Childhood Retinoblastoma Retinoblastoma is a cancerous tumor of the eye. It is the most common eye cancer of childhood and occurs in both hereditary and non-hereditary forms. The disease primarily affects very young children and may be present in one or both eyes. There may be one or more than one tumor in either eye. The anatomy of the eye The cornea is the convex outer portion of the eyeball that transmits light to the retina. Behind the cornea is the iris, which is the colored portion of the organ. The iris controls the amount of light entering into the eye by making the opening at the center, called the pupil, either larger or smaller. As light rays pass through the curved surface of the cornea, they are bent and then passed through the pupil. Inside the eye, sitting behind the pupil, is a disc-shaped structure called the lens. The lens is clear in the healthy eye, and has two curved surfaces which refract the light two more times on its journey to the back of the eye. As light rays are passed from the front to the back of the organ, they pass through a colorless, jelly-like material, called the vitreous, that fills the eyeball behind the lens. The inside lining of the eyeball consists of a structure called the retina. It is the retina that converts light energy into electrical impulses that are transmitted to the brain through the use of its sensory receptors, the rods and cones. The retina is a collection of nerve tissue in the eye and its job is to form the images that we see. The retina cells in babies and very young children are called retinoblasts. Retinoblastoma originates in the retina of the eye. Who gets retinoblastoma? Each year approximately 200 children in the United States and 20 children in Canada are diagnosed with retinoblastoma. This relatively uncommon childhood cancer accounts for about 2 percent of all childhood malignancies. There is no higher incidence in any particular race, and boys are affected as often as girls. There is a hereditary and non- hereditary form of this disease (see "Genetic factors"). This worried couple was relieved when they learned about their son's prospects for survival: John Allen was fifteen months old when he was diagnosed with unilateral retinoblastoma. The doctor didn't give us any information other than it was a fast growing cancer and that it needed to be taken care of right away. We couldn't see the specialist for another five days, so we cried and prayed. We didn't know whether we were going to lose our baby or not. When we saw the specialist, she answered all of our questions in detail. We were then referred to a pediatric oncologist and pediatric ophthalmologist surgeon. They, too, were fantastic. We were relieved when they explained the enucleation to us. What mattered most was that our little boy had an excellent chance of beating his disease. Retinoblastoma is usually diagnosed in very young children and may be present at birth. Although it may occur at any age, 90 percent of cases are diagnosed before the age of five. Those with more than one tumor or a tumor in both eyes (usually the hereditary form) are diagnosed at a younger age than those with only one tumor and one eye involved (usually the non-hereditary form). Genetic factors As with most types of childhood cancer, the exact cause of retinoblastoma is not known. However, more is known about the genetics and inheritance of this tumor than any other kind of childhood cancer. Because the tumor occurs at a very young age and within paired organs (eyes) and the gene involved is known, retinoblastoma is considered the model for genetic studies into childhood cancer. Scientists hope to use this model to learn more about other forms of childhood cancer. A mutation, or change, in a gene called RB1 is involved in the development of retinoblastoma. The RBI gene is located on chromosome 13. In about 60 percent of cases, there is a change in both copies of the RB1 gene but only in the retinoblast cells that make up the retinoblastoma tumor in the eye. If you look at cells from any other area in the body, chromosome 13 is completely unchanged with no mutation in the RB1 gene. It is not known what causes the mutation in this gene. Most of the time, these children develop one tumor only in one eye. This is called the non-hereditary form of the disease, which may be what this person had: Thirty years ago I was diagnosed with retinoblastoma when I was eighteen months old. I had one tumor in just one eye. The eye was surgically removed, and I had no chemotherapy or radiation. I have no late effects other than wearing a prosthesis and having vision in only one eye. In the other 40 percent of cases, the children are born with one variant RB1 gene that has a mutation. This mutated copy of the RB1 gene is found in all the cells of the body. In 85 percent of these cases, there is no one else in the family with retinoblastoma; the mutation happened in the egg or the sperm. This new or spontaneous mutation is passed on to the child. The remaining 15 percent of the children have a family member with the disease (usually a parent). In these instances, the parent had an abnormal copy of the RB1 gene in every cell in the body and passed it on to the child through the egg or sperm. This time it was not a new (or spontaneous) mutation. All of these children start their life with one variant copy of the RB1 gene in every cell, including all the retinoblasts in the eye. After conception, something happens to the copy of the RB1 gene in one or more than one retinoblast in one or both eyes. Now, in these eyes, both copies of the gene are mutated, and retinoblastoma occurs. In these children, the disease can occur in one or both eyes. There may be one or more than one tumor. New tumors may form in the first five years of life. This is called the hereditary form of retinoblastoma even if there is no one else in the family with the disease. It is not known what causes the changes in the RB1 gene in either of these forms of retinoblastoma. It is known that there is nothing parents can do to change these risks. No simple blood test is available to tell whether your child has the hereditary form or the non-hereditary form of retinoblastoma. The genetics are very complicated. Currently, oncologists decide on whether the disease is hereditary or non-hereditary based on a number of factors, including family history, age at diagnosis, number of tumors, and whether one or both eyes are involved. If your oncologist has not told you which type of retinoblastoma your child has, ask. Your oncologist can then explain how your child and other family members need to be followed. This affects treatment decisions, risk for having another child with retinoblastoma, risk of your child having a child with retinoblastoma, and the risk of your child getting other cancers later in life, something this man considered: Because I had bilateral retinoblastoma, the doctors told my mother long ago that I had a high chance of passing it on to any offspring. When I got married, my wife and I chose not to have any kids. Environmental factors No clear environmental factors have been linked to increased risk of retinoblastoma. Signs and symptoms In North America, most cases of retinoblastoma are diagnosed while the tumor remains within the eye. The most frequently observed sign of this malignancy is a white appearance of the pupil when exposed to light--called leukokoria. This is often referred to as "the cat's eye reflex." It is usually noticed when a flash picture is taken and is especially noticeable when only one eye is affected. Leukokoria brought this child's retinoblastoma to his doctor's attention: It took a few days to get a diagnosis. On a Friday morning, at Noah's two-month checkup, the pediatrician noticed a white reflex in one of his pupils and showed me the difference between the eyes. When I asked what would cause it he was vague and said he would call an ophthalmologist for an appointment for us. When the ophthalmologist's office called asking us to come in that same day we began to realize that something quite serious must be going on. The ophthalmologist said Noah either had cancer or another progressive condition and he would need to be seen by a retina specialist in Seattle (a 1 hour and 45 minute drive away). When we asked if he would be able to see out of the eye, he very matter-of-factly informed us that there was no question that he could not see and would not again from that eye. On Monday morning we were told that Noah had retinoblastoma, that the tumor was very large, and the eye would need to be removed. We were in shock and scared of the tests and surgery he would need. It was hard to imagine what it would be like for him to lose his eye, and we were worried about the possibility of metastases. Everything seemed very unreal, but we just did what had to be done. Another frequently seen symptom of retinoblastoma is strabismus--when the affected eye drifts inward (esotropia), or outward (exotropia). However, most children who have strabismus do not have retinoblastoma. Since young children generally do not complain of vision problems, vision loss is rarely noted by the parents. Pain is not common, and apart from the above noted symptoms, the child appears otherwise healthy. Diagnosis and staging After a parent or doctor notices the abnormality in a child's eye(s), the child is examined by an ophthalmologist. After an examination is done in the office, the child is then examined under anesthesia (EUA). An ultrasound is usually also done at this time. After a diagnosis of retinoblastoma is made, the child should be referred to a pediatric oncologist. The oncologist takes a full history, does a thorough examination, and together with the ophthalmologist decides on the best treatment plan. Staging the tumor is done to find out the extent of the disease. It is usually done by the oncologist, but part may also be done by the ophthalmologist. Computerized tomography (CT) or magnetic resonance imaging (MRI) is used to examine for disease in both eyes, orbits, optic nerves, and the brain. Rarely, retinoblastoma can go to the pineal gland in the brain. Even more rarely, it can spread to other places in the brain or the bone marrow. For this reason, a complete blood count (CBC) is done. If the CT, MRI, or CBC suggests that the disease has spread outside the eye, a lumbar puncture (spinal tap) and a bone marrow test will be done. These tests are rare, however. Parents can do many things to make their children more comfortable with the medical procedures they undergo, as this couple found: From the beginning, we always talked to our son about what was happening, about what he might be feeling, about how sorry we were that we couldn't avoid having him go through a specific procedure. He understood our love and concern. We always felt it was important to be honest with him about what was happening because he had a right to know. We bought him a doctor kit, a Playmobile operating room, and kept one of his anesthesia masks for him to play with. We gave him empty dilating drop bottles so he could be the one to put the eye drops in a willing patient (stuffed animal). Successful treatment of retinoblastoma depends largely on the size of the tumor and the extent of the disease. The staging system most widely used is the Reese-Ellsworth staging classification of retinoblastoma. This system allows the ophthalmologist and oncologist to better plan therapy. Children are grouped into very favorable, favorable, doubtful, unfavorable, or very unfavorable categories regarding the preservation of their vision based on several factors, such as tumor size, the location and number of lesions, and the presence of disease within the layers of the retina (seeding). Children with retinoblastoma should be followed closely for recurrence or spread outside the eye from diagnosis through age five. The intervals at which exams are done depends on many factors including whether the disease is in one or both eyes, the number, size, and location of tumors, family history, and the type of treatment. After age five, the chance of recurrence or spread is very low, but children should still be seen at least once a year by an ophthalmologist and an oncologist to monitor for late effects. Prognosis The prognosis for cure from retinoblastoma is excellent (close to 95 percent). In most cases, the child will be able to lead a very good life despite visual impairment or blindness in one or both eyes. Vision may be spared if the disease is diagnosed early and newer treatments are used. Treatment At diagnosis, many parents are confused about how to find the best doctors and treatments for their child. State-of-the-art care is available from physicians who participate in the Children's Cancer Group (CCG) and/or the Pediatric Oncology Group (POG). These study groups, composed of pediatric surgeons and oncologists, urologists, radiation oncologists, researchers, and nurses, establish the standard of care for patients worldwide, conduct new studies to discover better therapies, and establish follow-up for survivors. They are in the process of merging into one entity called the Children's Oncology Group (COG). If the treatment center you are referred to is a member of one of these groups, you can rest assured that your child will have access to the best thinking on the treatment of pediatric cancers. It is also important that your child be followed by a pediatric ophthalmologist who has experience treating retinoblastoma. He needs to work closely with the child's oncologist throughout treatment. The ophthalmologist and oncologist together choose the best treatment or clinical trial based on the extent of the tumor within and outside the eye. Treatment goals are both cure and preservation of sight. Depending on the situation, treatment may include surgery, radiation, chemotherapy, and local eye treatments. These parents synthesized information from many sources before selecting treatment for their daughter: We relied on the opinions of the surgeon, retina specialist, two pathologists, a retinoblastoma specialist from Canada, parents of children with retinoblastoma, and material from the medical journals when deciding on treatment for Hailee (fourteen months old). They all offered pieces of the puzzle, which allowed us to make an informed decision. Hailee had her eye enucleated, and since all the cancer was removed, further treatment wasn't necessary. She is followed every six months with EUA (exam under anesthesia) and MRI and has done very well. She has coped well with the enucleation, and she looks beautiful. Surgery and local eye treatments There are several types of procedures used to treat retinoblastoma: enucleation, cryotherapy, photocoagulation, and thermotherapy. The most appropriate treatment is chosen on an individual basis. Enucleation Enucleation is the surgical removal of an eye. The procedure may be used for the following situations: If the tumor is very large and there is no hope that the eye will have useful vision. If the tumor has spread to the optic nerve, choroid, or orbit. If other treatment methods have failed to eradicate the disease. If the retina is not able to be examined because of vitreous hemorrhage or cataract. The enucleation procedure is a relatively simple operation that is done under general anesthesia. In addition to removing the eye, the surgeon will also remove a section of the optic nerve. An orbital implant is placed into the socket immediately after the eyeball is removed. The child will be fitted for an artificial eye four to six weeks after the procedure. The prospect of an artificial eye may raise some anxiety, but children and their parents tend to adjust to it. These parents describe their experiences: We were very worried about how we would react to seeing John Allen without an eye, but the doctors prepared us, and when the time came, we were okay. It has been an interesting process dealing with his prosthesis. When the ocularist was making his artificial eye, my wife and I both almost began to cry, because it looked so real. It was almost as if nothing had happened. But, deep inside, we knew that this was only the beginning of a long journey for us and our son. We have had a difficult time learning how to take his eye out and put it back in. He cries, because he doesn't like anyone to mess with it. At first, it was heartbreaking, because he would take the eye from us, and try to put it back in himself. Of course, he couldn't do it, and we would have to continue to hold him and try to put it in. •  •  •  •  •   Hailee (fourteen months) never experienced any difficulties with her prosthetic eye. We spent a great deal of time preparing Hailee when the eye was about to be enucleated. We read her My Fake Eye, which helped a great deal with the prosthesis. She took the book to daycare and the caregiver read it to the other children. It has never been a big deal for her. She is now four years old and continues to do well . After the enucleation, a pressure patch is placed over the eyelid. When the patch is removed, the child is started on antibiotic drops, which are put into the socket. The eyelid is usually swollen and bruised for the next few days, but not always, as this parent relates: Noah had his left eye enucleated at age two months. We were able to take him home a couple of hours later. The most difficult part for me was handing him over to the nurse who took him into the operating room and not getting to see him until he had awakened. We were impressed that he recovered quickly from anesthesia, and, when the bandages were removed three days later, that there was virtually no bruising. Children who have one or both eyes removed before the age of three may have an altered facial appearance when they mature due to the slowing of the growth of the orbit. After enucleation, a prosthesis needs to be placed and replaced periodically to foster orbital growth. This retinoblastoma survivor expresses equanimity about the effects of the illness and enucleation early in life: I am a long-term survivor of bilateral retinoblastoma, diagnosed when I was ten months old. My first enucleation (surgical removal of the eye) was the left eye in May 1971, with radiation to the right eye. The enucleation of the right eye was in March 1972. I have had no subsequent treatment since then. Due to my loss of sight at such an early age, I had no traumatic adjustment period that losing sight later in life might have caused. I really can think of no significant effects that my retinoblastoma has had on my adult life other than the usual adaptations required for dealing with blindness. Cryotherapy Cryotherapy, also sometimes called cryosurgery, is used to treat small primary tumors or new tumors that develop. It is now often used in combination with chemotherapy. It can also be used after radiation therapy. Cryotherapy uses extreme cold applied by a small probe placed directly on the tumor. The surgeon uses ultrasound to guide the probe to ensure that healthy tissue around the tumor remains unharmed. The procedure is conducted under general anesthesia and may be repeated on several occasions if necessary. One advantage of this procedure is that it may help prevent the need for enucleation or radiation therapy. The major disadvantages are that larger tumors cannot be treated sufficiently, and the procedure may leave a retinal scar which damages vision. A parent tells about the good outcome of treatment that included cryotherapy: Zachary was ten months old when he was diagnosed with unilateral retinoblastoma in the left eye. He had several eye exams since birth because I had retinoblastoma when I was a child. He was treated with cryotherapy and radioactive plaques. Zachary did well, so our experience with cryotherapy was pretty positive. Of course, being so young, he didn't really know what was going on. Thermotherapy Thermotherapy is a method of delivering heat to the eye using ultrasound, microwaves, or infrared radiation. Like cryotherapy, it is only useful for very small tumors and can be combined with chemotherapy or radiation therapy. It leaves a relatively small scar, preserving more vision. Photocoagulation Photocoagulation, also called light coagulation, is another method for treating small tumors. This technique cauterizes tissues with focused light from an argon laser while the child is anesthetized. The light is delivered through an ophthalmoscope and is used to kill the tumor by destroying its blood supply. Photocoagulation is sometimes used in combination with chemotherapy. Radiation Retinoblastoma is a radiosensitive tumor. Radiation is used to destroy local disease while attempting to maintain vision. The two methods of radiotherapy that are used to treat retinoblastoma are external-beam radiation and radioactive plaques. External-beam radiation External-beam radiation is used most frequently with large tumors, multiple tumors, tumors that are very close to the optic nerve or fovea (a tiny area on the retina), or those with extensive seeding into the vitreous. Because of the need to sedate young children and the importance of precise delivery, the child should be treated only by professionals who specialize in pediatric radiation therapy. Radiation is produced by a linear accelerator and targeted at the tumor. While doses may vary, use of 180 to 200 cGy fractions given over four and a half to six weeks to a total dose of 3500 to 4600 cGy are common. Investigators are looking into the possibility of using lower doses in combination with other treatments. Since precise delivery is vital, most children are anesthetized. The actual treatment takes approximately two or three minutes; the preparation, however, takes significantly longer. This parent describes mild side effects from a son's radiation treatment: The doctor had been optimistic that he would be a unilateral case, so we were all quite devastated to learn five months later that Noah had new tumors in his remaining eye. Both were small enough to treat with laser, but unfortunately one was adjacent to the optic nerve so Noah had to have radiotherapy. The treatment was very localized. His white count dropped some but not seriously. He experienced a mild radiation burn on the opposite side of the eye being treated and some eyebrow hair loss. Late effects that may develop after external beam radiation are cataracts, slowed growth of the bones in the orbit, vision loss, abnormal tear production, chronic conjunctivitis, damage to the retina and optic nerve, and second cancers in the radiation field. Children who have had radiation to the eye need expert follow-up evaluations on a routine basis. Radioactive plaque therapy Radioactive plaque therapy, also called brachytherapy, is used primarily to treat small, single tumors in children with unilateral, early-stage disease or if the disease returns after external beam radiation. It is also used in combination with chemotherapy if local eye treatments don't work. This technique, which uses radioactive iodine, cobalt, or ruthenium, can only be used on tumors that are of a certain size and distance from the area of central vision. Children who get radioactive plaque therapy are isolated for one to three days, depending on the actual dose of radiation that is administered. Parents and hospital staff can spend only short periods of time in the child's room. Pregnant women and children are not permitted to visit the child in isolation. Chemotherapy Chemotherapy is being used with increased frequency to treat some children with retinoblastoma. Until recently, chemotherapy was used only to treat retinoblastoma that had spread outside the eye. Now, in order to prevent the long-term problems that can occur after enucleation or radiation, more doctors are using chemotherapy to treat retinoblastoma in the eye. The decision to use chemotherapy is complex and depends on a number of factors, including your child's age, the number, size, and location of tumors, ability of the ophthalmologist to use local treatments, family history, and other medical problems. It is almost always given together with local eye treatments, so it may require visits as often as every three weeks. Chemotherapy works better for lower-stage tumors and for tumors without seeding. Usually chemotherapy is used to destroy the tumor. In retinoblastoma, it is used to shrink the tumor and help prevent new ones from growing. This is called chemoreduction therapy. The chemotherapy drugs that are most commonly used in retinoblastoma are vincristine, carboplatin, and etoposide. Cyclosporine A is also used in some centers. All of these chemotherapy protocols are being done in clinical trials to evaluate their effectiveness in treating retinoblastoma. Newest treatment options To learn about the standard treatment for your child's illness, call (800) 4-CANCER and ask for the PDQ (physician's data query) for retinoblastoma. This free statement explains the disease, state-of-the-art treatments, and ongoing clinical trials. Two versions are available: one for patients, which uses simple language and contains no statistics, and one for health professionals, which is technical, thorough, and includes citations to scientific literature. The PDQ can also be read on the Internet at http://cancernet.nci.nih.gov/. Advice and perspective on dealing the condition gained over many years from a retinoblastoma survivor: I am a long-term survivor of bilateral retinoblastoma. I think that parents can be very instrumental in their child's recovery. Even though it may not be easy, I feel that it is important to be strong and positive. Seek all of the information possible, and don't hesitate to ask questions. Times will be tough, so please find support, whether it be family counseling focusing on cancer or corresponding with other parents who have had similar experiences. Don't hold all of your feelings in. Have the same expectations for your child with retinoblastoma as you would for any other. Don't set limitations for your child, there are already plenty of those out there. Although I am blind, when I was a child I tap danced, rode horses, and I was a competitive roller skater. Now I ride in mountain bike competitions. I attend college full-time and have many good friends. I have matured into a woman with strong character, spirit, and motivation, and this has helped me overcome many challenges. This fact sheet was adapted from Childhood Cancer: A Parent's Guide to Solid Tumor Cancers, by Honna Janes-Hodder and Nancy Keene, © 2001 by Patient-Centered Guides For more information, call (800) 998-9938 or see www.patientcenters.com.