Unilateral Tumors

Patients can have one or more tumors in one eye. Median age of presentation is 23 months, with few presenting under a year of age. Tumor development within the affected eye can be synchronous or metachronous. For those with unifocal unilateral disease, it is likely that these patients have the nonhereditary form of the disease. Patients with multifocal unilateral disease or those that present at a younger age are more likely to have the hereditary form of the disease.

Bilateral Tumors

Patients have one or more tumors in both eyes. Tumor development can be synchronous or metachronous. It is presumed that these patients have the hereditary form of the disease, even in the absence of a positive family history. These patients almost always present prior to age 2 years and most present in the first year of life. The severity of tumors may be variable in the two eyes, and this becomes important in weighing up potential treatment options.

The Two-Hit Hypothesis

Knudson’s two-hit hypothesis proposes that as few as two stochastic events are required for tumor initiation. The first can be either germline or somatic and the second occurs somatically in the individual retinoblast cells.

The RB1 Gene

RB occurs as a result of mutations of the RB1 gene located on chromosome 13q14. This was the first tumor suppressor gene cloned. It spans 183 kilobases of genomic DNA, consisting of 27 exons, and coding for a 110-kd protein p110, with 928 amino acids. Regulation of transcription, and thus, cell proliferation are linked to the phosphorylation of the RB protein. Involved in this process are E2F1, a transcription factor that regulates the cell cycle during G1, histone deacetylase 1, and downstream cell cycle-specific kinases. Loss of function is the initiating event for RB. Mutations may be germline or somatic and there are a broad array of types and locations of mutations, ranging from single base changes to large deletions. No hot spots of common mutation have been identified.

Hereditary RB

A “two-hit” model has been proposed to explain the different clinical features of hereditary and nonhereditary cases of RB. These patients inherit a germline mutation in the RB1 gene that is present in every cell of the body. Eighty-five percent of these are new spontaneous mutations (sporadic), while the remaining 15% have a positive family history (familial). For the sporadic cases, the paternal allele is affected in approximately 94% of cases. Postconception, a second somatic mutation occurs in the remaining RB1 gene in one or more retinoblasts and tumor results. These cases are at risk of multifocal and bilateral tumors.

Nonhereditary RB

These patients inherit two normal copies of the RB1 gene. Postconception two somatic mutations occur, one in each copy of the RB1 gene in a retinoblast and tumor results. These cases are usually unifocal or unilateral tumors.

Genetic Counseling

The RB1 gene is inherited in an autosomal dominant fashion. Penetrance is high, at approximately 95%. Genetic counseling should be an integral part of the therapy for a patient with RB, whether unilateral or bilateral. Genetic counseling, however, is not always straightforward. A significant proportion (10–18%) of children with RB have somatic genetic mosaicism, making the genetic story more complex and contributing to the difficulty of genetic counseling.

Testing, including sequencing, duplication and deletion testing, MYCN copy number and promoter methylation analysis, is done on the tumor and then compared to somatic tissue (usually blood). If the globe is salvaged, then testing proceeds with a blood sample alone. Of note, in situations where the tumor is not available a negative peripheral blood test does not conclusively rule out that the patient has heritable RB, although it makes it significantly less likely. Environmental exposures associated with development of RB have been inconsistent in epidemiologic studies.

Prenatal Diagnosis and Further Genetic Counseling

With sequencing of the RB1 gene available, prenatal diagnosis can be undertaken, particularly if there is a family history and the mutation has been identified. However, a negative result cannot categorically rule out disease, as 100% of mutations are not picked up by current screening methods. The positive predictive value of screening, however, is rapidly improving.

Pseudoretinoblastoma

The diagnosis of RB is made visually. There are multiple conditions that can mimic RB and in a review of almost 3000 patients referred to a major center with the diagnosis of RB, 22% had a simulating lesion referred to as pseudo RB. In children under the age of 2 years, these most commonly included persistent fetal vasculature (also termed persistent hyperplastic primary vitreous), Coats disease, and vitreous hemorrhage. Older children may have toxocariasis or familial exudative vitreoretinopathy.

Intraocular

• 1.
  

  With endophytic growth, there is a white hazy mass.

  
  
• 2.
  

  With exophytic growth, there is retinal detachment.

  
  
• 3.
  

  Most tumors have combined growth.

  
  
• 4.
  

  Retinal cells frequently break off from the main mass and seed the vitreous, or new locations on the retina.

  
  
• 5.
  

  Glaucoma may result from occlusion of the trabecular network or from iris neovascularization.

Extraocular

• 1.
  

  RB spreads first to soft tissues surrounding the eye or invades the optic nerve. From there it can spread directly along the axons to the brain, or may cross into the subarachnoid space and spread via the cerebrospinal fluid to the brain.

  
  
• 2.
  

  Hematogenous spread leads to metastatic disease, most commonly to brain, lungs, bone marrow, or bone.

  
  
• 3.
  

  RB can spread lymphatically to the preauricular and submandibular nodes.

In patients with the genetic form of RB, central nervous system (CNS) disease is less likely the result of metastatic or regional spread than pineoblastoma, which is also termed trilateral RB.