Eric Shinohara, MD, MSCI, Updated by Dava Szalda, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 7, 2015
What is Retinoblastoma?
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. Retinoblastoma is generally limited to the eye but can spread. The majority (90%) of children who develop retinoblastoma are cured.
Retinoblastoma is an uncommon childhood cancer, 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. So, there may not be a family history, even though one of the parents is a carrier of the gene.
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 causes 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 many times 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 another cancer.
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 like bone, soft tissue or skin cancers. Hence, people who have the inheritable form of retinoblastoma should be carefully monitored for a second cancer for life.
Who is at Risk for Retinoblastoma?
This is a cancer seen more frequently in economically disadvantaged countries. Retinoblastoma 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.
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.
If a child is noted to have no red reflex (as described below), they should be brought to medical attention.
What Screening Tests are Available?
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 many children. 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 can be a presentation of retinoblastoma (though less frequently).
Retinoblastoma is a visual diagnosis. 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 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 in these family members.
What is the staging for Retinoblastoma?
The International Grouping System:
Group A: Small tumors: RB less than or equal to 3 mm in size
Group B: Larger tumors: Bigger than 3 mm, but confined to the retina
Group C: Focal seeds: Small focuses of tumor outside of the main mass are present and there can be a small amount of retinal detachment.
Group D: Diffuse seeds: Focuses of tumor have spread throughout the eye
Group E: Extensive retinoblastoma: RB involving >50% of the globe of the eye, invading deeper into the structure of the eye, or is causing glaucoma.
It is also important to know whether the retinoblastoma is unilateral (affecting one eye) or bilateral (affecting two eyes). Treatment is typically based on the tumor that has the higher “group” classification.
In order to see if the retinoblastoma has spread, the physician will order blood counts and imaging of the brain. Abnormal blood counts could indicate the retinoblastoma has spread. A brain MRI checks for another brain tumor which is associated with retinoblastoma (called a pineoblastoma). When this is present at diagnosis it is sometimes called trilateral disease. Pineoblastomas have a poor prognosis. Luckily, there is a decreased incidence of pineoblastoma since chemoreduction of tumors has been used.
What are the Treatments for Retinoblastoma?
The goals of retinoblastoma treatment are first to save the child’s life, and second to preserve as much vision as possible. Children with less involved tumors (Group A and B) are great candidates for therapies that treat the tumor and preserve vision, where children with more extensive tumors may not have their vision maintained, or in some cases, even have to have their eye surgically removed.
Chemotherapies used for retinoblastoma include carboplatin, etoposide and vincristine. These medications are given by IV (intravenous), with the exact doses varying based on the group of the tumor. Long-term effects of this chemotherapy have been studied and there is a small risk of hearing loss as a result of the treatment. There is also a possible, but not likely, issue with fertility or development of secondary cancers due to this chemotherapy.
Some groups also use chemotherapy that is given in the blood vessels that directly supply the eye (called intra-arterial chemotherapy). This is a newer technique, so less research is available to know the long term effects of this treatment.
Cryotherapy, photocoagulation and radiation are other treatments that have been used. Cryotherapy works by freezing the cancer cells, which damages them permanently and causes them to die. Photocoagulation is the use of a laser to burn tumors. Thermotherapy is a similar technique, which uses microwaves to burn the tumor. Radiation used to be used frequently for retinoblastoma, but has fallen out of favor because of the long-term effects of giving radiation to the eye and brain in young children.
The cure rate for retinoblastoma is over 90%, though the exact cure rate will depend on the extent of disease. A child who does not develop recurrence of retinoblastoma within five years after treatment is considered cured.
For children who have the inheritable form of retinoblastoma, follow-up is life long in order to check for the development of second cancers. These cancers are most often of the bone or soft tissues (sarcomas). It is essential that children with the inheritable form not smoke, as this has been shown to increase the risk of another cancer developing. 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 eye exams. Generally, if retinoblastoma is going to affect the other eye, it does so within three years of the diagnosis. Screening MRI's are done every six months after the diagnosis of retinoblastoma, until the age of five.
References & Further Reading
Retinoblastoma – the American Cancer Society
Retinoblastoma – St. Jude Children’s Research Hospital
Retinoblastoma – The Eye Cancer Network (includes a picture of the white pupil "leukocoria")
Abramson DH, Beaverson K, Sangani P, et al. "Screening for retinoblastoma: presenting signs as prognosticators of patients and ocular survival. Pediatrics 2003; 112:1248
Dryja, TP, Morrow, JF, Rapaport, JM. Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene. Human Genetics 1997; 100:446.
Eng, C, Li, FP, Abramson, DH, Ellsworth, RM, et al. Mortality from second tumors among long-term survivors of retinoblastoma. Journal of the National Cancer Institute 1993; 85:1121.
Kremens, B, Wieland, R, Reinhard, H, et al. High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 2003; 31:281.
Lawson B, Saktanasate J, Say EA, Shields CL. Intravitreal chemotherapy provides control for massive vitreous seeding from retinoblastoma. J Pediatr Ophthalmol Strabismus. 2014 Dec 12:51.
Namouni, F, Doz, F, Tanguy, ML, et al. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. European Journal of Cancer 1997; 33:2368.
National Cancer Institute. Retinoblastoma (PDQ): Treatment. www.cancer.gov
Rubenfeld, M, Abramson, DH, Ellsworth, RM, Kitchin, FD. Unilateral vs. bilateral retinoblastoma. Correlations between age at diagnosis and stage of ocular disease. Ophthalmology 1986; 93:1016.
Shields, CL, Meadows, AT, Shields, JA, Carvalho, C. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Archives of Ophthalmolology 2001; 119:1269.
Tamboli, A, Podgor, MJ, Horm, JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Achieves of Ophthalmology 1990; 108:128.
Turaka K, Shields C, Meadows A, Leahey A. Second malignant neoplasms following chemoreduction with carboplatin, etoposide and vincristine in 245 patients with intraocular retinoblastoma. Pediar Blood Cancer. 2012 Jul 15;59(1):121-5.
Wong, FL, Boice, JD, Abramson, DH, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. Journal of the American Medical Association 1997; 278:1262.
Zantay M, Barros G, Chalouhi N, Starke RM, Manasseh P, Tjoumakaris S, Shields CL, Hasan D, Bulsara K, Rosenwasser RH, Jabbour P. Update on intra-arterial chemotherapy for retinoblastoma. ScientificWorldJournal. 2014.