Retinoblastoma
Summary
Retinoblastoma is the most common primary intraocular malignancy in childhood. It is a neuroblastic tumour arising from the retina. Although life-threatening if untreated, it has one of the highest cure rates of any cancer (>95%) in developed nations due to early detection and advanced therapy. It presents typically before the age of 5. [1,2]
Genetics: The Two-Hit Hypothesis
- The RB1 gene (Chromosome 13q14) is a Tumour Suppressor.
- Alfred Knudson's "Two-Hit Hypothesis" explains the two forms:
- Heritable (40%): Child inherits one mutated allele (Germline 1st hit). The second allele mutates spontaneously (Somatic 2nd hit). Tumours are bilateral, multifocal, and present early (less than 1 year).
- Non-Heritable (60%): Both alleles mutate spontaneously in a single retinal cell (Somatic 1st and 2nd hits). Tumours are usually unilateral and present later (~2 years).
Clinical Pearls
Leukocoria (The White Pupil): The classic sign. Instead of a Red Reflex, the pupil reflects white/cream. Often noticed in flash photography ("Cat's Eye") or by parents in dim light.
Strabismus is a Red Flag: Any child with a new squint needs a dilated fundal exam. A tumour destroying the macula (central vision) causes the eye to drift because it cannot fixate.
Trilateral Retinoblastoma: The combination of Bilateral Retinoblastoma + Pinealoblastoma (a midline brain tumour). The pineal gland is essentially a "third eye" (photosensitive) and shares the same embryonic lineage and RB1 defect.
Demographics
- Incidence: 1 in 15,000 live births.
- Age: Average diagnosis 18 months. Rare after age 5.
- Gender: Male = Female.
Mechanism
- The RB1 protein (pRb) normally inhibits the cell cycle at the G1/S checkpoint.
- Loss of function leads to uncontrolled cell division.
- Histology: Small blue round cell tumour. Flexner-Wintersteiner Rosettes (clusters of cells around a central lumen) are pathognomonic.
Symptoms
Signs
- Red Reflex Test: Using a direct ophthalmoscope at arm's length in a dim room. Both pupils should glow red.
- Hirschberg Test: Corneal light reflex to detect squint.
Diagnosis
- Examination Under Anaesthesia (EUA): The Gold Standard. Evaluation of the retina with full dilation and scleral indentation.
- Ultrasound B-Scan: Shows calcification inside the tumour (highly specific).
- MRI Brain/Orbits: Mandatory to assess:
- Optic Nerve invasion.
- Trilateral disease (Pineal).
- Note: CT is avoided to reduce radiation risk (Rb patients are radiosensitive).
Contraindication
- NEVER BIOPSY: Inserting a needle risks seeding tumour cells into the orbit, changing a curable intraocular disease into a fatal extraocular one.
Management Algorithm
CHILD WITH LEUKOCORIA
↓
OPHTHALMOLOGY REFERRAL (URGENT)
↓
EXAMINATION UNDER ANAESTHESIA (EUA)
+ ULTRASOUND + MRI BRAIN
↓
STAGING & GENETIC COUNSELLING
↓
TREATMENT STRATEGY
(Save Life > Eye > Vision)
┌───────────┴───────────┐
GROUP A-D GROUP E
(Small/Med) (Large/Glaucoma)
↓ ↓
CHEMREDUCTION ENUCLEATION
(Shrink tumour) (Remove Eye)
↓
LOCAL THERAPY
(Laser/Cryo)
Treatment Modalities
- Enucleation: Removal of the eye. Curative for unilateral large disease. Implant placed for cosmesis.
- Systemic Chemotherapy: (Vincristine, Etoposide, Carboplatin). Shrinks tumours ("Chemoreduction").
- Intra-Arterial Chemotherapy (IAC): Melphalan delivered directly into the Ophthalmic Artery via a micro-catheter in the femoral artery. High local dose, low systemic SE.
- Local Therapy: Laser (Photocoagulation) or Cryotherapy (Freezing) for small recurrences.
- Metastasis: To Bone Marrow and Brain.
- Secondary Malignancies: Survivors of heritable Rb have a 30-50% risk of second cancers (Osteosarcoma, Melanoma, Soft Tissue Sarcoma) within 50 years. Radiotherapy greatly increases this risk and is avoided where possible.
- Survival: >95% in high-income settings. less than 50% in low-income settings (late presentation).
- Vision: Depends on macular involvement.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Screening | AAO / RCPCH | Red reflex testing at birth and 6 weeks. |
| Classification | IIRC | Group A-E staging system replaces Reese-Ellsworth. |
Landmark Evidence
1. Knudson's Study (PNAS 1971)
- Statistical analysis of Rb ages led to the "Two-Hit Hypothesis", laying the foundation for all modern tumour suppressor genetics.
What is Retinoblastoma?
It is a rare cancer of the eye that affects young children. It starts in the retina (the camera film at the back of the eye).
Why the white eye?
Normally, the pupil looks black or red (in photos) because light goes in and reflects off the blood-rich retina. The tumour is white/cream, so it reflects white light back.
Is it hereditary?
About 4 in 10 cases are hereditary. We will do genetic blood tests to check. If it is, brothers and sisters (and future children) need screening.
Will they lose the eye?
Our priority is finding the safest way to cure the cancer. If the tumour is small, we can treat it with laser or chemotherapy. If it is very large and the eye is blind, removing the eye (Enucleation) is often the safest way to ensure the cancer is gone forever. Children adapt amazingly well to monocular vision.
Primary Sources
- Dimaras H, et al. Retinoblastoma. Nat Rev Dis Primers. 2015.
- Fabian ID, et al. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol. 2020.
- Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971.
Common Exam Questions
- Genetics: "Chromosomal abnormality?"
- Answer: 13q14 deletion/mutation.
- Diagnosis: "Child with squint - next step?"
- Answer: Dilated fundoscopy (Red Reflex).
- Management: "Role of Biopsy?"
- Answer: CONTRAINDICATED.
- Association: "Teenager with leg pain who had eye surgery as baby?"
- Answer: Osteosarcoma (Second primary).
Viva Points
- Flexner-Wintersteiner Rosettes: The histological hallmark.
- EUA: Why anaesthesia? You cannot perform scleral indentation (to check the far periphery of the retina) on an awake toddler.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.