History of present illness
A 2-year-old male patient with no medical history presented to clinic with 4 months of an “enlarged, gold right pupil” with some “turning out of the right eye and pain” per the patient’s mother.
Ocular examination findings
Visual acuity was assessed as “fixes and follow” in both eyes. Intraocular pressure was normal to palpation in both eyes. There was a 4+ relative afferent pupillary defect in the right eye. Extraocular movements were full, and the patient was orthophoric with intermittent right eye exotropia.
Anterior segment examination was overall unremarkable, as both eyes exhibited normal adnexa, white and quiet conjunctiva, clear corneas, deep and quiet anterior chambers, and clear lenses. On later examination under anesthesia, neovascularization of the iris of the right eye was present; the left iris was normal.
Dilated funduscopic examination in the right eye revealed leukocoria with diffuse vitreous cells that obscured the view of the optic nerve and macula. Inferiorly, there were snowball-like opacities present. Superiorly, there was a region of subretinal white exudate or possible calcification. The left eye revealed a healthy-appearing optic nerve, well-perfused retinal blood vessels, flat and attached macula, and no abnormalities in the periphery ( Fig. 46.1 ).
Imaging
B-scan ultrasonography demonstrated numerous vitreous opacities and posterior exudative retinal detachment, along with a hyperechoic mass lesion in the subretinal space. When the gain was decreased to zero dB, there were still opacities present inferiorly, which with higher gain demonstrated posterior shadowing, highly suggestive of calcification. The left eye was normal. A representative B-scan illustrating similar findings is shown in Fig. 46.2 .
Magnetic resonance imaging (MRI) of the brain and orbits (with and without contrast) revealed a mildly hyperintense enhancing tissue mass measuring 0.8 cm × 2.2 cm in the posterior third of the right globe and retina with some extension of enhancement into the distal 5 mm of the optic nerve. The tissue exhibited a gradient echo susceptibility, likely secondary to calcification ( Fig. 46.3 ).
Questions to ask
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What is the patient’s medical history? Specifically, is there any history of inflammatory or infectious conditions? Any history of TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus) infections? Trauma?
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None. Inflammatory or infectious conditions would have more suggestive history and may also be bilateral. Old trauma may present as dehemoglobinized, white vitreous hemorrhage that could mimic cells of inflammation or seeds of retinoblastoma. Congenital infections may also be bilateral.
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Does the patient have any systemic signs or symptoms?
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None. Inflammatory or infectious causes may have more systemic manifestations. TORCH infections, tuberculosis and sarcoidosis, and other alternative diagnoses may present with systemic manifestations, as well as with eye findings. However, these would be unlikely to include an ocular mass lesion resembling retinoblastoma. Only a late presentation of retinoblastoma with metastatic spread would likely have systemic findings beyond the eye.
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Is there a family history of any ocular conditions or systemic malignancies?
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No eye conditions.
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Paternal grandfather has a history of non-Hodgkin lymphoma.
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Assessment
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This is a 2-year-old male patient with no medical history who presented with leukocoria in his right eye, with examination and imaging findings concerning for retinoblastoma.
Differential diagnosis
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Cataract
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Coats disease (retinal telangiectasis)
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Familial exudative vitreoretinopathy (FEVR)
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Incontinentia pigmenti
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Myelinated retinal nerve fiber layer
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Persistent fetal vasculature (PFV)
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Retinoblastoma
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Toxocariasis
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Uveitis (infectious and/or inflammatory)
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Old vitreous hemorrhage
Working diagnosis
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Unilateral nonhereditary retinoblastoma, group E (International Classification of Retinoblastoma)
Multimodal testing and results
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Fundus photographs
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Fundus photographs are useful to document the presence of vitreous seeds and the tumor appearance if visible on examination.
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Ultrasound
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B-scan ultrasound generally demonstrates a hyperechoic mass with dense opacities and posterior shadowing in the presence of calcifications. Dimensions of the tumor can also be estimated.
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MRI
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MRI is important both for ocular assessment of retinoblastoma along with any potential extraocular extension. Pineal gland assessment is also important to determine whether pineoblastoma is present.
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MRI is preferred over computed tomography scan to avoid radiation exposure, which can be particularly harmful in patients with retinoblastoma, especially in the heritable subtype.
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Our patient’s MRI showed possible extension 5 mm into the distal optic nerve.
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Genetic testing
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Genetic testing was negative, consistent with sporadic, unilateral retinoblastoma.
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Management
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Intravenous chemotherapy involves a combination of agents, typically vincristine, etoposide, and carboplatin, in six to nine consecutive cycles and is pursued with germ-line mutation, a positive family history, or invasive disease.
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Intraarterial chemotherapy provides local treatment that can achieve higher drug delivery and may be well suited for unilateral disease but requires special centers for administration. It may also be employed for globe salvage in refractory tumors and even tandem therapy in select cases. ,
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Local treatments with cryotherapy and transpupillary thermotherapy with diode laser can aid in tumor consolidation with the above systemic therapies and for small, focal intraocular seeds.
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Intravitreal chemotherapy may be considered with refractory or recurrent vitreous seed involvement, , and intracameral injection can be performed to attend to anterior chamber seeding. ,
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Brachytherapy (plaque-radiotherapy) may be used with diffuse anterior segment involvement and in medium-sized chemoresistant tumors that have recurred after systemic therapy. ,
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Enucleation remains an important option especially in group E disease and in other select circumstances, such as realized or suspicion for extraocular extension or after failed salvage therapies.
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External beam radiation can be employed after enucleation with orbital or optic nerve extension or recurrence; however, this increases the risk of secondary malignancies in patients with germline mutations. ,
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Our patient underwent enucleation soon after the initial visit, with pathology confirming a diagnosis of retinoblastoma with extension into the choroid and optic nerve beyond the lamina cribrosa, though the nerve surgical margin was free of tumor. Per the hematology/oncology service, the patient was considered high risk for systemic metastasis and initiated intravenous chemotherapy (vincristine, carboplatin, etoposide) for a total of six rounds. The patient has since been disease free with no evidence of recurrence.
Follow-up care
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Patients should be surveilled closely after successful treatment, with high attention paid to local recurrence within 3 years after completion of treatment when risk of disease recurrence is highest, and at least through 7 years of age. Late ocular recurrences are less common but remain possible. ,
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Genetic testing to determine the presence of germline retinoblastoma or mosaicism is important to assess lifetime risk of other malignancies in the patient as well as the need for examinations under anesthesia for surveillance. Family members may also undergo retinoblastoma genetic testing in heritable cases.
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The patient should follow with a pediatric, and later, adult oncologist or cancer survivor clinic for monitoring for secondary malignancies associated with germline mutations in retinoblastoma, which represent a 20% risk. These germline patients are at particular risk of secondary malignancy after external beam radiation, who are at 40% risk.
Key points
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Retinoblastoma can masquerade as other ophthalmic diseases and delay treatment.
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Multiple assessments are integrated simultaneously and in parallel to confirm the diagnosis of retinoblastoma ( Fig. 46.4 ).
