Jerry A. Shields
• Eye cancer of children
• Tends to manifest between 6 months and 3 years of age
• Accounts for 4% of all childhood malignancies
• Can occur in one (unilateral) or both (bilateral) eyes
• Can have a sporadic or familial tendency
• Can be germline or somatic mutation
• Appears as a white mass within the retina, best seen on dilated eye examination
• In more advanced stages can present with white pupil (leukocoria), red eye, or glaucoma
• International Classification of Retinoblastoma (RB) includes
– Group A – RB <3 mm
– Group B – RB >3 mm or in the macula or with clear subretinal fluid
– Group C – RB with subretinal or vitreous seeds <3 mm from tumor
– Group D – RB with subretinal or vitreous seeds >3 mm from tumor
– Group E – extensive RB fill >50% globe or with hemorrhage or iris neovascularization
Any child with leukocoria (white pupil) or strabismus (drifting eye) should have a dilated examination by a qualified ophthalmologist to evaluate for fundus abnormalities, particularly malignancies such as retinoblastoma.
The intraocular scar from this malignancy should be followed for life. More important consideration in the older population with retinoblastoma is the risk for second cancers in those with germline mutation.
Retinoblastoma nearly always manifests in children, usually those under age 3 years.
If a pregnant woman has a family history of retinoblastoma, then the fetus should be imaged with ultrasonography at 8-month gestation in utero to evaluate the eyes. If retinoblastoma is detected, then early but safe delivery can be considered.
1/15,000 newborn infants
Retinoblastoma develops in 5,000 children worldwide and 300 children in the USA annually.
There is no known cause for Rb1 mutation.
• In 1971, Knudson “2 hit” hypothesis for the development of retinoblastoma was proposed.
• In 1980, research confirmed that both alleles of retinoblastoma gene (RB1) at chromosome 13q14 locus were mutated in retinoblastoma.
• Currently, there are arguments that genomic instability and aneuploidy are likely responsible for the genesis of Rb.
• For patients with known germline mutations, there are several methods of prevention, including the following:
– Avoid having children.
– Use donor germ cells to avoid transmission of the genetic defect.
– In vitro fertilization with preimplantation genetic sampling at the 8-cell morula stage for the Rb gene can identify affected individuals. Those not affected can be implanted.
• For patients with somatic mutations, the defect does not transmit to future generations but it is important to examine the eyes of all children within 2 weeks from birth.
Some authorities believe that retinoblastoma develops from an undifferentiated cell or a retinal progenitor cell whereas others believe that a fully differentiated horizontal cell of the retina is the cell of origin.
The etiology for retinoblastoma is a genetic mutation on chromosome 13q14 in all cells in the body in germline retinoblastoma and in only the tumor in somatic retinoblastoma.
COMMONLY ASSOCIATED CONDITIONS
• 13q syndrome:
– This syndrome is related to the phenotypic abnormalities from the mutated portion of chromosome 13.
– Features include microcephaly, broad nasal bridge, hypertelorism, microphthalmos, epicanthus, ptosis, micrognathia, short neck, low set ears, facial asymmetry, anogenital malformations, hypoplastic thumbs and toes, mental and psychomotor retardation.
• The infant or toddler gives no history
• The parent might note leukocoria or strabismus
• The most common sign is the white pupil (leukocoria) in an otherwise quiet comfortable eye.
• The second most common sign is crossed eye (strabismus) where the eye drifts inward or outward.
• Red eye
• Bulging eye
• Droopy eyelid (ptosis)
DIAGNOSTIC TESTS & INTERPRETATION
Complete blood count
• Ultrasonography to confirm the mass, retinal detachment, and calcification
• Fundus photography to document tumor size and location
• Intravenous fluorescein angiography to document blood supply to the tumors
• Brain and orbit magnetic resonance Imaging to rule out extraocular spread and rule out pinealoblastoma
Follow-up & special considerations
Monitor monthly for tumor regression then slowly increase the interval between visits if all malignancy stable.
Do not perform fine needle aspiration biopsy as this could seed the tumor.
• Gross findings:
– Chalky white friable tumor
– Dense foci of calcification
– Retinal detachment
– Scleral, optic nerve, or epibulbar invasion
• Microscopic findings:
– Small to medium sized round neuroblastic cells with large hyperchromatic nuclei and scanty cytoplasm
– Well or poorly differentiated cells
– Growth patterns:
Exophytic – growth underneath the retina
Endophytic – growth superficial to the retina in the vitreous
Intraretinal – growth within the retina
Diffuse – flat infiltration
• Coats disease
• Persistent hyperplastic primary vitreous
• Retinal astrocytic hamartoma
• Retinal astrocytoma
• Combined hamartoma of the retina and retinal pigment epithelium
• Retinal detachment
• Familial exudative vitreoretinopathy
• Intravenous chemoreduction consisting of vincristine, carboplatin, and etoposide followed by thermotherapy or cryotherapy
• Intraarterial chemotherapy with melphalan
• If group A, treat with laser photocoagulation or cryotherapy
• If group B, treat with chemoreduction or plaque radiotherapy
• If group C, treat with chemoreduction
• If group D or E, treat with chemoreduction or enucleation
• Note that intraarterial chemotherapy can be substituted for intravenous chemoreduction in certain select cases.
Issues for Referral
All children with retinoblastoma should be referred to and managed at retinoblastoma centers of excellence. There are perhaps only 6 such centers in the USA.
• Enucleation for advanced tumors or massive tumor recurrence
• Plaque radiotherapy for smaller tumors or tumor recurrence
• External beam radiotherapy
Ophthalmic treatment is outpatient.
• If germline mutation, then mag resonance imaging of the eye and brain to rule out pinealoblastoma or related brain tumor and lifelong follow-up for second malignancies
• If somatic or germline mutation:
– Fundus examination with treatment every month until the retinoblastoma is completely regressed and stable for 3 months; then slowly increase the interval of the follow-up to every 2 months, then every 3 months, and so on.
Examination under anesthesia until age 4 years for the eyes, and evaluation by pediatric or adult oncology for life.
• In developed countries, prognosis has improved from 5% survival in the early 1900s to 50% in the 1930s to 98% currently.
• In undeveloped countries prognosis currently remains approximately 50% survival, likely related to delay in diagnosis.
• Vision loss
• Loss of the eye
• Dry eye
• Retinal atrophy
• Retinal detachment
• Facial deformity
• Second cancers
• Hungerford JL, Toma NM, Plowman PN, et al. External beam radiotherapy for retinoblastoma: I. Whole eye technique. Br J Ophthalmol 1995;79:109–111.
• Kivela T. Trilateral retinoblastoma: A meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 1999;17:1829–1837.
• Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with retinoblastoma. Ophthalmology 1988;95:1583–1587.
• Shields CL, Au A, Czyz C, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113(12):2276–2280.
• Shields CL, Honavar SG Meadows AT, et al. Chemoreduction plus focal therapy for retinoblastoma: Factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 2002;133:657–664.
• Shields CL, Shields JA. Basic understanding in the current classification and management of retinoblastoma. Curr Opin Ophthalmol 2006;17(3):228–234.
• Shields JA, Shields CL. Management and prognosis of retinoblastoma. Intraocular tumors: A text and atlas. Philadelphia: WB Saunders 1992:377–392.
• Shields JA, Shields CL. Retinoblastoma. In: Shields JA, Shields CL, eds. Atlas of intraocular tumors. Philadelphia: Lippincott Williams Wilkins 1999:207–232.
• Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: Long term tumor control and treatment complications in 208 tumors. Ophthalmology 2001;108:2116–2121.
• Toma NM, Hungerford JL, Plowman PN, et al. External beam radiotherapy for retinoblastoma: II. Lens sparing technique. Br J Ophthalmol 1995;79:112–117.
190.5 Malignant neoplasm of retina
• Any child with leukocoria or strabismus should be evaluated by an experienced ophthalmologist familiar with retinoblastoma.
• Chemotherapy has become the most common method for management.
• Enucleation is still a powerful method of tumor control and life salvage.