RETINOBLASTOMA Presented by-Dr.Puneet SharmaPost graduate student ( 2nd yr )Department of Ophthalmology

MMIMSR,MullanaAmbala

History Pawius described retinoblastoma in 1597. In 1809, wardop referred to tumor as fungus

haematodes as suggested enucleation as primary mode of management.

Discovery of ophthalmoscope in 1851 facilitated reconginition of clinical features of retinoblastoma.

Thought to be derived from glial cells, was called glioma of retina by virchow (1864).

Flexner (1891) and wintersteiner (1897) believed it to be a neuroepithelioma because of presence of rosettes.

Later, consensus was that tumor originated from retinoblasts and officially american ophthalmological society (1926) accepted the term retinoblastoma.

Introduction Most common intraocular malignancy in

children ( 1 in 15,000 to 1 in 18,000 live births).

No racial or gender predisposition.

Bilateral in 25 to 35% cases.

Age of diagnosis is 18 months.

Unilateral cases around 24 months & bilateral before 12 months.

Genetics RB gene is located on long arm of

chromosome 13 (13q14) containing 27 exons & 26 introns.

2 normal copies of RB gene present in most human cells. RB gene product is 928 AA phosphoprotein whose normal func. is to suppress cell growth.

RB represents phenotypic expression of abnormal or absent tumour suppressor gene aka RB1.

Most RB1 mutations are minute deletions, duplications & point mutations.

Out of newly diagnosed cases

6% familial

94% sporadic

Bilateral RB involve germinal mutations

Approx. 15% unilateral sporadic RB caused by germinal mutation, affecting one eye , 85% sporadic

Genetic counselling

Imp. Aspect in management of RB

Pts, positive family history, 40% siblings would be at risk & 40% offspring of affected patient may develop RB

Pts, no family history, if affected child has unilateral RB, 1% of sibilings are at risk & 8% of offspring may develop RB

Bilateral RB, no family history 6% siblings & 40% offspring have chance of developing RB

Histopathology On low magnification, basophilic

areas of tumor are seen along with eosinophilic areas of necrosis & more basophilic areas of calcification within the tumor.

Poorly differentiated tumors consist of small to medium sized round cells with large hyperchromatic nuclei & scanty cytoplasm with mitotic figures.

Well defined tumor show Rosettes & Fleurettes,

.

Histopath. cut section

Rosettes Flexner-wintersteiner rosettes

consist of columnar cells arranged around a central lumen,highly characteristic of retinoblastoma, also seen in medulloepithelioma.

Homer wright rosettes, cells arranged around central neuromuscular

tangle (neuroblastomas, medulloblastomas & medulloepitheliomas)

Pseudo-rossettes

Arrangement of tumor cells around blood vessels.

Fleurettes Fleurettes -eosinophilic structures,

composed of tumor cells with pear shaped eosinophilic processes, projecting through fenestrated membrane.

Basophilic deposits,precipitated DNA (released from tumor necrosis) can be found in walls of lumen of blood vessels.

Classification of retinoblastoma

Reese-Ellsworth classification (1960)

Was designed for treatment with EBRT. Was in use till 1980

Now not used as EBRT has been replaced by chemotherapy as preferred mode of treatment

International classification of R.B.(shields)

Group A Small tumor

R.B < 3 mm in basal dimension/thickness

Group B Larger tumor

R.B > 3 mm in basal dimension/thickness

Macula location ( < 3 mm to foveola)

Juxtapapillary location ( < 1.5 mm to disc)

Clear subretinal fluid < 3 mm from margin

Group C Focal seeds

C1 Subretinal seeds < 3 mm from R.B

C2 Vitreous seeds < 3 mm from R.B

C3 Subretinal & vitreous seeds < 3 mm from R.B

Group D Diffuse seeds

D1 Subretinal seeds > 3 mm

D2 Vitreous seeds > 3mm

D3 Subretinal & vitreous seeds > 3 mm

Group E Extensive R.B

Occupying > 50% globe

Neovascular glaucoma

Opague media from haemorrhage in A.C & vitreous or subretinal space.

Invasion of postlaminar optic nerve, choroid (> 2 mm), sclera, orbit, A.C

Common presenting features ofR.B

Leucocoria 56% Strabismus 20% Red painful eye 7% Poor vision 5% Asymptomatic 3% Orbital cellulitis 3% Unilateral mydriasis 2% Heterochromia iridis 1% Hyphema 1%

Types of RB

Endophytic

Exophytic

Diffuse infiltrating tumor

Endophytic Tumor grows into vitreous cavity

yellow white mass

Progressively fills vitreous cavity &

vitreous seeds occur

Retinal vessels not seen on tumor surface

Vitreous seeding

Vitreous seeding

Exophytic

Tumor grows towards sclera Solid R.D usually occurs Retinal vessels seen on tumor surface

Diffuse infiltrating tumor Tumor diffusely involves retina

causing placoid thickness of retina (not mass)

Seen in older children

Grades of optic nerve involvement

Grade 1superficial involvement of optic nerve

head only

Grade 2 Involvement upto or involving lamina

cribrosa

Grade 3Involvement beyond lamina cribrosa

Grade 4Involvement upto surgical margin

Diagnosis

History

Prenatal/natal/postnatal Maternal rubella ( cong. Cat.) Gestation period or delivery ( ROP ) Oxygen therapy ( ROP )

Family history 6% of RB pts have positive family history

Physical examination

Rule out tuberous sclerosis, cong. defects asso. with trisomy 13-15, rubella syndrome

Ocular examination

Squint, leukocoria, heterochromia, proptosis, lymphadenopathy ( adv. cases )

pseudohypopyon, rubeosis iridis

Detailed Anterior segment examination

I O P

Indirect Ophthalmoscopy with Scleral indentation

Fundus drawing denoting site & extent

Gross systemic examination

Fundus drawing

Fully Dilated fundus examination

Bilateral with 360 degree scleral depression

Indirect ophthalmoscopy (diagnostic in 90%

cases)

Wide angle fundus camera ( Retcam)

RB on scleral indentation

U S G B-SCAN

rounded or irregular intraocular mass

representing typical intralesional calcification

3 D U S G

C T SCAN

delineates extraocular extension, can detect asso. Pinealoblastoma Cases with atypical manisfestations

Diagnostic dilemma Extraocular &intracranial tumor extension is suspected

M R I

optic nerve invasion or intracranial extension

M R I

F F A

Not required in routine work up.

Can be used to differentiate viable tumour from an avascular residue following radiotherapy or spontaneously regressed retinoblastoma.

Active lesion shows hypervascularity,dilated feeders and late staining

BIO-CHEMICAL TESTS

helpful in endophthalmitis like presentation

AQUEOUS HUMOUR ENZYME ASSAY

normal aqueous to plasma LDH >1.0

increased phosphoglucoisomerase levels

increased neuron specific enolase levels

Fine needle aspiration biopsy

Rarely done, invasive procedure

Approach through peripheral cornea, A/C, zonules, vitreous is recommended

Complication potential of needle track

dissemination of tumor cells

BONE MARROW BIOPSY & LUMBAR PUNCTURE

Useful in ruling out intracranial or distant spread as primary mode of spread of RB is hematogenous.

EXAMINATION OF SIBLINGS/PARENTS

To detect small lesions which may otherwise go undetected in siblings.

Parents may harbour regressed RB lesions. Blood specimens of patient/parents/siblings

should be taken for DNA analysis which could aid in genetic counselling.

To be continued.

D/D of leukocoria

Congenital cataract

10% of all vision loss in children world wide

prevalence of 1 to 6 cases per 10,000 live

births

 cataract resulting from congenital rubella syndrome

PHPV

rare congenital developmental anomaly

purely anterior (

persistent tunica vasculosa lentis and persistent posterior fetal fibrovascular sheath of the lens)

  purely posterior (falciform retinal septum) and a combination of both

Norrie disease

Genetic disorder (inherited X link recessive)

Features – shrinkage of globewasting of the iris30-50%have developmental

delay/mental retardationPsychotic like featuresBehavioral abnormalities

Coat’s diseaseVery rare, congenital non hereditary

eye disorder

Unilateral 6-8 years of age range ( 5 mnths to 71 yrs )Blood leaks from abnormal vessels in

back of the eye, leaving cholesterol deposits & damaging retina

RD, Glaucoma, Atrophy, Cataracts secondary to Coat’s.

ROP

Oxygen toxicity, relative hypoxia

Disorganized growth of retinal blood vessels ( scarring & RD )

Stage 1 is a faint demarcation line

Stage 2 is an elevated ridge

Stage 3 is extraretinal fibrovascular tissue

Stage 4 is sub-total retinal detachment

Stage 5 is total retinal detachment.

Toxocariasis

Uveitis

Endophthalmitis

Retinal dysplasia

Retinoma

Enucleation

Special considerations for enucleation in R.B Minimal manipulation Avoid perforation of eye Harvest long ( >15 mm) optic nerve

stump Inspect the enucleated eye for

macroscopic extraocular extension & optic nerve involvement

Harvest fresh tissue for genetic studies Place a primary implant Avoid biointegrated implant if

postoperative radiotherapy is necessary

Cryotherapy Equatorial & Peripheral retinal tumors

upto 4 mm in diameter & 2 mm in thickness.

Triple freeze thaw cryotherapy at 4-6 week interval until complete tumor regression.

Complications of Cryotherapy

Transient serous R.D

Retinal tear

Rhegmatogenous R.D

Laser photocoagulation Small post. tumors 4 mm basal

diameter & 2 mm in thickness.

Idea is too

Delimit tumor

Restrict blood supply to tumor by surrounding it with 2 rows of overlapping laser burns

Complications of L.P

Transient serous R.D

Retinal vascular occlusion

Retinal hole

Retinal traction

Preretinal fibrosis

Large visual field defect ( tumor in juxtapapillary area)

Contraindication in L.P

Pt on active chemoreduction protocol, restricts blood supply to tumor & reduces intraocular concentration of chemotherapeutic agent

Systemic chemotherapy

Day 1: vincristine + Etoposide + Carboplatin

Day 2: Etoposide

Standard dose: (3 weekly, 6 cycles): Vincristine 1.5 mg/m2 (0.05 mg/kg for children < 36 mnths of age & maximum dose < 2 mg), Etoposide 150 mg/m2 (5 mg/kg for children < 36 mnths of age ), Carboplatin 560 mg/m2 (18.6 mg/kg for children < 36 mnths of age)

High – dose (3 weekly, 6-12 cycles) : Vincristine 0.025 mg/kg, Etoposide 12 mg/kg, Carboplatin 28 mg/kg

Thermotherapy Focused heat generated by infrared

radiation, applied to tissues at subphotocoagulation levels to induce tumor cell apoptosis.

Achieve slow & sustained ( 40 to 60 degree C) within tumor, sparing retinal vessels.

Transpupillary thermotherapy using infrared radiation from semiconductor diode laser delivered (1300 micron large spot indirect ophthalmoscope, operating microscope, transscleral route with diopexy probe).

Tumor heated till it turns gray Satisfactory control for small

tumors(4 mm basal diam. & 2 mm thickness).

Complete tumor regression 85% (3-4 sessions)

Complication of Thermotherapy

Focal iris atrophy

Focal paraxial lens opacity (minimised using 1300 micron indirect ophthalmoscope, duration 5 mins in single session)

Retinal traction

Serous R.D

Plaque Brachytherapy

Placement of radioactive implant on sclera corresponding to base of tumor,transsclerally irradiate tumor.

Radioactive materials – Ruthenium 106 & Iodine 125

Tumors < 16mm basal diameter & < 8 mm thickness

Primary or Secondary Primary- chemotherapy is

contraindicated, secondary treatment in eyes that fail to respond to chemoreduction & external beam radiotherapy or tumor recurrences.

Tumor thickness measured by ultrasonography

Plaque design depending on basal tumor dimensions, its location & configuration e.g notched plaque used to protect optic nerve ( tumors peripapillary in location)

Dose – 4000 – 5000 cGy

Plaque sutured to sclera after tumor centration & left for duration of exposure (ranging 36 to 72 hrs)

90% tumor control

Regressed RB after exposure to iodine 125

Advantages of P.B

Focal delivering of radiation, minimal damage to surrounding normal structures

Minimal periorbital tissue damage

Cosmetic abnormality absent, retarded bone growth in field of irradiation ( as in external beam radiotherapy )

Reduced risk of second malignant neoplasm

Shorter duration of treatment

Complications of P.B

Radiation papillopathy

Radiation retinopathy

External beam radiotherapy

Used less often, newer chemotherapy protocols

Indicated- primary chemotherapy & local therapy has failed or rarely chemotherapy is contraindicated.

Delivered using Cobalt 60 (gamma rays) or linear accelerator ( X-rays)

Linear accelerator with multi-beam technique, image guided radiotherapy & stereotactic radiotherapy, better treatment accuracy.

EBRT

RB AFTER EBRT

Complication of EBRT

Stunting of orbital growth Dry eye Cataract Radiation retinopathy Optic neuropathy Second malignant neoplasms (hereditary

form of retinoblastoma) 30% chance of another malignancy by

30 yrs Risk of second malignant neoplasm

greater in children under 12 mnths

Orbital implants

Buried

Non-buried

Buried implants

Better cosmosis & safety

Materials used- plastic, silicone & hydroxyappatite ( currently recommended )

Non- buried implants

have problems of -

migration

extention

infection

Orbital Retinoblastoma

Rare in developed countries Common in developing countries In Mexico, 18% of 500 pts presented

with orbital RB Taiwanese group, 36% (42 of 116)

pts manifested orbital RB In Nepal, incidence is higher 40% (19

of 43) with proptosis being most common manifestation of RB

Clinical manifestations of orbital RB

Primary orbital RB- clinical or radiologically

detected orbital extension of intraocular RB at

initial clinical presentation with or without

proptosis or fungating mass.

Silent proptosis without orbital & periocular inflammation in pt will manifest intraocular tumour,with inflammation indicates reactive sterile orbital cellulitis sec. to intraocular tumor necrosis.

Secondary orbital RB-

recurrence following uncomplicated

enucleation for intraocular RB.

Unexplained displacement, bulge or extrusion of previously well fitting conformer or prosthesis is an ominous finding sugg. of orbital recurrence

Accidental orbital RB-

Inadvertent perforation

Fine-needle aspiration biopsy

Intraocular surgery with unsuspected intraocular RB

Overt orbital RB

Unrecognized extrascleral or optic n. extension discovered during enucleation.

Pale pink to cherry red episcleral nodule (juxtapapillary location or at site of vortex v.)

Enlarged and inelastic optic n. with or without nodular optic n. sheath is an indicator of optic n. extension.

Microscopic orbital RB

Detection of full thickness scleral infiltration, extra scleral extension & invasion of optic n. on histopathologic evaluation on enucleated eye

Tumor cells in choroidal & scleral emissaria & optic n. sheath indicates orbital extension.

Diagnosis

General physical examination- includes regional lymph nodes palpation

MRI or CT Scan of orbit & brain (axial & coronal orientation)

FNAC Chest X-RAY USG abdomen Bone marrow biopsy CSF cytology

Treatment of orbital RB

Combination therapy more effective

Vincristine, Etoposide, Carboplatin high dose chemotherapy (3-6 cycles or even 12 cycles) followed by enucleation, extended enucleation or orbital exenteration