Retinoblastoma is the most common primary intraocular malignancy of childhood and accounts for 2 percent of malignant tumors in children. Retinoblastoma typically presents as leukocoria (abnormal white reflection in the eye) in a child under the age of two years. The disease may affect one or both eyes and can appear sporadically or be familially inherited. The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell.

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Retinoblastoma

Image : “Retinoblastoma” by unknown. License: Public Domain


Epidemiology

  • Occurs in approximately 1 in 20,000 live births in the US
  • >300 cases in the US and Canada each year
  • Most common primary intraocular malignancy of childhood 
  • Accounts for 2% of malignant tumors in children
  • The main age of its manifestation is the first year of one’s life.
  • 80% of affected children are younger than 4 years of age 
  • The survival rate in the developing world for children with retinoblastoma is 50%.
  • 25–30% of cases of retinoblastoma are bilateral.
  • Girls and boys are both affected equally.
  • No racial predilection

Video Gallery

Retinoblastoma by Carlo Raj, MD
Retinoblastoma in Children by Brian Alverson, MD

Pathophysiology

  • Retinoblastoma is caused by a genetic mutation of the Rb1 or retinoblastoma gene
    • Oncogenic tumor suppressor gene located on chromosome 13 at 13q14
    • Involved in cell cycle regulation
    • Usually prevents the cell from going through G1 phase to the S phase by inactivating the E2F transcription factors
    • Mutation allows for the activation of E2F through hyperphosphorylation by the cyclin D1/cdk4 enzyme.
    • See Carcinogenesis
Retinoblastoma

“Retinoblastoma: Molecular Pathology” Image by Lecturio.

  • Familial or heritable form: (45% of cases) 
    • Child will inherit a non-functional allele of the Rb1 gene for all somatic cells.
    • Requires only one more sporadic mutation of the second allele in a retinal cell to induce the growth of a retinoblastoma
      • Inheritance is autosomal dominant with incomplete, but high penetration.
    • Tend to be bilateral and presents before the age of 1
    • Significantly higher risk of developing secondary tumors (osteosarcoma, spindle cell sarcoma, chondrosarcoma, rhabdomyosarcoma, glioma, leukemia, squamous cell carcinoma, and malignant melanoma)
  • Sporadic form: (55% of cases)
    • Child inherits two functioning alleles of the Rb1 gene.
    • “Two-hit hypothesis or phenomenon”: Two spontaneous somatic mutations occur in the retinal cells which leads to the development of a retinoblastoma.
    • Tends to be unilateral and presents between the ages of 2–5 years
    • Since the mutation is specific to the retinal cell, it does not increase the risk of malignancies in any other parts of the body.

Image: Two forms of retinoblastoma development Diagram of retinoblastoma development: familial, heritable, or one-hit form (Red arrow) on the left and sporadic or two-hit form on the right. The affected genes are represented in blue, while the healthy genes are in red. By Lecturio.

Video Gallery

Retinoblastoma – Carcinogenesis by Carlo Raj, MD
Cancer Hereditary by Georgina Cornwall, PhD

Clinical manifestation

    • Most common symptom: leukocoria or amaurotic cat’s eye reflex
      • White pupil is caused by the tumor-infiltrating the vitreous body
    • May present with a squint, nystagmus, strabismus, and defective vision
    • In rare cases, unilateral mydriasis, heterochromia iridum, or hyphema can be observed.
    • Clinical stages of retinoblastoma
      • Quiescent stage: The growth patterns can be classified into intraretinal (limited to the retina), endophytic (invades the vitreous cavity), and exophytic (grows externally from the retina). 
      • Glaucomatous stagearises from untreated tumors that present with redness, pain, and excessive tearing
      • Extraocular stage: Due to progressive tumor enlargement, the tumor burst the ocular globe open through the sclera at the limbus. This results in fungating masses and proptosis.
      • Stage of metastasis: may be lymphatic to preauricular lymph nodes, by direct extension via the optic nerve to the brain, and hematogenous to the brain and other organs

Diagnosis

  • Start by taking detailed history, performing adequate physical examination, and using a set of ocular examinations (including external ocular examination, slit-lamp examination, and binocular indirect ophthalmoscopy).
  • Tumors can be visualized by examining the ocular fundus.
    • Present as calcium deposits and may cause retinal detachment
    • Infiltration of the vitreous body or anterior chamber can be seen clearly with indirect ophthalmoscopy. 
  • Order ancillary imaging to determine extent of the malignancy.
    • Fluorescein angiography is used to assess the vascularity of the tumor.
    • Ultrasonography and CT scans of the orbit help determine the extent of the tumor. 
    • MRI is helpful in evaluating the status of the optic nerve, orbit, and brain.
  • If skeletal metastasis is suspected, bone scintigraphy may be required.
  • Genetic testing is recommended in order to determine germline vs somatic mutations and ensure tumor surveillance/risk for the patient and its family.
  • Reese-Ellsworth classification: Staging and planning of therapy is made on the basis of a spinal tap and a bone marrow examination.
    1. Single tumor diameter < 4 mm or multiple tumors none over 4 disc-diameters in size all at or behind the equator
    2. Single tumor diameter 4-10 mm or multiple tumors with 4 to 10 disc-diameters behind the equator
    3. Tumor diameter > 10 mm or any tumor anterior to the equator
    4. Multiple tumors with a disc diameter larger than 10mm or any lesion extending anteriorly to the ora serrata
    5. Tumor involving more than half of the retina or vitreous seeding

Treatment

  • The main goals of treatment are saving the patient’s life and saving the ocular globe for aesthetic, psychological, and social reasons.
  • Conservative treatment is only indicated when it’s possible to retain a certain degree of vision. 
    • Photocoagulation: therapy of choice for small retinoblastomas behind the equator of the eye
    • Cryotherapy 
    • External beam radiotherapy: Consequent checkups are crucial to prevent or diagnosis certain complications early (osteosarcoma, radiogenic cataract).
    • Brachytherapy: ruthenium-106 patched onto sclera
    • Adjuvant chemotherapy: recommended when the tumor has metastasized
  • Enucleation: treatment of choice in the following cases
    • Advanced disease (Reese-Ellsworth group IV or V)
    • No hope for useful vision in the affected eye
    • Invasion of the optic nerve, choroid, or orbit
  • In the case of large tumors, chemo-reduction with or without external beam radiotherapy might salvage the globe, which is then followed by photocoagulation or cryotherapy.

Differential diagnoses

  • Glaucoma: a group of eye diseases traditionally characterized by elevated intraocular pressure (IOP). However, glaucoma is more accurately defined as an optic neuropathy involving characteristic atrophy of the optic nerve head, which may or may not be accompanied by elevated IOP.
  • Cataracts: a clouding of the lens in the eye which leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble with bright lights, and trouble seeing at night.
  • Strabismus: the misalignment of an eye in regards to the normal visual axis. This will result in the impairment or inability to fuse the images perceived by both eyes.
  • Retinal detachment: the detachment of the inner layer of the retina from the retinal pigment epithelium. Usually caused by direct trauma to the eye or tears due to vitreous degeneration.
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