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06-16-2012, 08:08 PM

4 month old boy with a "blur" in one eye since birth according to his mother.

James Coombs , M.D., H. Culver Boldt, M.D.
February 21, 2005
Chief Complaint: 4 month old boy with a "blur" in one eye since birth according to his mother.
History of Present Illness: At 2 months of age, his eyes would "wander off." At 4 months, a local MD noted poor red reflex in left eye. The child was subsequently referred to pediatric ophthalmologist.
PMH/FH/POH: Normal spontaneous vaginal delivery at 38 weeks. FH non-contributory.

Brief fix and follow OD, Responds to light OS
RAPD OS, Normal pressure
15 prism diopter left exoptropia
Normal anterior segment
Fundus OD & OS: see figure 1
Figure 1: Fundus Exam http://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB_11112004.jpg
http://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB2_11112004.jpgOD: Multiple tumors in the posterior pole. OS: Amelanotic large endophytic mass. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB3_11112004.jpg

OD: 3 lesions, one in the macula with choroidal shadowing.
OS: Large, multilobulated calcified lesion with maximum height of 9 mm and choroidal shadowing.
No extraocular extension of mass
Figure 2 http://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB4_11112004.jpghttp://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB5_11112004.jpgOD. One month after chemoreductive therapy. OS. One month after chemoreductive therapy. Left eye was removed later.
Figure 3: Tumor recurrence. Tumor recurrence of superonasal lesion 2 months after enucleation of left eye. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/cases/RB6_11112004.jpg
Figure 4: Pathology - Decision was made to enucleate the left eye. Gross Photo of Left Eye
Anterior-Posterior section through the eye
H&E Stain
H&E Stain
Flexner-Wintersteiner & Homer-Wright Rosettes
Islands of blue cells in a sea of necrosis are typical of retinoblastoma. The bottom left panel shows both types of rosettes: Flexner-Wintersteiner rosettes (with central lumens) and Homer-Wright rosette (eosinophillic centers).

Retinoblastoma is the most common intraocular malignancy in children. Fortunately, 95% of children with retinoblastoma survive (because of early detection). The gene is located on the long arm of chromosome 13. The intact gene protects against expression of retinoblastoma. Knudson proposed that "2 hits" were necessary to eliminate both alleles and therefore inhibit tumor suppression.
Ocular signs include leukocoria, strabismus, uveitis, hyphema, iris neovascularization, or a transparent lesion in the neurosensory retina.
Other ocular disorders in children can present similar to retinoblastoma. The most common is persistent hyperplastic primary vitreous followed by Coats’ disease, ocular toxocariasis and ROP. 1 Diagnosis is usually obtained by an experienced observer due to its classic appearance. Ultrasonography is able to show calcium within the mass.
The number one goal in approaching treatment in patients with retinoblastoma is patient survival, followed by globe salvage then visual acuity. Treatment options include chemoreduction therapy, focal therapies alone, enucleation and external beam radiation. Chemoreduction therapy has emerged as an important initial approach to retinoblastoma treatment. The use of carboplatin, etoposide, and vincristine has been shown to shrink the size of the tumor allowing focal treatments such as cryotherapy, focal laser therapy, or thermotherapy to further preserve vision and avoid enucleation. Recent studies have shown a decrease of 35% of tumor base and 50% decrease of tumor thickness after 2 cycles. Ocular salvage rates have improved as well.
The two major concerns associated with treating with external beam radiation are the germline alteration of the RB gene producing an increase risk of secondary malignancies (osteosarcoma) and the risk of side effects of radiation on the eye (retinopathy, neuropathy and cataract).
Histologic specimens of retinoblastoma show cells with round, oval nuclei that are twice the size of lymphocytes. As tumor extends into the vitreous and outgrows its blood supply, a characteristic pattern of "islands of blue cells in a sea of necrosis" is formed. (Figure 4)
A feature of retinoblastoma includes the formation of Flexner-Wintersteiner rosettes which are formations of retinal differentiation. (See Figure 4) The cells of these rosettes surround a central lumen. Another pattern seen in retinoblastomas is the Homer-Wright rosette where the rosette is filled with an eosinophilic substance. These rosettes are also seen in other neuroblastic tumors.

Most common pediatric intraocular tumor
250-300 new cases per year
1 in 15,000-20,000 live births 95% of US children survive, only 50% survive worldwide (delayed detection/limited access)
60-70% unilateral (avg. age of Dx 24 months)
30-40% bilateral (avg. age of Dx 14 months)

RB gene: tumor suppressor on chromosome 13 (13q14)
Knudson "two hit" hypothesis (1971)
94% without family history (15% with germline mutation)
5% chance of patient’s sibling developing RB


Transparent, lucent lesion in sensory retina
Larger tumors show chalk-like calcification
Vitreous hemorrhage
Iris neovascularization

Life threatening problems

1. Metastasis: within first year
Risk factors for metastasis:

Invasion beyond lamina cribosa of optic nerve
>2mm invasion of choroid
Orbital extension
Anterior chamber involvement
2. Trilateral retinoblastoma

Neuroblastic intracranial malignancy in patients with hereditary form
Most often pineoblastoma
Found in 3% of all patients
5-15% of patients with bilateral disease
Uniformally fatal
Decreased incidence since use of chemoreduction
3. Secondary Malignancies

primary tumors
Occur with germline mutation
5% of developing another malignancy during first 10 years
30 year cumulative incidence 35%
Higher for those receiving EBRT
Most common osteogenic sarcoma of femur

Treatment Goals:

Patient survival
Preservation of the globe
Visual acuity

Chemoreduction: reduces tumor volume with systemic chemotherapy to allow focal treatments such as thermotherapy, cryotherapy, laser photocoagulation or plaque radiotherapy. Recent studies have shown a decrease of 35% of tumor base and 50% decrease of tumor thickness after 2 cycles. Ocular salvage rates have improved as well.
Focal therapies alone
External beam radiotherapy- Negatives include recurrence, radiation side effects and possibility of induction of a second cancer

Differential diagnoses for endophytic masses and leukocoria in children

Persistent hyperplastic primary vitreous
Coats’ disease
Ocular toxocariasis
Retinopathy of prematurity
Astrocytic hamartoma

Shields CL, Meadows AT, Shields JA. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy. Arch Ophthalmol. 2001 Sep;119(9):1269-72.
Shields JA, Parsons HM, Shields CL, et al. Lesions simulating retinoblastoma. J Pediatr Ophthalmol Strabismus. 1991; 28:338-340.
Shields CL, Shields JA, De Potter P, Himelstein BP, et al. The effect of chemoreduction on retinoblastoma- induced retinal detachment. J Pediatr Ophthalmol Strabismus. 1997; 34:165-169
Hungerford JL, Toma NM, Plowman PN, et al. External beam radiotherapy for retinoblastoma: I. Whole Eye Technique. Br J Ophthalmol. 1995; 79:109-111
Shields CL, Shields JA. Diagnosis and Management of Retinoblastoma. 2004; Cancer Control. 11(5):317-327.
Ophthalmic Pathology and Intraocular Tumors, Section 4, Basic and Clinical Science Course. San Francisco: American Academy of Ophthalmology; 2003. p. 148-15.