Chapter 461. Retinoblastoma

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. Incidence rates vary from 1 in 14,000 to 1 in 22,000 live births, and it is estimated that 300 children develop retinoblastoma in the United States annually.1 There is no race or gender predilection. Approximately 80% of children are diagnosed before the age of 3 years. More than half of patients diagnosed in the first year of life have bilateral disease compared with less than 10% of older children.

Retinoblastoma occurs sporadically in the majority of affected children. Of all cases, approximately 60% are unilateral and 25% are bilateral.2 All bilateral cases and 15% of unilateral cases are hereditary. Only 10% to 20% of hereditary cases have an affected parent; therefore, unilateral cases without an affected parent can be determined to be hereditary only with mutation analysis (Fig. 461-1).

Genetics

Retinoblastoma (RB) appears to develop only when both alleles of a tumor suppresser gene (RB1) located on 13q14 are absent or defective. In hereditary RB every cell in the body inherits one absent or defective gene. During normal development, a mutagenic “hit” to the remaining normal allele results in the loss of normal cellular growth regulation and tumor development.2 In sporadic, nonhereditary RB, a single retinal cell must receive 2 mutagenic hits to the 13q14 tumor suppressor gene before RB can be expressed. Point mutations of the RB1 gene are the most common events. Variable deletions of the long arm of chromosome 13 are not commonly found in patients with RB and patients who are developmentally delayed should not be presumed to have the chromosome 13q deletion syndrome.3,4

Genetic counseling for patients with retinoblastoma and their families is complex, but a few generalizations can be made. Patients with the hereditary form are at risk for other cancers later in life, including soft tissue and bone sarcomas and melanoma. This risk is increased in patients treated with radiation therapy.5 A survivor of hereditary retinoblastoma has a 50% chance of transmitting the gene to his or her offspring. In patients with unilateral disease, the overall risk of transmitting the gene to offspring is estimated to be 2.5%. With no previous family history, the risk for a sibling is 2% if the affected child has bilateral disease and 1% if the affected child has unilateral disease.6 These empiric risk estimates are based on the possibility of gonadal mosaicism. In addition, it is estimated that 10% of individuals who carry an abnormal RB1 gene do not develop retinoblastoma because the second event did not occur in any cell; however, they are still at risk to develop other cancers during their lifetime.

Pathology

Retinoblastoma arises from the inner layer of the retina and usually extends into the vitreous cavity as a white or cream-colored nodular mass. In advanced disease, vitreous seeding and retinal detachment usually occur. The tumor tends to outgrow its blood supply, and patchy necrosis and degeneration with calcium deposition develop.7 Histopathologically, the tumor is composed of small, round blue cells that show variable degrees of photoreceptor differentiation (rosettes and fleurettes).

Clinical Features and Differential Diagnosis

The clinical characteristics of retinoblastoma (RB) depend on the stage of tumor growth at the time of its discovery. When a tumor is small and at the macula, the initial sign may be sensory strabismus. As the tumor grows, leukocoria (white pupil) develops (Fig. 461-2). This is the most common presenting sign of RB, representing 56% to 62% of cases diagnosed.8 When disease is very advanced, presenting symptoms may include pain due to secondary glaucoma, buphthalmos, proptosis, hyphema, and orbital cellulitis.

The differential diagnosis of RB includes persistent hyperplastic primary vitreous (PHPV), retinal detachment, Coats disease, glial hamartomas, retinal hemangiomas, myelinated nerve fibers, congenital cataract, chorioretinal coloboma, uveitis, larval granulomatosis, congenital retinal folds, retinal dysplasia, and retinopathy of prematurity.9

Diagnostic Evaluation

The diagnosis of retinoblastoma is usually established by ophthalmoscopic and radiographic examination. A detailed ophthalmology examination under general anesthesia is required to adequately visualize the eyes and map the tumors. An ultrasound of the globe or computed tomography (CT) scan of the orbits is required to demonstrate the presence of calcium. In addition, a magnetic resonance image (MRI) of the brain is an essential part of the assessment of all children with hereditary retinoblastoma because of the association of a primitive neuroectodermal tumor in the brain, most commonly located in the pineal region. This trilateral retinoblastoma syndrome is usually diagnosed at a very young age, and screening and early detection may improve survival.10 When the possibility of metastatic disease is considered, an MRI of the brain and spine, bone scan, bone marrow aspiration and biopsy, and spinal fluid examination for tumor cells should be performed.

Treatment

Treatment efforts are focused on survival and preservation of useful vision, without irradiation or enucleation. The treatment approach depends on the size and location of tumors and the degree of ocular and extraocular involvement. Eyes with extensive tumor, tumor seeding of the vitreous cavity, or neovascular glaucoma are enucleated. Traditionally, external beam radiotherapy and scleral plaque brachytherapy have been used to treat the second eye of patients with bilateral retinoblastoma after the eye with more advanced tumor has been enucleated. Since the early 1990s, however, systemic chemotherapy has played an integral role in managing patients with bilateral intraocular retinoblastoma. Agents most commonly used are carboplatin, etoposide, and vincristine. Chemotherapy is primarily used to debulk advanced tumors to allow the successful administration of local ophthalmic therapy such as laser photocoagulation, thermotherapy, and cryotherapy. Photocoagulation can be used for small tumors confined to the retina. Peripheral tumors too large to treat effectively with photocoagulation may be treated more appropriately with cryotherapy. This chemoreduction approach has been shown to improve visual outcome and delay or avoid external beam radiation and enucleation.11,12 Chemotherapy is also used as an adjunct to primary surgery in those cases that are high risk for metastasis, such as eyes with optic nerve, massive choroidal, or scleral invasion.13 Children with metastatic retinoblastoma require more intense therapy. Modalities include systemic chemotherapy, external beam radiation therapy, as well as high-dose chemotherapy followed by autologous hematopoietic stem cell rescue.14

Prognosis

Approximately 95% of children with retinoblastoma in the United States and medically developed countries are cured through early detection and successful management of intraocular disease.11 This is in contrast to patients in developing countries, who commonly present with orbital involvement and metastatic disease. Prognosis for those patients with extraocular extension or metastatic disease is poor.15 Individuals with an abnormal RB1 gene are at increased risk for developing second cancers in their lifetime, predominantly sarcomas and melanomas.5 This risk is further increased by exposure to radiation therapy. In addition, there is some evidence that the presence of lipomas in survivors of hereditary retinoblastoma may be associated with an increased probability of developing a nonocular malignancy.16 For hereditary patients, radiation therapy increases the cumulative probability of developing cancer to 38.2% at 50 years compared with 21% for the nonirradiated patients.5 Other effects of radiation therapy include cataracts, midfacial deformities, retinal hemorrhage, and dry eye.17 The long-term effects of chemotherapy in this population are still unknown.