The ocular history was negative. The infant was born at 38-weeks gestation to a mother with gestational diabetes. Birth weight was 7 lbs. Current weight was 20 lbs., 10 oz. The child had asthma treated with albuterol. Family history was negative.

Examination

On examination, the child seemed to be able to fix and follow in both eyes. Pupils were equally round with no afferent pupillary defect. Leukocoria was noted in the right eye. Extraocular movements appeared to be full. Slit lamp examination showed a clear cornea and no lens opacities in both eyes.

Figure 1. A solid-looking, round, elevated, yellow-white lesion was seen within the macula, abutting the optic nerve. Images: Patron ME, Duker JS

In the right eye, dilated fundus examination showed a solid-looking, round, elevated, yellow-white lesion within the macula, abutting the optic nerve (Figure 1). Some calcification was noted within the lesion. The vitreous was clear. Examination of the left eye was normal.

B-scan ultrasound (Figures 2a and 2b) measured the lesion to be 3.25 mm in height. The dimensions were 7.01 mm × 7.33 mm. The A-scan showed a high spike of internal reflectivity (Figure 2c), suggesting probable calcium within the lesion.

What is your diagnosis?

Mass within macula

The differential diagnosis for leukocoria in an infant includes posterior segment pathology such as retinoblastoma, Coats’ disease, persistent hyperplastic primary vitreous, retinopathy of prematurity, familial exudative vitreoretinopathy, toxoplasmosis, toxocariasis, retinal detachment, coloboma, Norrie’s disease and myelinated nerve fibers. Anterior segment pathology such as cataract, corneal opacities, and high myopia and anisometropia can also mimic a white reflex.

Based on the clinical appearance of a solid yellow-white mass within the macula with calcium within the lesion by ultrasound, a diagnosis of retinoblastoma was made.

Discussion

Retinoblastoma is the most common primary intraocular malignancy of infancy and early childhood. The cell of origin is thought to be a precursor cone photoreceptor cell or a multipotent retinoblast. Most cases present in the first or second year of life, although presentation in the teenage years can occur with rare cases of spontaneously regressed retinoblastoma reported in asymptomatic adults.

The overall incidence of retinoblastoma is estimated to be one in 15,000 to 30,000 live births. Retinoblastoma comprises about 4% of all pediatric malignancies. In the U.S., there are approximately 300 new cases each year, with that number rising to 5,000 to 8,000 worldwide.

Two-thirds of retinoblastoma cases are unilateral, and one-third are bilateral. Retinoblastoma is a disease of childhood, with most cases diagnosed by age 3 years and 90% by age 5 years. The age at presentation is 3 to 18 months for the heritable form and 18 to 24 months for the sporadic form. Germline tumors are diagnosed earlier because patients with a known family history typically undergo early screening exams before developing symptoms.

These tumors can be classified as sporadic or familial, unilateral or bilateral, and non-heritable/somatic or heritable/germline. True germline tumors account for 40% of cases and are due to a genetic mutation present in all cells of the body. These cases are usually bilateral and familial, and these patients are at risk for other non-ocular malignancies, including osteogenic sarcoma and pinealoblastoma. Somatic tumors account for 60% of cases. The mutation is only present in the abnormal retinal cells. These tumors are generally unilateral and sporadic. Genetic testing is available to identify germline mutations of the RB1 gene that has been mapped to chromosome 13q14.

Leukocoria is the most common presenting sign. Because a tumor in the posterior pole has to be large enough to generate a white reflex, leukocoria is often a late-presenting sign with poorer prognosis. Strabismus is the second major presenting sign. Patients may also present with other atypical signs or symptoms including red, painful eyes; cloudy cornea; poor vision; hyphema; vitreous hemorrhage; and signs of orbital inflammation mimicking cellulitis.

Funduscopically, retinoblastoma appears as a small, transparent lesion in its early states. The tumor becomes opaque and more visible when larger. As the tumor grows, it can be identified as endophytic or exophytic. Endophytic tumors are white to cream-colored masses. These tumors arise from the inner retinal layer, grow toward the vitreous cavity and have a tendency for vitreous seeding. The exophytic form is yellow-white and occurs in the subretinal spaces. These tumors arise from the outer retinal layers and expand beneath the retina toward the choroid, causing a solid retinal detachment. They can simulate Coats’ disease when there is associated subretinal fluid. These tumors can also invade the choroid and sclera.

Diagnostic evaluation includes a thorough eye examination, often under anesthesia. B-scan ultrasound is used to measure the tumor’s height and dimensions and to look for other tumors or vitreous seeding. Ultrasound can also detect calcium within the lesion, which is characteristic for retinoblastoma. A staging MRI of the brain and orbits is used to look for extraocular extension, infiltrative spread into the optic nerve and pinealoblastoma. Bilateral retinoblastoma with pinealoblastoma is known as trilateral retinoblastoma. A basic metastatic workup may include a bone scan, bone marrow biopsy and lumbar puncture with cytology.

The first goal of treatment is survival, followed by globe salvage, then preservation of vision. Systemic chemotherapy is the most common primary treatment. Chemotherapy is used to shrink the tumor until it is accessible to adjuvant focal treatment. Focal treatment options include laser photocoagulation, cryotherapy, plaque brachytherapy, subconjunctival chemotherapy and external beam radiation. Small, localized tumors may be treated with focal therapy alone. Enucleation is reserved for advanced tumors with no hope for useful vision or if there is concern for invasion into the nerve, choroid or orbit.

Summary

In summary, a 6-month-old girl with difficulty tracking and leukocoria in the right eye was found to have an exophytic macular retinoblastoma. Staging MRI showed no extraocular disease. There was no family history of retinoblastoma, and both parents were examined and found to have normal retinae. Genetic testing was negative for a germline mutation. After a detailed discussion with the parents, they elected to have the child undergo single treatment with no systemic chemotherapy. The patient underwent radiation iodine plaque therapy.

Figure 3. At 6 months, the retinoblastoma had regressed to a flat calcified lesion.

Examination under anesthesia at 6 weeks after plaque removal showed a flattened lesion with primarily calcium remaining. B-scan ultrasound measured the residual lesion to be 2.47 mm in height with dimensions 5.71 mm × 6.27 mm. At 6 months, the retinoblastoma had regressed to a flat calcified lesion (Figure 3). B-scan did not show any significant thickness to the lesion. There were no radiation complications, new tumors or evidence of systemic disease.

References:

• Kiss S, Leiderman YI, Mukai S. Diagnosis, classification, and treatment of retinoblastoma. Int Ophthalmol Clin. 2008;48(2):135-147.
• Lin P, O’Brien JM. Frontiers in the management of retinoblastoma. Am J Ophthalmol. 2009;148(2):192-198.
• Murphree AL, Samuel MA, Harbour JW, Mansfield NC. Retinoblastoma. In: Ryan SJ. Retina, Volume 1. 4th ed. Philadelphia: Elsevier; 2006:557-608.
• Poulaki V, Mukai S. Retinoblastoma: genetics and pathology. Int Ophthalmol Clin. 2009;49(1):155-164.
• Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol. 2006;17(3):228-234.

• Mark E. Patron, MD, and Jay S. Duker, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; Web site: www.neec.com.

• Edited by Mark E. Patron, MD, and Andre J. Witkin, MD. Drs. Patron and Witkin can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; Web site: www.neec.com.

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