Retinoblastoma

Clinical characteristics.

Retinoblastoma is a malignant tumor of the developing retina that occurs in children, usually before age five years. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of RB1. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma with a mean age of diagnosis of 24 months; about 40% have bilateral retinoblastoma with a mean age of diagnosis of 15 months. Heritable retinoblastoma is an autosomal dominant susceptibility for retinoblastoma. Individuals with heritable retinoblastoma are also at increased risk of developing non-ocular tumors.

Diagnosis/testing.

The diagnosis of retinoblastoma is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma or by identification of a heterozygous germline pathogenic variant in RB1.

The following staging has been recommended for individuals with retinoblastoma and/or risk of heritable retinoblastoma to include "H" to describe the genetic risk for an individual to have a germline pathogenic variant in RB1:

• HX. Unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant
• H0. Normal RB1 alleles in blood tested with demonstrated high-sensitivity assays
• (H0*. Normal RB1 in blood with <1% residual risk for mosaicism)
• H1. Bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial CNS midline embryonic tumor), family history of retinoblastoma, or RB1 pathogenic variant identified in blood

Management.

Treatment of manifestations: Early diagnosis and treatment of retinoblastoma and non-ocular tumors can reduce morbidity and increase longevity; care is best provided by multidisciplinary teams of specialists including ophthalmology, pediatric oncology, pathology, and radiation oncology. Treatment options depend on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.

Prevention of secondary manifestations: If possible, radiation (including x-ray, CT scan, and external beam radiation) should be avoided in H1 individuals with heritable retinoblastoma to minimize the lifetime risk of developing late-onset second cancers.

Surveillance: Children known to have an RB1 germline pathogenic variant (H1) have eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years, in order to identify retinoblastoma tumors as early and small as possible. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life. Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant (H0*) are still at risk for low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound. Individuals with retinomas are followed with retinal examinations and imaging every one to two years. To detect second non-ocular tumors in H1 individuals with retinoblastoma, physicians and parents should promptly evaluate complaints of bone pain or lumps because of the high risk for sarcomas and other cancers; however, effective screening protocols have not yet been developed.

Agents/circumstances to avoid: Limiting exposure to DNA-damaging agents (radiation, tobacco, and UV light) may reduce the excess cancer risks in H1 survivors of heritable retinoblastoma.

Evaluation of relatives at risk: Molecular genetic testing for early identification of asymptomatic at-risk children in a family reduces the need for costly screening procedures in those family members who have not inherited the pathogenic variant (i.e., H0).

Genetic counseling.

Heritable retinoblastoma is inherited in an autosomal dominant manner. Individuals with heritable retinoblastoma (H1) have a heterozygous de novo or inherited germline RB1 pathogenic variant. Offspring of H1 individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RB1 pathogenic variant has been identified in an affected family member.

Suggestive Findings

Retinoblastoma should be suspected in children with any of the following:

• Leukocoria (white pupil)
• Strabismus
• Change in eye appearance
• Reduced visual acuity

Heritable retinoblastoma should be suspected in an individual with any of the following:

• A diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
• A retinoma
• A family history of retinoblastoma

Establishing the Diagnosis

The diagnosis of retinoblastoma is established in a proband by retinal examination with full pupillary dilation by an ophthalmologist or optometrist. Confirmation of the diagnosis and determination of the disease extent is accomplished by examination under anesthesia. Ocular imaging can help confirm the diagnosis. Pathology is not required. Note: Biopsy may cause the tumor to spread beyond the eye, endangering the life of the individual.

The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma. However, the majority of individuals with retinoblastoma do not have a family history of the disorder. These patients require identification of a heterozygous germline RB1 pathogenic variant on molecular genetic testing (see Table 1) to determine if the retinoblastoma is heritable. Identification of an RB1 pathogenic variant in the proband allows for early diagnosis and screening for relatives at risk for retinoblastoma.

The following staging has been recommended to clarify genetic risk of a germline RB1 pathogenic variant [Mallipatna et al 2017, Soliman et al 2017a]:

• HX. Individual with unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant
• H0. Individual who did not inherit a known familial germline RB1 pathogenic variant confirmed by molecular genetic testing
• (H0*. Individual with retinoblastoma or retinoma with no germline RB1 pathogenic variant identified on molecular genetic testing; residual risk of mosaicism is <1%.)
• H1. Individual with bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial CNS midline embryonic tumor), retinoblastoma and a family history of retinoblastoma, or identification of a germline RB1 pathogenic variant

Molecular genetic testing approaches to identify individuals with heritable retinoblastoma can include single-gene testing and chromosomal microarray (CMA).

Single-gene testing

• Individuals with bilateral, unilateral familial, or unilateral multifocal retinoblastoma. Sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA. Note: Targeted analysis for recurrent pathogenic variants may be offered by some laboratories (see Table 1).
• Individuals with unilateral unifocal retinoblastoma and a negative family history
  • If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA.
  • If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on tumor DNA. If pathogenic variants are identified, DNA from blood is tested for the presence of these variants. If no pathogenic variants are identified, methylation analysis of the RB1 promoter CpG island is performed to identify epigenetic inactivation of RB1 due to hypermethylation of the RB1 promoter. If no hypermethylation is identified at the promoter, DNA from tumor is tested for the amplification of MYCN, which is the cause of retinoblastoma in the absence of RB1 pathogenic variants in about 1.5% of individuals with isolated unilateral retinoblastoma.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including RB1) that cannot be detected by sequence analysis. CMA may be considered in individuals with retinoblastoma associated with developmental delay and/or other congenital anomalies [Mitter et al 2011, Castéra et al 2013].

Note: (1) If neither RB1 pathogenic variant identified in tumor tissue is found in the DNA of non-tumor cells (constitutional DNA), the affected individual has a low probability of having an RB1 germline pathogenic variant. (2) Because blood mosaicism as low as 20% can usually be detected by conventional molecular analysis such as sequencing, the failure to detect an RB1 pathogenic variant in constitutional DNA reduces but cannot eliminate the probability that the individual has an RB1 pathogenic variant in his/her germline.

Clinical Description

Retinoblastoma. The most common presenting sign is a white pupillary reflex (leukocoria). Strabismus is the second most common presenting sign and may accompany or precede leukocoria [Abramson et al 2003]. Unusual presenting signs include glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous hemorrhage. Most affected children are diagnosed before age five years. Atypical manifestations are more frequent in older children.

Probands with retinoblastoma usually present in one of the following clinical settings:

• Negative family history and unilateral retinoblastoma (60% of probands)
• Negative family history and bilateral retinoblastoma (30% of probands)
• Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see Establishing the Diagnosis) with a positive family history who undergo clinical surveillance via serial retinal examinations, tumors are often identified in the first month of life.
• Chromosome deletion involving band 13q14. Up to 5% of all index cases with unifocal retinoblastoma and 7.5% of all index cases with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [Mitter et al 2011, Castéra et al 2013].

Retinoblastoma is:

• Unilateral if only one eye is affected by retinoblastoma. About 60% of affected individuals have unilateral retinoblastoma with a mean age at diagnosis of 24 months. Usually, in individuals with unilateral retinoblastoma the tumor is also unifocal (i.e., only a single tumor is present). Some individuals have multifocal tumors in one eye (unilateral multifocal retinoblastoma). Intraocular seeding may mimic primary multifocal tumor growth. In most persons with unilateral retinoblastoma without a family history, the tumor is large and it is not possible to determine if a single tumor is present.
• Bilateral if both eyes are affected by retinoblastoma. About 40% of affected individuals have bilateral retinoblastoma with a mean age at diagnosis of 15 months. In most children with bilateral tumors, both eyes are affected at the time of initial diagnosis. In individuals with bilateral retinoblastoma both eyes may show multiple tumors. Some children who are initially diagnosed with unilateral retinoblastoma later develop a tumor in the contralateral unaffected eye.
• Trilateral if bilateral (or, rarely, unilateral) retinoblastoma and a pinealoblastoma develop (see Pinealoblastomas).

Retinoma and associated eye lesions. Benign retinal tumors (called retinoma) that have undergone spontaneous growth arrest may present within retinal scars [Dimaras et al 2008]. Calcified phthisic eyes may result from spontaneous regression of retinoblastoma associated with vascular occlusion [Valverde et al 2002]. The spectrum of RB1 pathogenic variants in individuals with retinoma and a family history for retinoblastoma and individuals who had retinoma in one eye and either retinoma or retinoblastoma in the other eye appears to be indistinct from that of individuals with bilateral retinoblastoma [Abouzeid et al 2009].

Pinealoblastomas occur in "retina-like" tissue in the pineal gland of the brain. Concurrence of pinealoblastomas or primitive neuroectodermal tumors and retinoblastoma is referred to as trilateral retinoblastoma. Pinealoblastoma is rare and usually fatal, unlike retinoblastoma of the eye, which is generally curable [de Jong et al 2014].

Other tumors. There is an increased risk for other specific extraocular primary neoplasms (collectively called second primary tumors). Most of the second primary tumors are osteosarcomas, soft tissue sarcomas (mostly leiomyosarcomas and rhabdomyosarcomas), or melanomas [Kleinerman et al 2007, Marees et al 2008, Kleinerman et al 2012]. These tumors usually manifest in adolescence or adulthood. The incidence of second primary tumors is increased to more than 50% in individuals with retinoblastoma who have received external beam radiation therapy [Wong et al 1997]. Survivors of heritable retinoblastoma who are not exposed to high-dose radiotherapy also have a high lifetime risk of developing a late-onset cancer [Dommering et al 2012b, Kleinerman et al 2012, MacCarthy et al 2013, Temming et al 2015].

Genotype-Phenotype Correlations

In the majority of families with heritable retinoblastoma, all members who have inherited the germline pathogenic variant develop multiple tumors in both eyes. It is not unusual to find, however, that the founder (i.e., the first person in the family to have retinoblastoma) has only unilateral retinoblastoma. Most of these families segregate RB1 null alleles that are altered by frameshift or nonsense variants. With few exceptions, RB1 null alleles show nearly complete penetrance (>99%) [Taylor et al 2007, Dommering et al 2014, Frenkel et al 2016].

Fewer than 10% of families show a "low-penetrance" phenotype with reduced expressivity (i.e., increased prevalence of unilateral retinoblastoma) and incomplete penetrance (i.e., ≤25%). This low-penetrance phenotype is usually associated with RB1 in-frame, missense, or distinct splice site variants, certain indel variants in exon 1, or pathogenic variants in the promoter region.

A third category of families shows differential penetrance depending on the parental origin of the pathogenic allele (parent-of-origin effect) [Klutz et al 2002, Eloy et al 2016, Imperatore et al 2018].

Cytogenetically visible deletions involving 13q14 that also result in deletions of additional genes in the same chromosome region as RB1 may cause developmental delay [Castéra et al 2013] and mild-to-moderate facial dysmorphism. As sizeable deletions of 13q14 show reduced expressivity, a considerable proportion of individuals with such deletions show unilateral retinoblastoma only; some of these children do not develop any tumors [Mitter et al 2011]. Contiguous loss of MED4, which is located centromeric to RB1, explains reduced expressivity in individuals with large deletions that include both RB1 and MED4 [Dehainault et al 2014].

Penetrance

See Genotype-Phenotype Correlations.

Nomenclature

Glioma retinae is a historical name for retinoblastoma.

Prevalence

The incidence of retinoblastoma is estimated at between 1:15,000 and 1:20,000 live births [Moll et al 1997, Seregard et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with retinoblastoma, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [Mallipatna et al 2017]. Extent of the tumor is estimated by clinical examination under anesthetic and ultrasound or MRI, particularly focusing on the tumor - optic nerve relationship. Brain MRI is also useful to evaluate for a pinealoblastoma, indicating trilateral retinoblastoma. CT examination is NOT recommended because of the increased risk for second primary cancer potentially induced by radiation.
• For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or performed when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
• If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care of the child.
• In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherent tomography [Soliman et al 2017b].
• Consultation with a clinical geneticist and/or genetic counselor is appropriate.

Treatment of Manifestations

Goals of treatment in order of priority are preservation of life and then of sight. As optimal treatment may be complex, specialists skilled in the treatment of retinoblastoma from various fields including ophthalmology, pediatric oncology, pathology, and radiation oncology collaborate to deliver optimized care.

In addition to eye and tumor stage, choice of treatment depends on many factors, including the number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available.

Treatment options for the eye include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.

Prevention of Secondary Complications

If possible, any radiation (including x-ray, CT scan, and external beam radiation) are avoided to minimize the lifetime risk of developing late-onset second cancers. Such tests should only be used if absolutely necessary in essential health care.

Surveillance

Further information regarding medical surveillance for those who have had or are at risk of developing retinoblastoma is available in the guidelines for retinoblastoma care. Guidelines for clinical screening for children at risk are published [Skalet et al 2018].

Detection of subsequent retinoblastoma after initial diagnosis. Following successful treatment, children require frequent follow-up examination for early detection of newly arising intraocular tumors, as indicated in guidelines [Skalet et al 2018]:

• It is recommended that children known to have an RB1 germline pathogenic variant (H1) have an eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life.
• Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant are at risk for low-level mosaicism (H0*) and can develop a tumor in the other eye [Temming et al 2013]. This risk is small enough that examination under anesthesia may be replaced with regular clinical examination of the eyes, including clinical ultrasound (a simple, noninvasive procedure).
• Individuals with retinomas (premalignant retinal lesions associated with retinoblastoma) are followed with retinal examinations and imaging every one to two years, to detect any change early.

Detection of second non-ocular tumors in individuals with retinoblastoma. Because of the high risk for second cancers, including sarcomas, melanoma, and specific other cancers, prompt investigation of any signs or symptoms is indicated. Total-body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for second cancers in persons with a heterozygous germline RB1 pathogenic variant.

Agents/Circumstances to Avoid

It has been suggested by Fletcher et al [2004] that cancer risks in survivors of heritable retinoblastoma may be reduced by limiting exposure to DNA-damaging agents (radiotherapy, tobacco, and UV light). It is plausible that cancer risks in these individuals may be reduced by limiting exposure to chemotherapy.

Evaluation of Relatives at Risk

The American Society of Clinical Oncologists identifies heritable retinoblastoma as a Group 1 disorder – i.e., a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from eye examination by an experienced ophthalmologist and allow for early identification of a retinoblastoma.

Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [Noorani et al 1996, Richter et al 2003];
• Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth as described above (see Surveillance, Detection of subsequent retinoblastoma after initial diagnosis. Young or uncooperative children may require examination under anesthesia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There are not many clinical trials for this disorder.