Medicine – Retinoblastoma

Retinoblastoma is a rare malignant tumour of the developing retina and is the most common primary intraocular malignancy of childhood. It arises from immature retinal cells following loss of normal function of the RB1 tumour-suppressor gene.

Early recognition is extremely important because retinoblastoma is potentially life-threatening, but treatment can achieve excellent survival when the disease is detected before extraocular spread.

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1. Age of Presentation

Retinoblastoma occurs almost exclusively in young children, with most cases diagnosed before the age of 5 years.

Heritable and bilateral disease tends to present particularly early, often during the first few years of life.

Therefore, the traditional association with a child younger than 3 years is a useful clinical clue, although it should not be regarded as an absolute age limit.

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2. The RB1 Tumour-Suppressor Gene

Retinoblastoma is strongly associated with abnormalities of the RB1 gene, a tumour-suppressor gene located on chromosome 13q14.

The normal RB protein helps regulate progression through the cell cycle and prevents inappropriate cellular proliferation.

When both functional copies of RB1 are lost within a retinal precursor cell, normal cell-cycle control is disrupted and a malignant tumour can develop.

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3. The Two-Hit Hypothesis

Retinoblastoma is the classic disease used to explain Knudson’s two-hit hypothesis.

Both copies of the RB1 tumour-suppressor gene must effectively be inactivated within a susceptible retinal cell for tumour formation.

However, the way these two genetic “hits” occur differs between heritable and non-heritable retinoblastoma.

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4. Heritable Retinoblastoma

In heritable retinoblastoma, the child already carries a pathogenic RB1 variant in one copy of the gene in the germline.

Therefore:

First hit → inherited or newly arising germline RB1 pathogenic variant.

A retinal cell subsequently loses or inactivates its remaining functional RB1 copy:

Second hit → somatic loss/inactivation of the remaining normal RB1 allele.

This leads to tumour formation.

Because every retinal cell already carries the first hit, several independent retinal cells may acquire a second hit.

Consequently, heritable disease is more likely to be bilateral and multifocal.

Importantly, the germline RB1 alteration may be inherited from a parent or arise de novo in the affected child, so absence of a family history does not exclude heritable disease.

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5. Non-Heritable Retinoblastoma

Not every child with retinoblastoma inherits an abnormal RB1 gene.

In non-heritable or sporadic retinoblastoma, both RB1 abnormalities generally arise somatically within the same retinal cell lineage.

Because two independent events must occur in one retinal cell, these tumours tend to occur somewhat later and are usually unilateral and unifocal.

Therefore, the original statement that all patients inherit one abnormal RB1 gene applies specifically to the heritable form, not to every retinoblastoma.

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Clinical Presentation

The classic presenting features are leukocoria, strabismus, and an abnormal or absent red reflex.

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6. White Pupil – Leukocoria

The most characteristic presentation is leukocoria, meaning a white pupillary reflex.

Instead of the normal reddish-orange reflection seen when light enters the pupil, the affected eye may show a white reflection because light is reflected from the retinal tumour.

Parents sometimes first notice leukocoria in a flash photograph, where one pupil appears white rather than showing the expected red reflex.

Leukocoria in a child requires urgent ophthalmological assessment.

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7. Squint – Strabismus

Strabismus, or squint, is another important presentation.

The affected eye may deviate because the tumour interferes with central vision, preventing normal binocular visual alignment.

A new unexplained squint in a young child therefore requires proper ocular assessment rather than being assumed to be benign.

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8. Loss of the Red Reflex

A normal eye produces a symmetrical red reflex when examined with an ophthalmoscope.

Retinoblastoma may replace this normal reflex with an abnormal, reduced, asymmetric, or white reflex.

The red-reflex examination is therefore an important part of evaluating infants and young children.

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9. Other Presentations

More advanced retinoblastoma can occasionally cause reduced vision, a red or painful eye, glaucoma, or enlargement/protrusion of the eye.

These presentations generally suggest more advanced intraocular disease and are less desirable than detecting the tumour at the leukocoria stage.

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10. Diagnosis

A child suspected of having retinoblastoma requires urgent specialist ophthalmological assessment.

Detailed examination of the retina, often under anaesthesia in young children, is central to diagnosis.

Imaging such as ocular ultrasonography and MRI can help assess the tumour and determine whether there is involvement of structures such as the optic nerve or central nervous system.

MRI is particularly useful because it avoids unnecessary ionising radiation, which is especially relevant in children with germline RB1 abnormalities.

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11. Treatment

Treatment depends on whether disease is unilateral or bilateral, the size and location of the tumour, whether vision can be preserved, and whether disease has spread beyond the eye.

Modern treatment aims first to save the child’s life, then whenever possible to preserve the eye and useful vision.

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12. Local Treatment

Small tumours may sometimes be treated with local therapies such as laser treatment or cryotherapy.

These approaches destroy tumour tissue while attempting to preserve surrounding ocular structures.

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13. Chemotherapy

Chemotherapy may be used to shrink or control retinoblastoma.

Modern specialist treatment may involve systemic chemotherapy, intra-arterial chemotherapy delivered through the ophthalmic artery, or intravitreal chemotherapy depending on the pattern and extent of disease.

These techniques have improved the ability to preserve affected eyes in selected children.

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14. Enucleation

Enucleation, or surgical removal of the affected eye, may be required for a large advanced tumour when useful vision cannot be preserved or when the tumour presents a significant risk of extraocular spread.

Although eye preservation is desirable, control of potentially fatal malignancy remains the priority.

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15. Association with Osteosarcoma

Children with heritable RB1-related retinoblastoma have an increased lifetime risk of developing second primary malignancies.

One of the classic associations is osteosarcoma.

The underlying germline RB1 abnormality predisposes cells elsewhere in the body to malignant transformation, explaining why the cancer risk extends beyond the retina.

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16. Other Second Malignancies

The increased risk is not limited to osteosarcoma.

Patients with heritable retinoblastoma may also have an increased risk of other malignancies, including soft-tissue sarcomas and melanoma, among others.

Historically, radiotherapy could further increase the risk of subsequent malignancy, particularly in genetically susceptible patients.

Long-term surveillance is therefore important.

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17. Retinoblastoma – Note Form

Definition: malignant tumour arising from the retina in young children.

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Typical age: usually presents in early childhood, commonly before 5 years and often before 3 years.

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Gene: associated with loss of the RB1 tumour-suppressor gene on chromosome 13q14.

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Mechanism: both functional copies of RB1 must be inactivated—the classic two-hit hypothesis.

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Heritable disease: one RB1 pathogenic variant is already present in the germline, followed by somatic loss of the remaining functional allele.

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Pattern of heritable disease: tends to present earlier and is more likely to be bilateral and multifocal.

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Sporadic/non-heritable disease: both RB1 hits usually occur somatically within retinal cells.

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Pattern of sporadic disease: more commonly unilateral and unifocal.

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Most characteristic presentation: leukocoria—a white pupillary reflex.

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Other important presentation: strabismus (squint).

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Red reflex: may be absent, asymmetric, abnormal, or replaced by a white reflex.

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Treatment: specialist therapy may include local laser/cryotherapy, chemotherapy, and enucleation for selected advanced tumours.

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Important association: patients with heritable RB1 disease have an increased risk of subsequent malignancies, classically osteosarcoma.

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Key Clinical Pattern

Think of retinoblastoma when a very young child develops:

White pupil (leukocoria) + abnormal/lost red reflex ± squint.

The genetics can be remembered as:

RB1 tumour suppressor → two hits required → loss of both functional copies → retinoblastoma.

Heritable disease already has the first RB1 hit in the germline, making early, bilateral, or multifocal tumours more likely and increasing the lifetime risk of other malignancies, particularly osteosarcoma.

The most important examination association is:

Child + leukocoria → retinoblastoma must be urgently excluded.