Clinical Focus cancer

Recognizing the signs of

Juliette Carter etinoblastoma is a malignancy which dition but that person will then have a 50% develops in the retina of children chance of passing the genetic mutation onto explains the Rusually under the age of 5 years. It is his/her future children. When a child is diag- most commonly detected by parents (Wallach nosed, the parents’ will be checked for a importance of et al, 2006) who seek advice in general regressed tumour and genetic testing can be recognizing the practice or from an optician. Unfortunately, done to detect where the gene mutation first many patients face a delay in diagnosis and occurred. signs of retinal treatment owing to a lack of awareness of the Patients with bilateral disease or multifocal significance of the signs described by parents tumours in one have heritable retinoblas- cancer in children or observed by primary health professionals toma. This accounts for approximately 44% as early as (Goddard et al, 1999). The common signs of of all retinoblastoma patients (Draper et al, retinoblastoma will be highlighted in this 1992). Those with unilateral retinoblastoma possible to avoid article and the investigations and management have the sporadic form. Although retinoblas- of a patient in general practice will be toma is highly treatable, the severity and unnecessarily discussed. impact of treatment will depend on the size of aggressive the tumour(s) and their location at the time Epidemiology of diagnosis. treatment Retinoblastoma is a rare cancer but is the most common primary ocular tumour in chil- Signs and symptoms dren (Butros et al, 2002, Wallach et al, 2006). The most common sign of retinoblastoma is It accounts for approximately 1 in 20 000 live , a white pupillary reflection births and on average 40 cases are diagnosed (Figure 1). , a squint, is also a in the UK each year (MacCarthy et al, 2009). common indicator. Other signs which may be One or more tumours may be present in one picked up by a parent, relative, or primary eye (unilateral retinoblastoma) or both eyes health professional may be poor or decreased (bilateral retinoblastoma). Tumours grow in vision, or pseudo-orbital cellulitus; and a the developing retina, the light-sensitive lin- known family history of retinoblastoma ing of the eye. Some children are born with (Goddard et al, 1999; Butros et al, 2002; retinoblastoma tumours; for others, retino- Abramson et al, 2003; Lin, 2003; Wallach et blastoma can develop any time until the age al, 2006). A few extremely rare signs which of approximately 5 years, when the retina has are still worth noting are heterochromia (a finished developing. difference in iris colour between the eyes), There are two forms of retinoblastoma: secondary glaucoma and proptosis. sporadic and heritable. A child can be the first Retinoblastoma may occasionally cause some in his/her family to develop the heritable con- localized pain but in general, apart from the often intermittent signs mentioned above, children seem well, happy and active, making it more difficult to realize the child has a life- threatening disease.

Juliette Carter is support worker and Presentation information officer, Childhood Eye Cancer Children present to general practice with sus- Trust, The Royal London Hospital, pected retinoblastoma at different ages Whitechapel Road, London E1 1BB depending on the form the child may have. A child with the heritable form is usually diag- Submitted for peer review 6 April 2009; nosed within the first year of life, with the accepted for publication 7 April 2009 average age at diagnosis being 9 months. Cases of sporadic retinoblastoma usually Key words: Retinoblastoma, eye cancer, present much later and the average age at childhood cancer, squint, white eye reflex Figure 1. Boy with white reflex in his eye diagnosis is 24 months (Wallach et al, 2006).

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Table 1. Signs of retinoblastoma

Problem Symptoms and implications Description by family Investigation Leukocoria White reflection in the . ‘Flashes like a cat’s eye’ Red reflex test Intermittently present or seen ‘Looks like a jelly in flash photographs ‘Sometimes I can see into the back of the eye’ Strabismus A squint ‘Lazy eye’ Red reflex test An eye is ’turned in’ ‘One eye moves independently’ Poor vision A child with retinoblastoma may ‘Their eyes won’t fix or follow’ Red reflex test have always had poor vision ‘One eye moves independently’ or it may have deteriorated Red or The areas around the eye are Red reflex test inflamed eye red or inflamed—it may look like orbital cellulitis Family There is a 50% chance a parent Not every adult who had retinoblastoma Red reflex test history of will pass the heritable form of as a child is aware of the risks to his/her and referral to retinoblastoma retinoblastoma onto the child. children—so the children need to be a retinoblastoma There is a small chance a child screened. Some adults were never told centre of someone with the sporadic by their parents what condition they form will be affected had as a baby

Parents often find it difficult to describe the professional should consider retinoblastoma abnormality they have seen in their child and as a possible cause. A simple red reflex test may have no idea what it could be. Leukocoria can be performed to help identify whether may only be visible intermittently. It occurs there are any unusual areas on the retina. A when the are dilated in low artificial swift referral to an ophthalmologist to inves- light. It can also be caught in flash photogra- tigate further will ensure that if a child has phy as an absence of red eye. One eye may retinoblastoma, diagnosis and treatment will show up as normal with red eye but the other be necessarily prompt. may look white, yellow or in some cases black. It is possible that both pupils may look Examination unusual in a photograph. Some parents take If a child under the age of 5 years presents a photograph with them when they see a pri- with any of the possible retinoblastoma mary health professional. In a small number symptoms, a red reflex test should be - per of cases the tumour has grown so large that formed, even though retinoblastoma is rare. leukocoria, sometimes a red or yellow mass A red reflex examination is non-invasive and or a change in iris colour is visible most of the can help when deciding whether the child time (Table 1). needs to be referred. The red reflex test needs It is important to consider when examining to be performed by someone who is experi- children with any of these symptoms that enced in doing it as it can sometimes present consulting rooms are generally well-lit, which false negative or false positive results. may prevent a primary health professional Someone in a general practice may be trained from noticing any of the signs. Many parents to do this test but, if not, it can be done at an whose children have strabismus are reassured clinic. that a squint is normal in babies. In truth it is The investigation involves looking into the common but it needs to be investigated as a back of the child’s eye at the retina. It is per- child with retinoblastoma tumours cannot formed using a halogen ophthalmoscope and wait the usual 3 months for a squint referral. should be done in a dark room. The profes- In this time the tumours may grow rapidly sional performing the red reflex test will need resulting in the need for more aggressive to look at the whole of the retina, right to the treatment, with the possibility of losing an peripheries. It can be difficult to do this test eye and/or some vision. With any of the on babies and young children as they will not symptoms mentioned above, no matter how be able to cooperate; however, they can be common the symptoms may appear or how encouraged to look at a toy behind the pro- healthy the child looks, the primary health fessional while he/she is working.

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Figure 2. Eyes with normal red reflex

Ophthalmoscopy A halogen ophthalmoscope can show some of the symptoms of retinoblastoma. Figure 2 shows a normal presence of the red reflex. This is caused by the flash from the camera Figure 6. Normal retina bouncing off the retinas at the back of the eye. Some people refer to this as ‘red eye’. Referral Figure 3 shows an absence of the red reflex in If retinoblastoma is suspected, or there are the child’s left eye. It may be absent from one concerns but a red reflex examination cannot or both eyes. This is a sign of serious eye dis- be done in general practice, refer the child to ease such as retinoblastoma, and will need a local ophthalmologist. The referral should investigation. be made within a few days. Health profes- Figure 4 shows a red reflex which is the sionals should not delay, as retinoblastoma wrong colour and brightness. This may be tumours grow very rapidly and put the child’s present in one or both eyes. It suggests serious life at risk. eye disease such as retinoblastoma and needs If retinoblastoma is strongly suspected, investigation. Figure 5 shows the red reflex is parents can be prepared, even though a full reduced in the left eye and the corneal reflex diagnosis cannot be made until the child is is not central. This is a squint which requires seen under anaesthetic by a specialist oph- prompt investigation to exclude serious thalmologist. An understanding of the treat- underlying disease. ment of retinoblastoma can enable practice When specialist consultants in retinoblast- nurses to help prepare a child and his/her oma diagnose children, they take a photo of family if necessary for the treatment ahead. the retina on a RetCam. Figure 6 shows a If a patient is referred to an ophthalmolo- healthy retina and Figure 7 shows a retino- gist, it is appropriate to inform the patient blastoma tumour. Tumours will differ in each about the concerns and suspicions. This can individual child. They may be different in be done by telling a child and his/her parents size, shape, position and quantity. that a specialist is taken for many reasons and that it is important to rule out anything serious. Other conditions which may present with leukocoria are cataract, Coats’ disease, toxoplasmosis and persistent hyperplastic primary vitreous. It is not neces- sary to tell the families of all patients that eye Figure 3. Red reflex absent in left eye cancer is suspected, but some families will

Figure 4. White reflex showing leukocoria

Figure 5. Eyes showing strabismus (squint) Figure 7. Retinoblastoma tumour

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already know about eye cancer as there have Conclusions been articles in the mass media alerting peo- Retinoblastoma is a rare malignancy of the Key Points ple to the warning signs. If parents already retina which affects children under the age of have such concerns then reassure them that 5 years. It can be detected by four main signs, ➤➤Childhood eye cancer is eye cancer is very rare and sometimes the leukocoria, strabismus, poor or decreased very treatable if signs and symptoms are indicative of some- vision and red inflamed eye. These signs are diagnosed early thing else less severe. Most importantly most commonly noticed by parents. inform them that retinoblastoma is treatable Leukocoria particularly can be difficult for ➤➤Many children need to and survival rates extremely high. Childhood parents to describe. If a child presents to the have an eye removed as cancers are different from adult cancers with practice with any of these signs, a red reflex a result of delayed which they may be more familiar. test should be done and if suspicions remain, diagnosis it is necessary to refer the child quickly to the ➤➤The main signs of Treatment for retinoblastoma local ophthalmology department. Children retinoblastoma are a In the treatment of retinoblastoma the first with strabismus often wait far too long to be white reflection in the principle is to save the patient’s life and then seen by an ophthalmologist; this must not be pupil, a squint and to save his/her vision. Each eye is assessed the case if eye cancer is suspected. A delay of reduction of vision. One individually. The type of treatment used will a few months often means treatment is or all symptoms may be be determined by the size and location of the unnecessarily aggressive. present tumour(s). Acknowledgments: Figure 1 is reproduced with For small or relapsed tumours, cryotherapy parental permission, and Figures 6 and 7 with the ➤➤The child’s retinas (freezing) or laser therapy can be used. kind permission of Mr Ashwin Reddy, consultant should be checked using paediatric ophthalmologis, Barts and the London Chemotherapy is used to treat bigger NHS Trust the red reflex test tumours; this is usually given in six cycles and Conflict of interest: none ➤ is likely to be the first option for children ➤If anything unusual is with tumours in both eyes. References noticed in the retina Abramson D, Beaverson K, Sangani P et al (2003) then the child needs an In cases where the tumour is so large it is in Screening for retinoblastoma: presenting signs as danger of metastasizing or becoming extraoc- prognosticators of patient and ocular survival. urgent referral to an ular, enucleation (surgical removal of the eye) Pediatrics 112(6): 1248–55 ophthalmologist Butros L, Abramson D, Dunkel I (2002) Delayed diag- is performed. Of 104 children with treatment nosis of retinoblastoma: analysis of degree, cause details diagnosed with unilateral retinoblast- and potential consequences. Pediatrics 109(3): e45 oma without family history between 2001– Draper G, Sanders B, Brownbill P, Hawkins M (1992) Patterns of risk of hereditary retinoblastoma and 2005, 90 (86.5%) had enucleation according applications to genetic counselling. Br J Cancer to unpublished data from the National 66(1): 211–9 Registry of Childhood Tumours. Goddard A, Kingston J, Hungerford J (1999) Delay in diagnosis of retinoblastoma: risk factors and treat- They will have an implant inserted during ment outcome. Br J Ophthalmol 83(12): 1320–3 surgery to improve the cosmetic effect and a Lin Y (2003) Early recognition of infant malignancy: prosthetic eye will be fitted 6 weeks after the five most common infant cancers. Neonatal Netw 22(5): 11–9 surgery. The removed eye will be sent for MacCarthy A, Birch J, Draper G, Hungerford J et al histology testing and checked to see if tumour (2009) Retinoblastoma: treatment and survival in cells have invaded any structures within the Great Britain 1963 to 2002. Br J Ophthalmol 93(1): 38–9 eye, for example, the choroid (pigmented Wallach M, Balmer A, Munier F et al (2006) Shorter layer in the eye) and the optic nerve. If this is time to diagnosis and improved stage at presenta- tion in Swiss patients with retinoblastoma treated the case chemotherapy is needed. from 1963 to 2004. Pediatrics 118(5): e1493–8 Other treatment of retinoblastoma may include second-line chemotherapy, radioac- tive plaque therapy or radiotherapy. These Further information treatments are only used if the initial treat- Childhood Eye Cancer Trust ments mentioned above have not worked, www.chect.org.uk when new tumours develop or if old tumours ‘See Red’ is a poster which explains how to do the become active again. red reflex test. For a free copy, telephone In the past radiotherapy and enucleation 020 7377 5578 or email [email protected] were the first-line treatment options before Barts and the London NHS Trust chemotherapy became widely used by spe- www.bartsandthelondon.nhs.uk/Retinoblastoma_ Service/ cialists to treat retinoblastoma. All children who have been treated for retinoblastoma Birmingham Children’s Hospital NHS will have to be regularly checked after treat- Foundation Trust www.bch.org.uk/departments/retinoblastoma.htm ment for any recurrence.

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