Retinoblastoma overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Simrat Sarai, M.D. [3]
Overview
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Retinoblastoma Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Retinoblastoma overview On the Web |
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American Roentgen Ray Society Images of Retinoblastoma overview |
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Risk calculators and risk factors for Retinoblastoma overview |
Retinoblastoma is the abnormal overgrowth of the retina, the most inner layer of the eye. RB1 gene mutation is the common cause of this malignancy. This tumor affects mostly young children and may result in loss of the vision. Retinoblastoma was first described in 1809 by Dr. James Wardrop. Then, Dr. Flexner, in 1891, was the first to discover the rosette structure within the tumor. In 1953, Dr. Kupfer was the first ophthalmologist who tried a combination of chemotherapy and radiotherapy for the treatment of the tumor. There are several classification system available for retinoblastoma. As the treatment of the tumor has evolved, a new classification system has been introduced. For intraocular diseases the available grouping systems include the International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB) and cTNMH systems. For extraocular diseases, the International Retinoblastoma Staging System (IRSS) and cTNMH schemes can be used. Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene, located on the long arm of the chromosome 13. Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene. This disorder may occur in the familial or sporadic form. (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle. Loss of this active, functional protein (Rb) causes cell cycle dysregulation and subsequent overgrowth and tumor formation. Retinoblastoma may be caused by mutation in both allels of RB1 tumor suppressor gene or due to somatic amplification of the MYCN oncogene. Retinoblastoma must be differentiated from other diseases that cause leukocoria. leukocoria may occur in several ocular conditions including tumors, vascular disease, inflammatory disorders, and also due to trauma. The incidence of retinoblastoma in the United States has been reported 1.2 cases per 100,000 child aged 4 years or younger. The median age at diagnosis of retinoblastoma is 18 months. The average age at diagnosis of retinoblastoma for children with unilateral disease and bilateral disease is 24 months and 12 months respectively. Retinoblastoma affects males and females equally. There is no racial predilection to the development of retinoblastoma. Risk factors associated with the development of retinoblastoma are mutation in RB1 gene, a positive family history of retinoblastoma, living in areas with high incidence rate of the disease, HPV viral exposure and other environmental factors. Early diagnosis of retinoblastoma is necessary to obtain the best outcomes for vision and eye salvage. In 2018, a group of experts in clinical retinoblastoma care and ophthalmic pathology and genetics suggest a risk-stratified schedule for ophthalmic screening examinations. Estimated risk of retinoblastoma development is calculated according to the relativity of individuals to the family member with retinoblastoma. If left untreated, retinoblastoma may progress to develop seeding in the eye, leading to retinal detachment, necrosis and invasion of the orbit, optic nerve invasion, and central nervous system invasion. The majority of untreated patients die of intracranial extension and disseminated disease within one year. Spontaneous regression of the tumor is a rare occurrence but may occur in a small number of cases. Common complications of retinoblastoma include metastasis, tumor recurrence, trilateral retinoblastoma, and subsequent neoplasms. Prognosis is generally good, and the survival rate of patients with retinoblastoma with treatment is approximately 95% in the United States. Ultrasound imaging is the gold standard test for the diagnosis of retinoblastoma. MRI can also be helpful in the diagnosis making. A common method of retinoblastoma classification is critical to plan treatment, evaluate prognosis and compare outcomes. Available grouping systems include the International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB) and cTNMH systems diseases. The hallmark of retinoblastoma is leukocoria which is an abnormal appearance of the retina as viewed through the pupil, also known as amaurotic cat's eye reflex. Other common symptoms include strabismus and proptosis. The clinical presentation depends on the stage of the disease. Patients with retinoblastoma usually appear normal. Physical examination of patients is usually remarkable for leukocoria, strabismus, and proptosis, particularly in advanced cases. Other findings in physical examination of retinoblastoma include anisocoria, orbital cellulitis, hyphema, heterochromia iridis, poor visual acuity, unilateral mydriasis, rubeosis iridis, vitreous hemorrhage, and findings of intrinsic calcification on fundoscopic examination. There are no diagnostic laboratory findings associated with retinoblastoma. There are no x-ray findings associated with retinoblastoma. On ultrasound imaging, retinoblastoma is characterized by echogenic soft-tissue masses with variable shadowing due to calcifications and heterogeneity due to necrosis and/or hemorrhage. CT scan has been the standard imaging study of retinoblastoma. Retinoblastoma usually appears as an intra-ocular mass with calcification (in 80% of the cases). On head and neck MRI, retinoblastoma is characterized by hyperintense mass on T1-weighted MRI and hypointense mass on T2-weighted MRI. Optical coherence tomography may be helpful in the diagnosis of Retinoblastoma. Other diagnostic studies for retinoblastoma include fluorescein angiography and electroretinogram. The optimal therapy for retinoblastoma depends on the stage at diagnosis. Systemic chemotherapy via carboplatin, etoposide, and vincristine (CEV) is the most common regimen used to treat retinoblastoma. There are different modalities of treatment available for retinoblastoma. The feasibility of each strategy depends on the stage of retinoblastoma at the time of diagnosis. There are no established measures for the primary prevention of retinoblastoma. There are no established measures for the secondary prevention of retinoblastoma.
Historic Perspective
Retinoblastoma was first described in 1809 by Dr. James Wardrop. Then, Dr. Flexner, in 1891, was the first to discover the rosette structure within the tumor. In 1953, Dr. Kupfer was the first ophthalmologist who tried a combination of chemotherapy and radiotherapy for the treatment of the tumor.
Classification
There are several classification system available for retinoblastoma. As the treatment of the tumor has evolved, a new classification system has been introduced. For intraocular diseases the available grouping systems include the International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB) and cTNMH systems. For extraocular diseases, the International Retinoblastoma Staging System (IRSS) and cTNMH schemes can be used.
Pathophysiology
Retinoblastoma is a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene, located on the long arm of the chromosome 13. Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene. This disorder may occur in the familial or sporadic form. (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle. Loss of this active, functional protein (Rb) causes cell cycle dysregulation and subsequent overgrowth and tumor formation.
Causes
Retinoblastoma may be caused by mutation in both allels of RB1 tumor suppressor gene or due to somatic amplification of the MYCN oncogene.
Differentiating Retinoblastoma from Other Diseases
Retinoblastoma must be differentiated from other diseases that cause leukocoria. leukocoria may occur in several ocular conditions including tumors, vascular disease, inflammatory disorders, and also due to trauma.
Epidemiology and Demographics
The incidence of retinoblastoma in the United States has been reported 1.2 cases per 100,000 child aged 4 years or younger. The median age at diagnosis of retinoblastoma is 18 months. The average age at diagnosis of retinoblastoma for children with unilateral disease and bilateral disease is 24 months and 12 months respectively. Retinoblastoma affects males and females equally. There is no racial predilection to the development of retinoblastoma.
Risk factors
Risk factors associated with the development of retinoblastoma are mutation in RB1 gene, a positive family history of retinoblastoma, living in areas with high incidence rate of the disease, HPV viral exposure and other environmental factors.
Screening
Early diagnosis of retinoblastoma is necessary to obtain the best outcomes for vision and eye salvage. In 2018, a group of experts in clinical retinoblastoma care and ophthalmic pathology and genetics suggest a risk-stratified schedule for ophthalmic screening examinations. Estimated risk of retinoblastoma development is calculated according to the relativity of individuals to the family member with retinoblastoma.
Natural history, Complications, and Prognosis
If left untreated, retinoblastoma may progress to develop seeding in the eye, leading to retinal detachment, necrosis and invasion of the orbit, optic nerve invasion, and central nervous system invasion. The majority of untreated patients die of intracranial extension and disseminated disease within one year. Spontaneous regression of the tumor is a rare occurrence but may occur in a small number of cases. Common complications of retinoblastoma include metastasis, tumor recurrence, trilateral retinoblastoma, and subsequent neoplasms. Prognosis is generally good, and the survival rate of patients with retinoblastoma with treatment is approximately 95% in the United States.
Daignosis
Diagnostic Study of Choice
Ultrasound imaging is the gold standard test for the diagnosis of retinoblastoma. MRI can also be helpful in the diagnosis making. A common method of retinoblastoma classification is critical to plan treatment, evaluate prognosis and compare outcomes. Available grouping systems include the International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB) and cTNMH systems diseases.
History and Symptoms
The hallmark of retinoblastoma is leukocoria which is an abnormal appearance of the retina as viewed through the pupil, also known as amaurotic cat's eye reflex. Other common symptoms include strabismus and proptosis. The clinical presentation depends on the stage of the disease.
Physical Examination
Patients with retinoblastoma usually appear normal. Physical examination of patients is usually remarkable for leukocoria, strabismus, and proptosis, particularly in advanced cases. Other findings on physical examination of retinoblastoma include anisocoria, orbital cellulitis, hyphema, heterochromia iridis, poor visual acuity, unilateral mydriasis, rubeosis iridis, vitreous hemorrhage, and findings of intrinsic calcification on fundoscopic examination.
Laboratory Findings
There are no diagnostic laboratory findings associated with retinoblastoma.
Electrocardiogram
There are no ECG findings associated with retinoblastoma.
X Ray
There are no x-ray findings associated with retinoblastoma.
Echocardiography and Ultrasound
On ultrasound imaging, retinoblastoma is characterized by echogenic soft-tissue masses with variable shadowing due to calcification and heterogeneity due to necrosis and/or hemorrhage.
CT scan
CT scan has been the standard imaging study of retinoblastoma. Retinoblastoma usually appears as an intra-ocular mass with calcification (in 80% of the cases).
MRI scan
MRI findings of retinoblastoma include hyperintense mass on T1-weighted MRI and hypointense mass on T2-weighted MRI.
Other Imaging Findings
Optical coherence tomography may be helpful in the diagnosis of Retinoblastoma.
Other Diagnostic Studies
Other diagnostic studies for retinoblastoma include fluorescein angiography and electroretinogram.
Treatment
Medical therapy
The optimal therapy for retinoblastoma depends on the stage at diagnosis. Systemic chemotherapy via carboplatin, etoposide, and vincristine (CEV) is the most common regimen used to treat retinoblastoma.
Surgery
There are different modalities of treatment available for retinoblastoma. The feasibility of each strategy depends on the stage of retinoblastoma at the time of diagnosis.
Primary Prevention
There are no established measures for the primary prevention of retinoblastoma.
Secondary Prevention
There are no established measures for the secondary prevention of retinoblastoma.