Retinoblastoma

Genetics & Pathophysiology - The Two-Hit Tumour

• Knudson's "Two-Hit" Hypothesis: Requires inactivation of both alleles of the RB1 tumour suppressor gene on chromosome 13q14.

• Hereditary Retinoblastoma (~40%)

  • Hit 1: Germline mutation (inherited). All somatic cells have one mutated allele.
  • Hit 2: Somatic mutation in a retinal cell.
  • Typically bilateral, multifocal, and presents at an earlier age.

• Sporadic Retinoblastoma (~60%)

  • Hit 1 & 2: Both are somatic mutations in a single retinal cell.
  • Typically unilateral and unifocal.

⭐ Patients with hereditary retinoblastoma have a significantly increased lifetime risk of secondary primary malignancies, most commonly osteosarcoma.

Clinical Features & Diagnosis - The Cat's Eye Clue

• Leukocoria ("Cat's Eye Reflex"): Most common sign (~60%).
  • White pupillary reflex, often first noticed in flash photographs.
• Strabismus (Squint): Second most common sign (~20%).
  • Misalignment of the eyes (esotropia or exotropia).
• Other Key Signs: Proptosis (bulging eye), hyphema (blood in anterior chamber), secondary glaucoma, and orbital inflammation.

• Diagnosis:
  • Ophthalmoscopy: Reveals a chalky, off-white retinal mass. Calcification is common.
  • Histopathology:
    • Flexner-Wintersteiner rosettes: Highly specific; cuboidal cells around a clear central lumen.
    • Homer Wright rosettes: Less specific (neuroblastic tumors); cells around a tangle of nerve fibers.

⭐ Leukocoria is the most frequent presenting sign of retinoblastoma.

Staging & Management - Saving Sight & Life

• International Classification of Retinoblastoma (ICRB) - Eye-Salvage Potential:
  • Group A: Very good (Small tumors <3 mm)
  • Group B: Good (Larger tumors/macula involvement)
  • Group C: Fair (Localized vitreous/subretinal seeding)
  • Group D: Poor (Diffuse vitreous/subretinal seeding)
  • Group E: Very poor (Extensive tumor, neovascular glaucoma, etc.)

• Treatment Modalities:
  • Chemoreduction: Vincristine, Etoposide, Carboplatin (VEC) is the standard regimen to shrink the tumor.
  • Focal Therapy: Laser photocoagulation or cryotherapy for smaller tumors.
  • Enucleation: Surgical eye removal for Group E or failed primary treatment.
  • EBRT (External Beam Radiotherapy): Largely replaced by chemotherapy due to risk of secondary malignancies.

⭐ Trilateral Retinoblastoma: Describes the occurrence of bilateral hereditary retinoblastoma with an associated intracranial midline neuroblastic tumor, most commonly in the pineal gland (pineoblastoma).

• Most common intraocular malignancy in children, from a mutation in the RB1 tumor suppressor gene (chromosome 13q14).
• Key presentation is leukocoria (white pupillary reflex) and strabismus. A key differential for a "cat's eye reflex".
• Bilateral and multifocal tumors are typically hereditary (germline mutation), while unilateral is often sporadic.
• Histopathology shows Flexner-Wintersteiner rosettes (specific) and Homer Wright rosettes.
• High risk of secondary malignancies, especially osteosarcoma.