Retinoblastoma

introduction to management

1. RETINOBLASTOMA Presentor - Dr. Brijesh Moderator – Dr. Arvind Kumar

2. sources

3. The normal retina extends from the posterior “pole” forward to a region just behind the lens, in cross-section called the ora serrata ANATOMY The eye is composed of three layers. Outer fibrous layer- sclera posteriorly and the cornea anteriorly. Inner layer- sensory retina In between these vascular layer – the uvea or choroid –which supplies the retina. Lens sits just behind iris, suspended from the ciliary body. No lymphatic drainage.

4. HISTORY First description was by PETER PAWIUS of Amsterdam. The term retinoblastoma was coined by VEORHOFF. In 1970 TSO established that tumour arise from photoreceptor precursor.

5. INTRODUCTION I t is rare childhood cancer( 1:18000 live birth )(2% of all childhood cancer) Sixth most common cancer (*as per American cancer society 2019)affecting children and most common primary intra-ocular malignancies. The incidence is higher in developing countries, and although the reason for this is not clear , lower socioeconomic status and the presence of certain human papillomavirus sequences have been implicated. Histologically , Rb develops from immature retinal cells and replaces the retina and other intraocular tissues.

6. EPIDEMIOLOGY M:f=1.15:1.0 More than 90% of cases occur around the age of 2 yr seldom found in the children older than 6 . Rarely diagnosed congenitally or even within the first 3 months of life, except in familial cases. Most common among blacks & africans Unilateral: 2/3 rd of the cases (occur in 14-16 months) Bilateral: not that common can occur with tumor with pineal glad i.e trilateral disease (occur in 29-30 months) Etiology: unknown

7. ETIOLOGY Retinoblastoma is caused by a mutation in the RB1 tumor suppressor gene located at long arm of chromosome 13 at locus(13q14) Both copies of RB1 gene must be mutated in order for tumour to form . It is an autosomal dominant disorder.

8. TWO HIT HYPOTHESIS GIVEN BY ALFRED KNUDSON

9. SPORADIC ( NON HEREDITATORY) FAMILIAL (HEREDITARY) Unilateral, unifocal 85% bilateral, multifocal 60% of all cases 40% of all cases Present later Present earlier Children of affected are normal Children of affected have 45% chance of inheritance. Relatives have a low risk of RB development. Relatives have a high risk of RB development.

10. PATHOLOGY PATHOLOGY Flexner Wintersteiner rosettes -columnar cells around a central lumen -also seen in medulloepithelioma Homer Wright -rosettes around a central neuromuscular core -neuroblastoma, medulloepithelioma , medulloblastomas Fleurettes Tumor cells with pear shaped eosinophilic processes projecting through fenestrating membrane and appearance resembles to bouquet of flower

11. CLINICAL FEATURES 1) LEUCOCORIA 2)STRABISMUS

12. LEUCOCORIA(56%) STABISMUS(20%) RED PAIN FULL EYE(7%) POOR VISION(5%) ASYMPTOMATIC(3%) ORBITAL CELLULITS(3%) UNILATERAL MYDRIASIS(2%) HETERECHROMIA IRIDIS(1%) HYPHEMA(1%)

13. GROWTH AND ROUTES OF SPREAD OF RETINOBLASTOMA

14. WORK- UP 1)Clinical history 2)Physical examination: EUA –complete opthalmic evaluation including dilated fundus examination. 3)360 degree scleral depression is mandatotry . 4)Visualization of tumor by IO is diagnostic in 90% of cases The diagnosis of retinoblastoma is based on examination by an ophthalmologist and imaging studies. Biopsy is generally not performed due to the theoretical risk for extraocular dissemination, which could convert an intraocular, curable tumor into extraocular , metastatic disease.

15. 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. Ultrasonography of the eyes is often performed to evaluate the intraocular mass with attention to heterogeneity and calcifications, which support a diagnosis of Rb B-scan of an eye with retinoblastoma

16. CT Ultrasonography is not as sensitive as CT. Ct scan is the imaging choice to detect intraocular calcifications. Although ct raises the concern of exposure to radiation in children <1 year of age with germ line mutations it is still frequently used to confirm the diagnosis, particularly in developing countries.

17. MRI TO KNOW, 1) EXTRA OCULAR EXTENSION 2)OPTIC NERVE INVASION 3)EXTEND OF RECURRENT DISEASES 4)TRILATERAL RB SYNDROME 5)SUB-ARACHNOID SEEDING 6) INVOLVEMENT OF BRAIN

18. Magnetic resonance imaging (MRI) of the brain and orbits is the most sensitive means of evaluating for extraocular extension and also Provides better delineation of the optic nerve and the pineal area. Mri of the brain and spinal cord and cerebral spinal fluid examination are indicated when There is gross invasion of the optic nerve by imaging studies Evidence of microscopic involvement beyond the lamina cribrosa on histopathologic examination of the enucleated eye.

19. FLUORESCEIN ANGIOGRAPHY IMG1 -MINIMALLY DILATED FEEDING VESSELS IN THE ARTERIAL PHASE. IMG2 -BLOTCHY HYPERFLOUROSCENCE IN VENOUS PHASE IMG3 -LATE STAINING

20. TREATMENT TEAM WORK 1)PEDIATRIC OPTHALMOLOGIST 2) PEADIATRIC SURGEON 3)RADIATION ONCOLOGIST 4) NEUROLOGIST 5) GENETICIST INTENTION TREAT THE CHILD NOT THE EYE PRIMARY GOAL:SAVE LIFE SECONDARY GOAL:SALVAGE THE ORGAN TERTIARY GOAL: VISION

21. CLASSIFICATION(REESE ELLSWORTH)

22. TREATMENT MODALITIES SURGERY- 1)ENUCLEATION 2) EXENTERATION CRYOTHERAPY PHOTOCOAGULATION LASER HYPERTHERMIA RADIOTHERAPY 1) EBRT 2) BRACHYTHERAPY CHEMOTHERAPY

23. SURGERY 1)ENUCLEATION DEFINITIVE TREATMENT INDICATIONS TUMOUR INVOLVING > 50% OF GLOBE ORBIT OR OPTIC NERVE INVOLVEMENT ANTERIOR SEGMENT I NVOLVEMENT NEOVASCULAR GLAUCOMA LIMITED VISUAL POTENTIAL ENUCLEATION IS CURATIVE IN > 95% CASES WITH UNILATERAL DISEASES

24. 2)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

25. 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

26. 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

27. 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 46 c and decreases by 2 c for each mm outside the temperature spot

28. The first patient to be treated using radiotherapy Was 2 year old child name ‘GORDAN ISAACS’.

29. RADIOTHERAPY EBRT Rb is a highly radiosensitive tumor as first shown by Hilgartner . By virtue of its radiosensitive nature, Rb was historically treated with first-line EBRT in a majority of cases, with doses of 42 to 50 Gy given in 1.5 to 2 Gy /fraction resulting in 87% eye preservation in R-E groups I to IV. EBRT also has a special role in treating eyes with vitreous seeds. The investigators concluded that EBRT was highly effective in preserving eyes with useful vision in bilateral Rb in cases refractory to chemotherapy and focal therapies.

30. Radiation techniques in rb should provide uniform coverage of the entire retina approaching the ora serrata and coverage of up to 10 mm of the optic nerve while sparing the lens and bony anatomy to the extent possible. A single lateral field was used for the management of one eye and parallel-opposed fields for the management of both eyes. The traditional border for these “d-shaped” fields was the lateral rim of the bony orbit, which could result in under-dosing of the anterior retina with associated local failure. Intensity-modulated radiation therapy ( imrt ) is well suited for the treatment of small tumors such as rb

31. 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. The radiation is usually given under anaesthesia : KETAMINE Energy : Co-60 or 4-6 MV photons

32. METHOD 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 serrata Modified lateral beam technique Two lateral opposed D-shaped fields are used

33. 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

34. 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

35. 3D CONFORMAL 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 chiasma, pituitary gland, brainstem, posterior most upper teeth, and upper cervical spine. The tumor volume is treated to the 98% or 95% line , with the above mentioned organs and tissues receiving significantly less dose.

36. ADVERSE EFFECT OF EBRT Historically, patients with hereditary disease who received EBRT have; A) Cumulative incidence of second cancers of 35%, compared with 6% among non-irradiated patients. B)Cataracts C)Optic nerve damage D)Total retinal vascular occlusion E)Vitreous hemorrhage F)Facial and temporal bone hypoplasia

37. BRACHYTHERAPY Brachytherapy with iodine 125, gold , and more recently ruthenium have been used in selected cases of Rb . The intention is to deliver a dose of 40 to 45 Gy trans sclerally to the apex of the tumor over a period of 2 to 4 days. local control at 5 years using this method. Side effects are generally less common than with EBRT and include optic neuropathy, radiation retinopathy, and cataract formation.

38. CHEMOTHERAPY Chemotherapy has been used to treat intraocular retinoblastoma since the early 1990s. Eyes with diffuse vitreous seeding rarely respond to chemotherapy alone. Therapies for patient with vitreous or subretinal seeding include intra-arterial chemotherapy (IAC) with selective catheterization of the ophthalmic artery. Gohssemi and colleagues tested combined intravitreal melphalan and topotecan in 9 such eyes followed by cryotherapy and control was achieved in 6 eyes (66%) using 1 to 3 injections, with 33% requiring enucleation because of the disease persistence.

39. 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.

40. EXTRA OCCULAR MANIFESTATIONS Patients with extraocular disease historically have had a poor prognosis. Chantada reported a 5-year EFS rate of 84% in 15 patients with orbital or preauricular disease treated with chemotherapy that included vincristine, doxorubicin, and cyclophosphamide or vincristine, idarubicin , cyclophosphamide, carboplatin, and etoposide. These patient received radiation dose of 45 GY

41. It is rare childhood cancer( 1:18000 live birth)(3% of all childhood cancer ) Retinoblastoma is caused by a mutation in the RB1 tumor suppressor gene located at long arm of chromosome 13 at locus(13q14 ). More than 90% of cases occur before age of 5 year Unilateral: 2/3 rd of the cases (occur in 14-16 months) Bilateral: not that comman can occur with tumor with pineal glad i.e trilateral disease. Flexner Wintersteiner rosettes,fleurettes , Homer Wright are pathological features of retinoblastoma. Leucocoria , red pain ful eye, stabismus are most comman diagnostic clinical features. 4 modes of growth exophytic , endophytic,mixed , diffuse infiltration. Biopsy is generally not performed due to the theoretical risk for extraocular dissemination.

42. 10. Radiological mode of investigation B-SCAN,CT (IOC), MRI,FLOUROSCENT ANGIOGRAPHY. 11. Reese elseworth and international classification of retinoblastoma are two ways to classify retinoblastoma. 12. Various treatment modalities surgery, cryotherapy, photocoagulation, laser hyperthermia, EBRT, brachytherapy ,chemotherapy. 13. Radiotherapy dose : 40-45 gy , 1.8-2 gy per fraction, 5 days a week. 14. Six cycles of vincristine, carboplatin and etoposide is the preffered regimen of chemotherapy

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