Retinoblastoma is a pediatric cancer that requires careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient’s life and uses an individualized, risk-adapted approach to minimize systemic exposure to drugs, optimize ocular drug delivery, and preserve useful vision. For patients presenting with extraocular retinoblastoma, treatment with systemic chemotherapy and radiation therapy is likely to be curative. However, extraorbital disease requires intensive chemotherapy and may include consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue with or without radiation therapy. While 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 it may grow under the retina and/or toward the vitreous cavity. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses.
Focal invasion of the choroid is common, although the 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. Tumors that invade 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 (refer to Figure 1).
EnlargeFigure 1. Anatomy of the eye showing the sclera, ciliary body, canal of Schlemm, cornea, iris, lens, vitreous humor, retina, choroid, optic nerve, and lamina cribrosa. The vitreous humor is a gel that fills the center of the eye.
Recent consensus reports from the American Association of Ophthalmic Oncologists and Pathologists and the American Association for Cancer Research Childhood Cancer Predisposition Workshop describe surveillance guidelines for screening children at risk of developing retinoblastoma.[2,3]
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.[2,3]
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 (refer to Table 1 and Figure 2).[2,3]
Table 1. Pretest Risk for Relatives to Carry the Mutant RB1 Allele of the Proband
Relative of ProbandPretest Risk for Mutant Allele (%) Bilateral Proband (100)
Unilateral Proband (15)Offspring (infant)
0.007 EnlargeFigure 2. Management guidelines for childhood screening for retinoblastoma. The presented schedules are general guidelines and reflect a schedule for examinations in which no lesions of concern are noted. It may be appropriate to examine some children more frequently. Decisions regarding examination method, examination under anesthesia (EUA) versus nonsedated examination in the office, are complex and best decided by the clinician in discussion with the patient’s family. The preference of the majority of the clinical centers involved in the creation of this consensus statement is reflected, but individual centers may make policy decisions based on available resources and expert clinician preference. Examination under anesthesia will be strongly considered for any child who is unable to participate in an office examination sufficiently to allow thorough examination of the retina. *A minority of clinical centers also prefer EUA for high- and intermediate-risk children (calculated risk >1%) from birth to 8 weeks of age. Reprinted from Ophthalmology, Volume 125, Issue 3, Alison H. Skalet, Dan S. Gombos, Brenda L. Gallie, Jonathan W. Kim, Carol L. Shields, Brian P. Marr, Sharon E. Plon, Patricia Chévez-Barrios, Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists, Pages 453–458, Copyright (2018), with permission from Elsevier.
It is common practice to use ophthalmic examinations to screen the parents and siblings of patients with retinoblastoma to exclude an unknown familial disease. However, in the absence of genetic testing, the screening plan for a child with a biological parent who had unilateral retinoblastoma is not well defined.
Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life.
Most patients 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.
Diagnostic and Staging Evaluation
Diagnostic evaluation of retinoblastoma includes the following:
- Eye examination. Intraocular retinoblastoma is usually diagnosed 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.
- Ocular ultrasound and magnetic resonance imaging (MRI). Bidimensional ocular ultrasound and 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.
- Reverse transcriptase–polymerase chain reaction (RT-PCR). The detection of the synthetase of ganglioside GD2 mRNA by RT-PCR 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, the following procedures may be performed:
- Bone scintigraphy.
- Bone marrow aspiration and biopsy.
- Lumbar puncture.
Genetics and Genomics 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 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.[9,10] 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.
Children with heritable retinoblastoma tend to be diagnosed at a younger age than are children with the nonheritable form of the disease.
It was thought that unilateral retinoblastoma in children younger than 1 year raises concern for the presence of heritable disease,
whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease. However, in a retrospective single-institution report of 182 patients with unilateral retinoblastoma, patients with a positive genetic result (n = 32) were diagnosed at a mean age of 26 months, and patients without genetic results were diagnosed at a mean age of 22 months (P = .31).
The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[13,14] 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.[13-15] 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 MYCN amplification. The functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1 by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification.
Genetic counseling is recommended for all patients with retinoblastoma. (Refer to the Genetic Counseling section of the PDQ summary on Retinoblastoma Treatment for more information.)
Blood and tumor samples can be tested to determine whether a patient with retinoblastoma has a germline or somatic 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 plus the promoter regions.
- Duplication/deletion analysis.
- Methylation analysis of the RB1 promoter region on DNA isolated from the tumor.
In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected; more exhaustive techniques such as karyotyping, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed. Deep (2500x) sequencing of an RB1 genomic 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. Current technologies will not discover some mosaic mutations at very low levels of amplification, mutations outside of the RB1 coding exons or the flanking intronic regions, mutations not found in lymphocytes but in other tissues (mosaic), 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.[19-21]
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. However, MYCN amplification has also been reported to coexist with RB1 mutations. 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 includes a discussion of the main forms of retinoblastoma, which assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members. Counseling also includes guidance towards appropriate screening for both patients and their families, especially if the risk of developing a second primary malignancy is increased.
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 partly 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.)
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.)
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. 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 for patients in the first decade after their diagnosis. (Refer to the Late Effects From Retinoblastoma Therapy section of this summary for more information about subsequent neoplasms.)
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, the 5-year overall survival rate was 67% for patients with tumors that were 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.