Retinoblastoma pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathology
In children with the heritable genetic form of retinoblastoma there is a mutation on chromosome 13, called the RB1 gene. The genetic codes found in chromosomes control the way in which cells grow and develop within the body. If a portion of the code is missing or altered (mutation) a cancer may develop.
The defective RB1 gene can be inherited from either parent; in some children, however, the mutation occurs in the early stages of fetal development. Inheritance is autosomal dominant with 90% penetrance.
Inherited forms of retinoblastomas are more likely to be bilateral. In addition inherited uni- or bilateral retinoblastomas may be associated with pineoblastoma and other malignant midline supratentorial primitive neuroectodermal tumors (PNET) with a dismal outcome; retinoblastoma that concurs with such a PNET is also known as trilateral retinoblastoma. A recent meta-analysis has shown that survival of trilateral retinoblastoma has increased substantially over the last decades.
The development of retinoblastoma can be explained by the two-hit model. According to the two-hit model, two events are necessary for the retinal cell or cells to develop into tumors. The first mutational event can be inherited (germline or constitutional) and would then be present in all cells in the body. The second “hit” results in the loss of the remaining normal allele (gene) and occurs within a particular retinal cell. In the sporadic, nonheritable form of retinoblastoma, both mutational events occur within a single retinal cell after fertilization (somatic events), resulting in unilateral retinoblastoma.
Several methods have been developed to detect the RB1 gene mutations. Attempts to correlate gene mutations to the stage at presentation have not shown convincing evidence of a correlation.
Somatic amplification of the MYCN oncogene is responsible for some cases of non-hereditary, early-onset, aggressive, unilateral retinoblastoma. Although MYCN amplification accounted for only 1.4% of retinoblastoma cases, researchers identified it in 18% of infants diagnosed at less than 6 months of age. Median age at diagnosis for MYCN retinoblastoma was 4.5 months, compared with 24 months for those who had non-familial unilateral disease with two RB1 gene mutations.
Gross appearance
Gross and microscopic appearances of retinoblastoma are identical in both hereditary and sporadic types. Macroscopically, viable tumor cells are found near blood vessels, while zones of necrosis are found in relatively avascular areas.
Microscopic appearance
- Microscopically, both undifferentiated and differentiated elements may be present. Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei; differentiated elements include Flexner-Wintersteiner rosettes, Homer-Wright rosettes and fluerettes from photoreceptor differentiation.