Eric Shinohara, MD, MSCI
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 8, 2008
The retinoblastoma gene is a type of gene known as a "tumor suppressor gene." Tumor suppressor genes act as a "brake" on cell division. The retinoblastoma gene is present in all cells of the body. If an unwanted mutation forms in one of the cells of the body, the retinoblastoma protein (also known as pRB) acts as a brake to prevent that mutant cell from dividing. However, if the retinoblastoma gene is damaged (mutated), a defective pRB may be produced and the cell can then divide unchecked, leading to cancer.
Retinoblastoma arises from the retina of the eye; it affects one eye in approximately 75% of cases, and both eyes in 25% of cases. It causes a tumor to form within the eye, which can then grow and destroy the internal structures of the eye. It can also spread to other areas such as the eye socket, brain, lungs, and bones. However, retinoblastoma is generally limited to the eye, and 90% of children who develop retinoblastoma are cured.
Retinoblastoma is the most common childhood cancer involving the eye. Having said that, it is still relatively uncommon among all childhood cancers, making up about 3% of all childhood cancers in children less than 15 years old. It is diagnosed in about 4 out of every million children per year. Although retinoblastoma can be diagnosed at any age, most children are diagnosed before the age of 2, and about 95% of cases are diagnosed in children younger than 5 years of age.
Retinoblastoma is thought to occur based on the "two-hit" hypothesis. There are two copies of the retinoblastoma gene in each cell, and in order for retinoblastoma to occur, both copies of this gene need to be defective. There are two patterns of retinoblastoma that can occur: an inheritable, or germline form (40% of cases), and a sporadic form (60% of cases). There are two ways that the inheritable form can occur. One way is through direct inheritance of one defective gene from a parent, which causes about 25% of the inheritable cases of the disease. This also means that one parent is a "carrier" of the defective gene. However, if the parent never developed a second retinoblastoma mutation, he or she would have never manifested any symptoms of the disease. Hence, there may not be a family history, even though one of the parents is a carrier, and indeed less than 10% of children diagnosed with retinoblastoma have a family history of the disease. The second way is through a germline mutation of one copy of the retinoblastoma gene, which causes about 75% of the inheritable form of the disease. A germline mutation occurs when the retinoblastoma gene is mutated during conception, and this new mutation can then affect all cells in the body. Hence, all children with the inheritable form of retinoblastoma already have one defective retinoblastoma gene, and only one additional mutation is required to cause the disease. In the sporadic form of the disease, the child does not inherit a defective copy of the gene, and thus in order for the child to develop the disease, two "hits" are required to cause defects in the two normal copies of the retinoblastoma gene.
The inheritable and sporadic forms of retinoblastoma also manifest themselves in different fashions. Either form of retinoblastoma can affect just one eye. However, only the inheritable form of retinoblastoma can cause disease in both eyes. The inheritable form of the disease causes tumors in one eye about 15% of the time, tends to occur at an earlier age, and is associated with multiple tumors in the eye. As the inheritable form tends to occur in younger children, infants presenting with one or both eyes affected most likely have the inheritable form of the disease. Studies have found that people who are diagnosed with the inheritable form of retinoblastoma are at increased risk for developing secondary cancers.
Studies have shown that within 50 years of diagnosis, approximately 51% of people with the inheritable form and 5% of those with the sporadic form of retinoblastoma will develop another cancer. Radiation treatment affects the rate of secondary cancer development in children with the inheritable form of retinoblastoma. Approximately 58% of children who received radiation developed secondary cancers, compared to 26.5% of children who did not receive radiation therapy. However, these studies were based on older radiation techniques, and it appears that this risk is reduced in children treated with lower doses of radiation and at ages greater than 1 year. Even in children who were spared radiation, there was an increased risk of death from several types of cancer in children with the inheritable form of retinoblastoma. These cancers included bladder, lung, and epithelial cancers (cancers of the lining of intestines and the lining of the body cavities). It also appears that people with the inheritable form of retinoblastoma are at increased risk for developing bone, soft tissue, and skin cancers. Hence, people who have the inheritable form of retinoblastoma should be carefully monitored for a second cancer for life. The general guideline for children with the inheritable form of retinoblastoma is to have routine examinations every 2 to 4 months for at least 28 months. For those who are treated, routine examinations should be performed until the child is 7 years of age.
This cancer appears to equally affect boys and girls as well as African Americans and Caucasians. The retinoblastoma gene is located on chromosome 13q. Children who have a parent or sibling with this disease or children with a known mutation of chromosome 13q are at increased risk for developing retinoblastoma. There is no way to correct or prevent these inheritable genetic defects at present. What causes the sporadic form of retinoblastoma is not well known at this time, and there are no specific recommendations regarding ways to prevent retinoblastoma.
It is also important to monitor for other cancers in children who have the inheritable form of retinoblastoma. Defective retinoblastoma gene is known to play an important role in other types of cancer, and children who have the inheritable form of retinoblastoma are at increased risk for several other types of tumors. These tumors include osteogenic sarcoma (bone tumors), soft tissue sarcomas, and melanomas. This risk is not seen to the same degree in people with the sporadic form of the disease. Tobacco use also appears to increase the risk of secondary cancers in people with the inheritable form of retinoblastoma and should be avoided.
Unfortunately, aside from the genetic risk factors, the specific exposures or other conditions which lead to retinoblastoma are not well known. Hence, there are no good guidelines regarding how to best prevent retinoblastoma. However, for children who are known to have a family history of retinoblastoma, frequent follow up examinations may allow for early detection of the disease. If there is a family history of RB, the child should be examined by an eye doctor (ophthalmologist) soon after the child is born. These exams should continue every three to four months until the child is three to four years of age. The exams are then done every six months until the child reaches five to six years of age. Alternatively, if the child has genetic testing and it is found that they do not carry the inheritable form of RB, this intensive testing may not be needed, but this decision should be discussed with a phyician. If a child is noted to have no red reflex (as described below), they should be brought to medical attention.
Children have evaluation of their eyes during pediatric visits. During these visits, the pediatrician will check for several things, including the red reflex, the corneal light reflex, and the general function of their eyes. The red reflex is caused by light being reflected from the retina. The retina has numerous blood vessels and a reddish appearance, thus light reflected from the pupil appears red. The red reflex is the same phenomenon responsible for "red eye" seen when taking photos with a flash. In children with retinoblastoma, this reflex causes the light reflected from the pupil to appear white rather than red. This is known as leukocoria, and is seen as the first sign of retinoblastoma in about 54% of children with this disease. The red reflex exam can be performed at home by dimming the room lights and looking at the child's eyes with a flashlight. Also, if the parents notice that that the child's eyes appear to have a white reflection, they should inform their pediatrician.
The corneal light reflex is the shine that is present on the surface of the eyes when light is reflected off of them. Both eyes should reflect the light in the same place on each eye. If the light is not reflected back symmetrically from each eye, this may mean the eyes are not aligned with one another properly. This is known as strabismus, and is the first sign of retinoblastoma in about 19% of children with the disease.
The general visual acuity of the child is also evaluated by the physician. In infants older than six months, this can be done by seeing how well they track moving objects. Rarely, a decrease in vision can be a presenting sign of retinoblastoma. Other rare first signs of retinoblastoma include bleeding into the eye itself, causing the pupil to appear black rather than white, and bleeding into the front of the eye, which can cause a discoloration in the retina (the colored portion of the eye).
A fundoscopic eye exam (examination of the back of the eye, or retina) using an opthalmoscope is also done to look into the eye. The pupil needs to be dilated for a better view of the inside of the eye, and may need to be done under anesthesia because of the young age of the children examined.
If retinoblastoma is suspected, further imaging studies, such as MRI, CT, or ultrasound may be ordered. There are also genetic tests available to determine if the retinoblastoma gene is present to confirm the diagnosis. This test also determines if the child has the inheritable form or the sporadic form of the disease. If they are found to have the inheritable form, parents and siblings should be tested and be referred to a genetic counselor. Blood tests may also be ordered to check for abnormalities.
The screening tests for retinoblastoma are used to detect the signs associated with retinoblastoma, hence much of the information here is similar to that presented in "What Screening Tests are Available."
Leukocoria- when the pupil (or the center black portion of the eye) appears white as a light is shined on it in a dim room. This is due to the retinoblastoma tumor in the eye, as normally the pupils will appear red in this setting, similar to what is seen in "red eye" in photos.
Strabismus- also known as "crossed eyes". When light is shined on the child's eyes, the reflection is not in the same place on both eyes. This indicates that the eyes are not aligned properly and may be the first sign of retinoblastoma.
Decreased visual acuity- the child's vision may worsen as a result of retinoblastoma. In infants older than 6 months, this may manifest itself as the infant not tracking moving objects as well as before.
Hyphema - is when blood leaks into the front portion of the eye, and forms a layer of blood in front of the pupil, or colored portion of the eye.
Vitreous Hemorrhage - when blood leaks into the eye itself. Instead of leukocoria where the pupil appears white, the pupil will appear black.
Ocular inflammation - can present with a red, painful eye with light sensitivity and change in vision.
After initial screening tests have been completed, usually a more comprehensive exam of the eye is performed. This usually includes an opthalmalogic exam under anesthesia, ultrasound of the eye, and CT of the eye and head. There are also several factors which can be related to a worse prognosis, including a history of surgery to the eye with retinoblastoma (which may spread tumor cells), a delay in diagnosis of greater than six months, cataracts in the eye, involvement of the optic nerve, or other disease beyond the eye.
As RB grows, it can fill the globe of the eye and cause vision problems by destroying the internal structures of the eye which are important for vision, such as the retina. The tumor can then spread directly into the orbit, which houses the eye, or the optic nerve which connects the eye to the brain. It can also spread locally to the eyelid or the surface of the eye. RB can also spread to the brain and even the other eye through the cerebrospinal fluid which bathes the brain. RB can also spread through the blood to other organs such as the lung. Spontaneous regression can occur (RB disappearing on its own, with no treatment), but is a rare occurrence. It is important to determine the extent of spread to determine the best treatment for a given child as well as the prognosis. This is usually done with a staging system. There are several staging systems used in retinoblastoma, the most common of which is the Reese and Ellsworth staging system. This staging system is used to categorize children, based on the extent of the tumor, to determine which treatments may work best. There are five groups as follows:
Group I: Children in group I are excellent candidates for therapies that preserve vision. Solitary tumor fall into this category if they are smaller than 4 optic discs in size and are located in the back half of the eye. The optic disc is a part of the back of the eye which can be used as a reference to measure the size of tumors. If there are multiple tumors, none can be bigger than 4 discs in size and all must be located in the back half of the eye.
Group II: Children in group II are good candidates for therapies that preserve vision. Solitary tumors must measure between 4-10 optic discs in diameter and must be in the back half of the eye. In multiple tumors, none may be larger than 4-10 discs and the tumors must be in the back half of the eye.
Group III: Children in group III may be candidates for therapies which preserve vision. Solitary tumors greater than 10 optic discs in diameter located in the back half of the eye fall into this category. Any lesion which extends into the front half of the eye is in this category.
Group IV: Children in group IV have a poor chance of preserving vision. Multiple lesions, which some are larger than 10 optic discs in diameter, fall into this category. Any lesion which is in the very front of the eye, near the lens, fall into this category.
Group V: Children in group V have very little chance of preserving vision. Large tumors, which involve more than half of the retina (the lining of the eye), fall into this category. If the gel within the eye develops tumors, then this also qualifies as group V disease.
There is also an International Staging system which is currently being used in clinical trials and is gaining broader acceptance. A simplified version is presented below:
Group A: Small tumors: RB less than or equal to 3 mm in size
Group B: Larger tumors: Bigger than 3 mm or those which are very close to portions of the eye which are important for vision such as the macula or the optic nerve.
Group C: Focal seeds: Small focuses of tumor outside of the main mass are present, but they are close to the main mass (less than of equal to 3 mm away).
Group D; Diffuse seeds: Small focuses of tumor have spread throughout the eye (greater than 3 mm from the primary tumor).
Group E: Extensive retinoblastoma: RB involved >50% of the globe of the eye or is invading deeper into the structure of the eye or is causing glaucoma.
Another simpler classification system divides children with retinoblastoma into intraocular disease (within the eye) and extraocular disease (outside of the eye). Intraocular disease can not extend beyond the eye, and the 5-year survival without recurrence of disease is better than 90%. Extraocular disease extends beyond the eye. It may be directly adjacent to the eye, or have spread to the brain or other parts of the body. The 5-year survival without recurrence of the disease is less than 10%.
The discussion of treatment will be based on this simpler classification system, with treatments divided into those used in intraocular versus extraocular disease.
Intraocular disease can be further divided into those that involve one eye versus both eyes. Disease involving one eye tends to be bulkier, thus if other therapies are not expected to preserve useful vision, surgical removal of the eye (enucleation) is performed. Enucleation may also be performed if the eye is painful, tumor covers the optic nerve, or the eye is already blind. After enucleation, if there is felt to be a risk for spread, adjuvant (meaning postoperative) chemotherapy or radiation may be used. If the physician believes that useful vision can be preserved, there are several other treatment options available.
Vincristine and carboplatin are the most commonly used chemotherapies in retinoblastoma, and generally still require additional local treatment such as radiation or laser treatments to cure the disease.
Radiation can be delivered in several different ways. External-beam radiation uses X-ray beams similar to those used in diagnostic radiology, but these beams have a far higher energy. Generally, after treatment with radiation, recurrence of tumor is rare at 7%. There are newer techniques being used to improve the targeting of the radiation specifically to the tumor. Intensity-modulated radiation therapy (IMRT) allows the radiation oncologist to use several different beams, which can then be shaped and the intensity adjusted for precise treatment of the tumor while sparing normal tissues. Stereotactic radiation works like a magnifying glass. It focuses hundreds of small beams to one small point. That one focal point is located in the tumor and receives the full dose of radiation while normal tissues around the tumor receives only a fraction of the dose. Proton-beam radiation uses a different type of particle compared with traditional radiation therapy. Protons work at a distance; they pass through normal tissue without releasing much of their energy. When they get to a specific depth in the tissue (what this depth is depends on the energy of the protons, and can be adjusted) -- ideally matched to where the tumor is -- they release a large amount of energy into the tumor. Brachytherapy uses implantable radioactive sources. Brachytherapy uses a plaque which is made of gold, to hold radioactive seeds. The seeds are arranged to deliver an optimal dose of radiation to the tumor while sparing normal tissues around the eye. An eye surgeon then places the plaque on the outside of the eye, directly adjacent to the tumor on the inside of the eye. The child then wears a shield over the eye while being treated. After enough dose has been given, the surgeon removes the plaque.These newer techniques can limit dose to normal tissues and thus limit the risk of developing a second cancer later in life. As mentioned earlier, secondary cancers are a problem in the inheritable form, but not in the sporadic form of the disease. In the inherited form of retinoblastoma this is an important problem, as more children die from the secondary cancer than retinoblastoma. There are ongoing trials which are trying to perfect the ideal dose of chemotherapy to use with radiation in order to reduce the dose of radiation required. Recent studies have also examined the early use of chemotherapy to try to shrink the tumor, such that local treatments with fewer side effects, such as cryotherapy or photocoagulation, can be used alone. This is also known as "chemoreductive therapy." Unfortunately, during the first few years after chemoreductive therapy, recurrences are seen, although they can usually be salvaged with local therapies.
Cryotherapy works by freezing the cancer cells, which damages them permanently and causes them to die. Generally, cryotherapy is used with radiation treatment and in lesions smaller than 4 optic discs in size in the anterior portion of the eye. Photocoagulation is the use of a laser to burn tumors. It is rarely used alone in small tumors. Usually, it is used in conjunction with radiation in tumors less than 4 optic discs in size on the posterior portion of the eye. It can also be used if there is a recurrence after radiation treatment. Thermotherapy is a similar technique which uses microwaves to burn the tumor.
Generally, in smaller lesions in a single eye, vision preserving therapies should be considered in place of enucleation. In disease involving only one eye, chemoreductive therapy can be used to reduce the number of children who will ultimately need treatment with enucleation or external beam radiation and may help preserve vision. By giving chemotherapy early, the hope is to shrink the tumor to the point where local therapies can be effective. In children with group II or III disease, only 11% needed enucleation or external beam radiation within 5 years of treatment. However, in more advanced groups, this number increases to 60% in children with group IV and 100% of children with group V.
Recently it has been suggested that adding another chemotherapy agent - etoposide - may improve cure rates. However, there may be an increased risk of developing leukemias later in life, though clinical trials have not shown this after 10 years of follow up. Another experimental technique using chemotherapy involves injecting a chemotherapeutic drug - carboplatin - directly into the eye. This is also known as subtenon chemotherapy. There is a concern that by introducing a needle into the eye for treatment, that tumor cells may be able to spread beyond the eye through the needle tract.
Treatment is different when a child has retinoblastoma in both eyes. Generally if one eye has a large amount of tumor and the other eye has limited disease, the worse eye is surgically removed. If both eyes have small tumors, usually vision preserving therapies like radiation or chemotherapy can be used with close follow-up for recurrence. Some larger centers are now trying to treat children with bigger tumors in both eyes with chemoreductive therapy to shrink them to the point where they can be treated with local therapy.
The cure rate for retinoblastoma is about 93%. A child who does not develop recurrence of retinoblastoma within five years after treatment is considered cured. In other words, if recurrences do occur, they usually happen within the first year after treatment. The prognosis for children with metastatic disease is worse, with 50% survival at 12-18 months.
Rarely, children will have disease that has spread beyond the eye at time of diagnosis. Areas where retinoblastoma can spread include the brain, spine, lungs, and bone. In children with the inheritable form of the disease, a neuroblastic tumor may arise directly from the brain itself. When this occurs with tumors affecting both eyes as well, this is known as trilateral retinoblastoma. In light of this, head CT is often performed at the time of diagnosis. There is no standard treatment for retinoblastoma that has spread beyond the eye; however, there are several treatments available. These include radiation to the brain and spine, with or without chemotherapy treatments injected into the spine (intrathecal chemo). Usually, the chemotherapy used is a combination of methotrexate, cytarabine and hydrocortisone. There are also several treatments under investigation currently. High-dose chemotherapy followed by stem cell transplant is in clinical trials. Generally the chemotherapy that has been used is a combination of vincristine, cyclophosphamide, and doxorubicin. Another chemotherapy combination - carboplatin, ifosfamide, and etoposide - is also under investigation. There have also been some studies of the use of gene therapy in the treatment of retinoblastoma.
For children who have the inheritable form of retinoblastoma, follow-up is life long in order to check for the development of second malignancies. These malignancies are most often of the bone or soft tissues (sarcomas). It is thought that many of these are due to radiation treatment; however, even in children, who were not treated with radiation, there is an increased risk of secondary malignancies. This can be diagnosed significantly later in life and involve the lung, bladder, and lining of the body cavities. It is essential that children with the inheritable form not smoke, as this has been shown to increase the risk of secondary cancers. It is also critical to monitor for disease in the opposite eye in children who are only affected in one eye. Disease in the other eye occurs most commonly in the inherited form of the disease, and children with this form should have frequent repeat eye exams. Generally, if retinoblastoma is going to affect the other eye, it does so within three years of the diagnosis. An intracranial neuroblastic tumor in addition to bilateral eye tumors is known as trilateral retinoblastoma. Another name for these neuroblastic tumors is primitive neuroectodermal tumors or PNET. These tumors commonly affect the pineal gland, which is in the center of the brain. This can occur in the inheritable form of the disease. Screening MRI's are done every six months after the diagnosis of retinoblastoma until the age of five to check for PNET tumors. This condition is almost always fatal but does best when caught early. In the sporadic form of retinoblastoma the only cancer that appeared to increase in frequency is breast cancer.
After enucleation, the time for recurrence, if a recurrence occurs, is usually within 12-18 months of treatment. Hence, follow up should be especially aggressive during this period with exams every 3 months. Usually this can be decreased to every 6 months after 18 months of follow up.
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