Retinoblastoma

• Summary
• Epidemiology
• Genetics
• Clinical features
• Physical examination
• Fundus examination
• Ultrasound examination
• Histopathology
• Screening
• Diagnosis
• Classification
• Management
• References
• Author(s)

Summary

Retinoblastoma is an intraocular malignancy of neuroectodermal origin that arises in the retina. It primarily affects young children, and overall is the most common intraocular malignancy in children. Retinoblastoma typically presents with leukocoria (a white pupillary reflex) or strabismus (a squint). Treatment is very effective, curing 98% of children with retinoblastoma.

Epidemiology

Retinoblastoma typically affects young children, and is most common in children under 4 years old. About 40 cases of retinoblastoma are diagnosed each year in the UK (approximately 1:17,000 births).

Genetics

It has long been known that there is a genetic predisposition to some forms of retinoblastoma due to familial cases. Knudson’s “two-hit” hypothesis for tumourigenesis describes that mutations in both active copies of a gene are required for the development of retinoblastoma. The first “hit” (mutation) can occur in somatic or germline cells; and the second “hit” occurs in somatic cells in the developing retina.

The retinoblastoma gene (RB1), a tumour suppressor gene on chromosome 13q14 (the long arm of chromosome 13), was identified by Friend in 1986. As a tumour suppressor gene, RB1 restricts uncontrolled progress through the cell cycle (compared to oncogenes, which promote cell growth). Both alleles of a tumour suppressor gene must be inactivated for tumour development.

There are two forms of retinoblastoma, depending on whether the first “hit” (mutation) is genetic or somatic.

1. Familial (germline) cases (40% of retinoblastoma cases) - all cells in the body carry one mutated copy of RB1, and the second mutation is somatic. These patients tend to have bilateral and multifocal tumours. They have a significantly increased risk of secondary tumours, including primitive neuroectodermal tumours in the brain - termed “trilateral retinoblastoma”. There is a 45% chance that offspring will develop retinoblastoma (because the trait is inherited in an autosomal dominant fashion with 〜90% penetrance).
2. Sporadic cases (60%) - two RB1 mutations occur in a somatic cell of the developing retina. This form is not heritable. Patients present with unilateral disease.

Table summarising the key differences between familial and sporadic retinoblastoma.

Clinical features

As mentioned, 40% of retinoblastoma cases are bilateral and 60% are unilateral.

Physical examination

Typical clinical signs on physical examination include:

• Leukocoria (whitening of the red reflex) - this is the most common sign of retinoblastoma, and indicates that the pupil is not reflecting light. It is often picked up on flash photography, with the child’s affected eye appearing white in the photograph
• Strabismus (squint)
• Deterioration of vision
• Painful/inflamed eye - this is a rare presentation, but may occur when the tumour is large or has spread outside the globe. Retinoblastoma should be a differential in children presenting with a red eye or cellulitis-like picture

Fundus examination

The classical finding is one or multiple nodular, white/cream-coloured masses, often with increased vascularisation.

There are two main patterns of retinoblastoma growth:

• Endophytic growth: the tumour grows anteriorly into the vitreous, causing vitreous seeding —> vitreous haze and opacities. This can progress into the anterior chamber —> secondary glaucoma and inflammation
• Exophytic growth: the tumour grows posteriorly, extending beneath the retina (subretinal) —> exudative retinal detachments and subretinal seeding

Retinoblastoma can also invade locally into the choroid or sclera, or spread along the optic nerve directly into the orbit. It can metastasise haematogenously to the brain, bone, liver and other organs.

Ultrasound examination

The classical sign of intra-tumoural calcification on ultrasound is diagnostic for retinoblastoma.

Histopathology

• Flexner-Wintersteiner rosettes - a retinoblastoma “buzzword”, these are rings of cells surrounding a lumen
• Homer Wright pseudorosettes (rings of cells with fibrin centre)
• Fleurettes (retinoblastoma cells, less likely to be examined on!

Screening

Where there is a family history of retinoblastoma, children will be screened by:

1. A blood test to look for a mutation in the RB1 gene
2. Regular ophthalmoscopy starting shortly after birth

Regardless of family history, every newborn should have an examination of the red reflex during the newborn and infant physical examination (NIPE). An abnormal red reflex requires immediate referral to an ophthalmologist.

Diagnosis

Early diagnosis of retinoblastoma optimises the child’s visual prognosis and survival rate.

Unlike other types of cancer, diagnosing retinoblastoma does not involve a biopsy. Instead, it is diagnosed on examination under anaesthesia (EUA) with extensive ophthalmoscopy.

Other useful investigations include:

• Ultrasound scan and MRI: to determine tumour size and location. CT scans are avoided because radiation can be harmful to children and increase the risk of secondary tumours.
• Lumbar puncture, bone marrow biopsy and bone scan: to look for metastasis to the cerebrospinal fluid or bones
• Blood test: genetic testing for RB1 mutations is recommended in all retinoblastoma cases

Classification

The International Classification of Retinoblastoma (ICRB) is a staging system used to predict which patients are likely to be cured of intraocular retinoblastoma without the need for enucleation or external-beam radiotherapy. It divides intraocular retinoblastoma into 5 groups, A-E, based on the extent of the tumour, with worsening prognosis as we go from A —> E.

Management

When managing retinoblastoma, the priorities in order of importance are:

1. Preserve life
2. Preserve globe
3. Preserve vision

Minimising side effects from treatment is also very important in young children.

Definitive treatment for intraocular retinoblastoma, particularly in advanced unilateral disease with poor visual prognosis, is enucleation. At least 1cm of optic nerve is removed to ensure the nerve is free from tumour and reduce risk of relapse. After enucleation, an orbital implant is placed so help the orbital develop normally, and an ocular prosthesis is fitted.

When the globe is salvageable, chemotherapy with focal consolidation therapy and intra-arterial chemotherapy may be used.

For small tumours, focal consolidation therapy alone can be used. This includes:

• Laser photocoagulation
• Cryotherapy
• Hyperthermia
• Plaque irradiation

Intravitreal chemotherapy is a new treatment that is useful for treating vitreous seeding. In the past, external beam radiotherapy (EBRT) was used for recurrent tumours and vitreous seeding, but it is best to avoid exposing young children to radiation.

References

1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.
2. ‘Review of Retinoblastoma’. American Academy of Ophthalmology, 28 Apr. 2016, https://www.aao.org/disease-review/review-of-retinoblastoma.
3. Retinoblastoma. https://www.cclg.org.uk/Retinoblastoma. Accessed 14 Sept. 2022.
4. Retinoblastoma Stages. https://www.cancer.org/cancer/retinoblastoma/detection-diagnosis-staging/staging.html. Accessed 30 Sept. 2022.
5. Aerts, Isabelle, et al. ‘Retinoblastoma’. Orphanet Journal of Rare Diseases, vol. 1, Aug. 2006, p. 31. PubMed, https://doi.org/10.1186/1750-1172-1-31.
6. Shah, Parag K., et al. ‘In Vivo Growth of Retinoblastoma in a Newborn Infant’. Indian Journal of Ophthalmology, vol. 58, no. 5, 2010, pp. 421–23. PubMed Central, https://doi.org/10.4103/0301-4738.67066.

Author(s)

Jessica Mendall

Jessica is a final year medical student studying in London. She previously studied preclinical medicine in Oxford, intercalating in Systems Neuroscience and Molecular Pathology. She is particularly interested in Ophthalmology, medical education and clinical research.