Retinoblastoma

Retinoblastoma is a rare tumor but the most common primary intraocular malignancy 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 (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.

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Epidemiology

  • Most common primary intraocular malignancy of childhood 
  • Incidence: 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 age of diagnosis is 1820 months. 
  • Approximately 40% of cases are heritable. 
  • Survival
    • In resource-rich countries: > 95%
    • In resource-limited/developing countries: < 30%

Pathophysiology

  • Retinoblastoma is caused by a genetic mutation of the retinoblastoma gene (RB1 or RB) in 98% of cases.
    • RB1 is a key negative regulator of the G1/S cell cycle 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 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 of the RB1 gene, which is present in all somatic cells.
    • Only 1 more (sporadic) mutation of the 2nd allele 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 form” (now called the “Non-heritable form”) on the right. In the heritable form, a mutated RB1 gene (in blue) is passed on to the child, and only one additional mutation in the paired normal allele (in red) is needed to develop the tumor. In the nonheritable form, the RB1 gene 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 in both alleles and thereby creating a retinoblastoma tumor.

Image by Lecturio.

Clinical Presentation

  • Cardinal signs: 
    • Leukocoria 
    • Strabismus
  • Less common signs and symptoms: 
    • Decreased vision
    • Ocular inflammation 
    • Vitreous hemorrhage
    • Glaucoma
    • Anisocoria
    • Apoptosis
  • Histology:
    • Rarely needed to confirm the diagnosis
    • A biopsy is contraindicated because of the risk of tumor seeding. 
    • Three growth patterns are seen: exophytic (beneath the retina), endophytic (into the vitreous), and diffusely infiltrating (rare, grows within the retina).

Diagnosis

  • Urgent referral to ophthalmologist
  • Ophthalmoscopic examination under anesthesia, with ultrasound imaging
  • Magnetic resonance imaging (MRI) of the brain and orbits
  • No need for formal staging studies (i.e., bone marrow examination, lumbar puncture, and/or radionuclide bone scan) → metastases rarely present at time of diagnosis
  • Genetic testing is recommended.

Management and Prognosis

Management

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

  • Small, uncomplicated extrafoveal tumors: cryotherapy or laser photocoagulation
  • More advanced stages: local and systemic chemotherapy, radioactive plaques 
  • Anatomical or functional impairment by tumor: 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

  • Survival: > 95% in resource-rich countries; < 30% in countries with very limited resources
  • Prognosis for vision depends on extent of tumor: 50% of patients reach a final visual acuity of 20/40 or better.

Differential Diagnosis

The differential diagnosis includes any condition that can cause leukocoria.

  • Persistent fetal vasculature: failure of the embryonic primary vitreous and hyaloid vascular system to involute during gestation. Visual prognosis is poor. 
  • Retinopathy of prematurity (ROP): a potentially blinding eye disorder that primarily affects premature 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. Most cases of ROP are mild.
  • Cataract: a congenital or acquired condition in which the lens of the eye becomes progressively opaque, resulting in blurred vision.
  • Coats disease: an idiopathic disorder characterized by retinal telangiectasia with breakdown of the blood-retinal barrier. Most commonly affects children. Can cause retinal detachment and blindness.
  • Vitreous hemorrhage (VH): the presence of blood within the vitreous cavity. Three conditions cause most VH cases: ocular trauma, posterior vitreous detachment associated with retinal detachment, and proliferative diabetic retinopathy.  
  • Ocular toxocariasis (ocular larva migrans): a rare infection caused by roundworms, Toxocara canis, and Toxocara cati. Presents with posterior uveitis and is associated with reduced vision, photophobia, floaters, and leukocoria.
  • Familial exudative vitreoretinopathy: a group of rare inherited diseases with abnormal retinal angiogenesis causing incomplete vascularization of the peripheral retina. Can lead to secondary neovascularization with progression to blindness.
  • Coloboma: a development disorder due to failure of the optic (choroid) fissure to fuse so that a defect may be present anywhere along the inferior portion of the eye, from the optic disc to the iris. A large optic disc and chorioretinal coloboma can cause leukocoria.
  • Retinal astrocytic hamartoma: a usually indolent tumor that occurs in roughly half of patients with tuberous sclerosis complex. 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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