PanOph

Retinoblastoma

Pediatric Ophthalmology

Key Points

  • •Retinoblastoma is the most common intraocular malignancy of childhood, caused by biallelic RB1 inactivation on chromosome 13q14 (Knudson's two-hit hypothesis)
  • •Leukocoria is the most common presenting sign; any child with leukocoria must be evaluated urgently to rule out retinoblastoma
  • •95% of tumours show intralesional calcification on imaging — the key diagnostic feature distinguishing RB from simulating lesions
  • •The ICRB (Groups A–E) has replaced the Reese-Ellsworth classification for treatment planning; Group E usually requires enucleation
  • •Germline RB1 carriers face lifelong risk of secondary malignancies (especially osteosarcoma) — avoid external beam radiotherapy and ensure lifelong surveillance
1. Definition

Retinoblastoma is the most common primary intraocular malignancy of childhood, arising from immature retinal cells (retinoblasts) due to biallelic inactivation of the RB1 tumour suppressor gene on chromosome 13q14. It may be unilateral (60%) or bilateral (40%), and can be heritable or sporadic. Early diagnosis is critical as untreated retinoblastoma is uniformly fatal, yet cure rates exceed 95% in developed nations with timely management.

2. Epidemiology

Incidence: 1 in 15,000–20,000 live births worldwide (approximately 8,000 new cases per year globally).

Median age at diagnosis: 18 months (bilateral: ~12 months; unilateral: ~24 months). 95% of cases are diagnosed before age 5.

No sex or racial predilection.

Bilateral disease: 40% of all cases — virtually all bilateral cases are heritable (germline RB1 mutation).

Unilateral disease: 60% of cases — approximately 15% of unilateral cases also harbour germline mutations.

Familial retinoblastoma accounts for 10% of all cases; the remaining 90% have no family history.

In developing countries, retinoblastoma accounts for 10–15% of all childhood cancers; late presentation with extraocular disease is common.

3. Aetiology and causes

RB1 gene (chromosome 13q14) — a tumour suppressor gene encoding the retinoblastoma protein (pRb), which regulates the G1-to-S cell cycle transition by binding and inhibiting E2F transcription factors.

Knudson's two-hit hypothesis (1971):

  • Heritable (germline) retinoblastoma: First hit is a germline mutation (inherited or de novo) present in every cell of the body → second somatic hit in any retinoblast triggers tumour formation. Results in bilateral, multifocal disease; earlier onset; risk of secondary malignancies (especially osteosarcoma).
  • Non-heritable (sporadic) retinoblastoma: Both hits are somatic mutations occurring in the same retinoblast → unilateral, unifocal disease; later onset; no risk of secondary tumours.

MYCN amplification: A small subset (1.5–2%) of unilateral, non-hereditary retinoblastoma has MYCN oncogene amplification without RB1 mutation — typically presents early (median age 4 months) with aggressive, unilateral disease and distinctive histology (large cells, prominent nucleoli).

Loss of RB1 function leads to uncontrolled retinoblast proliferation. Additional genomic changes (gains of 1q, 2p, 6p; loss of 16q) drive tumour progression and correlate with higher-risk histopathology.

4. Pathogenesis
  1. Biallelic RB1 inactivation removes the G1/S checkpoint → retinoblasts undergo uncontrolled proliferation.
  2. Tumour arises from the inner nuclear or outer nuclear layer of the retina and grows in one of three patterns:
  • Endophytic — grows towards the vitreous cavity; visible as a white mass on fundoscopy; can seed the vitreous (vitreous seeds)
  • Exophytic — grows towards the subretinal space; causes retinal detachment; can seed the subretinal space
  • Diffuse infiltrating (1–2%) — flat, infiltrative growth without a discrete mass; mimics uveitis; older children; commonly misdiagnosed
  1. Tumour cells may undergo apoptosis forming areas of necrosis and dystrophic calcification (95% of tumours show calcification on imaging — key diagnostic feature).
  2. Flexner-Wintersteiner rosettes (pathognomonic), Homer Wright rosettes, and fleurettes (most differentiated, best prognosis) are characteristic histological features.
  3. Extraocular extension occurs via: optic nerve invasion (most common route), scleral invasion, orbital extension. Haematogenous spread to bone, bone marrow, liver. Leptomeningeal spread (trilateral retinoblastoma — bilateral retinoblastoma + pinealoblastoma).
5. Classification

International Classification of Retinoblastoma (ICRB) — used for intra-arterial/intravitreal chemotherapy planning:

  • Group A: Small tumour (<=3 mm), away from fovea and disc
  • Group B: Larger tumour (>3 mm) or macular/juxtapapillary location, no seeding
  • Group C: Focal vitreous or subretinal seeding (<=3 mm from tumour)
  • Group D: Diffuse vitreous or subretinal seeding (>3 mm from tumour)
  • Group E: Extensive tumour — neovascular glaucoma, haemorrhage, tumour touching lens, phthisis; enucleation usually required

Reese-Ellsworth Classification (historical — developed for external beam radiotherapy era, now largely replaced by ICRB):

  • Group I–V based on tumour size, number, and location relative to the equator
  • Group I (very favourable) → Group V (very unfavourable)
  • Still referenced in older literature and some exams

International Retinoblastoma Staging System (IRSS) — for extraocular disease:

  • Stage 0: Eye salvaged
  • Stage I: Enucleated, completely resected
  • Stage II: Enucleated, microscopic residual
  • Stage III: Regional extension (orbit, preauricular nodes)
  • Stage IV: Metastatic — IVa (haematogenous), IVb (CNS)

Histopathological classification:

  • Well-differentiated: Flexner-Wintersteiner rosettes, fleurettes — better prognosis
  • Poorly differentiated: Anaplastic cells, mitotic figures, necrosis — worse prognosis
  • High-risk features: optic nerve invasion beyond lamina cribrosa, massive choroidal invasion (>3 mm), scleral invasion, anterior chamber seeding
6. Risk factors and associations
  • Family history of retinoblastoma (10% of cases; autosomal dominant with ~90% penetrance)
  • Germline RB1 mutation — risk of bilateral retinoblastoma, trilateral retinoblastoma, and secondary malignancies
  • 13q deletion syndrome — large deletion including RB1 locus; associated with intellectual disability, dysmorphic features, and retinoblastoma
  • Parental age: slightly increased risk of de novo germline mutations with advanced paternal age
  • MYCN amplification — rare subset, aggressive unilateral disease in young infants
  • Secondary malignancies in germline RB1 carriers: osteosarcoma (most common, 69–406x increased risk depending on radiation history), soft tissue sarcomas, melanoma, brain tumours — cumulative risk 36% by age 50
  • Trilateral retinoblastoma: bilateral retinoblastoma + pineoblastoma (midline intracranial primitive neuroectodermal tumour) — occurs in 3–5% of heritable cases; screened with MRI
7. Clinical features

Symptoms and presenting signs:

  • Leukocoria (white pupillary reflex) — most common presenting sign (56–62%); often noticed in flash photographs; differential: see leukocoria DDx
  • Strabismus — second most common (20–25%); develops when tumour involves the macula, causing visual loss
  • Decreased vision (preverbal children may not report)
  • Red eye, pain, tearing (from secondary glaucoma or inflammation)
  • Proptosis (advanced extraocular disease)
  • Failure to thrive / systemic features (metastatic disease)

Ocular examination findings:

  • White-yellow retinal mass — may be single or multiple
  • Calcification within the tumour mass (visible on B-scan as high reflectivity with shadowing)
  • Vitreous seeds (endophytic growth) — white floating particles
  • Subretinal fluid, exudative retinal detachment (exophytic growth)
  • Pseudohypopyon (tumour cells in anterior chamber)
  • Iris neovascularisation, neovascular glaucoma (advanced disease)
  • Heterochromia iridis (rare)
  • Diffuse infiltrating type: no discrete mass; mimics endophthalmitis/uveitis; pseudohypopyon; older age group (4–8 years); commonly misdiagnosed

Systemal associations in 13q deletion syndrome:

  • Intellectual disability
  • Broad prominent nasal bridge
  • Ear abnormalities
  • Genital anomalies
8. Investigations

Fundoscopy under anaesthesia (EUA) — gold standard for initial evaluation and staging. Performed with dilated indirect ophthalmoscopy, RetCam wide-field imaging, and documentation.

B-scan ultrasonography:

  • High-amplitude intraocular mass with intralesional calcification and acoustic shadowing
  • Calcification present in 95% of cases — key differentiating feature from simulating lesions

MRI of orbits and brain (preferred imaging):

  • Tumour appears as T1 hyperintense (moderate), T2 hypointense mass with enhancement
  • Assess optic nerve invasion, extraocular extension
  • Screen for trilateral retinoblastoma (pinealoblastoma) — mandatory in bilateral cases
  • MRI preferred over CT in children to avoid radiation exposure (important in RB1 carriers who are already predisposed to secondary malignancies)

CT scan: demonstrates calcification better than MRI but avoided as first-line in children with known/suspected germline RB1 mutation due to radiation risk. Consider only if MRI unavailable.

Genetic testing:

  • RB1 gene sequencing and deletion analysis (peripheral blood)
  • Identifies germline vs somatic mutation → determines heritability, risk to siblings/offspring, risk of secondary malignancies
  • Cascade screening of family members

Aqueous/vitreous biopsy: Generally AVOIDED due to risk of tumour dissemination. Reserved for atypical presentations where diagnosis is uncertain.

Lumbar puncture and bone marrow biopsy: In advanced disease (stage III–IV) to assess for CNS and haematogenous metastases.

RetCam documentation: wide-field digital retinal imaging for monitoring treatment response.

Note: No fine-needle aspiration biopsy (FNAB) of a suspected retinoblastoma — risk of orbital seeding. Diagnosis is clinical + imaging.

9. Differential diagnosis

Leukocoria differential (conditions simulating retinoblastoma):

Retinopathy of prematurity (ROP):

  • History of prematurity and oxygen therapy
  • Bilateral; temporal retinal changes
  • No calcification on imaging

Persistent fetal vasculature (PFV):

  • Unilateral microphthalmos
  • Persistent hyaloid artery, retrolental fibrovascular membrane
  • No calcification (key differentiator from RB)

Coats disease:

  • Unilateral, males predominate (3:1)
  • Telangiectatic vessels with lipid exudation (yellow subretinal fluid)
  • No calcification; older children (8–10 years)

Toxocara granuloma:

  • Unilateral posterior pole or peripheral granuloma
  • History of pica, pet exposure
  • Vitreous bands, tractional retinal detachment
  • Positive ELISA for Toxocara antibodies

Astrocytic hamartoma (tuberous sclerosis):

  • White mulberry-like mass, often calcified
  • Associated findings: facial angiofibromas, ash-leaf spots, seizures

Retinal detachment (various causes):

  • No solid mass; no calcification
  • B-scan shows membrane without solid component
10. Complications

Ocular:

  • Vision loss (macular involvement, retinal detachment)
  • Secondary glaucoma (neovascular or from lens displacement)
  • Phthisis bulbi (end-stage)
  • Vitreous haemorrhage

Tumour-related:

  • Optic nerve invasion → intracranial extension → CSF dissemination
  • Orbital extension → proptosis, orbital mass
  • Haematogenous metastasis → bone, bone marrow, liver (most common sites)
  • Trilateral retinoblastoma — pineoblastoma with bilateral RB; poor prognosis if not detected early

Treatment-related:

  • External beam radiotherapy (largely abandoned): secondary malignancies (osteosarcoma, soft tissue sarcoma) in germline RB1 carriers — risk increases with younger age at treatment and higher radiation dose
  • Enucleation: cosmetic concerns, prosthetic eye management
  • Systemic chemotherapy (carboplatin, etoposide, vincristine): myelosuppression, ototoxicity, nephrotoxicity
  • Intra-arterial chemotherapy (melphalan): periocular oedema, transient ophthalmic artery spasm, eyelash loss, rarely retinal detachment or optic neuropathy

Long-term:

  • Secondary malignancies in germline carriers: cumulative risk 36% by age 50; osteosarcoma most common; lifelong surveillance required
  • Psychosocial impact of enucleation, visual impairment, cancer survivorship
11. Management

Principles: preserve life first, then preserve the eye, then preserve vision. Treatment is multidisciplinary (pediatric ophthalmologist, ocular oncologist, pediatric oncologist, radiation oncologist).

1. Enucleation:

  • Indicated for: Group E eyes, unilateral advanced disease with no visual potential, failed conservative therapy
  • Technique: obtain long section of optic nerve (>=10 mm) — to ensure clear margin; avoid perforation of the globe
  • Enucleated eye sent for histopathology — high-risk features (optic nerve invasion beyond lamina cribrosa, massive choroidal invasion >3 mm, scleral invasion) mandate adjuvant chemotherapy
  • Orbital implant + prosthetic eye

2. Systemic (intravenous) chemotherapy — chemoreduction:

  • Regimen: VEC protocol — Vincristine + Etoposide + Carboplatin; 6 cycles, 3–4 weekly
  • Used for Groups B–D to reduce tumour size (chemoreduction) before focal consolidation
  • Also used as adjuvant therapy for high-risk histopathology post-enucleation

3. Intra-arterial chemotherapy (IAC):

  • Melphalan (most commonly used), topotecan, carboplatin delivered via ophthalmic artery catheterisation
  • Increasingly used as primary therapy for unilateral Group D and select Group E eyes
  • Achieves higher local drug concentration with fewer systemic side effects

4. Intravitreal chemotherapy (IViC):

  • Melphalan 20–30 mcg injected directly into vitreous
  • Specifically for vitreous seeds resistant to other therapies
  • Safety technique: injection through tumour-free pars plana, cryotherapy at injection site to prevent tumour cell reflux

5. Focal therapy (consolidation after chemoreduction):

  • Laser photocoagulation (diode/argon): for small posterior tumours (<=3 mm); surrounds tumour to destroy feeding vessels
  • Transpupillary thermotherapy (TTT): infrared laser (810 nm); heats tumour to 45–60 degrees C; for small tumours <=3 mm
  • Cryotherapy: for small anterior/peripheral tumours (<=3.5 mm, <=2 mm thick); triple freeze-thaw technique

6. External beam radiotherapy (EBRT):

  • Largely abandoned as primary therapy due to risk of secondary malignancies in germline RB1 carriers
  • May still be used for recurrent/refractory disease or extraocular extension

7. Brachytherapy (plaque radiotherapy):

  • Iodine-125 or Ruthenium-106 plaque sutured to sclera over the tumour base
  • For localised recurrence after chemoreduction

Screening and genetic counselling:

  • All patients with retinoblastoma should undergo RB1 genetic testing
  • Germline mutation carriers: screen siblings from birth; regular EUA every 3–4 weeks until age 3, then every 3–6 months until age 7
  • MRI screening for trilateral retinoblastoma every 6 months until age 5
  • Lifelong cancer surveillance for secondary malignancies
12. Prognosis

In developed nations: 95–98% overall survival with early diagnosis and modern treatment.

In developing nations: survival drops to 40–70% due to late presentation (extraocular disease).

Group A–B eyes: 95–100% globe salvage with focal therapy + chemoreduction.

Group C eyes: 85–90% globe salvage.

Group D eyes: 50–70% globe salvage with IAC; improving with combined IAC + IViC.

Group E eyes: poor globe salvage; enucleation usually required.

Metastatic disease (Stage IV): poor prognosis; survival with intensive chemotherapy and stem cell transplant is 20–30%.

Trilateral retinoblastoma: historically fatal; improving with early MRI detection and chemotherapy.

Second malignancies in germline carriers: cumulative risk 36% by age 50; ~6% mortality from secondary cancers.

Visual outcomes: depend on tumour location relative to macula and optic disc. Eyes with macular involvement or requiring focal treatment near fovea have limited visual potential.

Clinical Pearls

1
A parent who notices a white glow in their child's eye in flash photographs is describing leukocoria until proven otherwise — this is the most common way retinoblastoma is detected by families.
2
Bilateral retinoblastoma = germline mutation in virtually all cases. Even 15% of unilateral cases have germline mutations — genetic testing is mandatory for ALL retinoblastoma patients.
3
MRI is preferred over CT for retinoblastoma imaging because germline RB1 carriers have an increased risk of radiation-induced secondary malignancies. CT should only be used if MRI is unavailable.
4
The diffuse infiltrating variant (1–2%) has no discrete mass and mimics uveitis/endophthalmitis — classic exam trap. It presents in older children (4–8 years), commonly misdiagnosed, and often has a pseudohypopyon of tumour cells.
5
Trilateral retinoblastoma = bilateral retinoblastoma + pineoblastoma — occurs in 3–5% of heritable cases. Screen with brain MRI every 6 months until age 5.
6
The single most important prognostic factor after enucleation is the extent of optic nerve invasion. Invasion beyond the lamina cribrosa dramatically worsens prognosis and mandates adjuvant chemotherapy.
7
Flexner-Wintersteiner rosettes are pathognomonic for retinoblastoma. Fleurettes indicate the highest degree of differentiation (best prognosis). Homer Wright rosettes are non-specific (also seen in neuroblastoma, medulloblastoma).
8
Never perform FNAB or incisional biopsy of a suspected retinoblastoma — risk of extraocular tumour dissemination. Diagnosis is clinical + imaging.
9
Intravitreal melphalan has revolutionised treatment of vitreous seeds — but the injection must be performed through tumour-free pars plana with cryotherapy at the injection site to prevent tumour cell reflux along the needle track.
10
In the VEC chemoreduction protocol, carboplatin is the most active agent against retinoblastoma. Monitor for carboplatin-related ototoxicity — audiometric screening is essential during treatment.

Oral-exam questions

  • What gene is responsible for retinoblastoma and where is it located? — RB1 tumour suppressor gene on chromosome 13q14. It encodes pRb protein which regulates the G1/S cell cycle checkpoint by inhibiting E2F transcription factors.
  • Explain Knudson's two-hit hypothesis. — In heritable RB, the first hit is a germline mutation (in every cell); the second somatic hit in any retinoblast initiates the tumour (bilateral, multifocal, early onset). In sporadic RB, both hits are somatic in the same retinoblast (unilateral, unifocal, later onset).
  • What is the pathognomonic histological feature of retinoblastoma? — Flexner-Wintersteiner rosettes — ring of tumour cells surrounding an empty lumen with an outer limiting membrane. Fleurettes indicate the highest differentiation. Homer Wright rosettes are non-specific.
  • Why is MRI preferred over CT for retinoblastoma imaging? — Germline RB1 carriers have a markedly increased risk of radiation-induced secondary malignancies. CT exposes the child to ionising radiation, whereas MRI does not. MRI also better evaluates optic nerve invasion and intracranial extension.
  • What is trilateral retinoblastoma? — Bilateral retinoblastoma + midline intracranial pineoblastoma (primitive neuroectodermal tumour). Occurs in 3–5% of heritable cases. Screened with MRI every 6 months until age 5.
  • How do you differentiate retinoblastoma from Coats disease? — Retinoblastoma: solid white mass with calcification, any laterality, younger age. Coats disease: telangiectatic vessels with yellow lipid exudation, unilateral, male predominance, no calcification, older children.
  • What high-risk histopathological features mandate adjuvant chemotherapy after enucleation? — Optic nerve invasion beyond the lamina cribrosa, massive choroidal invasion (>3 mm), scleral invasion, anterior chamber seeding, and extrascleral extension.
  • What is the current standard chemoreduction regimen for retinoblastoma? — VEC protocol: Vincristine + Etoposide + Carboplatin for 6 cycles at 3–4 weekly intervals. Carboplatin is the most active agent. Goal is to reduce tumour size for focal consolidation therapy.

Mnemonics

RETINO

R — RB1 gene (13q14) — tumour suppressor E — Enucleation for Group E T — Trilateral RB (bilateral RB + pineoblastoma) I — ICRB classification (A–E) N — No FNAB (risk of tumour dissemination) O — Osteosarcoma (most common secondary malignancy)

Two-Hit Rule

Hit 1 — Germline (hereditary) or somatic Hit 2 — Always somatic Bilateral = Germline first hit (younger, multifocal) Unilateral = Both hits somatic (older, unifocal) Exception: 15% of unilateral cases have germline mutations

Comparison Tables

ICRB Classification (International Classification of Retinoblastoma)
A
Description
Small tumour (<=3 mm), away from fovea/disc
Vitreous/Subretinal Seeding
None
Globe Salvage Rate
~100%
Typical Management
Focal therapy alone (laser/cryo)
B
Description
Larger tumour (>3 mm) or macular/juxtapapillary, no seeding
Vitreous/Subretinal Seeding
None
Globe Salvage Rate
~95%
Typical Management
Chemoreduction + focal consolidation
C
Description
Focal seeding (<=3 mm from tumour)
Vitreous/Subretinal Seeding
Localised
Globe Salvage Rate
~85–90%
Typical Management
Chemoreduction + focal therapy +/- IAC
D
Description
Diffuse seeding (>3 mm from tumour)
Vitreous/Subretinal Seeding
Diffuse
Globe Salvage Rate
~50–70%
Typical Management
IAC +/- IViC + focal therapy
E
Description
Extensive: NVG, haemorrhage, touching lens, phthisis
Vitreous/Subretinal Seeding
Extensive
Globe Salvage Rate
Poor (<10%)
Typical Management
Enucleation (primary)
Leukocoria Differential Diagnosis at a Glance
Retinoblastoma
Laterality
Unilateral (60%) or bilateral (40%)
Calcification
Present (95%)
Age at Presentation
<3 years
Key Distinguishing Feature
White retinal mass with calcification
Persistent fetal vasculature
Laterality
Unilateral
Calcification
Absent
Age at Presentation
Birth
Key Distinguishing Feature
Microphthalmos + persistent hyaloid artery
Coats disease
Laterality
Unilateral
Calcification
Absent
Age at Presentation
8–10 years (males)
Key Distinguishing Feature
Telangiectatic vessels + yellow exudate
ROP
Laterality
Bilateral
Calcification
Absent
Age at Presentation
Premature infants
Key Distinguishing Feature
Prematurity history + temporal retinal changes
Toxocara granuloma
Laterality
Unilateral
Calcification
Absent
Age at Presentation
6–10 years
Key Distinguishing Feature
Pica history + vitreous bands + ELISA positive
Astrocytic hamartoma
Laterality
Unilateral or bilateral
Calcification
Present
Age at Presentation
Any age
Key Distinguishing Feature
Mulberry-like + tuberous sclerosis features

Self-Assessment (5)

MCQ

A 14-month-old child presents with bilateral leukocoria. B-scan ultrasonography shows calcified intraocular masses in both eyes. What is the most likely diagnosis?

MCQ

Which classification system is currently used for planning intra-arterial and intravitreal chemotherapy in retinoblastoma?

MCQ

A child with retinoblastoma undergoes enucleation. Histopathology reveals tumour invasion of the optic nerve beyond the lamina cribrosa. What is the next step?

MCQ

Which secondary malignancy is most commonly associated with germline RB1 mutation carriers?

MCQ

What is the technique to prevent tumour cell reflux during intravitreal melphalan injection for retinoblastoma vitreous seeds?

References

  1. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21(3):203-212.
  2. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820-823.
  3. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005;18(1):41-53.
  4. Linn Murphree A. International Classification of Retinoblastoma (ICRB). In: Reynolds JD, Olitsky SE, eds. Pediatric Retina. Springer; 2011.
  5. Wright KW, Spiegel PH, Thompson LS. Handbook of Pediatric Eye and Systemic Disease. Springer; 2006.
  6. AAO Basic and Clinical Science Course (BCSC), Section 6: Pediatric Ophthalmology and Strabismus, 2023-2024

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