Retinoblastoma (RB) is a childhood ocular malignancy that most commonly presents as leukocoria. Early diagnosis can lead to excellent outcomes. Otherwise, the disease progresses to a massive tumor, with invasion of surrounding structures via he optic nerve or sclera, with risk of metastasis and subsequent mortality. Survival is therefore variable: approximately 30% in underdeveloped countries but 97% in developed countries.

Inactivation of both alleles of the RB gene (RB1) predisposes an individual to develop RB. The disease can be categorized as hereditary (25–35%) or nonhereditary (65–75%). Hereditary RB develops from a predisposition due to a de novo or inherited germline RB1 mutation with subsequent loss of the function of the second allele (loss of heterozygosity [LOH]) due to a somatic mutation. Familial RB accounts for approximately 6% of newly diagnosed RB. De novo hereditary RB occurs due to the inactivation of the first RB1 allele at the time of conception. This is uncommon. In nonhereditary RB, each allele is mutated in situ as a somatic change after conception. All cases of nonhereditary RB are sporadic.

In the hereditary RB, 85% of tumors are early onset, bilateral, and multifocal with a cumulative average of five tumors, the distribution being random between the two eyes. In nonhereditary RB, tumors are solitary and unilateral with later onset.

Management of a patient with RB aims primarily to preserve life, and secondarily the globe and, ultimately, visual potential. Treatment alternatives include enucleation, radiotherapy, systemic and intra-arterial chemotherapy, and focal treatments (cryotherapy, transpupillary thermotherapy, and laser photocoagulation).

29.2 Molecular Genetics

The RB1 gene is located at 13q14.2. RB1 is a tumor suppressor gene, the product of which plays a role in cell cycle regulation. Tumor development requires mutations in both copies of the gene. The first allele to be mutated may be found in the germline (hereditary RB) or in a somatic cell (nonhereditary RB). Approximately 10% of RB1 germline mutations are due to germline mosaicism. Mosaicism is suggested when a parent with more than one affected child does not show the same mutant allele present in their children. In all forms of RB, the second allele is inactivated somatically due to mitotic nondisjunction, duplication, mitotic recombination between the RB1 locus and the centromere, or gene conversion and deletion. LOH is the most frequent mechanism of second hit in RB. In unilateral RB, silencing of the RB1 gene due to methylation of the promoter region is also a known mechanism by which the function of at least one allele is lost.

More recent studies also show that RB tumors may demonstrate different mutagenic pathways from normal to malignant cell. A small subset of RB is caused by amplification of the MYCN gene in tumor cells. It is unknown whether MYCN amplification is the only genomic event driving malignancy of these tumors. Further investigation is needed to examine if these tumors are different than those caused by RB1 pathogenic variants.

In addition, RB1 gene inactivation alone is insufficient to induce tumorigenesis. Additional genetic and stochastic events lead to uncontrolled retinal precursor cell proliferation. Comparative genomic hybridization and gene expression studies have facilitated the probing of genes controlling basic events in cellular development, proliferation, differentiation, and apoptosis. The minimal regions most frequently gained in chromosomes of RB are 1q31 (52%), 6p22 (44%), 2p24–25 (30%), and 13q32–34 (12%), and the most commonly lost is 16p22 (14%). Proposed candidate genes responsible for some of these chromosomal imbalances include the leukemic oncogene DEK and the transcriptional factor E2F3. MYCN or KIF14 amplification, or overexpression, and CDH11 (cadherin II) loss of expression are other candidates proposed to affect RB development and progression.

A small subset of hereditary RB are due to germline de novo chromosomal deletion of various sizes of the RB1 locus chr 13q. The phenotype in del13q syndrome with RB includes prominent eyebrows, broad nasal bridge, anteverted ear lobes, a high and broad forehead, bulbous tip of the nose, large mouth, thin upper lip, thick lower lip, and long philtrum, hypertelorism, proptosis, cleft palate, macroglossia, hypotonia with severe developmental delay, and/or motor impairment (▶ Fig. 29.1). Approximately 5 to 15% of patients with RB are heterozygous for a deletion that includes 13q14.2. The frequency of unilateral RB in these patients is likely higher than patients with intragenic mutations. Deletion of 13q has variable phenotype, depending on the location and size of the deletion: deletions proximal to 13q32 (group 1) have mild to moderate developmental delay, variable dysmorphic features, and growth retardation; deletions affecting 13q32 (group 2) have one or more major malformations including brain, genitourinary or gastrointestinal, or severe microcephaly; distal deletions involving 13q33q34 (group 3) have variable presentation.

Patients with an interstitial 13q deletion involving RB1 can show less aggressive phenotypic expression of RB with deletions larger than 1 Mb, which contains the MED4 gene. Other genes affected, such as NUFIP1 and PCDH8, may contribute to psychomotor delay, MTLR1 to microcephaly, and loss of EDNRB to feeding difficulties and deafness.

Small RB1 mutations that produce premature termination codons almost always cause bilateral RB. It has been suggested that the tendency for total deletions to cause fewer tumors is due to contiguous deletion of an adjacent unknown gene that is essential for cell survival. Therefore, fewer and less aggressive tumors would develop in larger deletions.

29.3 Differential Diagnosis

29.3.1 Astrocytic hamartoma

These are glial tumors of the retinal nerve fiber layer that arise from retinal astrocytes. They appear as a cream-white, well-circumscribed, elevated lesion that may present as multiple or solitary sites. A lesion is commonly seen with a multilobulated appearance, but can also be seen as flat and semitranslucent. It is most frequently associated with tuberous sclerosis but may also be seen in affected individuals with neurofibromatosis. It can also be found as an isolated presentation.

29.3.2 Ocular toxocariasis

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