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Presented By: Dr. Vandana Dept. of Radiotherapy CSMMU

Retinoblastoma dr vandana

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Presented by Dr. VandanaCSMMU, LucknowEarlier King George Medical University.

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Page 1: Retinoblastoma dr vandana

Presented By:Dr. VandanaDept. of RadiotherapyCSMMU

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Clinical Anatomy The eye is composed of three

layers. Outer fibrous layer formed

by the sclera posteriorly and the cornea anteriorly.

Inner layer , sensory retina with vision concentrated at the fovea which is lateral to the optic nerve and directly posterior to the lens.

In between these vascular layer – the uvea or choroid –which supplies the retina. The iris is the outer continuation of the vascular layer

Lens sits just behind iris, suspended from the ciliary body.

No lymphatic drainage

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RetinoblastomaMid 18th century: 1st clinical report of RB was recognized1920-“ Vernoff” coined the term retinoblastoma2.5-4% of paediatric malignanciesMost common intraocular malignancy of childhood2nd most common primary intraocular malignancy in any

age groupTumor is of neuroepithelial origin & arises from

unidentified progenitor cell in nucleated layers of one or both eyes

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

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EpidemiologySlight male preponderance 1.15:1.0More than 90% of cases occur before age of 5 year Most common among blacks & Africans Age: average age in hereditary cases: 12-14 months,

sporadic cases 24-30 months Unilateral: 65-80%Bilateral: 20-35%

Aetiology: unknown

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GeneticsDeletion of long arm of chromosome 13, 13q14, which is

a tumor suppressor gene termed as RB gene.

‘Alfred Knudson’ hypothesis: 2 types

Hereditary Non-hereditary

Familial Sporadic

Germline mutations 2 hitsBilateral, multifocal Unilateral, unifocal

Young age older age

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Clinical featuresFamily history: 10%Leukocoria (white pupillary reflex):

50% , commonestStrabismus [esotropia]: 20%Ocular inflammation: due to necrosis of

tumor or tumor cells may enter AC resembling hyphema [pseudohypopyon]

Secondary glaucoma: angle-closureLoss of visionProptosis: extra ocular invasion Trilateral retinoblastoma; bil RB+

pineoblastomaDistant metastases

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Routes of spreadLocal spread; anteriorly- seeding of vitreous & aqueous;

posteriorly, sub retinal space and choroidsMay spread through optic nerveAlong the central retinal vessels: tumor cells pass through

the lamina cribrosa and enter subarachnoid spaceDistant metastases: CNS, skull, bones, lymph nodes, spinal

cord, bone marrowOrbital involvement

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Staging

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Reese-Ellsworth Classification

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International Classification of RetinoblastomaGroup 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

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AJCC Tumour Staging System for RBT1/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

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St. Jude’s Tumor Staging SystemStage I: Tumor (unifocal or multifocal) confined to retina

a. Occupying one quadrant or less

b. Occupying two quadrants or less

c. Occupying more than 50% of retinal surface

Stage II: Tumor (unifocal or multifocal) confined to globe

a. With vitreous seeding

b. Extending to optic nerve head

c. Extending to choroid

d. Extending to choroid and optic nerve head

e. Extending to emissaries

Stage III: Extraocular extension of tumor

a. Extending beyond cut end of optic nerve (including subarachnoid extension)

b. Extending through sclera into orbital contents

c. Extending to choroid and beyond cut end of optic nerve (including subarachnoid extension)

d. Extending through sclera into orbital contents and beyond cut end of optic nerve (including subarachnoid extension)

Stage IV: Distant metastases

a. Extending through optic nerve to brain

b. Blood-borne metastases to soft tissue(s) and bone(s)

c. Bone marrow metastases

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Diagnostic workupDiagnosis of retinoblastoma is made without

pathologic confirmation and is based on a clinical examination.

Clinical history Physical examination: EUA

Direct ophthalmoscopy: white reflex Indirect ophthalmoscopy:

RB seen as projecting into vitreous, creamy white in color, neovascularisation seen on surface, calcification gives cottage cheese appearance (glistening white)

RB diagnosed owing to vitreous hemorrhage, RD, severe inflammatory reaction

(A) A fundus photograph of an eye with retinoblastoma

(B) The corresponding sketch of the disease in the eye diagram.

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Ophthalmic USG: Non-invasive, safe, repeatable, and immediately interpretable.

B-scan USG reveals a 2D cross-sectional view, confirms presence and the relationship, the size and shape of the tumors. Orbital involvement, optic nerve invasion can be seen, extrascleral extension, and calcification.

.

B-scan of an eye with retinoblastoma

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CT scan, dense heterogenous lesion with hyper dense foci corresponding to calcification.

for assessing extraocular extension and invasion of the optic nerve.

A computed tomography scan of a large calcified retinoblastoma in the right eye.

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Instead, as part of an extent-of-disease work-up, MRI is routinely performed.

Involvement of the optic nerve, extraocular extension, and intracranial midline neoplasm in trilateral retinoblastoma are best detected.

Used in differentiating retinoblastoma from simulating lesions.

MRI

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Other tests Anterior chamber para-centesis: to assay LDH. Elevated ratio of aqueous

LDH5/LDH1 iso-enzymes, elevated ratio of aqueous LDH/ serum LDH Fluorescein angiography: tumor blush CSF cytology Bone marrow biopsy &aspiration Bone scan Lab tests: Hemogram, Blood chemistries, KFT, LFT

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Treatment of RetinoblastomaPrimary goal

to ensure the survival of children. retention of eyes and vision. Avoidance of side effects- second malignancies, facial

bony deformities, or other physical changes that can affect functional well-being.

Treatment approaches are guided by the presence of intraocular or extraocular disease.

5 yr. DFS > 90% for intraocular disease pts., but < 10% for extra-ocular disease.

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Treatment Modalities

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Surgery

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Enucleation Procedure: removal of globe after severing the rectus muscles, optic

nerve is cut (10-20mm) near its exit from the socket Indications:

Unilateral RB with blind eye Bilateral RB with both eyes blind- bilateral enucleation Uni/bilateral RB with glaucoma (rubeosis iridis) with visual loss Local recurrence after conservative measures fail bilateral retinoblastoma in which the previously mentioned conditions exist

in only one eye a tumor present in the anterior chamber retinoblastoma unresponsive to other forms of local therapy cases with permanent vision loss in which intraocular tumor is suspected.

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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

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Local therapies Used for small tumors < 3 – 6 mm Usually in patients with bi-lateral disease and In combination with Chemo- Radiation.

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Cryotherapy

Procedure: tumor is localized (by indirect ophthalmoscope), indented trans-sclerally with nitrous oxide cryoprobe, freeze is applied (-80°c),

Indications: Small tumor anterior to equator (4-7 mm in size) Small recurrence or tumor persisting after radiotherapy In conjunction with chemotherapy (may increase the intravitreal

penetration of carboplatin)

Side effects: Can induce acute retinal edema Accumulation of sub retinal fluid → retinal detachment

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Photocoagulation

Procedure: obliteration of retinal vessels by creating retinal burn with laser beam

Indications: Tumor ≤4.5mm at base and ≤2.5mm thick Away from macula or disc Small tumor recurrence after prior irradiation Contraindication: vitreous seeding

Laser hyperthermia

Procedure: generated by Diode laser (810 nm) on continuous mode Single spot 0.8-2 mm placed on center of tumor Tumor is heated for 10-30 min per session. Central tumor

temperature 460c and decreases by 20c for each mm outside the temperature spot

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Radioactive plaque application

Isotopes used: Co-60, Ir-192, I-125, 106Rh (ß emitter) Co-60: circular, crescentic to fit around

optic nerve I-125: seeds glued within a carrier and

gold shield, circular or notched configuration

Procedure: 1st USG of eye done: for tumor dimensions: maximum basal diameter, max height → surgical exploration → applicators are applied over sclera overlying the tumor → 1.5-2 mm margin on either side of basal diameter → retention sutures → Rx → Re-exploration for removal of plaques

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Iodine 125 plaques

Indications: Solitary lesion 2-16

mm basal diameter Unifocal lesions Located greater than

3 mm from optic nerve or fovea

Thickness <10 mm Two lesions, small or

close enough to be covered by one plaque

Local recurrence (small) following radiotherapy [EBRT]

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Cont…

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Radiotherapy

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External beam radiotherapyIndications

Multi-focal retinoblastoma RB close to macula or optic nerve Large tumor with vitreous seeding

Positioning Proper immobilization is

important thermoplastic or Perspex shell

with the patient supine and the chin in a neutral position

Treatment is done under anesthesia: Ketamine

Energy: Co-60 or 4-6 MV photons

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TechniqueLateral field technique

Started in 1930’s D – shaped lateral field with anterior

border kept at bony orbit Disadvantage: tumor recurrence at or

near ora serrata

Modified lateral beam technique

Two lateral opposed D-shaped fields are used

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Direct anterior field [Hungerford et al ] Whole eye is treated Disadvantage:

Cataract formation Dose exits through brain Lacrimal gland irradiation-impaired tear production

Advantages: Simple, easy to setup Reproducible Homogenously irradiates entire retina

Anterior lens sparing technique (ALD) [Abramson et al ]

Lateral D-shaped field: Day1-Day 4 by photons Anterior electron beam field with central circular contact lens as lens

shaped shield: on Day 5

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Unilateral disease: one lateral field or 2 oblique portals [superior and

inferior]

Bilateral disease: parallel opposed lateral fields

The anterior beam edge is placed at the bony canthus and the beam is angled 1.5 degrees posteriorly if the contralateral eye remains in place.

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Dose Ideal: 40-45 Gy, 1.8-2 Gy per fraction, 5 days a week For large tumor /vitreous seeding: 48-50 Gy Palliative radiotherapy:

Extra-ocular involvement: 20-25 Gy Metastatic disease: CNS, bones: 5 Gy/1#, 15 Gy/3#

Unilateral : single lateral field With anterior extension: anterior field + lateral field tilted 5-15°

posteriorly Bilateral disease: parallel opposed lateral fields

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3D conformal radiotherapy technique

based on 3D CT scan planning In unilateral RB, 4 non-coplanar fields are used. fields are anterior oblique: superior, inferior, medial, and lateral. 0.5-cm bolus can be used. entire retina should be treated, including 5 to 8 mm of the

proximal optic nerve.

critical structures such as the opposite eye, optic chiasm, pituitary gland, brainstem, posteriormost upper teeth, and upper cervical spine.

the tumor volume is treated to the 98% or 95% line,with the aforementioned organs and tissues receiving significantly less dose.

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bilateral disease, six noncoplanar fields are used: two lateral opposing,

and two anterior oblique

fields to each eye following the same criteria described previously.

3D CT scan reconstruction image showing beam arrangement for unilateral RB : anterior medial and lateral fields (A), anterior superior and inferior fields (B), sagittal view of composite isodose distribution (C), and axial transverse view of isodose distribution (D)

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Side effects of RT

Cataract formation: lens Lacrimal gland: decreased tear film production Vascular: retinal vasculitis → hemorrhage, and vitreous opacity Bone & soft tissue: temporal bone hypoplasia, molar tooth

abnormalities Mid-facial hypoplasia: hypotelorism, enophthalmos, atrophy of

temporalis muscle, narrow and deep orbits, depressed nasion. Second malignancies: overall incidence: 3-5%

Most common are osteosarcoma, fibrosarcoma, other spindle cell sarcomas

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Chemotherapy

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“Chemoreduction” (using chemotherapy to reduce the size of tumors) area of active clinical and basic science research, avoid enucleation and external beam radiation

Indications for patients who have visual potential in eyes containing tumors that

are too large to treat with focal methods. In patient with extra-ocular disease Subgroup of patient with introcular disease with high risk histologic

features. Patient with bilateral disease in conjunction with Aggressive local

therapy.

Currently, six cycles of vincristine, carboplatin and etoposide are employed as the standard starting regimen.

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Treatment recommendations

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Follow up

1st 6 months: 4-6 week intervals Upto 3 years: at 4-6 month intervals Later, yearly Family history positive: all family members [other children

at birth] should be examined yearly

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