DESCRIPTION

Retinoblastoma is a highly curable malignant primitive neuroectodermal tumor arising in the retina and is the most common intraocular tumor in children. It is caused by changes in the RB1 gene at 13q14 resulting in impaired production of the retinoblastoma protein (pRb). These changes can occur in germline or somatic (retinal) cells.

EPIDEMIOLOGY

• In the United States, retinoblastoma occurs approximately once in every 18,000 live births.
• Approximately 300 new pediatric cases of retinoblastoma are diagnosed each year in the United States, which represents 3% of all childhood cancers.
• 30% of patients will present with bilateral disease at diagnosis, which signifies germline retinoblastoma. 40% of all retinoblastoma cases are germline. All children with bilateral disease have germline (heritable, but not necessarily inherited) retinoblastoma, whereas approximately 15% of children who present with unilateral involvement also have germline defects and thus their disease is also heritable (not inherited).
• Median age at diagnosis is 24 months in patients with unilateral disease and 12 months in patients with bilateral tumors.
• Incidence appears to vary somewhat geographically, with apparently higher rates in countries in some regions of the global south including some populations in Asia and Africa.

ETIOLOGY

Mutations in the RB1 gene predispose to retinoblastoma, pineoblastoma, osteosarcoma, and other cancers. Patients with germline RB1 mutations have a 30% lifetime risk of secondary malignancies including these previously mentioned tumors, as well as younger age at onset for common adult tumors including skin tumors, breast, and lung cancer.

RISK FACTORS

• Germline mutations in the RB1 gene are inherited in an autosomal dominant pattern.
• The majority (90%) of retinoblastoma occurs in children with no prior family history of the disease. Several environmental exposures during retinal development appear to increase risk for retinoblastoma.
• Family history of retinoblastoma in parents or siblings warrants early screening and genetic studies to determine the risk of disease.

GENERAL PREVENTION

Although there is no known way to prevent retinoblastoma, careful eye exams documenting presence of the red reflex during well-child examinations facilitate earlier detection of the disease.

PATHOPHYSIOLOGY

• Tumor development requires loss of function of both alleles of the RB1 gene, which protein product, pRb, is a cell cycle regulator.
• Constitutional loss of one RB1 allele predisposes a patient to cancer. Loss of the second allele with other genetic or epigenetic changes in the retinal lesion will initiate formation of retinoblastoma.
• Somatic retinoblastoma has no germline RB1 mutation and thus requires biallelic inactivation of the RB1 gene in a single retinal cell.
• Other genetic changes have been described in tumor cells such as MYCN oncogene amplification. Additional molecularly based groupings have recently been described, which appear to correlate with likelihood for disease progression.
• There are three common growth patterns for disease within the eye (intraocular):
  • Intraretinal (growth only in the retina)
  • Endophytic (inner surface of retina to vitreous)
  • Exophytic (outer surface of retina to subretinal space)
• Tumor cells may seed from the primary mass to grow independently in the vitreous or subretinal space.
• Children with loss of RB1 with large chromosomal deletions of surrounding genes are at risk for developmental anomalies such as facial dysmorphism and mental and/or motor impairment (13q deletion syndrome).
• Patients with bilateral retinoblastoma are also at risk for involvement of the pineal gland, termed “trilateral” retinoblastoma.