Retinoblastoma

Retinoblastoma is the most common primary intraocular malignancy in children and is caused by inherited or spontaneous mutations in the retinoblastoma gene (RB1 gene). The characteristic clinical presentation is leukocoria with or without strabismus in children < 5 years of age. Diagnostic evaluation is performed by a specialist and includes dilated fundoscopic examination, imaging, and genetic testing. Management is determined by tumor stage and includes focal treatments (e.g., cryotherapy, brachytherapy, laser), enucleation of the eye, chemotherapy, and/or radiation. Prognosis is favorable with early diagnosis and treatment. Routine screening with red reflex examination is recommended for all children as part of pediatric vision screening. Individuals with a first-degree relative or second-degree relative with retinoblastoma should be referred to an ophthalmologist with pediatric training for appropriate screening (e.g., genetic counseling, genetic testing, frequent dilated fundoscopic examination).

• Most common primary intraocular malignancy among children ^[1]
• Incidence: more common in young children
  • Individuals < 20 years of age: 3/1,000,000 ^[2]
  • Children ≤ 4 years of age: ∼18/1,000,000 ^[3]

Epidemiological data refers to the US, unless otherwise specified.

The retinoblastoma gene (RB1 gene) is a tumor suppressor gene found on chromosome 13.

• Sporadic retinoblastomas (∼ 70%): due to spontaneous mutation ^[3]
  • Two spontaneous mutations must occur in the same retinal cell, affecting both Rb alleles.
  • Sporadic retinoblastomas tend to be unilateral.
• Heritable retinoblastomas (∼ 30%): autosomal dominant inheritance ^[3][4]
  • Two-hit hypothesis
    • A germline mutation occurs in one of the alleles of the RB1 gene, which renders this allele nonfunctional 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 nonfunctioning RB1 gene and the development of a retinoblastoma.
  • Inherited retinoblastomas tend to be bilateral.
  • A child whose biological parent had a heritable retinoblastoma has a 50% chance of acquiring the mutated RB allele. ^[5]

Individuals with inherited RB1 gene mutations also have a significantly higher risk of developing osteosarcomas and pinealomas.

• Age of onset
  • Usually affects children < 5 years of age (majority before 2 years of age) ^[6]
  • Approx. one-third of patients have bilateral retinoblastoma, which usually manifests by 12 months of age. ^[3][7]
• Initial features ^[3][4]
  • Leukocoria (“white pupil”)
  • Strabismus
• Features of advanced disease ^[3][4]
  • Signs of advanced intraocular involvement
    • Eye pain and/or redness
    • Sudden or progressive vision loss ; (e.g., from retinal detachment, tumor growth)
    • Nystagmus ^[8]
    • Signs of orbital involvement (e.g., proptosis)
  • Signs of metastasis
    • Regional lymphadenopathy (e.g., preauricular, submandibular, and cervical lymph nodes)
    • Signs of distant metastases (e.g., headache, focal neurological deficits, bone pain)

Leukocoria is highly concerning for retinoblastoma; refer for an urgent examination by an ophthalmologist. ^[9]

Strabismus may be normal in early infancy. Refer to ophthalmology if isolated strabismus is present at ≥ 4 months of age. ^[9]

General principles ^[3][4][6]

• Refer all young children with leukocoria urgently to an ophthalmologist with pediatric training for further assessment.
• Initial assessment includes dilated fundoscopic examination with or without ocular ultrasound.
• All patients then require:
  • MRI
  • Genetic testing
• Patients with evidence of extraocular involvement: workup for metastatic disease

Biopsy of retinoblastomas is not recommended due to the risk of tumor seeding. ^[3][4][10]

Initial assessment

Dilated fundoscopic examination ^[3][9][11]

• Performed by a specialist (e.g., ophthalmologist with pediatric training), usually under general anesthesia
• Findings ^[6][11]
  • White or yellow retinal mass
  • Other findings adjacent to the tumor may include:
    • Subretinal fluid
    • Subretinal seeding
    • Retinal detachment

Ocular ultrasound

• Indications include: ^[12]
  • Diagnostic uncertainty
  • Obstructed retinal views because of retinal detachment, intraocular hemorrhage, or cataract
• B scan findings include hyperechoic mass with intratumor calcifications. ^[11]

Further imaging ^[10][11][12]

• High-resolution contrast-enhanced MRI (orbits and brain) is used to:
  • Confirm clinical diagnosis and ultrasound findings
  • Assess for tumor characteristics and spread, e.g.:
    • Invasive disease (optic nerve, extraorbital, and/or intracranial invasion)
    • Trilateral retinoblastoma: bilateral retinoblastoma and a primary midline intracranial lesion ^[10][13]
• Other imaging modalities include: ^[11]
  • Optical coherence tomography: used to assess for small tumors, monitor treatment response, and assess recurrence
  • Fluorescein angiography: assesses for posttreatment changes

CT is not recommended in the evaluation of patients with retinoblastoma because exposure to ionizing radiation may increase the risk of secondary malignancies. ^[10]

Genetic testing of RB1 gene ^[3][10]

• All patients: blood testing for a germline mutation
• If enucleation of the eye has been performed: testing of tumor tissue for somatic mutations

Metastatic evaluation ^[3]

• Indications: patients with features of extraocular involvement on clinical evaluation or imaging
• Options: bone scintigraphy, lumbar puncture, bone marrow aspiration

If enucleation of the eye is performed, tumor pathology typically shows the following: ^[3]

• Flexner-Wintersteiner rosettes: tumor cells that surround a central lumen composed of cytoplasmic extensions of the surrounding cells
• Homer-Wright rosettes: a collection of halo-like clusters of cells that surround a central pale area that contains neuropil

• See “Differential diagnosis of leukocoria.”
• See “Ocular motility disorders and strabismus.”

The differential diagnoses listed here are not exhaustive.

Initial management ^[3][4][14]

Treatment is individualized and developed by a multidisciplinary team; it may include one or more of the following:

• Focal therapy
  • Indicated for focal lesions when the eye may be salvageable, e.g.:
    • Low-risk lesions confined to the eye
    • Residual tumors (e.g., after chemotherapy)
  • Options are cryotherapy, brachytherapy, and laser (e.g., thermotherapy, photocoagulation).
• Surgical treatment (enucleation of the eye)
  • Indicated when the eye and/or vision is not salvageable
  • The entire eyeball and part of the optic nerve are removed.
• Chemotherapy and external beam radiotherapy
  • Often combined with other treatment modalities to treat the following:
    • Extraocular spread (e.g., optic nerve involvement, metastases)
    • High-risk pathology features following enucleation
    • Disease progression on other treatment modalities
  • Options for chemotherapy include intra-arterial, intravitreal, and intravenous.

Ongoing management

• Ongoing monitoring ^[3][15]
  • Regular specialist follow-up to assess for:
    • Recurrence, progression of the tumor
    • New retinoblastoma lesions (in either eye)
    • Other malignancies, e.g., primitive neuroectodermal tumor, radiation-induced subsequent neoplasms
    • Adverse effects of treatment
  • Frequency of monitoring is based on individual risk.
• Genetic counseling ^[1][4]
  • Recommendation that all first-degree relatives and second-degree relatives receive retinoblastoma screening for at-risk individuals
  • Discussion of risk of transmission to offspring and available reproductive planning options

Individuals with retinoblastoma (especially those with heritable retinoblastoma and those who received radiation therapy) are at an increased risk of subsequent malignancies. ^[3]

Routine screening ^[16]

• Retinoblastoma is one of the conditions screened for using red reflex examination during pediatric vision screening.
• If leukocoria is detected on neonatal or well-child examination, refer urgently to opthalmology. ^[16][17]

Retinoblastoma screening for at-risk individuals ^[1][3]

Screening at-risk individuals should be performed by an ophthalmologist with pediatric training.

• Indication: all individuals with a first-degree relative or second-degree relative with retinoblastoma
• Screening includes:
  • Genetic counseling and possible testing for risk stratification
  • Dilated fundoscopy examination
• Frequency of dilated fundoscopy
  • Initial screening should start within 2–4 weeks of birth.
  • Further screening is based on risk stratification (more frequent in infancy and then spaced out). ^[1][3]
• Discontinuation of screening: Screening is not recommended after 7 years of age unless the individual has an RB1 germline mutation. ^[1]

• The 5-year survival with treatment is > 95%. ^[4]
• Factors associated with a poor prognosis include: ^[3][14]
  • Late diagnosis and late initiation of treatment
  • Choridal invasion and postlaminar infiltration of the optic nerve ^[10][11]
  • CNS involvement (e.g., trilateral retinoblastoma)

Individuals with hereditary retinoblastoma have elevated mortality from subsequent malignant neoplasms. ^[15][18]