USMLE – Retinoblastoma
Retinoblastoma is the most common malignant eye tumor of childhood and is responsible for approximately 1% of all deaths from cancer in the age group of newborns to 15 years. Retinoblastoma is worldwide in distribution and affects all racial groups. Its frequency is approximately 1 in 17,000 live births. It is a tumor of infancy and childhood; cases with tumors present at birth are not exceptional. The risk for retinoblastoma decreases with age, with well over 90% of cases being diagnosed before the age of 7 years. It affects both sexes with equal frequency. The tumor is usually fatal once it spreads outside the eye and orbit. Most cases in developed countries are diagnosed before extraocular spread. Radiation therapy, laser photocoagulation, and cryotherapy are used to treat intraocular tumors in eyes with a potential for useful vision; in eyes with large tumors, enucleation is the preferred therapy.
Etiologically, retinoblastoma is unusual because it appears to be simply the result of defects in a single gene, the retinoblastoma gene (RB). If a mutant RB allele arises in the germ line, it can be transmitted as a dominant trait, and carriers are at high risk (greater then 90% risk for most mutations) for retinoblastoma in childhood and for other cancers (e.g., osteosarcoma) later in life. Most of such cases of hereditary retinoblastoma have tumors affecting both eyes (bilateral retinoblastoma); a small percent have, in addition, independently arising tumors, also occurring in childhood, either in the pineal gland or in the suprasellar or parasellar region (trilateral retinoblastoma). A small number of carriers remain unaffected. Most patients with hereditary retinoblastoma have no previous family history of the disease because they have a new germ line mutation. In nonhereditary retinoblastoma (about 60 to 70% of all patients), the initial mutation affecting one copy of the RB gene arises in a somatic retinal cell or in a somatic cell that is a precursor of the developing retina. Almost all nonhereditary cases have only one tumor in one eye; they are not at increased risk for other cancers later in life.
In both hereditary and nonhereditary retinoblastoma, the retinoblastomas are clonal proliferations of sensitive retinal cells that have the initial germ line or somatic mutation affecting one RB allele and that also have lost the function of the remaining wild-type RB allele. The loss of the second RB allele can occur because of an independently arising somatic mutation, because of chromosomal nondisjunction or recombination occurring during mitosis, or because of epigenetic modification such as methylation of the promoter region.
The RB gene is a prototype tumor-suppressor gene. The loss of both allelic, wild-type copies of the respective cancer-suppressor gene appears to be a key step in malignant transformation. As we have seen, each tumor-suppressor gene underlies the origin of more than one tumor type, such as the RB gene causing retinoblastoma and osteosarcoma, or the neurofibromatosis type 2 gene causing acoustic neuroma or meningioma.
Retinoblastoma is believed to arise from a cell of neuroepithelial origin in the retina. The tumors tend to be nodular masses, often with satellite seedings. On light microscopic examination, undifferentiated areas of these tumors are composed of small, round cells with hyperchromatic nuclei and scanty cytoplasm. The resemblance of these cells to undifferentiated retinoblasts, which are precursors of the differentiated retinal cells, led to the use of the term retinoblastoma. Differentiated structures are found within many retinoblastomas, the most characteristic of these being the rosettes described by Flexner and Wintersteiner (Flexner Wintersteiner rosettes). These structures consist of clusters of cuboidal or short columnar cells arranged around a central lumen. The nuclei are displaced away from the lumen, which by light microscopy appears to have a limiting membrane resembling the external limiting membrane of the retina. Photoreceptor-like elements protrude through the membrane, and some taper into fine filaments. Less common are the rosettes described by Wright: these are radial arrangements of cells around a central tangle of fibrils (Homer Wright rosettes). An additional differentiated structure in a few percent of tumors is the fleurette, which represents an attempt at photoreceptor differentiation by tumor cells.
Tumor cells may disseminate through the choroidal vasculature or may spread beyond the eye through the optic nerve or subarachnoid space. Bone marrow aspiration, peripheral blood smears, and cerebrospinal fluid examinations assess the extent of spread in patients with metastatic retinoblastoma. In advanced cases, the tumor may penetrate through the sclera and grow in the orbit. Metastases to the preauricular and cervical lymph nodes commonly follow overt extraocular extension. The most common sites of distant metastases are the central nervous system, skull, distal bones, and lymph nodes.
Spontaneous necrosis or regression of a retinoblastoma is marked by calcification and severe inflammation. The mechanism responsible for spontaneous necrosis, which is rare, is unknown. Rarely, tumors composed of uniformly benign-appearing cells exhibiting photoreceptor differentiation and the formation of fleurettes have been reported. These have been referred to as retinocytomas and are believed to be a benign variant of retinoblastoma.