Retinoblastoma

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.

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]

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]}

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]

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]

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.

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 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.

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]

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]

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]

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 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.

There are no diagnostic laboratory findings associated with retinoblastoma.

There are no ECG 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 calcification 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).

MRI findings of retinoblastoma include 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.

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]}

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]

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]

There are no established measures for the primary prevention of retinoblastoma.

There are no established measures for the secondary prevention of retinoblastoma.

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]

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.

• In 1657, Dr. Petrus Pawius, an anatomist from Amsterdam, described a tumor resembling retinoblastoma for the first time.^[1]
• In 1767, Dr. Hayes, a surgeon, was first to describe the bilateral form of retinoblastoma.
• In 1809, Dr. James Wardrop, a Scottish surgeon and ophthalmologist, first described the retinoblastoma tumor.
• In 1971, Dr. Knudson proposed the two-hit hypothesis which gives the light to the pathogenesis of the familial and sporadic form of the tumor.^[2]
• In 1891, Dr. Flexner was the first to discover the rosette structure within the tumor.^[1]
• In the 1920s, Verhoeff claimed that the tumor arose from embryonic retinal cells and hence proposed the name “retinoblastoma”.
• Retinoblastoma is the first cancer in which the role of genetics was discovered.^[3]
• In 1977, Dr. Jakobiec and colleagues were the first to describe the association between bilateral intraocular retinoblastoma and intracranial malignancy, also known as trilateral retinoblastoma.^[4]

• In 1851, Mr. Helmholtz invented ophthalmoscope, with which the study of tumor became possible.^[1]
• Dr. James Wardrop was also the first who proposed the idea that early enucleation of the eye might save the life of the patient.
• Dr. William Mackenzie of Glasgow was the first who suggested a less painful method for the enucleation of the eye.
• In 1903, Dr. Hilgartner, was the first who tried to treat the tumor via x-ray.
• In 1953, Dr. Kupfer was the first ophthalmologist who tried a combination of chemotherapy (a nitrogen mustard agent) and radiotherapy for the treatment of the tumor.

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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]

There are several classification systems available for retinoblastoma. As the treatment of the tumor has evolved, a new classification system has been introduced. For intraocular disease, the available grouping systems include International Intraocular Retinoblastoma Classification (IIRC), Intraocular Classification of Retinoblastoma (ICRB), and cTNMH systems. For extraocular disease, the International Retinoblastoma Staging System (IRSS) and cTNMH schemes can be used.

• Retinoblastoma has been classified according to different classification systems for variable purposes.^[1]
• Each classification system has been developed depending on the change in the management of the tumor.
• For treatment purposes, retinoblastoma is classified into:

• • This classification system incudes the following:
    • International Intraocular Retinoblastoma Classification (IIRC)^[2][3][4]
    • Intraocular Classification of Retinoblastoma (ICRB)
    • The cTNMH system of American Joint Committee on Cancer (AJCC)

	International Intraocular Retinoblastoma Classification (IIRC)	Intraocular Classification of Retinoblastoma (ICRB)
Group A (very low risk)	Small intraretinal tumors away from foveola and optic nerve 3mm or smaller in the greatest dimension, confined to the retina Located > 3 mm from the foveola and 1.5 mm from the optic disc	Tumors ≤ 3 mm (in basal dimension or thickness)
Group B (low risk)	Tumors confined to the retina Not in group A Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding	Tumors > 3 mm (in basal dimension or thickness) or Macular location (≤ 3 mm to foveola) Juxtapapillary location (≤ 1.5 mm to disc) Additional subretinal fluid (≤3 mm from margin)
Group C (moderate risk)	Local disease with minimal subretinal or vitreous seeding with the following characteristics: Discrete Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina Local fine vitreous seeding may be present close to the discrete tumor Local subretinal seeding less than 3 mm (2 DD) from the tumor	Tumor with: Subretinal seeds ≤ 3 mm from tumor Vitreous seeds ≤ 3 mm from tumor Both subretinal and vitreous seeds ≤ 3 mm from the tumor
Group D (high risk)	Diffuse tumor with significant vitreous or subretinal seeding Maybe massive or diffuse Subretinal fluid present or past without seeding, involving up to total retinal detachment The diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses Diffuse subretinal seeding may include subretinal plaques or tumor nodules	Tumor with: Subretinal seeds > 3 mm from tumor Vitreous seeds > 3 mm from tumor Both subretinal and vitreous seeds > 3 mm from retinoblastoma
Group E (very high risk)	Presence of any one or more of the following poor prognostic features: Tumor touching the lens Tumor anterior to anterior vitreous face involving the ciliary body or anterior segment Diffuse infiltrating retinoblastoma Neovascular glaucoma Opaque media from hemorrhage Tumor necrosis with aseptic orbital cellulitis Phthisis bulbi	Extensive tumor filling >50% globe or with neovascular glaucoma Opaque media from hemorrhage in the anterior chamber, vitreous, or subretinal space Invasion of the post-laminar optic nerve choroid (>2 mm), sclera, orbit, and anterior chamber

• This classification system was first introduced in 1960 and used to predict the chance of salvaging the eye after external beam radiotherapy.
• However, following the introduction of chemotherapy for retinoblastoma treatment, it lost its significance.

Stage	Sub-stage	Features	Prognosis
Group I	a	Solitory tumor < 6 mm at or behind the equator	Very favorable
	b	Multiple tumors, none > 6 mm, all are at or behind the equator	Very favorable
Group II	a	Solitary tumor, 6 to 15 mm, all at or behind the equator	Favorable
	b	Multiple tumors, 6 to 15 mm, behind the equator	Favorable
Group III	a	Lesion anterior to the equator	Undetermind
	b	Solitary tumor larger than 15 mm, behind the equator	Undetermined
Group IV	a	Multiple tumors, some larger than 15 mm	Unfavorable
	b	Any lesions extending to the ora serrata	Unfavorable
Group V	a	Massive tumor occupying over half the retina	Very unfavorable
	b	Vitreous seeding	Very unfavorable

• • This classification system includes the following:
    • International retinoblastoma staging system
    • cTNMH system of American Joint Committee on Cancer (AJCC)^[7]

• To see the full staging system click here.

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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]

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 a neoplasm which is caused by the inactivation of RB1 gene, a tumor suppressor gene.^[1]
• Normally, RB1 gene is necessary for the normal differentiation and growth of retinal stem cells and its mutation results in unregulated growth of these cells and development of the tumor.
• Mutation in both alleles of the RB1 gene is necessary for the inactivation of the gene.^[2]
• This disorder may occur in the familial or sporadic form.
• In the familial form (48% of the cases), the first mutation occurs during germ cell division and the second mutation occurs later during the division of somatic cells.^[3]
• In the sporadic form, both mutations occur during the lifetime of the individual.
• (Rb) gene product limits the cell progression from the G1 phase to the S phase of the cell cycle.^[4]
• Active form of RB protein prevent the interaction of E2F, a transcription factor. Loss of this active, functional protein (Rb) causes transcribing the gene and subsequent cell cycle dysregulation, overgrowth and tumor formation.

• Retinoblastoma occurs due to mutational inactivation of RB1 gene located on the chromosome 13.^[5]
• The RB1 gene acts as tumor suppressor gene.^[6]
• Two mutational events are needed for the development of retinoblastoma.
• In familial form, with autosomal dominant inheritance, one mutation occurs in the germline and the second one during the somatic division of the retinal cells.
• In the acquired form, both mutations occur during somatic divisions.
• Another gene which has been associated with the pathogenesis of retinoblastoma is MYCN gene.^[7]
• Retinoblastoma may also occur as part of 13q deletion syndrome.^[8]
  • This syndrome is the result of the deletion of the long arm of chromosome 13.
  • Symptoms may vary according to the size of the deletion, but it may lead to developmental delay as well.
  • Children with chromosome 13q14 deletions may develop retinoblastoma at a later age and they develop a unilateral tumor.
• Mosaicism, presence of RB1 gene mutation in some cells of the affected person, may occur in retinoblastoma.
  • Patients with mosaic mutation often have unilateral retinoblastoma, later onset of the tumor, and no family history of the disease.

• Heritable form of this disorder is associated with the development of non-ocular malignancies including:^[9]
  • Different types of Sarcoma
  • Small cell lung cancer
  • Bladder cancer
  • Breast cancer
  • Glioblastoma

• Macroscopic appearance of the tumor varies according to the staging of the tumor.^[10]
• The tumor is white and has areas of calcification and necrosis.
• The presence of calcium is more noticeable when the tumor is treated via prior chemotherapy or radiotherapy.
• The tumor can be classified into five sub-groups according to its growth pattern:^[11]
  • Endophytic
  • Exophytic
  • Mixed
  • Diffuse infiltrative
  • Necrotic variant

These growth patterns are described in the table below:

Growth patterns	Features
Endophytic	Growth occurs inwards into the vitreous
Exophytic	Growth occurs outwards towards choroid Associated with non-rhegmatogenous retinal detachment
Mixed	Most common type Mixed components of endophytic and exophytic are seen
Diffuse Infiltrative	More commonly seen among older children Diffuse growth of the tumor without an obvious retinal mass Frequently involves anterior chamber and causes pseudohypopyon of tumor cells Clinically can be mistaken for an inflammatory process
Necrotic	May present as an inflammatory process and can be mistaken for orbital cellulitis with chemosis and proptosis Associated with increased risk of metastasis

• Microscopically, retinoblastoma is characterized by:^[12]
  • Small hyperchromatic cells with a high nuclear to cytoplasmic ratio
  • Large areas of necrosis
  • Multifocal area of calcifications

• Retinoblastoma histopathology is a combination of undifferentiated cells and areas of tumor differentiation shown as rosettes and fleurettes.^[13]

• The most differentiated part is formed from a bouquet-like aggregates of cells called fleurettes, where mitoses or necrosis are not present.
  • These cells resemble the photoreceptors and are arranged similar to flowers.
• The rosettes are composed of cells with varying degrees of differentiation.
• There are two types of rosettes:
  • Flexner–Wintersteiner rosette: Composed of a ring of cells surrounding a clear center resembling the subretinal space.
  • Homer Wright rosette: Comprises of a rim of cells with a lumen filled by cytoplasmic prolongations of the tumor cells.

• Retinoblastoma may be classified according to the degree of differentiation to well/poor-differentiated.
  • Well-differentiated tumor is > 50% Homer-Wright (HW) rosettes.
  • Poor-differentiated tumor is < 50% Flexner-Wintersteiner (FW) rosettes.

• There is no specific immunohistochemical marker for the diagnosis of retinoblastoma.^[14][15]
• The most commonly applied marker is neuron specific enolase (NSE).
• Other useful markers are:
  • Synaptophysin
  • CD56
  • Glial fibrillary acidic protein (GFAP)
• Although there is no specific biomarker for the diagnosis of retinoblastoma, it may be needed for the diagnosis of undifferentiated form of the tumor.^[16][17]
• IHC may be useful for the identification of photoreceptors and glial cells in the retinoblastoma.
• IHC may also be useful in identifying the level of differentiation of the tumor by detecting red and green cones found in the rosettes and fleurettes and blue cones which do not form rosettes and fleurettes.

​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Sahar Memar Montazerin, M.D.[3]

Retinoblastoma may be caused by mutation in both alleles of RB1 tumor suppressor gene or due to somatic amplification of the MYCN oncogene.

Heritable Retinoblastoma

• In children with the heritable genetic form of retinoblastoma, there is a mutation of RB1 gene on chromosome 13.^[1]
• Somatic amplification of the MYCN oncogene is responsible for some cases of non-hereditary, early-onset, aggressive, and unilateral retinoblastoma.

Sporadic Heritable Retinoblastoma

• The exact cause of the sporadic heritable form of the disease is still unclear.
• Since the sporadic form of retinoblastoma occurs due to a new germline mutation, it should occur before conception. For this reason, preconception exposure to mutagens is hypothesized to be a potential risk factor.^[2]
• 13q deletion syndrome may also cause retinoblastoma. However, the tumor tends to occur at a later age and unilaterally.^[3]

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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]

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 must be differentiated from other diseases that cause leukocoria. Differential diagnosis of leukocoria in children include:

Leukocoria

Tumors

Congenital malformations

Vascular diseases

Inflammatory diseases

Trauma

Retinoblastoma Medulloepithelioma Leukemia Combined retinal hamartoma Astrocytic hamartoma (Bourneville’s tuberous sclerosis)

Persistent fetal vasculature (PFV) Posterior coloboma Retinal fold Myelinated nerve fibers Morning glory syndrome Retinal dysplasia Norrie’s disease Incontinentia pigmenti Cataract

Retinopathy of prematurity (ROP) Coats’ disease Familial exudative vitreoretinopathy (FEVR)

Ocular toxocariasis Congenital toxoplasmosis Congenital cytomegalovirus retinitis Herpes simplex retinitis Other types of fetal iridochoroiditis Endophthalmitis

Intraocular foreign body Vitreous hemorrhage Retinal detachment

The above algorithm is adopted from Clinical Ophthalmic Oncology book [1]

Retinoblastoma should be differentiated from the following conditions that cause leukocoria:

Disease/Condition	Clinical presentation	Demographics/History	Diagnosis	Other notes
Retinoblastoma[2][3]	Retinal mass Gross examination reveals a whitish tumor with prominent vascularity Vitreous seeding in endophytic tumors exudative retinal detachment in exophytic tumor	Sporadic in 90% of the cases The median age of diagnosis is 18 months Bilateral in 70% of the cases	P/E: leukocoria Ultrasound imaging: A dome or placoid-shaped intraocular mass +/- intralesional calcification CT imaging: Presence of calcification within the tumor	Associated with 13q deletion syndrome
Coats’disease[4][5]	Yellowish appearance of leukocoria P/E: Exudative retinal detachment with vascular tortuosity and telangiectasia +/- neurovascular glaucoma Absence of calcification	Sporadic in 100% of the cases Almost always unilateral More common among boys The median age of diagnosis 5 to 9 years	P/E is diagnostic in most of the cases Ultrasound imaging: Complete retinal detachment Absence of calcification Exudative, mobile lipid material under retina	Fluorescein angiography reveals characteristic telangiectasias of small to medium-sized retinal vessels
Persistent fetal vasculature (formerly known as persistent hyperplastic primary vitreous)[5]	Presence of leukocoria in infancy which is commonly accompanied by microphthalmia Presence of retrolental fibrovascular tissue +/- secondary cataract	Sporadic in the majority of cases Always congenital (present at birth) Rarely bilateral	P/E: microphthalmia and increasedintraocular pressure Presence of elongated ciliary processes contracting into the retrolental mass Ultrasound imaging: Vitreous band from lens to optic nerve Short axial length of eyes	Bilateral cases has been accompanied byprotein C deficiency
Astrocytic hamartoma[1]	Presence of gray-yellow or translucent tumors involving the posterior pole near optic nerve	Presents at any age Some has been associated with neurofibromatosis type 1/tuberous sclerosis	P/E: A sessile shape tumor arising from the inner aspect of the sensory retina Presence of small areas of calcification/complete calcification in older patients	Reticular pattern of fine blood vessels on fluorescein angiography
Retinopathy of prematurity (ROP)[1]	Absence of calcification Presence of retinal contraction in one or both eyes	History of: Prematurity (< 32 weeks gestation) Low birth weight (< 1.5 kg/3.3 lbs) Oxygen supplementation Leukocoria is a late presentation of the disease Always bilateral	P/E: Bilateral retinal avascularity and non-perfusion in temporal peripheral retina with fibrovascular proliferation in advanced cases Ultrasound imaging: Retinal detachment with retinal bands	Short axial length of eyes
Ocular toxocariasis [1]	Presence of retinal and/or vitreous traction in approximately all of the cases	Presents at any age Mostly unilateral Ingestion of larvae leads to the infection	P/E: Presence of granuloma and retinal traction Ultrasound imaging: Peripheral mass Vitreoretinal band Traction retinal detachment Presence of eosinophils in the anterior chamber tap	Classified into three sub-types: Macular granuloma Peripheral granuloma Endophthalmitis
Familial Exudative Vitreoretinopathy (FEVR)[6]	Presents at birth The majority are asymptomatic May present with leukocoria, strabismus, and vision loss	Autosomal dominant pattern of inheritance May occur sporadically Findings include asymmetry of both eyes	P/E: Avascularity of the temporal retina with peripheral fibrovascular proliferation Fluorescein angiography: Peripheral non-perfusion of the fundus	Fundus findings are similar to retinopathy of prematurity except for the history of prematurity
Norrie’s Disease[1][7]	Presents with microcephaly, congenital blindness, deafness, and progressive neuropsychiatric illness	X-linked disorder More common in males	P/E: bilateral retinal dysplasia, sometimes with anterior segment abnormalities and microphthalmia	–
Coloboma[1]	Presents at birth Failure of the embryonic fissure to close completely results in an absence of normal retina and choroid	The majority are sporadic Congenital disorder that affects male and female equally May be unilateral or bilateral	P/E: Whitish depressed lesion of retina which is typically inferonasal and its margins may encompass the macula or optic nerve	It may be accompanied by CHARGE syndrome

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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]

The incidence of retinoblastoma in the United States has been reported to be 1.2 cases per 100,000 children 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.

• The incidence of retinoblastoma in the United States has been reported to be 1.2 cases per 100,000 children aged 4 years or younger.^[1]
• The tumor incidence has been reported 0.049 cases per 100,000 child aged 5 to 9.

• There is no data on the prevalence of retinoblastoma.

• The mortality rate of retinoblastoma differs according to the stage of the disease as well as the geographic region.^[2]
• In extraocular form of this disorder is reported to be greater than 50%.^[3]
• However, tumors involving the optic disc superficially, are associated with 10% mortality rate.^[4]

• The median age at the time of diagnosis is 18 months.^[5]
• The average age at diagnosis of retinoblastoma for children with unilateral disease and bilateral disease is 24 months and 12 months respectively.^[6]
• Cases of newly diagnosed retinoblastoma have been reported in children as old as 18 years and even in adults.^[7][8]
• In adults, retinoblastoma tends to present between 20 to 50 years of age.^[9]
• Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.

• Retinoblastoma affects males and females equally.^[5]

• There is no racial predilection to the development of retinoblastoma.^[5]

• Epidemiological data indicates that retinoblastoma has a higher incidence in some geographic areas.^[10]
• The table below provides the highest worldwide incidence rate of retinoblastoma in children aged 0 – 4:

Country	Incidence
Mali	4.25
Uganda	2.4
Zimbabwe	2.33
Hawaii	2.25
India	1.96
Vietnam	1.89
Singapore	1.88
New Zealand	1.78 – 1.86
Spain	1.78
Philippines	1.74
Colombia	1.71
Ecuador	1.66
Nigeria	1.61
Costa Rica	1.57
Peru	1.55

​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Sahar Memar Montazerin, M.D.[3]

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 exposure and other environmental factors.

• Retinoblastoma has been associated with the following genetic disorders:
  • RB1 gene mutation
  • Deletion of chromosome 13 long arm of (13q deletion syndrome)^[1]
  • Fragile-X syndrome

• Approximately 10% of patients with retinoblastoma have a previously established family history of the disease.^[2]
• The magnitude of risk among offsprings of the proband depends upon the tumor presentation in the proband (unilateral or bilateral) and the relationship of the individual to the patient with retinoblastoma.
• The table below provides the estimated risk percentage of developing retinoblastoma in individuals with a positive family history of retinoblastoma:

Relative of patient	Bilateral involvement (100%)	Unilateral involvement (15%)
Offspring (infant)	50	7.5
Parent	5	0.8
Sibling	2.5	0.4
Niece/nephew	1.3	0.2
Aunt/uncle	0.1	0.007
First cousin	0.05	0.007

The above table adopted from Ophthalmology journal [3]

• The presence of HPV sequences in retinoblastoma tumor tissue may play a role in the development of sporadic retinoblastoma.^[4]
• There is evidence suggesting that the mutations of RB1 are more common during spermatogenesis than oogenesis.^[5]

• Epidemiological data indicates that retinoblastoma has higher incidence in some geographic areas. For more information click here.
• Other factors associated with an increased risk of retinoblastoma development include:^[6]
  • Mother’s use of insect or garden sprays during pregnancy
  • Diagnostic x-ray with direct fetal exposure
  • Father’s employment as a welder, machinist, or related metal worker

​

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]

Early diagnosis of retinoblastoma is necessary to obtain the best outcomes for preservation of the vision and the eye. In 2018, a group of experts in clinical retinoblastoma care and ophthalmic pathology and genetics suggested 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.

• In 2018, a group of experts in clinical retinoblastoma care and ophthalmic pathology and genetics suggested a risk-stratified schedule for ophthalmic screening examinations.^[1]
• This panel of experts recommended that all children with an elevated risk of retinoblastoma (above the population risk) should be screened via regular fundoscopic examinations.
• To schedule a screening plan, the risk of tumor development must be determined using the infant relationship to the family member with retinoblastoma.
• The table below is an estimate of patients’ risk for the development of retinoblastoma depending on the relation of the patient to the affected individual:

Relative of patient	Bilateral involvement (100%)	Unilateral involvement (15%)
Offspring (infant)	50	7.5
Parent	5	0.8
Sibling	2.5	0.4
Niece/nephew	1.3	0.2
Aunt/uncle	0.1	0.007
First cousin	0.05	0.007

The above table adopted from Ophthalmology journal [1]

• Next step in assessing the risk of these children is to estimate the approximate relative risk of retinoblastoma development according to the percentage mentioned in the above table.

• Relatives are categorized into three categories:
  • High risk: Those with a risk percentage > 7.5%
  • Intermediate risk: Those with a risk percentage between 1% and 7.5% (including 7.5%)
  • Low risk: Those with a risk percentage < 1%
• American Association of Ophthalmic Oncologists and Pathologists (AAOOP) guideline recommends scheduled eye examination for the screening of children at high risk of developing retinoblastoma. Screening should be initiated at birth and continued till the age of 7 years.^[1]
• No further examination is required after the age of 7 years except for those who are known carriers of the RB1 gene mutation.
• For those who are carries of the RB1 gene mutation, screening should be continued indefinitely after the age of 7 years and should be done annually or every 2 years.

• The following table is the recommended eye examination schedule for unaffected children of families with retinoblastoma depending on their age and risk percentage of tumor development:

Risk category or Age	High risk	Intermediate risk	Low risk
Birth to 8 weeks	Every 2 – 4 weeks	Monthly	Monthly
> 8 – 12 weeks	Monthly	Monthly	Monthly
> 3 – 12 months	Monthly	Every 2 months	Every 3 months
> 12 – 24 months	Every 2 months	Every 3 months	Every 4 months
> 24 – 36 months	Every 3 months	Every 3 months	Every 6 months
> 36 – 48 months	Every 4 months	Every 4 – 6 months	Every 6 months
> 48 – 60 months	Every 6 months	Every 4 – 6 months	Annually
5 – 7 years	Every 6 months	Annually	Annually

This table is adopted from Ophthalmology journal[1]

• The schedule presented above is general guideline for at-risk children when no lesions of concern have been noted. Some children may require more frequent examinations.

• The American Association of Ophthalmic Oncologists and Pathologists (AAOOP) guideline also suggests a single dilated fundus examination to evaluate for asymptomatic spontaneously regressed retinoblastoma or retinoma in all first-degree relatives of a patient with retinoblastoma, including older siblings if the RB1 genetic analysis of the relatives is not done.

Genetic testing for children with Retinoblastoma

Not available

Blood: RB1 mutation(+) (germline mutation)

Blood: RB1 mutation(-) Tumor: RB1 mutation(+)

Blood: RB1 mutation(-) Tumor: RB1 mutation(-)

Blood: RB1 mutation(-) Tumor: not available

Ophthalmic screening for all the relatives with greater risk than the population

Assessment of relatives for familial retinoblastoma

Ophthalmic screening and genetic analysis not required for first degree relatives

No need for genetic analysis of first degree relatives

Relatives with RB1 mutation

Relatives without RB1 mutation

Ophthlamic screening for future offspring unless negative for parent’s mutation

Future offspring of affected child require ophthalmic screening

Ophthalmic screening for children as high risk

Ophthalmic screening not required

The above table is the recommended genetic analysis guidline for families with affected individuals and adopted from Ophthalmology journal[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Sahar Memar Montazerin, M.D.[3]

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.

• Retinoblastoma usually presents with leukocoria.^[1]
• If left untreated, retinoblastoma can be fatal. The tumor will continue growing and can invade the entire globe of the eye with subsequent metastasis.
• The tumor remains within the globe of the eye and curable within 3 to 6 months of its first presentation (when it presents with leukocoria). Delay in the diagnosis will decrease the survival rate.^[2]
• Death may occur within one year of metastasis.
• Metastasis may occur via the following four possible pathways:^[3][4][5][6]
  • Direct invasion of the central nervous system via the optic nerve
  • Through the subarachnoid space to the contralateral optic nerve
  • Through the cerebrospinal fluid to the central nervous system
  • To the lungs, bone, and brain via the hematogenous route
  • The tumor may also spread via the lymphatics if the tumor invades anteriorly into the conjunctivae, eyelids, or extraocular tissue.
• Spontaneous regression of the tumor is a rare occurrence but may occur in a small number of cases.^[7]

• Metastasis
• Massive choroidal invasion
• Tumor invasion into the anterior chamber
• Large tumor size with vitreous seeding
• Neovascularization of the iris
• Glaucoma

• Recurrence of tumor
• Trilateral retinoblastoma^[8][9]

• Elevated intracranial pressure (ICP)

• Subsequent neoplasms^[10]

• Those with heritable form of the disease have 50% risk of transmitting the mutation to their offspring.^[11]
• Regarding the variable accessibility of patients to the resources, the survival rate may range from < 30% in low and middle income societies to > 90% in developed countries.^[12]
• The overall 5-year survival rate increased over the years and was reported 97.3% from 2000 to 2012.^[13]
• Prognosis is generally good, and the survival rate of patients with retinoblastoma with treatment is approximately 95%, in the United States.^[14]
• The survival rate is higher for unilateral involvement than the bilateral form of the tumor.
• It has been observed that survival rate varies depending upon the following factors:
  • Laterality of the tumor
  • Age at the time of diagnosis
  • Decade of diagnosis
• The overall prognosis of trilateral retinoblastoma is poor and patients usually die within the first year of the diagnosis.^[15]
• Intraocular Classification of Retinoblastoma (ICRB) has been observed to have the ability to predict the outcome of chemotherapy:^[16]
  • Category A – C is associated with ≥ 90% chance to salvage the eye.
  • Category D is associated with a 47% chance to salvage the eye.
  • Category E is excluded due to eye enucleation.
• Prognosis is usually poor with non-ocular tumor and it usually occurs in individuals who have received radiation therapy for their primary retinoblastoma tumors.^[17]