Retinoblastoma is a malignant tumour of the retina and is caused by a loss of function of the RB tumour suppressor gene (Ch13q14)
Gene (Locus) = RB1 (13q)
Gene Product (Function) = RB (cell cycle regulator)
- The most common intraocular malignancy of childhood.
- Exists in SPORADIC (new germline mutation) and HERITABLE (germline mutation from parents) forms.
- Leukocoria frequently present.
- Requires immediate urgent referral to ophthalmology and paediatric specialists upon suspicion of disease.
- Most common malignant tumour of the eye in children
- Accounts for 3% of all childhood cancers
- Arises once in every 15,000-18,000 live births in developed countries
- Often present at birth
- 80% of cases occur prior to the child reaching four years
- 60% of cases are non-hereditable and unilateral
- 40% are hereditable, of which 15% are unilateral and 25% are bilateral
- Often present at birth, but some cases of retinoblastoma in early adulthood have been reported
- No gender or race predispositions
- Retinoblastoma is caused by a mutational inactivation of both alleles of the retinoblastoma (RB1) gene, which maps onto chromosome 13q14.
- RB1 encodes a tumour suppressor nuclear protein.
- A “two-hit” model has been proposed.
- There is incomplete penetrance with approximately 90% of genotypic carriers expressing malignancy.
- Forms with lower penetrance are probably related to only partial inactivation of the RB1 gene.
- Mutation at the RB1 locus present in all cells of individual
- Second somatic mutation occurring later in development affects remaining RB1 allele within retinal cells
- More likely to be multifocal and bilateral
- Both allelic mutations arise spontaneously in a single somatic cell of the retina
- More likely to be unifocal and unilateral
Routes of spread
- Direct infiltration via the optic nerve to the CNS
- Spread via the choroid to the orbit
- Dispersion of tumour cells through subarachnoid space to contralateral optic nerve or to the CNS
- Spread by blood to lung, bone and/or brain
- Spread by lymphatics if tumour spreads anteriorly into the conjunctivae and eyelids or extends into extraocular tissue
Common and uncommon
- Leukocoria is most common presenting finding (though not necessary for diagnosis)
- Known family history of disease
- Decreased vision
- Ocular inflammation
- Iris heterochromia, may be caused by neovascularisation of iris (rubeosis iridis)
- Vitreous haemorrhage (dark instead of white light reflex)
- Hyphaema (blood in anterior chamber of eye) in absence of trauma
- Anisocoria (unequal size of pupils)
- Orbital cellulitis from tumour necrosis with proptosis and eye pain
- Solitary or multifocal
- Intraretinal mass
- Tumour becomes more pink
- Dilated feeding blood vessels
Would grow in one of three ways
- Exophytic (Vertical growth beneath retina towards and into subretinal space)
- Endophytic (Vertical growth is towards and into the vitreous cavity)
- Diffuse infiltrating retinoblastoma (Little vertical growth, remains flat, grows intraretinally and mimics retinitis)
Children that present with the following must be seen by a specialist within a week
- White pupillary reflex (leukocoria)
- Noted by the parents
- Identified in photographs
- Found on examination
- A new squint or change in visual acuity with an accompanying family history of retinoblastoma
Dilated indirect ophthalmoscopic examination performed under anaesthesia reveals
- Chalky, white-gray retinal mass with a soft, friable consistency
- Multifocal tumours and/or subretinal or vitreous seeding
Ocular ultrasonography and/or computed tomography (CT) reveals
- Solid intraocular tumour with characteristic intratumoural calcifications
Magnetic resonance imaging (MRI) reveals
- Intraocular mass (especially important if Coats’ disease is differential)
- Tumour size
- Optic nerve involvement
- Presence of an associated intracranial lesion
Main differential diagnoses are diseases that present with leukocoria
- Persistent fetal vasculature
- Coats' disease
- Ocular toxocariasis
Reese-Ellsworth Staging Classification of Retinoblastoma
Group I Very Favourable
A Solitary tumour smaller than 4 disc diameters (at or behind equator)
B Multiple tumours smaller than 4 disc diameters (at or behind the equator)
Group II Favourable
A Solitary tumour 4-10 disc diameters (at or behind equator)
B Multiple 4-10 disc diameters (at or behind equator)
Group III Doubtful
A Any lesion anterior to the equator
B Solitary tumours larger than 10 disc diameters behind the equator
Group IV Unfavourable
A Multiple tumours, some larger than 10 disc diameters
B Any lesion extending anteriorly to the ora serrata
Group V Very unfavourable
A Tumours involving more than half the retina
B Vitreous seeding
Taken from Table 33 of NICE guidelines CG27: Referral for suspected cancer
Treatment of retinoblastoma is determined by
- Disease laterality
- Genetic inheritance
- Risk of metastasis
- Risk of recurrence or second tumour
- Systemic wellbeing
- Age of patient
Tumour Characteristics and Likely Treatment Options
Small Tumours : Transpupillary thermotherapy or cryotherapy.
Medium-Sized Tumours : Thermotherapy or cryotherapy if possible. Brachytherapy if there is no seeding, and chemotherapy (Carboplatin, Vincristine, Etoposide with or without Ciclosporin) if there is seeding.
Large Tumours : Chemotherapy, augmented by thermotherapy or cryotherapy. Enucleation if former can't be done.
Extraocular Extension : Enucleation followed by chemotherapy. Irradiation of affected orbit and exenteration may be performed.
Metastatic Disease : High-dose chemotherapy.
*All treatment options bode complications, for instance, cataract formation, orbital growth abnormalities and secondary malignancies in the case of radiotherapy.
*After successful treatment, follow-ups must still be done on a regular basis.
Natural History and Prognosis
- Untreated, retinoblastoma grows to fill the eye and destroys the internal architecture of the globe.
- Spontaneous regression is possible but rare.
- Retinocytoma, a small benign tumour with surrounding chorioretinal atrophy, is a rare condition caused by RB1 mutation.
- Metastatic spread usually after 6 months, with death ensuing within 2 years.
- In developed countries, mortality is 2-5% depending on size, location, stage and grade.
- Older age of child, CNS spread along optic nerve, spread to orbit or distant metastases and trilateral tumour are associated with early mortality.
- Later mortality is strongly associated with formation of other tumours.
- Cumulative incidence is approximately 1% a year and may occur as late as 20 years on from original presentation.
Oxford Clinical Handbook 8th Edition
Uptodate article on Retinoblastoma
Interesting Videos and Websites
(Homemade video of an ex-retinoblastoma sufferer)
(National Cancer Institute)
(BBC Health, written for lay people)