Retinoblastoma is a rare childhood cancer of the eye. It arises from the retina, the nerve tissue in the back of the eye that is sensitive to light. Thanks to advances in diagnosis and treatment, more than 95% of children with retinoblastoma can now be cured.
- Retinoblastoma is usually diagnosed before the age of 2, and more than 90% of cases are diagnosed by age 5.
- The tumor(s) may be present in one or both eyes, and rarely spreads to other parts of the body.
- Retinoblastoma may be inherited within a family or may occur in a child without any family history of the disease.
Retinoblastoma Treatment at Dana-Farber/Boston Children's
Through the Dana-Farber/Boston Children's Retinoblastoma Program, we offer the full range of multidisciplinary treatment options for retinoblastoma, including intra-arterial chemotherapy – a recently-developed treatment option that often can provide the most effective retinoblastoma treatment with the fewest side effects.
Find in-depth details on retinoblastoma on the Dana-Farber/Boston Children's website, including answers to:
- How is retinoblastoma diagnosed?
- What is the best treatment for retinoblastoma?
- What is the latest research on retinoblastoma?
- What is the long-term outlook for children with retinoblastoma?
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 4 per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis.
Hereditary and Nonhereditary Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Hereditary disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may be known in those patients with a positive family history (25%) or may have occurred in utero at the time of conception, in those patients with sporadic disease (75%). Hereditary retinoblastoma may manifest as unilateral or bilateral disease. Most patients with unilateral diseases do not have the hereditary form of the disease, whereas all children with bilateral diseases are presumed to have the hereditary form of the disease, even though only 20% have an affected parent. In hereditary retinoblastoma, tumors tend to occur at a younger age than in the nonhereditary form of the disease. Unilateral retinoblastoma in children younger than 1 year should raise concern for the hereditary disease, whereas older children with a unilateral tumor are more likely to have the nonhereditary form of the disease.
Children with the hereditary form of retinoblastoma may continue to develop new tumors for a few years after diagnosis. For this reason, children with hereditary retinoblastoma who have a normal examination in at least one eye on initial presentation need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months. Following treatment, patients require careful surveillance until age 5 years. The interval between exams is based on both the age of the child (more frequent visits as the child ages) and the stability of the disease.
The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.
Blood and/or tumor samples can be screened to determine if a retinoblastoma patient has a mutation in the RB1 gene. Commercial laboratories are now available to perform this service. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1gene demonstrates germline mutation in 90% of patients with hereditary retinoblastoma.Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. The multistep assay includes DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. This expanded analysis is showing promise in better defining the functional significance of apparently novel mutations in pilot investigations performed at the University of Pennsylvania. Such testing should be performed only at institutions with expertise in RB1 gene mutation analysis. In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification (MLPA), and fluorescence in situ hybridization (FISH) may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.
Genetic counseling should be an integral part of the therapy for a patient with retinoblastoma, whether unilateral or bilateral. It is of utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate risk of disease in family members. Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism, making the genetic story more complex and contributing to the difficulty of genetic counseling.
Factors Influencing Mortality
The present challenge for those who treat retinoblastoma is to prevent loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and second malignant neoplasms, have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (hereditary) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with hereditary retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma. Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis. While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging (MRI) for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for 5 years. It is unclear if this will have an impact on outcome or survival. Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Second malignant neoplasms
Patients with hereditary retinoblastoma have a markedly increased frequency of second malignant neoplasms (SMN). The cumulative incidence was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year. However, more recent studies have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. Most of the SMN are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma.
A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two U.S. institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histologic subtype. Leiomyosarcoma was the most frequent subtype, with 78% being diagnosed 30 or more years after the retinoblastoma diagnosis. Risks were elevated in patients treated with or without radiation therapy, and, in those treated with radiation therapy, sarcomas were seen both within and outside the field of radiation. The carcinogenic effect of radiation increased with dose, particularly for secondary sarcomas where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of the second cancers occur within irradiated tissue and one-third occur outside the radiation field. The risk for SMN is heavily dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic type of SMN may be influenced by age. These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma.
It has become apparent that patients with hereditary retinoblastoma are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.
Survival from second malignancies is certainly suboptimal and varies widely across studies. However, with advances in therapy, it is essential that all second malignancies be treated with curative intent. Those who survive SMN are at a 7-fold increased risk for developing a subsequent malignancy. The risk further increases 3-fold when patients are treated with radiation therapy for their retinoblastoma. There is no clear increase in second malignancies in patients with sporadic retinoblastoma beyond that associated with the treatment.
Late Effects from Retinoblastoma Therapy
Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method. One study of visual acuity following treatment with systemic chemotherapy and focal ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.
Since systemic carboplatin is now commonly used in the treatment of retinoblastoma, concern has been raised about hearing loss related to therapy. However, an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram.