Retinoblastoma

The commonest primary intraocular malignancy of childhood, arising from primitive retinal cells.

It occurs in both hereditary and non-hereditary forms. The hereditary form is bilateral or, in a proportion, unilateral. It reflects a germline RB1 gene mutation and carries substantial implications for the individual's future risk of second malignancy and for genetic counselling of the family.

The non-hereditary form is unilateral and sporadic. It reflects a somatic mutation confined to the tumour, without germline involvement.

The characteristic presenting feature is leukocoria: an abnormal white pupillary reflex replacing the normal red reflex. This is an essential clinical sign warranting urgent ophthalmological referral.

Prompt diagnosis and treatment bear directly on survival and on preservation of vision and, where feasible, the eye itself.

Pathophysiology and genetics

• Retinoblastoma arises from biallelic inactivation of the RB1 tumour suppressor gene within a developing retinal cell, following the classical "two-hit" model.
• In hereditary retinoblastoma, an inherited or de novo germline mutation affects one allele. This "first hit" is present in every cell of the body from conception.
• Tumour develops after a subsequent somatic "second hit" affects the corresponding allele within a retinal cell.
• The very large number of retinal cells already carrying the germline mutation makes a second hit substantially more probable. This explains the tendency toward bilateral, multifocal tumours and earlier onset in the hereditary form.
• Non-hereditary retinoblastoma reflects two independent somatic mutational events within the same retinal cell, without any germline RB1 mutation. This accounts for the characteristic unilateral, unifocal presentation and generally somewhat later onset.
• Individuals with hereditary retinoblastoma carry a substantially increased, lifelong risk of second primary malignancy. This occurs within the field of any radiotherapy received, should it be used, and independently at other sites, including osteosarcoma and soft tissue sarcoma.
• This reflects the tumour suppressor function of RB1 across multiple tissue types beyond the retina. It is an essential consideration for long-term surveillance and for choice of treatment modality.

• Leukocoria is the classic and commonest presenting sign. It is an abnormal white or whitish-yellow pupillary reflex replacing the normal red reflex.
• A parent may first notice it in a flash photograph, where the affected eye looks white rather than red. It reflects light reflection from the white, tumour-replaced retinal surface.
• It warrants urgent ophthalmological referral, as it is associated with this and other serious conditions. Congenital cataract is an important alternative diagnosis requiring careful clinical distinction.
• Strabismus is a further common presenting feature. It reflects visual impairment from a macular or more central tumour disrupting normal binocular visual development and alignment.
• Less common features include a visibly red, painful eye, reflecting secondary glaucoma or intraocular inflammation with more advanced tumour.
• Proptosis reflects extraocular tumour extension. It occurs in advanced presentations, which are now uncommon because of earlier detection.
• In known hereditary disease with an established family history, tumour may be identified through proactive ophthalmological screening of at-risk infants before any symptom develops.
• Any abnormal red reflex or suspected leukocoria in an infant or young child warrants urgent ophthalmological assessment. This applies whether it is noted by a parent, in a photograph, or on routine examination. Timely, accurate diagnosis is critical to optimal management.

• Full ophthalmological examination under anaesthesia is the essential diagnostic approach. It allows thorough examination of the retina and identification of the characteristic tumour appearance: a white or cream-coloured retinal mass, with a chalky, calcified appearance frequently apparent on imaging.
• Assess both eyes carefully, given the possibility of bilateral, multifocal disease.
• Diagnosis is generally established clinically rather than by biopsy, because of the substantial risk of tumour seeding along a biopsy tract. Biopsy is avoided wherever the characteristic clinical and imaging appearance suffices.
• Ocular ultrasound and magnetic resonance imaging characterise tumour extent, including optic nerve invasion or extraocular extension. This is essential for staging and treatment planning.
• Magnetic resonance imaging is also used in bilateral, hereditary retinoblastoma to screen for the rare but recognised association with intracranial pineal region tumour, historically termed "trilateral retinoblastoma".
• Genetic testing for RB1 mutations is performed in every confirmed case. It classifies disease as hereditary or non-hereditary.
• The result informs prognostic counselling on future second malignancy risk. It also informs genetic counselling for the family on recurrence risk in future pregnancies and the need for structured screening of at-risk siblings.
• Proactive ophthalmological screening of at-risk infants (siblings or offspring of an individual with confirmed hereditary retinoblastoma) starts from birth and continues at regular intervals through early childhood. It supports earlier tumour detection, before symptoms develop, in this higher-risk population.

• Treatment is individualised according to tumour size, location, laterality, and the presence or absence of high-risk features, including optic nerve invasion.
• The goals, in order of priority, are preservation of life, preservation of the eye, and preservation of useful vision. The balance and achievability of these goals vary with tumour characteristics.
• Smaller, localised tumours are frequently managed with focal treatment: laser photocoagulation, cryotherapy, or thermotherapy. The aim is to destroy the tumour while preserving the eye and, where location permits, useful vision.
• Intra-arterial chemotherapy is delivered directly by selective catheterisation of the ophthalmic artery. It is an effective and increasingly used approach for more advanced intraocular disease.
• It delivers a high local drug concentration to the tumour while minimising systemic exposure, a significant advance in eye-preserving treatment.
• Systemic chemotherapy is used for bilateral disease, more advanced intraocular tumours, or evidence of extraocular extension.
• Intravitreal chemotherapy injection is used for tumours with vitreous seeding.
• Enucleation (surgical removal of the affected eye) remains necessary for advanced, unilateral disease not amenable to eye-preserving treatment. It is also used where there is significant concern about optic nerve invasion or other high-risk features carrying substantial risk of extraocular spread.
• Where the goals conflict, adequate oncological treatment and preservation of life take priority over eye preservation.
• External beam radiotherapy, historically important, is now generally avoided or used with particular caution, particularly in hereditary disease. There is substantial concern about radiation-induced second malignancy in this genetically predisposed population.
• This reflects an evolution in approach as effective alternatives, particularly intra-arterial chemotherapy, have become more widely available.
• Structured, long-term surveillance follows successful treatment. It monitors for local tumour recurrence and, in confirmed hereditary disease, provides lifelong surveillance for second primary malignancy.
• Genetic counselling for the family covers recurrence risk and the need for structured screening of at-risk relatives.
• Support addresses the visual and psychosocial needs of the child and, where enucleation was required, prosthetic and cosmetic needs.