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Although very rare, retinoblastoma (Rb) is the most common primary malignant intraocular tumour of childhood and the second most common of all ages. It accounts for 3 per cent of all childhood cancers1 and is incident in 1:15,000-20,000 live births:2 between 50 and 60 cases are diagnosed each year in the UK. There is no gender or race predisposition. One or more tumours may be present in one eye (unilateral Rb) or both eyes (bilateral Rb). Tumours grow in the retinal cells, which are developing rapidly in early life. The process of cell development continues throughout infancy and the retina is largely developed at approximately five years of age. Histopathology shows that fast-growing cells undergo a malignant transformation and grow to invade the vitreous, the sub-retinal space or both. Tumours can then infiltrate the brain and spinal cord via the optic nerve and subarachnoid space, as well as penetrating the blood supply into the bone and bone marrow.3
It is a life-threatening disease, but vital prognosis is good, with 98 per cent of children surviving Rb in the UK. Preservation of visual function is dependent on treatment success, and currently over 70 per cent of UK patients with unilateral Rb will lose an eye due to the late stage of cancer at the point of diagnosis. Some treatment, while saving the eye (and life) can have an effect on visual function. Over the past four decades, the management of this disease has evolved tremendously in developed countries, changing Rb from being a deadly childhood cancer to a largely curable disease. A swift referral pathway for a suspected case is vital to reduce loss of vision and the risk of mortality. Where such referral pathways are not available, such as in developing countries, mortality from Rb is about 70 per cent.
Retinoblastoma occurs in two forms: heritable (germline) and non-heritable (somatic). Children with bilateral disease or multiple tumours in one eye have the heritable Rb, with a change in the Rb gene. This accounts for around 45 per cent of cases. The heritable form can occur with no prior family history of Rb (sporadic).
In about two thirds of children, only one eye is affected, but in one third tumours develop in both eyes. In some children who only have one eye affected at diagnosis, particularly those who are very young, it is possible for a tumour to develop in the second eye several weeks or even months after the diagnosis of Rb in the first eye.
A child who inherits the altered Rb gene has a 90 per cent chance of developing Rb, so screening from birth at an Rb treatment centre is vital. Adults who had Rb, who wish to have children should be offered genetic counselling and testing.4
How does Rb 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 Rb can occur; this can happen in several different ways.
One possibility is that a child inherits one altered copy of the Rb gene (germline) from a parent. If the normal copy of the gene does not become damaged in a retinal cell no Rb will develop. If damage occurs to the normal copy, a Rb can develop. This is the heritable form of Rb. About 90 per cent of people who inherit an altered Rb gene from a parent will develop Rb; most will have bilateral disease (ie both eyes affected), 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 per cent 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. As a random, isolated event during retinal development, one cell loses both copies of the RB1 gene. Again, as a result of these alterations a Rb can develop. In these circumstances the child will develop the non-heritable type of Rb, and there will be one tumour in one eye.
Signs and symptoms
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There are several signs which could indicate Rb but it is important to remember that a child with Rb may appear systemically well. The initial signs are confined to the eye and are most commonly detected by parents. Unfortunately, many patients face a delay in diagnosis and treatment owing to a lack of awareness of the significance of the signs described by parents5 or observed by primary health professionals.6 The two most common symptoms are leukocoria and strabismus. Rb is responsible for half of all cases of leukocoria7 and 60 per cent of all Rb cases have leukocoria as their first presenting sign. In 2012 and 2013, 25 per cent of all children diagnosed with Rb had a squint as a presenting symptom.8
- Leukocoria (intermittent) white pupillary reflex noticed in dim lighting or a photo (Figure 1). It can be difficult for parents to describe
- Strabismus (squint). Rb must be ruled out for all new 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
- Nystagmus
- Parental history of Rb – the condition is heritable so children of an affected parent with Rb must be screened from birth
- Parental concern over vision or eye appearance.
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Age of presentation
Children present with suspected Rb at different ages depending on the type. A child with the heritable form is usually diagnosed within the first year of life, with the average age at diagnosis being nine months. Cases of non-heritable unilateral Rb usually present much later and the average age at diagnosis is 24 months,9 but very occasionally up to 12 years of age.
Neonatal screening services – Newborn and Infant Physical Examination Programme (NIPE)
- The NIPE programme covers:
- The newborn physical examination which should be carried out within 72 hours of birth, ideally before hospital discharge
- The infant physical examination which is repeated at 6-8 weeks of age
- Referrals from the examination for further assessment, up to the point of discharge or diagnosis.
Eyes are a key component of this check, and an examination of the opacities and red reflex is carried out.
Routine physical examinations of the newborn baby, and 6-8 week infant, are an integral part of the universal Healthy Child Programme, and eyes are one of the four screening components of these examinations.
Investigations
If an infant or child presents to the optometrist with a sign or indication of Rb, the usual eye examination appropriate to the age of the infant/child should be performed, which will include red reflex test and ophthalmoscopy. When Rb is suspected or if the test shows anything unusual, or if it is not possible to carry out an adequate examination due to the age or co-operation of the child, urgent referral needs to be made (according to local referral protocols) to a local ophthalmology department, A&E or GP stating the cause for concern. If the local ophthalmology department identifies or suspects Rb an urgent referral is made to one of two Rb hospitals in the UK.
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.
Although this cancer has a very high survival rate in the UK, many children live with the consequences of a delayed diagnosis. Late diagnosis for a child with Rb can mean loss of one or both eyes, life with an artificial eye, a visual impairment or, in some cases, complete blindness.
Opticians’ protocol
Although in general optometrists are good at recognising and referring children with Rb, anecdotally national charity the Childhood Eye Cancer Trust (CHECT) is aware of problems where non-medical staff in optometry practices can unwittingly cause delays. This stems from a lack of awareness and understanding of the signs and symptoms of Rb and the need for urgent examination to rule out its presence. As a result, staff may either give the family a non-urgent appointment, or turn them away saying their practice does not examine small children, without stressing to the family the importance of ensuring the child is examined urgently elsewhere. In response to this issue, CHECT has developed an Opticians’ Protocol to be distributed to optical stores. This ensures that all practice staff, including receptionists and dispensing opticians, are aware of the most common signs of Rb (white or abnormal pupil reflex in a photo or new squint) and the need for any suspected case to have an urgent assessment by GP or optometrist. The Opticians’ Protocol is a one-page summary describing in lay language the key signs and symptoms of Rb and the appropriate action required. It is approved by the Royal College of Ophthalmologists and the College of Optometrists, and has been adopted by Vision Express and Boots Opticians, along with a growing number of independent practices. The protocol can be downloaded at www.chect.org.uk/index.php/about-rb/information-for-professionals/opticians
Differential diagnosis
Although Rb is one of the most common causes of leukocoria it is important to be aware of the possible differential diagnoses. Even though on rare occasions leukocoria may be from an observation of the normal optic disc, a pathological cause should always be actively ruled out. Some possible differential diagnoses of leukocoria are congenital cataract, Coats’ disease, retinopathy of prematurity (ROP), optic disc coloboma, myelinated nerve fibres, Toxocariasis and persistent hyperplastic primary vitreous.
Staging
The International Classification for Intraocular Retinoblastoma divides intraocular Rbs into five groups, labelled A through E, based on the chances that the eye can be saved using current treatment options (Table 1).
Treatment
In the UK, treatment is carried out at one of two designated national treatment centres at the Royal London Hospital or Birmingham Children’s Hospital. In the treatment of Rb the first principle is to save the patient’s life and then to save their vision. Each eye is assessed individually. The type of treatment used will be determined by the size and location of the tumour(s), risk for metastasis or second tumour, systemic status and the age of the patient. The treatment options include cryotherapy, laser therapy, plaque therapy, chemotherapy, and to a lesser extent intra-arterial chemotherapy, intra-vitreal chemotherapy or radiotherapy.
Effects of treatment
The Rb itself may affect the vision depending upon its location. However, the lifesaving treatment may also cause visual loss and other late effects.
Chemotherapy for Rb can cause hearing problems, kidney problems and second malignancies, and children will usually be monitored at their local hospital for many years.
Radiotherapy can cause cataracts, optic nerve damage, dry eye, facial asymmetry and retinal detachment.
Lifelong effects of Rb
Any individual who has suffered with Rb should be monitored to detect and manage any long-term problems caused by the disease and treatment in order to ensure the best possible quality of life.
There is an increased risk of second primary cancers in individuals with the heritable form of Rb.10 This group includes cases of Rb where the tumour is bilateral or multifocal or where there is a family history. Patients surviving this form of Rb have an increased risk of developing sarcomas within about 5-25 years of treatment. They are also at an increased risk of developing other forms of cancer in later life. The level of risk also depends on the treatment received for Rb. Adults who had Rb should be seen regularly in an adult oncology clinic. Patients with a visual impairment may seek frequent appointments with their GP for a complete body skin check, since they will not be able to see any potentially malignant skin lesions themselves.
Genetic testing
The Rb gene (RB1 gene) is found on chromosome 13 and there are two copies of it. Adults who have heritable Rb and wish to have children, should be offered genetic counselling and testing. Information on the genetics of Rb was scarce 20 years ago, therefore many patients who carry the altered gene may not be aware of the risks associated with this. Patients planning a family should be referred to a geneticist who can offer genetic counselling. The patient may wish to consider testing to identify the gene change, so that the risk to offspring can be assessed. If the gene change is found, other techniques include pre-implantation genetic diagnosis; chorionic villus sampling at 11 weeks of pregnancy, or amniocentesis at 16 weeks of pregnancy. Anyone considering having testing in pregnancy should be seen by a geneticist before they plan a pregnancy so that the necessary background work can be done.11
Artificial eyes and vision
Many patients have one or both eyes enucleated. People in the UK can visit the National Artificial Eye Service (NAES) and other NHS prosthetic services or a private ocularist about their artificial eye. Fewer socket problems occur if the patient is under the care of a prosthetist. If problems persist a referral to a local oculoplastic/orbital surgeon via the GP is important as reconstruction of the socket may be possible or necessary.
Eye protection
Any child who has Rb, especially those with an artificial eye must do what they can to protect their remaining vision. Parents must be advised to ensure their children protect their eyes from injury during sporting activities at school.
Some medical professionals recommend buying glasses with special polycarbonate shatterproof lenses, fixed in damage-proof frames regardless of visual status. These, or prescription glasses if the child needs them, can be worn with a sports band during general sporting activities and should offer sufficient protection. If the child is taking part in more regular or competitive sporting activities, or sports representing a higher risk of injury either from balls or other players such as football, squash or similar then they will need proper protective sports goggles.
Parents often ask whether their child needs to wear swimming goggles and whether they should swim at all with an artificial eye – the answer is yes, to both. The idea of wearing the goggles is to protect the eye should it come out while swimming. Some children find the traditional goggles can put unwanted pressure onto the socket though, so may prefer specialised goggles.
Further advice and information
For referrals and information for UK patients contact the Rb teams in London and Birmingham:
- The Retinoblastoma Service, The Royal London Hospital, 020 3594 1419. Visit www.bartsandthelondon.nhs.uk
- The Retinoblastoma Service, Birmingham Children’s Hospital, 0121 333 9475. Visit www.bch.nhs.uk
- For more information about Rb and the work of the Childhood Eye Cancer Trust visit www.chect.org.uk or call 020 7377 5578
Model answers
The correct answer is in bold italic
1 Which of the following statements about retinoblastoma is true?
A It is more common in female offspring
B It is a unilateral condition
C The vast majority of children with retinoblastoma survive
D It is only locally invasive
2 If a child is known to be born with the altered Rb gene, what is the likelihood of them developing retinoblastoma?
A 50 per cent
B 75 per cent
C 90 per cent
D 100 per cent
3 Which of the following statements about leukocoria is true?
A It is due to retinoblastoma in half of the presenting cases
B It is always due to retinoblastoma
C It only manifests with flash photography
D It is due to loss of iris pigment making the pupil appear pale
4 Which of the following is not likely to be related to the presence of retinoblastoma?
A Nystagmus
B Strabismus
C Circumlimbal hyperaemia
D Purulent discharge
5 Which of the following is a known risk of radiotherapy for retinoblastoma?
A Secondary malignancy
B Cataract
C Renal damage
D Hearing impairment
6 Which of the following describes the prognosis for a well defined tumour with subretinal seeding?
A Low risk
B Moderate risk
C High risk
D Very high risk
References
1 2006-2007 National Registry of Childhood Tumours, Childhood Cancer Research Group http://www.ccrg.ox.ac.uk/datasets/registrations.shtml
3 Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE, Hurwitz R (2007) Retinoblastoma: Review of current management. The Oncologist 12: 1237-1246
4 Dommering CJ, Garvelink MM, Moll AC, van Dijk J, Imhof SM, Meijers-Heijboer H,Henneman L. Reproductive behavior of individuals with increased risk of having a
child with retinoblastoma. Clin Genet. 2012 Mar; 81(3):216-23. doi: 10.1111/j.1399-0004.2011.01791.x. Epub 2011 Oct 22. PubMed PMID: 21954974.
5 Wallach M, Balmer A, Munier F et al (2006). Shorter time to diagnosis and improved stage at presentation in Swiss patients with retinoblastoma treated from 1963 to 2004. Paeditrics 118(5): e1493-8
6 Goddard A, Kingston J, Hungerford J (1999). Delay in diagnosis of retinoblastoma: risk factors and treatment outcome. Br J Ophthalmol 83(12): 1320-3.
7 Balmer A, Munier F (2007) Differential diagnosis of leukocoria and strabismus, first presenting signs of retinoblastoma. Clinical Ophthalmology 1(4): 431-439.
8 Childhood Eye Cancer Trust, results of interviews with parents of children diagnosed with retinoblastoma 2012 – 2013.
9 Wallach M, Balmer A, Munier F et al (2006). Shorter time to diagnosis and improved stage at presentation in Swiss patients with retinoblastoma treated from 1963 to 2004. Paeditrics 118(5): e1493-8
10 Halford L, Cole T, Kingston J, Onadin Z, Reddy A Retinoblastoma for life. Focus: The Royal College of Ophthalmologists Summer 2008 5-6.
11 Gallie B. Canadian guidelines for retinoblastoma care. Can J Ophthalmol. 2009 Dec;44(6):639-42. Lifelong effects of Rb
Background reading
- Sugano K, Yoshida T, Izumi H, Umezawa S, Ushiama M, Ichikawa A, Hidaka A, Murakami Y, Kodama T, Suzuki S, Kaneko A. Outpatient clinic for genetic counseling and gene testing of retinoblastoma. Int J Clin Oncol. 2004 Feb;9(1):25-30. Review. PubMed PMID: 15162822.
- Simpson JL, Carson SA, Cisneros P. Preimplantation genetic diagnosis (PGD) for heritable neoplasia. J Natl Cancer Inst Monogr. 2005;(34):87-90. Review. PubMed
- PMID: 15784832.
- Dimaras H, Kimani K, Dimba EA, Gronsdahl P, White A, Chan HS, Gallie BL. Retinoblastoma. Lancet. 2012 Apr 14;379(9824):1436-46.
- Parulekar MV. Retinoblastoma - current treatment and future direction. Early Hum Dev. 2010 Oct;86(10):619-25.
- MacCarthy A, Birch J, Draper G, Hungerford J et al (2009) Retinoblastoma: treatment and survival in Great Britain 1963-2002. Br J Ophthalmol 93(1): 38-9
- Draper G, Sanders B, Brownbill P, Hawkins M (1992) Patterns of risk of hereditary retinoblastoma and applications to genetic counselling. Br J Cancer 66(1): 211-9
- Lahrouchi N, Bosscha MI, Moll AC. A child with a white pupil. JAMA. 2014 May 7;311(17):1799-800.
- Shields C; Shields J, (2006) Basic understanding of current classification and management of retinoblastoma. Current Opinion in Ophthalmology 17(3): 228-234
- Batra R, Abbott J, Jenkinson H, Ainsworth JR, Cole T, Parulekar MV, Kearns P. Long-term retinoblastoma follow-up with or without general anaesthesia. Pediatr Blood Cancer. 2014 Feb;61(2):260-4. doi: 10.1002/pbc.24755. Epub 2013 Sep 4. PubMed PMID: 24038735.
- National Institute for Health and Care Excellence guideline (2005) Referral guidelines for suspected cancer: cancer in children and young people
Rachael Smith is Optometrist Director with Rawlings Opticians, Winchester and Petra Maxwell is Information & Research Officer for the Childhood Eye Cancer Trust