What is the recommended evaluation and treatment algorithm for a child under 5 years with suspected retinoblastoma, based on International Classification groups A‑E and bilateral or germline disease?

Evaluation and Treatment Algorithm for Suspected Retinoblastoma in Children Under 5 Years

For any child under 5 years presenting with leukocoria or suspected retinoblastoma, immediately obtain MRI of the head and orbits with and without IV contrast, followed by examination under anesthesia by a pediatric ophthalmologist, and initiate universal germline RB1 testing regardless of laterality or family history. 1, 2, 3

Initial Diagnostic Evaluation

Imaging Protocol

• MRI of the head and orbits with and without IV contrast is the definitive imaging modality for suspected retinoblastoma, as it evaluates tumor extent, optic nerve involvement, choroidal-scleral infiltration, orbital invasion, and possible intracranial spread (including pineal/sellar regions for trilateral disease). 1, 2
• CT orbits with IV contrast may serve as an adjunct to differentiate causes of leukocoria and evaluate optic nerve extension, but MRI remains superior for treatment planning. 1
• Ocular ultrasound performed by the ophthalmologist confirms the presence of an intraocular mass. 2

Clinical Examination

• Fundoscopic examination under sedation or general anesthesia by a pediatric ophthalmologist is the definitive diagnostic method—tissue biopsy should be avoided due to risk of tumor seeding. 2
• Look specifically for: calcifications within the mass (distinguishes retinoblastoma from Coats disease, PHPV, or retinopathy of prematurity), globe size (microphthalmia suggests PHPV or retinopathy of prematurity rather than retinoblastoma), and bilateral involvement (always indicates hereditary disease). 1, 2

Genetic Testing

• Universal germline RB1 testing must be performed for every child with retinoblastoma, whether unilateral or bilateral, regardless of family history. 2, 3, 4
• Testing protocols should detect mosaicism, which occurs in 3-5% of hereditary cases. 3
• Up to 40% of hereditary cases arise from de novo germline mutations, making family history unreliable for risk stratification. 3, 4
• Approximately 15% of unilateral cases harbor germline mutations and are hereditary. 2, 3

Treatment Algorithm Based on International Classification

Bilateral Disease (Always Hereditary)

• Bilateral retinoblastoma (30-40% of cases) always indicates hereditary disease and requires management as such regardless of germline testing results. 2, 3, 5
• Presents earlier at 18-24 months of age. 2, 4, 5
• Intravenous chemotherapy is the first-line approach for bilateral cases, with excellent tumor control for groups A, B, and C, and intermediate control for group D eyes. 6, 7
• Avoid external beam radiotherapy when possible due to 10% per decade increased risk of second cancers in the radiation field in hereditary cases. 2, 3

Unilateral Disease by Group

Groups A-B (Small tumors):

• Intravenous chemotherapy with excellent tumor control rates. 7
• Focal consolidation therapies: laser photocoagulation, cryotherapy, or transpupillary thermotherapy. 5

Group C (Moderate-sized tumors):

• Intra-arterial chemotherapy as primary therapy for nongermline mutation (unilateral) cases with excellent control. 6, 7
• Intravenous chemotherapy remains an option with good control rates. 7

Group D (Large tumors):

• Intra-arterial chemotherapy as primary or secondary therapy for solid retinoblastoma and subretinal seeds. 6, 7
• Periocular chemotherapy as adjunct to boost local chemotherapy dose or for localized recurrences. 6, 7
• Intravitreal chemotherapy for persistent/recurrent vitreous seeds. 6, 7

Group E (Advanced intraocular disease):

• Consider enucleation as acceptable management, particularly for advanced unilateral disease. 7, 5
• If eye salvage attempted: combination of intra-arterial chemotherapy, periocular chemotherapy, and intravitreal chemotherapy for vitreous seeds. 6, 7
• Intracameral chemotherapy can help control intraocular seeds. 5

Extraocular or Metastatic Disease

• Intravenous chemotherapy is mandatory for patients at high risk for metastases (optic nerve invasion beyond lamina cribrosa, massive choroidal invasion, orbital extension). 7
• Advanced extraocular or metastatic tumors carry poor prognosis despite aggressive treatment. 5

Critical Surveillance and Long-Term Management

Immediate Post-Diagnosis

• At-risk infants (positive family history or known germline mutation) require ophthalmologic examination within 24 hours of birth, with follow-up frequency adjusted according to genetic risk status. 3, 4
• Children with bilateral disease require management as hereditary retinoblastoma regardless of germline test results due to possible mosaicism. 3

Lifelong Surveillance for Hereditary Cases

• Annual dermatologic examination for melanoma throughout life. 2, 3
• Immediate evaluation of any head-and-neck signs or symptoms suggestive of sarcoma (bone and soft tissue sarcomas are the most common second malignancies). 2, 3
• Do not perform routine whole-body MRI surveillance in asymptomatic survivors—this lacks supporting evidence and leads to unnecessary procedures and false-positive findings. 3
• Most common second malignancies: bone and soft tissue sarcomas, melanomas, uterine leiomyosarcoma, and radiation-associated CNS tumors. 2, 3

Common Pitfalls to Avoid

• Do not assume unilateral disease excludes hereditary risk—15% of unilateral cases are hereditary and require the same genetic counseling and surveillance. 2, 3
• Do not rely on family history alone—40% of hereditary cases are de novo mutations. 3, 4
• Do not perform tissue biopsy—this risks tumor seeding and is unnecessary when clinical and imaging findings are diagnostic. 2
• Do not delay imaging or ophthalmologic examination—retinoblastoma accounts for 50% of leukocoria cases in infants and is life-threatening. 2
• In children older than 5 years, maintain high index of suspicion despite low incidence, as diagnosis is frequently delayed due to low clinical suspicion, resulting in advanced-stage presentation. 8