Epidemiology And Pathogenesis
- Most common primary intraocular malignancy of childhood.
- Incidence: 1 in 17,000 to 20,000 live births.
- Median age at diagnosis: 2 years; >90% diagnosed before 5 years.
- 66-75% present with unilateral tumors; remainder bilateral.
- Bilateral involvement always heritable; typically presents <1 year of age.
- Originates from embryonic retina; likely cone photoreceptor precursor cell.
- Histology exhibits small round blue cells with pathognomonic Flexner-Wintersteiner rosettes.
Genetic Classification
Pathogenesis follows Knudson "two-hit" model of oncogenesis, requiring biallelic inactivation of RB1 tumor suppressor gene on chromosome 13q14.
| Feature | Hereditary (Heritable) | Sporadic (Non-Heritable) |
|---|---|---|
| Frequency | ~50% of cases. | ~50% of cases. |
| Presentation | Bilateral, multifocal, earlier onset (<2 years). | Unilateral, unifocal, later onset. |
| Mutation Origin | First hit germline; second hit somatic. | Both hits somatic within retinal cells. |
| Second Malignancies | High risk (osteosarcoma, soft tissue sarcoma, melanoma). | No increased risk. |
| Note: Approximately 10-15% of unilateral unifocal cases harbor germline RB1 mutations. |
International Classification
The standard classification for intraocular retinoblastoma is the International Classification for Retinoblastoma (ICRB). It is primarily used to predict the likelihood of saving the eye (ocular salvage) with modern therapies like chemotherapy.
| Group | Description / Criteria | Ocular Salvage Potential |
|---|---|---|
| Group A | Very low-risk small tumors ($\le 3\text{ mm}$) away from critical structures: • All tumors $\le 3\text{ mm}$ in greatest dimension. • Located $> 3\text{ mm}$ from the fovea and $> 1.5\text{ mm}$ from the optic disc. • No vitreous or subretinal seeding. | Very High ($> 95\%$) |
| Group B | Low-risk larger or central tumors: • All remaining tumors confined to the retina not in Group A. • Tumors $> 3\text{ mm}$ or located close to the fovea ($\le 3\text{ mm}$) or optic disc ($\le 1.5\text{ mm}$). • Clear subretinal fluid ($\le 3\text{ mm}$ from tumor margin) but no seeding. | High |
| Group C | Moderate-risk localized seeding: • Discrete, localized tumors with focal vitreous or subretinal seeding. • Seeding must be $\le 3\text{ mm}$ from the primary tumor margin. | Moderate |
| Group D | High-risk diffuse seeding: • Massive or diffuse tumors. • Diffuse vitreous or subretinal seeding located $> 3\text{ mm}$ from the primary tumor. • Subretinal fluid involving more than half the retina. | Low to Moderate |
| Group E | Very high-risk, extensive disease with no hope of vision preservation: • Tumor touches the lens or causes anterior segment invasion. • Neovascular glaucoma, opaque media, or phthisis bulbi (shrunken eye). • Tumor necrosis causing aseptic orbital cellulitis or retrobulbar optic nerve involvement. | Very Low (Enucleation usually required) |
Clinical Manifestations
- Leukocoria (white pupillary reflex): Most common presenting sign.
- Strabismus: Frequent initial complaint.
- Advanced signs: Decreased visual acuity, orbital inflammation, hyphema, proptosis, irregular pupil, secondary glaucoma, phthisis bulbi.
- Trilateral Retinoblastoma: Bilateral disease accompanied by pineal region primitive neuroectodermal tumor (pineoblastoma); occurs in 4-5% of familial cases.
- 13q Deletion Syndrome: Increased risk; phenotype includes microcephaly, broad forehead, hypertelorism, micrognathia.
Diagnostic Evaluation
- Examination under anesthesia (EUA): Essential for complete visualization, tumor mapping using RetCam, and optical coherence tomography.
- Neuroimaging: Orbital and brain Magnetic Resonance Imaging (MRI) assess intraocular extent, optic nerve invasion, and intracranial disease.
- Avoid biopsy: Strictly contraindicated to prevent extraocular tumor seeding.
- Avoid Computed Tomography (CT): Minimizes ionizing radiation exposure.
Management Principles
Treatment hierarchy: Cure disease, preserve vision and globe, minimize late effects.
- Enucleation: Indicated for advanced/massive tumors (Group E) without salvageable vision, or high risk of extraocular spread.
- Focal Ophthalmic Therapy: Laser photocoagulation or cryotherapy utilized for small tumors.
- Systemic Chemotherapy: Chemoreduction shrinks tumors prior to focal therapy. Standard regimen includes Carboplatin, Etoposide, Vincristine (CEV).
- Targeted Chemotherapy: Intra-arterial (melphalan, topotecan, carboplatin via ophthalmic artery) and intravitreal delivery reduce systemic toxicity while maintaining efficacy.
- Radiation Therapy: External beam radiation strictly avoided in heritable disease due to massive secondary malignancy risk. Episcleral plaque brachytherapy (I-125) serves as a safer, localized alternative.