A White Reflex in a Previously Healthy 21-Month-Old Boy

A 21-month-old boy presents to the ophthalmology clinic after an injury to the eye from a toy. His family describes that the patient’s right eye has been developing a “shiny center” prominent under light starting around 12 months of age. The family noticed this spot continued to grow until around 18 months when they no longer noted any black part of the eye. The patient regularly follows with a pediatrician and has been healthy, meeting all developmental milestones. The family explains they forgot to mention the patient’s eye at pediatrician appointments, and they do not recall any eye examination abnormalities mentioned at well-child visits. On examination, the patient favors keeping his right eye closed and is fussy when the left eye is covered. The left eye is central, is steady, and maintains fixation on objects during the examination, but the right eye is central, steady, and unmaintained. The right eye is deviated outward consistent with exotropia. Both pupils are round, but the right pupil does not constrict in response to light. Intraocular pressure measures 38 and 14 in the right and left eye, respectively (normal 10–21). The right eye appears injected with a white pupillary reflex (Figure 1). The lens is clear. The left eye is unremarkable (Figure 1). Dilated fundus examination of the right eye reveals a white mass with irregular, intrinsic vasculature occupying more than 50% of the globe with associated serous retinal detachment and no view of the optic disc (Figure 2). B-scan ultrasonography of the right eye confirms an intraocular mass with intrinsic calcifications (Figure 3). Ocular examination and ultrasonography results confirm the diagnosis.Leukocoria is an altered pupillary reflex that appears white.1 The differential diagnosis for leukocoria is wide, including Coats disease, persistent fetal vasculature, retinoblastoma, ocular toxocariasis, retinal detachment, and cataract.1,2 This patient had leukocoria with a partially calcified mass present on ultrasound, pointing toward a diagnosis of retinoblastoma. Biopsy is not recommended or needed to diagnose retinoblastoma. Examination findings and imaging are sufficient to diagnose this cancer.Retinoblastoma is the most common malignancy of the eye in children with an incidence of approximately 1 in 17 000 live births.3 Most cases are identified by age 5, and two-thirds are diagnosed by age 2.4 Retinoblastoma occurs as the result of mutations in the retinoblastoma gene, RB1.4 Retinoblastoma can occur in a bilateral, heritable form in about 25% of cases, or a unilateral, sporadic fashion in approximately 75% of cases.4 The highly proliferative nature of retinoblastoma subsequently causes tissue damage and necrosis leading to calcification.5 Therefore, calcifications are often more prominent in advanced tumors.5 Although survival in patients with retinoblastoma is favorable in high-income countries, mortality is significantly higher in low- and middle-income countries where disease is often discovered in later stages.6In more than half of retinoblastoma cases, the initial clinical manifestation is leukocoria.7 In a review by Shields et al, the most common lesions mimicking retinoblastoma were persistent hyperplastic primary vitreous, Coats disease, and presumed ocular toxocariasis.2 These conditions can present with leukocoria and disrupt visual development, potentially leading to vision loss. Coats disease, an idiopathic disease characterized by abnormal retinal vasculature, can be distinguished on examination by the presence of xanthocoria, a yellow/orange pupillary reflex, rather than the white reflex of a partially calcified tumor.8 Parents are more likely to notice findings of leukocoria and strabismus rather than the pediatrician or ophthalmologist.9 Therefore, asking parents about white or shiny pupils can help identify leukocoria early. Whether leukocoria is secondary to retinoblastoma or another diagnosis, a workup and ophthalmology evaluation are indicated.The second most common presenting sign of retinoblastoma is strabismus, misalignment of the eyes.7 When strabismus is a presenting sign of retinoblastoma, this often indicates the tumor has worsened visual acuity in one eye by growing near the fovea.7 Therefore, the brain diverts attention toward the better seeing eye and away from the eye with retinoblastoma and poor vision, causing the eye to drift. If parents or patients mention drifting or lazy eyes, checking for leukocoria with an ophthalmoscope and a referral to ophthalmology are indicated.Imaging studies such as ultrasound and magnetic resonance imaging (MRI) differentiate retinoblastoma from other causes of leukocoria by demonstrating a mass in the eye. Use of computed tomography imaging in suspected retinoblastoma is not preferred because radiation exposure can increase the risk of a second primary cancer in children with germline retinoblastoma.6 Calcifications within the eye tumor can be detected by ultrasound, so computed tomography is not needed for diagnosis. Retinal detachment or vitreous hemorrhage can present concurrently with retinoblastoma.7 After a diagnosis of retinoblastoma, an important initial step is evaluating for metastasis. This can include imaging of the brain, lumbar puncture for cerebrospinal fluid evaluation, bone scans, and bone marrow aspiration and biopsy. Extensive workup may not be required in clearly localized disease, but all children require an MRI to look for pinealoblastoma. Pinealoblastoma can occur concurrently with bilateral retinoblastoma in patients with germline mutations; this is often referred to as trilateral retinoblastoma and carries a poor prognosis.10Retinoblastoma is a disease that can go unnoticed until late in its course. Examining every child for leukocoria with a direct ophthalmoscope is a simple, efficient way to help detect retinoblastoma earlier when there is a better prognosis. When discovered late such as in this patient, the likelihood of metastasis increases. Although leukocoria does not unequivocally mean a retinoblastoma diagnosis, detecting leukocoria on physical examination is an important step in the detection of retinoblastoma, as well as other vision threatening conditions.Retinoblastoma classification and staging are important for developing a proper treatment plan. Classification and staging often require an eye examination under anesthesia to fully assess the extent of the tumor.6 The American Joint Committee on Cancer cTNMH scheme is used for retinoblastoma. This system involves categorizing retinoblastoma based on characteristics of the primary tumor (T), regional lymph node involvement (N), metastasis (M), and presence of the heritable trait (H).11 Classification of intraocular disease burden is often done with the International Classification of Retinoblastoma, which classifies tumors from A to E.12 Genetic testing is also indicated in retinoblastoma cases to determine if a germline mutation is present, which influences management.6 Although most germline mutations result in bilateral disease, 16% of patients with a unilateral retinoblastoma demonstrate a germline mutation, highlighting the importance of genetic testing in all cases.10Treatment of retinoblastoma depends on the staging and classification. Treatment can involve intravenous chemotherapy, intra-arterial chemotherapy, which delivers medication specifically to the ophthalmic artery, intraocular chemotherapy, cryotherapy, transpupillary thermotherapy, and potentially enucleation.6 Enucleation is typically reserved for more advanced or refractory disease.6 Retinoblastoma treatment requires important care coordination among pediatricians, oncologists, and ophthalmologists, often with both an ocular oncologist and a pediatric ophthalmologist for cancer treatment and visual rehabilitation, respectively. A connected care team knowledgeable about retinoblastoma is important for quality care for these patients. Pediatricians are often the first and only contact for young, otherwise healthy patients. Their role to recognize potential signs of retinoblastoma and refer appropriately is essential.The goal of retinoblastoma treatment is to first save the patient’s life, ideally with therapies that avoid radiation. Although the eye can sometimes safely be saved, in cases of extensive disease such as our patient, vision and globe-sparing therapies may not be compatible with best practices for prevention of metastatic disease. Retinoblastoma can be a devastating diagnosis when caught late. When left untreated, retinoblastoma can extend to tissues beyond the eye. Thus, early detection is important not only to facilitate preserving eyesight but also to avoid life-threatening advanced disease.An MRI was done urgently to determine if globe-sparing treatment options could be offered. The MRI confirmed an enhancing, calcified right intraocular mass with serous retinal detachment (Figure 4). The right optic nerve was involved extending to the prechiasmatic segment. There was no other intracranial disease. Because of extensive optic nerve involvement, globe-sparing treatment was not safe, and a surgically clean optic nerve margin would not be feasible. The eye was enucleated with partial removal of the optic nerve stump with positive margins (Figure 5), with a plan to follow with chemotherapy. Metastatic workup at the time of initial treatment showed no metastasis. Under the direction of pediatric oncology, the patient received ARET 0321 chemotherapy consisting of 4 cycles with vincristine, cisplatin, cyclophosphamide, and etoposide followed by autologous stem cell transplant and proton beam irradiation to the unresectable involved optic nerve stump. Genetic testing revealed no germline retinoblastoma mutation. Unfortunately, about 1 year after his original diagnosis, an MRI demonstrated a new intracranial tumor suggestive of metastasis (Figure 6). The frontal lobe mass was successfully resected, but several months later, tumor growth was seen again in the anterior cranial fossa and right temporal lobe. The patient transitioned to hospice care and died a year and a half after his initial diagnosis.SummaryRetinoblastoma is the most common intraocular malignancy of childhood and comprises 3% of all pediatric cancers.4Prognosis and survival rates in retinoblastoma are dependent on the stage of disease when treatment is initiated. Later stage tumors are associated with poor prognosis.12The most common clinical sign of retinoblastoma is leukocoria, a white pupillary reflex, often initially noticed by a family member.7,9 Although leukocoria can be seen with direct ophthalmoscopy, subtle leukocoria may be difficult to detect in an undilated pupil, especially if the child is moving during examination. Any parental concerns including reflections or shine in the pupil should prompt ophthalmology referral.Strabismus is another possible presenting sign of retinoblastoma, which also warrants referral to an ophthalmologist.7Assessing the red reflex is a critical part of the well-child examination for infants. Recognizing the clinical signs of retinoblastoma at pediatric well visits can play a key role in discovering retinoblastoma as early as possible when prognosis is more favorable.Workup of retinoblastoma should always involve genetic testing and eye examination under anesthesia with fundus photography, B-scan ultrasonography, and MRI of the brain and orbits.Treatment of retinoblastoma involves coordination of care among multiple medical teams and can involve different modalities of chemotherapy, focal laser or cryotherapy, and potentially enucleation.6