Retinoblastoma: Eye Cancer in Children - Symptoms, Causes & Treatment

What Is Retinoblastoma?

Retinoblastoma is a rare cancer that originates in the retina, the light-sensitive tissue at the back of the eye. It primarily affects children under 5 years old and is caused by mutations in the RB1 tumor suppressor gene. With early detection and proper treatment, the survival rate exceeds 95%.

Retinoblastoma develops when cells in the retina undergo genetic changes that cause them to grow uncontrollably. The retina is the part of the eye that senses light and sends visual signals to the brain through the optic nerve. When cancer develops here, it can threaten both vision and life if not treated promptly.

This cancer accounts for approximately 3% of all childhood cancers and is the most common primary intraocular (inside the eye) malignancy in children. Globally, retinoblastoma affects about 1 in every 15,000 to 20,000 live births, which translates to roughly 8,000 new cases worldwide each year. The median age at diagnosis is around 18 months, with most cases discovered before the child turns 5 years old.

Understanding the nature of retinoblastoma is crucial for parents and caregivers because early detection dramatically improves outcomes. The disease can occur in one eye (unilateral) or both eyes (bilateral), and this distinction has important implications for treatment and genetic counseling. Approximately 60-70% of cases affect only one eye, while 30-40% involve both eyes.

Hereditary vs. Non-Hereditary Retinoblastoma

Retinoblastoma exists in two forms: hereditary and non-hereditary (sporadic). This distinction is fundamental to understanding the disease and its implications for the child and family members.

Hereditary retinoblastoma accounts for about 40% of all cases. In this form, the child inherits a mutation in the RB1 gene from a parent, or a new mutation occurs in the egg or sperm before conception. Children with hereditary retinoblastoma have this mutation in every cell of their body, which explains why they often develop tumors in both eyes and at an earlier age. They also have an increased lifetime risk of developing other cancers, particularly osteosarcoma (bone cancer) and soft tissue sarcomas.

Non-hereditary (sporadic) retinoblastoma represents about 60% of cases. In this form, the genetic mutations occur only in the retinal cells and are not present throughout the body. These children typically develop cancer in only one eye and do not have the increased risk of secondary cancers that hereditary patients face. Non-hereditary cases cannot be passed on to future generations.

What Are the Early Warning Signs of Retinoblastoma?

The most common early sign is leukocoria, a white pupil reflex that appears in photographs when flash is used, instead of the normal red-eye effect. Other warning signs include strabismus (crossed eyes), a red or painful eye, poor vision, and different colored irises. Any white glow in a child's pupil should prompt immediate medical evaluation.

Recognizing the early signs of retinoblastoma is crucial because early detection significantly improves the chances of saving both the child's life and their vision. Parents are often the first to notice something unusual about their child's eyes, and their observations are invaluable for early diagnosis.

Leukocoria (White Pupil Reflex)

The hallmark sign of retinoblastoma is leukocoria, which literally means "white pupil." Instead of the familiar red-eye effect seen in flash photographs, the affected eye shows a white, yellow, or pink glow. This occurs because the tumor reflects light back through the pupil instead of allowing normal light absorption by the retina.

Parents often first notice leukocoria in photographs, especially those taken with flash in dimly lit conditions. The white reflex may not be visible in every photo, as it depends on the angle of the flash and the size and location of the tumor. Some parents describe it as a "cat's eye" or "glowing eye" appearance. While leukocoria can have other causes, it should always prompt an urgent eye examination.

Strabismus (Crossed or Misaligned Eyes)

Strabismus, commonly known as crossed eyes or squint, is the second most common presenting sign of retinoblastoma. When a tumor affects vision in one eye, the brain may stop using that eye for focusing, causing the eyes to become misaligned. While strabismus is common in young children and usually not caused by cancer, new-onset strabismus should be evaluated by an eye specialist to rule out serious conditions including retinoblastoma.

Other Warning Signs

While leukocoria and strabismus are the most common presenting signs, parents should also be aware of other potential symptoms:

• Red or painful eye: Inflammation or increased pressure within the eye can cause redness and discomfort
• Poor vision or visual tracking problems: A child may have difficulty following objects or seem to have trouble seeing
• Different colored irises (heterochromia): The colored part of one eye may appear different from the other
• Eye swelling or bulging: In advanced cases, the eye may protrude or the eyelid may swell
• Nystagmus: Involuntary, rhythmic eye movements
• Glaucoma symptoms: Increased eye pressure can cause eye enlargement and corneal clouding

What Causes Retinoblastoma?

Retinoblastoma is caused by mutations in the RB1 tumor suppressor gene. In hereditary cases (40%), children inherit one mutated gene copy and acquire a second mutation. In sporadic cases (60%), both mutations occur randomly in a retinal cell. There are no known environmental causes or preventable risk factors.

Understanding the genetic basis of retinoblastoma is essential for families dealing with this diagnosis, as it has implications for treatment, surveillance, and family planning. Unlike many adult cancers, retinoblastoma is not caused by environmental factors, lifestyle choices, or anything the parents did or didn't do during pregnancy.

The Role of the RB1 Gene

The RB1 gene, located on chromosome 13, was the first tumor suppressor gene ever discovered. Its discovery in retinoblastoma research revolutionized our understanding of cancer genetics. The RB1 gene produces a protein that acts as a "brake" on cell division, preventing cells from multiplying uncontrollably.

Every cell in the body has two copies of the RB1 gene (one from each parent). For retinoblastoma to develop, both copies must be inactivated or mutated in the same retinal cell. This "two-hit hypothesis," proposed by Dr. Alfred Knudson in 1971, explains the difference between hereditary and sporadic forms of the disease.

Hereditary Retinoblastoma Genetics

In hereditary retinoblastoma, the child is born with one mutated copy of the RB1 gene in every cell of their body. This mutation can be inherited from a parent who had retinoblastoma or carries the mutation, or it can occur as a new (de novo) mutation in the egg or sperm before conception.

Because these children already have one "hit" in all their cells, only one additional mutation is needed to cause cancer. This explains why hereditary retinoblastoma typically develops earlier, often affects both eyes, and may involve multiple tumors. Children with hereditary retinoblastoma have approximately a 90% chance of developing the disease, usually before age 5.

Sporadic Retinoblastoma Genetics

In sporadic (non-hereditary) cases, the child is born with two normal copies of the RB1 gene. Both mutations must occur by chance in the same retinal cell after birth. The probability of this happening is relatively low, which is why sporadic retinoblastoma typically affects only one eye and usually involves a single tumor.

These mutations are not present in other cells of the body, so children with sporadic retinoblastoma do not have an increased risk of other cancers and cannot pass the condition to their children (though a small percentage of apparently sporadic cases may actually be hereditary with incomplete penetrance).

How Is Retinoblastoma Diagnosed?

Retinoblastoma is diagnosed through a comprehensive eye examination under anesthesia, allowing thorough visualization of the retina. Imaging tests including ultrasound and MRI help determine tumor size and whether cancer has spread. Unlike most cancers, biopsy is avoided to prevent spreading cancer cells. Genetic testing identifies hereditary cases.

The diagnostic process for retinoblastoma requires specialized expertise and equipment. When a child is referred with suspected retinoblastoma, the evaluation is typically performed by a team including pediatric ophthalmologists, pediatric oncologists, and genetic counselors.

Eye Examination Under Anesthesia (EUA)

The cornerstone of retinoblastoma diagnosis is a detailed examination of both eyes while the child is under general anesthesia. This procedure, called Examination Under Anesthesia (EUA), allows the ophthalmologist to fully dilate the pupils, examine the entire retina, and document the findings accurately.

During the EUA, the doctor uses specialized instruments to examine the retina through the pupil. They can identify tumors, measure their size and location, and assess whether there are multiple tumors. Photographs and drawings are made to document the findings and plan treatment. This examination is typically repeated regularly during treatment to monitor the response.

Imaging Studies

Several imaging tests help characterize the tumor and determine if cancer has spread beyond the eye:

• Ocular ultrasound: This painless test uses sound waves to create images of structures inside the eye. It can show the tumor's size and presence of calcifications (calcium deposits), which are characteristic of retinoblastoma
• MRI (Magnetic Resonance Imaging): MRI provides detailed images of the eye, optic nerve, and brain without using radiation. It helps determine if the tumor has extended beyond the eye or along the optic nerve
• CT scan: While less commonly used due to radiation exposure, CT can show calcifications within the tumor and may be used in certain situations

Staging and Classification

Once diagnosed, retinoblastoma is classified according to several systems that help guide treatment decisions:

The International Classification of Retinoblastoma (ICRB) groups tumors from A to E based on their size, location, and likelihood of eye salvage:

• Group A: Small tumors away from critical structures, excellent prognosis for eye salvage
• Group B: Larger tumors or those closer to critical structures
• Group C: Localized seeding (tumor cells floating in the eye's fluid)
• Group D: Diffuse seeding or larger tumors
• Group E: Extensive disease, eye salvage unlikely

Genetic Testing

Genetic testing for RB1 mutations is an essential part of the diagnostic workup. This testing serves multiple purposes:

• Determines whether the child has hereditary retinoblastoma, affecting surveillance and prognosis
• Identifies family members who may need screening
• Guides recommendations for monitoring the child for secondary cancers
• Informs family planning decisions for parents considering future children

Testing can be performed on blood samples or, if the eye is removed, on tumor tissue. Results may take several weeks and should be discussed with a genetic counselor who can explain the implications.

How Is Retinoblastoma Treated?

Treatment options include chemotherapy (systemic, intra-arterial, or intravitreal), focal therapies like laser and cryotherapy, radiation therapy, and surgical eye removal (enucleation) for advanced cases. The goal is always to save the child's life first, then preserve the eye and vision when possible. Treatment is highly individualized based on tumor characteristics.

Treatment for retinoblastoma has advanced dramatically over the past few decades, with modern approaches focusing on preserving both life and vision whenever possible. Treatment decisions are complex and depend on multiple factors including whether one or both eyes are affected, the size and location of tumors, the child's age, and whether there are hereditary implications.

A multidisciplinary team typically coordinates care, including pediatric oncologists, ocular oncologists, radiation oncologists, pediatric anesthesiologists, and genetic counselors. The treatment approach is always individualized, and families are involved in decision-making throughout the process.

Chemotherapy

Chemotherapy uses medications to kill cancer cells and has become a cornerstone of retinoblastoma treatment. Several delivery methods are used:

Systemic chemotherapy involves giving chemotherapy drugs intravenously so they circulate throughout the body. This approach is often used to shrink tumors before focal treatments (chemoreduction), to treat bilateral disease, or when there's concern about cancer spreading beyond the eye. Common drugs include carboplatin, vincristine, and etoposide.

Intra-arterial chemotherapy (IAC) delivers chemotherapy directly to the eye through a tiny catheter inserted into the blood vessel supplying the eye. This revolutionary technique allows high drug concentrations at the tumor while minimizing side effects on the rest of the body. IAC has dramatically improved eye salvage rates and reduced the need for enucleation.

Intravitreal chemotherapy involves injecting chemotherapy directly into the eye's vitreous gel. This approach is particularly useful for treating tumor seeds that float in the eye's fluid and are difficult to treat by other means.

Focal Therapies

Focal therapies treat specific tumors while sparing surrounding healthy tissue:

Laser therapy (photocoagulation) uses intense light to destroy small tumors and their blood supply. It's typically used for tumors smaller than 3mm that are located away from critical structures like the optic nerve and macula.

Cryotherapy uses extreme cold to freeze and destroy tumor tissue. A probe applied to the outside of the eye freezes the tumor through the eye wall. It's effective for small peripheral tumors and is often used in combination with chemotherapy.

Thermotherapy uses heat from infrared laser to destroy tumor cells. It can be used alone for small tumors or combined with chemotherapy for larger tumors.

Radiation Therapy

Radiation uses high-energy beams to kill cancer cells. While effective, radiation is used more selectively now due to concerns about side effects, particularly in children with hereditary retinoblastoma who have an increased risk of secondary cancers.

External beam radiation therapy delivers radiation from outside the body and is reserved for cases where other treatments have failed. Modern techniques like intensity-modulated radiation therapy (IMRT) can minimize damage to surrounding tissues.

Brachytherapy (plaque radiation) involves placing a small radioactive disc on the eye wall directly over the tumor. This delivers a high radiation dose to the tumor while sparing most of the eye and surrounding tissues.

Enucleation (Surgical Eye Removal)

While always considered a last resort, enucleation remains an important treatment option when the eye cannot be saved or when removing the eye is necessary to ensure the child's survival. Indications for enucleation include:

• Extensive disease filling most of the eye
• Tumor invasion of the optic nerve or other structures outside the eye
• Failed eye-salvaging treatments
• Painful eye with no useful vision
• When removing the eye is the safest option to prevent cancer spread

After enucleation, children receive a custom-made prosthetic eye that closely matches their natural eye. While the prosthetic doesn't provide vision, it moves with the other eye and provides excellent cosmetic results. Many children adapt remarkably well and go on to live full, active lives.

What Is the Prognosis for Retinoblastoma?

Retinoblastoma has an excellent prognosis when detected early. In developed countries, the survival rate exceeds 95-98%. Vision preservation depends on tumor location and size. Children with hereditary retinoblastoma need lifelong monitoring for secondary cancers. Most survivors lead normal, productive lives.

The outlook for children diagnosed with retinoblastoma has improved dramatically over the past several decades. With modern treatment approaches, the vast majority of children not only survive but also retain useful vision in at least one eye. Understanding prognosis helps families navigate the journey from diagnosis through treatment and long-term follow-up.

Survival Rates

In developed countries with access to specialized pediatric oncology care, the survival rate for retinoblastoma exceeds 95-98%. This makes retinoblastoma one of the most curable childhood cancers. The key factors affecting survival include:

• Stage at diagnosis: Tumors confined to the eye have excellent outcomes, while those that have spread beyond the eye have lower survival rates
• Access to specialized care: Treatment by experienced ocular oncologists at specialized centers improves outcomes
• Timely diagnosis and treatment: Early detection before the cancer spreads is critical

Unfortunately, outcomes in developing countries remain lower due to delayed diagnosis and limited access to specialized treatment. Global initiatives are working to improve early detection and treatment access worldwide.

Vision Outcomes

Vision preservation depends on several factors:

• Tumor location: Tumors involving the macula (central vision area) or optic nerve have greater impact on vision
• Tumor size: Smaller tumors are more likely to be treated while preserving vision
• Treatment effects: Some treatments can affect surrounding retinal tissue

Many children retain useful vision in at least one eye. Even children who lose vision in one eye typically adapt well and can participate fully in school, sports, and other activities. Children who lose both eyes receive comprehensive rehabilitation services and can lead fulfilling, independent lives.

Long-Term Considerations

Children who survive retinoblastoma may face certain long-term considerations:

Secondary cancers: Children with hereditary retinoblastoma have an increased lifetime risk of developing other cancers, particularly osteosarcoma, soft tissue sarcomas, and melanoma. This risk is higher if external beam radiation was part of treatment. Lifelong surveillance and healthy lifestyle choices are important.

Trilateral retinoblastoma: A small percentage of children with hereditary retinoblastoma develop a related brain tumor (usually pinealoblastoma). Regular MRI screening during the first few years helps detect this early.

Psychological and social aspects: Children may need support adjusting to vision changes or prosthetic eyes. Many families find support groups and counseling helpful.

What Is Life Like After Retinoblastoma Treatment?

Most retinoblastoma survivors lead normal, active lives. Follow-up care includes regular eye examinations, monitoring for secondary cancers in hereditary cases, and vision rehabilitation if needed. Support services help children and families adjust. Survivors can participate fully in education, careers, and family life.

Life after retinoblastoma treatment involves ongoing medical follow-up, but most survivors go on to thrive in all aspects of life. Understanding what to expect during survivorship helps families plan for the future and access appropriate support services.

Follow-Up Care

Regular follow-up is essential after retinoblastoma treatment:

• Eye examinations: Frequent examinations under anesthesia continue during treatment and afterward to monitor for new tumors or recurrence. The frequency decreases as the child gets older and the risk of new tumors diminishes
• Vision assessments: Regular vision testing helps identify needs for corrective lenses or rehabilitation services
• Secondary cancer screening: Children with hereditary retinoblastoma need lifelong monitoring. This includes annual physical examinations and awareness of symptoms that might indicate secondary cancers
• Brain MRI: For the first few years after diagnosis, children with hereditary retinoblastoma typically have periodic brain MRIs to screen for trilateral retinoblastoma

Vision Rehabilitation

Children with vision changes benefit from early intervention and support services:

• Low vision aids and assistive technology for children with reduced vision
• Orientation and mobility training if needed
• Educational accommodations and support in school
• Sports and recreation adaptations

Many children adapt remarkably well to vision changes, especially those affected in early childhood. The brain has remarkable plasticity, and children often develop compensatory strategies naturally.

Psychosocial Support

Emotional support is an important component of survivorship:

• Counseling for children and families adjusting to diagnosis and treatment
• Support groups connecting families with shared experiences
• Resources for addressing body image concerns, particularly for children with prosthetic eyes
• Transition support as children move from pediatric to adult care

Future Family Planning

For survivors considering having children, genetic counseling is important:

• Survivors with hereditary retinoblastoma have a 45% chance of having an affected child
• Prenatal testing and preimplantation genetic diagnosis are available options
• Children of survivors with hereditary disease need early screening examinations