Retinoblastoma

Retinoblastoma

Epidemiology

Retinoblastoma occurs at a rate of 3.7 cases/million in the United States, with no racial or gender predilection. Overall, about 60% of cases are unilateral and nonhereditary, 15% unilateral and hereditary, and 25% bilateral and hereditary. Bilateral involvement is found in 42% of those presenting when younger than 1 yr of age but in only 21% of those presenting during 1 yr of age and is even less common at older ages of presentation.

The hereditary form is associated with a germline defect in the retinoblastoma gene (RB1) located on the long arm of chromosome 13. RB1 encodes a tumor suppressor protein. Familial cases are generally multifocal and bilateral, whereas nonfamilial cases tend to have unilateral, unifocal involvement. According to the “two-hit” model, two mutational events are required for tumor development. In the heritable form, one mutated RB gene is inherited through the germ line and a second mutation occurs subsequently in the somatic retinal cell. In the noninherited form, both mutations occur in retinal cells.

Pathogenesis

The histology of retinoblastoma is a small, round, blue cell tumor with rosette formation. It may arise in any of the nucleated layers of the retina and exhibits various degrees of differentiation; it tends to outgrow its blood supply, resulting in necrosis and calcification.

Endophytic tumors arise from the inner surface of the retina, grow into the vitreous, and tend to seed to other areas of the retina. Exophytic tumors grow from the outer retinal layer and may produce retinal detachment. Hematogenous or lymphatic spread to more distant sites can occur with extension to the choroid or along the optic nerve beyond the lamina cribrosa.

Clinical Manifestations.

Only about 10% of retinoblastomas are detected by routine ophthalmologic screening in the context of a positive family history. Retinoblastoma classically presents with leukocoria, a white pupillary reflex (Image 1) . This abnormality is often first noticed when a red reflex is not present at routine newborn or well-child examination or in a flash photograph of the child. Strabismus is commonly the initial presenting complaint. Orbital inflammation, hyphema, or pupil irregularity occurs with advancing disease. Pain is usually a feature if secondary glaucoma is present. In more severe stage, the tumour mass is so big that it could appear as meat coming out from the eye cavity (Image 2).

Image 1.The whittish gleam of the pupil of the left eye is a typical finding in retinoblastoma in early stages. Early treatment made possible for this situation to be reversible

Image 2. An obvious tumour mass in late stage of retinoblastoma. This requires enucleation which will sacrifice the vision of the right eye.

Diagnosis.

The diagnosis does not require a biopsy but is established by characteristic ophthalmologic findings. Evaluation generally requires an examination under general anesthesia by an ophthalmologist to obtain a complete visualization of both eyes, which also facilitates photographing and mapping of the tumors. Retinal detachment or vitreous hemorrhage can complicate the evaluation.

Orbital ultrasonography and CT or MRI are used to evaluate the extent of intraocular disease and extraocular spread. Occasionally, a pineal area tumor will be detected, a phenomenon known as trilateral retinoblastoma. MRI allows for better evaluation of optic nerve involvement. Bone scan, cerebrospinal fluid evaluation, and bone marrow evaluation are necessary only if indicated by other clinical, laboratory, or imaging studies.

The differential diagnosis includes hyperplastic primary vitreous, Coats disease, cataract, visceral larva migrans, choroidal coloboma, and retinopathy of prematurity.

Treatment

The treatment is determined by the size and location of the tumor, with the primary goal being cure and a secondary goal of preserving vision. As newer modalities for local control of intraocular tumor and more effective systemic chemotherapy have been developed, primary enucleation is less frequently undertaken routinely.

Most unilateral disease presents as a large tumor. Enucleation is undertaken if there is no potential for useful vision. In bilateral disease the traditional approach involves enucleation of the more severely affected eye and irradiation of the remaining eye in hope of salvaging some useful vision. With the availability of effective chemotherapy, an attempt can be made to salvage both eyes with some degree of functional vision. If feasible, small tumors can be treated with laser photocoagulation or cryotherapy with careful follow-up for evidence of recurrence or new tumor growth. Larger tumors often respond to multiagent chemotherapy, including carboplatin, vincristine, and etoposide, thus facilitating successful focal therapy. If this approach fails, external-beam irradiation or brachytherapy should be considered, although this approach may result in significant orbital deformity and increased incidence of second malignancies in patients with germ line mutations. Enucleation may be required for nonresponsive or recurrent tumors.

Prognosis

Close to 95% of retinoblastomas are cured in the United States, where extraocular extension is rarely seen. Current efforts using chemotherapy in combination with local therapy are focused on trying to preserve useful vision and avoidance of irradiation or enucleation. Routine ophthalmologic examinations should continue until about 6 yr of age to detect new lesions. The prognosis for patients with metastases is poor.

Children with germ line RB1 mutations are at significant risk for development of second malignancies, primarily osteosarcoma. This risk is further increased by the use of radiation therapy. Other radiation-related complications include cataracts, orbital growth deformities, lacrimal dysfunction, and late retinal vascular injury.

REFERENCES

1. Herzog C. Retinoblastoma. in : Nelson Textbook of Pediatrics 17th edition.2003.Saunders
2. Lang GK. Ophtalmology - A Pocket Textbook Atlas.2000.Thieme