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Retinoblastoma

Retinoblastoma

Retinoblastoma is a rare tumor Tumor Inflammation but the most common primary intraocular malignancy Malignancy Hemothorax of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or nonheritable. The condition typically presents as unilateral or bilateral leukocoria Leukocoria Cataracts in Children (abnormal white reflection in the eye) in a child under the age of 2. Retinoblastoma is fatal if not treated but early recognition accounts for a high survival rate in resource-rich countries.

Last updated: 13 Sep, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Epidemiology

  • Most common primary intraocular malignancy Malignancy Hemothorax of childhood 
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 15,000 live births in the United States
  • Girls and boys are affected equally. 
  • Accounts for about 4% of malignant tumors in children < 15 years of age
  • Approximately 95% of affected children are diagnosed before the age of 5. 
  • The median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion age of diagnosis is 18–20 months. 
  • Approximately 40% of cases are heritable. 
  • Survival
    • In resource-rich countries: > 95%
    • In resource-limited/developing countries: < 30%

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Pathophysiology

  • Retinoblastoma is caused by a genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the retinoblastoma gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (RB1 or RB RB Chlamydia) in 98% of cases.
    • RB1 is a key negative regulator of the G1/S cell cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation transition and is directly or indirectly inactivated in most human malignancies.
  • Nonheritable form: (60% of cases)
    • Two spontaneous somatic mutations occur in the RB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics progenitor cells, leading to the development of retinoblastoma.
    • Tends to be unilateral and unifocal
    • Presents between the ages of 2 and 5
  • Familial or heritable form: (40% of cases)
    • The child inherits a non-functional allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics of the RB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, which is present in all somatic cells.
    • Only 1 more ( sporadic Sporadic Selective IgA Deficiency) mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the 2nd allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics in a neuronal progenitor cell is necessary to form a retinoblastoma.
    • Tends to be bilateral and/or multifocal
    • Presents before the age of 1
Retinoblastoma forms - heritable and nonheritable

Diagram of the two forms of retinoblastoma development: a familial form (now called the “Heritable form,” on the left and a ” Sporadic Sporadic Selective IgA Deficiency form” (now called the “Non-heritable form”) on the right. In the heritable form, a mutated RB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (in blue) is passed on to the child, and only one additional mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the paired normal allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics (in red) is needed to develop the tumor Tumor Inflammation. In the nonheritable form, the RB1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics may be mutated de novo in the germline of the offspring (not shown in this figure) so that it then behaves as in the heritable form, or a retinal precursor cell may acquire an RB1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in both alleles and thereby creating a retinoblastoma tumor Tumor Inflammation.

Image by Lecturio.

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Clinical Presentation

  • Cardinal signs: 
    • Leukocoria Leukocoria Cataracts in Children 
    • Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus
  • Less common signs and symptoms: 
    • Decreased vision Vision Ophthalmic Exam
    • Ocular inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation 
    • Vitreous hemorrhage Vitreous Hemorrhage Hemorrhage into the vitreous body. Diseases of the Vitreous Body
    • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
    • Anisocoria Anisocoria Unequal pupil size, which may represent a benign physiologic variant or a manifestation of disease. Pathologic anisocoria reflects an abnormality in the musculature of the iris (iris diseases) or in the parasympathetic or sympathetic pathways that innervate the pupil. Physiologic anisocoria refers to an asymmetry of pupil diameter, usually less than 2mm, that is not associated with disease. Pupil: Physiology and Abnormalities
    • Proptosis
  • Histology:
    • Rarely needed to confirm the diagnosis
    • A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is contraindicated because of the risk of tumor Tumor Inflammation seeding Seeding The local implantation of tumor cells by contamination of instruments and surgical equipment during and after surgical resection, resulting in local growth of the cells and tumor formation. Grading, Staging, and Metastasis. 
    • Three growth patterns are seen: exophytic (beneath the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy), endophytic (into the vitreous), and diffusely infiltrating (rare, grows within the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy).
  • Child with retinoblastoma

    Child with retinoblastoma of the right eye Right Eye Refractive Errors, presenting with leukocoria Leukocoria Cataracts in Children

    Image: “Pathology: Patient: Retinoblastoma” by The National Cancer Institute. License: Public Domain
  • Extra-ocular retinoblastoma

    Child presenting with orbital cellulitis Orbital cellulitis Orbital and preseptal cellulitis are infections differentiated by the anatomic sites affected in the orbit. Infection posterior to the septum is orbital cellulitis. Inoculation with the pathogen can occur through trauma or surgery. Cellulitis also occurs via extension from a nearby structure (such as from sinus infection or sinusitis). Orbital and Preseptal Cellulitis of the right eye Right Eye Refractive Errors caused by locally advanced retinoblastoma

    Image: “ Orbital cellulitis Orbital cellulitis Orbital and preseptal cellulitis are infections differentiated by the anatomic sites affected in the orbit. Infection posterior to the septum is orbital cellulitis. Inoculation with the pathogen can occur through trauma or surgery. Cellulitis also occurs via extension from a nearby structure (such as from sinus infection or sinusitis). Orbital and Preseptal Cellulitis” by The Pan African Medical Journal. License: CC BY 2.0

Diagnosis

  • Urgent referral to ophthalmologist
  • Ophthalmoscopic examination under anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts, with ultrasound imaging
  • Magnetic resonance imaging (MRI) of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and orbits
  • No need for formal staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis studies (i.e., bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow examination, lumbar puncture Lumbar Puncture Febrile Infant, and/or radionuclide bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types scan) → metastases rarely present at time of diagnosis
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies is recommended.
  • Fundus retinoblastoma

    Ocular fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy aspect of retinoblastoma

    Image: “ Fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy retinoblastoma” by Aerts, I, Lumbroso-Le Rouic. License: CC BY 2.0
  • Retinoblastoma

    Enucleated eye showing a large exophytic retinoblastoma

    Image: “Retinoblastoma” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain
  • Retinoblastoma rosette

    Retinoblastoma with characteristic Flexner-Wintersteiner rosettes featuring a circular alignment of short columnar cells around a central lumen

    Image: “Flexner-Wintersteiner rosettes” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

Management and Prognosis

Management

Treatment depends on the stage, with multiple “vision-sparing” therapies available:

  • Small, uncomplicated extrafoveal tumors:  cryotherapy Cryotherapy A form of therapy consisting in the local or general use of cold. The selective destruction of tissue by extreme cold or freezing is cryosurgery. Chondrosarcoma or laser photocoagulation
  • More advanced stages: local and systemic chemotherapy Chemotherapy Osteosarcoma, radioactive plaques 
  • Anatomical or functional impairment by tumor Tumor Inflammation: enucleation
  • Metastatic disease:
    • Rarely (2%–3%) present at time of diagnosis
    • Autologous stem cell transplantation after intensive multimodal therapy 
  • Lifetime follow-up to detect secondary malignancies is necessary!

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Survival: > 95% in resource-rich countries; < 30% in countries with very limited resources
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas for vision Vision Ophthalmic Exam depends on extent of tumor Tumor Inflammation: 50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship reach a final visual acuity Visual Acuity Clarity or sharpness of ocular vision or the ability of the eye to see fine details. Visual acuity depends on the functions of retina, neuronal transmission, and the interpretative ability of the brain. Normal visual acuity is expressed as 20/20 indicating that one can see at 20 feet what should normally be seen at that distance. Visual acuity can also be influenced by brightness, color, and contrast. Ophthalmic Exam of 20/40 or better.

Differential Diagnosis

The differential diagnosis includes any condition that can cause leukocoria Leukocoria Cataracts in Children.

  • Persistent fetal vasculature Persistent Fetal Vasculature Diseases of the Vitreous Body: failure of the embryonic primary vitreous Embryonic Primary Vitreous Diseases of the Vitreous Body and hyaloid vascular system to involute during gestation. Visual prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is poor. 
  • Retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome of prematurity Prematurity Neonatal Respiratory Distress Syndrome (ROP): a potentially blinding Blinding Epidemiological Studies eye disorder that primarily affects premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis infants. The disorder is caused by neovascularization with abnormal and fragile vessels due to growth factors released by incompletely developed peripheral retinal vessels. The vessels bleed easily and cause scarring Scarring Inflammation. Most cases of ROP are mild.
  • Cataract Cataract Partial or complete opacity on or in the lens or capsule of one or both eyes, impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). Neurofibromatosis Type 2: a congenital Congenital Chorioretinitis or acquired condition in which the lens Lens A transparent, biconvex structure of the eye, enclosed in a capsule and situated behind the iris and in front of the vitreous humor (vitreous body). It is slightly overlapped at its margin by the ciliary processes. Adaptation by the ciliary body is crucial for ocular accommodation. Eye: Anatomy of the eye becomes progressively opaque, resulting in blurred vision Blurred Vision Retinal Detachment.
  • Coats disease: an idiopathic Idiopathic Dermatomyositis disorder characterized by retinal telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency with breakdown of the blood-retinal barrier. Most commonly affects children. Can cause retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment and blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity.
  • Vitreous hemorrhage Vitreous Hemorrhage Hemorrhage into the vitreous body. Diseases of the Vitreous Body (VH): the presence of blood within the vitreous cavity. Three conditions cause most VH cases: ocular trauma Ocular Trauma Cataracts in Children, posterior vitreous detachment Vitreous Detachment Detachment of the corpus vitreum (vitreous body) from its normal attachments, especially the retina, due to shrinkage from degenerative or inflammatory conditions, trauma, myopia, or senility. Retinal Detachment associated with retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment, and proliferative diabetic retinopathy Diabetic retinopathy Disease of the retina as a complication of diabetes mellitus. It is characterized by the progressive microvascular complications, such as aneurysm, intraretinal edema, and intraocular pathologic neovascularization. Chronic Diabetic Complications.  
  • Ocular toxocariasis Toxocariasis Toxocariasis is caused by the nematodes Toxocara canis and T. cati. These species frequently infect dogs and cats and are most commonly transmitted to humans via accidental ingestion of eggs through the fecal-oral route. Toxocara are not able to complete their life cycle in humans, but they do migrate to organs (including the liver, lungs, heart, brain, and eyes), where they cause inflammation and tissue damage. Toxocariasis ( ocular larva migrans Ocular Larva Migrans Toxocariasis): a rare infection caused by roundworms Roundworms Anthelmintic Drugs, Toxocara Toxocara A genus of ascarid nematodes commonly parasitic in the intestines of cats and dogs. Toxocariasis canis, and Toxocara cati Toxocara Cati Toxocariasis. Presents with posterior uveitis Posterior Uveitis Diseases of the Uvea and is associated with reduced vision Vision Ophthalmic Exam, photophobia Photophobia Abnormal sensitivity to light. This may occur as a manifestation of eye diseases; migraine; subarachnoid hemorrhage; meningitis; and other disorders. Photophobia may also occur in association with depression and other mental disorders. Migraine Headache, floaters Floaters Chorioretinitis, and leukocoria Leukocoria Cataracts in Children.
  • Familial exudative vitreoretinopathy: a group of rare inherited diseases with abnormal retinal angiogenesis Angiogenesis Bartonella causing incomplete vascularization of the peripheral retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy. Can lead to secondary neovascularization with progression to blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity.
  • Coloboma Coloboma Congenital anomaly in which some of the structures of the eye are absent due to incomplete fusion of the fetal intraocular fissure during gestation. Esophageal Atresia and Tracheoesophageal Fistula: a development disorder due to failure of the optic ( choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy) fissure Fissure A crack or split that extends into the dermis Generalized and Localized Rashes to fuse so that a defect may be present anywhere along the inferior portion of the eye, from the optic disc Optic disc The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. Eye: Anatomy to the iris Iris The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers – the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. Eye: Anatomy. A large optic disc Optic disc The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. Eye: Anatomy and chorioretinal coloboma Coloboma Congenital anomaly in which some of the structures of the eye are absent due to incomplete fusion of the fetal intraocular fissure during gestation. Esophageal Atresia and Tracheoesophageal Fistula can cause leukocoria Leukocoria Cataracts in Children.
  • Retinal astrocytic hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer: a usually indolent tumor Tumor Inflammation that occurs in roughly half of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with tuberous sclerosis complex Tuberous sclerosis complex Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosis. The condition is also associated with neurofibromatosis.

References

  1. Kaufman PL, Kim J, Berry JL. (2018). Retinoblastoma: Clinical presentation, evaluation, and diagnosis. UpToDate. Retrieved August 30, 2020 from: https://www.uptodate.com/contents/retinoblastoma-clinical-presentation-evaluation-and-diagnosis#H3
  2. Kaufman PL, Kim J, Berry JL. (2018). Retinoblastoma: Treatment and outcome. UpToDate. Retrieved August 30, 2020 from https://www.uptodate.com/contents/retinoblastoma-treatment-and-outcome?topicRef=6275&source=see_link
  3. Lazar, A.L. (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.), Robbins & Cotran Pathologic Basis of Disease. (10 ed., pp. 1324, 290-294). Elsevier, Inc.
  4. Berry JL, Polski A, Cavenee WK, Dryja TP, Murphree AL, Gallie BL. The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene. Genes (Basel). 2019 Nov 1;10(11):879. doi: 10.3390/genes10110879.
  5. Hurwitz RL, Hurwitz M. Retinoblastoma. National Organization for Rare Disorders (NORD). Retrieved on August 31, 2020 from: https://rarediseases.org/rare-diseases/retinoblastoma/
  6. Demirci H, Shields CL, Meadows AT, Shields JA. Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol. 2005;123(11):1525. 
  7. Shields, C.L., Schoenberg, E.,  Kocher, K., et al. (2013), Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation. Ophthalmology. 2013;120(2):311-316.

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