What is retinoblastoma?
Retinoblastoma is a rare cancer of the retina. The retina is the innermost layer of the eye, located at the back of the eye that receives light and images necessary for vision.
About 250 children in the United States are diagnosed with this type of cancer each year. It mostly occurs in children under the age of 5; the highest incidence of the disease occurs between infancy and age 2.
Both males and females are affected equally. Retinoblastoma can occur in either eye; however, in about 25 to 30 percent of the cases, the tumor is present in both eyes. Retinoblastoma cells can, in rare cases, spread (metastasize) to other areas of the body, including the bone marrow.
What causes retinoblastoma?
Retinoblastoma occurs due to mutations in a tumor suppressor gene (called RB1) located on chromosome #13. Two mutations (or gene changes) are necessary to "knock-out" this gene, and cause uncontrolled cell growth. In inherited retinoblastoma (40 percent of the cases), the first mutation is inherited from a parent, while the second occurs during the development of the retina. In sporadic retinoblastoma (60 percent of the cases), both mutations occur during development of the retina. Sporadic means "occurs by chance."
Most children with inherited retinoblastoma generally have tumors involving both eyes. (In fact, all cases involving both eyes should be considered hereditary). The RB1 gene is an autosomal dominant gene, which means that both males and females are equally affected, and there is a 50/50 chance, with each pregnancy, for a parent to transmit the gene to a child. When a child inherits the gene, there is about a 90 percent chance for the second mutation to occur, resulting in retinoblastoma. This means that some children who inherit the mutation may never get the second mutation, and may, therefore, never develop retinoblastoma. (They can still transmit the gene to their offspring, however, so that their children could develop the disease.)
Consider the following statistics:
- 70 to 75 percent of retinoblastoma cases involve one eye (unilateral). Of these, 15 to 20 percent are inherited, and the remainder cases are sporadic.
- 25 percent of retinoblastoma cases are bilateral (both eyes) and hereditary.
- 15 percent of retinoblastoma cases are unilateral (one eye) and hereditary.
Any individual with a positive family history of retinoblastoma may want to seek genetic counseling to identify the specific risks of passing the gene or disease to their children.
What are the symptoms of retinoblastoma?
The following are the most common symptoms of retinoblastoma. However, each child may experience symptoms differently. Symptoms may include:
- leukocoria - a white light reflex that occurs at certain angles when light is shown into the pupil.
- strabismus (Also called wandering eye or crossed-eyes.) - a misalignment of the eyes; when one or both eyes do not appear to be looking in the same direction.
- pain or redness around the eye(s)
- poor vision or change in child's vision
Often the symptoms may not appear if the disease is diagnosed early. The symptoms of retinoblastoma may resemble other conditions or medical problems. Always consult your child's physician for a diagnosis.
How is retinoblastoma diagnosed?
In addition to a complete medical and physical examination, diagnostic procedures for retinoblastoma may include:
- complete eye examination
- funduscopic examination - with the child under anesthesia, the pupils are dilated so the entire retina can be viewed and examined.
- computerized tomography scan (Also called a CT or CAT scan.) - a diagnostic imaging procedure that uses a combination of x-rays and computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general x-rays.
- magnetic resonance imaging (MRI) - a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.
- blood tests
- tests of the fluid surrounding the tumor
- genetic and/or DNA testing
A diagnosis may be made before symptoms are present. If a family history is positive for retinoblastoma, frequent eye examinations may be necessary at many stages of the child's development to determine the presence of any tumor.
When retinoblastoma is diagnosed, tests will be performed to determine the size, number, location of the tumors, and if the tumors have spread to the other parts of the body. This is called staging and is an important step toward planning a treatment program.
What are the stages of retinoblastoma?
There are various staging systems that can be used for retinoblastoma. Always consult your child's physician for more information on staging. One method of staging is the Reese-Ellsworth stages of retinoblastoma:
- Group I - either one or more tumors that are less than 4 disc diameters (DD) in size and located at or behind the equator.*
- Group II - either one or more tumors that are 4 to 10 DD in size located at or behind the equator.
- Group III - any lesion in front of the equator or any tumor(s) larger than 10 DD.
- Group IV - multiple tumors with some or all greater than 10 DD in size or any lesions that extend beyond the back of the eye.
- Group V - very large tumors involving more than half of the retina and have spread to other sites in the body.
*The "equator" is an imaginary line that divides the eye into two equal parts.
What are the treatments for retinoblastoma?
Specific treatment for retinoblastoma will be determined by your child's physician based on:
- your child's age, health and medical history
- extent of the disease
- your child's tolerance for specific medications, procedures, or therapies
- how your child's physician expects the disease to progress
- your opinion or preference
The primary goal of treatment is to remove the tumor and prevent metastasis (spreading) of the cancer to other parts of the body.
Treatment may include one or more of the following:
- enucleation (removal of part or all of the eye or eyes involved with the tumor)
- chemotherapy - a drug treatment that works by interfering with the cancer cell's ability to grow or reproduce. Different groups of drugs work in different ways to fight cancer cells and shrink tumors. Chemotherapy may be used alone for some types of cancer or in conjunction with other therapy such as radiation or surgery. Often, a combination of chemotherapy drugs is used to fight a specific cancer. Certain chemotherapy drugs may be given in a specific order depending on the type of cancer it is being used to treat. While chemotherapy can be quite effective in treating certain cancers, the agents do not differentiate normal healthy cells from cancer cells. Because of this, there can be many adverse side effects during treatment. Being able to anticipate these side effects can help the care team, parents, and child prepare, and, in some cases, prevent these symptoms from occurring, if possible. Chemotherapy is systemic treatment, meaning it is introduced to the bloodstream and travels throughout the body to kill cancer cells. Chemotherapy can be given:
- as a pill to swallow
- as an injection into the muscle or fat tissue
- intravenously (directly to the bloodstream; also called IV)
- intrathecally - chemotherapy given directly into the spinal column with a needle
- radiation therapy - using high-energy rays (radiation) from a specialized machine to damage or kill cancer cells and shrink tumors
- stem cell transplant - a treatment involving stem cells, a specific type of cell from which all blood cells develop. Stem cells develop into red blood cells to carry oxygen, white blood cells to fight disease and infection, and platelets to aid in blood clotting. Transplantation of normal stem cells from another person is used to help restore normal blood production in patients whose own ability to make any or all of these blood cells has been compromised by cancer, intensive cancer treatment, or other types of damage or abnormality. The use of cells from another individual is called allogeneic transplantation. Stem cells collected form patients themselves prior to intensive treatment can also be used to supplement the recovery of the patient's own cells after particularly aggressive course of chemotherapy or radiation therapy. The use of a patient's own cells is referred to as autologous transplantation.
Stem cell transplantation and the treatment needed to manage its effects are complex. Your physician will give you more detailed information on what to expect.
- laser therapy or photocoagulation
- cryotherapy - uses a freezing process to destroy the tumor
- fitting and training for a prosthesis
- blind or decreased vision adaptation training
- supportive care - any type of treatment to prevent and treat infections, side effects of treatments, and complications, and to keep your child comfortable during treatment
What is the long-term outlook for patients with retinoblastoma?
Prognosis greatly depends on the following:
- the extent of the disease.
- the size and location of the tumor.
- presence or absence of metastasis.
- the tumor's response to therapy.
- the age and overall health of your child.
- your child's tolerance of specific medications, procedures, or therapies.
- new developments in treatment.
As with any cancer, prognosis and long-term survival can vary greatly from child to child. Every child is unique and treatment and prognosis is structured around the child's needs. Prompt medical attention and aggressive therapy are important for the best prognosis.
Continuous follow-up care is essential for a child diagnosed with retinoblastoma. Secondary cancers have a high incidence among survivors of retinoblastoma. These secondary cancers are not a relapse or recurrent retinoblastoma, but are primary tumors (brand new tumors) of other organs. The most common secondary cancer is osteosarcoma (cancer of the bone). However, retinoblastoma has been linked to melanoma, breast, lung, bladder, and other types of cancers much later in life. The cause of the secondary cancers is not known at this time.
What is the latest research on retinoblastoma?
Dana-Farber/Boston Children's Cancer and Blood Disorders Center is conducting numerous research studies that will help clinicians better understand and treat retinoblastoma.
In addition, the Dana-Farber/Boston Children's Transplant Program is one of only eight institutions around the country that are investigating the use of umbilical cord transplantation. Also under study is a novel method for preventing graft versus host disease, a serious complication that occurs when transplanted cells do not recognize the tissues and organs of the recipient's body and react against the recipient's tissue. The result of this treatment approach, if it continues to be as successful, will be that the degree of match between donor and the recipient will not need to be particularly close, greatly increasing the pool of potential donors for each patient. This could also eliminate the need for long-term drug therapy traditionally needed to treat graft versus host disease.
Other types of treatment currently being studied include:
- angiogenesis inhibitors - substances that may be able to prevent the growth of tumors by blocking the formation of new blood vessels that feed the tumors
- biological therapies - a wide range of substances that may be able to involve the body's own immune system to fight cancer or lessen harmful side effects of some treatments
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 4 per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis.
Hereditary and Nonhereditary Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Hereditary disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may be known in those patients with a positive family history (25%) or may have occurred in utero at the time of conception, in those patients with sporadic disease (75%). Hereditary retinoblastoma may manifest as unilateral or bilateral disease. Most patients with unilateral diseases do not have the hereditary form of the disease, whereas all children with bilateral diseases are presumed to have the hereditary form of the disease, even though only 20% have an affected parent. In hereditary retinoblastoma, tumors tend to occur at a younger age than in the nonhereditary form of the disease. Unilateral retinoblastoma in children younger than 1 year should raise concern for the hereditary disease, whereas older children with a unilateral tumor are more likely to have the nonhereditary form of the disease.
Children with the hereditary form of retinoblastoma may continue to develop new tumors for a few years after diagnosis. For this reason, children with hereditary retinoblastoma who have a normal examination in at least one eye on initial presentation need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months. Following treatment, patients require careful surveillance until age 5 years. The interval between exams is based on both the age of the child (more frequent visits as the child ages) and the stability of the disease.
The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.
Blood and/or tumor samples can be screened to determine if a retinoblastoma patient has a mutation in the RB1 gene. Commercial laboratories are now available to perform this service. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1gene demonstrates germline mutation in 90% of patients with hereditary retinoblastoma.Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. The multistep assay includes DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. This expanded analysis is showing promise in better defining the functional significance of apparently novel mutations in pilot investigations performed at the University of Pennsylvania. Such testing should be performed only at institutions with expertise in RB1 gene mutation analysis. In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification (MLPA), and fluorescence in situ hybridization (FISH) may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.
Genetic counseling should be an integral part of the therapy for a patient with retinoblastoma, whether unilateral or bilateral. It is of utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate risk of disease in family members. Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism, making the genetic story more complex and contributing to the difficulty of genetic counseling.
Factors Influencing Mortality
The present challenge for those who treat retinoblastoma is to prevent loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and second malignant neoplasms, have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (hereditary) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with hereditary retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma. Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis. While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging (MRI) for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for 5 years. It is unclear if this will have an impact on outcome or survival. Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Second malignant neoplasms
Patients with hereditary retinoblastoma have a markedly increased frequency of second malignant neoplasms (SMN). The cumulative incidence was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year. However, more recent studies have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. Most of the SMN are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma.
A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two U.S. institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histologic subtype. Leiomyosarcoma was the most frequent subtype, with 78% being diagnosed 30 or more years after the retinoblastoma diagnosis. Risks were elevated in patients treated with or without radiation therapy, and, in those treated with radiation therapy, sarcomas were seen both within and outside the field of radiation. The carcinogenic effect of radiation increased with dose, particularly for secondary sarcomas where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of the second cancers occur within irradiated tissue and one-third occur outside the radiation field. The risk for SMN is heavily dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic type of SMN may be influenced by age. These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma.
It has become apparent that patients with hereditary retinoblastoma are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.
Survival from second malignancies is certainly suboptimal and varies widely across studies. However, with advances in therapy, it is essential that all second malignancies be treated with curative intent. Those who survive SMN are at a 7-fold increased risk for developing a subsequent malignancy. The risk further increases 3-fold when patients are treated with radiation therapy for their retinoblastoma. There is no clear increase in second malignancies in patients with sporadic retinoblastoma beyond that associated with the treatment.
Late Effects from Retinoblastoma Therapy
Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method. One study of visual acuity following treatment with systemic chemotherapy and focal ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.
Since systemic carboplatin is now commonly used in the treatment of retinoblastoma, concern has been raised about hearing loss related to therapy. However, an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram.