RetinoblastomaDr Shylesh B DabkeResident, Dept of Ophthalmology, KMC Mangalore

Introduction

1st clinical report of RB : Mid 18th Century.

“ Vernoff” coined the term retinoblastoma : 1920

Most common intraocular malignancy of childhood.*

Untreated children typically die within 2-4years.

Epidemiology

More than 90% of cases occur before age of 5 year.

3% of paediatric malignancies.

Accounts for 1:17,000-34,000 live births worldwide.

Age of presentation : 12months - Bilateral(30-40%) 24months - Unilateral(60-70%)

Similar incidence in males and females.

Genetics

Retinoblastoma gene, Rb1 – Tumor suppressor gene - long arm of chromosome 13

Loss or inactivation of both normal alleles of the Rb gene(Knudson two-hit Hypothesis).

Retinoblastoma inherited as an autosomal recessive trait(cellular level), however behaves clinically as if it has an autosomal dominant pattern with 90% penetrance.

Timing of this loss or inactivation determines whether disease is- Somatic or Sporadic(60%)- Germinal or Hereditary(40%)

Sporadic Retinoblastoma

First hit occurs after conception in utero or in early infancy.

All cells in body are not affected as germ cells are not involved.

Second somatic mutation results in loss of other normal allele.

Hereditary Retinoblastoma

Child starts with heterozygous alleles.

Only one mutation is required to produce disease.

First hit occurs in utero in germ cells before conception

or is inherited from a parent.

All cells of body affected.

Sporadic Vs Hereditary

Sporadic Hereditary

Unilateral, Unifocal Bilateral, Multifocal

Early presentation Late presentation

Low risk of Rb development in relatives High risk or Rb development in relatives

Increased risk of second malignancy- Osteoscarcoma, pinealoblstoma, melanoma etc.

Genetics

All new patients

Positive family history

bilateral unilateral

Negative family history

bilateral

7% 93%

Unilateral67% 33% 25% 75%

Hereditary probabilities & laterality

Screening

Parents and siblings of retinoblastoma patients should be screened.

Parents may have undetected regressed retinoblastoma and new onset of disease in siblings may be detected at an early age.

Siblings at risk of Rb should be screened by ophthalmoscopy soon after birth and then regularly until the age of 4-5years.

Retinoblastoma

Unilateral

Affected Parents

30%

Unaffected Parents

Less than 1%

Clinical presentation

Leucocoria(60%) : white reflex in pupillary area.

Strabismus(20%) : Esotropia(11%), Exotropia (9%)

Painful eye with Secondary Glaucoma(7%) & buphthalmos.

Pseudohypopyon : Anterior chamber involvement.

Orbital cellulitis(3%)

Proptosis and fungating orbital extension

Unexplained hyphema or onset of phthisis bulbi

Signs

Early tumor presents as a small white or almost translucent intra retinal lesion.

Endophytic tumor grows towards vitreous and projects as white mass from retina.*

An exophytic tumor grows as sub retinal mass and can present with retinal detachment.

Exo

Pattern of tumor spread

Growth pattern may be endophytic(into the vitreous), with seeding of tumor cells throughout the eye or exophytic(into sub retinal space) causing retinal detachment.

Optic nerve invasion, with spread of tumor along the subarachnoid space to brain.

Diffuse infiltration of the retina, without exophytic or endophytic growth.

Metastatic spread is to regional nodes, bone, lung, brain and bone.

Child with bilateral RB may present with second intra cranial tumor (Trilateral Rb) commonly Pinealoblastoma.

Staging

Reese-Ellsworth staging system- Predicts chance of visual preservation well but not of survival.

The International Classification (“ABCDE”) system for Rb is under modification and is used in recent clinical protocols.

The AJCC TNM system.

Reese-Ellsworth staging system

International Classification of Retinoblastoma

Group Features

A Small tumor: ≤3 mm

B Large tumor: >3 mm

Macular: ≤3 mm to foveola

Juxtapapillary: ≤1.5 mm to disc

Subretinal fluid: ≤3 mm from the margin

C Focal seeds

Subretinal seeds: ≤3 mm

Vitreous seeds: ≤3 mm

Both subretinal and vitreous seeds: ≤3 mm

D Diffused seeds

Subretinal seeds: >3 mm

Vitreous seeds: >3 mm

Both subretinal and vitreous seeds: >3 mm

E Extensive retinoblastoma occupying more than 50% or

neovascular glaucoma

or opaque media from hemorrhage in anterior chamber, vitreous or subretinal space

Invasion of postlaminar optic nerve, choroid (> 2mm), sclera, orbit, anterior chamber

AJCC Tumour Staging System

T1/p1 <25% of retina

T2/pT2 >25 to 50% of retina

T3/Pt3 >50% of retina and/or intraocular beyond retina

T3a/pT3a >50% of retina and/or cells in vitreous

T3b Optic disk

pT3b Optic nerve up to lamina cribrosa

T3c Anterior chamber and/or uvea

pT3c Anterior chamber and/or uvea and/or intrascleral

T4/pT4 Extraocular

T4a Optic nerve

pT4a Beyond lamina cribrosa, not at resection line

T4b Other extraocular

pT4b Other extraocular and/or at resection line

N1/pN1 Regional

MI Distant metastases

Histology

Tumor is composed of small basophilic cells(retinoblasts) with large hyperchromatic nuclei and scanty cytoplasm.

Shows areas of high mitotic activity and areas of necrosis and calcifications.

Most Retinoblastomas are undifferentiated but varying degree of differentiation results in formation of rosettes. Characteristically,

- Flexner-Wintersteiner rosettes- Homer-Wright rosettes- Fleurettes

Investigations

CBC, urinalysis and liver function tests.*

Aqueous humor to serum LDH ratio : more then 1.0

Examination under anesthesia : - Indirect ophthalmoscopy with scleral indentation must be performed on both eye after full mydriasis.

- General examination of congenital abnormalities of face and hands.

- Tonometry.

- Measurement of corneal diameter.

- Anterior chamber examination with hand held slit lamp.

Ultrasound

Demonstrates a mass more echogenic than the vitreous on B mode.

Highly reflective intrinsic echoes of fine calcifications on A mode.

Detect size and extent of tumor.

Accuracy 80 %.

Computed Tomography

Detect dense heterogenous lesion with hyper dense foci (Calcifications).

Detect extraocular extension in proptotic eye.

Detect optic nerve and intracranial extension.

Magnetic resonance imaging

Tumor size. Optic nerve involvement. Detect presence of associated intracranial lesion - Tri-lateral RB. preferred in children less then 1year of age - avoid cancer risk that

increase with CT.

Bone marrow biopsy, cerebrospinal fluid cytology & Bone scan.

Risk factors for metastasis are present such as tumor involving anterior segment, choroid or optic nerve or extending extrasclerally.

FNAC from tumor should be avoided - increase risk of vitreous seeding.

Differential Diagnosis

Congenital CataractPHPV Inflammatory cyclitic membrane

Coats DiseasePosterior polar toxocara granuloma Advanced retinopathy of prematurity

Other DD’s

Exudative Retinal detachment.

Vitreoretinal dysplasia.

Incontinentia pigmenti

Retinocytoma(Retinoma).

Retinal Astrocytoma.

Treatment

Primary goal- Ensure the survival.- Retention of eyes and vision. - Avoidance of side effects of therapy.

Treatment approach depends on tumor size, extent, intraocular or extraocular extension.

Treatment Modalities

Surgery• Enucleation• Exenteration

Local therapy• Cryotherapy• Photocoagulatio

n• Laser

hyperthermia• Radioactive

plaque applications

Radiotherapy• EBRT• Radioactive

plaque

Chemotherapy• Systemic• Local• Intra-arterial

Treatment of small tumors - <3mm diameter <2mm thick

Chemotherapy- Without other treatment can be attempted for macular tumors.*

Photocoagulation- Focal consolidation after chemotherapy.

Cryotherapy(triple freeze-thaw technique)- Pre equatorial tumors without deep invasion or vitreous seeding.

Treatment of medium size tumors – Upto 12mm wide6mm thick

Primary Chemotherapy- IV Carboplatin, Etoposide &Vincristine.- Sub Tenons Carboplatin injections.- Followed by local cryotherapy.

Brachytherapy(Iodine-125 or Ruthenium-106)

Treatment of large tumors

Chemotherapy- Shrinks tumor – subsequent local therapy – avoiding enucleation or EBRT.- Beneficial for smaller tumors in fellow eye and incase of Pinealoblastoma.

Enucleation, Exenteration.

Treatment of extraocular extension

Adjuvant chemotherapy- 6months course of CEV after enucleation if there is retrolaminar or massive choroidal spread.

External Beam Radiotherapy- Tumor extending to the cut end of Optic nerve at enucleation.- Extension through sclera.

Chemotherapy

Most retinoblastomas are large at the time of presentation - reduce tumor volume - enhances the success of local therapies.

As initial treatment of retinoblastoma - improves the ocular salvage rate.

Currently, 6 cycles of Vincristine, Carboplatin and Etoposide are employed as the standard starting regimen.

Standard dose: (3 weekly, 6 cycles)Vincristine (0.05 mg/kg for children < 3yrs & maximum dose < 2 mg) Etoposide (5 mg/kg for children < 3yrs )Carboplatin (18.6 mg/kg for children < 3yrs)

Chemotherapy Statistics

Numerous studies suggests chemotherapy to be effective in globe salvage in R-E Group I–IV eyes with success rate 85%.

chemoreduction is generally considered for group A, B, and C eyes, and is less effective for more advanced disease.

Ocular salvage in a series of patients in Group E, at the 2 year follow-up:

Chemoreduction + EBRTx : 91%

Chemoreduction alone : 53%

Following chemoreduction, tumor respond well to thermotherapy and rarely require EBRT or enucleation.

Local Chemotherapy

Sub-Tenon’s carboplatin though associated with a higher failure rate, is currently considered for possible use as a “boost” with chemoreduction for groups C, D, and E tumors

Intra-arterial chemotherapy:- Catheterization of the ophthalmic artery and injection of chemotherapy, usually Melphalan (with or without Topotecan(.

Macular Rb showing complete regression with 6 cycles of Chemoreduction alone

Juxtapupillary Rb – Partially regressed with 3 cycles Chemoreduction – complete regression with 6 cycles

Laser Photocoagulation(Argon/Diode laser/Xenon arc)

Small post. tumors 4 mm basal diameter & 2 mm in thickness.

Restrict blood supply to tumor by surrounding it with 2 rows of overlapping laser burns.

Most tumors require 2 to 3 sessions to be cured.

Contraindications: - Tumor located at or near macula or pupillary area.- Tumors arising from a vitreous base.- Patient on active chemoreduction protocol.*

- Presence of vitreous seeding.

Thermotherapy

Focused heat - Infrared Radiation(wavelength 810nm) - applied to tissues at sub-photocoagulation levels to induce tumor cell apoptosis.

Achieve slow & sustained temperature ( 40 to 60 degree C) within tumor, sparing retinal vessels.

Transpupillary thermotherapy using infrared radiation from semiconductor diode laser is most commonly used.

- 3 Focal Rb treated with Transpupillary Thermotherapy

- Flat scar with patent vessels coursing through

Multifocal Rb following Chemoreduction and Transpupillary thermotherapy.

Cryotherapy

Equatorial & Peripheral retinal tumors upto 4 mm in diameter & 2 mm in thickness.

Under GA, pencil like probe is placed precisely on the sclera directly behind the intraocular focus of RB.

Rapid freezing forms intracellular crystals which ruptures tumor cells and causes vascular occlusion.

Triple freeze thaw cryotherapy at 4-6 week interval until complete tumor regression.

Plaque Brachytherapy

Placement of radioactive implant on sclera corresponding to base of tumor, transsclerally irradiate tumor.

Tumors < 16mm basal diameter & < 8 mm thickness

Tumor thickness measured by ultrasonography

Plaque design depending on basal tumor dimensions, its location & configuration.

Plaque sutured to sclera & left for duration of exposure (ranging 36 to 72 hrs)

90% tumor control

- Ruthenium 106 & Iodine 125- Dose – 4000 – 5000 cGy

Advantages

- Focal delivering of radiation.*

- Absence of cosmetic abnormality due to retarded bone growth(EBRT)

- Shorter duration of treatment

Disadvantage - Placement of plaques can be technically difficult and requires a second surgical procedure for removal.

Complications

- Radiation papillopathy

- Radiation retinopathy

External Beam Radiotherapy(EBRT)

It is currently rarely utilized

Indications

- Large bilateral tumors.- Vitreous seeding.- Thick tumors near the optic nerve or fovea in the eye with visual potential.- Multiple tumors that are too large for cryotherapy or laser photocoagulation.- Recurrent or no response from chemoreduction.

Delivered using Cobalt 60 (gamma rays) or linear accelerator ( X-rays)

Complications- Second cancers, particularly in patients with hereditary RB.

- Damage to the retina, optic nerve, lacrimal gland, lens and loss of eyelashes.

- Midface hypoplasia. - Dry eye - Cataract - Radiation retinopathy - Optic neuropathy

The risk of tumor recurrence following EBRTx is 7 % within 40 months.

- Osteosarcoma of frontal bone in patient who underwent EBRT for Bilateral Rb at 1yr of age

Enucleation

Indications 1. Rubeosis, vitreous haemorrhage or optic nerve invasion.2. Chemotherapy fails or normal fellow eye makes aggressive chemotherapy inappropriate.3. Diffuse retinoblastomas.4. Blind painfull eye.

Enucleation should be performed with minimal manipulation and it is imperative to obtain long piece of optic nerve(15mm)

Orbital implant should be as large as possible, implanted at the time of operation. Tenons and conjunctiva should be sutured separately.

Post-enucleation follow-up: Child must be monitored closely for orbital relapse in the two years

after surgery. * the incidence of orbital recurrence after enucleation is 4.2%. The majority of patients (85 %) with orbital recurrence also developed

metastatic disease.

Exenteration

Procedure: removal of globe, extra ocular muscles, lids , nerves and orbital fat. Indications:

Extensive local tumor breaching the globe. Recurrence of tumor in socket after enucleation.

Followup

After radio or chemotherapy tumor regress to a “Cottage-cheese” calcified massor a translucent “Fish-flesh” mass or a mixture of both or as a flat atrophic scar.

If Rb has been treated conservatively EUA should be performed every 2-8weeks until 3years of age after this time examination without anesthesia is performed every 6months until 5years of age, then annually until 10years of age.

References

Ophthalmology – Myron Yanoff & Jay Duker Clinical Ophthalmolgy – Jack J Kanski Clinical Eye Atlas – Daniel Gold & Richard Lewis Post Graduate Ophthalmology Internet