A 5-year-old boy with a history of unilateral retinoblastoma (diagnosed at age 2) now presents with a new orbital mass. Which investigation is most appropriate to confirm the diagnosis and assess for bilateral disease?

## Investigation of Choice for Retinoblastoma Recurrence and Bilateral Disease ### Clinical Context - Unilateral retinoblastoma diagnosed at age 2 (early onset suggests possible germline RB1 mutation) - New orbital mass at age 5 (raises concern for bilateral disease or metastasis) - Need to confirm diagnosis AND assess for contralateral involvement **Key Point:** RB1 gene mutation analysis combined with bilateral retinal imaging is the gold standard for confirming hereditary retinoblastoma and detecting bilateral disease, which occurs in 20–30% of RB1 mutation carriers. ### Why This Combination? | Investigation | Purpose | Yield in RB1 Carriers | |---|---|---| | **RB1 sequencing** | Identifies germline mutation; confirms hereditary form; enables cascade testing in siblings | ~90% mutation detection in familial cases | | **MRI/Ultrasound (bilateral)** | Detects contralateral retinal tumors; assesses orbital extension; evaluates for metastasis | Detects bilateral disease in 20–30% of RB1 carriers | | **LDH/Catecholamines** | Nonspecific markers of disease burden; not diagnostic for RB | Cannot distinguish RB from neuroblastoma | | **Bone marrow/CSF** | Assesses for metastatic disease (late-stage workup) | Not first-line for diagnosis confirmation | | **Fluorescein angiography** | Functional retinal imaging; does not detect structural lesions | Useful for monitoring but not diagnostic | **High-Yield:** RB1 is the prototype tumor suppressor gene. Germline mutations confer: - ~90% risk of retinoblastoma (often bilateral, multifocal) - Increased risk of second malignancies (osteosarcoma, melanoma, lung cancer) in adulthood - Autosomal dominant inheritance with high penetrance **Clinical Pearl:** Early-onset unilateral RB (age <18 months) or any bilateral RB should raise suspicion for germline RB1 mutation. Genetic counseling and testing of parents/siblings is mandatory. **Mnemonic: RB1-RETINA** — RB1 mutations require Retinal imaging (bilateral) to detect Early, Treatable Intraocular Neoplasia in At-risk carriers. [cite:Robbins 10e Ch 7]