Abstract
Summary
Retinoblastoma is a rare eye tumor of childhood that arises in the retina and represents the most common intraocular malignancy of infancy and childhood. The incidence is 1 in 15,000–20,000 live births. In 60% of cases, the disease is unilateral and the median age at diagnosis is two years. Of these cases, 15% are hereditary. Retinoblastoma is bilateral in about 40% of cases with a median age at diagnosis of one year.
Retinoblastoma is the first disease for which a genetic etiology of cancer has been described and the first tumor suppressor gene identified. Knudson in 1971 developed the hypothesis that retinoblastoma is a cancer caused by two mutational events. This led to the understanding that there are two forms of retinoblastoma, germinal and non germinal. Loss or mutations of both alleles of the retinoblastoma gene RB1, localized to chromosome 13q14, are required to develop the disease.
In hereditary cases (representing approximately 55% of the cases) patients carry a germline inactivated RB1 allele present in all cells in the body and somatic loss of the second allele in retinal cells. Germinal RB1 mutations with a high penetrance rate (> 90%) concern all patients with bilateral retinoblastoma as well as 15% of patients with the unilateral form. In non hereditary cases (45% of all patients) both RB1 alleles are inactivated somatically in a single developing retinal progenitor cell. In these cases, retinoblastoma is always unilateral and unifocal.
Genetic counseling should be proposed to every parent having a child with retinoblastoma and to patients having a familial history of retinoblastoma. During this consultation, the progress of management of retinoblastoma and anticipated examination schedule for testing should be presented to the family. An analysis of the child’s personal and familial history, and direct and indirect molecular studies should be performed by the geneticist.
Leukocoria and strabismus are the most frequent clinical manifestations of retinoblastoma. Some other signs may be observed, including iris rubeosis, hypopyon, hyphema, buphthalmos, orbital cellulitis, and exophthalmos. Some children with retinoblastoma may have no symptoms. Screening in case of familial history or dysmorphic syndrome with a 13q14 deletion may lead to diagnosis of retinoblastoma. Most affected children are diagnosed before the age of three years.
An examination of the ocular fundus under general anesthesia leads to diagnosis. The lesion appears as a white tumor with angiomatous dilatation of the vessels. Ocular ultrasound demonstrates a mass more echogenic than the vitreous, with fine calcifications. Retinal detachment may also be observed in exophytic forms. CT typically shows an intraocular mass with a higher density than the vitreous body, calcified in 90% of cases and moderately enhanced after iodine contrast agent injection. MRI is the imaging modality of choice to assess the local extension. The mass has a signal equivalent to or a slightly more intense than that of the vitreous on T1-weighted sequences, with a relatively low-intensity signal on T2-weighted sequences.
The rare, invasive, diffuse forms of retinoblastoma, usually not calcified, are very difficult to diagnose due to their atypical and radiological features, mimicking an advanced form of Coats disease and Toxocara Canis eye infection. Coats disease corresponds to a unilateral retinal disease with telangiectasia and subretinal exudates. Persistence of the primitive vitreous may also be mistaken for retinoblastoma.
Several classifications of retinoblastoma have been developed including the Reese Ellsworth classification (according to the chance of preserving the eye using external beam radiotherapy) and the more recent International Classification of Retinoblastoma (covering the whole spectrum of the disease from intraretinal to the presence of overt extra-ocular extension).
Treatment of retinoblastoma is based on the bilateral or unilateral characteristics of the retinoblastoma, on the staging performed by the fundoscopy and the extension of the disease. Management of a child with retinoblastoma requires constant re-evaluation of the situation according to the response to treatment, with survival the primary aim, followed by globe salvage and the best possible visual function.
Enucleation has become less common with earlier diagnosis and better alternative therapies, but remains the treatment of choice for advanced cases (massive involvement of the retina/vitreous, rubeosis iridis, secondary glaucoma) with no visual potential or with high risk of dissemination (massive choroidal or optic nerve invasion, anterior segment involvement, extraocular extension).
External beam irradiation is no longer considered a first-line conservative treatment due to its important long-term side effects. It remains indicated in advanced bilateral cases with or without vitreous seeding, or in the case of a relapse inaccessible to conservative focal treatment methods. Radioactive plaques (Iodine-125, Ruthenium-106) can be used for the primary treatment of medium sized tumors (under 16 mm in diameter and 9 mm in thickness), but more often as a secondary measure after prior failed treatment or in the case of a relapse.
Treatment approaches changed notably in the 1990s with chemoreduction, gradually replacing external beam radiation and enucleation as first-line treatment, shrinking the lesions until accessible to adjuvant focal tumor control. This new strategy has reduced the frequency of enucleation and spared the complications associated with primary external beam radiation, in particular the risk of second nonocular radiation-induced cancers, a risk particularly high during the first year of life.
Vital prognosis, related to retinoblastoma alone, is now excellent in patients with unilateral or bilateral forms of retinoblastoma, with a cure rate of 95% in industrialized countries. The preservation of visual function depends on ocular preservation, the initial tumor volume, the anatomical relationships of the tumors with the macula and the optic disk and the adverse effects of the treatments (cataract, vitreous hemorrhage).
Strategies for treating intraocular retinoblastoma continue to evolve as new therapies are developed and others fall out of use. There are significant challenges in improving visual outcomes and globe salvage rates in patients with retinoblastoma. |
