Retinoblastoma: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Retinoblastoma is the most common primary intraocular malignancy in children, arising from retinal precursor cells in the developing retina. It most commonly presents in children under the age of 5, with bilateral disease typically manifesting at a younger age (median 12 months) than unilateral disease (median 24 months). Approximately 9,000 new cases occur globally each year, with the majority arising in low- and middle-income countries where delayed diagnosis significantly worsens outcomes. The molecular basis of retinoblastoma involves biallelic inactivation of the RB1 tumor suppressor gene, as established in Knudson's landmark two-hit hypothesis (1971). Bilateral disease (approximately 40% of cases) implies germline (hereditary) RB1 mutation present in all somatic cells from conception, conferring elevated lifetime risk of secondary malignancies. Unilateral unifocal retinoblastoma arises predominantly from two somatic mutations in a single retinal cell. The International Classification of Retinoblastoma (ICRB) groups A through E describe increasing tumor severity and guide treatment approach.

Biallelic inactivation of the RB1 tumor suppressor gene on chromosome 13q14 is the molecular event required for retinoblastoma development. In hereditary retinoblastoma (approximately 40% of cases), one RB1 allele is inactivated in the germline, inherited from an affected parent or arising as a de novo germline mutation; a second somatic mutation in any retinal progenitor cell is sufficient for tumor initiation. In sporadic non-hereditary retinoblastoma (approximately 60% of cases), both RB1 alleles are inactivated by somatic mutations in a single retinal progenitor cell, with no germline predisposition. Children of a parent with hereditary retinoblastoma have a 50% probability of inheriting the RB1 mutation. Survivors of hereditary retinoblastoma have a substantially elevated lifetime risk of secondary malignancies — particularly osteosarcoma (the most common), soft tissue sarcomas, melanoma, and brain tumors — with external beam radiation amplifying this risk by several-fold. MYCN amplification without RB1 mutation is identified in a small subset of aggressive unilateral retinoblastoma with distinct biology.

The most common presenting sign of retinoblastoma is leukocoria (also called cat's eye reflex) — an abnormal white reflection in the pupil that is most easily noticed in flash photographs where the eye appears white or whitish instead of the normal red-orange reflex. Leukocoria is identified in approximately 60% of retinoblastoma cases. Strabismus (a misaligned or crossed eye) is the second most common sign, present in approximately 20% of patients, occurring because the tumor disrupts the foveal reflex necessary for binocular fusion. Less common presenting signs in more advanced disease include decreased visual acuity, red and painful eye (resembling preseptal cellulitis — a dangerous diagnostic pitfall), spontaneous hyphema (blood in the anterior chamber), pseudohypopyon (tumor cells in the anterior chamber mimicking pus), or frank orbital cellulitis-like presentation. Advanced local disease may produce proptosis (forward protrusion of the eyeball) from orbital extension. In low-income countries, metastatic retinoblastoma presenting with systemic symptoms (bone pain, CNS signs) is unfortunately not uncommon due to severe diagnostic delay.

Diagnosis is established clinically by fundoscopic examination under general anesthesia (EUA) using a RetCam wide-angle digital fundus camera, which allows complete retinal mapping and documentation of tumor location, size, and character. Biopsy is strictly contraindicated due to the risk of tumor seeding. MRI of the orbits and brain (without gadolinium, or with gadolinium in older children) detects optic nerve involvement and trilateral retinoblastoma (pineoblastoma). B-scan ophthalmic ultrasound quantifies intralesional calcification — characteristic of retinoblastoma in over 90% of cases. The ICRB classification (Groups A-E) is the cornerstone staging system: Group A (smallest tumors, confined to the macula or optic disc), Group B (larger or juxtapapillary/macular), Group C (localized vitreous or subretinal seeds), Group D (diffuse vitreous or subretinal seeds), Group E (highest risk: neovascular glaucoma, massive tumor filling the vitreous, anterior segment tumor, tumor anterior to the vitreous face). Germline RB1 genetic testing for all patients guides family counseling and dictates surveillance intensity.

Treatment of retinoblastoma is guided by the ICRB group, laterality (bilateral versus unilateral), and hereditary status, with the primary goals being life preservation, eye preservation (globe salvage), and visual function preservation, in that priority order. Intra-arterial chemotherapy (IAC) — direct ophthalmic artery infusion of melphalan, topotecan, or carboplatin via transfemoral catheter guided by fluoroscopy — has become the primary globe-salvage treatment for most groups, achieving globe salvage in approximately 50-70% of Group D eyes that would otherwise require enucleation. Intravitreal chemotherapy (IViT) with melphalan injection directly into the vitreous chamber effectively treats vitreous seeds (Group C and D disease) with minimal systemic toxicity. Focal therapies complement IAC: laser photocoagulation (for small posterior tumors and treatment of residual seeds), cryotherapy (for anterior and equatorial tumors), and transpupillary thermotherapy (TTT, for small central tumors). Systemic intravenous chemotherapy (vincristine-etoposide-carboplatin, VEC) is used for bilateral disease, to facilitate globe salvage in the contralateral eye, or for high-risk pathological features after enucleation. Enucleation (surgical removal of the eye) remains the definitive treatment for Group E eyes and for recurrent globe-threatening disease. External beam radiotherapy is now reserved for orbital or CNS disease due to the marked secondary malignancy risk in germline RB1 mutation carriers.

For hereditary retinoblastoma, prenatal genetic diagnosis (preimplantation genetic testing for monogenic conditions, PGT-M) allows selection of RB1 mutation-negative embryos in families where the specific mutation is known. Neonatal genetic testing of infants born to an affected parent enables immediate ophthalmologic surveillance from birth, allowing detection of very early-stage tumors amenable to focal therapy with vision preservation. Red reflex examination — a simple pediatric screening test using an ophthalmoscope to elicit the normal orange-red pupillary reflex — should be performed at every well-child visit from birth through school age by pediatricians and family physicians. Absence of the red reflex or an abnormal (white, grey, or yellow) reflex requires same-day ophthalmology referral. Flash photographs taken by parents can capture leukocoria and should always be evaluated by a physician. Genetic counseling is essential for all families of children with retinoblastoma, as hereditary status profoundly affects screening recommendations, family planning, and survivor surveillance protocols.

Any infant or young child who appears to have a white or unusual pupillary reflex — noticed directly or in photographs — must be seen by an ophthalmologist or emergency department within 24-48 hours; this is a true pediatric oncological urgency. A new-onset squint (strabismus) in a young child, particularly one that appears suddenly without a clear cause, requires ophthalmologic evaluation within days. A painful red eye in an infant or toddler that does not respond to antibiotic drops, or that is accompanied by decreased vision or unusual pupillary appearance, should be evaluated urgently to exclude retinoblastoma before attributing it to conjunctivitis or cellulitis. Parents who have themselves been treated for retinoblastoma should have all their children evaluated by an ophthalmologist within the first days of life and undergo genetic counseling before the pregnancy if possible. Any family member of a patient with hereditary retinoblastoma should undergo ophthalmologic screening and genetic counseling regardless of symptom status.

Overall survival exceeds 97% in high-income countries with specialist care. Globe salvage: Group A/B over 95%; Group C approximately 90%; Group D approximately 65%; Group E approximately 30-40%. Low-income countries: survival approximately 30-40% due to late diagnosis and limited access to advanced treatments. Hereditary survivors require lifelong surveillance for secondary malignancies, which occur in approximately 30-50% by age 50 in germline RB1 carriers, particularly those who received external beam radiation. The prognosis for Retinoblastoma: Causes, Symptoms, Diagnosis and Treatment varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.