The most common presentation of retinoblastoma in the United States is leukocoria, although its specificity to the malignancy is low.1 Of such lesions simulating retinoblastoma, Coats’ disease may be particularly confounding because of overlapping features such as total retinal detachment and abnormal retinal vasculature,2 which can delay retinoblastoma diagnosis and worsen patient prognosis.3 Several of the presentations that retinoblastoma may masquerade as result at least in part from the inflammatory reaction necrotic tumor cells elicit, with simulation of conjunctivitis, endophthalmitis, and even orbital cellulitis well documented.1,4,5 We report two cases notable in that the diagnosis of retinoblastoma was equivocated by an exuberant Coats’ response—a rare manifestation that if incorrectly deemed the primary pathological process would almost certainly result in patient death.
A 19-month-old girl was referred to the pediatric ophthalmology clinic by an outside physician with a chief complaint of an erythematous, swollen right eye first noted 1 month prior. The patient’s medical, ocular, perinatal, and family history were unremarkable. The patient’s affected eye was unable to fix and follow with pupillary examination revealing a right relative afferent pupillary defect. Adnexal examination demonstrated mild ptosis and esotropia of the patient’s right eye. Anterior segment examination of both eyes was unremarkable with an intraocular pressure of 12 mm Hg noted in both eyes. Posterior segment examination (performed under anesthesia) demonstrated a complex exudative retinal detachment overlying a multifocal tumor mass with subretinal and vitreous seeding. Vascular dilatation with a massive Coats’ response was also noted throughout the retina and confounded a view of the entire tumor and right optic nerve (Fig. 1A). The posterior segment of the patient’s left eye was unremarkable.
Figure 1. (A) Montage photograph of the right fundus of case 1. Complex exudative retinal detachment with an underlying multifocal (stage 5b) retinoblastoma. Subretinal and vitreous seeding was noted as was diffuse retinal vascular dilatation. (B) Montage photograph of the right fundus of case 1 after chemoreduction and laser application. Tumor demonstrated calcified (type 1) involutional regression. (C) Histopathologic examination disclosed a largely undifferentiated exophytic tumor with numerous clefts (asterisks) representing areas of exudate lost in tissue processing (hematoxylin–eosin, original magnification ×100). (D) Higher magnification identifying areas of tumor necrosis and calcification with adjacent exudate. Approximately 15% of the tumor was viable at the time of enucleation (hematoxylin–eosin, original magnification ×250).
Contact ultrasonography of the right eye done under anesthesia demonstrated dense and diffuse vitreous opacities with a detached and diffusely thickened retina inserting into the optic disc and partially adherent to the fundus at the 8-o’clock position. This area demonstrated marked calcification and maximal retinal thickening (8.2 mm). No increase in the optic nerve diameter nor extraocular extension of the tumor was noted. The patient was therefore diagnosed as having unilateral, non-familial stage 5B retinoblastoma and a concomitant Coats’ response.
She was initially treated with large spot size diode laser and systemic work-up revealed a single cluster of potential metastatic foci identified on bone marrow biopsy. The patient then underwent nine cycles of systemic chemoreduction therapy (carboplatin, vincristine, and cyclosporine) with several more diode laser applications. Serial follow-up examinations demonstrated diffuse type 1 mixed tumor involutional regression (Fig. 1B), although with regions of persistent vascular activity. Repeat systemic assessment (bone marrow biopsies, lumbar punctures, and magnetic resonance imaging) were consistently negative, but the patient developed neovascular glaucoma and intumescent lenticular changes prompting definitive enucleation. Histopathologic analysis revealed a primarily exophytic tumor (Figs. 1C and 1D) with large areas of calcification, necrosis, and intraretinal and subretinal exudates.
A 4-year-old girl was seen in consultative evaluation after being referred for leukocoria and decreased visual acuity in the right eye. The patient’s medical, ocular, perinatal, and family history were unremarkable. On examination, her visual acuity was 5/200 and 20/30 in the right and left eyes, respectively, with her right eye demonstrating both leukocoria and an afferent pupillary defect. Both of her eyes were soft to palpation. Anterior segment examination of both eyes was otherwise unremarkable. Posterior segment examination revealed a diffuse subretinal exudative retinal detachment with overlying telangiectasias, cotton wool spots, and a secondary angioma (Figs. 2A and 2B). Although the appearance of the lesion was most consistent with Coats’ disease, there was suspicion for an underlying late presentation (atypical) retinoblastoma with Coats’ response.
Figure 2. (A) Montage photograph of the right fundus of case 2 demonstrating retinal detachment with massive exudative response. (B) Area of retinal detachment demonstrating telangiectatic vessels and aneurysms. (C) B-scan ultrasonography reveals a smooth, dome-shaped, endophytic mass of low to medium internal reflectivity consistent with a small retinoblastoma lesion. (D) Follow-up examination reveals underlying tumor most consistent with retinoblastoma. (E) Progressive tumor involutional response and decrease in exudative retinal detachment following direct laser ablation and intra-arterial superselective melphalan chemotherapy. (F) Further tumor involution and metaplastic pigment alterations following treatment.
B-scan ultrasonography demonstrated an endophytic mass most consistent with early retinoblastoma (Fig. 2C). Thus, intravitreal therapy was avoided and the patient was treated on several separate occasions with laser ablative therapy and observed closely. After three laser applications on subsequent visits, the lesion demonstrated tumor progression most consistent with retinoblastoma (Fig. 2D). Thus, the patient underwent three further large spot size diode laser treatments and three treatments with unilateral superselective intra-arterial melphalan chemotherapy to the right eye over the following 3 months. Follow-up fundus examinations have demonstrated involutional response with decreased vascularity but persistent subretinal exudates and hemorrhage (Figs. 2E and 2F).
We present two cases of retinoblastoma with a Coats’ response that demonstrate both the challenge in identifying intraocular tumors and the need to continually reassess patient diagnoses, particularly in instances when they initially appear equivocal.
Clinical examination remains the most important tool by which the pediatric fundus is assessed, with prior reports noting several signs favoring the diagnosis of retinoblastoma versus Coats’ disease. When visibility of a tumor is not possible, careful evaluation of the retinal vasculature aids in diagnosis.2,6 Specifically, Coats’ disease usually presents with telangiectatic vessels and “light bulb aneurysms,” whereas retinoblastoma generally presents with diffusely dilated vessels that become attenuated proximal to the tumor itself.2,6–8 The cases we describe serve as both archetype (case 1) and exception (case 2) to this tendency, as illustrated in Figures 1, 2A, and 2B, respectively. Furthermore, the presence of a retinal detachment obscuring an intraocular tumor itself can also render evaluation of retinal vessels challenging, with a Coats’ response (likely elicited by diffuse retinal ischemia from tumor infiltration and the detachment itself6) further confounding visualization.
Similarly, age of presentation may also assist in yielding a diagnosis. In general, retinoblastoma presents earlier than Coats’ disease, with the average age at diagnosis 18 months and between 6 and 11 years, respectively.5,9–11 Thus, the age of case 1 (19 months) would be more in accordance with a diagnosis of retinoblastoma, whereas the age of case 2 (4 years) would not definitively favor one diagnosis over the other. Previous authors have also cited this overlap in age of presentation between the two diseases as often abetting misdiagnosis.10
The use of ancillary testing further aids in evaluation of challenging cases, largely relying on the tendency of retinoblastoma to calcify, reportedly at a rate as high as 95%.12 In case 1, ultrasonography proved a valuable adjunct in identifying an area of subretinal calcification corresponding to an area of retinal thickening, thus suggesting an underlying tumor. This was not visible on fundus examination due to both the overlying retinal detachment and exudative response. Although not used in this case series, magnetic resonance imaging has been suggested to help distinguish retinoblastoma from Coats’ disease. The former generally demonstrates high-intensity T1-weighted images, low-intensity T2-weighted images, and post-contrast lesion enhancement (often with a nodular and irregular retinal appearance), whereas Coats’ disease demonstrates high intensity subretinal fluid enhancement on both T1- and T2-weighted images but no enhancement on post-contrast images.13–15 However, documented exceptions and lack of large-scale studies of these tendencies make sole reliance on them imprudent.14,16
Although often understood as historically challenging,17,18 evaluation of the pediatric fundus in retinoblastoma remains an imperfect science. Post-enucleation pathologic evaluation demonstrates misdiagnosis rates as high as 19%18–20 with clinical studies citing misdiagnosis rates perhaps even double this.7,18 However, who performs the evaluation may be an important facet because these relatively high rates of misdiagnosis apply to the physicians referring patients to tertiary ocular oncology centers, which putatively have a diagnostic accuracy over 99%.18 As demonstrated in several large studies,7,10,18 Coats’ disease remains one of the most common retinoblastoma simulating lesions. However, our cases demonstrate the inverse: that a Coats’ response may easily be mistaken for Coats’ disease. Therefore, careful ophthalmoscopic evaluation with appropriate ancillary testing should accompany a high level of clinical suspicion and repeated examinations before a diagnosis such as retinoblastoma is dismissed.