Introduction to retinoblastoma

The most common primary ocular malignancy of childhood is retinoblastoma.¹ Retinoblastoma arises from a cone precursor cell.² Although retinoblastoma is relatively rare, it has been the subject of great interest because of its well-studied genetic inheritance pattern and molecular biology.

Retinoblastoma has an incidence rate of 1 in 18,000–30,000 live births worldwide. Surveys suggest a relatively constant occurrence in this century. The incidence in the United States is relatively low, at 3.58 cases for each million children under the age of 15 years, and decreases with advancing age. The overall median age at diagnosis in the United States is 18 months, with the median age of diagnosis of bilateral cases occurring at 12 months and of unilateral cases at 24 months. In rare instances, retinoblastoma is detected prenatally via ultrasound or during adulthood.

Survival rates for retinoblastoma patients in the developed world have increased dramatically over the past century. The mortality of retinoblastoma was reported as 83% in 1897 in children who were treated with enucleation, and as 43% in all children in 1916.³ In contrast, cancer registry reports in Europe and the United States have demonstrated 5-year survival rates of 90% and 98%, respectively. The improved survival rate is due to earlier detection of the tumor and improved techniques for local tumor control. In contrast to developed countries, however, developing nations report dramatically low survival rates, as patients in these countries typically present with widespread metastatic disease. Worldwide approximately 50% of patients still die of metastatic retinoblastoma.

There are no differences in incidence by sex, race, or right versus left eye. Some data suggest geographic clustering, but convincing evidence is lacking. Retinoblastoma does appear to occur more commonly in poor patients worldwide.

Molecular biology of retinoblastoma

The traditional view of retinoblastoma genetics, widely held until recently, was that the disease occurs in two forms, germinal and nongerminal. Both forms occur as a result of loss or mutation of both alleles of the retinoblastoma gene (rb1). In nongerminal cases, both rb1 alleles are inactivated somatically in a single developing retinal progenitor cell, whereas in germinal cases, the first mutation occurs in the germline and only the second mutation is somatic. Nongerminal retinoblastoma is always unilateral and unifocal, although the tumor may break apart resulting in hundreds of tiny intraocular seeds. Recent evidence has indicated that nearly all retinoblastoma patients probably demonstrate a degree of mosaicism for the rb1 mutation. Furthermore, evidence suggests that genomic instability, microsatellite instability, defects of the DNA mismatch repair system, and alterations in DNA methylation and acetylation/deacetylation may also be necessary for the malignant transformation of retinoblastoma after the loss of pRB.⁴

The proposed retinoblastoma gene was localized to chromosome 13ql4 through deletion studies and linkage analysis. The protein is a regulator at the cell cycle checkpoint between G1 and entry into the S-phase (Figure 1). Loss of normal rb1 function, as in the case of the tumors, allows for uncontrolled entry into the S-phase and more rapid cell division. Recently, it was discovered that Rb1 wild-type tumors may occur in the context of MYCN oncogene amplification.⁵

Rb1 was the first tumor suppressor gene to be identified. The tumor-suppressive function of the rb1 gene was confirmed in studies that demonstrated the loss of both alleles of the gene in tumor tissue specimens. Later studies showed that a germinal rb1 mutation was present in virtually all retinoblastoma kindreds and that inheritance of the mutant rb1 allele predicted disease.⁶ The tumor-suppressive function of the gene has furthermore been demonstrated in transfection studies showing that the introduction of wild-type expression in pRB-defective cell lines partially reverses the malignant phenotype.

Genetic testing

Both population data gathered from families and our current understanding of the molecular mechanisms of inheritance of the disease have enabled us to predict the likelihood that new offspring in families affected by retinoblastoma will develop the disease (Table 2). Karyotypic studies, which analyze the morphology of entire chromosomes, are generally not useful for the clinical diagnosis of retinoblastoma because they can only identify deletions spanning 2–5 million base pairs and only 3–5% of retinoblastoma patients carry deletions this large.⁷ Instead, more sophisticated indirect and direct techniques that detect smaller mutations are used. At the present time, a single genetic test is unlikely to detect all germline RB gene mutations in patients with retinoblastoma because of the variety of types and locations of mutations that occur. However, adaptation of a routine clinical protocol including a series of complementary tests based on the observation that most mutations alter the protein size and disrupt the large pocket domain may be able to rapidly detect the majority of mutations.⁸

^a If parent is a carrier, then the chance of next sibling having retinoblastoma is 45%.

Presenting signs and symptoms of retinoblastoma

The most common presenting signs and symptoms of retinoblastoma vary depending on the socioeconomic conditions in which the patient presents. In developing countries, children have often developed extraocular disease before they are diagnosed and frequently present with proptosis and an orbital mass (Figure 2). These children are older at diagnosis (age 4–6 years) compared patients in the United States and few survive. Many large retrospective studies over the past quarter-century have examined the most common presentations of retinoblastoma in large developed nations.⁸ In the United States, the most common presenting sign (60% of cases) is leukocoria, a white pupillary reflex (Figure 3). The reflex is caused either by the reflection of incoming light off the tumor or by the retinal detachment caused by the underlying tumor.

Presenting signs in the United States that occur less commonly include strabismus (misalignment of the eyes), inflammatory signs (mimicking orbital cellulitis), anisocoria (different sized pupils), heterochromia (different colored irides), hyphema (blood in the anterior chamber), tumor hypopyon (tumor in the anterior chamber), and nystagmus. Two large retrospective studies on large populations of retinoblastoma patients have recently examined the patterns of detection of retinoblastoma in the United States. The vast majority of patients’ disease was discovered by a family member (80%) rather than by a pediatrician (8%) or an ophthalmologist (10%).⁸

Diagnostic testing

The differential diagnosis of retinoblastoma includes lesions that can simulate a solitary ocular tumor such as astrocytic hamartomas and toxocara canis and lesions that can cause a total retinal detachment such as Coats’ disease, retinopathy of prematurity, and persistent hyperplastic primary vitreous [persistent fetal vasculature (PFV) syndrome] (Table 3). Patients suspected of having retinoblastoma should undergo indirect ophthalmoscopy and fundus photography as well as ophthalmic ultrasonography. Ultrasonography is useful as it demonstrates masses with high reflectivity that block sound, causing characteristic shadowing behind the tumor. Needle biopsies are rarely performed for suspected retinoblastoma, as puncturing the eye and aspiration can lead to tumor seeding with orbital invasion and even death from metastatic disease.

Staging of intraocular retinoblastoma

The Reese–Ellsworth classification scheme was the worldwide gold standard for describing intraocular tumors (Table 4a).⁹ It is not a true staging scheme (for untreated patients do not progress from group I to higher groups), but it has served as an excellent ocular reference for comparison of different series and treatment schemes. A higher numeric classification signified that a tumor was more anterior and that there was a decreased success rate in treating the lesion with lateral port external-beam radiation. Its usefulness has been questioned by many ophthalmic oncologists, who feel that it is no longer appropriate given the current trend away from the use of external-beam radiation. An alternate classification system was developed and has been used clinically by several centers in a collaborative study (Table 4b).¹⁰ It has been shown to correlate with the response to treatment of intraocular disease with systemic chemotherapy combined with focal therapy. As with the Reese–Ellsworth classification, this system may also become antiquated as treatment trends inevitably change in the future.

Treatment of intraocular retinoblastoma

Survival rates in excess of 95% are currently achieved for most patients treated at major centers in developed countries with a multimodal treatment approach that may include enucleation, external-beam radiation, brachytherapy, transpupillary thermotherapy (TTT), cryotherapy, and chemotherapy (systemic, intra-arterial, periocular, and intravitreal). The treatment strategy for each patient depends on several factors: involvement of one or both eyes, heredity of the disease, age of the patient, tumor volume and localization, stage of disease (including Reese–Ellsworth classification), and presence of extraocular disease.¹

Intra-arterial chemotherapy

Clinicians in Japan were the first to postulate that another method of local drug delivery, intra-arterial infusions of chemotherapy, may increase penetration of the drug into small intraocular tumors and decrease systemic side effects.¹³ Our group introduced a technique in which the ophthalmic artery is selectively cannulated and a combination of up to three drugs (melphalan, topotecan, and carboplatin) are injected at the ostium.¹ Other techniques to access the ophthalmic artery include catheterization of the middle meningeal artery or the use of a balloon. Treatment typically consists of monthly infusions given an average of three times. This technique has been adopted by many centers worldwide and is our primary method of treatment for both unilateral and bilateral retinoblastoma. It can be used to treat eyes of all classifications, whether naïve or prior treated, and bilateral cases can be infused in the same session with tandem therapy. In children <3 months of age or 6 kg, bridge therapy is employed: single-agent carboplatin is given until the child reaches an adequate age and weight for intra-arterial chemotherapy. Two-year Kaplan–Meier estimates of ocular event-free survival are estimated at 82% for naïve eyes and 60% for prior treated eyes,¹⁴ although with the recent adoption of intravitreal chemotherapy, these numbers are likely higher (Figure 4).

Ocular side effects are minimal and may include periocular inflammation, medial forehead erythema, and chorioretinal changes.¹⁴ Electroretinogram monitoring of retinal function demonstrates that carboplatin and topotecan have no impact on retinal function; and while melphalan may have an effect, these changes are minimal and likely clinically irrelevant. Approximately 30% of children have at least one episode of grade 3 or 4 hematotoxicity during their treatment course (particularly when melphalan dose exceeds 0.4 mg/kg) and therefore monitoring of blood counts is advised. Vascular complication is a rare complication and no death has been reported from this procedure.

Periocular chemotherapy

Periocular injections of carboplatin or topotecan have been used, particularly as salvage or adjuvant treatment. However, side effects, particularly with carboplatin, include scarring and loss of vision. Furthermore, its long-term efficacy of this delivery method has been questioned.

Intravitreal chemotherapy

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