MD2B - Pediatric Oncology: Retinoblastoma

Overview

Retinoblastoma is the most common primary intraocular tumor to occur in children. It is a relatively uncommon type of pediatric cancer, accounting for only 3% of all malignancies in children younger than 15 years. In the United States, approximately 300 new cases of retinoblastoma are diagnosed each year. Most cases are diagnosed in children under the age of 2, and 95% occur before the age of 5. Sex and race are not risk factors for retinoblastoma. Retinoblastoma can be inherited, or it can occur sporadically. The tumor occurs unilaterally in 75% of cases, and bilaterally in 25% of cases. The prognosis for retinoblastoma is excellent, with 90% of children achieving long-term survival.

Cause

Retinoblastoma is one of the few cancers with a well-understood cause. It occurs when both alleles (copies) of the retinoblastoma (RB) gene on chromosome 13 are mutated. Normally, this gene acts as a tumor suppressor, but when both alleles are mutated, abnormal cells are no longer regulated leading to uncontrolled tumor growth.

Retinoblastoma can occur in both germline (40%) and sporadic (60%) forms. The germline form includes patients with a family history of retinoblastoma and those with a new germline mutation that occurs at conception. A positive family history is present in only 5-10% of children who develop this disease. A "two-hit" model explains the difference in clinical features between germline and sporadic forms. In the germline form, one allele is already mutated at birth in every cell of the body. When a second mutation occurs, a tumor forms. Therefore, in this form of the disease, there is a risk of bilateral tumor formation. In addition, the same genetic abnormality that causes retinoblastoma can also predispose patients to osteogenic sarcoma (bone tumor), soft tissue sarcoma, and malignant melanoma (skin cancer). Patients with heritable retinoblastoma must be carefully monitored and screened for other malignancies throughout their lives.

In the sporadic form, no mutations are present at birth and both alleles must mutate for cancer to develop. Therefore, children with the non-inherited form of retinoblastoma most often (but not always) present with unilateral, rather than bilateral disease.

Symptoms

Retinoblastoma can present with various abnormalities in function or appearance of the eye. The most common symptom is leukocoria (where the pupil appears to have a white reflex rather than the normal red reflex). The second most common symptom is strabismus (where the eyes appear crossed or misaligned). Other symptoms include decreased vision, glaucoma, retinal detachment, vitreous hemorrhage, proptosis (bulging of the eye), orbital cellulitis (infection), and heterochromia (two different colored eyes). Eye pain can occur secondary to glaucoma. Fever may occur as a result of infection and necrosis (tissue breakdown).

Diagnosis

Any child with an eye abnormality or positive family history for retinoblastoma should be evaluated by a physician. Under anesthesia, an ophthalmologist can perform a dilated examination so that the retina (portion of the eye where retinoblastoma arises) can be directly visualized. Ultrasounds, CT scans, and MRI scans of the head, eye, and the surrounding structures can aid in diagnosis and prognosis as many benign conditions can mimic retinoblastoma.

Staging

The Children’s Oncology Group (COG) uses the International Classification for Intraocular Retinoblastoma to stage newly diagnosed retinoblastoma

Group A: <3mm and limited to retina away from the foveola and optic disc

Group B: >3mm and/or close to the foveola and optic disc but still limited to retina

Group C: Well-circumscribed tumors with minimal invasion under the retina or into the vitreous humor

Group D: Large and/or poorly circumscribed tumor with extensive invasion under the retina or into the vitreous humor

Group E: A large, infiltrating tumor that has a poor prognosis of saving the eye. May have features such as hemorrhage, glaucoma or invasion to the front of the eye

Treatment

There are many treatment options available for children with retinoblastoma. The choice of treatment depends upon patient age, tumor size, tumor location, and degree of spread. The primary goals of treatment are to eliminate the cancer, preserve vision when possible, and minimize treatment side effects.

Surgery

• Globe sparing: Only a portion of the eye is removed
• Enucleation: A surgical procedure where the eye is removed. This surgery is performed on patients who have large tumors that extend into surrounding structures or those with loss of vision or eye pain. Enucleation is also used in children who have tumor recurrence after initial globe sparing surgery

Radiation therapy

• Retinoblastoma is generally responsive to radiation. Radiation can be delivered in the form of external beam radiotherapy (EBRT) or plaque brachytherapy. The major disadvantage to external beam radiotherapy is that it may induce secondary cancers in up to 35% of patients

Cryotherapy

• Use of a freezing process to destroy small tumors

Laser Therapy

• Use of an argon laser beam to treat small tumors

Phototherapy

• Use of a light beam to destroy the blood vessels supplying a tumor

Chemotherapy

• Chemotherapy plays a key role in the treatment of retinoblastoma. It may help avoid the need for external beam radiotherapy or enucleation, reducing the risk of secondary malignancies and preserving vision. Usually, a combination of vincristine, carboplatin and etoposide is used

Prognosis

If undiagnosed and untreated, retinoblastoma can cause permanent damage to the eye and spread to nearby structures. Metastatic spread typically begins after six months, and death can occur within a few years. However, with early diagnosis and treatment, the prognosis is excellent. The overall ten-year survival rate for children with retinoblastoma in the United States is 97%.