• Practical Tips for Diagnosing and Treating Retinoblastoma


    A primer on retinoblastoma genetics, a tool for preimplantation diagnosis, and a new aqueous humor biopsy were among the topics discussed by Carol L. Shields, MD, in the Genetic Disorders in Pediatric Ophthalmology session this morning. 

    Updated terms for retinoblastoma diagnosis. Clinicians previously referred to retinoblastoma as “familial” or “sporadic,” but those terms are outdated, said Dr. Shields.

    The condition is now described as either “germline”’ (the RB1 mutation affects all cells in the body) or “somatic” (the mutation is found only in tumor cells). About 90% of germline mutations are sporadic, rather than inherited, and 10% of people with germline mutations have features so mild that they remain undiagnosed.

    Nearly 3% of individuals with unilateral retinoblastoma show no evidence of RB1 mutation. An estimated 1% of individuals have an MYCN oncogene amplification, and they tend to develop aggressive signs of disease at an early age (around 4.5 months).  

    Genetic testing is key to improved treatment and outcomes. Patients with germline retinoblastoma have very different risks and outcomes than do those with somatic mutations, so prompt and accurate testing is key.

    Germline cases are at risk for:

    • bilateral or unilateral retinoblastoma
    • multifocal or unifocal retinoblastoma
    • pinealoblastoma (prevalence has dropped from 8% in the 1990s to < 1% in 2017, likely due to conventional and high-dose chemotherapy with stem cell rescue)
    • second cancers (these affect about 4% of children on systemic chemoreduction, compared with 22% of children on supplemental external beam radiation therapy)
    • 50% risk of transmission to offspring

    Somatic cases are at risk for:

    • unilateral retinoblastoma
    • unifocal retinoblastoma

    Early testing is crucial. Children with retinoblastoma should undergo genetic testing early in the treatment course, said Dr. Shields.  This has implications for family counseling and can help predict the child’s risk of brain tumors, second cancers, and other effects. A recent paper in JAMA Ophthalmology1 unveiled a method for tumor biopsy using samples of aqueous humor from the retinoblastoma eye. This biopsy provides unprecedented access to tumor-derived, cell-free DNA and information about chromosomal copy number variations.

    Recent advances in genetic testing have redefined the term early—now preimplantation genetic testing can be performed even before the fetus develops. Prospective parents at risk of passing down the RB1 mutation can undergo in vitro fertilization to reduce the risk to their offspring. At the 8-cell stage, clinicians can identify and remove cells carrying the RB1 mutation, then implant the remaining cells into the mother.

    “This helps to engineer the RB1 mutation out of the genome, hence putting me out of business,” Dr. Shields said.—Anni Griswold

    1 Berry JL et al. JAMA Ophthalmol. 2017;135(11):1221-1230. 

    Financial disclosures. None.

    Disclosure key. C = Consultant/Advisor; E = Employee; L = Speakers bureau; O = Equity owner; P = Patents/Royalty; S = Grant support.