Retinoblastoma

Dr. Rupal

Introduction

Retinoblastoma is most common intraocular malignancy in children

Incidence 1:15000 to 1:18000 livebirth

Second to uveal melanoma

No racial or gender predisposition

History The first description : Peter Pawius of

Amsterdam In 1805, William Hey : coined the term fungus

haematodes. In 1809,Scottish surgeon James Wardrop:

described metastasis to optic nerve, brain and different parts of body.

In 1864, Virchow:named glioma of the retina.In 1864, Virchow:named glioma of the retina. In 1891, Flexner of Johns Hopkins : first to In 1891, Flexner of Johns Hopkins : first to

notice rosettes within the tumor.notice rosettes within the tumor.

In 1897, Wintersteiner : proposed the name In 1897, Wintersteiner : proposed the name neuroepithelioma.neuroepithelioma.

Veorhoff : coined the term retinoblastomaVeorhoff : coined the term retinoblastoma

It is bilateral in 25% to 35% cases Average age at diagnosis 18mth Unilateral cases being diagnosed at around

24mth Bilateral cases being diagnosed before 12mth

Genetics of Rb Rb gene is tumor suppressor gene located on

long arm of 13th chromosome 13q14. Produces Rb protein that binds to cellular

protein & suppresses cell growth The gene is recessive oncogene at cellular

level Primitive retinal cells disappear within first few

yrs of life.So Rb is usually is not seen after 3-4yrs of age.

Hereditary Rb(40% of cases)

Patients inherits abnormal allele from parents and 1normal allele which undergoes a subsequent mutation after conception

The risk of 2nd hit is very high hence Rb is inherited as Autosomal Dominant

Risk of bilateral Rb is high as all cells have inherited 1 mutant allele

Risk of nonocular malignancies is also high for same reasons

Early age of presentation -1yr

Nonhereditary Rb(60% of cases)

Both alleles are normal after fertilization but subsequent mutations inactivate both alleles.This are somatic mutation in same retinal cells

No risk of bilateral Rb. In fact most of them are unilateral

No risk of nonocular malignancies

Two hit hypothesis

Proposed by Knudson in 1971 He stated that for retinoblastoma to

develop,two chromosomal mutations are needed.

In hereditary cases the initial hit is a germinal mutation,inherited and found in all cells

Therefore hereditary cases are predisposed to development of nonocular tumors.

Second hit develops in somatic retinal cells

In unilateral sporadic cases,both hits occurs during retina development and are somatic mutations.

Therefore there is no risk of second nonocular tumors.

Clinical manifestations Leukocoria (56.1%) Strabismus

Secondary changes : includes glaucoma, retinal detachment, and inflammation secondary to tumor necrosis. Pseudouveitis : characteristic of an infiltrating type

of retinoblastoma Orbital inflammation mimicking orbital cellulitis

Proptosis

Diagnosis

Ultrasonography : useful in distinguishing retinoblastomas from non-neoplastic conditions. It is also useful in detecting calcifications.

MRI

beneficial in estimating the degree of

differentiation of retinoblastomas

CT scan: delineates

extraocular extension and can detect associated pinealoblastoma

On FFA smaller tumors shows minimally dilated feeding vessels in arterial phase,blotchy hyperflourescence in venous phase and late staining

X-ray studies: identifying intraocular calcium in patients with opaque media.

Histopathology

Poorly differentiated tumors shows small to medium sized round cells with large hyperchromatic nuclei and scanty cytoplasm with mitotic figures

Well differenciated tumors show rosettes and fleurettes.

Flexer Wintersteiner rosettes

consist of columnar cells arranged around central lumen,highly

characteristic of retinoblastoma

Homer Wright rosettes consist of cells arranged around central neuromuscular tangle

Fleurettes are eosinophilic structures composed of tumor cells with pear shaped eosinophilic processes through fenestrating membrane

areas of necrosis and calcifications

Endophytic growthTumor breaks through the internal limiting

membrane and has an ophthalmic appearance of a white-to-cream mass showing either no surface

vessels or small irregular tumor vessels.

Exophytic growthExophytic growth occurs in the subretinal space.

This growth pattern often is associated with subretinal fluid accumulation and retinal detachment.

Diffuse infiltrating growthThis is a rare subtype comprising 1.5% of all retinoblastoma.

It is characterized by a relatively flat infiltration of the retina by tumor cells but without a discrete tumor mass.

It grows slowly compared with typical retinoblastoma.

Differential Diagnosis Congenital cataract Coats disease PHPV ROP Retinal detachment Coloboma Retinal dysplasia Norries disease

FEVR Toxocariasis

International Classification Of Intraocular Retinoblastoma

Management of Retinoblastoma

Primary goal is to save life Salvage of organ and function Needs team approach including an ocular

oncologist,pediatric oncologist,radiation oncologist and physicist,genetic and ophthalmic oncopathologist.

Management strategy depends on the stage of disease.

Management of Rb is highly individualised Based on following considerations:1. age at presentation2. Laterality3. Tumor location4. Tumor staging5. Visual prognosis6. Systemic condition7. Family and societal perception8. Cost effectiveness of treatment

Methods to Manage Intraocular Rb

1. Focal— Cryotherapy Laser

photocoagulation Transpupillary

thermotherapy Transcleral

thermotherapy Plaque

brachytherapy

2. Local— External beam

radiotherapy Enucleation3. Systemic— Chemotherapy

Cryotherapy Performed for small and

peripheral tumors measuring upto 4mmin basal diameter and 2mm in thickness

Triple freeze thaw cryotherapy applied at 4-6wk interval until complete tumor regression

It produces scar larger than tumor

Complications: Transient serous retinal detachment Retinal tear Rhegmatogenous retinal detachment

Cryotherapy administered 2-3hrs prior to chemotherapy increase the drug delivery across the blood retinal barrier and thus has synergistic effect.

Laser Photocoagulation

Used for small posterior tumors 4mm in basal

diameter and 2mm in thickness

Delimits the tumor and coagulate the blood

supply to tumor by surrounding it with two rows

of overlapping laser burns.

It is contraindicated while patient is on active

chemoreduction protocol.

Complications:

Transient serous retinal detachment Retinal vascular occlusion Retinal hole Retinal traction Preretinal fibrosis Less often employed now with advent of

thermotherapy

Thermotherapy

Mechanism: focused heat generated by infrared radiation is applied to tissues at subphotocoagulation levels to induce tumor necrosis

Goal is to achieve slow and sustained temperature range from 40-60degC within tumor,thus sparing damage to retinal blood vessels

Performed for small tumors-4mm in basal diam and 2mm thickness

Complete tumor regression achieved in 85% tumors using 3-4 sessions

TTT done using infrared radiation from a semiconductor diode laser delivered with 1300micron large spot indirect ophthalmoscope delivery system

Can be applied transpupillary through operating microscope or by transcleral route with diopexy probe

Tumor is heated until it turns subtle gray

Complications: Focal iris atrophy Focal paraxial lens opacity Retinal traction and serous detachment Major application :as an adjunct to

chemoreduction This synergistic combination is termed

chemothermotherapy.

Plaque Brachytherapy Involves placing

radioactive implant on sclera corrosponding to base of tumor to transclerally irradiate tumor

Ruthenium 106 and Iodine125 commonly used

Contd

Advantages: Focal delivery of radiation and minimal

damage to normal tissue Minimal periorbital tissue damage Absence of cosmetic abnormality because of

retarded bone growth Reduced risk of second malignant neoplasm Shorter duration of treatment

Contd. Indication: tumors less than 16mm in basl diam and

less than 8mm thickness It could be primary or secondary modality of

treatment Currently performed only in cases where

chemotherapy is contraindicated Most usefull in eyes that fail to respond to

chemoreduction and external beam radiotherapy or for tumor recurrences

Complications: radiation papillopathy and retinopathy

Contd. Plaque brachytherapy requires precise tumor

localisation and measurement of its basal dimensions

Thickness is measured on USG Dose to tomor apex ranges from 4000-

5000cGy Plaque is sutured to sclera after confirming

tumor centration and left for 36-72hrs Results in 90% tumor control

External beam radiotherapy Indication: In eyes where primary chemotherapy and local

therapy has failed When chemotherapy is contraindicated Problems with EBT: Stunting of orbital growth Dry eye Cataract Radiation retinopathy Optic neuropathy

Contd EBT can induce second

malignant neoplasm esp in patients with hereditary form of Rb

The risk of second malignant neoplasm is greater in children under 12 mth of age.

Enucleation Most common method for managing advanced Rb

Treatment of choice for: Advanced intraocular Rb with NVI Secondary glaucoma Anterior chamber tumor invasion Tumor occupying >75% vitreous volume Necrotic tumor with secondary orbital inflammation Tumors associated with hyphema or vitreous

hemorrhage

Special Considerations for Enucleation in Rb

Minimal manipulation Avoid perforation of eye Harvest long (>15mm)optic

nerve stump Inspect the enucleated eye

for macroscopic extraocular extension and optic nerve involvement

Harvest fresh tissue for genetic studies

Avoid biointegrated implant if postoperative radiotherapy is necessary

Chemotherapy

Chemoreduction, defined as the process of reduction in tumor volume with chemotherapy

Chemotherapy alone is not curative and must be associated with intensive local therapy

This can minimize the need for enucleation or EBT without significant systemic toxicity

Commonly used drugs are

Vincristine

Etoposide

Carboplatin

Chemoreduction is most usefull for tumors without associated subretinal fluid or vitreous seeding

Vincristine (Vincasar, OncovinPFS)

Mechanism: Cycle specific and phase specific, which blocks mitosis in metaphase. Blocks ability of tubulin to polymerize to form microtubules, which leads to rapid cytotoxic effects and cell destruction.

Pediatric Dose: For retinoblastoma: 1.5 mg/m2 (0.05 mg/kg for children younger than or = 36 mo and maximum dose, or = 2 mg)Intravenous administration q3wk for 9 cycles

Contraindications: Documented hypersensitivity to vinca alkaloids; pregnancy

Carboplatin (Paraplatin)

Mechanism: Inhibits both DNA and RNA synthesis. Binds to protein and other compounds containing SH group.

Pediatric Dose: For retinoblastoma: 560 mg/m2 (18.6 mg/kg for children, or = 36 mo) IV q3wk for 9 cycles

Contraindications: Documented hypersensitivity; preexisting severe renal impairment and myelosuppression; severe allergy to platinum components

Etoposide (Toposar, VePesid)

Mechanism: Blocks cells in the late S-G2 phase of the cell cycle.

Pediatric Dose: For retinoblastoma: 150 mg/m2 (5 mg/kg for children younger than or = 36 mo) IV q3wk for 9 cycles

Contraindications: Documented hypersensitivity; myelosuppression; liver impairment; IT administration may cause death

Contd

Favourable signs to chemotherapy:1.Considerable shrinkage after 2 cycle2.Reduce vascularization 3.Calcification : cottage cheese appearance 4.Clearing of vitreous seeds5.Resolution of RD

Contd

Adverse effects :1.Myelosuppression 2.Febrile episodes3.Neurotoxicity 4.Nonspecific gastrointestinal toxicity

Periocular chemotherapy

Carboplatin delivered deep posterior subtenon has been demonstrated to be efficacious in management of advanced intraocular retinoblastoma with vitreous seed

It can penetrate sclera & achieve effective concentration in vitreous

This modality is under trial It achieves 70% eye salvage in patients with

RB with diffuse vitreous seeds

Follow up schedule

Chemoreduction therapy: every 3 weeks with each cycle of chemotherapy

Focal therapy: every 4-8 weeks until complete tumor regression

Following tumor regression : 3 mnthly for 1st yr , 6mthly for 3yrs or until child is 6yrs age & yrly there after

Histopathologic high risk factors predictive of metastasis1.Anterior chamber seeding 2.Iris infiltration 3.Ciliary body infiltration4.Massive choroidal infiltration5.Invasion of optic nerve lamina cribrosa6.Retrolaminar optic nerve invasion 7.Invasion of optic nerve transection8.Scleral infiltration 9.Extra scleral extension

Orbital Retinoblastoma

Clinical manifestation:1. Primary2. Secondary3. Accidental4. Overt5. Microscopic

Orbital retinoblastoma

Clinical manifestation: 1.Primary orbital Rb: Refers to clinically or radiologically detected

orbital extension of intraocular Rb at initial clinical presentation with/without proptosis or fungating mass.

2.Secondary orbital Rb : Orbital recurrence following uncomplicated

enucleation for intraocular Rb Unexplained displacement , bulge or

extrusion of previously well fitting conformer or prosthesis is an omnious finding suggestive of orbital recurrence

3.Accidental orbital Rb: Inadvertent perforation , FNAB or intraocular

surgery in eye with unsuspected intraocular Rb

4.Overt orbital Rb: Previously unrecognized extrascleral or optic

nerve extension discovered during enucleation

Enlarged & inelastic optic nerve with/without nodular optic nerve sheath are clinical indicators of optic nerve extension of Rb that should be recognized during enucleation

5.Microscopic orbital Rb: Orbital extension may not be clinically evident

& may only be miocroscopic Detection of full thickness scleral infiltration ,

extra scleral extension & invasion of optic nerve transection on histopathologic evaluation are unequivocal features of orbital Rb

Management of orbital Rb

Primary orbital Rb: High dose chemotherapy(3-6cycles) followed

by surgery (enucleation , extended enucleation or exenteration as appropriate) , orbital radiotherapy & additional 12 cycle std dose chemotherapy

Accidental , Overt or Microscopic orbital Rb: Orbital EBT (fractionated 45-50 Gy) &12 cycle

of dose chemotherapy

Metastatic Rb

Metastatic disease at the time Rb diagnosis is very rare

Common sites for local spread & metastasis include orbital & regional lymph node extension, CNS, bone & bone marrow , liver,spleen, pleura

After the diagnosis of metastasis , the period of survival varies from 6-12 mths

Treatment of metastatic disease:1.Chemotherapy intense: cyclophophamide 20mg/kg IV, vincristine 50mg/kg IV doxorubicin2.Palliative local radiotherapy3.Craniospinal radition4.Intrathecal methotrexate(0.5mg/kg) & intrathecal

diazoquone help to induce remissions

Follow up schedule

Include fundoscopy & IDO under full dilatation under GA

FFA in cases with radio/cryo/photocoagulation is done to detect vascularity

6 wks after therapy every 3mnths for 1st yr every 4mnths for 2nd yr every 6mnth till 6 yrs of age once a yr upto 20 yrs of age

Second cancers / non Rb malignancies

Incidence:hereditary: 6% over lifetime Hereditary Rb with EBT : 1% / yr in field of

radiation Avg. age of diagnosis is 13 yrs Tumors: Osteogenic sarcoma-most common Pineoloblastoma-2yrs after diagnosis of Rb

Beyond 2 yrs:1.Bony and soft tissue tumors:Ewings

sarcoma,chondrosarcoma & rhabdomyosarcoma

2.Skin tumors: malignant melanoma , SCC , sebaceous cell CA

3.Neurobalstoma , medulloblastoma , leukemia

Prognosis

Overall survival rate is 90% 5 yr mortality rate of Rb cases :1.Optic nerve involvement : not involved 8% upto lamina cribrosa 15% beyond lamina cribrosa 44% surgical end of section 65%2.Choroidal invasion 25% 3.Orbital invasion 91%

Newer modalities

1.Thermotherapy: entire eye sparing the anterior segment – u wave strip

line applicator Inducing focal hyperthermia- using ultrasonically

induced hyperthermia2.Radiosensitisers : SR 2508 & SZR 2555 better absorption with lesser

toxicity. Misionidazole-hypoxic cell sensitiser but is toxic for clinical use

3.Local chemotherapy: Serial Aggressive Local Therapy (SALT ): fluorouracil,

methotrexate, cytosine arabinoside, azoquinone 4.Monoclonal antibodies5.PDT

Thank you