Etiology and Epidemiology

The incidence of retinoblastoma is higher (6 to 10 cases per million children) in Africa, India, and children of Native American descent in North America. The increased incidence occurs primarily in unilateral cases. In industrialized countries, an increased incidence of retinoblastoma is associated with poverty and low levels of maternal education, that suggests environmental factors in its etiology.^3,4 Recent studies have suggested a role for human papillomaviruses in the pathogenesis of retinoblastoma. The viral oncoprotein E7 of high-risk human papillomavirus types has been shown to bind to and inactivate the RB1 gene product (pRB), acting functionally to create the biallelic loss of RB1.^5,6 High-risk human papillomavirus sequences have been detected in 28% to 36% of tumors.⁶

Biology

In 1971, based on the mathematical analysis of the age at presentation of bilateral (hereditary) and unilateral (mostly nonhereditary) cases of retinoblastoma, Knudson⁷ proposed the “two-hit hypothesis,” in which two mutational events in a developing retinal cell lead to the development of retinoblastoma. This hypothesis was subsequently extended to suggest that the two events could be mutations of both alleles of the RB1 gene, located on chromosome 13q14 and identified in 1986.^8,9 Its product, pRb, is required for the transition of the cell through the G1 phase of mitosis. pRb appears to function as a tumor suppressor at least in part by inhibiting cell cycle progression past the G1-S restriction point; on entry to the S phase, cells become irreversibly committed to division. pRb is the major gatekeeper to control this critical point in growth regulation; lack of pRb activity removes the pRb constraint on cell cycle control, resulting in deregulated cell proliferation.

The RB1 gene is a large gene, containing 27 exons over about 200 kilobases of DNA, and mutations have been described in almost every exon.¹⁰ New germline mutations have an overwhelming preference for the paternal allele. Penetrance of the trait is greater than 90%.¹¹

In both hereditary and nonhereditary retinoblastoma the second tumorigenic event is usually chromosomal, often as a result of mitotic recombination errors.¹² This second hit occurs at a much higher frequency than the first hit, and it is more sensitive to environmental factors such as ionizing radiation, perhaps explaining the increased risk of radiation-induced malignancies in survivors of retinoblastoma.

Prevention, Early Detection, and Genetic Counseling

The successful management of retinoblastoma depends on the ability to detect the disease while it is still intraocular. Disease stage correlates with delay in diagnosis.¹⁴ In developing countries, late diagnosis is associated with orbital and metastatic disease.¹⁵ Eye assessment is encouraged in all neonates and at subsequent health visits. Mass screening is being considered, especially where the tumor is common in areas of South America and Asia.

Retinoblastoma is a unique neoplasm in that the genetic form imparts a predisposition to developing tumor in an autosomal dominant fashion with almost complete penetrance (85% to 95%).¹⁶ The majority of such children acquire the first mutation as a new germline mutation, with only 15% to 25% having a positive family history. However, some families display an inheritance pattern characterized by reduced penetrance and expressivity. Also, the RB1 gene mutation can occur at a late stage of embryogenesis, resulting in a variable expression depending on the tissue, causing mosaicisms in 10% to 15% of the patients or their progenitors.¹⁷ Recognizing the inheritance pattern and the existence of mosaicisms, the following familial risk estimates can be made¹⁶:

Genetic counseling is of the utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate the risk in relatives. With the refinement in methods of mutational analysis over the past decade, detection rates have increased to more than 90%.¹⁰

Pathology and Pathways of Spread

Macroscopically, retinoblastoma is soft and friable, tending to outgrow its blood supply with resultant necrosis and calcification. Dissemination within the vitreous and retina in the form of small, white nodules (seeds) is common, sometimes making it difficult to distinguish a multicentric primary tumor from a disseminated tumor.¹⁸ The microscopic appearance depends on the degree of differentiation. Undifferentiated retinoblastoma is composed of small, round, densely packed cells with hypochromatic nuclei and scant cytoplasm. Several degrees of photoreceptor differentiation have been described, characterized by distinctive cellular arrangements. Flexner-Wintersteiner rosettes (clusters of low columnar cells arranged around central lumens bounded by eosinophilic membranes analogous to the external membrane of the normal retina) are specific for retinoblastoma and are noted in 70% of tumors. Fleurettes (composed of larger cells with abundant eosinophilic cytoplasm arranged in a distinctive fleur-de-lis pattern) are less frequent; cells exhibit ultrastructural characteristics of photoreceptor differentiation. Especially well-differentiated tumors composed almost entirely of fleurettes have been called retinomas or retinocytomas. Ultrastructurally, retinoblastoma cells demonstrate photoreceptor differentiation with the presence of the 9-0 microtubule doublet pattern, abundant cytoplasmic microtubules, synaptic ribbons, and neurosecretory granules.

Clinical Manifestations, Patient Evaluation, and Staging

Retinoblastoma is a tumor of young children. Bilateral retinoblastoma presents at a younger age (usually before 1 year of age) than patients with unilateral disease (typically at age 1 to 3 years).16,18,19 Half the cases of retinoblastoma diagnosed during the first year are bilateral, compared with fewer than 10% when diagnosed after 1 year of age.

In over 50% of cases, the presenting sign is leukocoria, sometimes first noticed after a flash photograph. Strabismus is the second most common presenting sign and is usually correlated with macular involvement. The differential diagnosis includes other childhood diseases that can present as leukocoria, such as persistent hyperplastic primary vitreous, retrolental fibrodysplasia, Coats disease, congenital cataracts, toxocariasis, and toxoplasmosis.

Although most patients with bilateral retinoblastoma carry a germline mutation of the RB1 gene, only 5% carry a deletion involving the 13q14 locus large enough to be detected by karyotyping. In those cases, retinoblastoma is part of a more complex syndrome resulting from the loss of additional genetic material. Patients with the 13q− syndrome are characterized by typical facial dysmorphic features, subtle skeletal abnormalities, and varying degrees of mental retardation and motor impairment.²⁰ The severity of deficits correlate with the size of the deletion; normal psychomotor development may be seen in those patients in whom the deletion is restricted to the 13q14 band.

Trilateral retinoblastoma refers to the association of bilateral retinoblastoma with a typically asynchronous brain tumor.²¹ The majority of tumors are pineal region primitive neuroectodermal tumors (PNETs, pineoblastomas); 20% to 25% of the tumors are suprasellar or parasellar. The PNETs exhibit varying degrees of neuronal or photoreceptor differentiation, suggesting an origin from the germinal layer of primitive cells. Trilateral disease occurs in 3% to 9% of patients with the genetic form of retinoblastoma and appears to be more common in familial cases. The prognosis until recently has been almost uniformly fatal. The median age at diagnosis of trilateral retinoblastoma is 23 to 48 months; the interval between initial diagnosis of bilateral retinoblastoma and the diagnosis of the brain tumor is usually more than 20 months.²² In recent years, with the more widespread use of chemoreductive therapy and less use of radiation therapy (RT) for patients with bilateral retinoblastoma, the incidence of trilateral retinoblastoma has decreased dramatically.²³ Approximately 5% of patients with bilateral disease develop pineal cysts, which appear to be a forme fruste of trilateral retinoblastoma.²⁴

The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina (Fig. 69-1). Endophytic tumors are those that grow inward to the vitreous cavity and may seed the vitreous cavity. Exophytic retinoblastoma grows into the subretinal space, causing progressive retinal detachment and subretinal seeding. A very detailed documentation of the number, location, and size of tumors, of the presence of retinal detachment and subretinal fluid, and of the presence of vitreous and subretinal seeds must be performed. Wide-angle real-time retinal imaging systems such as RetCam (Clarity Medical Systems, Pleasanton, Calif.) provide a 130-degree field of view and digital recording, thus facilitating diagnosis and follow-up.

Figure 69-1 A, Advanced intraocular retinoblastoma in a patient with bilateral disease. B, Same eye after 4 cycles of chemotherapy.

Imaging studies that aid in the diagnosis include bidimensional ultrasonography, computed tomography, and magnetic resonance imaging (MRI). Imaging is particularly important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria. Evaluation for the presence of metastatic disease also needs to be considered in a subgroup of patients. Metastatic disease occurs in 10% to 15% of patients, usually in association with advanced intraocular features, such as deep choroidal and scleral invasion, or involvement of the iris or ciliary body or of the optic nerve beyond the lamina cribrosa.¹³ In such cases, additional staging should include bone scintigraphy, bone marrow aspiration and biopsy, and lumbar puncture.

The Reese-Ellsworth grouping system has been the standard for intraocular disease. This system was designed to predict the outcome after external beam radiation therapy (EBRT). It divides eyes into five groups on the basis of the size, location, and number of lesions and on the presence of vitreous seeding²⁵ (Table 69-1). The changed paradigm for “conservative” chemoreduction strategies for intraocular retinoblastoma has made the Reese-Ellsworth system less predictive of ocular preservation. A new staging system (i.e., the International Classification of Retinoblastoma) has been developed to provide a simpler, more user-friendly classification applicable to current therapies. The new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space and seems to be a better predictor of treatment success²⁶ (Table 69-2).

TABLE 69-1 Reese-Ellsworth Grouping for Suitability for Treatment of Retinoblastoma by Radiation Therapy

dd, disc diameter (1.5 mm).

From Reese AB, Ellsworth RM: The evaluation and current concept of retinoblastoma therapy, Trans Am Acad Ophthalmol Otolaryngol 67:164-172, 1963.

TABLE 69-2 International Classification of Retinoblastoma

Modified from Shields CL, Mashayekhi A, Au AK, et al: The International Classification of Retinoblastoma predicts chemoreduction success, Ophthalmology 113:2276-2280, 2006.

For patients undergoing enucleation, pathologic staging incorporates features known to influence outcome, guiding the therapeutic approach; such factors include choroidal and scleral involvement, optic nerve extension, and presence of metastatic disease. A third proposed staging system developed by an international consortium of ophthalmologists and pediatric oncologists incorporates the most important elements of the older systems²⁷ (Table 69-3). Growth and invasion occur as a sequence of events, and extraretinal extension occurs only after the tumor has reached large intraocular dimensions. As part of this process, retinoblastoma extends into the ocular coats (choroids and sclera), the optic nerve, and the anterior segment. Extraocular disease is the next step in this progression; locoregional dissemination occurs by direct extension through the sclera into the orbital contents and preauricular lymph nodes. Extraorbital disease manifests as intracranial tumor, leptomeningeal dissemination, or hematogenous metastasis.

TABLE 69-3 International Retinoblastoma Staging System, Proposed

From Chantada G, Doz F, Antonelli CB, et al: A proposal for an international retinoblastoma staging system, Pediatr Blood Cancer 47:801-805, 2006.

Primary Therapy