Retinoblastoma

• 1:20,000
• Arises from embryonal retinal cells (primitive retinoblasts)
• Loss of function of the Rb tumour suppressor gene (Chromosome 13q14)
• F=M

Genetics

• Knudson’s two hit hypothesis, via:

  • Genetic/germline/hereditary form: every cell is missing one copy of Rb therefore any photoreceptor cell can potentially give rise to tumour
  • Somatic form: a single cell loses one copy during retinal development and the second hit is a random event

• Genetic cases often have multiple tumours in one or both eyes

• Somatic cases are always unilateral and unifocal

• Over 90% are sporadic: mostly the somatic form

  • 1/3rd of sporadic cases arise from new germline forms (can be passed on but are not inherited from parents)
  • 40% are bilateral but necessarily germline form
  • 60% are unilateral: 15% of these are germline

Appearance

• Smooth white mass

• Endophytic:

  • Grow from the retinal surface and project into the vitreous
  • More associated with vitreous seeding

• Exophytic:

  • Grow beneath the retina towards the scleral wall
  • More associated with serous retinal detachment

• Mixed or diffuse infiltrating

  • Generalised retinal thickening

• Yellow areas of necrosis

• White flecks of calcification visible on ophthalmoscopy

Clinical features

• Leucocoria (60%)
• Strabismus
• Reduced VA
• Red eye
• Orbital inflammation
• Tearing

Histology

• Small blue cells

• Scanty cytoplasm

• High mitotic rate

• Prominent apoptosis and necrosis

• Homer-Wright rosettes: multi-layered circle of nuclei (no central lumen). These are the most immature cells in a RB

• Flexner-Wintersteiner rosettes: circle of tumour cells with an internal membrane around a central lumen

  • Can also be seen in pineoblastomas and medulloepitheliomas

• Fleurettes: primitive photoreceptor bodies in a fleur de lys shape

• Neuroblasts

• Calcification

Spread

• To brain via optic nerve or meninges, haematogenous to bones or viscera
• 5% of Rb patients with germline mutation develop pinealoblastoma
• Retinoblastoma most commonly spreads outwith the eye via the optic nerve, therefore a long section of nerve must be taken at enucleation

Complications

• Optic nerve/CNS invasion
• Anterior segment invasion: glaucoma, buphthalmos/corneal oedema, heterochromia, pseudohypopyon, rubeosis
  • Glaucoma is usually neovascular or angle closure
• Extraocular spread: orbital inflammation, ectopic intracranial Rb
• Systemic spread
• Other tumour types due to RB1 tumour suppressor gene mutation eg osteosarcoma, chondrosarcoma, fibrosarcoma, epithelial tumours (eg. lung)
  • These risks are greater after radiation therapy which provides a second hit
  • Germline Rb patients have increased lifetime risk of cancer

Tests

• USS: high internal reflectivity and acoustic shadow
• CT/MRI: not routinely indicated but can be used to look for pinealoblastoma (trilateral Rb)
• Genetic testing: essential. Use a serum or tumour sample. Distinguishes somatic from germline cases

Management

• 95% cure rate

• Trans-pupillary diode laser

• Combination chemotherapy (carboplatin, etoposide, vincristine) with cryo/laser/brachytherapy

• Monitoring with EUA

• Radiotherapy: external beam radiotherapy for diffuse disease

  • Proton beam radiotherapy causes less radiation to adjacent tissues
  • Plaque brachytherapy: good for localised vitreous disease

• Enucleation: indications

  • Tumour occupying >50% of the globe
  • Optic nerve involvement
  • Anterior segment involvement

• Intra-arterial or intravitreal chemotherapy

• Supportive: ocular prosthesis, psychological support, protective eyewear, long-term surveillance, genetic counselling, cataract surgery

Prognosis

• Untreated: death within 2 years

• Prognostic parameters

  • Size
  • Older age
  • Differentiation
  • Choroidal invasion
  • Optic nerve invasion
  • Extrascleral invasion

• The Reese-Ellsworth classification scheme was previously used to give prognostic information about eye survival (outdated)