Retinoblastoma — Current treatment and future direction
Introduction
Retinoblastoma is a malignant tumour arising from the developing retina. It typically presents in the first 2–3 years of life, often during infancy. The tumour is confined to the eye in the early stages, and cure rates for intraocular retinoblastoma can be as high as 95%. Extraocular spread (Fig. 1) carries a very poor prognosis [1], with cure rates below 5–10%. Early diagnosis and prompt treatment is therefore crucial to save life and vision.
Section snippets
Epidemiology
Retinoblastoma is the commonest primary malignant intraocular tumour of childhood accounting for up to 1% of all tumours in infancy. The age adjusted annual incidence is 12 per million population [2] under the age of 4 years.
The incidence of sporadic retinoblastoma is 1 in 15,000–20,000 live births, with no gender or racial predilection. As expected, the burden of disease is highest in populous developing countries in proportion to the birth rate [3]. The median age at presentation is under 12
Genetics
Understanding the genetics of retinoblastoma is important when planning management. The tumour arises from primitive cells of the developing retina with loss of function of the Rb tumour suppressor gene (Ch13q14). [6] The retinoblastoma gene was the first oncogene to be cloned, and is the prototype genetic cancer syndrome [7]. Other genetic cancer syndromes include the Li–Fraumeni syndrome and Xeroderma pigmentosum.
There are two copies (alleles) of the Rb gene in every cell in the body, and at
Inheritance patterns
Retinoblastoma may be inherited or occur sporadically. Over 90% of cases are sporadic (with no family history). In most of these cases the mutation is somatic and gives rise to isolated unilateral disease. A third of the sporadic cases arise from new germline mutations which are heritable (can be passed to offspring but not inherited from the parent).
40% of all cases are bilateral (and necessarily germline), and 60% are unilateral (which could be somatic or germline). Of the unilateral cases,
Presentation
Unilateral and bilateral cases differ in the manner and timing of presentation.
Bilateral cases often present with poor vision, and nystagmus or searching eye movements as a result of the tumour involving the central part of the retina (macula) in both eyes (Fig. 2), or leukocoria (white reflex in the pupil) noticed by the parents in one or both eyes (Fig. 3). Early presentation within the first few months of life is usual for bilateral cases, and even at birth in some cases.
Unilateral cases
Diagnosis
The diagnosis of retinoblastoma is essentially clinical, and may be supported by imaging in some cases. Diagnostic biopsy is contraindicated because of the risk of extraocular spread [14], [15].
The typical findings are one or more round white retinal mass(es) growing into the vitreous cavity (endophytic) or growing into the sub retinal space (exophytic). Fragments of the tumour can spread as vitreous or sub retinal seeds (Fig. 2).
A characteristic feature highly supportive of the diagnosis is
Imaging
B scan ultrasonography: confirms the presence of masses in the posterior segment of the eye. Characteristic findings are intra-lesional calcification with high internal reflectivity and acoustic shadowing.
CT/MRI scan: apart from ultrasonography, imaging is not routinely indicated. MRI may be useful if there is suspicion of extraocular (particularly intracranial) spread, if the child presents with signs of raised intracranial pressure (to look for pinealblastoma–trilateral retinoblastoma) or if
Staging
The new international classification of intraocular retinoblastoma has 5 groups — A to E of increasing severity. There is also a staging system for extraocular disease [20].
Treatment
Retinoblastoma has evolved from a deadly childhood cancer to a largely curable cancer within the past 40 years. Current treatment strategies aim to salvage the eye and provide the best visual outcome possible. This requires significant multidisciplinary input and should be coordinated by a specialised centre.
The various modalities of treatment are:
Laser treatment: laser treatment is suitable for primary treatment of smaller tumours, or larger tumours after they have been shrunk to a treatable
Research directions
The relatively small numbers of cases seen by each centre, lack of a satisfactory animal model, and numerous non-comparable staging systems have hindered retinoblastoma research in the past. The widely accepted new international classification system, and multicentre studies currently underway will pave the way for a more evidence based approach to retinoblastoma management.
Current research is directed towards
- 1.
A better understanding of genotype–phenotype relationships in retinoblastoma that will
Treatment principles
Retinoblastoma is a unique cancer by virtue of its confinement within the scleral envelope, and has a 95% cure rate with appropriate treatment. The diagnosis is clinical, and it is important to avoid breaching this envelope with an intraocular procedure such as diagnostic biopsy to avoid the mortality associated with extraocular spread.
A combination of treatment modalities e.g. chemotherapy with laser, cryotherapy or plaque brachytherapy helps minimize adverse effects [28].
Close monitoring with
Supportive treatment
- 1.
Prosthesis fitting for enucleated eyes — is an important part of rehabilitation, usually a few weeks after surgery.
- 2.
Psychological support for children and families — to deal with loss of eye, vision and a chronic illness
- 3.
Protective eye wear for the better/remaining eye during contact sport
- 4.
Long term oncological surveillance especially for germline cases — this is best undertaken by oncologists.
- 5.
Counseling — parents should be counseled soon after diagnosis, and the patients when they reach
Prenatal diagnosis — the role of imaging and tissue sampling
If there is a family history of retinoblastoma and the mutation in the affected parent is known, there are several options to prevent retinoblastoma or enable early detection
- i.
Pre-implantation genetic diagnosis (PIGD) involves screening embryos at the blastocyst stage. One cell is removed from the embryo to look for the mutation. Unaffected embryos are selectively implanted ensuring the fetus is born free of the retinoblastoma mutation and does not require screening. Additionally, there is no
Screening for retinoblastoma
Screening close relatives of retinoblastoma patients is invaluable in early detection and treatment, saving eyes and lives. If the mutation for the index case is known, testing can be offered to relatives to determine if they are at risk of suffering/passing on the disease.
Screening is offered if
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mutation positive or
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if the mutation is not known for the index case, and risk cannot be excluded.
Most centres will have protocols for screening. A suggested protocol is shown in Table 2. Screening is
Prognosis for life
Most untreated tumours proceed to local invasion and metastasis to cause death within 2 years. Occasionally however, the tumour may spontaneously stop growing to form a retinoma, or necrose to cause phthisis bulbi (shrunken globe).
Most small/medium tumours without vitreous seeding can be successfully treated while preserving useful vision. Overall there is a 95% survival rate (in the developed world). Poor prognostic factors include: size of tumour, optic nerve involvement, extraocular spread
Recurrence
Recurrence can develop within the eye in previously treated tumours, and regular follow-up examinations are essential. Delayed extraocular recurrence in the orbit or distant metastases may be seen in a small number of advanced cases that appeared to be restricted to the eye at initial presentation, and/or were negative on metastatic workup. Metastases may occur several decades after the initial presentation. The management of these cases can be challenging [33].
Risk of second cancers and the role of long term surveillance
Patients with germline mutations are at increased risk of developing secondary malignancies such as pinealblastoma (trilateral retinoblastoma) [34] ectopic intracranial retinoblastoma, and osteogenic or soft tissue sarcomas, melanoma and bladder cancer [35].
The cumulative risk of second cancers has been reported between 20 and 48% over 50 years in various studies [36]. This risk is increased with radiation exposure [37]. The role of long term screening of retinoblastoma survivors is not clearly
Summary
There have been significant advances in our understanding and management of retinoblastoma over the past few decades. Early detection to minimize visual morbidity remains the focus of research in countries with universal access to healthcare. Late presentation with life threatening disease is a major challenge in economically underprivileged countries, and strategies must focus on raising awareness and acceptance of modern treatment methods through health workers. Developing a global network of
Key guidelines
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If diagnosed early and treated appropriately, cure rate for intraocular retinoblastoma is over 95%. Prognosis for extraocular disease is very poor.
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There are 2 forms- genetic and non genetic (somatic). Genetic retinoblastoma often presents in infancy while somatic retinoblastoma usually presents later.
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Unilateral cases can be somatic or germline. Bilateral cases are alwaysgermline. 90% cases are sporadic.
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Prenatal diagnosis is available, including PIGD.
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Leucocoria and squint are the commonest
Acknowledgements
My patients and their families who deal with the disease with such dignity and bravery, and my colleagues in the Birmingham Children's Hospital Retinoblastoma Unit who make my work enjoyable and from whom I learn so much.
References (38)
- et al.
Unilateral retinoblastoma in an adult: report of a case and review of the literature
Ophthalmology
(1997 Jan) - et al.
Vitrectomy in eyes with unsuspected retinoblastoma
Ophthalmology
(2000 Dec) - et al.
Retinoblastoma and simulating lesions. Role of CT, MR imaging and use of Gd-DTPA contrast enhancement
Radiol Clin North Am
(1998 Nov) - et al.
(106)Ruthenium brachytherapy for retinoblastoma
Int J Radiat Oncol Biol Phys
(2008 Jul 1) - et al.
Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors
Ophthalmology
(2001 Nov) - et al.
Radiation-induced osteosarcomas in the pediatric population
Int J Radiat Oncol Biol Phys
(2005 Nov 15) - et al.
Survival in extra-orbital metastatic retinoblastoma:treatment results
Clin Transl Oncol
(2006 Jan) - et al.
Cancer incidence among children and adolescents in Brazil: first report of 14 population-based cancer registries
Int J Cancer
(2010 Feb 1) - et al.
Retinoblastoma: one world, one vision
Pediatrics
(2008 Sep) - et al.
Retinoblastoma in the first year of life
Ophthalmic Paediatr Genet
(1992 Dec)