Persistent or recurrent vitreous seeding following retinoblastoma treatment is a common reason for therapeutic failure.1 Vitreous seeds typically appear as a non-calcified spherical mass free-floating in the vitreous cavity without surrounding fibrosis or hemorrhage. Munier2 designed a classification of retinoblastoma vitreous seeds and Francis et al.3 reported the frequency distribution including dust (46%), sphere (24%), and cloud (34%) formation.
Over the past decade, intra-arterial chemotherapy and intravitreal chemotherapy have been demonstrated to provide control of active vitreous seeding.4 In a single-center analysis of 192 injections of intravitreal chemotherapy for active vitreous seeds, tumor control was achieved in 100% of cases, causing the vitreous seeds to disappear or transform into calcified opacities.5 In a multi-center collaborative analysis of 3,553 intravitreal chemotherapy injections for vitreous tumor seeding, there was no case of extraocular extension.6 Side effects of injections can include localized retinal pigment epithelium mottling, cataract, posterior synechia, iris depigmentation, and, rarely, hemorrhagic retinopathy with retinal necrosis and scleral necrosis.5,6 For these reasons, accurate diagnosis is imperative.
Asteroid hyalosis can clinically resemble retinoblastoma vitreous seeding because both appear as white calcified vitreous opacities. We describe a patient with treated retinoblastoma who subsequently developed asteroid hyalosis mimicking tumor seeding. We discuss the clinical and imaging findings useful to differentiate these conditions.
A 37-year-old man with a history of treated retinoblastoma presented to his ophthalmologist with vitreous floaters in the left eye. He had an extensive family history of retinoblastoma in his father, son, paternal aunt, and paternal cousins. Our patient was diagnosed as having retinoblastoma at 12 years of age, with a unilateral unifocal tumor that was treated with laser photocoagulation and plaque radiotherapy. No vitreous seeds were noted at the time of diagnosis. Over 14 years of follow-up, there was no recurrence. He was lost to follow-up for 12 years and returned at age 37 years with floaters. Examination suggested retinoblastoma recurrence with vitreous seeding, and the patient was referred for our evaluation.
On examination, visual acuity was 20/20 in each eye. Intraocular pressures were normal and the anterior segment was quiet in both eyes. The right eye was clinically unremarkable. Fundus examination in the left eye revealed a superonasal yellow tumor scar measuring 6 mm in basal diameter with a central gelatinous tissue and overlying telangiectatic vessels (Figure 1A). Additionally, there were more than 500 calcified, homogenous, uniformly sized individual and linearly arranged vitreous deposits (Figure 1B). Optical coherence tomography (OCT) in the left eye showed intact fovea with attached posterior hyaloid and over-lying hyperreflective vitreous opacities (Figures 2A–2B). OCT through the peripheral scar demonstrated diffuse retinal atrophy and occasional hyperreflective vitreous opacities. An OCT image through the gelatinous portion of the tumor scar showed an elevated mass with posterior shadowing (Figures 2B–2C). B-scan ultrasonography demonstrated a calcified retinal mass of 2.8 mm in thickness with extensive calcified vitreous debris and a cortical vitreous “clear zone” in the preretinal region (Figure 3). The presence of regressed tumor scar and uniform, homogenous, calcified deposits on clinical examination and ultrasonography supported a diagnosis of asteroid hyalosis rather than tumor seeding. Periodic monitoring was advised. After 66 months of follow-up, the asteroid hyalosis remained unchanged.
(A) Regressed retinoblastoma scar in a 37-year-old man following laser photocoagulation and plaque radiotherapy treatment. (B) Extensive round calcified vitreous opacities filling the entire vitreous cavity and suspicious for vitreous seed recurrence.
Optical coherence tomography (OCT) demonstrated (A) intact macula in the left eye, but with overlying vitreous opacities. In the periphery at the site of the treatment scar, there was (B) retinal atrophy at the margin and (C) retinal elevation with shadowing centrally.
Ultrasonography demonstrated diffuse, homogeneous, calcified vitreous opacities with posterior “clear zone,” typical for asteroid hyalosis. The retinoblastoma scar measured 2.8 mm in thickness.
Asteroid hyalosis was first described by Benson in 1894.7 The cause and mechanism of asteroid hyalosis remains to be elucidated, but transmission electron microscopy and x-ray spectroscopy reveals a composition of complex lipids with calcium and phosphorus.8 The prevalence was found to be 1.96% in a large autopsy population with no racial predilection, and the age-specific prevalence increased from 0.27% in patients younger than 40 years to 6.76% in patients older than 90 years.9 The strong correlation with age has been corroborated in other studies.8 Although it is atypical to present with asteroid hyalosis at 37 years of age, as in our patient, the youngest patient determined to have asteroid hyalosis by autopsy was 9 years old.9
Given the history of previously treated retinoblastoma in our patient, the presence of new vitreous opacities was concerning. Despite improved rates of globe salvage for patients with retinoblastoma, vitreous seeds in the era of intravitreal chemotherapy, treatment can lead to vision-threatening side effects. Intravitreal melphalan has been associated with retinal pigment epithelial mottling (32%), paraxial subclinical cataract (25%), minor transient vitreous hemorrhage (13%), localized retinal hemorrhage (5%), and corneal epitheliopathy (5%), among others.5 Additionally, each injection is associated with a 5-mV decrease in ERG amplitude.10
The clinical appearance of asteroid hyalosis and retinoblastoma vitreous seeds can substantially overlap. Vitreous seeds have recently been divided into three classes based on distinct morphologic patterns: dust, spheres, and clouds.2 Histopathologic analysis of spheres disclose a diameter range between 15 and 300 µm,11 whereas scanning electron microscopy diameter measurements of asteroid bodies vary between 25 and 75 µm.8 Despite the similarity in size, asteroid hyalosis tends to be homogenous in size, shape, and distribution throughout the vitreous cavity, whereas vitreous seeds can vary in size and degree of calcification. In addition, the calcification within vitreous seeds is irregular with geometric margins, whereas the calcification in asteroid hyalosis tends to be smooth and round. Furthermore, ultrasonography of asteroid hyalosis reveals a “clear zone” between the calcified asteroid bodies and the retina, whereas vitreous seeds tend to be positioned near the retinal tumor, often resting on the surface of the retina. A recent publication demonstrated presumed vitreous seeding arising from the apex of a retinocytoma; however, the ultrasonographic features of uniform distribution of vitreous calcific nodules and “clear zone” suggests that this could also represent asteroid hyalosis.12
An interesting feature of asteroid hyalosis is that it arises in eyes that typically demonstrate absence of a posterior vitreous detachment.9 The lack of posterior vitreous detachment, found in 98.61% of patients with asteroid hyalosis, explains why asteroid bodies are likely suspended throughout the vitreous.9 Retinoblastoma arises from retinal progenitor cells, and vitreous seeding is often located near the active retinal tumor. In our case, ultrasonography and OCT documented a “clear zone” of cortical vitreous, even at the site of the inactive tumor. Additionally, retinoblastoma recurrence several decades after treatment is rare.13
We have described a 37-year-old man with treated retinoblastoma who developed marked calcific vitreous deposits, initially suspicious for tumor recurrence with vitreous seeds, but later believed to represent coincidental asteroid hyalosis.
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Munier FL. Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. Ophthalmic Genet. 2014;35:193–207. doi:10.3109/13816810.2014.973045 [CrossRef]
- Francis JH, Marr BP, Abramson DH. Classification of vitreous seeds in retinoblastoma: correlations with patient, tumor, and treatment characteristics. Ophthalmology. 2016;123:1601–1605. doi:10.1016/j.ophtha.2016.02.036 [CrossRef]
- Shields CL, Alset AE, Say EA, Caywood E, Jabbour P, Shields JA. Retinoblastoma control with primary intra-arterial chemotherapy: outcomes before and during the intravitreal chemotherapy era. J Pediatr Ophthalmol Strabismus. 2016;53:275–284. doi:10.3928/01913913-20160719-04 [CrossRef]
- Shields CL, Douglass AM, Beggache M, Say EA, Shields JA. Intravitreous chemotherapy for active vitreous seeding from retinoblastoma: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina. 2016;36:1184–1190. doi:10.1097/IAE.0000000000000903 [CrossRef]
- Francis JH, Abramson DH, Ji X, et al. Risk of extraocular extension in eyes with retinoblastoma receiving intravitreous chemotherapy. JAMA Ophthalmol. 2017;135:1426–1429. doi:10.1001/jamaophthalmol.2017.4600 [CrossRef]
- Benson AH. Disease of the vitreous: a case of monocular asteroid hyalitis. Trans Ophthalmol Soc UK. 1894;14:101–104.
- Topilow HW, Kenyon KR, Takahashi M, Freeman HM, Tolentino FI, Hanninen LA. Asteroid hyalosis: biomicroscopy, ultra-structure, and composition. Arch Ophthalmol. 1982;100:964–968. doi:10.1001/archopht.1982.01030030972015 [CrossRef]
- Fawzi AA, Vo B, Kriwanek R, et al. Asteroid hyalosis in an autopsy population: The University of California at Los Angeles (UCLA) experience. Arch Ophthalmol. 2005;123:486–490. doi:10.1001/archopht.123.4.486 [CrossRef]
- Francis JH, Brodie SE, Marr B, et al. Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience. Ophthalmology. 2017;124:488–495. doi:10.1016/j.ophtha.2016.12.015 [CrossRef]
- Amram AL, Rico G, Kim JW, et al. Vitreous seeds in retinoblastoma: clinicopathologic classification and correlation. Ophthalmology. 2017;124:1540–1547. doi:10.1016/j.ophtha.2017.04.015 [CrossRef]
- Garoon RB, Medina CA, Sclefo C, Harbour JW. Retinocytoma with vitreous seeding: new insights from enhanced depth imaging optical coherence tomography and high-resolution posterior segment ultrasonography [published online ahead of print February 21, 2018]. Retin Cases Brief Rep.
- Shields CL, Piccone MR, Shields JA, Eagle RC Jr, Singer M. Mushroom-shaped choroidal recurrence of retinoblastoma 25 years after therapy. Arch Ophthalmol. 2002;120:844–846.