What are the high risk features of retinoblastoma and their corresponding treatment options, particularly in pediatric patients?

High-Risk Features of Retinoblastoma

High-risk retinoblastoma is defined by specific pathologic features including retrolaminar optic nerve invasion, choroidal invasion, and scleral invasion, which determine the need for adjuvant chemotherapy after enucleation. 1

Pathologic High-Risk Features

The critical high-risk features identified on histopathology after enucleation include:

• Retrolaminar optic nerve invasion - tumor extending beyond the lamina cribrosa into the optic nerve requires adjuvant chemotherapy 1
• Scleral invasion - disruption of the sclera with microscopic invasion of orbital tissue necessitates systemic treatment 2
• Tumor beyond the cut end of the optic nerve - this finding mandates systemic and potentially intrathecal chemotherapy with local and cranial radiotherapy 2
• Choroidal invasion - while there is no consensus that chemotherapy is definitively needed for isolated choroidal invasion, it carries prognostic significance and should be carefully evaluated 3, 2

Clinical High-Risk Features

Beyond pathologic findings, certain clinical presentations indicate higher risk:

• Bilateral disease - always represents hereditary retinoblastoma (30-40% of cases) and carries elevated risks for trilateral retinoblastoma and subsequent malignant neoplasms throughout life 4, 3
• Trilateral retinoblastoma - bilateral disease with pineal gland involvement represents the highest risk presentation 3
• Tumor seeding - vitreous seeds and subretinal seeds indicate more aggressive disease requiring intensified treatment 5
• Gains of 6p on aqueous humor cell-free DNA - associated with more aggressive clinical phenotype 4

Treatment Based on Risk Stratification

Low-Risk Disease (Stage I, No High-Risk Features)

• No adjuvant chemotherapy is required after enucleation for patients without retrolaminar invasion or scleral invasion 1
• Conservative focal therapies (transpupillary thermotherapy, cryotherapy, laser photocoagulation) can be used for small tumors in eyes being salvaged 5, 6

High-Risk Disease (Retrolaminar or Scleral Invasion)

• Adjuvant chemotherapy with 8 alternating cycles is indicated: 4 cycles of cyclophosphamide (65 mg/kg/d with mesna), idarubicin (10 mg/m²/d), and vincristine (0.05 mg/kg/d) alternating with 4 cycles of carboplatin (500 mg/m²/d on days 1-2) and etoposide (100 mg/m²/d on days 1-3) 1
• This regimen achieved 97% event-free survival at 3 years in high-risk patients 1

Extraocular Extension

• Systemic and intrathecal chemotherapy combined with local and cranial radiotherapy is required when tumor extends beyond the cut end of the optic nerve or involves orbital tissue 2
• Prognosis remains poor for central nervous system involvement despite aggressive treatment 2

Hereditary Disease Considerations

All children with retinoblastoma, whether unilateral or bilateral, require germline RB1 testing because approximately 15% of unilateral cases are hereditary, and family history may be absent due to de novo mutations or reduced penetrance variants 4, 7

Surveillance for Hereditary Cases

• Ophthalmologic examination promptly after birth (ideally within 24 hours) for at-risk infants to maximize visual outcomes through early tumor detection 7
• Skin examination for melanoma throughout life, as survivors have significantly increased risk of subsequent malignant neoplasms, especially sarcomas and melanomas 4, 8
• CNS tumor surveillance is not routinely recommended for asymptomatic heritable retinoblastoma survivors, regardless of prior radiation exposure 8
• Breast cancer screening should follow local guidelines with preference for non-radiation imaging modalities when possible 8

Critical Pitfalls to Avoid

• Do not assume unilateral disease is non-hereditary - germline testing must be performed on all patients regardless of laterality 4, 7
• Distinguish true multifocal disease from tumor seeding - seeding from a primary tumor may mimic multifocal disease, which is especially challenging with larger primary tumors 4
• Avoid external beam radiotherapy when possible in hereditary cases due to 10% per decade increased risk of second cancers in the radiation field 4, 9
• Do not delay enucleation for eyes with large tumors, long-standing retinal detachments, neovascular glaucoma, or suspected optic nerve/extrascleral extension, as these eyes have no useful vision and carry metastatic risk 2