Retinoblastoma is the most common pediatric intraocular malignant tumor.1 A study from London showed that 5-year survival rate for children with unilateral retinoblastoma increased from 85% for those diagnosed from 1963 to 1967 to 97% for those diagnosed from 1998 to 2002.2 Although chemotherapy has played an important role in improved survival, others speculate that early diagnosis could also contribute. Timely diagnosis and appropriate treatment are crucial in the management of retinoblastoma.
The most common presenting signs of retinoblastoma are leukocoria (56%), strabismus (4%) and poor vision (8%).3 These presenting symptoms can be common to numerous pediatric eye conditions including hereditary, developmental and inflammatory disorders.4 Shields and co-workers5 studied 500 patients referred with the diagnosis of possible retinoblastoma and, following evaluation, found that 212 had simulating lesions and not retinoblastoma. The three conditions that most closely simulated retinoblastoma were persistent hyperplastic primary vitreous (PHPV) (28%), Coats disease (16%) and ocular toxocariasis (16%).5 (Table 1) In this review we discuss the differential diagnoses of retinoblastoma and elaborate the key features to distinguish them.
COATS DISEASE
Coats disease is an idiopathic condition characterized by
telangiectatic and aneurysmal retinal vessels with intraretinal
and subretinal exudates.6 The median age of diagnosis
is approximately 5 years (range, 1 month to 63 years).7
The stages of Coats disease8 are:
- Stage 1: Retinal telangiectasia only
- Stage 2: Telangiectasia and exudation
A: Extrafoveal exudation
B: Foveal exudation - Stage 3: Exudative retinal detachment
A: Subtotal detachment
1: Extrafoveal detachment
2: Foveal detachment
B: Total detachment - Stage 4: Total retinal detachment and glaucoma
- Stage 5: Advanced end stage disease The early stages of Coats disease can simulate retinoblastoma due to the presence of macular exudation (Figure 2B). The differentiating features9 include:
- Coats disease shows irregular lightbulb telangiectasia in the peripheral fundus;
- Coats disease shows yellow subretinal and intraretinal exudation; and
- the retinal vessels in Coats disease tend to
course over the detachment (Figure 2B) and do
not dip into it as in retinoblastoma (Figure 1B).
The advanced stages of Coats disease (total retinal detachment, xanthocoria, painful glaucoma secondary to angle closure glaucoma) are difficult to differentiate from retinoblastoma. In more advanced cases of Coats disease (Figure 2A) the differentiating features from retinoblastoma9 (Figure 1A) include: - yellow pupillary reflex (xanthocoria) in Coats disease compared with white reflex (leukocoria) in retinoblastoma;
- presence of yellow subretinal material (exudates) and peripheral telangiectasia in Coats disease; and
- fundus fluorescein angiography documentation of retinal telangiectasia in Coats disease.
- PHPV is usually a unilateral condition with no family history;
- PHPV displays microphthalmia, microcornea, shallow anterior chamber, persistent tunica vasculosa lentis, and
- history of exposure to puppies;
- lack of calcification on ultrasonography;
- marked vitreous inflammation with yellow grey vitreous strands extending from the chorioretinal lesion;
- retinal dragging with fixed folds in the retina; and
- solitary granulomas with a translucent center (in some cases this can resemble retinoblastoma, but the granuloma does not grow over time).
- systemic and ocular manifestations of tuberous sclerosis complex such as ash leaf macules, adenoma sebaceum, intracranial astrocytoma, cardiac rhabdomyoma, and renal angiomyolipoma;15
- lack of retinal detachment;
- the retinal blood vessels course under or around the astrocytic tumor showing subtle traction component; and
- in rare cases, astrocytic hamartoma shows retinal
exudation, unlike retinoblastoma.
In case of suspicion, the lesion can be monitored monthly to confirm stability, unlike retinoblastoma, which would typically show growth within 1 to 2 months. Fine needle aspiration biopsy can rarely be performed to establish diagnosis. - family history compatible with autosomal dominant inheritance; and
- bilateral peripheral retinal avascularity, which is more apparent on fundus fluorescein angiography.
- Other retinal findings include retinal neovascularization, fibrovascular mass, falciform retinal folds and retinal traction causing straightening of vessels.
Calcification is uncommon in Coats disease and if present appears as linear shadows along the retinal pigment epithelium (RPE) or minimally scattered in chronically detached retina on ultrasonography. The calcification seen in Coats disease is usually due to osseous metaplasia of the RPE.10
PERSISTENT HYPERPLASTIC PRIMARY
VITREOUS (PHPV)
Persistent hyperplastic primary vitreous
(PHPV) or persistent fetal vasculature (PFV) is a
disease of uncertain etiology that manifests in
healthy full-term infants.11 PHPV is the result of
anomalous development of the primary vitreous
as it persists into the period of formation of the secondary
vitreous.12 The severity of PHPV can range from
pupillary strands across the iris or an isolated
Mittendorf dot on the back of the lens to more severe
forms with retrolenticular membranes, retinal dysplasia,
or detachment.11
The features that help distinguish retinoblastoma from PHPV include:
OCULAR TOXOCARIASIS
Toxocariasis constitutes 1% to 2% of all uveitis in children,
and the average age at diagnosis is 8 years (ranging
from 2 to 31 years).13 There are three manifestations of
ocular involvement, including chronic endophthalmitis,
posterior granuloma, and peripheral granuloma.13
Chronic endophthalmitis due to toxocariasis presents as
severe granulomatous vitreitis with cyclitic membrane,
retinal detachment, leukocoria, and hypopyon. The granulomas
present as white pseudogliomatous mass with
vitreous traction membranes and retinal folds (Figure
2D). The features that aid in establishing the clinical diagnosis
of toxocariasis include:
A positive serologic test, such as enzyme immunoassay, is supportive but not diagnostic, as exposure to the toxocara organism is common.
RETINAL ASTROCYTIC HAMARTOMA
Retinal astrocytic hamartoma is the best-known ocular
manifestation of tuberous sclerosis complex and is generally
a sessile or slightly elevated lesion in the nerve fiber
layer of the retina (Figure 2E).14
The clinical features of astrocytoma that differentiate it from retinoblastoma include:
FAMILIAL EXUDATIVE
VITREORETINOPATHY
FEVR is characterized by failure of peripheral retinal
vascularization, and the complications result from subsequent
retinal ischemia.16 The diagnosis of FEVR (Figure 2F) is based on:
COLOBOMA
Optic nerve and retinochoroidal coloboma are caused
by incomplete closure of the embryonic fissure during
fetal development.17 A chorioretinal coloboma appears
as a sharply demarcated, glistening white, bowl-shaped
excavation in the fundus (Figure 2G), and the white color
is caused by the sclera being visible in the absence of the
choroid, retina, and RPE. If the coloboma is large enough,
it can present as leukocoria.17
RETINAL DETACHMENT
Retinal detachment caused by any condition can lead
to diagnostic dilemma due to suspicion of retinoblastoma.
Figure 2H demonstrates retinal detachment due to
morning glory disc anomaly. This can be differentiated
from retinoblastoma by the excavated anomalous disc
and presence of yellow subretinal exudation. Careful
ophthalmoscopic evaluation to detect tumor and seeds
has paramount importance to differentiate retinal
detachment from retinoblastoma and other disorders.
RETINOPATHY OF PREMATURITY
Retinopathy of prematurity results from the failure of
development of the normal retina in premature neonates
exposed to high levels of oxygen during the postnatal
period. It is associated with abnormal vascularization,
fibrosis, and retinal detachment, which can produce a
white reflex.18
MISCELLANEOUS CONDITIONS
The other conditions that can simulate retinoblastoma
include Norrie disease, incontinentia pigmenti, congenital
retinoschisis, endogenous endophthalmitis, medulloepithelioma,
and vitreous hemorrhage.4
SUMMARY
Many pediatric eye disorders can simulate
retinoblastoma. Timely diagnosis and treatment are of
paramount importance for preservation of the eye
and for life prognosis. Detailed history including family
history and meticulous ophthalmoscopic examination
is crucial for differential diagnosis. Ancillary testing like
ultrasonography, fluorescein angiography, computed
tomography, and magnetic resonance imaging, such as
aid in the diagnosis.
Support provided by the Eye Tumor Research Foundation, Philadelphia, PA (CLS).
The authors have no financial interests to disclose.
Aparna Ramasubramanian, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Carol L. Shields, MD, is the Co-Director of the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University. Dr. Shields is a member of the Retina Today Editorial Board. She may be reached at carol.shields@shieldsoncology. com; phone: +1 215 928 3105; fax: +1 215 928 1140.
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