Article: Retinoblastoma

Retinoblastoma is a cancer of the retina. Development of this tumor is initiated by mutations that inactivate both copies of the RB1-gene, which codes for the Rb-1 protein. It occurs mostly in children before the age 5 years and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence is approximately 4 per million children [1].

The tumor may begin in one or both eyes. Retinoblastoma is usually confined to the eye but can spread to the brain via the optic nerve.

Causes

Ultrasound of a retinoblastoma tumor within the eye of a three year old boy.

Retinoblastoma may occur on the basis of a hereditary (genetically inherited) predisposition. Children with hereditary predispostion to retinoblastoma usually develop tumors in both eyes (bilateral retinoblastoma). Children with non-hereditary form of retinoblastoma, which is present in about half of all patients, develop tumors in one eye only (unilateral retinoblastoma). When the disease occurs in both eyes or if this tumor has also occurred in relatives (familial retinoblastoma), it is hereditary. About 15% of patients with unilateral retinoblastoma and no family history of this tumor also have a hereditary predisposition to retinoblstoma. Because of the hereditary factor, patients and their brothers and sisters have an increased risk of retinoblastoma and should have periodic examinations during early childhood. Patients and their relatives usually profit from genetic counseling molecular risk prediction.

A statistical study by Alfred G. Knudson in 1971 led to a hypothesis (later known as the Knudson hypothesis) about why some retinablastomas are hereditary and others occur by chance. This hypothesis led to the identification of the RB1 gene, the first tumor suppressor gene, by a team led by Thaddeus P. Dryja in 1986. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

Hereditary retinoblastoma is caused by an inherited mutation in a single copy of the RB1-gene thus resulting in a heterzygous individual. The remaining functional copy prevents most retinal cells from becoming cancerous. However, one or more cells in the retina are likely to undergo a spontaneous loss of this functional copy, causing those cells to transform into cancer. This loss of the second copy of RB1 is frequently acompanied by loss of heterozygosity of intragenic and flanking polymorphic markers. This is a frequent event in cancer for which retinoblastoma is the canonical example.

Treatment

The patient's choice of treatment depends on the extent of the disease within and beyond the eye. Smaller tumors can be removed with laser surgery, thermo-, proton or cryotherapy. Larger tumors may require enucleation.

Genetic testing can identify the mutation that lead to the development of retinoblastoma. Testing in unilateral cases can identify the 15% of unilateral cases with a germline mutation, indicating risk in future children. Testing amniotic cells in an at-risk pregnancy can identify a fetus with the mutation, which can then be delivered early before retinal cells have fully developed and before tumors arise. This early treatment can lead to a fully sighted bilaterally affected patient.