Raising Awareness About Retinoblastoma

Robert M. Ellsworth, MD, Algernon B. Reese, MD, David H. Abramson, MD Robert M. Ellsworth Ophthalmic Oncology Center (OOC)NewYork Presbyterian Hospital-Weill Cornell Medical Center

Retinoblastoma is a malignant tumor of the developing retina. It is the seventh most common pediatric malignancy in the United States, but the most common primary malignancy to involve the eye during childhood. In fact, the incidence is 1/20,000 live births.

Currently, the largest center for the treatment and management of retinoblastoma exists at the Robert M. Ellsworth Ophthalmic Oncology Center (OOC) at NewYork Presbyterian Hospital-Weill Cornell Medical Center. Three physicians developed this program and have followed more than 1800 patients with retinoblastoma since 1914: Drs. Algernon Reese, Robert M. Ellsworth, and David H. Abramson. Dr. Abramson is the current director of the Center.

Retinoblastoma and Early Detection
Retinoblastoma occurs in both hereditary and non-hereditary patterns. Germline RB1 alterations underlie heritable forms of retinoblastoma including inherited cases of bilateral and unilateral disease, as well as all bilateral cases where there is no prior family history of the disease. Approximately 10% to 15% of newly diagnosed retinoblastoma patients have a family history of the disease. Dr. Alfred Knudson’s two mutational event (“2-hit”) model for the development of retinoblastoma provided the statistical support for the observation that patients who inherit one RB1 gene mutation develop retinal tumors earlier (15 months), and in most cases multifocal tumors, than patients who develop the nonhereditary form of the disease (32 months). Individuals with a germline RB1 mutation are predisposed to develop retinal tumors in childhood and non-ocular cancers throughout their lifetime.
The recognition of a positive family history of retinoblastoma has practical implications for patients, their families, and clinicians with regard to detection and outcome. For the clinician, a positive family history is an indication for an ophthalmologic examination in the newborn, as well as comprehensive, serial eye evaluations by an ophthalmologist. Aggressive surveillance is recommended for all patients with a family history of retinoblastoma until at least 28 months. If tumors are discovered, then follow-up is recommended until approximately 7 years of age. Although there is no consensus on recommended screening protocols for non-ocular cancers in survivors of heritable retinoblastoma, clinicians following such patients should be aware of the association for educational and for clinical management purposes.

In families with a prior history of retinoblastoma, some parents of an at-risk individual may be aware of the etiology and autosomal dominant pattern of inheritance of the disease, as well as the recommended earlier timing of eye examinations and screening. Their infants may present for routine clinical exams from birth, not because the parents noted any signs of the disease, but because parents were aware of the potential benefits of an early diagnosis. An increased risk for local tumor invasion, particularly in younger patients presenting with squint rather than leukocoria, and higher rates of death and blindness in a group of bilateral retinoblastoma patients diagnosed between 1945 and 1970, have been described as complications associated with a delay in the diagnosis of retinoblastoma.

Ongoing Research at OOC
In a recent study conducted by the OOC, 264 patients were eligible for early tumor surveillance based on the presence of a prior family history of retinoblastoma. Approximately 1/3 of these retinoblastoma patients initially presented to the center in the newborn period because of the family history, and subsequently received routine clinical exams as screening for retinal tumors. They were diagnosed younger (mean age of diagnosis was 8 months) than the non-family history cohort (mean age of diagnosis 21 months), and younger than the larger family history cohort (mean age of diagnosis 11 months). Patient survival was excellent in this cohort of 86 patients, with >93% surviving 5 years. They were diagnosed at an earlier stage of disease with >50% of presenting eyes classified as Reese-Ellsworth (RE) Group 1 (solitary tumor <4 disc diameters, at or behind the equator and multiple tumors, none >4 disc diameters, all at or behind the equator). Ocular outcome in the screened-patient group was improved by 44%, as demonstrated by a 68% survival rate of all presenting eyes at 5 years in the screened family-history cohort versus 38% ocular survival in the non-screened family history cohort.
Interestingly, while 1/3 of family history patients presented for early tumor surveillance, 1/3 still presented with late stage disease and leukocoria (RE Group V: massive tumors involving over _ the retina +/- vitreous seed). This latter observation emphasizes the need to develop and implement strategies that (1) educate families with heritable retinoblastoma regarding the benefits of early tumor surveillance and (2) raise awareness of retinoblastoma to geneticists and obstetricians, so that children with a family history of retinoblastoma can be seen earlier.

Reese-Ellsworth Group I Eye	Reese-Ellsworth Group V Eye

Editor’s note (about the authors):
David H. Abramson, MD, Director

Katherine Beaverson, MS, Genetic Counselor & Research Program Coordinator

Robert M. Ellsworth Ophthalmic Oncology Center
Department of Ophthalmology
NewYork Presbyterian Hospital-
Weill Cornell Medical Center

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