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.
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.
- Retinoblastoma occurs in approximately 1 in 18,000 live births.
- It accounts for 3% of all cancers diagnosed in children.
- There is no ethnic variation in incidence.
- In the UK, around 40 to 50 new cases are diagnosed each year.
- 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.
- Rb generally arises from a multi-potential precursor that could develop into almost any type of retinal cell. It then grows in up to three ways:
- Endophytic growth occurs when the tumour breaks through the internal limiting membrane and appears as a white-to-cream mass with few or no surface vessels. There may be vitreous seeding with tumour cells sometimes visible as spheroid masses floating in the vitreous and anterior chamber, suggesting uveitis and obscuring the retinoblastoma.
- Exophytic growth occurs subretinally, often with subretinal fluid accumulation and retinal detachment. Tumour cells may infiltrate the choroid and then invade either blood vessels or ciliary nerves. Retinal vessels increase in calibre and tortuosity over the mass.
- A few Rbs show flat infiltration of the retina without a discrete tumour mass. This type grows more slowly.
- Multifocal disease is the occurrence of more than one tumour in an eye.
- Rb occurs in a heritable form and a non-heritable form.
- Most heritable disease is bilateral and it is sometimes multifocal.
- If there is no history of the disease within the family, the disease is described as 'sporadic', although sporadic disease can be of the heritable type.
- Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumour are more likely to have the non-heritable form of the disease.
- Retinomas are non-progressive retinal lesions which may be benign precursors to Rb. Rarely, they remain benign and do not progress. Retinoma appears as a grey, translucent mass in the retina; there is cottage cheese-like calcification, and a hyperplastic retinal epithelium/chorioretinal scar. Retinoma is initiated by the same genetic abnormalities as retinoblastoma.
- 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 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.
- 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.
Initial signs are confined to the eye. The most common and obvious sign is an abnormal appearance of the pupil, leukocoria. Other less common and less specific signs and symptoms are deterioration of vision, a red and irritated eye, faltering growth or delayed development. Some children with retinoblastoma develop a squint. Affected children are likely to be systemically well.
- Patients with heritable disease present at a younger age, usually by 12 months.
- Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken.
- Strabismus is the second most common presenting sign and usually correlates with macular involvement.
- 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 Trust) 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).
- 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.
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.
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) - this X-linked dominant disease affects girls and is characterised by vesiculobullous dermatitis ± malformations of the teeth, bones and CNS. They may also develop a retinal detachment, giving rise to a white pupillary reflex.
- Retinal astrocytoma - see separate Retinal Tumours article.
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.
Diagnosis and evaluation
Diagnosis of intraocular retinoblastoma is usually made without pathological confirmation.
- Examination under anaesthesia with a maximally dilated pupil is required.
- A detailed documentation of tumours, any retinal detachment and subretinal fluid and any of subretinal and vitreous seeds must be performed.
- Additional imaging studies include bi-dimensional ocular ultrasound and MRI (preferred over CT to avoid radiation exposure). These imaging studies are to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria.
- 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.
Untreated, the tumours invade locally and then metastasise, causing death within two years. Very occasionally, the tumour may spontaneously stop growing.
- Growth is usually under the retina and toward the vitreous.
- Involvement of the ocular coats and optic nerve follow as the tumour progresses.
- Choroidal invasion is common, although massive invasion is usually limited to advanced disease.
- Through the choroid, the tumour gains access to systemic circulation with the potential for distant metastases.
- Further progression through the ocular coats leads to invasion of the sclera and the orbit.
- Anteriorly, tumour invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm.
- Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and CNS dissemination.
- Children with a germline Rb1 mutation may continue to develop new tumours for a few years after diagnosis and treatment and they need ongoing surveillance. Commonly examination is repeated every 2-4 months for at least 28 months.
- Because of the poor prognosis of trilateral Rb, screening with neuro-imaging until the age of 5 years is a common practice in the follow-up of children with the heritable form of the disease.
Different staging systems for extraocular Rb have been published; however, to date they have not been validated in large cohorts. 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:
- Group A: small tumours (3 mm across or less) that are only in the retina and are not near important structures such as the optic disc or the foveola.
- Group B: all other tumours (either larger than 3 mm or small but close to the optic disc or foveola) that are still only in the retina.
- Group C: well-defined tumours with small amounts of spread under the retina (subretinal seeding) or into the vitreous (vitreous seeding).
- Group D: large or poorly defined tumours with widespread vitreous or subretinal seeding. The retina may have become detached from the back of the eye.
- Group E: the tumour is very large, extends near the front of the eye, is bleeding or causing glaucoma, or has other features that mean there is almost no chance the eye can be saved.
- 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[4, 17].
- Hereditary retinoblastoma is associated with an increased risk of non-ocular cancers, particularly Ewing's sarcoma, olfactory neuroblastoma and osteosarcoma.
- There is a significant increased risk of soft tissue and bone sarcomas which persists for decades after the retinoblastoma diagnosis.
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. There are three options - surgery (including localised conservative surgical treatments), chemotherapy and radiation.
Eye-conserving treatments for localised retinoblastoma
- Photocoagulation can be used to treat selected small tumours that do not involve the optic disc or macula. Multiple sessions may be needed.
- Cryotherapy may be used as a primary or secondary treatment of small peripheral Rbs. Local vitreous haemorrhage and transient subretinal fluid have been reported complications of cryotherapy for retinoblastoma.
- Transpupillary thermotherapy: The aim is to achieve a temperature of 42-60°. It is used for small well localised peripheral tumours. It has a synergistic effect with chemotherapy and may be used in conjunction with chemotherapy for large tumours.
- Plaque radiotherapy can be effective for small solitary tumours and most respond dramatically within the first three weeks.
- Systemic chemotherapy is used as adjuvant in children previously considered candidates only for enucleation or bilateral external beam radiotherapy. It may make tumours more amenable to focal treatment or permit treatment with a lower dosage of radiation. In addition, there may be a role for pre-enucleation chemotherapy in reducing mortality in children with high-risk features.
- Periocular chemotherapy allows higher effective doses while limiting systemic side-effects. Carboplatin is used but is associated with serious adverse effects.
- Ophthalmic artery chemotherapy using melphalan has shown some encouraging results.
- Because of earlier tumour detection, as well as increased use of more conservative treatments, there has been a significant decrease in the frequency of enucleation in patients with retinoblastoma over the past forty years.
- Unfortunately, enucleation remains a frequent treatment and is indicated for all unilateral tumours that fill over half of the eye, or when there is extensive seeding into the vitreous, total detachment of the retina, new blood vessel growth on the iris, or involvement of other eye structures.
- Historically, in patients with bilateral disease, the eye with more advanced tumour has been enucleated and the less involved eye managed by other methods. Very rarely, if the disease is far advanced in both eyes, bilateral enucleation is justified.
- When a child has their eye removed an adult size implant is placed into the orbit to allow the eye muscles to be reattached. This allows more natural eye movements in the future. The implant is usually made from hydroxylapatite, a derivative of coral, which allows blood vessels to grow into the implant and seal it into place. Shortly after surgery, a shell-like prosthesis made to match the colour and shape of the other eye is fitted over the implant.
External beam radiotherapy
- RB is extremely sensitive to radiation. External beam radiotherapy is most often used to treat patients with bilateral disease who are not amenable to local treatment, particularly when tumour recurs or extends, when tumours in both eyes are large or near the optic disc or fovea, when multiple tumours are present, or when there is extensive vitreous seeding. It may also be used to treat the eye socket after enucleation if histology suggests extension beyond the excision margin.
- Complications include cataract, radiation retinopathy, optic neuropathy, dry eye, sunken orbit, atrophy of muscle and subcutaneous tissues, and periorbital bone maldevelopment (mid-facial hypoplasia). A long-term complication is an increased incidence of secondary tumours.
If possible, radiation (including X-ray, CT scan and external beam radiation) should be avoided in heritable retinoblastoma to minimise the lifetime risk of developing late-onset second cancers.
Treatment of disseminated disease
- Treatment of intracranial dissemination includes platinum-based intensive systemic chemotherapy and CNS-directed therapy. Intrathecal chemotherapy has been used but there is no evidence to support its use. Irradiation is controversial but favourable responses have been seen with craniospinal irradiation.
- Metastatic retinoblastoma is not curable with conventional chemotherapy. Extraocular Rb is currently treated with intensive chemotherapy, including consolidation with high-dose marrow-ablative chemotherapy and autologous haematopoietic stem cell rescue, as some small studies have shown cure is possible with these regimes.
- 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.
Invasion of the optic nerve is the most significant prognostic factor. Delayed treatment increases the risk of optic nerve invasion.
- 87% of children with this disease worldwide die, mostly in developing countries. Prognosis is worst in countries with the lowest incomes.
- Retinoblastoma has the highest survival of all the childhood cancers in the UK. Five-year survival in the UK improved from 86% in 1966-1970 to 99% in 2001-2005.
- In developed countries, 97% of those who live have moderate-to-severe visual impairment, or lose one or both eyes.
- 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.
- 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.
- Osteosarcoma rates are believed to be 250-500 times that of the general population.
- There is also an increased incidence of secondary tumours in children with hereditary retinoblastoma who have not been irradiated.
- 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.
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.
- 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.
- 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.
- 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.
Further reading and references
; Diagnosis of retinoblastoma: how good are referring physicians? Ophthalmic Genet. 2009 Dec30(4):199-205.
; Epidemiology and Rb1 gene of retinoblastoma. Int J Ophthalmol. 20114(1):103-9. doi: 10.3980/j.issn.2222-3959.2011.01.24. Epub 2011 Feb 18.
; Retinoblastoma. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle 1993-2016. 2000 Jul 18 [updated 2015 Nov 19.
; The effect of race on the incidence of retinoblastoma. J Pediatr Ophthalmol Strabismus. 2009 Sep-Oct46(5):288-93. doi: 10.3928/01913913-20090903-06. Epub 2009 Sep 22.
; The Incidence of Trilateral Retinoblastoma: A Systematic Review and Meta-Analysis. Am J Ophthalmol. 2015 Dec160(6):1116-1126.e5. doi: 10.1016/j.ajo.2015.09.009. Epub 2015 Sep 12.
; Online Mendelian Inheritance in Man (OMIM)
; Retinoblastoma. Adv Exp Med Biol. 2010685:220-7.
; Characteristics of Germline and Non-germline Retinoblastomas. J Ophthalmic Vis Res. 2014 Apr9(2):188-94.
; Retinoblastoma, Digital Journal of Ophthalmology, January 13, 2003
; Retinoblastoma. Singapore Med J. 2012 Feb53(2):128-35
; Retinoblastoma with Coats' response. Ophthalmic Surg Lasers Imaging. 2011 Dec 1642 Online:e139-43. doi: 10.3928/15428877-20111208-04.
; Online Mendelian Inheritance in Man (OMIM)
; NICE CKS, November 2015 (UK access only)
; Current concepts for diagnosis and treatment of retinoblastoma in Germany: aiming for safe tumor control and vision preservation. Klin Padiatr. 2012 Oct224(6):339-47. doi: 10.1055/s-0032-1327563. Epub 2012 Nov 9.
; Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol. 2013 Sep131(9):1127-34. doi: 10.1001/jamaophthalmol.2013.260.
; National Cancer Institute
; Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol. 2013 Oct156(4):825-9. doi: 10.1016/j.ajo.2013.05.023. Epub 2013 Jul 20.
; Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms. Med Pediatr Oncol 200136(2): 290-4.
; Sarcomas in hereditary retinoblastoma. Clin Sarcoma Res. 2012 Oct 42(1):15. doi: 10.1186/2045-3329-2-15.
; A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008 Aug115(8):1398-404, 1404.e1. doi: 10.1016/j.ophtha.2007.12.014. Epub 2008 Mar 14.
; At what age could screening for familial retinoblastoma be stopped? A register based study 1945-98. Br J Ophthalmol 200084:1170-1172.
; Review of 20 years' clinical experience with retinoblastomas in southern Taiwan. Chang Gung Med J. 2008 Sep-Oct31(5):484-91.
; Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer. 2009 Dec45(18):3245-53. doi: 10.1016/j.ejca.2009.05.011. Epub 2009 Jun 1.
; Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005 Apr 123(10):2272-9.
; Hereditary retinoblastoma: host resistance and second primary tumors. J Natl Cancer Inst. 1980 Jul65(1):47-51.
; Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol. 2005 Nov123(11):1525-30.
; Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol. 2012 Apr 130(10):1034-41. doi: 10.1200/JCO.2011.36.9744. Epub 2012 Feb 27.
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