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.
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.