Retinoblastoma: An Overview and Latest Advances

 Luai Kawar

Introduction

Retinoblastoma is the most common paediatric intraocular malignancy, accounting for around 3% of all childhood cancers (1). Due to their aggressive and potentially life-threatening nature, early diagnosis and treatment are essential. Recent advances in genetic testing, imaging, and targeted therapies have significantly improved outcomes in those affected by retinoblastoma. This article explores the latest advancements in the diagnosis and management of this potentially life-threatening disease.

Molecular pathology

The primary genetic insult in retinoblastoma is an inactivation mutation of the RB1 gene. This gene encodes a regulatory protein that stops progression from G1 to S phase of the cell cycle (2). The latest evidence suggests that the cone photoreceptor cells in the retina are primarily affected by this inactivation mutation (3). Other genetic culprits have been found to cause retinoblastomas, including MYCN oncogene amplification (4).

Knudson’s two-hit hypothesis forms the basis for retinoblastoma formation – with two successive mutational events required. In hereditary retinoblastomas, the initial mutation is present in all cells, which makes it more likely to have bilateral or multifocal disease. Those that are not inherited (which account for 60% to 70% of retinoblastomas) are more likely to be unilateral (5).

Clinical features

The most common sign of a retinoblastoma is leukocoria. Other presenting features may include strabismus, glaucoma, proptosis or reduced visual acuity. The tumour can either extend into the vitreous from inner retinal layers or spread into the subretinal space from outer retinal layers (6). They can also cause diffuse thickening of the retina.

A biopsy is contraindicated due to risk of tumour dissemination. Instead, retinoblastomas can be graded by ocular examination under anaesthesia. The anterior chamber may be involved due to tumour seeding; presenting with a hyphema, pseudo-hypopyon, rubeosis iridis or corneal edema. Don’t forget to regularly examine the fellow eye on follow-up!

Advances in Diagnosis

Wide-angle fundus imaging, such as RetCam, has revolutionised the diagnosis and monitoring of retinoblastoma, especially since it facilitates fluorescein angiography to detect angiogenesis (7). Optical coherence tomography (OCT) is also an invaluable tool – especially for smaller intraretinal tumours. Other imaging techniques offer unique benefits. For example, MRI can detect extraocular involvement and other high-risk features (eg, scleral invasion, pre-laminar optic nerve spread), ultrasound B-scan can identify calcifications and vitreous seeds and ultrasound biomicroscopy (UBM) enhances the ability to evaluate anterior segment involvement, uveal extension, and angle closure (5).

Genetic testing is essential to detect underlying heritable mutations in order to provide adequate genetic counselling and optimise targeted therapies. Modern techniques, including next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA), have improved high mutation detection rate (8).

Liquid biopsy is an emerging innovation in the management of retinoblastoma. By analysing cell-free DNA (cfDNA) present in aqueous humour samples, this minimally invasive technique allows for genomic profiling in cases where eye salvage is pursued. Acting as a substitute for conventional tumour biopsy, which is contraindicated due to the risk of dissemination, liquid biopsy overcomes the historical reliance on tumour DNA from enucleated eyes. This method holds immense potential for advancing genomic analysis and facilitating personalised treatment strategies for retinoblastoma (9).

Advances in Treatment

Different modalities for managing retinoblastomas exist with continual research onto the effectiveness of different techniques. The choice of treatment depends on a multitude of factors, including age, laterality, underlying germline mutation and visual potential. 

Intravenous chemotherapy (IVC) is an option for bilateral, germline-associated retinoblastomas or those with choroidal or optic nerve invasion. Regimens include vincristine, etoposide and carboplatin (VEC). Intra-arterial chemotherapy (IAC) is a technique in which chemotherapy is injected directly into the ophthalmic artery via fluoroscopy-guided microcatheterisation. This is a useful option for unilateral, non-germline tumours. Intravitreal chemotherapy (IVitC) and intracameral chemotherapy (ICamC) have shown promising results in mitigating dissemination risks, inducing regression and salvaging globes (10).

Focal treatments may be used to consolidate tumour control or treat small recurrences, including transpupillary thermotherapy (TTT) where diode laser induces hyperthermia for small tumours, cryotherapy and plaque brachytherapy (11).

Conclusion

Advances in the diagnosis and treatment of retinoblastoma have significantly improved survival rates and quality of life for affected children. Innovations such as intra-arterial and intravitreal chemotherapy, genetic testing, and emerging molecular therapies offer new hope for treatment. These developments underscore the importance of multidisciplinary collaboration and ongoing research in the management of retinoblastoma.

References

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  2. Yun J, Li Y, Xu CT, Pan BR. Epidemiology and Rb1 gene of retinoblastoma. International journal of ophthalmology [Internet]. 2011 Feb 18;4(1):103–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340672/
  3. Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, et al. Retinoblastoma. Nature Reviews Disease Primers [Internet]. 2015 Aug 27 [cited 2020 Jan 12];1(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744255/
  4. Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Thériault BL, et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. The Lancet Oncology [Internet]. 2013 Apr 1;14(4):327–34. Available from: https://www.thelancet.com/journals/lancet/article/PIIS1470-2045(13)70045-7/fulltext
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  6. Houston SK, Murray TG, Wolfe SQ, Fernandes CE. Current Update on Retinoblastoma. International Ophthalmology Clinics. 2011;51(1):77–91.
  7. Gündüz AK, Tetik D. Follow-up of retinoblastoma using RetCam fluorescein angiography and correlation with clinical findings. European journal of ophthalmology [Internet]. 2023 Nov;33(6):2290–302. Available from: https://pubmed.ncbi.nlm.nih.gov/36935642/
  8. Soliman SE, Racher H, Zhang C, MacDonald H, Gallie BL. Genetics and molecular diagnostics in retinoblastoma—An update. Asia Pac J Ophthalmol (Phila) 2017;6:197–207. doi: 10.22608/APO.201711.
  9. Berry JL, Xu L, Murphree AL, Krishnan S, Stachelek K, Zolfaghari E, et al. Potential of aqueous humor as a surrogate tumor biopsy for retinoblastoma. JAMA Ophthalmol. 2017;135:1221–30. doi: 10.1001/jamaophthalmol.2017.4097.
  10. Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R, et al. Targeted retinoblastoma management: When to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol. 2014;25:374–85. doi: 10.1097/ICU.0000000000000091.
  11. Chawla B, Jain A, Azad R. Conservative treatment modalities in retinoblastoma. Indian J Ophthalmol. 2013;61:479–85. doi: 10.4103/0301-4738.119424.

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