Retinoblastoma is a 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, therefore, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims to minimize systemic exposure to drugs, optimize ocular drug delivery, and preserve useful vision. For patients presenting with extraocular retinoblastoma, treatment with intensive chemotherapy is required, including consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue. While most patients with orbital disease and a large proportion of patients with systemic extra–central nervous system (CNS) metastases can be cured, the prognosis for patients with intracranial disease is dismal.
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. Thus, while the estimated annual incidence in the United States is approximately 4 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 1 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. After invading 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. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and CNS dissemination.
The following screening and monitoring strategies reflect common practices in the management of retinoblastoma.
In children with a positive family history of retinoblastoma, early-in-life screening by fundus exam is performed under general anesthesia at regular intervals according to a schedule based on the absolute estimated risk, as determined by the identification of the RB1 mutation in the family and the presence of the RB1 mutation in the child. Infants born to affected parents have a dilated eye examination under anesthesia as soon as possible in the first month of life, and a genetic evaluation is performed. Infants with a positive genetic test are examined under anesthesia on a monthly basis. In infants who do not develop disease, monthly exams continue throughout the first year; the frequency of those studies may be decreased progressively during the second and subsequent years. Screening exams can improve prognosis in terms of globe sparing and use of less intensive, ocular-salvage treatments in children with a positive family history of retinoblastoma.
Common practice for the parents and siblings of patients with retinoblastoma is to have screening ophthalmic examinations to exclude an unknown familial disease. Siblings continue to be screened until age 3 to 5 years or until it is confirmed that they do not have an RB1 gene mutation.
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, orbital cellulitis, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the preauricular and laterocervical lymph nodes, in the CNS, or systemically (commonly in the bones, bone marrow, and liver).
In the United States, children of Hispanic origin and children living in lower socioeconomic conditions have been noted to present with more advanced disease.
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.
Bidimensional ocular ultrasound and magnetic resonance imaging (MRI) can be useful to differentiate retinoblastoma from other causes of leukocoria and in the evaluation of extrascleral and extraocular extension in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement; cautious interpretation of those findings is needed. The detection of the synthetase of ganglioside GD2 mRNA by reverse transcriptase–polymerase chain reaction in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.
Evaluation for 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). Patients presenting with these pathological features in the enucleated eye are at high risk of developing metastases. In these cases, bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture may be performed.
Genetic counseling is recommended for all patients with retinoblastoma. (Refer to theGenetic Counseling section of this summary for more information.)
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 RB1gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis 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 polymorphisms.[7,8] 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.
The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[10,11] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods. Other recurring genomic changes that occur in a small minority of tumors include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.[10-12] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MYCNamplification.
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.
Because of the poor prognosis for patients with trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the monitoring of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information.)
Blood and tumor samples can be tested to determine whether 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 with targeted sequencing.
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; 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. Allele-specific deep (2500x) sequencing of an RB1genomic amplicon from lymphocyte DNA can reveal low-level mosaicism. Because mosaicism is caused by a postzygotic mutation, such a finding obviates the need for serial examination of siblings under anesthesia. Some RB1 mutations thought to be heterozygous with Sanger sequencing were also found to be mosaic. Deep sequencing will not discover some mosaic mutations with very low levels of amplification, mutations outside of the RB1 amplicon, mutations not found in lymphocytes but in other tissues, or mosaic large rearrangements of RB1. Combining the above techniques, a germline mutation may be detected in more than 90% of patients with heritable retinoblastoma.[16,17]
The absence of detectable somatic RB1 mutations in approximately 3% of unilateral, nonheritable retinoblastoma cases suggests that alternative genetic mechanisms may underlie the development of retinoblastoma. In one-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. In another small subset of tumors without detectable somatic RB1 mutations, chromothripsis is responsible for inactivating the RB1 gene.
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. In addition, for one specific mutation, the risk of retinoblastoma in a sibling may depend, in part, on whether the mutation is inherited from the mother or father. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Causes of Retinoblastoma-Related Mortality
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 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, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality in the first and subsequent decades of life.
Death from a second neoplasm is the most common cause of death and contributes to more than 50% of deaths in patients with bilateral disease. In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease and the implementation of neuroimaging screening, 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. It is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.
Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life. Because of the poor prognosis for patients with trilateral retinoblastoma and the apparent improved survival with early detection and aggressive treatment, screening with routine neuroimaging could potentially detect most cases within 2 years of first diagnosis. Routine baseline brain MRI is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series of patients, the 5-year overall survival rate was 67% for those detected at baseline, compared with 11% for the group with a delayed 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 patients suspected of having heritable disease or those with unilateral disease and a positive family history. Computed tomography scans are generally avoided for routine screening in these children because of the risk related to ionizing radiation exposure.
A cystic pineal gland, which is commonly detected by surveillance MRI, needs to be distinguished from a cystic variant of pineoblastoma. In children without retinoblastoma, the incidence of pineal cysts has been reported to be 55.8%. In a case-control study that included 77 children with retinoblastoma and 77 controls, the incidence of pineal cysts was similar (61% and 69%, respectively), and the size and volume of the pineal gland was not significantly different between the groups. However, a cystic component has been described in up to 57% of patients with histologically confirmed trilateral retinoblastoma. An excessive increase in the size of the pineal gland seems to be the strongest parameter indicating a malignant process.
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.[21,29,30] A possible association between the type of RB1 mutation and incidence of SNs may exist, 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.[32,33]
Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of developing 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. A German series of 633 patients with heritable retinoblastoma demonstrated a 5-year survival of 93%; however, 40 years later, only 80% of patients survived, with most succumbing to radiation-induced SNs (hazard ratio, approximately 3). Other studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the SN rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. In a nonrandomized study that compared two contemporary cohorts of patients with hereditary retinoblastoma who were treated with either photon (n = 31) or proton (n = 55) therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015). A longer follow-up will be required to further define the risk of SNs associated with proton radiation.
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; 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.[30,35,37,39]
Age at time of radiation therapy. The risk of SNs also appears to depend on the patient's age at the time that external-beam radiation therapy (EBRT) is administered, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.[37,40,41]
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.
The issue of balancing long-term tumor control with the consequences of chemotherapy is unresolved. Most patients who receive chemotherapy are exposed to etoposide, which has been associated with secondary leukemia in patients without a predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma. Despite the known increased risk of acute myeloid leukemia (AML) associated with the use of etoposide, patients with heritable retinoblastoma are not at an increased risk of developing this SN.[44-46] An initial report conducted by informal survey methods described 15 patients who developed AML after chemotherapy. One-half of the patients also received radiation therapy. This finding has not been substantiated by formal studies. In a single-institution study of 245 patients who received etoposide, only 1 patient had acute promyelocytic leukemia after 79 months. Additionally, the Surveillance, Epidemiology, and End Results (SEER) Program calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary AML in patients treated for retinoblastoma was zero.
Survival from SNs is certainly suboptimal and varies widely across studies.[29,32,48-51] However, with advances in therapy, it is essential that all SNs in survivors of retinoblastoma be treated with curative intent.
Late Effects from Retinoblastoma Therapy
In a report from the Retinoblastoma Survivor Study (N = 470), 87% of survivors of retinoblastoma (mean age, 43 years; median follow-up, 42 years) had at least one medical condition and 71% had a severe or life-threatening condition. The adjusted relative risk of a chronic condition in survivors, compared with nonretinoblastoma controls, was 1.4 (P < .01); the relative risk of a grade 3 or 4 condition was 7.6 (P < .01). After excluding ocular conditions and SNs, this excess risk was found to persist only for those with bilateral disease.
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 of Intraocular Retinoblastoma and Treatment of Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While two large studies that included children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed an incidence of treatment-related hearing loss of lower than 1%,[57,58] a separate series documented some degree of hearing loss in 17% of patients. In the latter study, age younger than 6 months at the time of treatment and higher carboplatin systemic exposures correlated with an increased risk of ototoxicity.[59,60]
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