Introduction
It is the most common primary intraocular tumours of children, and usually before 5 years.
- Average age of diagnosis is 2 years
- Causes 1% of childhood cancer deaths, and 5% of childhood blindness
- Arises from the neuroectodermal cells, and the most suggested cell is the cone photoreceptor progenitors
- Incidence of ~1 in 16,000 live births and in the USA affects ~250-350 children a year
- Is bilateral 25% of the time
- 90% are sporadic, 10% are inherited, and inheritance is typically AD.
- RB1 genetic mutation are the most common association with retinoblastoma, yet 1.4% of unilateral Rb tumours lack mutation.
- Small group of MYCN also noted.
Mortality:
- Decreased worldwide from 95% to 50%, yet delayed diagnosis can still lead to death
- Secondary cancers may occur later in life, such as osteosarcomas
Two Hit Mechanism:
- Proposed by Knudson, suggests some cancers like retinoblastoma develop due to the inactivation of tumour suppression genes
- Unlike the oncogenes, tumour suppressor genes require both alleles to function. The first hit disables the first allele, and the second hit disables the second.
- Germline mutation -> RB1 mutation followed by single hit, or two somatic hits. Subsequent hits can occur
- Sporadic/somatic mutation -> can cause benign retinoma after 1 or 2 hits. Further subsequent hits are required for Rb malignancy
- MYCN mutations can also lead to retinoblastoma, yet the exact pathophysiology is unknown.
Dead Giveaways
Leukocoria and Fundus Examination
Provides the indicator, along with age, of Rb.
Note the leukocoria, and noticeable lumps, as well as very noticeable retinal vessels 
Retinoblastoma is progressive and can have different fundus manifestations. E represents a non-salvageable state
CT Scan:
Will reveal calcification, which is a response to tissue degeneration and necrosis
Important to check for ON involvement, orbital, CNS, pineal gland
Left eye and parts of the right eye show the calcification
Histology:
Retinoblastoma has cone cells differentiating but is not fully differentiated. They will group together into a pattern called rosette
Flexner-Wintersteiner Rosette, from AAO 
Homer Wright Rosette, from AAO. Contains eosinophils
Stages of Retinoblastoma:
A --> Small tumours restricted and confined to the retina, present in restricted sites, all behind the equator
Small tumours of no more than 3mm, and are >3mm from foveola, >1.5mm from disc
B --> Large tumours that may be present in any retinal location, but confined to the retina and behind the equator
Tumours larger than 3mm in macular or juxtapapillary location.
Can have a cuff of SRF<3mm frum tumour without seeding
C --> Local seeding occurs to the vitreous and SRF, invading adjacent spaces
Tumour with localised subretinal or vitreous seeding within 3mm of tumour, and up to 1 quadrant of SRF
D --> Diffuse seeding occurs to the vitreous and SRF, invading adjacent spaces
Tumours with diffuse subretinal or vitreous seeding >3mm from tumour and extensive SRF
E --> Unsalvageable, Destroyed, Dangerous
Neovascular glaucoma, tumour anterior to vitreous face, diffuse infiltrating Rb, phthisis bulbi, aseptic orbital cellulitis
diagnostic features
Poor Prognostic Factors:
ON involvement
Choroidal or orbital invasion
Large tumours
Anterior eye involvement
Cytogenetic factors (RB1 gene mutations)
Poor cellular differentiation
RB1 Dysfunction:
RB1 is a tumour suppressor gene that typically controls the cell cycle
It provides negative feedback to transcription factors like E2F and DP from G1 to S phase
pRB provides a spectrum of roles in differentiation, chromatin remodelling, genome stability and apoptosis
Long Term Sequelae and Malignancies:
Children with Rb have an increased risk of death from one or more non-retinoblastomic malignancies over a lifetime, such as osteosarcoma
Up to 35% of children with bilateral Rb and external beam radiation therapy will develop a second cancer by age 25
Life-long multidisciplinary follow-up, very active patient support groups
Rb should always be referred
Treatment:
Appropriate and urgent referral + plus communication + review/observation + multimodal imaging + excellent record keeping + multidisciplinary team
The ultimate goal is to prevent invasion and metastatic growth, and in the eye to save vision and save the eye
Goals:
Referral --> Confirm disease, tumour pathology, stage
Physical Therapy --> laser cryotherapy, radiation (external beam), proton beam
Local Vs General Therapy --> radioactive plaque, chemotherapy (systemic or local), targeted therapy antibody
Last Resort --> Enucleation, Exenteration, Evisceration