# 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.

![Photograph demonstrating leukocoria in a child with retinoblastoma](/images/ophthalmology/retinoblastoma-leukocoria.jpg)

## 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.

![Fundus photograph (RetCam) showing a dome-shaped retinoblastoma with intrinsic calcification and feeder vessels](/images/ophthalmology/retinoblastoma-fundus-retcam.jpg)

## 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.

![MRI of the orbits demonstrating retinoblastoma with optic nerve extension](/images/ophthalmology/retinoblastoma-mri-optic-nerve.jpg)

## 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

1. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21(3):203-212.
2. Munier FL, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited. Ophthalmology. 2012;119(5):1078-1083.
3. Abramson DH, et al. Intra-arterial chemotherapy for retinoblastoma. Ophthalmology. 2012;119(8):1453-1456.
4. American Academy of Ophthalmology. Pediatric Ophthalmology and Strabismus. BCSC Section 6. 2023-2024.