Retinoblastoma

15.2Incidence

•Two to three percent of all neoplasias in childhood

•Annually 3 in 1 million children less than 16 years old are newly diagnosed

•Annually 11 in 1 million children less than 5 years old are newly diagnosed; after the fifth year of life, occurrence is rare

•Median age at diagnosis: 2 years

•Male to Female ratio of 1:1

•Bilateral or multifocal involvement in up to 40% of children, either as a result of defective copy of the RB1 gene from affected parent (15–25%) or a new germline mutation (75–85%)

•Bilateral involvement more frequent in females

•Unilateral involvement in two thirds of the children affected by the disease, mainly during the second and third years of life

15.3Etiology, Genetics, and Pathogenesis

•Sporadic form (60%): members of the family and relatives without retinoblastoma

•Hereditary form (40% overall: 15% unilateral, 25% bilateral): two mutational events in the RB gene are required for tumor occurrence:

–Step 1: mutation of the germ cell

–Step 2: mutation of the target cell (retina cell)

–Hereditary retinoblastoma is an autosomal dominant trait with high penetrance, that is, nearly 50% of relatives develop a retinoblastoma (mostly bilateral)

•The chromosomal alteration is located on chromosome 13q14, involving the RB1 retinoblastoma gene; this is also the chromosomal region linked to the development of osteosarcoma, which is the most frequent secondary tumor following retinoblastoma

•RB1is also expressed in normal human tissues, including brain, kidney, ovary, spleen, liver, placenta, and retina; it is involved in cell cycle regulation, inducing the transition from G1 to S-phase

•In the hereditary form of retinoblastoma, siblings and family members should be tested for genetic mutations and screened by an ophthalmologist within the first 4 years of life

•Occasionally, there is combined congenital malformations, including microencephaly, microphthalmia, and skeletal and urogenital anomalies

•Retinoblastoma, neuroblastoma, and medulloblastoma have a common neuroectodermal origin and also common characteristics such as similar necrotic nests in the tumor and radiosensitivity; retinoblastoma and neuroblastoma both undergo spontaneous regression

15.4Pathology and Reese–Ellsworth Classification

15.4.1 Macroscopic Features

•One or more tumor sites, mainly arising from the ora serrata retinae

•Two types of spread:

–Exophytic: from the retina into the subretinal space, with detachment of the retina

–Endophytic: Growing into the vitreous cavity, producing floating tumor spheres, named vitreous seeds

•Extension of tumor toward the choroid, lamina cribrosa sclerae, the optic nerve, or via the subarachnoid space and central nervous system (CNS)

•Distant metastases in lymph nodes, bone marrow, bone, and liver; rarely pulmonary metastases (similar to neuroblastoma)

15.4.2 Microscopic Features

•High cellularity with small hyperchromatic cells and high nuclear-to-cytoplasm ratio, often grouped in cell rosettes (similar to neuroblastoma)

•Frequently mitotic cells and necrotic areas, some containing calcium deposits

•Eighty percent of unilateral retinoblastoma and 90% of bilateral retinoblastoma have group five classification at time of diagnosis