The normal retina extends from the posterior “pole” forward to a region just behind the lens, in cross-section called the ora serrata . The anterior chamber of the eye is between the cornea and the iris; the posterior chamber is just behind it, between the iris and the lens.Behind the lens is the vitreous chamber, with vitreous humor, a thick clear gel-like substance. In advanced retinoblastoma, “seeding” of the tumor is noted in this chamber.
The Reese- Ellsworth classification, still the most widely used retinoblastoma organization system, is based on intraocular tumor staging and globe salvage prediction after EBRT; survival is not taken into account in this categorization.
Retinoblastoma dr vandana
Presented By:Dr. VandanaDept. of RadiotherapyCSMMU
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
Retinoblastoma Mid 18th century: 1st clinical report of RB was recognized 1920-“ Vernoff” coined the term retinoblastoma 2.5-4% of paediatric malignancies Most common intraocular malignancy of childhood 2nd most common primary intraocular malignancy in any age group Tumor 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
Epidemiology Slight male preponderance 1.15:1.0 More 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
Genetics Deletion 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 hits Bilateral, multifocal Unilateral, unifocal Young age older age
Clinical features Family history: 10% Leukocoria (white pupillary reflex): 50% , commonest Strabismus [esotropia]: 20% Ocular inflammation: due to necrosis of tumor or tumor cells may enter AC resembling hyphema [pseudohypopyon] Secondary glaucoma: angle-closure Loss of vision Proptosis: extra ocular invasion Trilateral retinoblastoma; bil RB+ pineoblastoma Distant metastases
Routes of spread Local spread; anteriorly- seeding of vitreous & aqueous; posteriorly, sub retinal space and choroids May spread through optic nerve Along the central retinal vessels: tumor cells pass through the lamina cribrosa and enter subarachnoid space Distant metastases: CNS, skull, bones, lymph nodes, spinal cord, bone marrow Orbital involvement
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
AJCC Tumour Staging System for RBT1/p1 <25% of retinaT2/pT2 >25 to 50% of retinaT3/Pt3 >50% of retina and/or intraocular beyond retinaT3a/pT3a >50% of retina and/or cells in vitreousT3b Optic diskpT3b Optic nerve up to lamina cribrosaT3c Anterior chamber and/or uveapT3c Anterior chamber and/or uvea and/or intrascleralT4/pT4 ExtraocularT4a Optic nervepT4a Beyond lamina cribrosa, not at resection lineT4b Other extraocularpT4b Other extraocular and/or at resection lineN1/pN1 RegionalMI Distant metastases
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 surfaceStage 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 emissariesStage 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
Diagnostic workup Diagnosis 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.
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
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.
MRI 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.
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
Treatment of Retinoblastoma Primary 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.
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.
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
Local therapies Used for small tumors < 3 – 6 mm Usually in patients with bi-lateral disease and In combination with Chemo- Radiation.
CryotherapyProcedure: 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
PhotocoagulationProcedure: obliteration of retinal vessels by creating retinal burn with laser beamIndications: Tumor ≤4.5mm at base and ≤2.5mm thick Away from macula or disc Small tumor recurrence after prior irradiation Contraindication: vitreous seeding Laser hyperthermiaProcedure: 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
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
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] Iodine 125 plaques
External beam radiotherapy Indications 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
Technique Lateral field technique Started in 1930’s D – shaped lateral field with anterior border kept at bony orbit Disadvantage: tumor recurrence at or near ora serrataModified lateral beam technique Two lateral opposed D-shaped fields are used
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
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.
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
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.
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 axialtransverse view of isodose distribution (D)
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
“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.