Retinoblastoma is a cancer that starts in the retina, the very back part of the eye. It is the most common type of eye cancer in children.

ABOUT THE EYE:

The main part of the eye is the eyeball (also known as the globe), which is filled with a jelly-like material called vitreous humor. The front of the eyeball has a clear lens with an iris (the colored part of the eye that acts like a camera shutter), which allows light to enter the eye and focuses it on the retina.

The retina is the inner layer of cells in the back of the eye. It is made up of special nerve cells that are sensitive to light. These light-sensing cells are connected to the brain by the optic nerve, which runs out the back of the eyeball. The pattern of light (image) that reaches the retina is sent through the optic nerve to an area of the brain called the visual cortex, allowing us to see.

 

DEVELOPMENT OF RETINOBLASTOMA:

The eyes develop very early as babies grow in the womb. During the early stages of development, the eyes have cells called retinoblasts that divide into new cells and fill the retina. At a certain point, these cells stop dividing and develop into mature retinal cells.

Rarely, something goes wrong with this process. Instead of maturing into special cells that detect light, some retinoblasts continue to divide and grow out of control, forming a cancer known as retinoblastoma.

The chain of events inside cells that leads to retinoblastoma is complex, but it almost always starts with a change (mutation) in a gene called the retinoblastoma (RB1) gene. The normal RB1 gene helps keep cells from growing out of control, but the change in the gene stops it from working like it should. Depending on when and where the change in the RB1 gene occurs, 2 different types of retinoblastoma can result.

CONGENITAL (HEREDITARY) RETINOBLASTOMA

In about 1 out of 3 children with retinoblastoma, the abnormality in the RB1 gene is congenital (present at birth) and is in all the cells of the body, including all of the cells of both retinas. This is known as a germline mutation.

In most of these children, there is no family history of this cancer. Only about 25% of the children born with this gene change inherit it from a parent. In about 75% of children the gene change first occurs during early development in the womb. The reasons for this are not clear.

Children born with a mutation in the RB1 gene usually develop retinoblastoma in both eyes (known as bilateral retinoblastoma), and there are often several tumors within the eye (known as multifocal retinoblastoma).

Because all of the cells in the body have the changed RB1 gene, these children also have a higher risk of developing cancers in other areas as well.

  • A small number of children with this form of retinoblastoma will develop another tumor in the brain, usually in the pineal gland at the base of the brain (a pineoblastoma). This is also known as trilateral retinoblastoma.
  • For survivors of hereditary retinoblastoma, the risk of developing other cancers later in life is also higher than average.

SPORADIC (NON-HEREDITARY) RETINOBLASTOMA

In about 2 out of 3 children with retinoblastoma, the abnormality in the RB1 gene develops on its own in only one cell in one eye. It is not known what causes this change. A child who has sporadic (non-hereditary) retinoblastoma develops only one tumor in one eye. This type of retinoblastoma is often found at a later age than the hereditary form.

Children with this type of retinoblastoma do not have the same increased risk of other cancers as children with congenital retinoblastoma.

SPREAD OF RETINOBLASTOMA:

If retinoblastoma tumors are not treated, they can grow and fill much of the eyeball. Cells might break away from the main tumor on the retina and float through the vitreous to reach other parts of the eye, where they can form more tumors. If these tumors block the channels that let fluid circulate within the eye, the pressure inside the eye can rise. This can cause glaucoma, which can lead to pain and loss of vision in the affected eye.

Most retinoblastomas are found and treated before they have spread outside the eyeball. But retinoblastoma cells can occasionally spread to other parts of the body. The cells sometimes grow along the optic nerve and reach the brain. Retinoblastoma cells can also grow through the covering layers of the eyeball and into the eye socket, eyelids, and nearby tissues. Once the cancer reaches tissues outside the eyeball, it can then spread to lymph nodes (small bean-shaped collections of immune system cells) and to other organs such as the liver, bones, and bone marrow (the soft, inner part of many bones).

Signs and Symptoms of Retinoblastoma:

Retinoblastomas nearly always occur in young children. They are often found when a parent or doctor notices a child’s eye looks unusual.

WHITE PUPILLARY REFLEX

This is the most common early sign of retinoblastoma. Normally when you shine a light in the eye, the pupil (the dark spot in the center of the eye) looks red because of the blood vessels in the back of the eye. In an eye with retinoblastoma, the pupil often appears white or pink instead, which is known as a white pupillary reflex (or leukocoria).

This white glare of the eye may be noticed by a parent after a flash photograph is taken, especially if the pupils are different colors. It also might be noted by the child’s doctor during a routine eye exam.

LAZY EYE

Sometimes the eyes don’t appear to look in the same direction, a condition often called lazy eye. (Doctors call this strabismus.) There are many possible causes of this in children. Most of the time lazy eye is caused by a mild weakness of the muscles that control the eyes, but it can also be caused by retinoblastoma.

Other possible signs and symptoms

Less common signs and symptoms of retinoblastoma include:

  • Vision problems
  • Eye pain
  • Redness of the white part of the eye
  • Bleeding in the front part of the eye
  • Bulging of the eye
  • A pupil that doesn’t get smaller when exposed to bright light
  • A different color in each iris (the colored part of the eye)

Many of these signs and symptoms are more likely to be caused by something other than retinoblastoma.

DIAGNOSIS OF RETINOBLASTOMA:

ULTRASOUND

Ultrasound uses sound waves to create images of tissues inside the body, such as the inner parts of the eye. For this test, a small ultrasound probe is placed up against the eyelid or eyeball. The probe gives off sound waves and detects the echoes that bounce off the tissues inside and around the eye. The echoes are converted by a computer into an image on a computer screen.

Ultrasound is one of the most common imaging tests for confirming the diagnosis of retinoblastoma. It is painless and does not expose the child to radiation, but the child may need to be given medicine to help keep them calm or even asleep so the doctor can get a good look at the eye. This test can be very useful when tumors in the eye are so large they prevent doctors from seeing inside the whole eye.

Optical coherence tomography (OCT) is a similar type of test that uses light waves instead of sound waves to create very detailed images of the back of the eye.

MAGNETIC RESONANCE IMAGING (MRI) SCAN

MRI scans are often used for retinoblastomas because they provide very detailed images of the eye and surrounding structures without using radiation. This test is especially good at looking at the brain and spinal cord. For children with bilateral retinoblastomas (tumors in both eyes), many doctors continue to do MRI scans of the brain for several years after treatment to look for tumors of the pineal gland (sometimes called trilateral retinoblastoma).

COMPUTED TOMOGRAPHY (CT) SCAN

CT scans use x-rays to make detailed images of parts of the body. CT scans can help determine the size of a retinoblastoma tumor and how much it has spread within the eye and to nearby areas.

Normally, either a CT or an MRI scan is needed, but usually not both. Because CT scans give off radiation, which might raise a child’s risk for other cancers in the future, most doctors prefer to use MRI. However, a CT scan can show deposits of calcium in the tumor much better than an MRI, which can be very helpful when the diagnosis of retinoblastoma is not clear.

BONE SCAN

A bone scan can help show if the retinoblastoma has spread to the skull or other bones. Most children with retinoblastoma don’t need to have a bone scan. It is normally used only when there is a strong reason to think retinoblastoma might have spread beyond the eye.

BIOPSY

For most cancers, a biopsy (removing a tissue sample from the tumor and looking at it under a microscope) is needed to make a diagnosis. Trying to biopsy a tumor at the back of the eye can often damage the eye and may spread tumor cells, so this is almost never done to diagnose retinoblastoma. Instead, doctors make the diagnosis based on eye exams and on imaging tests such as those listed above.

LUMBAR PUNCTURE (SPINAL TAP)

Retinoblastomas can sometimes grow along the optic nerve, which connects the eye to the brain. If the cancer has spread to the surface of the brain, this test can often find cancer cells in samples of cerebrospinal fluid (the fluid that surrounds the brain and spinal cord). Most children with retinoblastoma don’t need to have a lumbar puncture. It is used mainly when there is a reason to think retinoblastoma might have spread into the brain.

BONE MARROW ASPIRATION AND BIOPSY

These 2 tests may be done to see if the cancer has spread to the bone marrow, the soft, inner part of certain bones. These tests are usually not needed unless the retinoblastoma has grown outside the eye and doctors suspect that the cancer may have also spread through the bloodstream to the bone marrow.

The tests are typically done at the same time. The samples are usually taken from the back of the pelvic (hip) bone, but in some cases they may be taken from other bones.

STAGING RETINOBLASTOMA:

The Reese-Ellsworth staging system

The Reese-Ellsworth system was developed in the 1960s, when most children were being treated with external beam radiation therapy (EBRT). While this is no longer a common treatment, some doctors may still use this system to classify retinoblastomas that have not spread beyond the eye. This system can help determine the likelihood of preserving vision while still treating the tumor.

Group 1 (very favorable for saving [or preserving] the eye)

  • 1A: one tumor, smaller than 4 disc diameters (DD), at or behind the equator
  • 1B: multiple tumors smaller than 4 DD, all at or behind the equator

Group 2 (favorable for saving [or preserving] the eye)

  • 2A: one tumor, 4 to 10 DD, at or behind the equator
  • 2B: multiple tumors, with at least one 4 to 10 DD, and all at or behind the equator

Group 3 (doubtful for saving [or preserving] the eye)

  • 3A: any tumor in front of the equator
  • 3B: one tumor, larger than 10 DD, behind the equator

Group 4 (unfavorable for saving [or preserving] the eye)

  • 4A: multiple tumors, some larger than 10 DD
  • 4B: any tumor extending toward the front of the eye to the ora serrata (front edge of the retina)

Group 5 (very unfavorable for saving [or preserving] the eye)

  • 5A: tumors involving more than half of the retina
  • 5B: vitreous seeding (spread of tumors into the jelly-like material that fills the eye)

TREATMENT OF RETINOBLASTOMA:

Surgery (Enucleation) for Retinoblastoma

Surgery is not needed for all retinoblastomas, especially for smaller tumors. But if a tumor gets quite large before it is found, vision in the eye has often already been destroyed, with no hope of getting it back. The usual treatment in this case is enucleation, an operation to remove the whole eye, plus part of the optic nerve attached to it. This is done while the child is under general anesthesia.

During the same operation, an orbital implant is usually put in to take the place of the eyeball. The implant is made out of silicone or hydroxyapatite (a substance similar to bone). It is attached to the muscles that moved the eye, so it should move the same way as the eye would have.

Radiation Therapy for Retinoblastoma

This treatment uses high energy x-rays or particles to kill cancer cells. Radiation therapy is an effective treatment for some children with retinoblastoma. Compared with surgery, it has the advantage of possibly saving vision in the eye.

EXTERNAL BEAM RADIATION THERAPY

External beam radiation therapy (EBRT) focuses radiation beams from a source outside the body on the cancer. This was once a common treatment for retinoblastoma. But because of the side effects it can cause, it is now most often used only for cancers that are not well-controlled with other treatments.

Radiation is usually given 5 days a week for several weeks. Before treatments start, the radiation team takes careful measurements with imaging tests such as MRI scans to determine the correct angles for aiming the radiation beams and the proper dose of radiation.

Each treatment is much like getting an x-ray, but the dose of radiation is much higher. For each session, your child will lie on a special table while a machine delivers the radiation from precise angles.

The actual treatment each day lasts only a few minutes, but the setup time – getting your child into place for treatment – usually takes longer. The child’s head is positioned in a custom-fitted mold that is similar to a cast used to treat broken bones. The treatment is not painful, but young children may be given medicine to make them sleep so they will stay still during treatment.

Intensity modulated radiation therapy (IMRT): IMRT lets doctors shape the radiation beams and aim them at the tumor from several angles, as well as adjust the intensity (strength) of the beams to limit the dose reaching the nearby normal tissues. This may let the doctor deliver a higher dose to the tumor, while reducing side effects. Many major hospitals and cancer centers now use IMRT.

Proton beam therapy: Protons are positive parts of atoms. Unlike the x-rays used in standard radiation, which release energy both before and after they hit their target, protons cause little damage to tissues they pass through and then release their energy after traveling a certain distance. Proton beam radiation may be able to deliver the same level of radiation to the tumor while causing much less damage to nearby normal tissues.

BRACHYTHERAPY (PLAQUE RADIOTHERAPY)

The use of brachytherapy, also known as internal radiation therapy or episcleral plaque radiotherapy, is limited to small tumors. During brachytherapy, a small amount of radioactive material is placed on the outside of the part of the eyeball where the tumor is for several days. The radioactive material is put in a small carrier (known as a plaque), which is shaped like a very small bottle cap. The plaque is made of gold or lead to shield nearby tissues from the radiation. The radiation travels a very short distance, so most of it will be focused only on the tumor.

The plaque is sewn in place on the eyeball with tiny stitches during a short operation. It is then removed during a second operation several days later. Both operations are done while the child is under general anesthesia. The child typically stays in the hospital while the plaque is in place.

Chemotherapy for Retinoblastoma

Systemic chemotherapy: In most cases, chemo drugs are injected into a vein (IV) or given by mouth. These drugs enter the bloodstream and reach throughout the body. This is known as systemic chemotherapy.

Periocular (subtenon) chemotherapy: For some advanced intraocular cancers, higher doses of chemo are needed inside the eye. Along with systemic chemotherapy, one of the drugs (carboplatin) may be injected in the tissues around the eye, where it slowly diffuses into the eyeball. This is called periocular or subtenon chemotherapy.

Intra-arterial chemotherapy: A newer approach sometimes used instead of systemic chemotherapy is to inject chemo directly into the ophthalmic artery, the main artery that supplies blood to the eye. In this technique, a very thin catheter (a long, hollow, flexible tube) is inserted into a large artery on the inner thigh and slowly threaded through the blood vessels all the way up into the ophthalmic artery. The chemo is then infused into the artery. The drug used most often is melphalan, but other drugs such as carboplatin and topotecan can also be used.

Intravitreal chemotherapy: In this newer approach, chemotherapy is given directly into the vitreous humor, the jelly-like substance inside the eye.

Follow-up exams and tests

Once treatment is finished, your health care team will discuss a follow-up schedule with you, including which tests should be done and how often. It’s very important to go to all follow-up appointments. Follow-up is needed to check for cancer recurrence, as well as possible side effects of certain treatments. Doctor visits and tests are done more often at first. If nothing abnormal is found, the time between tests can then be extended.