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] Alberto Castro Molina, M.D.
Overview
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Treatment |
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Retinoblastoma overview On the Web |
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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.
Retinoblastoma is a highly curable childhood cancer when detected early and treated in centers with multidisciplinary expertise; however, survival varies globally and delays in diagnosis and access to care contribute to preventable death and vision loss in some regions.[1][2][3] Approximately 40% of patients have heritable disease due to a germline RB1 pathogenic variant (often associated with bilateral disease and increased risk of second primary malignancies), while most unilateral cases are nonheritable.[1][4]
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.
Modern eye-salvage strategies emphasize focal consolidation therapies (laser, cryotherapy, thermotherapy), chemoreduction with systemic chemotherapy, and targeted delivery approaches including intra-arterial chemotherapy and intravitreal chemotherapy for vitreous seeds, with reduced use of external-beam radiotherapy because of long-term toxicity and second cancer risk in heritable disease.[5][6][7]
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.
Genetic and molecular milestones include the two-hit model of tumor suppressor inactivation and identification of the RB1 locus, which established retinoblastoma as a foundational cancer genetics paradigm.[4][8][9][10]
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.
Consistent staging and grouping are essential to guide eye-salvage strategies, assess prognosis, and compare outcomes across centers, including contemporary approaches that incorporate vitreous and subretinal seeding and response to targeted chemotherapy delivery.[5][2][1]
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.
Retinoblastoma is initiated by loss of RB1 function in a retinal precursor context, and multiple lines of evidence support cone-precursor lineage programs contributing to tumorigenesis in many cases.[11][12]
A subset of retinoblastomas arise without RB1 inactivation and are driven by somatic amplification of MYCN, with distinct clinical and imaging features; MRI-based patterns may help distinguish MYCN-amplified, RB1 wild-type tumors and inform management strategies.[13][14][1]
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.
Population outcomes vary substantially by region, and global disparities in survival and eye salvage are driven by differences in access to early detection, specialized care, and supportive services.[1][3]
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.
Risk-stratified surveillance commonly incorporates genetic counseling and RB1 testing when available, with frequent ophthalmic examinations in early childhood for at-risk infants and children. In heritable disease, screening may also include MRI-based surveillance for intracranial tumors in selected contexts, balancing risk, feasibility, and local practice patterns.[15][1]
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.
Heritable retinoblastoma is associated with elevated lifetime risk of subsequent malignancies, and survivorship care commonly includes counseling on long-term surveillance and avoidance of unnecessary ionizing radiation when feasible.[1]
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.
In contemporary practice, diagnosis is typically based on examination under anesthesia with indirect ophthalmoscopy plus imaging (ultrasound and MRI). MRI is preferred for evaluating optic nerve involvement and intracranial extension, and to avoid ionizing radiation exposure associated with CT, particularly in children with heritable disease.[1]
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.
Molecular diagnostics are increasingly used to guide risk stratification and management, and include next-generation sequencing approaches in select settings and analysis of aqueous humor cell-free DNA as a tumor-derived liquid biopsy, which may be particularly useful because tumor biopsy is generally avoided in retinoblastoma.[16][17][18][19][20][21]
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.
Contemporary regimens integrate systemic chemotherapy with focal consolidation, and targeted delivery approaches (intra-arterial chemotherapy and intravitreal chemotherapy) to improve eye salvage while limiting systemic exposure in selected cases, especially for advanced intraocular disease with seeding.[5][6][7] Treatment-related adverse events and long-term sequelae are important considerations, including ototoxicity, myelosuppression, and secondary malignancy risk, and require multidisciplinary follow-up.[22]
For patients with extraocular disease, intensive multimodality therapy protocols have been studied, including contemporary cooperative group experience for newly diagnosed extraocular retinoblastoma.[23]
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.
Pathology informs adjuvant therapy decisions after enucleation in advanced cases, and high-risk histopathologic features (including optic nerve invasion and massive choroidal invasion) are associated with metastatic risk and guide additional treatment in many protocols.[24]
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.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cobrinik D (2024). "Retinoblastoma Origins and Destinations". N Engl J Med. 390: 1408–1419. doi:10.1056/NEJMra1803083.
- ↑ 2.0 2.1 Munier FL, Beck-Popovic M, Chantada GL, et al. Conservative management of retinoblastoma: a model of care for “success with no comorbidity.” Prog Retin Eye Res 2019;73:100764.
- ↑ 3.0 3.1 Bowman R. Retinoblastoma: a curable, rare and deadly blinding disease. Community Eye Health 2018;31:1-4.
- ↑ 4.0 4.1 Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820-823.
- ↑ 5.0 5.1 5.2 Fabian ID, Onadim Z, Karaa E, et al. The management of retinoblastoma. Oncogene 2018;37:1551-1560.
- ↑ 6.0 6.1 Schaiquevich P, Francis JH, Cancela MB, Carcaboso AM, Chantada GL, Abramson DH. Treatment of retinoblastoma: what is the latest and what is the future. Front Oncol 2022;12:822330.
- ↑ 7.0 7.1 Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012;96:1078-1083.
- ↑ Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;323:643-646.
- ↑ Fung YK, Murphree AL, T’Ang A, Qian J, Hinrichs SH, Benedict WF. Structural evidence for the authenticity of the human retinoblastoma gene. Science 1987;236:1657-1661.
- ↑ Dunn JM, Phillips RA, Becker AJ, Gallie BL. Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 1988;241:1797-1800.
- ↑ Xu XL, Singh HP, Wang L, et al. Rb suppresses human cone-precursor-derived retinoblastoma tumours. Nature 2014;514:385-388.
- ↑ McEvoy J, Flores-Otero J, Zhang J, et al. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell 2011;20:260-275.
- ↑ Blixt MKE, Hellsand M, Konjusha D, et al. MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma. Oncogenesis 2022;11:34.
- ↑ Jansen RW, de Bloeme CM, Cardoen L, et al. MRI features of MYCN-amplified, RB1 wild-type retinoblastoma. Radiology 2023;307:e222264.
- ↑ Staffieri SE, McGillivray G, Elder JE, et al. Managing the risk of retinoblastoma: surveillance and the role of imaging in screening. Prenat Diagn 2015;35:174-178.
- ↑ Afshar AR, Pekmezci M, Bloomer MM, et al. Next-generation sequencing of retinoblastoma identifies pathogenic alterations beyond RB1 inactivation that correlate with aggressive histopathologic features. Ophthalmology 2020;127:804-813.
- ↑ Li H-T, Xu L, Weisenberger DJ, et al. Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy. Nat Commun 2022;13:5523.
- ↑ Xu L, Shen L, Polski A, et al. Simultaneous identification of driver alterations and therapeutic targets from aqueous humor of retinoblastoma eyes. Ophthalmic Genet 2020;41:526-.
- ↑ Polski A, Xu L, Prabakar RK, et al. Cell-free DNA tumor fraction in aqueous humor is associated with disease burden in retinoblastoma patients. Transl Vis Sci Technol 2020;9:30.
- ↑ Abramson DH, Mandelker D, Francis JH, et al. Retrospective evaluation of cell-free DNA from blood in retinoblastoma. Ophthalmol Sci 2021;1:100015.
- ↑ Gerrish A, Jenkinson H, Cole T. The impact of cell-free DNA analysis on the management of retinoblastoma. Cancers (Basel) 2021;13:1570.
- ↑ Rizzuti AE, Dunkel IJ, Abramson DH. The adverse events of systemic chemotherapy for retinoblastoma: what are they? Do we know? Arch Ophthalmol 2008;126:862-865.
- ↑ Dunkel IJ, Piao J, Chantada GL, et al. Intensive multimodality therapy for newly diagnosed extraocular retinoblastoma: a Children’s Oncology Group trial (ARET0321). J Clin Oncol 2022;40:3839-3847.
- ↑ Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 2009;133:1203-1209.