Retinoblastoma:

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

Retinoblastoma:

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

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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.

EXAM OCULAR:

• 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

OD: Multiple tumors in the posterior pole.	OS: Amelanotic large endophytic mass.

ECHOGRAPHY:

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

OD. 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.

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).

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Discussion

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.

EPIDEMIOLOGY 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) Genetics 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

SIGNS MAJOR COMPONENTS Transparent, lucent lesion in sensory retina Larger tumors show chalk-like calcification Leukocoria Strabismus Uveitis/Endophthalmitis Vitreous hemorrhage Hyphema Iris neovascularization

SYMPTOMS 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 Treatment Goals: Patient survival Preservation of the globe Visual acuity Options: 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 Enucleation

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Differential diagnoses for endophytic masses and leukocoria in children

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