General Information About Retinoblastoma
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach is particularly important in the management of retinoblastoma; it incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
- An ophthalmologist with extensive experience in the treatment of children with retinoblastoma.
- Primary care physician.
- Pediatric surgical subspecialists.
- Radiation oncologists.
- Pediatric medical oncologists/hematologists.
- Rehabilitation specialists.
- Pediatric nurse specialists.
- Social workers.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Retinoblastoma is a rare pediatric cancer that requires a careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient's life and preserve useful vision, and thus, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims at minimizing systemic exposure to drugs, optimizing ocular drug delivery, and preserving useful vision.
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.
Retinoblastoma is a cancer of the very young child; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years, and 95% of cases are diagnosed before age 5 years. Thus, while the estimated annual incidence in the United States is approximately four cases per 1 million children younger than 15 years, the age-adjusted annual incidence in children aged 0 to 4 years is 10 to 14 cases per 1 million (approximately one in 14,000–18,000 live births).
Retinoblastoma arises from the retina, and its growth is usually under the retina and toward the vitreous. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses. Invasion of the choroid is common, although occurrence of massive invasion is usually limited to advanced disease. Following invasion of the choroid, the tumor gains access to systemic circulation and creates the potential for metastases. Further progression through the ocular coats leads to invasion of the sclera and the orbit. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and central nervous system (CNS) dissemination. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm.
Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life. Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the CNS or systemically (commonly in the bones, bone marrow, and liver).
The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. A very detailed documentation of the number, location, and size of tumors, the presence of retinal detachment and subretinal fluid, and the presence of subretinal and vitreous seeds must be performed. Additional imaging studies include bidimensional ocular ultrasound and magnetic resonance imaging (MRI) (preferred over computed tomography [CT] to avoid radiation exposure). These imaging studies are important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria.
Evaluation of the presence of metastatic disease also needs to be considered in the subgroup of patients with suspected extraocular extension by imaging or high-risk pathology in the enucleated eye (i.e., massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). In these cases, bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture are performed.
Genetic counseling is recommended for all patients with retinoblastoma.
Heritable and Nonheritable Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in utero at the time of conception in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.
Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4.[6,7] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.
In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.
Children with a germline RB1 mutation may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently. It is common practice for examinations to occur every 2 to 4 months for at least 28 months. The interval between exams is based on the stability of the disease and age of the child (i.e., less frequent visits as the child ages).
A proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye. Periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.
Genetic Testing and Counseling
Blood and tumor samples can be tested to determine if a patient with retinoblastoma has a mutation in the RB1 gene. 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 RB1 gene demonstrates germline mutation in 90% of patients with heritable retinoblastoma.
Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. A multistep assay that includes the following may be performed for a complete genetic evaluation of the RB1 gene:
- DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions.
- Southern blot analysis to characterize genomic rearrangements.
- Transcript analysis to characterize potential splicing mutations buried within introns.
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, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed.
The absence of detectable RB1 mutations in some patients suggests that alternative genetic mechanisms may underlie the development of retinoblastoma. Approximately 3% of unilateral, nonheritable retinoblastoma cases have no somatic RB1 alterations. In half of these cases, high levels of MYCN amplification have been reported; these patients had distinct, aggressive, histologic features and a median age at diagnosis of 4 months.
Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation; counseling assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members. Genetic counseling, however, is not always straightforward. Approximately 10% of children with retinoblastoma have somatic genetic mosaicism, which contributes to the difficulty of genetic counseling. (Refer to the PDQ summaries on Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information.)
Because of the poor prognosis of trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the follow-up of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section of this summary for more information.)
While retinoblastoma is a highly curable disease, the challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the patient's 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 and subsequent decades of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. Death from an SN is the most common cause of death and contributes to more than 50% of deaths for patients with bilateral disease. In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral 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 heritable retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.
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 most cases within 2 years of first diagnosis. Although it is not clear whether early diagnosis can impact survival, screening with MRI has been recommended as often as every 6 months for 5 years for those suspected of having heritable disease or those with unilateral disease and a positive family history. CT scans are generally avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation. At the time of diagnosis, patients who are asymptomatic of an intracranial tumor have a better outcome than do patients who are symptomatic.
Approximately 5% to 10% of children with heritable retinoblastoma develop pineal gland cysts detected by MRI; these cyst abnormalities must be distinguished from the pineoblastoma that typically defines trilateral retinoblastoma.[18,19]
Subsequent neoplasms (SNs)
Survivors of retinoblastoma have a high risk of developing SNs. Factors that influence this risk include the following:
- Heritable retinoblastoma. Patients with heritable retinoblastoma have a markedly increased incidence of SNs, independent of treatment with radiation therapy.[15,20,21] A possible association may exist between the type of RB1 mutation and incidence of SNs, with complete loss of RB1 activity associated with a higher incidence of SNs. With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they 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.[23,24] Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of an SN than are those with a de novo mutation; this increase appears to be most significant for melanoma.
- Past treatment for retinoblastoma with radiation therapy. The cumulative incidence of SNs 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 analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. Preliminary data suggest that proton radiation therapy may further lower the risk of radiation-induced malignancies in survivors of retinoblastoma.
The most common SN is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas, and a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field.[21,26,27,29]
- Age at time of radiation therapy. The risk of SNs also appears to be dependent on the patient's age at the time that external-beam radiation therapy is administered, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.[27,30,31] These data support a genetic predisposition to soft tissue sarcomas in addition to the risk of osteosarcoma.
- Previous SN. Those who survive SNs are at a sevenfold increased risk for developing another SN. The risk increases an additional threefold for patients treated with radiation therapy.
An increased incidence of acute myeloid leukemia in children with heritable retinoblastoma has been suggested; however, no evidence is available to support this suggestion.; [Level of evidence: 3iiiA] Of 245 patients who received etoposide, only one patient had acute promyelocytic leukemia after 79 months.
Late Effects from Retinoblastoma Therapy
As previously discussed, patients with heritable retinoblastoma have an increased incidence of SNs. (Refer to the Subsequent neoplasms section of this summary for more information.) Other late effects that may occur after treatment for retinoblastoma include the following:
- Diminished orbital growth. Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.
- Visual-field deficits. 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 after treatment with systemic chemotherapy and local 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 of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.
- Hearing loss. Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Treatment Options for Unilateral and Bilateral Retinoblastoma and Treatment Options for Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While 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, another series documented hearing loss in 17% of patients. Age younger than 6 months at the time of treatment and higher carboplatin systemic exposures appear to correlate with an increased risk of otologic toxic effects.[45,46]
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