Approximately 250-350 new cases of retinoblastoma are diagnosed each year in the USA, with no known racial or gender predilection. The cumulative lifetime incidence of retinoblastoma is approximately 1:20,000 live births, and retinoblastoma accounts for 4% of all pediatric malignancies. The median age at diagnosis is approximately 2 yr, and over 90% of cases are diagnosed in children under 5 yr of age. Overall, about two thirds to three quarters of children with retinoblastoma have unilateral tumors, with the remainder having bilateral retinoblastoma. Bilateral involvement is more common in younger children, particularly in those diagnosed under the age of 1 yr.
Retinoblastoma can be either hereditary or sporadic. Hereditary cases usually are diagnosed at a younger age and are multifocal and bilateral, while sporadic cases are usually diagnosed in older children who tend to have unilateral, unifocal involvement. The hereditary form is associated with loss of function of the retinoblastoma gene (RB1) via gene mutation or deletion. The RB1 gene is located on chromosome 13q14 and encodes the retinoblastoma protein (Rb), a tumor suppressor protein that controls cell-cycle phase transition and has roles in apoptosis and cell differentiation. Many different causative mutations have been identified, including translocations, deletions, insertions, point mutations, and epigenetic modifications such as gene methylation. The nature of the predisposing mutation can affect the penetrance and expressivity of retinoblastoma development.
According to Knudson’s “two-hit” model of oncogenesis, two mutational events are required for retinoblastoma tumor development (Chapter 486). In the hereditary form of retinoblastoma, the first mutation in the RB1 gene is inherited through germinal cells and a second mutation occurs subsequently in somatic retinal cells. Second mutations that lead to retinoblastoma often result in the loss of the normal allele and concomitant loss of heterozygosity. Most children with hereditary retinoblastoma have spontaneous new germinal mutations, and both parents have wild-type retinoblastoma genes. In the sporadic form of retinoblastoma, the two mutations occur in somatic retinal cells. Heterozygous carriers of oncogenic RB1 mutations demonstrate variable phenotypic expression.
