Retinoblastoma

  • What is retinoblastoma?

    Retinoblastoma is a rare cancer originating in the part of the eye called the retina. The retina is a thin layer of nerve tissue that coats the back of the eye and enables the eye to see. Most cases (about 60 percent) involve only one eye (unilateral), but in some children, both eyes may be involved (bilateral).

    About 300 children are diagnosed with retinoblastoma in the United States each year. The disease occurs most often in children younger than 4 years old, and accounts for about 3 percent of all cancers in children from birth to 14 years old. The average age of children diagnosed with retinoblastoma is 18 months old — and boys and girls are affected equally. Children may be born with retinoblastoma, but the disease is rarely diagnosed at birth.

  • Symptoms

    Often, doctors find retinoblastoma on a routine well-baby examination. Most often, however, parents notice symptoms such as:

    • White (leukocoria) or red pupil instead of the normal black
    • Misaligned eyes (strabismus) looking toward the ear or nose
    • Reddened, painful eye
    • Enlarged pupil
    • Different-colored irises
    • Poor vision
  • Diagnosis 

    The diagnosis of retinoblastoma is made by examining the eyes. If your baby has a family history of retinoblastoma, your baby should be examined shortly after birth by an ophthalmologist (medical eye doctor) who specializes in cancers of the eye.

    If you or your child's pediatrician notice your child has a white pupil or strabismus (crossed-eyes), your child should be referred to an ophthalmologist familiar with the treatment of retinoblastoma.

    The doctor will do a thorough examination to check your child's retina for a tumor. Depending on your child's age, general anesthesia may be used for the eye examination. The ophthalmologist will make a drawing or take a photograph of the tumors in the eyes to provide a record for future examinations and treatments, and may use additional tests to confirm or detect tumors.

    Additional tests

    Children who are diagnosed with retinoblastoma will require a complete physical examination and, if there are any additional symptoms or abnormal findings, may also undergo additional tests to determine if the cancer has spread elsewhere in the body. Some of these tests also will be performed when your child starts therapy. 

    • Magnetic resonance imaging (MRI). MRI uses electromagnetic waves to create computer-generated pictures of the brain and spinal column. This may be recommended to determine if there is an abnormality of the pineal gland for children with the genetic form of retinoblastoma. This includes children with bilateral disease (in both eyes) and those with unilateral disease (in one eye) with a positive family history. Very young children with a tumor in one eye but do not have a positive family history may also be at risk, and these studies may be recommended for them. Scans may also be recommended years after treatment for children who have received external beam radiation, either as a baseline in the event that problems arise, or to follow-up on a symptom or sign.
    • Blood tests. These tests evaluate your child's blood and check for problems with the liver and kidneys. The doctor may also look at your child's blood for changes in chromosome 13. Chromosomes are the part of the cell that contains genes. In a few cases of retinoblastoma, these genes are either missing or nonfunctional.
    • Lumbar puncture (spinal tap). In this test, a small amount of cerebrospinal fluid is removed with a needle from the child's back and examined under a microscope to detect cancer cells.  This test is only done if the MRI is abnormal.
    • Bone marrow aspiration. This procedure is performed to determine if any retinoblastoma cells have spread to the bone marrow. For this test, a small amount of bone marrow is removed from your child's hip with a needle and then examined under a microscope. This test is only done if your child's complete blood count (CBC) is abnormal.
    • Hearing test. Children with retinoblastoma taking certain chemotherapy drugs may have their hearing tested (audiology test). In a young child, a normal newborn hearing screen can serve as a baseline.

    Staging

    After a retinoblastoma has been detected, the doctor will determine the extent of disease in the eye and if the disease has spread (metastasized) outside the eye. This is called staging, and it helps doctors plan treatment.

    • Intraocular. This means that cancer occurs in one or both eyes, but has not spread into surrounding tissues or other parts of the body.
    • Recurrent. The cancer has recurred (come back) in the eye or continued to grow after it has been treated.
    • Extraocular. The cancer has spread to tissues around the eye or to other parts of the body.
  • Treatment

    Most children who begin treatment before the retinoblastoma has spread beyond the eye are cured. A major goal of treatment in children with retinoblastoma is preserving vision. Most children retain their vision and more than 95 percent of children with retinoblastoma can be cured.

    Treating unilateral retinoblastoma

    The amount of retinoblastoma in a child’s eye is graded by the International Retinoblastoma Classification Grouping.  Group A designates the least involvement whereas Group E is the most advanced intraocular group.

    When only one eye is involved, and the eye is Group E, enucleation (removal of the involved eye) is usually the treatment of choice. Children adjust very well to the loss of one eye, and their vision does not suffer a great deal.

    However, if a child is very young, there is a risk that a tumor will develop in the other eye, so the goal in these children is to remove as much of the tumor as possible while preserving vision.  In these cases, chemotherapy can be recommended.

    Small tumors can often be treated successfully using local measures, including:

    • Cryotherapy. Extreme cold may be used to destroy cancer cells. The procedure is done in the operating room. The child is discharged the same day after recovering from anesthesia.
    • Thermotherapy. Heat may be used to destroy cancer cells.
    • Plaque radiotherapy.  Radioactive plaques, sewn into the back of the eye and removed after the required dose of radiation is delivered, are also successful. The procedure is performed in the operating room (OR). The plaque will have to stay in place for a few days while it delivers the planned dose to the tumor. The child can be an outpatient during this time until the plaque is then removed in the OR.

    Treating bilateral retinoblastoma

    Chemotherapy

    Chemotherapy is medication used to destroy cancer cells. When tumors are too large to apply local measures, we may recommend chemotherapy to shrink the tumors so local therapy can be used successfully.

    Because chemotherapy can also affect normal cells along with cancer cells, certain side effects can occur. Any plan of chemotherapy will include a discussion of the potential side effects, the ways in which they can be prevented, and what tests we may need to do to look for them.

    All of the chemotherapy medications given for retinoblastoma can be given via an intravenous (IV) catheter placed in your child's arm or foot. Some children may require a semi-permanent type of IV catheter, called a central venous catheter, which is placed under the skin in the chest.

    Each child is affected differently by chemotherapy. Before each cycle of chemotherapy, a pediatric oncologist will examine your child.

    Radiation therapy

    Historically, radiation therapy was the treatment of choice for children with bilateral disease. However, radiation may produce damage to the retina many years after it has been given. That damage can result in loss of vision.

    Radiation, when given to very young children, also results in decreased growth of the bone surrounding the orbit. It can also increase the risk of second non-retinoblastoma cancers from 10 to 50 years after treatment. For these reasons, radiation therapy is no longer considered a front-line therapy for children with retinoblastoma.

  • Genetics of retinoblastoma

    Hereditary retinoblastoma 

    Retinoblastoma can occur in one of two forms: hereditary retinoblastoma and nonhereditary (sporadic) retinoblastoma. 

    About 40 percent of retinoblastoma patients have the hereditary form of disease. Hereditary retinoblastoma is caused by alterations, also known as mutations, to specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

    In patients with hereditary retinoblastoma, the disorder develops as the result of alterations in a specific gene known as RB1, which is located on chromosome 13 at position q14.1-q14.2. RB1 is the only gene known to be associated with hereditary retinoblastoma. The protein produced by the RB1 gene acts as a “tumor suppressor,” which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death.

    With the exception of egg and sperm cells, each cell of the body normally has two working copies of the RB1 gene. Patients with hereditary retinoblastoma generally carry an alteration in one copy of the RB1 gene in all the cells of their body. If the second copy of the gene undergoes a change within a developing retinal cell, a retinoblastoma tumor can develop. Since every cell of the body already has an alteration in the first copy of RB1, it is relatively common for more than one retinal cell to undergo a change in the second RB1 gene copy. Therefore, about 85-90 percent of children with hereditary retinoblastoma develop multiple tumors that affect both eyes (bilateral disease). The remaining 10-15 percent of patients with hereditary retinoblastoma develop only a single eye tumor (unilateral disease).

    During the first five years of life, almost all individuals carrying an alteration in RB1 will develop retinoblastoma. However, in some families, the risk to develop retinoblastoma is much less. In these families, the alterations in the RB1 gene appear to be less damaging.

    Children with the hereditary form of retinoblastoma are also at a slightly increased risk to develop tumors in the pineal gland (a small gland located in the brain) and possibly another cancer, such as a bone or muscle cancer, later in life. Individuals with hereditary retinoblastoma who receive external beam radiation therapy have an increased risk (30-50 percent or higher) to develop second primary tumors, most commonly within the radiation field, over the course of their lives.

    How is hereditary retinoblastoma inherited?

    In 10-20 percent of cases of hereditary retinoblastoma, children inherit an alteration in one RB1 gene copy from an affected parent who carries the same genetic mutation. Interestingly, most children with hereditary retinoblastoma do not have a parent with retinoblastoma.

    In many of these cases, a child develops hereditary retinoblastoma as the result of a “new” mutation in the RB1 gene in one of the father’s sperm, the mother’s eggs, or in a cell of the developing fetus. If this is the case, the child will carry the RB1 gene alteration in all the cells of the body, although they will be the first person in the family to have hereditary retinoblastoma.

    Less commonly, one parent may have a condition known as “gonadal mosaicism," meaning that the parent carries a genetic alteration in one copy of the RB1 gene in only certain cells of the body, such as the egg or sperm cells, while other cells of the body (including the cells in the retina) have two working copies of RB1. Therefore, this parent will not develop retinoblastoma, but a proportion of their children can inherit the genetic alteration present in the egg or sperm cells.

    All children with hereditary retinoblastoma have a 50 percent (or one in two) chance of passing the RB1 genetic alteration on to each of their offspring.

    Cancer risks

    During the first five years of life, almost all individuals carrying an alteration in RB1 will develop retinoblastoma. However, in some families, the risk to develop retinoblastoma is much less. In these families, the RB1 gene alterations appear to be less damaging.

    

Individuals with hereditary retinoblastoma are also at a slightly increased risk to develop tumors of the pineal gland.

 Later in life, patients may develop other tumors, most commonly bone or muscle tumors. Individuals with retinoblastoma who receive external beam radiation therapy have an increased risk (30-50 percent or higher) to develop second primary tumors over the course of their lives.

    Recommended cancer screening protocol for individuals at risk to develop retinoblastoma

    Individuals at risk to develop retinoblastoma who should undergo cancer surveillance include:

    • Individuals with retinomas (benign tumors of the retina)
    • Children who have inherited an RB1 disease-causing mutation OR children at risk for hereditary retinoblastoma who have not yet had genetic testing

    For these children, it is recommended that they undergo eye exams by an ophthalmologist knowledgeable about retinoblastoma starting directly after birth, performed every three to four weeks until age 1 and then less frequently until 5 years old. Young or uncooperative children may need to be examined under anesthesia.

    To monitor for the development of pineal gland involvement, patients should undergo MRI examinations of the brain every six months until age 5. There is currently no consensus regarding recommendations for surveillance for older children with hereditary retinoblastoma who are at-risk to develop second malignancies. These individuals should lead a healthy lifestyle, avoid the use of tobacco products and excess sun exposure, and wear sunscreen and a hat when outdoors. They should also be vigilant for unexplained aches and pains, and seek medical attention should these occur, as they could indicate an underlying malignancy.

    Non-hereditary (sporadic) retinoblastoma

    About 60 percent of children with retinoblastoma have the non-hereditary form of disease, which always manifests as unilateral disease. They do not carry an alteration in one RB1 gene copy in every cell of the body. It is believed that most children with non-hereditary disease develop a retinoblastoma tumor because both RB1 gene copies become damaged within in a single developing retinal cell. Children with sporadic retinoblastoma are not at increased risk to develop pineal gland or other tumors. They are also not at increased risk to transmit the trait to develop retinoblastoma to their children.

    If neither parent has had retinoblastoma and the child is at least 2 years old at diagnosis, the probability of having the hereditary form is very small. There is a genetic test that can be done to determine whether a child has hereditary or non-hereditary retinoblastoma.

    Your child’s oncologist will discuss with you which form of retinoblastoma your child might have, whether genetic testing is warranted, and what this information means for follow-up for the child and for other members of your family.

    Retinoblastoma genetic testing

    All children with bilateral eye involvement and somewhere between 10 and 15 percent of children with unilateral disease have the hereditary form of retinoblastoma. To determine on a molecular level whether a person has the hereditary or nonhereditary form of retinoblastoma, a genetic test may be performed.

    Testing when eye tumor tissue is available

    If eye tumor tissue from the affected individual is available, DNA is isolated from the tumor sample and the two copies of the RB1 gene are evaluated by direct DNA sequencing. Sequencing is a process by which a person’s genetic code is compared to a “normal” reference code. DNA sequencing is performed on the tumor tissue first in order to identify the two RB1 alterations present in the tumor. DNA from a sample of peripheral blood is then screened for the presence of one of the two RB1 gene alterations that was found in the tumor.

    If one of the RB1 alterations identified in the tumor sample is also identified in the affected individual’s blood sample, this would strongly support a diagnosis of hereditary retinoblastoma. The absence of any retinoblastoma gene abnormalities in DNA from the blood sample typically confirms a diagnosis of sporadic (non-hereditary) retinoblastoma.

    Testing when eye tumor tissue is not available

    Eye tumor tissue may not be available for testing in all cases. DNA sequencing can still be performed on a blood sample from the affected individual to investigate for the presence of an alteration in RB1. However, when no tumor is available for comparative genetic study, the failure to identify an alteration in RB1 alteration in the individual’s blood sample does not rule out the possibility that the individual has hereditary retinoblastoma as it remains possible that this individual carries an RB1 mutation that escaped detection due to technical issues related to the genetic testing process.

    RB1 genetic test results can provide important information for other family members. Knowing the specific alteration that is present in a person with cancer allows other family members to have testing to determine whether they also carry this alteration in the RB1 gene. 

    Options for people considering pregnancy

    There are several options for an individual who is found to have an alteration in RB1 and who does not want to pass this alteration on to his or her future children. To do prenatal testing, the familial RB1 mutation must be identified in the affected parent.

    • Prenatal diagnosis. DNA is isolated from the cells of the developing baby though one of two procedures — chorionic villus sampling (CVS) or amniocentesis. Each type of prenatal test is offered at a different time during the pregnancy.
    • Preimplantation Genetic Diagnosis (PGD). Available to individuals who are known to have a genetic alteration that causes a condition such as hereditary retinoblastoma. PGD is performed in combination with in vitro fertilization (IVF) and offers a way to test the potential parent's embryos for genetic disorders before transferring them into the uterus.

    If a parent carrying an RB1 alteration does not wish to undergo prenatal testing for retinoblastoma, genetic testing can be performed at birth to determine whether the child inherited the familial mutation. Children who have inherited the familial mutation are at risk to develop retinoblastoma and should follow the surveillance guidelines listed below. Children who did not inherit the familial mutation do not have hereditary retinoblastoma. These children should have eye exams performed as needed for routine pediatric care.

    Late effects/cancer survivorship

    Some children treated for retinoblastoma develop complications years later. Our Cancer Survivorship Program provides information about the potential long-term effects of the specific treatment your child received, including ways of monitoring and treating these effects.

Reviewed by Ann-Marie Leahey, MD, Kim E. Nichols, MD, Kristin Zelley, MS on March 18, 2014