RETINOBLASTOMA FINAL (2)

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RETINOBLASTOMA : 

RETINOBLASTOMA DR. PADMAJA PHADE

Slide 2: 

Also known as: RB Retinal Glioblastoma Retinal Glioma Retinal Neuroblastoma

Epidemiology : 

Epidemiology Most common intraocular malignancy in children 1/14,000-1/20,000 live births Mean age of diagnosis known family history 4 months B/L 14 months (30-40%) U/L 24 months (60-70%) No racial predilection Occurs equally in males and females

Slide 4: 

Hereditary possibility of RB family history (7%) Sporadic(93%) B/L (5%) U/L (2%) B/L (23%) U/L(70%) heritable(8%) non heritable(62%)

Genetics : 

Genetics Autosomal Dominant Inheritance with incomplete peneterance Initiated by loss of function of RB1 alleles due to mutation of chromosome 13q14 Both copies must be mutated B/L RB there is 98% chance that it represents a germ line mutation Children of hereditary RB survivor have 45% chance of affected ,siblings have 40 % chance Children of U/L sporadic ,RB survivor have 7% chance of being affected, and siblings 1% chance Children of b/l sporadic RB have 40 % chance of affection and siblings have 6% chance.

Slide 6: 

Normal parents of child with B/L RB have 5% chance of next child having RB If two or more children are affected chances of next child being affected increase to 45% Only 7 % RB cases have family history Sporadic cases are 93% 60 % have UL disease with no germline mutation Only 15 % have germline mutation.

Genetics : 

Genetics Progression from retina to RB Cell of origin- unknown Arise in inner nuclear layer of retina, may display photoreceptor differentiation Additional genomics changes associated with loss of both functional alleles of RB1 gene.

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RB1 is tumor suppressor gene pRb plays role as check point in cell cycle control by inhibiting cellular proliferation by binding to E2F transcription factors halting cell cycle at G1 stage Thus loss of RB1 gene function leads to unhindered cell proliferation .

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KNUDSONS TWO HIT HYPOTHESIS RB +/+ M1(deletion, insertion, splice mut.) RB +/- M2 / LOH (non dysjunction duplication) RB -/- No additional genomic insult genomic gain at 1q 6p genomic loss at 16q loss of P75 NTR Retinoma Retinoblastoma

PATHOLOGY : 

PATHOLOGY Primitve retinal cells of neuroblastic origin of photoreceptor lineage Cells with scanty eosinophilic cytoplasm and large hyperchromatic nuclei High mitotic activity Arise in primitive photoreceptor cells. Characteristic histology: Retinoblastomas are composed of poorly differentiated neuroblastic cells with scanty cytoplasm and prominent basophilic nuclei. The tumour proliferates rapidly, with a tendency to outgrow its blood supply and undergo spontaneous necrosis. Necrotic tumour being eosinophilic stain pink.

Pathology : 

Pathology Calcification is another feature of retinoblastomas, usually occurring in necrotic areas. Calcium stains with H&E. Distinguishing feature FLEXNER WINTERSTEINER ROSETTES HOMER WRIGHT ROSETTES PSEUDUROSETTES FLEURETTES

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Tumour cells stain positive for neuron specific enolase rod outer seg photoreceptor sp Ag Tumour cells secrete inter photoreceptor retinoid binding protein Express red and green photoreceptor gene

Slide 20: 

Clinical Presentation Leukocoria (54-62%) Strabismus (18-22%) Red eye Excessive Tearing Corneal clouding ( elevated IOP) Hypopyon Discoloration of the iris (neovascularization) Proptosis Spontaneous Globe perforation Low vision Hyphaema Orbital cellulitis Cataract Incidental finding “Cat’s Eye” appearance

EXAM : 

EXAM Visual acuity squint SLE cornea AC for cells pseudouveitis NVI lens IOP IDO – No,extent,location of tumour presence of RD intravitreal,subretinal seeds subretinal efussion LYMPHADENOPATHY SIGNS OF RAISED ICP

METASTASIS : 

METASTASIS COMMONLY ESCAPES EYE VIA OPTIC NERVE HAEMATOGENOUS SPREAD THRU CHOROID SCLERA VIA EMISSARY CANALS FROM AC THRU TM INTO COJUNCTIVA AND THEN LYMPH GLANDS COMMON SITES OF METASTASIS SKULL BONES DISTAL BONES BRAIN SPINAL CORD LYMPH NODES ABDOMINAL VISCERA

REESE ELLSWORTH CLASSIFICATION : 

REESE ELLSWORTH CLASSIFICATION

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International Classification for Intraocular Retinoblastoma --- grouping system A) Group A (Very Low Risk) - Small discrete intraretinal tumors away from the foveola and disc - All tumors are 3 mm or smaller in greatest dimension, confined to the retina and - All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc B) Group B (Low Risk) - All remaining discrete retinal tumors without seeding - All tumors confined to the retina > 3MM - cuff of clear subretinal fluid < 6mm from tumour - Any tumor size and location with no vitreous or subretinal seeding C) Group C (Moderate Risk) - Discrete local disease with minimal focal subretinal or vitreous seeding -Tumor(s) must be discrete - Subretinal fluid, present or past, without gross seeding, involving up to one quadrant of retina - Local subretinal seeding, present or past, less than 5 mm from the tumor - if more than one seedings total of these <= 6mm - Focal fine vitreous seeding close to discrete tumor D) Group D (High Risk) - Diffuse disease with significant vitreous and/or subretinal seeding - Tumor(s) may be massive or diffuse - Subretinal fluid, present or past up to total retinal detachment ,or > 6mm from tumour,or > one retinal quadrant - Diffuse subretinal seeding, may include subretinal plaques or tumor nodules > 6mm from margin - Diffuse or massive vitreous disease may include "greasy" seeds or avascular tumor masses - exophytic masses with necrosis and calcfication E) Group E (Very High Risk)

Slide 32: 

Tumour with any one of following Tumour in AC Tumour in cilliary body NVG VH ,hyphaema Pthysical,prethysical eye Orbital cellulitis like picture Blood stained cornea Tumour ant to ant. Hyloid phase/ touching lens.

INTERNATIONAL CLASSIFICATION SYSTEM – STAGING : 

INTERNATIONAL CLASSIFICATION SYSTEM – STAGING O- intraocular tumour only I- tumour completely removed by enucleation II- residual orbital tumour ( at optic N. resection site) III-overt regional disease( orbital or LN inv) 1. orbital extention 2. cervical, pre auricular LN IV-metastatic disease not inv CNS with CNS inv A Single lesion a prechiasmatic B Multiple lesions b sol c leptomeningeal disease

INVESTIGATIONS : 

INVESTIGATIONS USG shows characteristic V-Y Pattern CT SCAN MR For sellar and parasellar masses optic nerve orbital soft tissues FFA - intralesional capillary leak flourescein so the tumour stains bright in the late phase also detects recurrances RET CAM 120 –wide angle retinal photography confirms NVI FNAC SPECULAR MICROSCOPY – detects RB cells on corneal endothelium BONE MARROW ASPIRATION LUMBAR PUNCTURE BONE SCAN CBC PEDIGREE CHARTING

DIFFERENTIAL DIAGNOSIS OF LEUCOCORIA : 

DIFFERENTIAL DIAGNOSIS OF LEUCOCORIA COATS DISEASE PERSISTANT FETAL VASCULATURE OCULAR TOXOCARIASIS RETINOPATHY OF PREMATURITY CONGENITAL CATARACT. FAMILIAL EXUDATIVE VITREORETINOPATHY NORRIES DISEASE INCONTINENTIA PIGMENTI RETINOPATHY

DD OF VITREOUS SEEDS PARS PLANITIS ENDOPHTHALMITIS LEUKAEMIC INFILTRATION DD OF DISCRETE RETINAL TUMOURS RETINAL ASTROCYTOMAS MEDULLOEPITHELIOMAS RETINAL CAPILLARY HAEMANGIOMA FOCAL MYELINATED RETINAL NERVE FIBRE PATCH

LEUKOCORIA : 

LEUKOCORIA PUPILLARY AREA VITREOUS RETINA CONG CATARACT FOLDS DEFECTS PATCH PFV CMV medu coloboma NF. toxoplasma

Slide 40: 

VITREOUS CELLS MASS RETROLENTAL MEMB Endo. RB RED WHITE CLUMPS RD FIBROVAS TRACTN VH Endoph RB Uveits PFV EXUDATIVE TRACTIONAL RHEGMATOGENOUS TELANGECTESIA - Coats dis ROP High myopia MASS WITH CA++ - RB Familial exudative Trauma GRANULOMA - Toxocariasis vitreoretinopathy

RETINOPATHY OF PREMATURITY (ROP) : 

RETINOPATHY OF PREMATURITY (ROP)

COLOBOMA : 

COLOBOMA OPTIC DISC COLOBOMA

TREATMENT : 

TREATMENT CHEMOTHERAPY PHOTOCOAGULATION TRANS PUPILLARY THERMOTHERAPY CRYOTHERAPY EBRT BRACHYTHERAPY ENUCLEATION

CHEMOTHERAPY : 

CHEMOTHERAPY Chemotherapy Globe preserving in 85% pts with groups I to IV Reese Ellsworth classification Bulky tumor with intra vitreal and sub retinal seeds shrink with first two cycle Primary treatment in Extra ocular extention B/L RB Extension detected on enucleated eye

Slide 46: 

Triple agent 6 cycle protocol IV Carboplatin + Vincristin + Etopocide AND Sos Cyclosporin given over 2 days every 3-4 weekly for 6-9 month / cycles REGIMEN– D1 CEV THEN D2 E STANDARD DOSE CHEMOTHERAPY All group E tumours in ISC DOSE C - 18.6 MG /KG (560 MG/ M2) E- 5MG /KG (150 MG/M2) V- 0.05 MG/KG (1.5 MG/M2) HIGH DOSE CHEMOTHERAPY Reese Ellsworth 5.recurrent tumours, metastatic,,all extraocular disease DOSE C- 28 MG/KG E- 12 MG / KG V- 0.025 MG/KG 6 to 18 mths CEV + high dose CEV+ASCT F/B EBRT or enucleation S/E- neutropenia, cytopenia, neurotoxicity, GI toxicity, Hepatotoxicity,otoxicity,SIADH.

Slide 47: 

Periocular Chemotherapy Subconjunctival/ subtenons inj. Of carboplatin All group C and D tumours 20 mg in 2 ml is total dose Given on same day as systemic chemotherapy S/E- orbital myositis (Rx oral steroid), periorbital edema, optic neuropathy, mod. Loss of orbital volume.

CHEMOREDUCTION : 

CHEMOREDUCTION Shrinks tumour so local Rx delivered to small vol. of tumour and causes less morbidity Avoid EBRT and delays enucleation Early vol. red upto 50% after 2 cycles 80 % eyes with chemored are salvaged Macular tumours Larger tumours Used even with presence of total RD 2 to 6 cycles of CEV Post RX monitoring a necessity

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Exclusion criteria : NVI NVG AC,choroid,ON invasion Extraocular disease Vitrectomy in an eye wih unsuspected RB Recurrence following chemoreduction Retinal tumours in 4m Vitreous and sub retinal seeds in 2m

Algorithm for chemoreduction for Rx of Intraocular RB : 

Algorithm for chemoreduction for Rx of Intraocular RB SYSTEMIC METASTATIC WORKUP Micro/ overt metastic localized intraocular tumour Disease 2 to 6 cycles of chemoreduction NO chemored. reduction in size progressive disease focal Rx EBRT CT 6 cycles Enucleation F/U for recerrance

ALGORITHM FOR Rx OF METASTATIC DISEASE : 

ALGORITHM FOR Rx OF METASTATIC DISEASE Orbital/ regional mets distant Exenteration CT f/b CT 2 -4 cycles, local f/b CT and enucleation RT and/or Sx RT f/b adjuvant CT and RT HDT with prog dis. SALT alt Rx

CHEMOPREVENTION : 

CHEMOPREVENTION Post enucleation in high risk cases to prevent metastasis HPE criteria for chemoprevention: AC seeds Iris seeds Cilliary body infiltration Choroidal infiltration ON r laminar invasion Invasion of ON transection Retrolaminal ON invasion Scleral infiltration or extrascleral extension 6 cycles of standard dose CEV

REGRESSION PATTERNSFOLLOWING PRIM. CHEMOTHERAPY : 

REGRESSION PATTERNSFOLLOWING PRIM. CHEMOTHERAPY

Photocoagulation : 

Photocoagulation Group I tumor Using argon(532nm), Xenon arc Tissue temp. raised more than 600 C Three step procedure 1-2mm area around tumor hit for 1 sec. Blood vessels feeding the tumor are coagulated Tumor mass coagulated Complication RD vitreoretinal traction retinal hole Retinal vascular oclusion Pre-retinal fibrosis

Transpupillary thermotherapy : 

Transpupillary thermotherapy Diode infrared laser (812nm) mounted on IDO or operating microscope Primary treatment for tumor <3mm 2-3mm wide spots applied till complete choreo-retinal atrophy occurs S/E- Iris atrophy, Cataract, RD, disc edema

Cryotherapy : 

Cryotherapy Small peripherally located tumor <3.5X 3 Obsolete Double / triple freeze and thaw technique repeted 2-3 weekly Tumor ant. To equator are treated trans conjunctivally and those post. Are treated through conjunctival incision Temp. upto -90o C causes intracellular ice crystal, protein denaturation, pH changes and cell rupture S/E- conjuntival, lid edema, VH, localise RD

Radiation therapy : 

Radiation therapy Group V Reese Ellsworth Small tumor located at post. Pole Tumors with diffuse subretinal or intravitreal seed Prior chemo or local therapy failure 4000-5000 cGy spilt into daily fractions 5times/week with 4-6 week interval S/E- Second primary neoplasms Facial hypoplasia Cataract VH, Radiation retinopathy IMRT, gamma knife, proton beam

Plaque radiotherapy/ Brachytherapy : 

Plaque radiotherapy/ Brachytherapy Reese Ellsworth stage IV or less, preferably ant. Tumors I 125, Ruthenium 106 placed on sclera in gold carries Lead shield placed sup to plaque Target dose of 40-45 cGy daily for 3-5 days S/E- Radiation Retinopathy Papilopathy NVG Cataract

ENUCLEATION : 

ENUCLEATION For advanced disease falling in group E and when extra ocular extension is seen Effective in 99% cases with ul dis. With no extra ocular extension Porous hrdroxy appatitte implant used for cosmesis Special considerations Least 10 mm optic N obtained min manipulation Aviod inadvertant globe perforation Careful inspection of specimen Tumour at surgical margin of optic N. has mortality rate of 50 to 81%

Enucleation : 

Enucleation

Ocular Prosthesis : 

Ocular Prosthesis The objective is to give child a normal looking face and to make his/her eye natural looking. The surgeon keeps the muscles intact during the operation. The muscles are then sutured to an implant which replaces the volume of the eyeball. In addition to maintaining the optical cavity, the volume filled shall also stimulate the prosthesis to move, thus making the prosthesis less noticeable. A conformer, a transparent and perforated shell is placed under the eyelid prior to inserting the prosthesis. Once the contours of the space have stabilised the conformer is removed and the prosthesis can be inserted. An ocular prosthesis is a large custom made rigid lense which reproduces the color of the iris and sclera. It is made of PMMA. Prosthesis can be inserted one month after surgery. Trials and fittings are simple and painless. No anaesthesia or hospitalisations are required. Wearing a prosthesis is in itself painless. In most cases, wearing a good quality ocular prosthesis goes completely unnoticeable. Ocular prostheses are worn during the day and at night. Manipulating the prosthesis frequently may cause irritation or increased secretions.

CURRENT SUGGESTED TREATMENT PROTOCOL : 

CURRENT SUGGESTED TREATMENT PROTOCOL INTRAOCULAR RB – REESE ELLSWORTH 1 TO 4 U/L OR B/L < 3mm by 2mm-focal Rx Larger post. Tumours- prim. Chemo + SALT RESIDUAL- small tumours-focal Rx large u/l – enucleation large B/L-EBRT or brachy therapy INTRAOCULAR RB REESE ELLSWORTH 5A AND 5B U/L- enucleation b/l- high dose chemo.+SALT Residual– small –focal Rx large- EBRT or brachy therapy.

Slide 65: 

ADVANCED INTROCULAR DIS. GROUP E OF ISC Primary enucleation EXTRAOCULAR TUMOURS High dose chemo. f/b enucleation or EBRT then chemo for 12 wks TUMOURS WITH HIGH RISK HISTOLOGICAL FACTORS Std 6 w chemo High dose chemo with orbital EBRT

RECURRANCE : 

RECURRANCE Most imp risk factor is family history of RB Early focal RB- slight elevation with a pink blush of vascularization FFA RET CAM 120 F/U schedule 3 weekly for first year 6 monthly for 3 years or age of 6 y Annually throughout life

Treatment of recurrence : 

Treatment of recurrence Orbital recurrence postenucleadtion Tumor debulking orbital irradiation Systemic chemo Systemic mets except CNS High dose chemo Autologous stem cell rescue

SECOND PRIM. NEOPLASMS IN RB : 

SECOND PRIM. NEOPLASMS IN RB RISK IS O.5 TO 1 % PER YR F>M NEOPLASMS OSTEOGENIC SARCOMAS OF SKULL OSTEOGENIC SARCOMAS OF LONG BNES SOFT TISSUE SARCOMAS PNET OF BRAIN PINEALOBLASTOMA CUTANEOUS MELANOMAS EPITHELIAL CANCERS HODGKINS DISEASE LUNG CA BREAST CA CA BLADDER

Risk factors a/w second prim neoplasms : 

Risk factors a/w second prim neoplasms Germline Rb 1 gene mutation Dose of external beam radiation Radiation at age < 1yr Dose dependent relationship Increased incidence of malignancy in field of radiation Asso p53 mutation – Li Fraumeni syndrome Soft tissue sarcimas Breast ca Adrenocortical tumours Lipomas Chemotherapy GH therapy Smoking Uv rays exposure Advanced paternal age

Slide 70: 

Increased mortality from second tumours in U/L RB Females Radiation exposure

TRILATERAL RB : 

TRILATERAL RB B/L RB a/w a intracranial PNET in sellar and suprasellar region . Rarely present prior to ocular disease Usually seen with Familial ( 2 to 5%) b/l ocular dis EBRT Median survival at diagnosis is 6m MC cause of death in RB survivors of 5to 10 yrs Serial MRI evaluation of at risk pts Not a/w metastatic disease elsewhere Show features of photoreceptor differenciation.

Prognosis : 

Prognosis In absence of disease in fellow eye pt. is regarded out of danger, if no orbital recurrence in 3 years Survival rate of treated RB is 90-95% Untreated die within 2-4 yrs. Grave indicators at diagnosis Older age Larger tumors Optic nerve invasion Systemic mets Trans-scleral spread on CT Treated children who die, die within 2-3 yrs of treatment initiation 20% of germline RB survival develop non RB malignancy within 25yrs Extraocular RB survival rate <10% Intraocular RB survival rate is >90%

GENE THERAPY : 

GENE THERAPY Transfer of specific targeted gene or genetic material to a diseased cell for therapeutic purpose Vector or non vector Vectors used Viral - non viral Adenovirus liposomes AAV Retrovirus Naked DNA bullets used in non vector gene therapy Ex vivo or In vivo Somatic or germline

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MODALITIES OF GENE THERAPY Addition Replacement Deletion Repair

GENE THERAPY IN RB : 

GENE THERAPY IN RB Is still in preclinical stages ADENOVIRUS MEDIATED SUICIDE GENE THERAPY Tumor reduction RB cells when transduced with an adenovirus vector containing HSV thymidine kinase (AdVTK) are killed when followed by GANCICLOVIR therapy NUTLIN 3 NUTLIN 3 antagonizes MDMX – P53 interaction which leads to tumor supression.s

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ANTIANGIOGENIC GENE THERAPY Adenovirus or liposomal delivery of sol. FLT 1 inhibits action of VEGF leading supression of tumor growth. INTERFERON B AAV deliver INF b into tumor cells

GENETIC COUNCELLING AND GENE DIAGNOSIS : 

GENETIC COUNCELLING AND GENE DIAGNOSIS At risk families These asymptomatic children are tested by RB 1 Mutation analysis Eye exams every 2 to 4 weekly till age of 3 yr Gene diagnosis AIM is to detect the exact disease causing mutation and to predict carrier status in unaffected individuals of RB kindred

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Modalities Southern blot technique Karyotyping SSCP – single strand confirmation polymerization Direct DNA sequencing WBC DNA analysis CVS and amniocentesis

REFRENCES : 

REFRENCES Principles and practice of ophthalmology-Albert and Jakobiec”s Yanoff and Durker American Academy of Ophthalmology Stephen Ryan text book

THANK YOU. : 

THANK YOU.

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