Retinoblastoma

Retinoblastomas are the most common primary intraocular malignancy in children. They are caused by sporadic or inherited mutations in the retinoblastoma gene (Rb). While sporadic retinoblastomas tend to occur unilaterally, hereditary retinoblastomas usually occur bilaterally and may be associated with other malignancies (e.g., osteosarcoma). The characteristic clinical features of retinoblastomas are leukocoria (white fundal reflex instead of the usual red) and strabismus. All children who present with leukocoria should undergo funduscopic examination. Enucleation of the affected eye is the treatment of choice if the eye is not salvageable. A more conservative approach that spares vision may be attempted in the case of small, localized retinoblastomas. The prognosis is favorable if the tumor is diagnosed and treated early. If left untreated, retinoblastomas are almost always fatal.

• Incidence: 1/14,000 live births annually ^[1]
• Most common primary intraocular malignancy among children ^[2]
• Age of onset: < 4 years ^[3]
• ∼ 40% of children develop retinoblastomas in both eyes. ^[4]

Epidemiological data refers to the US, unless otherwise specified.

The retinoblastoma gene (Rb) is a tumor suppressor gene found on chromosome 13.

• Heritable retinoblastomas (autosomal dominant inheritance) ^[2]
  • Two-hit hypothesis: A germline mutation occurs in one of the alleles of the Rb gene; , which renders this allele non-functional in all cells of the affected individual → The presence of the second functional allele prevents the development of a retinoblastoma → However, a spontaneous somatic mutation in the second allele in any retinal cell results in a non-functioning Rb gene and the development of a retinoblastoma.
  • Inherited retinoblastomas tend to be bilateral.
  • A child born to a parent who has had a heritable retinoblastoma has a 50% chance of acquiring the mutated Rb allele! ^[5]
• Sporadic retinoblastomas: due to spontaneous mutation →
  • Two spontaneous mutations must occur in the same retinal cell, affecting both Rb alleles.
  • Sporadic retinoblastomas tend to be unilateral

Patients with inherited Rb gene mutations also have a significantly higher risk of developing osteosarcomas and pinealomas.

• Leukocoria (“cat's eye pupil”)
• Strabismus
• A painful, red eye
• Loss of vision
• Retinal detachment (later stages) ^[2]
• Rarely: orbital cellulitis, nystagmus, proptosis

Evaluation of the retinoblastoma

• Fundus examination: grayish white, vascularized retinal tumor
• Following fundus examination:
  • Ocular ultrasound
    • Irregular intraocular mass that is hyperechogenic when compared to vitreous humor and has foci of acoustic shadowing (due to calcifications)
    • The growth pattern (endophytic, exophytic, diffuse infiltrative) and the presence/absence of vitreous seeding can be confirmed by ocular ultrasonography.
  • Contrast-enhanced MRI of the cranium: identify optic nerve involvement and extent of tumor

CT scan should be avoided because of the risk of radiation-induced tumors in patients with Rb1 mutation! Biopsies of retinoblastomas are contraindicated because of the risk of tumor seeding!

Molecular genetic testing of leukocytes for mutations in the Rb1 gene is recommended for all patients with retinoblastomas. If the patient has a germline mutation, genetic testing and tumor surveillance of the patient's siblings and parents are necessary.

Metastatic work-up

Metastatic evaluation is not done routinely but is indicated if the choroidal layer and/or optic layer is involved.

• Lumbar puncture
• Bone marrow biopsy
• Skeletal scintigraphy

• See “Differential diagnosis of leukocoria.”
• For the differential diagnosis of strabismus in childhood see “Ocular motility disorders and strabismus.”

Leukocoria is considered a retinoblastoma until proven otherwise; a fundus examination of an infant presenting with leukocoria should be conducted as quickly as possible.

Strabismus is normal until three months after birth. Strabismus that persists after three months should be evaluated by an ophthalmologist.

The differential diagnoses listed here are not exhaustive.

• If the eye is potentially salvageable
  • Low-risk retinoblastomas
    • Retinoblastomas that are located anteriorly, away from the disc and macula: cryotherapy
    • Retinoblastomas that are located posteriorly: photocoagulation
    • Brachytherapy
  • High-risk retinoblastomas : chemotherapy
• If the eye is not salvageable (either anatomically or functionally)
  • Enucleation: involves complete removal of the eyeball, along with a part of the optic nerve. This is done because the retinoblastoma spreads intracranially along the optic nerve.
  • Adjuvant systemic chemotherapy and/or adjuvant external beam radiotherapy
• In the case of metastatic disease: high-dose chemotherapy with/without radiotherapy

• Factors associated with a poor prognosis
  • Late diagnosis and late initiation of treatment
  • Infiltration of the tumor into the choroidal layer or the optic nerve
  • Bilateral involvement (hereditary retinoblastomas)