What is a Retinoblastoma?
Retinoblastoma is the most common cancer of the eye in children worldwide. Affecting 1 in every 12000 to 15000 children, it is typically seen around 2 years of age, although not infrequently seen as early as 6 months and as late as 5 years of age.
Retinoblastoma is a tumour that arises from the retina. The retina is the inner lining in the back of the eye that enables us to see. Retinoblastomas are the most common primary paediatric ocular neoplasm.
Left untreated, most patients have spread of disease outside the eye into the eye socket, the brain and eventually to other parts of the body resulting in death. Thus, it not just sight-threatening but life-threatening as well.
Who Manages Retinoblastoma at NUH?
At NUH, Retinoblastoma is primarily managed by a team of experienced eye specialists and paediatric oncologists. The eye specialists include paediatric ophthalmologists, retinal specialists and eye plastic surgeons, all of whom form an ocular oncology team. Other members of the Retinoblastoma team include geneticists, ocularists (artificial eye specialists), interventional radiologists, radiation oncologists and pathologists.
We have been treating Retinoblastoma more than 20 years. We manage 8-10 new retinoblastoma patients annually with long term follow up of all of our seeing and surviving children. Appropriate investigations are performed to stage the disease and treatment plans are customised for the child, who will be followed up long term by both ophthalmologists and oncologists. All children are also referred to the Geneticist for genetic counselling.
Is Retinoblastoma Deadly?
When diagnosed and treated early, over 90-95 % of children are survivors, functioning as normal children, going to school and participating in all activities like normal children. However, when left untreated or poorly treated, almost all children with confirmed retinoblastoma have spread of disease outside the eye(s) into the eye socket or the brain, and eventually to other parts of the body resulting in death.
What Are the Signs / Symptoms of a Retinoblastoma?
It is most commonly presented as an altered light reflex in the affected eye (white reflex, leucocoria) typically seen in a flash photograph of a child in the first 1-2 years of life, as seen in Fig.1. Other manifestations include a new onset ‘cross eye’ (‘squint’, strabismus), a red eye that does not respond to treatment, or an eye that doesn’t see. Late manifestations include an enlarged eye compared to the other side or bulging eye(s). Advanced disease is presented as an irritable, sick child, failing to thrive, seizures or swelling in other parts of the body from spread of the disease (metastasis). This condition, almost always results in death unless treated aggressively. Parents are the first to notice any of the early features mentioned above and thus should seek early attention with an eye specialist or paediatrician.
Fig. 1 Leukoria (white coloured pupillary reflex) is present in the right eye due to retinoblastoma
How Is Retinoblastoma Diagnosed?
When any of the above conditions are present, the eye specialist usually performs a preliminary examination followed by either an examination under anesthesia or sedation. Typically the diagnosis is made exclusively on clinical examination based on the appearance and characteristics of the tumor. An ultrasound scan is often also used to look for ‘calcification’, measure the size and spread of tumor outside the eye. All retinoblastomas are documented with a special fundus camera (RetcamR) for documentation, family education, communication with other specialists and when necessary, for a second opinion as well. When the disease is suspected to have spread outside the eye, or if Retinoblastoma is present in both eyes, an imaging of the orbit (eye socket) and brain is performed to rule out spread outside the eye and the presence of a rare third tumor in the brain (pinealoblastoma). In patients who are presented late with obvious spread outside the eye, a lumbar puncture for analysis of the fluid surrounding the brain (CSF) and bone marrow may also be performed to confirm spread of the disease.
Note: This is one of the very few cancers of the human body where the diagnosis is made and treatment is started, without performing a biopsy.
Newer Forms of Treatments Options
There are several newer treatment options for Retinoblastoma during the past few years in various advanced cancer centres around the world, some of which are available at NUH. These include plaque brachytherapy (local radiation), intra-arterial chemotherapy (administered through blood vessels of the eye accessed through the thigh blood vessels), intra-vitreal chemotherapy (direct injections into the eye – not yet considered a primary treatment); and for late stage metastatic disease, Autologous Stem Cell Rescue (ASCR)/Bone Marrow Transplantation (BMT).
How Is Retinoblastoma Treated?
The priorities in the treatment of retinoblastoma are in order of preservation of life, eye, and then vision. Close teamwork between a multidisciplinary team comprising of the ophthalmologist, paediatric oncologist, geneticist, interventional radiologist and pathologist is essential to achieving those goals. At present, the goal of preventing mortality has largely been met, and retinoblastoma is now the most curable paediatric cancer.
Staging the disease
To determine the most suitable treatment, a thorough evaluation to stage the disease has to be performed first. In young children, they are generally unable to cooperate with the eye examination when they are awake. As such, they are usually examined under sedation or anaesthesia. The pupils are dilated so the entire retina can be thoroughly examined to determine whether there is one or more retinoblastoma is present. The examining doctor will also assess for seeding into the vitreous or front chamber of the eye.
An ultrasound of the eye (Fig. 1) is performed to evaluate for characteristic features for the tumour, such as calcification, and to measure the size of the tumour. To assess for spread of the tumour outside the eye, or into the brain, magnetic resonance imaging (MRI) of the brain and orbit is performed (Fig. 2). In both ultrasound and MRIs, there is no exposure to radiation.
Fig. 1 This is an ultrasound scan that demonstrates the tumour (arrow), which is in close proximity to the optic nerve (orange asterisk).
Fig. 2 This is an MRI scan that demonstrates the tumour (red arrow) in the right eye. The MRI is useful to assess for extension of the tumour outside the eye, and intra-cranial involvement of the disease.
Treatment options
Various treatment modalities are available in the management of a retinoblastoma.
- Photocoagulation or cryotherapy can be used in the treatment of small tumours.
- For medium to large sized tumours with no systemic spread, the treatment has rapidly evolved. Enucleation is an established treatment, but there is complete loss of visual potential in the operated eye. In cases with very advanced unilateral disease and no likelihood of functional vision, this is still be the treatment of choice.
- For less severe disease in eyes with vision potential, there are several globe salvage treatments that are available:
- Intra-arterial chemotherapy - NUH is the only institution in Singapore and the region to offer the state of art Selective Intraarterial Chemotherapy for Retinoblastoma, performed by our neurointerventional radiologist. This, complemented with intraocular laser therapy, cryotherapy, intravitreal chemotherapy performed by the Ophthalmologists and systemic chemoreduction offered by our pediatric oncologists makes multimodality multidisciplinary management of Retinoblastoma possible.
This treatment involves super-selective infusion of chemotherapy into the ophthalmic artery, the blood vessel that delivers blood to the eye. This maximises the bioavailability of the drug in the targeted ocular structure, while minimising systemic drug exposure. The current chemotherapeutic regimen used in intraocular chemotherapy comprises single or combined use of these three agents: melphalan (most commonly), topotecan or carboplatin. This treatment modality was first introduced in 2006. A review of patients with advanced group D or E disease, did not find any increase in the chance of orbital recurrence, metastatic disease, or death compared to primary enucleation. This procedure is generally safe but there are some potential side effects. Transient side effects that generally resolve within 6 months include swelling of the eyelid, drooping of the eyelid, loss of lashes, redness of the skin over the forehead, and temporary limitation in eye movements. More serious potential side effects include occlusion of the retinal artery or vein and choroidal atrophy, which can give rise to visual loss. Systemic side effects also include low white blood cell counts, risk of stroke and allergic reactions.
- Intra-vitreal chemotherapy – this involves the injection of the medication directly into the vitreous cavity of the eye, to treat refractory and recurrent seeding of the tumour into the vitreous. Reported complications include cataract formation, bleeding in the vitreous cavity, retinal haemorrhage and low eye pressures. There is also a risk of introducing infection into the eye which can cause loss of vision. There is also a theoretical risk that the tumour cells can spread through the needle track. Techniques used to minimize this risk include applying cryotherapy to the injection site before removing the needle, or using distilled water to wash the eye after needle removal, as distilled water has been shown to be effective at killing retinoblastoma cells in culture within a few minute.
- Systemic chemotherapy - systemic chemotherapy may also enable globe salvage, oftentimes with useful vision, but increases the risk of secondary tumours such as leukaemia, low blood counts, kidney toxicity and hearing loss. However, in patients with metastatic disease, multiple-agent intensive systemic chemotherapy is used to treat tumour cells have disseminated to other parts of the body.
- Radiotherapy – in general, this approach has been abandoned because of the subsequent risk of second cancers, and there are other more efficacious treatment options
Surveillance
The electroretinogram (ERG) is an objective and noninvasive method for evaluating the visual pathway (Fig. 3). An ERG is the recording of electrical signals produced by the retina when stimulated by a brief flash of light. Reduction in the ERG amplitude has been found to be grossly proportional to the degree of retinal disruption or toxicity. In our centre, ERGs are performed prior to each session of intra-arterial chemotherapy to monitor the retina function.
Following successful treatment with regression of the tumour, surveillance needs to be continued as there can be recurrence of disease or development of additional eye tumours.
Fig. 3 (a) This is the recording of the electrical activity in a normal eye
(b) This is the recording of the electrical activity in an eye affected by a retinoblastoma. There is reduced amplitudes and loss of the normal sinusoidal pattern.
(c)This is the recording of the electrical activity of the eye shown in (b), after 2 cycles of intra-arterial chemotherapy. There is improvement in the amplitudes and more semblance to the normal sinusoidal pattern.
Will the Eyes Be Taken Out?
Overall, the need for removal of the eye to treat Retinoblastoma has gone down substantially. Once considered the treatment of first choice, it is now considered only when all other forms of conserving the eye (systemic or intraarterial chemotherapy) have been exhausted or not possible. It is typically indicated in children with advanced cancer in only one eye, especially in older children (above 2 years), when it is rapidly therapeutic and avoids the risks and complications from other forms of treatment.
Note: An eye is usually removed only when absolutely indicated and no longer the treatment of first choice.
Will My Child Appear Normal After Removal of the Eye?
Yes, most children, even when they have their eye removed are rehabilitated adequately, such that for all practical purposes, will look and behave normally. Once removed and ensured that there is no residual tumor in the eye socket, an ‘orbital implant’ is placed within the socket during the initial surgery, attached to the child’s muscles of the eye to ensure good volume and reasonable movement. While the child recovers from the surgery, a temporary ‘artificial eye’ – a customized iris painted conformer is in place, until a definitive customized ‘artificial eye’ (prosthesis) is placed after 6-8 weeks when most of the swelling from the surgery has subsided.
Can My Child Go to School Once Treated?
All children who have been treated are advised to wear protective spectacles with polycarbonate lenses, preferably tinted, so that they not only protect the eye(s) but also masks subtle differences in appearance between the eyes. Children will be able to function normally including all physical activities and studies. Children wearing prosthesis (artificial eye) are advised to wear protective goggles during swimming and contact sport but are advised to avoid injury to the normal eye.
Once Treated, How Long Should My Child Be Followed Up?
Once treated and completely rehabilitated, most children require regular and close follow up until 5 years of age, and subsequently every 6- 12 months until 10 years of age. There will possibly be annual follow ups with their eye specialists and paediatricians on a lifelong basis.
Is This A Genetic Disease? Why Should We Consider Genetic Testing?
Retinoblastoma is the first cancer to be proven with an identifiable genetic mutation. All children with Retinoblastoma in both eyes and 15-20% of children with retinoblastoma in one eye only are likely to have a mutation identified. Once identified, this mutation can be used to screen siblings and parents for similar mutation. This will help counsel parents and identify other children at risk for developing retinoblastoma. This will also reduce the risk of the surviving children themselves passing on the mutation to their offsprings when they become adults. Most importantly, in children without mutation, the costs and trouble of aggressive repeated examination under anesthesia can be minimized while also allaying the anxiety of the parents.
How Is Genetic Testing Done?
Most children are referred to the paediatric geneticist and counselled based on the family history and presentation. With informed consent, blood samples are drawn and sent to national or international referral centres for genetic mutation analysis. In special situations when the eye is removed prior to chemotherapy, tumor samples may also be used to identify genetic mutation.
Where Do NUH’s Retinoblastoma Patients Come From?
Apart from treating the Retinoblastoma patients from Singapore (2-3 /year), our patients also come from Indonesia, Vietnam, Malaysia, Myanmar, Sri Lanka and Russia.