Retinoblastoma

Retinoblastoma is a disease in which malignant (cancer) cells form in the tissues of the retina, which is the nerve tissue that lines the inside of the back of the eye. The retina senses light and sends images to the brain by way of the optic nerve.

Although retinoblastoma may occur at any age, it usually occurs in children younger than five years of age. The tumor may be in one eye or in both eyes. Retinoblastoma rarely spreads from the eye to nearby tissue, or other parts of the body. Retinoblastoma is usually found in only one eye and can usually be cured.

The top panel shows the outside anatomy of the eye; the bottom panel shows the inside anatomy of the eye including the cornea, lens, ciliary body, retina, choroid, optic nerve, and vitreous humor. Source: National Cancer Institute

Other Names

• Retinal glioblastoma
• Retinal glioma
• Retinal neuroblastoma

Types

Familial (or inherited) retinoblastoma

Familial retinoblastoma, which represents 10% of cases, is hereditary and is passed from parent to child. It usually occurs at a younger age than non-inherited retinoblastoma. Hereditary retinoblastoma also increases the risk of developing other types of cancer in later years. Retinoblastoma that occurs in both eyes is always inherited. When hereditary retinoblastoma first occurs in only one eye, there is a chance it will develop later in the other eye.

A child who has hereditary retinoblastoma is at risk for developing tumors in a special gland (hormone producing region) in the brain mdash; called the pineal. This gland secretes melatonin. When a child with retinoblastoma develops a pineal tumour it is called trilateral retinoblastoma. Regular follow-up exams using magnetic resonance imaging (MRI) or computerized tomography (CT) scans are used to monitor for this condition. Often these tests are used until the child is five years of age.

Eyes of a child with retinoblastoma. Source: National Cancer Institute.

Unilateral retinoblastoma

This type of retinoblastoma, responsible for 70% of all new cases, affects only one eye. Unilateral retinoblastoma is usually not inherited, and carries no increased risk of a second tumor.

Signs and Symptoms

Below are some signs of retinoblastoma:

• Pupil of the eye appears white instead of red ("white pupil") when light shines into it. This may be seen in flash photographs of the child.
• Eyes appear to be looking in different directions
• Pain or redness in the eye

These signs are not specific to retinoblastoma. Other conditions may cause the same symptoms.

Causes

Both familial and non-hereditary retinoblastoma are caused by genetic changes (or mutations) on chromosome 13. Some of these genetic changes occur in all of the cells of the body, including sperm and egg cells (germline cells) and result in the risk of the mutation being passed down to any offspring. In other cases, the genetic change occurs only in non-germline (or somatic) cells and so only the individual is affected.

On chromosome 13, mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene or oncogene. These genes normally keep cells from growing and dividing too rapidly or in an uncontrolled way. Most mutations in the RB1 gene prevent it from regulating the growth of cells, so cells divide uncontrollably and form a tumor.

A small percentage of retinoblastoma cases are caused by removing a large region of DNA on chromosome 13 that contains the RB1 gene (a deletion). Geneticists refer to this region as 13q14. Children with these chromosomal deletions may also have mental retardation, slow growth, and characteristic facial features (such as prominent eyebrows, a short nose with a broad nasal bridge, and ear abnormalities).

The small number of retinoblastoma cases caused by chromosome 13 deletions are usually not inherited. These chromosomal changes occur as random events during the formation of reproductive cells (eggs and sperm) or during cell division early in fetal development.

Diagnosis

The following tests and procedures may be used to diagnose retinoblastoma:

• Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A family history of retinoblastoma is considered.

• Eye exam with dilated pupil: An exam of the eye in which the pupil is dilated (opened wider) with medicated eye drops to allow the doctor to look through the lens and pupil to the retina. The inside of the eye, including the retina and the optic nerve, is examined with a light. Depending on the age of the child, this exam may be done under anesthesia.

• Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.

• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the eye, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the eye. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Retinoblastoma is usually diagnosed without a biopsy (removal of cells or tissues for examination under a microscope).

After diagnosis of retinoblastoma in one eye, regular follow-up exams of the healthy eye are usually performed every 2 to 4 months for at least 28 months.

Genetic testing

Genetic tests for the RB1 gene are available. DNA from a blood sample and DNA from a tumor sample are used in the test. In the past, a fresh frozen tumor sample was not always preserved, but now with genetic testing available, it is important that a frozen sample is kept for future DNA analysis.

In an individual with unilateral retinoblastoma, genetic testing is used to determine whether this individual has a sporadic form (somatic mutation) or hereditary form (germline mutation) of the disease. Genetic testing detects more than 90% of RB1 mutations. If RB1 DNA testing indicates that an individual is a carrier of an RB1 germline mutation, then testing for the parents, siblings, and future pregnancies (through amniocentesis or chorionic villus sampling) can be performed to determine more accurately the potential health and reproductive risks for this family. Individuals with the heritable form of retinoblastoma have a 50% chance of passing down the cancer predisposing RB1 mutation to their offspring.

If the result of an RB1 DNA test indicates that an individual has the non-hereditary form of retinoblastoma, then further testing for that individual's parents and siblings aren't needed. However, DNA testing for the patient's offspring would be indicated because of the possibility of passing on undetected RB1 mutations.

Determining the Cancer Stage

After retinoblastoma has been diagnosed, tests are done to find out if cancer cells have spread within the eye or to other parts of the body. These tests are called staging. The information gathered from the staging process determines the stage of the disease. Staging directs the treatment. The following tests and procedures may be used in the staging process:

• Eye exam with dilated pupil
• Ultrasound exam
• CT scan (CAT scan)
• MRI (magnetic resonance imaging)
• Lumbar puncture: A procedure used to collect cerebrospinal fluid from the spinal column. This is done by placing a needle into the spinal column. This procedure is also called an LP or spinal tap. A lumbar puncture may be done if tests suggest that the cancer has spread out of the eye.

Intraocular

In intraocular retinoblastoma, the cancer is found to be within the eye but has not spread to tissues around the outside of the eye, or to other parts of the body.

Extraocular

In extraocular retinoblastoma, the cancer has spread beyond the eye. It may be found in tissues around the eye, or it may have spread to the central nervous system (brain and spinal cord), or to other parts of the body such as the bone marrow or lymph nodes.

Recurrent retinoblastoma

In recurrent reitnoblasgtoma, the cancer has recurred (come back) after it has been treated. The cancer may recur in the eye, in tissues around the eye, or in other places in the body. Tumors that were not treated with radiation therapy or surgery commonly recur, usually within six months.

Treatment

If the cancer is in one eye and the tumor is large, treatment is usually enucleation. Enucleaiton is a surgery that removes the eye and part of the optic nerve. The eye is checked with a microscope to see if there are any signs that the cancer is likely to spread to other parts of the body. This is done if there is little or no chance that vision can be saved. The patient is fitted for an artificial eye after this surgery.

If vision can be saved, treatment may include the following:

• Radiation therapy - A cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, plaques, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated. Methods of radiation therapy used to treat retinoblastoma include the following:
  • Intensity-modulated radiation therapy (IMRT) - A type of 3-dimensional (3-D) radiation therapy that uses a computer to make pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles. This type of radiation therapy causes less damage to healthy tissue near the tumor.
  • Stereotactic radiation therapy - Radiation therapy that uses a rigid head frame attached to the skull to aim high-dose radiation beams directly at the tumors, causing less damage to nearby healthy tissue. It is also called stereotactic external-beam radiation and stereotaxic radiation therapy.
  • Proton beam radiation therapy - Radiation therapy that uses protons made by a special machine. A proton is a type of high-energy radiation that is different from an x-ray.
  • Plaque radiotherapy - Radioactive seeds are attached to one side of a disk, called a plaque, and placed directly on the outside wall of the eye near the tumor. The side of the plaque with the seeds on it faces the eyeball, aiming radiation at the tumor. The plaque helps protect other nearby tissue from the radiation.

• Cryotherapy - A treatment that uses an instrument to freeze and destroy abnormal tissue, such as carcinoma. This type of treatment is also called cryosurgery.

• Photocoagulation - a procedure that uses laser light to destroy blood vessels to the tumor, killing the tumor. Photocoagulation may be used to treat small tumors. This is also called light coagulation.

• Thermotherapy - the use of heat to destroy cancer cells. Thermotherapy may be given using a laser beam aimed through the dilated pupil or onto the outside of the eyeball, or using ultrasound, microwaves, or infrared radiation (light that cannot be seen but can be felt as heat).

• Chemotherapy - a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ (such as the eye), or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
  • A form of chemotherapy called chemoreduction is used to treat retinoblastoma. Chemoreduction reduces the size of the tumor so it may be treated with local treatment (such as radiation therapy, cryotherapy, photocoagulation, or thermotherapy).

If the cancer is in both eyes, treatment may include the following:

• enucleation of the eye with the most cancer, and radiation therapy to the other eye.
• radiation therapy to both eyes or chemotherapy (chemoreduction) followed by local treatment. This may be done if there is a chance to save vision in both eyes.
• surgery only, when vision cannot be saved.

Treatment is overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other pediatric doctors who are experts in treating children with eye cancer and who specialize in certain areas of medicine. These may include a pediatric ophthalmologist (children's eye doctor) who has a lot of experience in treating retinoblastoma and the following specialists:

• pediatric surgeon
• pediatric hematologist
• radiation oncologist
• neurologist
• pediatric nurse specialist
• rehabilitation specialist
• psychologist
• social workers
• geneticist

Children with the inherited form of retinoblastoma have an increased risk of developing second cancers. Children who have been treated for retinoblastoma with radiation therapy or certain chemotherapy agents also have a risk of developing second cancers.

Genetic Counseling

Genetic counseling is important for families and individuals with retinoblastoma. Genetic counseling helps assess the family's risk for a heritable mutation in RB1. Before undergoing genetic testing, the genetic counselor will explain the benefits and limitations of such testing to the family. Limitations include the rare occurrence of uninformative results or mosaicism (in which only a portion of the blood cells carry an alteration in the RB1 gene). Whether a heritable RB1 mutation is found or not, genetic counseling will provide support for the families. Individuals with normal results in blood, although this reduces the risk for heritable retinoblastoma, will still have a small residual risk for an undetected RB1 mutation, and this will be an important topic of discussion in a genetic counseling session. If an individual has a detectable RB1 mutation, subsequent genetic counseling will involve testing of first-degree family members including healthy parents and siblings.

While genetic counseling and genetic testing for retinoblastoma can be a complicated and unexpected element in the diagnosis and treatment of this disease, it is an integral part of the process. The goal of genetic counseling is to identify those individuals who have a heritable mutation in RB1 and to inform families of the implications of this finding. The test results help to focus high-risk screening on those who carry a heritable mutation, and provide reassurance to individuals with sporadic, non-hereditary retinoblastoma. If a mutation is identified, risks to that individual and their family members can be clarified, and unnecessary examinations under anesthesia can be avoided in younger relatives who do not carry the mutation. Genetic testing also has implications for the future offspring of an individual with retinoblastoma and allows timely discussion of screening and treatment options for offspring that may be at risk.

Chances of Developing Retinoblastoma

Estimates suggest that between 250 and 500 children are diagnosed with retinoblastoma every year in the United States. Worldwide the incidence is approximately 11 cases in 1 million children under the age of 5 years. ^[1]The prevalence of retinoblastoma varies from country to country.

Clinical Trials

New types of treatment are being tested in Clinical Trials. These include the following:

• Subtenon chemotherapy - is the use of drugs injected through the membrane covering the muscles and nerves at the back of the eyeball. This is a type of regional chemotherapy. It is usually combined with systemic chemotherapy and local treatment (such as radiation therapy, cryotherapy, photocoagulation, or thermotherapy).

• High-dose chemotherapy with stem cell transplant - a way of giving high doses of chemotherapy and replacing blood -forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Controversy

Reports of children born from in vitro fertilization who had retinoblastoma surfaced in 2001 and 2002. In 2003, a study was published in the British medical journal The Lancet that suggested a link between the artificial fertilization procedure and retinoblastoma.^[2] The Dutch study found that the risk of having retinoblastoma increased five-times or more in children conceived through in vitro fertilization. A year later a study performed in the United Kingdom was published that refuted the association.^[3] The study claimed that in vitro fertilization is probably safe because the data showed no cases of retinoblastoma in 176 children born from in vitro fertilization. However, some problems with this study have been pointed out, and the link between in vitro fertilization and retinoblastoma remains controversial.^[4]

Expected Outcome

Many factors affect prognosis (chance of recovery) and treatment options:

• Stage of the cancer
• Likelihood of saving vision in one or both eyes
• Size and number of tumors
• Whether trilateral retinoblastoma occurs

References

1. ↑ American Cancer Society. What Are the Key Statistics for Retinoblastoma?
2. ↑ Moll AC, Imhof SM, Cruysberg JR, Schouten-van Meeteren AY, Boers M, van Leeuwen FE. Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet. 2003 Jan 25;361(9354):309-10. Abstract.
3. ↑ Bradbury BD, Jick H. In vitro fertilization and childhood retinoblastoma. Br J Clin Pharmacol. 2004 Aug;58(2):209-11. Abstract.
4. ↑ BenEzra D. In vitro fertilization and childhood retinoblastoma. Br J Clin Pharmacol. 2005 Jun;59(6):724. Full Text

External Links

Retinoblastoma International

Retinoblastoma.com: Parents Guide to Understanding Retinoblastoma

Eye Cancer Network: Retinoblastoma

St. Jude's Hospital Retinoblastoma PDF

Retinoblastoma Solutions.Org