developed countries (reported incidence is approximately 2-5%).

• In developing nations, extraocular disease contributes to half of all retinoblastoma cases presenting to a tertiary care referral centre. A combination of poverty, illiteracy, alternative systems of medicine and lack of access to healthcare resources accounts for this high rate of advanced disease.

• Retinoblastoma can spread or metastasise from the eye to the brain, the CNS (brain and spinal cord) and the bones.

• Intracranial dissemination occurs by direct extension through the optic nerve and is very rare in the UK. The prognosis is then very poor.

• Haematogenous metastases may develop in the bones, bone marrow and less frequently, in the liver. It is very rare in the UK. Although long-term survivors have been reported with conventional chemotherapy, these reports are anecdotal.

• While most patients with orbital disease and a large proportion of patients with systemic extra-CNS metastases can be cured, the prognosis for patients with intracranial disease is dismal.

Late outcomes^{23 24}

• Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies.

• There is an excess risk of mortality in hereditary retinoblastoma survivors. Fifty years after diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. This implies that lifelong follow-up is needed and patients and their physicians must be alerted to the increased second malignancy risks.

• The most common secondary neoplasm is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although many are radiation-induced.

• There is also an increased incidence of secondary tumours in children with hereditary retinoblastoma who have not been irradiated.

• Osteosarcoma rates are much higher than for the general population.

• Later death most often occurs in the context of second tumours, which contributes to more than 50% of deaths in patients with bilateral disease. The cumulative incidence of such tumours is approximately 1% a year and they may occur as late as 20 years on from original presentation.

Treatment consequences

Late effects that may occur after treatment for retinoblastoma include the following:

• Diminished orbital growth. Orbital growth is diminished after enucleation; this effect may be less after placement of an orbital implant.

• Visual field deficits. Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment. These defects are related to tumour size, location and treatment method.²⁵

• In one study of visual acuity after treatment with systemic chemotherapy and local ophthalmic therapy, 50% had a final visual acuity of 20/40 or better and 67% had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumour margin of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.²⁵

• Hearing loss. Because systemic carboplatin is now commonly used in the treatment of retinoblastoma, concern has been raised about hearing loss related to therapy and there has been some evidence for this.²⁶

Prevention²

• Retinoblastoma is a genetic condition which cannot be prevented.

• Prenatal testing for pregnancies at increased risk is possible if the exact Rb1 variant has been identified in an affected family member.

• Prevention of secondary cancers is important in patients with germline mutations: limiting exposures to DNA-damaging agents (radiation, tobacco and UV light) may reduce the excess cancer risks. MRI scanning is generally preferred to CT scanning where possible.

Dr Mary Lowth is an author or the original author of this leaflet.