Dr. Mahziba RahmanMCPS, FCPS

Eye Specialist & SurgeonBangladesh Eye Hospital Ltd.

• The most common primary intraocular malignancy of childhood

• 3% of all childhood cancer

• Occurs due to malignant transformation of primitive retinal cells before final differentiation

• Seldom seen after 3 yrs of age

• Incidence : 1/14000 – 1/20,000 live birth.

• 90% of case present before 3 yrs of age.

• Occurs equally in male & female.

• No racial predilection.

• 60% - 70% unilateral • 30% – 40% bilateral

• Prevents cellular replication

• Disrupton of this gene leads to growth of cancer cells

• Retinoblastoma occurs due to mutation of RB1 gene, located at 13q14

• Both alleles of RB1 must be mutated for a tumour to form.

.

• Two mutations requred to produce retinoblastoma

• The‘two hit hypothesis on’ was proposed by Knudson.

Hereditary case-

• First hit –one mutated allele is inherited & present in all somatic cells.

• Second hit – Further mutagenic event effects the second allele during the person’s lifetime.

In non- hereditary cases

• Affected individuals are born with two normal alleles

• Both the mutations (hits) occur somatically with in the single retinal cell.

Heritable retinoblastoma

Non-Heritable retinoblastoma

Occurrence 40% 60%

Family History Positive Negative

Age 1 year 2 years

Predisposition to other malignancies

Present Absent

Tumour Bilateral, multifocal Unilateral

Risk to sibling 2%- healthy parents40%-affected parents

1%

• LeukocoriaLeukocoria (white pupillary reflex)- 60%• Commonest presentation• Often first noticed in family photograph

• Strabismus (20%)

• • Secondary glaucoma occasionally associated with Buphthalmos

• Red eye due to tumour induced uveitis & iris nodule , pseudohypopyon (5%)

• Orbital inflammation

mimicking orbital or preseptal cellulitis

• Orbital invasion with proptosis

• Metastatic disease involving

regional lymph node & brain.

• Raised ICP due to trilateral

retinoblastoma.

• Bilateral retinoblastoma with intracranial retinoblastoma

• Usually present in pineal gland or parasellar region

• Present in 5% of children with hereditary type

• Visual function

• Slit lamp biomicroscopy

• Indirect Ophthalmoscopy with scleral indentation

• EUA

Corneal diameters

IOP

Ophthalmoscopy

Intraretinal tumour - • Dome shaped,• Gray to white , • Fed & drained by dilated & tortuous vessels, • Developing foci of calcification - chalky white appearance.

They may grow in 3 types

Subretinal, multilobular white masses Retinal detachment may occur

Projects into vitreous as white mass May seed into vitreous

• Rare

• Unilateral

• Detected in later age ( >5 years)

• Difficult to detect

• B-scan ultrasonography To assess tumour size

• CT scan Detect calcification Not preferred as radiation can lead to second tumour

• MRI Superior for ON evaluation, extra ocular extension or to detect

pinealoblastoma Used for follow up

• Systemic investigations

• Genetic studies

• Cells have round, oval or spindle-shaped nuclei ,

twice the size of lymphocyte

• Nuclei are hyper-chromatic with scanty cytoplasm.

• High mitotic activity

• Calcification with necrosis

Many retinoblastoma are undifferentiated but varying degree of differentiation are characterized by the formation of Rosettes

1.Flexner-Wintersteiner rosettes,

2.Homer-Wright rosettes,

3.Fleurettes.

Undifferentiated tumour

Tall columnar cell surrounding a central lumen

Nuclei lie away from lumen

Cells have undergone retinal differentiation

• Less common

• The lumen of a H W rosette is filled with a tangle of eosinophilic cytoplasmic processes

• Also be found in other neuroblastic tumour

• These cells exhibit photoreceptor differentiation.• Cluster of cells with long cytoplasmic process project

through a fenestrated membrane.• Appearance resembles a bouquet of flower.

• Congenital cataract• Retinopathy of prematurity• Persistent fetal vasculature• Coats disease• Toxocariasis• Uveitis• Retinal dysplasia• Retinoma (retinocytoma)• Retinal astrocytoma

Table: Reese-Ellsworth Classification of Retinoblastoma

Group Quick Reference Description Treatment

A Tumors≤3 mm

Small discrete tumors away from critical structures

•Confined to the retina• >3 mm from the foveola• >1.5 mm from the optic nerve

Focal therapy

B Discrete retinal tumor of any size or location

•Tumors not in group A

•No vitreous or subretinal seeding

•Subretinal fluid >3 mm from the base of the tumor

Small number of chemotherapy cycles

Focal therapy

C Minimal vitreous or subretinal seeding

•Subretinal fluid involves ¼ retina

•Subretinal & vitreous seeds ≤3 mm from the tumor

Chemotherapy

Focal therapy

Group Quick Reference Description Treatment

D Diffuse vitreous or subretinal seeding

•Massive and/or diffuse intraocular tumour

•More than one quadrant of retinal detachment

Fine greasy vitreous seeding or avascular massesSubretinal seeding include plaques

Chemotherapy

Focal therapy

E •Eyes that have been destroyed anatomically or functionally by the tumor• Eyes with one or more than the following

•Tumor touching the lens• Neovascular glaucoma•Tumor anterior to vitreous •Diffuse infiltrating retinoblastoma•Massive intraocular hemorrhage•Aseptic orbital cellulitis•Phthisis bulbi

Enucleation

• When treating retinoblastoma, it is first & foremost important to understand that it is a malignancy

• In deciding on a treatment strategy, the first goal must be -

Saving lifeSaving life,

then saving the sight

• Primary health care providers

• Pediatrician

• Ophthalmologist

• Paediatric oncologist

• Geneticist

• Important

Cause & prognosis of disease

Treatment options

Follow up

Genetic counselling

• Parents must be examined prior to treatment

• Photocoagulation

• Cryotherapy

• Plaque radiotherapy / Brachytherapy

• Transpupillary thermotheapy

• External beam radiotherapy

• Post-equatorial tumour for (IIRC group A,B,C,D)

• Tissue temperature raised > 60°c using a argon or diode laser

Encircling tumour double row of laser burns Destruction of blood supply

Regression

• Diode laser (810nm) is used over tumour surface

Temperature raised above 45°c for 1 min

Tumour cell death occurs by hyperthermia

• Pre-equatorial tumour (IIRC group A & B)

• Triple freeze thaw technique

Tumour cells killed while thawing

Full minute thaw before freezing again

• Repeated 4 weeks apart

• Solitary tumours <15mm, not near disc or macula

• Commonly used isotopes are iodine 125 & ruthenium 106

• The tumour is localized

Plaque sutured to sclera Before treatment

Before treatment

Left in situ for 3-5 days

Cottage-cheese appearance after

treatment

• Drugs used:

Carboplatin

Vincristin

Etoposide Before treatment

Cyclosporine

• Cycles: 4- 9 cycles every 3 to 4 weeks

6 months later after treatment

• Dose of 4000-4500 cGy in divided fractions over 3-4 weeks

• Indication-

Bilateral disease not responsive to laser or cryotherapy

• Should be avoided -

- Second tumour risk - Radiation retinopathy

- Cataract formation - Mid face hypoplasia

- Radiation optic neuropathy

• IIRC Group E , recurrent tumour & failure of other treatment

• Minimum manipulation of the globe

• Important to obtain a long optic nerve stump (8-12mm)

• Sent for histopathological examination & genetic studies

• Placement of orbital implant within muscle cone to allow orbital growth

• Local orbital recurrence : External beam radiation and systemic

chemotherapy

• Metastatic RB: Intensive chemotherapy with cyclosporine

• Meningeal spread of RB: Intrathecal or intra ventricular chemotherapy

• Intravitreal chemotherapy Administration of melphalan has been used for vitreous seeding High success rate Needle might create hole and allow tumour spread

• Intra-arterial chemotherapy Chemotherapy directly injected in ophthalmic artery Low dose required

Reduce systemic side-effects

• Periocular chemotherapy injection Increases intraocular level

• Complete and spontaneous necrosis

• Following treatment -Cottage-cheese calcified mass -Translucent fish-flesh mass Fig: Cottage-cheese mass

-Mixture -Flat atrophic scar

Fig: Before and after 2 cycles of chemotherapy

• Risk of secondary malignancies

• Detection of recurrence & new tumour growth

• Management of the complications of therapy

• Genetic counseling

• EUA every 2-8 wks until the age of 3 yrs

• Every 6 months until the age of 5 yrs

• Annually until the age of 10 yrs

Fig: Recurrent RB

Pictures courtesy of the department of Oculoplasty

Parent Affected child Siblings

Bilateral RB survivor

45%

Unilateral RB survivor

7%

Healthy Bilateral RB 5%

Healthy Unilateral RB 1%

• Survival rate

-95% , 5 year survival (intraocular tumour)

- 5%, 5 year survival (extraocular)

• Poor prognostic factors

-Size of timour

- Optic nerve involvement

- Extraocular spread

- Older age at presentation

• Extraocular extension

• Trilateral retinoblastoma

• Second malignancies

• Over the last decade dramatic improvement in management

• In the developed countries due to advancement in management protocol treatment now focuses on vision saving

• In developing countries much advancement still required