Retinoblastoma: Genetics, diagnosis, treatment and sequelae

There has been a conceptual breakthrough in our understanding of the molecular and genetic basis of the origins of human neoplasia. Mutations in three broad categories of genes have been shown to contribute to the origins and progression of neoplasia in humans: the oncogenes, the tumor suppressor genes, and the mutator genes. The retinoblastoma gene (RB1) is the best characterized tumor suppressor gene. It was first localized by Knudson and coworkers who observed an association between a deletion on the long arm of chromosome 13 and an inherited predisposition to retinoblastoma. The RB1 gene is composed of 27 exons encompassing more than 200 kilobases of genomic DNA. The product of the RB1 gene is a 105-107 kDa nuclear phosphoprotein which plays a part in regulating cellular DNA synthesis. Tumors arise, as predicted by Knudson's 'two-hit' hypothesis, as a result of biallelic mutation of the RB1 gene. Inactivating mutations of the RB1 gene have been identified in various tumors, showing the RB1 gene product has an important role in regulating cell proliferation beyond its effect on retinoblasts. The RB1 gene was cloned and identified in 1986. Returning the RB1 gene to a retinoblastoma cell in culture reduces its tumorgenic potential. Retinoblastoma is the most common malignant intraocular tumor of childhood. The tumor consists of undifferentiated small anaplastic cells which may be round or polygonal. Both Flexner and Wintersteiner described the arrangement of the more differentiated malignant retinoblastoma cells in neuroepithelial rosettes which appear to represent an attempt to differentiate into photoreceptor cells. The tumor commonly presents with a white pupillary light reflex. The diagnosis is generally made based on physical examination, confirmatory photographs and diagnostic imaging studies and, in many cases, a supportive family history. The most widely used grouping system was proposed by Algernon Reese and Robert Ellsworth. The primary goal of retinoblastoma treatment is cure. It is reasonable to assert that a secondary goal of treatment is preservation of vision in the affected eye. Surgical options for therapy include enucleation, exenteration, photo coagulation, cryotherapy, and radioactive plaque application. External beam radiotherapy has a significant role to play in sight-preserving therapy. There has been a resurgence of interest in the use of systemic cytotoxic chemotherapy, either in addition to conventional surgical and radiotherapy techniques or as an alternative to them. Several ophthalmic oncology centers have piloted therapy programs designed to avoid enucleation or whole eye external beam irradiation. Such programs rely on vigorous focal therapy plus chemotherapy. The RB1 gene unequivocally is involved in carcinogenesis. Heritable retinoblastoma has an appreciable rate of second malignant neoplasm development - the cumulative mortality for all second tumors at 40 years of follow-up for bilateral retinoblastoma has been calculated to be 26%. Therapy choice may influence the risk and type of second malignant neoplasms. This refresher course will survey the genetic basis of retinoblastoma, techniques of diagnosis, forms of therapy, proposals for protocols emphasizing chemotherapy plus focal therapy, and the long-term consequences of cure of this fascinating childhood malignancy