Basics
Description
Retinoblastoma is a malignant tumor of the retina. Due to current treatment options, survival rates are high in developed countries. Primary management focuses on the best treatment approach to spare the child 's life, while secondary goals focus on sparing vision and reducing risk of secondary malignancies.
Epidemiology
- Retinoblastoma is the most common intraocular malignancy in children.
- Hereditary retinoblastoma commonly presents with bilateral disease or multiple tumors in unilateral disease
- Median age at diagnosis for unilateral disease is 24 months and less than 12 months for bilateral disease.
- 25% of patients will present with bilateral disease.
- No association with race, gender, or laterality of eye involvement
- The greatest disease burden is found in countries with the largest populations and high birth rates such as Asia and Africa.
Incidence
- In the United States, there are about 4 cases per million children per year, with a higher incidence in children younger than age 5 years.
- Approximately 300 new pediatric cases of retinoblastoma are diagnosed each year in the United States.
- Retinoblastoma represents 3% of all pediatric malignancies.
Risk Factors
- Hereditary retinoblastoma, in which patients have a germline Rb gene mutation
- 25 " 45% of all retinoblastoma cases are hereditary.
- Family history of retinoblastoma in parents or siblings warrants early screening and continued follow-up to monitor for development of disease.
Pathophysiology
- Tumor development requires loss of function of the RB1 gene, which resides on chromosome 13.
- Constitutional loss of one RB1 allele predisposes a patient to cancer. Loss of the second allele or other mutations of retinal cells will initiate formation of retinoblastoma.
- Sporadic or nonhereditary retinoblastoma has no germline RB1 mutation but instead requires biallelic inactivation of the RB1 gene in a single retinal cell.
- There are 3 common growth patterns:
- Intraretinal (growth only in the retina)
- Endophytic (inner surface of retina to vitreous)
- Exophytic (outer surface of retina to subretinal space)
- Tumor cells that break off from the primary mass will invade the vitreous and grow independently in the vitreous.
- Children with loss of RB1 with large chromosomal deletions of surrounding genes are at risk for developmental anomalies such as facial dysmorphism and mental and/or motor impairment.
- Initial classification of tumor extent is imperative for assessment of prognosis and outcomes.
- International Classification of Retinoblastoma (ICRB), also known as the ABC classification system, is predictive of treatment success following systemic chemotherapy and focal laser treatment. However, the older Reese-Ellsworth classification system is still commonly used.
- ICRB groups eyes from less advanced disease, group A, to most advanced disease, group E.
- ICRB predicts high-risk retinoblastoma seen in group D or E eyes.
- High-risk features on histology include tumor invasion of the optic nerve and massive choroidal invasion. High-risk features will lead to metastases in about 24% of patients if not treated with systemic chemotherapy as compared to 4% of those treated with systemic chemotherapy.
- Patients with bilateral retinoblastoma are at risk for involvement of the pineal gland, termed trilateral retinoblastoma.
Etiology
Mutations in the RB1 gene lead to predisposition of retinal tumors.
Diagnosis
History
Parents often report noticing a white color in the pupil on photographs, eye(s) turning in or outward, and poor vision.
Physical Exam
- Most common presenting signs include the following:
- Leukocoria
- Strabismus
- Poor vision (poor tracking)
- Proptosis is worrisome for more advanced disease.
- Associated bone pain should be evaluated for metastatic disease.
Diagnostic Tests & Interpretation
Lab
- CBC to look for leukopenia, anemia, or thrombocytopenia
- CBC should be evaluated to determine bone marrow involvement.
- If cytopenias are noted, then evaluation of the bone marrow is indicated.
- Extraocular spread noted on imaging warrants evaluation of the cerebrospinal fluid.
- Chromosome analysis should be performed, particularly in patients with bilateral eye involvement or developmental delay.
Imaging
- Brain and orbit MRI can aid in distinguishing between retinoblastoma and Coats disease and will assess for trilateral disease. CT scan can provide information regarding tumor calcification but due to radiation is used less frequently.
- Ophthalmic ultrasonography can demonstrate retinal masses and calcifications.
- A technetium bone scan will show areas of intense primary tumor uptake and screen for bone metastasis and should be performed if concern for metastasis noted on exam.
Diagnostic Procedures/Other
- A biopsy is not performed due to risk for dissemination.
- The diagnosis of retinoblastoma is based on ophthalmologic exam.
- An experienced pediatric ocular oncologist should perform the exam under anesthesia (EUA).
- Early involvement of pediatric oncology should be initiated.
Differential Diagnosis
- Coats disease
- Persistent fetal vasculature
- Vitreous hemorrhage
- Congenital cataract
- Coloboma
- Toxocariasis
- Astrocytic hamartoma
- Retinopathy of prematurity
Treatment
Chemotherapy
- Systemic chemotherapy is currently the most common form of treatment for retinoblastoma, as it allows preservation of the globe and prevention of systemic metastasis.
- Systemic chemotherapy is combined with local retinal therapy for adequate treatment.
- Systemic chemotherapy may prevent development of trilateral retinoblastoma.
- Most common chemotherapeutic agents used for retinoblastoma include carboplatin, etoposide, and vincristine (CEV).
- Intra-arterial chemotherapy (IAC) is a newer modality for treatment of retinoblastoma and provides direct retinal chemotherapy via the ophthalmic artery.
- Less commonly used approaches to deliver chemotherapy include periocular or intravitreal injections.
Radiotherapy
- Retinoblastoma is a radiosensitive tumor.
- Radiation therapy can be provided by external beam therapy or plaque therapy (brachytherapy) and is a useful method to preserve vision.
- Use of radiation is generally avoided due to risk of secondary malignancies, particularly in children with hereditary retinoblastoma.
Surgery/Other Procedures
- Local retinal therapy with cryotherapy or laser photocoagulation is an important modality of treatment.
- Enucleation, removal of the eye, provides definitive treatment for retinoblastoma. Advanced eyes (group E) are usually managed with enucleation to prevent metastatic spread. Unilateral cases with less advanced disease also are frequently managed with enucleation.
Physical Therapy
- Physical therapy is not commonly required for children with retinoblastoma.
- Occupational therapy or speech therapy can help children cope with loss of vision or hearing changes that develop due to side effects of chemotherapy.
Ongoing Care
Issues for Referral
- Children suspected to have retinoblastoma should be immediately referred to a children 's hospital with expertise in these tumors. Prompt evaluation by an ocular oncologist is required for early diagnosis.
- Multidisciplinary teams include ocular oncologists, pediatric oncologists, nurses, pharmacists, and social workers.
- Children with bilateral retinoblastoma should be referred to a pediatric geneticist for genetic testing for RB1 mutations.
Prognosis
- Five-year overall survival in the United States is excellent at 96.5%.
- All forms of metastatic spread: Leptomeningeal disease, trilateral or pineal involvement, and distant metastases require aggressive therapy and still result in poor overall survival.
Complications
- Surgical
- Surgical site wound infections after enucleation
- Complications associated with orbital implants (infection, bleeding, conjunctival erosion, wound dehiscence)
- Acute systemic chemotherapy toxicity
- Myelosuppression
- Ototoxicity
- Infections
- Renal dysfunction
- Peripheral neuropathy
- Radiation
- Skin erythema
- Risk of cataract development
- Vascular endothelium damage
- Vitreous hemorrhage
- Facial and temporal bone hypoplasia
- Secondary malignancy
- IAC toxicity
- Myelosuppression
- Redness or swelling of the eyelid
- Vitreous hemorrhage
- Choroidal atrophy
- Rare risk of stroke or blindness
- Late effects
- Hearing loss and nephrotoxicity from carboplatin
- Secondary malignancy from radiation or chemotherapy (i.e., etoposide).
Patient Monitoring
- Patients should be followed regularly by an ocular oncologist for EUAs to monitor for reoccurrence.
- Patients should be followed by a pediatric oncologist with serial MRI of the brain and orbit and additional imaging based on sites of disease at presentation.
- Patients should be monitored for long-term side effects/complications of therapy, ideally within the context of a survivorship clinic.
Additional Reading
- Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004;24(6):828 " 848. [View Abstract]
- Dimaras H, Kimani K, O Dimba EA, et al. Retinoblastoma. Lancet. 2012;379(9824): 1436 " 1446. [View Abstract]
- Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye. 2013;27(2):253 " 264. [View Abstract]
Codes
ICD09
- 190.5 Malignant neoplasm of retina
ICD10
- C69.20 Malignant neoplasm of unspecified retina
- C69.21 Malignant neoplasm of right retina
- C69.22 Malignant neoplasm of left retina
SNOMED
- SNOMEDCT 370967009 Retinoblastoma (disorder)
FAQ
- Q: Are children with retinoblastoma at risk for developmental delays?
- A: Children who carry RB1 gene mutations should be followed closely for developmental delays with speech and/or motor skills. Children with deletions in chromosome 13 have been described to have an array of developmental delays in association with retinoblastoma.
- Q: Do siblings of children with retinoblastoma need to be evaluated?
- A: Given the high possibility of hereditary RB1 mutations, children of siblings or parents with retinoblastoma should be evaluated at an early age and followed by an ophthalmologist.
- Q: Do I need to worry about other cancers in my child who has retinoblastoma?
- A: Children with the hereditary form of retinoblastoma (RB1 gene mutation, bilateral disease, or family history) are at increased risk for other cancers such as osteosarcoma.
- Q: Is my child with retinoblastoma blind?
- A: The size and location of the tumor(s) will determine your child 's vision. Advanced retinoblastoma (group D or E) is more likely to have total retinal involvement and poor vision.