Retinoblastoma

Disease Overview

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinoblastoma is most commonly diagnosed in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so-called “cat’s eye reflex” (leukocoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball that prevents the normal drainage of fluid from the eye and potentially causes characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Retinoblastomas occur in two forms – heritable and non-heritable. Bilateral forms are heritable and usually diagnosed at a younger age. In most affected children, retinoblastoma is non-heritable; it occurs spontaneously for no apparent reason.

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Signs & Symptoms

In approximately 60 percent of children, the presenting sign of retinoblastoma is leukocoria. Initially, leukocoria may only be detectable at certain angles or under certain light conditions. Leukocoria is often seen on flash photography. Leukocoria can be caused by conditions other than retinoblastoma. The detection of leukocoria warrants an immediate evaluation by an eye specialist (ophthalmologist).

Another common initial sign of a retinoblastoma is misalignment of the eyes in which they often appear crossed (strabismus). Strabismus may develop before or at the same time as leukocoria. Other signs are a red, inflamed eye(s) or repetitive, uncontrolled movements of the eyes (nystagmus). Less often, symptoms may include differences in pupil size (anisocoria), differences in pupil color (heterochromia), enlargement of the eyeball (buphthalmos), protrusion or ‘bulging’ of the eyeball (exophthalmos), decreased vision, inflammation of the soft tissues of the eye socket (orbital cellulitis), or ocular inflammation (uveitis), an inflammation of the middle layer of the eye called the uvea.

Some infants may have vitreous hemorrhage, which is a leakage of blood near the vitreous of the eye. The vitreous is a clear, jelly-like fluid that fills the middle of the eye. Vitreous hemorrhage can cause vision loss. Some affected children may exhibit pooling or accumulation of blood in the space between the cornea and the iris of the eyes. This is called hyphema and the blood can cover most or all of the iris and the pupil, partially or completely blocking an infant’s vision. Hyphema is painful. Additional symptoms include clouding of the lenses of the eyes (cataract) or elevated fluid pressure within the eye preventing the normal outflow of fluid from the eye and potentially causing damage to the optic nerve (glaucoma). Pain in the eye can also occur, especially when glaucoma is present.

In two-thirds of children, only one eye is affected (unilateral). When both eyes are affected, the tumors usually develop simultaneously. In some instances, children with a tumor in one eye will develop a tumor in the unaffected eye later in life. In most children, retinoblastoma only affects the eye and does not spread to surrounding tissue. However, if a retinoblastoma is not detected early, the tumor may spread to affect the tissue surrounding the eye or other parts of the body such as the central nervous system, lymph nodes, skeleton, or lung. This is known as extraocular or metastatic retinoblastoma. Signs and symptoms of metastatic disease include unintended weight loss, vomiting, headaches, and neurological impairment.

Some infants and children develop retinoblastoma in the brain as well as the eye. The most common additional tumor, a pinealoblastoma, may form in the pineal gland. This condition is called trilateral retinoblastoma. Trilateral retinoblastoma develops in less than 5% of individuals with bilateral or heritable retinoblastoma. It is even rarer in unilateral or non-heritable retinoblastoma.

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Causes

Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes, 23 of which are inherited from the mother and 23 of which are inherited from the father. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 13q14.1-q41.2” refers to bands 14.1-14.2 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The retinoblastoma gene RB1 is located on the long arm (q) of chromosome 13 (13q14.1-q14.2).

A retinoblastoma forms when both copies of the RB1 gene are affected by a gene alteration (mutation). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. There are two kinds of genes that can cause cancer: those that cause cancer by their presence (oncogenes), and those that cause cancer by their absence (tumor suppressor genes). Both types are altered or incomplete versions of ordinary genes that normally regulate cell growth. The oncogenes tend to be dominant and cause out-of-control growth (cancer) when either one of the paired copies (alleles) is defective. Tumor suppressor genes like the RB1 gene normally limit or stop the growth of cells. They are recessive genes because both alleles have to be defective to cause disease. When the tumor suppressor genes are mutated, cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing.

Inheriting an alteration in one copy of the RB1 gene is not enough to cause a retinoblastoma to form. Cancer development in children with retinoblastoma is believed to follow the “two-hit” hypothesis first described by the Nobel laureate Dr. Albert Knudsen. This hypothesis states that a second hit that damages the remaining normal copy of the RB1 gene is required for cancer development. The second hit occurs in a retinal precursor cell at any point after conception (somatically). Researchers do not know what causes this second hit but it almost always occurs since most children who have a heritable mutation develop retinoblastoma. Geneticists would describe this as a genetically recessive, dominantly inherited disease with high penetrance. Dr. Knudsen’s concept of retinoblastoma contributed to the understanding of the cause all cancers.

Approximately 60 percent of cases of retinoblastoma are non-heritable and 40 percent are heritable. All of the non-heritable cases affect only one eye (unilateral). Of the 40 percent of cases that are heritable, approximately 85 percent of patients will develop multiple tumors affecting both eyes (bilateral). The remaining 15 percent of heritable cases affect only one eye. Some individuals with retinoblastoma, especially those with tumors affecting both eyes, may be at a greater risk than the general population of developing other types of cancer such as osteogenic sarcoma (a form of bone cancer) later in life. Genetic testing can identify whether a patient has non-heritable or heritable retinoblastoma and is critical for counseling families especially if they plan to have more children.

Most instances of retinoblastoma are caused by sequential mutations in both RB1 genes. Non-heritable cases of retinoblastoma are the result of somatic mutations that occur after fertilization and are not passed down from the parents. These types of mutations occur randomly for no apparent reason. A mutation occurs in one of the two RB1 genes. A second event occurs either by a mutation in the second gene or by loss of the second gene. This loss, termed “loss of heterozygosity”, leads to unchecked cellular growth and the formation of a tumor in one eye (unilateral). In about 25 percent of heritable retinoblastoma cases, the first mutation in the RB1 gene is passed down from one parent. These patients may have a family history of the disease but sometimes, a parent will be a carrier of the altered RB1 gene but not have any symptoms (asymptomatic). The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the other 75% of instances of heritable retinoblastoma, the first RB1 mutation occurs as a random (spontaneous) genetic change in a germ line cell. In these instances, a retinoblastoma is not inherited and the risk of another child in the same family developing the tumor is extremely low. The affected individual, however, can potentially pass along the altered gene.

In extremely rare instances, children develop a retinoblastoma because they are missing genetic material (known as a deletion or monosomy) on the long arm of chromosome 13. The missing genetic material includes the RB1 gene as well as several other nearby genes. Consequently, additional symptoms are present. These children are classified as having partial monosomy 13q. (For more information on this disorder, choose “partial monosomy 13q” as your search term in the NORD Rare Disease Database.)

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Affected populations

Although retinoblastoma is a rare disorder, it is the most common cancer of the eye in children, accounting for about 3% of all childhood malignancies. Retinoblastoma affects males slightly more often than females. The incidence in the United States and Europe is estimated to be 2-5 children per 1,000,000 people in the general population. The age-adjusted annual incidence for children aged 0-4 in the United States is 10-14 children per 1,000,000. This equates to about 1 in 14,000-18,000 live births. Incidence is the number of newly diagnosed people with a disorder identified in a given year. Two-thirds of children are affected before the age of 2 and more than 90% of retinoblastomas become apparent before the age of five years.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of retinoblastoma. Comparisons may be useful for a differential diagnosis:

Ocular toxocariasis is an infectious disease caused by the parasite Toxocara, a worm of dogs and cats. Infection occurs when there is purposeful or incidental ingestion of soil from hand to mouth through such activities as biting fingernails or inserting recently contaminated objects such as toys into the mouth. Consequently, the disorder is found disproportionately among children. Once ingested, the eggs hatch into larvae and burrow into body tissue of all types. When the larvae affect the eye, the disorder is known as ocular toxocariasis. Symptoms may include a brief redness of the sclera (white of the eye) without pain, a “whitish” appearance of the pupil, visual acuity changes, or blindness of one eye. (For more information on this disorder, choose “Toxocariasis” as your search term in the NORD Rare Disease Database.)

Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all cases of Coats disease, only one eye is affected. Rarely, both eyes may exhibit symptoms however one eye is often affected more than the other. The specific cause of Coats disease is not known. (For more information on this disorder, choose “Coats” as your search terms in the NORD Rare Disease Database.)

Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms include abnormally small eyes (microphthalmia), cataracts, and/or the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria) that causes the pupil to appear white when light reflects off it.

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information, choose “retinopathy of prematurity” as your search term in the NORD Rare Disease Database.)

Primary retinal dysplasia is a rare inherited condition characterized by an elevated retinal fold arising from the optic disc covering the macular area inside the eye, and widening toward the temporal fundus, which may cause blindness. This condition is thought to be inherited as an X-linked trait.

There are a variety of tumors that can affect the eye that should be included in a differential diagnosis. These tumors may include retinal astrocytoma, glioneuroma, and retinal hamartoma. (For more information on these disorders, choose the specific tumor name as your search term in the NORD Rare Disease Database.)

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Diagnosis

The diagnosis of retinoblastoma is made based upon a thorough clinical evaluation, detailed patient history, the identification of characteristic symptoms, and a variety of specialized tests. The presenting symptom is usually leukocoria. A complete examination of the interior of the eye (fundoscopic examination under anesthesia – EUA) may be performed to locate the presence of a tumor or tumors. Magnetic resonance imaging (MRIs) may be used to determine the extent of the tumor(s) and determine if the tumor has spread to surrounding structures or tissue. Ultrasonography may be used to rule out other conditions. Computed tomography (CT) scans are generally avoided because of the potential risk of additional radiation-induced tumors if the child has hereditary retinoblastoma.

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Standard Therapies

Treatment

The treatment of retinoblastoma is directed first toward preserving life and then preserving vision in the affected eye(s). Treatment is highly personalized, which means one affected individual may receive significantly different treatment than another individual.

Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians, surgeons, specialists who assess and treat eye problems (ophthalmologists or pediatric ophthalmologists), specialists who assess and treat cancer (oncologists or pediatric oncologists), specialists in the use of ionizing radiation to treat cancer (radiation oncologists), clinical social workers and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit for affected individuals and their families with inherited forms of retinoblastoma. Psychosocial support is essential for the entire family as well.

Specific treatment methods depend upon several factors including the size of the tumor(s), the exact location of the tumor(s), whether one or both eyes are affected, the extent of the primary tumor (stage), the degree of malignancy (grade), whether the tumor has spread (metastasized), an individual’s age and general health, and the associated likelihood of retaining adequate vision. Decisions concerning the appropriate therapeutic interventions to use should be made by physicians and other members of the healthcare team in careful consultation with the patient’s family, and based upon the specifics of his or her case with a thorough discussion of the potential benefits and risks, patient preference, and other appropriate factors.

Several different therapeutic methods are available to treat retinoblastoma including local and systemic chemotherapy, cryotherapy, laser photoablation, thermotherapy, radiotherapy, and surgical removal of the affected eye (enucleation). During the last few decades, the rate of enucleation as a treatment for retinoblastoma has dropped considerably and is usually reserved for individuals with disease that recurs after treatment or is resistant to treatment and who have no useful vision left in the affected eye. Doctors also try to limit systemic exposure to chemotherapy drugs and avoid using radiotherapy because of the increased risk of developing a second cancer later in life.

Individuals with smaller tumors may be treated with less invasive methods directed at preserving the vision of the affected eye. These methods include local chemotherapy, a procedure that uses extreme cold to destroy tissue and cancer cells (cryotherapy), a procedure that uses intense, focused light (e.g., laser therapy) to heat and destroy tissue and cancer cells (photocoagulation), the use of a different type of laser to heat and kill tumor cells (thermotherapy), or procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy or external beam radiotherapy.

Local chemotherapy can include injecting anti-cancer medications directly into the vitreous (intravitreal) or into the arteries (intra-arterial) of the eyes and is often used in conjunction with treatments such as cryotherapy, thermotherapy, and photocoagulation. Common chemotherapy medications for retinoblastoma include melphalan, carboplatin, etoposide, vincristine, and topotecan. Local chemotherapy is usually used when retinoblastoma affects one eye (unilateral) and sometimes when retinoblastomas affect both eyes (bilateral).

Brachytherapy is also known as internal radiation therapy or radioactive plaque therapy. During brachytherapy, radioactive material (implant) is placed within the eye socket usually near the base of a tumor. The implant is left there for several days. This procedure is used only for individuals with small tumors.

With external beam radiotherapy, laser beams are directed by a machine to the retina to destroy cancer cells. This form of radiotherapy can also be used to treat disease that has spread outside of the eye (extraocular disease) but is still within the eye socket, central nervous system involvement, and/or cancer that has spread to other sites in the body (metastatic disease). External beam radiotherapy can affect nearby healthy tissue and may increase the risk of developing a second cancer later during life. External beam radiotherapy is rarely used and is generally reserved for people who have failed to respond to other treatment options.

For individuals in whom only one eye is affected and when the prospects of retaining adequate vision are unlikely, enucleation of the affected eye may be performed. This is curative for about 90% of children who undergo this procedure.

Individuals with multiple or large tumors may be treated by a combination of certain anticancer drugs (chemotherapy) or surgical removal of the affected eye (enucleation) and part of the optic nerve. Sometimes, chemotherapy drugs are given to shrink the size of the retinoblastoma (chemoreduction) before the tumor is treated surgically or with radiotherapy.

In most children in whom both eyes are affected, the more severely affected eye is treated with enucleation. The remaining eye is treated with cryotherapy, radiation therapy, or photocoagulation to preserve vision.

Children who present with extraocular disease such as those with metastatic disease or trilateral retinoblastoma may be treated with systemic chemotherapy in combination with external beam radiotherapy. Systemic chemotherapy is the use of anti-cancer mediations that are delivered through the mouth or directly injected into the vein. For individuals with central nervous system involvement, chemotherapy may be delivered directly into the fluid surrounding the brain and spinal cord (intrathecally). These medications travel throughout the body.

Late Effects of Retinoblastoma Therapy
Late effects of cancer therapy refer to the risk that survivors of childhood cancer may develop problems years later in life as a consequence of treatment during childhood. Children treated with radiotherapy for retinoblastoma have a risk of developing a second, different cancer later in life. The most common cancer developed is osteogenic sarcoma (a form of bone cancer). Decreased clarity of vision (visual acuity) may develop in children treated with systemic chemotherapy or local ophthalmologic therapy. Hearing loss has been reported in some children treated with systemic carboplatin.

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Clinical Trials and Studies

Researchers are studying the use of a form of gene therapy known as suicide gene therapy as a treatment for retinoblastoma. In traditional gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. In suicide gene therapy, stimulation or introduction of ‘suicide’ genes into cancer cells are used as a method of making the cancer cells more vulnerable to chemotherapy. More studies are needed to determine the long-term safety and effectiveness of this treatment.

Researchers are studying systemic chemotherapy with autologous hematopoietic stem cell rescue for children with severe forms of retinoblastoma including those who have cancer that has spread to other areas of the body (metastatic disease) or trilateral retinoblastoma. Affected children undergo high-doses of chemotherapy followed by an autologous stem cell transplant. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, platelets). In autologous stem cell transplantation, an affected individual’s stem cells are removed after prior treatment. These healthy stem cells are later re-infused into the bone marrow to restore the child’s immune system that was damaged by the intense chemotherapy. More research is necessary to determine the long-term safety and effectiveness of this therapy for children with advanced forms of retinoblastoma.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, etc.)

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References

JOURNAL ARTICLES
Stark AE. Determining the incidence of the hereditary form of retinoblastoma. Ann Transl Med. 2016;4:171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876282/

Temming P, Arendt M, Viehmann A, et al. Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: a report from the German reference center. Pediatr Blood Cancer. 2016;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/27567086

Racher H, Soliman S, Argiropoulos B, et al. Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma. Cancer Genet. 2016;209:359-363. https://www.ncbi.nlm.nih.gov/pubmed/27318443

Abramson DH, Shields CL, Munier FL, Chantada GL. Treatment of retinoblastoma in 2015: agreement and disagreement. JAMA Ophthalmol. 2015;133:1341-1347. https://www.ncbi.nlm.nih.gov/pubmed/26378747

Rodriguez-Galindo C, Orbach DB, VanderVeen D. Retinoblastoma. Pediatr Clin North Am. 2015;62:201-223. https://www.ncbi.nlm.nih.gov/pubmed/25435120

Rushlow DE, Mol BM, Kennett JY, et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14:327-334. https://www.ncbi.nlm.nih.gov/pubmed/23498719

Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379:1436-1446. https://www.ncbi.nlm.nih.gov/pubmed/22414599

Dimaras H, Heon E, Doyle J, et al. Multifaceted chemotherapy for trilateral retinoblastoma. Arch Ophthalmol. 2011;129:362-365. https://www.ncbi.nlm.nih.gov/pubmed/21402997

Chévez-Barrios P, Chintagumpala M, Mieler W, et al. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol 2005, 23: 7927-7935. https://www.ncbi.nlm.nih.gov/pubmed/16258092

Idlefonso CJ, Kong L, Leen A, et al. Absence of systemic immune response to adenovectors after intraocular administration to children with retinoblastoma. Mol Ther. 2010;18:1885-1890. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951557/

Dunkel IJ, Chan HS, Jubran R, et al. High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer. 2010;55:149-152. https://www.ncbi.nlm.nih.gov/pubmed/20486181

Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE, Hurwitz R. Retinoblastoma: review of current management. Oncologist. 2007;12:1237-1246. https://www.ncbi.nlm.nih.gov/pubmed/17962617

Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, et al. Orphanet J Rare Dis. 2006;1:31. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-31

Balmer A, Zografos L, Munier F. Diagnosis and current management of retinoblastoma. Oncogene. 2006;25:5341-5439. https://www.ncbi.nlm.nih.gov/pubmed/16936756

Shields CL, Meadows AT, Leahey AM, Shields JA. Continuing challenges in the management of retinoblastoma with chemotherapy. Retina. 2004;24:849-862. https://www.ncbi.nlm.nih.gov/pubmed/15579981

Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971, 68:820-823. https://www.ncbi.nlm.nih.gov/pubmed/5279523

FROM THE INTERNET
Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2015 Nov. 19]. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1452/

Brisse H, Desjardins L, Doz F, et al. Retinoblastoma. Orphanet Encyclopedia, May 2014. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=790 Accessed: October 28, 2016.

Retinoblastoma Treatment (PDQ®) – Health Professional Version. National Cancer Institute. Sep. 19, 2016. Available: https://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq Accessed: October 28, 2016.

Kaufman PL, Kim J, Berry JL. Clinical presentation, evaluation, and diagnosis. UpToDate, Inc. 2016 Jul 11. Available at: https://www.uptodate.com/contents/retinoblastoma-clinical-presentation-evaluation-and-diagnosis Accessed: October 20, 2016.

Kaufman PL, Kim J, Berry JL. Retinoblastoma: Treatment and outcome. UpToDate, Inc. 2016 Aug 30. Available at: https://www.uptodate.com/contents/retinoblastoma-treatment-and-outcome Accessed: October 20, 2016.

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