Residency · Residency · Ophthalmology
Retinoblastoma: Diagnosis, Classification, and Current Treatment
Introduction
Retinoblastoma is the most common primary intraocular malignancy of childhood, arising from immature retinal cells. Early diagnosis is critical for both life-saving treatment and globe/vision preservation. Advances in chemotherapy and focal therapies have shifted management away from enucleation and external beam radiation toward globe-sparing approaches.
Epidemiology and Genetics
Incidence: approximately 1 in 15,000-20,000 live births. No racial or gender predilection. Mean age at diagnosis: 18 months (bilateral), 24 months (unilateral) 95% diagnosed before age 5 years.
Genetic Basis
Caused by biallelic inactivation of the RB1 tumor suppressor gene (chromosome 13q14) Knudson's two-hit hypothesis: both alleles of RB1 must be inactivated for tumor development. Heritable (germline mutation): ~40% of cases; bilateral in 80%; increased risk of second primary malignancies (osteosarcoma, soft tissue sarcoma) Non-heritable (somatic mutation): ~60%; unilateral; no increased risk of second cancers. All bilateral cases and 15% of unilateral cases are heritable. MYCN-amplified retinoblastoma: rare aggressive subset without RB1 mutation.
Clinical Presentation
Leukocoria (white pupillary reflex) -- most common presenting sign (60%) Strabismus -- second most common sign (20%); indicates macular involvement. Red eye, poor vision, hyphema, orbital cellulitis (advanced disease) Buphthalmos -- secondary glaucoma from tumor or neovascularization. Rarely presents with metastatic disease in developed countries.
Diagnosis and Workup
Ocular Examination
Examination under anesthesia (EUA) with indirect ophthalmoscopy through maximally dilated pupil. RetCam wide-field imaging -- documentation of tumor size, location, and features. B-scan ultrasonography -- intralesional calcification (>90% of tumors), tumor thickness. Fluorescein angiography -- tumor vascularity and feeder vessels.
Imaging
MRI orbits and brain (with gadolinium) -- evaluate for optic nerve invasion, extraocular extension, and trilateral retinoblastoma (pinealoblastoma) CT is avoided when possible to reduce radiation exposure in children with germline RB1 mutations. No biopsy -- risk of extraocular tumor dissemination; diagnosis is clinical.
Systemic Evaluation
Genetic testing -- RB1 mutation analysis on blood (germline) and tumor tissue. Metastatic workup if extraocular disease suspected (bone marrow, lumbar puncture, bone scan) Screening of siblings and offspring.
Classification
International Classification of Retinoblastoma (ICRB)
| Group | Description | Key Features | Treatment Approach |
|---|---|---|---|
| A | Small tumor | <= 3 mm, confined to retina, away from fovea/disc | Focal therapy (laser, cryo) |
| B | Larger tumor | >3 mm or macular/juxtapapillary; no seeding | Chemoreduction + focal therapy |
| C | Focal seeding | Vitreous or subretinal seeds <= 3 mm from tumor | Chemoreduction + focal; consider intravitreal chemo |
| D | Diffuse seeding | Vitreous or subretinal seeds >3 mm from tumor | Intensive chemo (systemic + intra-arterial/intravitreal) |
| E | Extensive disease | NVG, hemorrhage, anterior chamber tumor, phthisis | Enucleation (usually) |
Treatment
Globe-Salvage Strategies
Systemic chemotherapy (chemoreduction) -- vincristine, etoposide, carboplatin (VEC); used to reduce tumor size, then consolidated with focal therapy. Intra-arterial chemotherapy (IAC) -- selective ophthalmic artery infusion of melphalan (+/- topotecan, carboplatin); highly effective for Group B-D eyes. Intravitreal chemotherapy -- melphalan (20-30 mcg) for vitreous seeds; strict injection protocol to prevent extraocular seeding. Focal therapies: Transpupillary thermotherapy (TTT) -- diode laser for small posterior tumors. Cryotherapy -- for small peripheral tumors (<= 3.5 mm)
Plaque brachytherapy -- iodine-125 or ruthenium-106 for medium-sized unilateral tumors.
Enucleation
Indicated for Group E eyes, failed globe-salvage therapy, or when globe-salvage would risk metastasis. Long optic nerve section (>10 mm) to ensure clear margins. Orbital implant placement at the time of enucleation. Histopathologic evaluation for high-risk features: optic nerve invasion, choroidal invasion, scleral involvement.
External Beam Radiation Therapy (EBRT)
Largely abandoned as primary therapy due to risk of second malignancies in germline RB1 patients. Reserved for select salvage cases or trilateral retinoblastoma.
Prognosis and Follow-Up
Survival: >95% in developed countries with early detection. Globe salvage: 70-90% for Groups A-C with current therapies. Risk of second primary malignancy: 36% cumulative incidence by age 50 in heritable cases (higher if EBRT administered) Follow-up: frequent EUAs (monthly initially, then quarterly) until disease stability; lifelong cancer surveillance for germline carriers. Genetic counseling: essential for families; 45% risk of retinoblastoma in offspring of heritable cases.
Key Clinical Pearls
Leukocoria in a child is retinoblastoma until proven otherwise. Never biopsy a suspected retinoblastoma -- diagnosis is clinical. All bilateral retinoblastoma is heritable; 15% of unilateral cases are also heritable. Intra-arterial and intravitreal chemotherapy have transformed globe salvage rates. EBRT is avoided in germline RB1 patients due to markedly increased second malignancy risk.
References
- Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21(3):203-212.
- Munier FL, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited. Ophthalmology. 2012;119(5):1078-1083.
- Abramson DH, et al. Intra-arterial chemotherapy for retinoblastoma. Ophthalmology. 2012;119(8):1453-1456.
- American Academy of Ophthalmology. Pediatric Ophthalmology and Strabismus. BCSC Section 6. 2023-2024.