Retinoblastoma

Original Editor - Kapil Narale

Top Contributors - Kapil Narale and Kim Jackson  

Introduction

Retinoblastoma (historically called glioma retinae) is a malignant tumor that occurs in the developing retina. It is the most common ocular cancer that occurs in the pediatric population, generally under 5 years of age. It is lethal if it is left untreated. Retinoblastoma can unifocal or multifocal. It is seen that 60% of individuals have unilateral retinoblastoma, and are diagnosed at 24 months, while 40% of individuals have bilateral retinoblastoma and are diagnosed at 15 months. When retinoblastoma has a genetic onset, there can be a risk of retinoblastoma and/or non-ocular tumors.

Common Terminology

Retinoblastoma can be classified into various types:

Unilateral - one eye is affected. About 60% of affected individuals have unilateral retinoblastoma when diagnosed at 24 months. With unilateral retinoblastoma, the tumor is usually unifocal, which means that there is only one tumor present. It is possible that there may be multifocal tumors in one eye, which would be a unilateral multifocal retinoblastoma. In most people who have unilateral retinoblastoma, without the presence of family history, if the tumor is large, it is impossible to determine if it is a single tumor.

Bilateral - both eyes are affected. About 40% of affected individuals have bilateral retinoblastoma when diagnosed at 15 months. In children with bilateral, retinoblastoma, both eyes are affected when the condition is first diagnosed. It is possible that both eyes may present with multiple tumors. It is also possible that some children may initially have unilateral retinoblastoma, and may develop a tumor in their unaffected eye.

Trilateral - if bilateral, or or seldom unilateral, retinoblastoma and a pinealoblastoma develop.

Retinoma and associated eye lesions - benign retinal tumors (retinoma) which cease in growth may be present in retinal scars. Calcified phthisic eyes may occur from automatic ceasing of retinoblastoma relating to vascular occlusion. The spectrum of RB1 pathogenic variants in those with retinoma and a family history of retinoblastoma, and individuals who had retinoma in one eye and either retinoma or retinoblastoma in the other eye present similarly to individuals with bilateral retinoblastoma.

Pinealoblastomas - This occur in "retina-like" tissue in the pineal gland. If there is a simultaneous occurrence of pinealoblastomas or primitive neuroectodermal tumors and retinoblastoma, this would be classified as trilateral retinoblastoma. THis is a rare condition, and is generally fatal, whereas retinoblastoma of the eye can be cured.

Epidemiology

In high-income countries, retinoblastoma is known to be a curable disease, with close to 100% chance of survival. However, in middle- and low-income countries, the prognosis is extremely low. In addition, more than 80% of cases occur in these countries.

It is estimated that the majority of retinoblastoma cases occur in Asia (53%), then Africa (29%), Latin America (8%), North America (3%), and Europe (6%). With this information it is seen that global retinoblastoma patient survival is <30%. It is seen that the survival rate is 40% (23‑70%) in low‑income countries, while it is 79% (54‑93%) in upper‑middle‑income countries.

The incidence of retinoblastoma can be between 1 in 15 000 to 1 in 20 000 live births, therefore there is a very low chance of it occurring.

Family History

Heritable retinoblastoma can be transmitted via autosomal dominance. It is common that only one offspring in a family can be affected, which would be known as a simplex case. An RB1 pathogenic may be inherited from an affected parent. There is a 50% chance for each child of an affected parent to inherit the RB1 pathogenic variant.

Mode of Inheritance

Genetically transmitted retinoblastoma is an autosomal dominant disorder.

Genetically spreading the disorder within a family can occur through:

• Genetic transmission through parents
• Depending on the genotype and phenotype of the parents, can be transmitted to siblings of an affected individual.
• Genetic transmission to the offspring of the affected individial
• Can be genetically spread to other family members depending on the parents of the affected individual, and the parent's family.

Assessment

Prior to examining the patient, a thorough assessment must be completed. If there is any family history of the condition, a germline mutation may be present, and the child may need to undergo systemic chemotherapy to prevent pineoblastoma, even with a unilateral presentation of the disease.

An in-depth evaluation is warranted prior to determining the degree of the necessary treatment, and minimise and prevent from any secondary complications.

The treatment decision for retinoblastoma is dependent on the International Classification of Retinoblastoma (ICRB) classification (similar to the ICF), the presence of extraocular clinical factors, germline test results, family psychosocial status, and available medical facility resources. If there is presence of a germline disease, genetic testing should be conducted in all cases of retinoblastoma, for the patient and the rest of their family.

All patients should go through a baseline high‑resolution simple and contrast‑enhanced magnetic resonance imaging (MRI) of the brain and orbits. Special attention should be given for pineoblastoma or any features of disruption to the optic nerve.

As a part of the assessment, complete blood count, urine sample, and a general physical examination are performed by the pediatric oncologist. Subsequent to the general physical examination, a detailed examination using anesthesia is conducted, where ICRB staging is confirmed, and the first treatment can be administered.

Signs, Symptoms and Findings

Signs that retinoblastoma can be ruled in include:

• Leukocoria (white pupillary reflex)
• Strabismus (may occur with or before leukocoria)
• Change in eye appearance
• Reduced visual acuity

Signs that infrequently occur include, glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous hemorrhage. As mentioned, it is most common in children under 5 years of age. Abnormal occurrences are more common in older children.

Heritable retinoblastoma can be ruled in with:

• Diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
• Retinoma
• Family history of retinoblastoma

Diagnosis

Retinoblastoma can be diagnosed via a proband by retinal examination with the pupils dilatated, This would be conducted by an ophthalmologist or optometrist. The individual would need to be examined under anaesthesia to confirm the diagnosis and the extent of the disease. A biopsy may allow the tumor to spread past the eye, thus putting the individual's life at risk.

The diagnosis of heritable retinoblastoma is determined via genetic transmission of retinoblastoma or retinoma and a family history of retinoblastoma. However, it is see that many individuals with retinoblastoma are without a family history of the condition. In order to determine if the retinoblastoma is heritable, individuals would need to have a heterozygous germline RB1 pathogenic variant identified on molecular genetic testing. Identification of an RB1 pathogenic variant through the genetic transmission can facilitate early diagnosis and screening for family members at risk for retinoblastoma.

Examination of the fundus of the eye through indirect ophthalmoscopy can be used as a method of diagnosis. This can be confirmed with imaging studies, which will also help confirm the stage of the tumor.

In a developing retina, retinoblastomas can form subsequent to biallelic inactivation of RB1 in a cone cell precursor. Genetic retinoblastoma can be diagnosed in a proband, with retinoblastoma or retinoma, which is a benign potential precursor to retinoblastoma, and a family history of retinoblastoma or a heterozygous germline pathogenic variant in RB1 which can be denoted by molecular genetic testing. Epigenetic hypermethylation of the RB1 promotor results in inactivation of RB1. This cannot be transmitted by the germline. A non-genetic onset of retinoblastoma can occur with MYCN in a developing retinal cone cell.

The following sequence has been outlined for those with retinoblastoma and/or genetically caused retinoblastoma, which outlines the genetic risk of a germline pathogenic variant in RB1:

Hx	Individual with unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant
Ho	Individual who did not inherit a known familial germline RB1 pathogenic variant which can be confirmed by molecular genetic testing
Ho*	Individual with unilateral retinoblastoma or retinoma without a germline RB1 pathogenic variant identified with molecular genetic testing; residual risk of mosaicism is <1%
H1	Individual with bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial central nervous system midline embryonic tumor), retinoblastoma and with a family history, or denotation of a germline RB1 pathogenic variant

Testing Approaches

Molecular genetic testing approaches include for heritable retinoblastoma include single gene testing, and chromosomal microarray (CMA).

Single-gene testing

• This can be carried out on individuals with bilateral, unilateral familial, or unilateral multifocal retinoblastoma. Within this process, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are administered on peripheral blood DNA.
• For individuals with unilateral unifocal retinoblastoma and without a family history
  • With an unavailable tumor tissue, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are administered on peripheral blood DNA.
  • With the availability of the tumor tissue, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on tumor DNA.
    • With the identification of pathogenic variants, the testing of DNA from blood is carried out to identify these variants.
    • If a pathogenic variants are not detected in the tumor, methylation analysis of the RB1 promoter CpG island is carried out, which denotes epigenetic inactivation of RB1 resulting from hypermethylation of the RB1 promoter. If hypermethylation is not depicted at the promoter, the DNA from the tumor is analyzed for the amplification of MYCN. This leads to the cause of unilateral, non-heritable retinoblastoma without RB1 pathogenic variants in 1.5% of individuals with isolated unilateral retinoblastoma.

Chromosomal Microarray

This method uses oligonucleotide or SNP arrays, instead of sequence analysis, to detect genome-wide large deletions/duplications (including RB1). CMA may be appropriate in individuals who have retinoblastoma relating to a developmental delay, and/or other congenital anomalies.

Differential Diagnosis

There are many childhood ocular hereditary conditions that can represent retinoblastoma. These conditions are:

• NDP-related persistent fetal vasculature and NDP-related Coats disease (See NDP-Related Retinopathies.)
• Tuberous sclerosis complex
• Norrie disease (See NDP-Related Retinopathies.)
• Incontinentia pigmenti
• Familial exudative vitreoretinopathy (See Phenotypic Series: Exudative Vitreoretinopathy.)
• Von Hippel-Lindau syndrome
• Ocular infestation by Toxocara canis

Treatment

Although, as mentioned, retinoblastoma can be lethal if it is left untreated, having an early diagnosis can help reduce morbidity and increase quality of life. It is best when the patient receives multidisciplinary care from various healthcare professionals such as ophthalmologist, pediatric oncologist, pathologist, and radiation oncologist. Treatment options can be dependent on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localisation and size of the tumor(s) within the eye(s), vitreous seeding presence, any possibility of effective vision, intensity and type of extraocular extension, and available resources. THerefore, the initial goal of treatment would be to save the individual's life, followed by their sight.

The response to the initial treatment can be an indication of long‑term outcome progressions. The decision made by the ocular oncologist, in regards to treatment, would be crucial, as the therapy provided would need to be a sufficient strength, while minimising any secondary toxic effects. Enucleation has been the preferred mode of treatment, for advanced retinoblastoma, in low-middle-income countries. however, over the last 30 years, the globe-savaging techniques have been used.

Although the management of retinoblastoma may differ from place to place, and from clinic to clinic, the overall structure of treatment involves a similar framework.

There are various treatment options that can be utilized, which include,

• Enucleation,
• Cryotherapy,
• Laser,
• Systemic or local ocular chemotherapy, including intra-arterial chemotherapy, in addition to or followed by laser or cryotherapy
• Radiation therapy using episcleral plaques, and
• External beam radiotherapy. This would be used as a last resort.

Treatment Agents to Avoid

In individuals who have genetically transmitted retinoblastoma, it is best to avoid radiation especially from x-rays, CT scans, and external beam radiation, and DNA disrupting agents such as tobacco or UV light. This will help reduce any risks of future malignant neoplasms. It is possible that cancer risk may be minimised with limiting chemotherapy.

Intravenous Chemotherapy

IVC is an important mechanism for retinoblastoma therapy. It consists of 2-4 chemotherapeutic agents, which are given monthly via a central or peripheral catheter for 6-9 continuous cycles. The most commonly used method consists of 3 drugs, vincristine, etoposide, carboplatin (VEC). There ae cases where cyclophosphamide may replace vincristine when tehre may be a concernf or neurotoxicity. Despite this, vincristine is more likely to cause myelosupression and hemorrhagic cytitis. Another difference between VEC and cyclophosphamide is that transfusion of blood components may be necessary, granulocyte colony‑stimulating factor is usually not needed with standard VEC doses, but is should be used with cyclophosphamide.

Intravenous chemotherapy is known to effectively reduce tumor size, therefore can be referred to as chemoreduction.

Focal consolidation with thermotherapy, involving cryotherapy or transpupillary thermotherapy, can help with tumor control. Cryotherapy followed by chemotherapy is seen to heighten drug availability to the intraocular spaces when given within 48 hours of the thermal disruption.

Indications for IVC consist of, patients with bilateral disease, confirmed germline mutation, family history of retinoblastoma, or instances with possible optic nerve or choroidal invasion. Another indication to use IVC would be patients weighing less than 6 kg that are waiting to receive intra‑arterial chemotherapy (IAC). This is referred to as ‘bridge therapy’. As well, IVC acts as protection with preventing long‑term secondary cancers, metastases, and pineoblastoma.

Signs, symptoms, and side effects of systemic chemotherapies can include transient alopecia, cytopenia, and fever. Systemic toxicity of IVC for retinoblastoma can generally be mild.

A scheduled prophylaxis is administered for Pneumocystis jirovecii pneumonia. Side effects or symptoms such as chemotherapy‑induced nausea, emesis, and constipation may be medically managed.

In terms of effects on the renal system, long‑term renal toxicity is unlikely to occur if chemotherapeutic agents provided in proper amounts and concentrations.

Infertility is unlikely to occur with recommended doses of IVC. There can be a risk of infertility in Males with the addition of melphalan, especially when a total dose of 140 mg/m².

Another rare condition following the use of IVC is secondary acute myelogenous leukemia. This is correlated with increased doses of chemotherapy, with simultaneous external beam radiotherapy (EBRT) and other predisposing conditions.

Intra-Arterial Chemotherapy (IAC)

This method is especially used for unilateral tumors. This method is known to be costly, due to its complex procedure. DUe to its expense and specialization required, it is not used in developing countries.

It is performed in an angiography suite by an experienced neurosurgeon or interventional neuroradiologist. A microcatheter is directed by fluoroscopy to guide the chemotherapeutic agents with great precision into the ophthalmic artery.

IAC is seen to have a 10x higher chemotherapy dose, compared to IVC, that is transmitted into the eye. As mentioned for the IVC treatment, the chemotherapy treatment has 1-3 drugs transmitted into the eye, once a month, for an average of 3 sessions.

IAC has been more commonly used over the past decade, especially due to its efficacy with globe salvage in advanced retinoblastoma cases and refractory tumors.

Indications for IAC can include first‑line, and globe salvage therapies. It can be used as a primary therapy for non‑germline, unilateral, or as a secondary therapy for unilateral or bilateral advanced recalcitrant disease facing enucleation. IAC has high efficacy from preventing sub retinal and vitreous seeds, especially when proximal to the retina.

IAC can also be used as tandem therapy for advanced bilateral cases, minimal exposure (<2 cycles), and for a repeat treatment after an initial IAC treatment. However, tandem therapy may be questionable because of increased vascular toxicity in the eye with better acuity, an effect on pineoblastoma prevention that is unknown, and minimal effect on pre‑existing metastases, which can lead to higher chance of child mortality.

High risk retinoblastoma needs enucleation performed, and an additional 6‑9 cycles of high‑dose IVC to prevent metastatic disease. IAC is generally used for patients older than 3 or 4 months old, because of the smaller size and strength of vessels in younger individuals. In the younger individuals, bridge therapy with IVC is provided until the individual reaches a weight of 6 kg.

Signs, Symptoms, Side-effects

Even though localised delivery of chemotherapeutic agents is used, systemic toxicity is generally observed after IAC.

Transient neutropenia has been observed in 12% of patients.

Femoral artery occlusion and blue toe syndrome can occur. This can be managed and prevented using anticoagulation.

Complications that are more severe such as carotid artery dissection, stroke, and death, are possible, but hardly occur. The selection of appropriate treatments for individual patients is important. Undetected extraocular extension, optic nerve or massive choroidal invasion could lead to metastasis if a patient is treated with the use of IAC without systemic chemotherapy.

Periocular side effects are generally self‑limited. These include,

• Periorbital edema,
• Cutaneous hyperemia,
• Madarosis,
• Blepharoptosis,
• Scalp hair loss, and
• Extraocular dysmotility.

Serious ophthalmic vascular impairments can include,

• Choroidal occlusive vasculopathy,
• Branch or central retinal artery occlusion,
• Ophthalmic artery spasm or occlusion, or
• Vitreous hemorrhage, among others

Of the individuals treated primarily with IAC, rhegmatogenous retinal detachment, which may be secondary due to accelerated tumor regression of endophytic tumors, is reported in 8‑16% of cases.

Vascular impairments are not associated with reduced globe salvage, but can limit visual acuity. Risk for vascular impairments is similar whenever the IAC treatment is used.

Intraocular Chemotherapy

Intravitreal Chemotherapy

Intravitreal Chemotherapy (IvitC) was found to be effective when used with IAC, which helped to save many damaged eyes.

Indications for IvitC is the identification of a refractory or reemergent vitreous seeds subsequent to other interventions. It is hardly used a primary intervention, but as a globe salvage therapy, if there is uncertainty of the initial tumor. Contraindications include. identification of a tumor or vitreous seeds at the planned site of needle entry, tumor invasion of the pars plana, and anterior chamber seeding. This can be safely administered with a thorough examination and the use of ultrasound bimicroscopy.

Melphalan and/or topotecan are the most common pharmacological agents used in IvitC. The recommended doses, to effectively control vitreous seeds and prevent any toxic side effects, are 20‑30 μg every 2‑4 weeks.[

Precision Intravitreal Chemotherapy

Precision Intravitreal Chemotherapy (p-IvitC) was initially used to treat localised vitreous seeding. Modified from the standard technique which treats diffuse vitreous

seeds, p‑IvitC was designed to inject the chemotherapeutic

drug(s) in close proximity to a single or localized group of

vitreous seeds under indirect ophthalmoscopy, rather than

directing the needle toward the center of the globe and dispersing

the agent(s) throughout the vitreous cavity.

Ongoing Evaluation and Assessment

These steps should be performed before diagnosis and continuously after initial diagnosis as a means of reassessment.

The extend of the tumor inside and outside of the eye should be determined. the stage of cancer or tumor should also be determined for each eye depending on the intensity of the cancer spreading outside the eye, which can be predicted using ultrasound or MRI, and noting the tumor-nerve optic nerve relationship. CT examination is however not recommended due to the exposure to radiation therapy.

If there is a presence of very large tumor(s) with a possibility of an extraocular disease, it is recommended that bone marrow aspiration and analysis of cerebrospinal fluid can be carried out at diagnosis. This can also be carried out when pathologic examination of the enucleated eye presents optic nerve intrusion with a high for spreading outside the eye. If it spreads outside the eye, the most suitable care would then need to be determined.

It is possible that the the retinal tumors can be small and noticed by optical coherent tomography In those with a family history of retinoblastoma, and if the child displays strabismus or poor vision.

Families speaking with Health professionals such as a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform to gather information the nature, inheritance, and complications of retinoblastoma which can assist with medical and personal decision making.