Retinoblastoma

RETINOBLASTOMA

RETINOBLASTOMADr. Amina Abdul Rahman

Junior Resident

Dept of Radiotherapy

Medical College, Calicut

RETINOBLASTOMA

• Malignant Primary Intraocular Tumor that arises in the Retina

• MC age < 3 years• MC pediatric intraocular tumor• 4% of all childhood malignancy• Arises in cells that lose the protein product of the RB1

gene

Epidemiology

• Incidence is 1 in 18,000 – 30,000 live births/yr in the world

• Non hereditary RB : increased frequency in poorer, tropical regions, 50 fold increase freq in African countries

• Human Papilloma infection, diet deficient in fruits and veg

Hereditary RB• Hereditary retinoblastoma has no

gender/racial/environmental/ socioeconomic predilection• Occurs due to

a) Inherited mutation from the carrier or diseased parent

b) Germ line mutations occurring during spermatogenesis or oogenesis

c) During Early Embryonic development• MC in spermatogenesis > oogenesis• Fathers working in metal manufacturing industries,

smoking, welding fumes• Mothers : diet def in vitamins, maternal inf with HPV

Genetic and Molecular basis of RB

Proto oncogenes :

Constitutive activation uncontrolled

proliferation

Mutation in single allele of the diploid pair leads to oncogenesis

Tumor Suppressor Genes :

Negative Modulators, inhibit cellular replication

Both alleles should be inactivated to cause loss of function

Retinoblastoma gene is a Tumor Suppressor Gene

Knudson’s Two Hit Hypothesis

“In the dominantly inherited form of RB, one mutation is inherited via the germ line and the second occurs in somatic cells. In the non inherited form, both mutations occur in the somatic cells”

Based on his observations:

1. Younger age at presentation for Hereditary RB

2. Multifocality and Bilaterality in Hereditary RB

Hereditary RB

• 40% of all RB is hereditary

• Out of which only 10% have Family History

• Babies with Her RB are born heterozygous for the mutant gene (RB1+/RB1-)

a) Either from the carrier/affected parent

b) From de novo germ line mutations

c) Occurs during early embryonic development

First Hit

First Hit

First Hit

Second Hit

Hereditary RB

These babies now require only a single inactiv mutation in the functioning wild type RB1gene in a single retinoblast

Biallelic Loss of function

Tumor genesis

Hereditary RB

• Probability of at least one retinoblast, out of all the retinoblasts harboring the mutant gene, getting a random second hit is high, as high as 90%

• this explains why most Her RB are B/L and multi focal

• Thus Retinoblastoma inheritance is recessive at the level of the gene but inherited as a Autosomal Dominant Trait phenotypically.

Non Hereditary RB• Accounts for 60% of cases

• Babies are born homozygous for the normal wild type (RB1+/RB1+)

• Require two distinct somatic inactiv mutations in both RB1 alleles for the functional loss of RB protein

• Universally U/L and unifocal

it

First Hit

Second Hit

Retinoblastoma Gene• Chromosome 13q• Encodes for the RB protein• Master regulator of a number of subordinate proteins

mediating cell replication• pRB interacts with E2F family of proteins and prevents

cells from entering the cell cycle

• Hypophosph form binds with E2F

• Hyperphosph form is inactive

Cell of Origin

• Retinal stem cell• Retinal Progenitor cell• Newly post mitotic retinal cell• Differentiated retina

Anatomy of the Eye ball

CLINICAL FEATURES

Leucocoria• White Pupil• 60%• Mainly large and central tumors• Light being reflected back from the white tumor• More in dim/night light• White reflex rather than the normal red reflex in a

photograph taken in poor light

Strabismus• Eye turns inward or outward• 20%• Even a small tumor obscuring the central vision may

cause strabismus• Directly by involving fovea• Indirectly by causing RD or vitreous seeding

Locally Advanced Disease• Red painful eye (neovascular glaucoma)• Cloudy cornea• Poor vision• Nystagmus• Vitreous hemorrhage• Orbital inflammation• Older children may present with exudative RD mimicking

Coat’s disease• Orbit may be filled with tumor

DIAGNOSIS

Indirect ophthalmoscopy

• Creamy white colour• Unique vascular pattern• Serous RD• Vitreous seeding/ subretinal seeding

Biopsy

• Not required for diagnosis

• Not recommended due to risk of intra ocular seeding and extra ocular spread

• Inadvertent surgery or biopsy in an eye not suspected to have RB should undergo sys chemo

Ultrasound • Recommended when retina cannot be visualised

Vitreous hemorrhage

Vitreous seeding

Hazy cornea• Assess

Shape, Size, Height, presence of calcification,

Retinal Detachment

CT Scan

• Was used in the past as a part of systemic work up

• Now not recommended in view of radiation induced risk of second non ocular tumors in hereditary RB

MRI

• Better than CT as no radiation exposure

• For assessing orbit and CNS

• Screen for primary neuroectodermal tumors esp pinealoblastoma

Family History

• Enquire about a history of Retinoblastoma in sibling or parent

• A family history of retinoma, a benign tumor believed to be a precursor of RB

• A family history or personal history of non ocular malignancies associated with RB

SCREENING

Screening all children

• Parents and pediatricians should look for white reflex

• Using penlight for red reflex in darkened room

• Three annual checks up to 3 years

• Only large and central tumors may be detected

Screening babies at risk

• Indirect Ophthalmoscopy every 3 months up to 3 years of age

• First exam at first few weeks : directly observe

• Subsequent exams :

Dilated retinal exam by IO

Peripheral retinal exam by scleral indentation

PATHOLOGY

Pathology• Gross

Multi focal

Calcification

Retinal detachment• Microscopy

Densely packed small hyperchromatic cells with scant cytoplasm with background of necrosis and calcification

Clusters surrounding a blood vessel – psuedorosette

Flexner-Wintersteiner Rosettes

Homer Wright Rosettes

Gross Pathology

Flexner-Wintersteiner Rosettes

• Spoke and wheel cell clusters surrounding a distinct lumen containing small cytoplasmic extentions of encircling cells

Homer Wright Rosettes

• Clusters of cells surrounding a tangle of cytoplasmic filaments without a lumen

• Also seen in Neuroblastoma

Routes of Spread1) Optic Nerve:

Most common route of spread

Reaches the CNS via the subarachnoid space

2) Choroid:

Next common route

Absent/focal/massive

Highly vascular structure, so risk of hematogenous spread

3) Scleral Vessels:

Intraocular fluid filters into venous channels, risk of both hematogenous and lymphatic spread

4) Orbital soft tissues: highly vascular

Metastases • Most common site of metastases is Bone• Next is CNS• So in locally advanced malignancy

Bone marrow aspirate

CSF study

should be done prior to chemotherapy

Histopathological Factors that predict Extraocular spread

1. Invasion of Optic N posterior to lamina cribrosa 29%

2. Positive surgical margins at Optic Nerve 80%

3. Massive extension into choroid

4. Extension of tumor into anterior segment

5. Extrascleral spread

Secondary Malignant Neoplasms• More in B/L her RB than in U/L• Increase freq with time

10% at 10 yrs

20% at 20 yrs

25% at 30 yrs

51% at 50 yrs• Survivors of B/L RB who received RT• And those who received cyclophosphamide

Secondary Malignant Neoplasms• Tumors in RT field

Osteosarcoma

Fibrosarcoma

Other spindle cell cancers• Outside RT field

Osteosarcoma

Soft tissue sarcomas

Malignant Melanoma

Thyroid cancers

Pinealoblastoma

Trilateral RB• B/L RB with ectopic RB in the pineal or suprasellar region• Patients may present with signs of raised ICT• And in case of suprasellar regions : Diabetes Insipidus• Recommended intracranial imaging in patients with B/L

RB at diagnosis and during Follow Up every 3 – 6 months for 3 – 4 yrs

• Patients with trilateral RB have a poorer outcome• Orbital RT Chemo Craniospinal RT

CLASSIFICATION

CLASSIFICATION OF RB

1. Reese-Ellsworth Classification of intraocular RB

Based on response to RT

2. International Classification of Retinoblastoma (ICRB)

Grouping system for Intraocular Retinoblastoma

Based on response to Chemo

3. Abramson/Grabowski Staging System

Reese Ellsworth Classification

Stage 1 : tumor less than 4 DD posterior to equator

Stage 2 : tumor 4 -10 DD posterior to equator

Stage 3 : any tumor anterior to equator or > 10 DD

Stage 4 : multiple tumors > 10 DD or ant to ora serrata

Stage 5 : more than half the retina / vitreous seeding

Abramson/Gabrowski – Extraocular

MANAGEMENT

MANAGEMENT

Selection of Therapy:

1. Primary Goal : CURE

2. Secondary goal :Preserve Vision• The method of treatment is decided based on• Size, number, location of the lesion as well as whether the

patient has hereditary or non hereditary RB

Management

• Local Ablative Therapy

• Radiotherapy

• Systemic Chemotherapy

• Enucleation/ Exenteration

Management • Small tumors

Local ablative therapy• Small tumors that are near OD/Fovea or with Vitreous

seeding

Chemo f/b local ablative therapy or Radiotherapy• Medium Tumors

Chemoreduction (chemo f/b local ablative therapy)

Radiation Therapy• Large Tumors

Chemo f/b RT

Management • Vitreous Seeding

Sys chemo and/or RT

Severe seeding : subconj/ sub Tenon chemo• Persistent / Recurrent Tumor after Chemo

RT• Persistent/ Recurrent Tumor after RT

Local ablative Therapy• No chance of saving vision

Enucleation

LOCAL ABLATIVE THERAPY

Local Ablative Therapy

• Cryotherapy

• Photocoagulation

• Laser Hyperthermia

Cryotherapy • Cryotherapy is done by the application of a cryoprobe on

the sclera after tumor localization and freezing the cells up to – 80 degree Celsius

• The tumor plus a margin of normal tissue is covered by frozen vitreous

• The formation of ice crystals within the cell causes membrane rupture

• The probe is removed only after it is completely thawed• 3 cycles of alternating freezing and thawing is done• Should obtain a flat scar• Persistent elevation represents residual tumor

Indications of Cryotherapy• Small tumors < 3mm ICRB A• Anterior to equator• Focal vitreous seeds just above the tumor• In conjunction with chemo• Local recurrence/ residual disease after chemo or RT

• Side Effects : Vitreous Hemorrhage, Acute retinal edema, exudative retinal detachment, retinal break

Photocoagulation

• Green lasers of wavelength 532nm is used• The laser photocoagulates the retinal feeding vessels of

the tumor creating a white retinal burn surrounding the tumor by 1mm to interrupt the blood supply

• The beam should not be directed at the tumor due to risk of tumor seeding

• Local tumor control rate of 70%• Complications : vitreal seeding, retinal fibrosis, retinal

vascular occlusions

Indications • Small tumors < 3 mm in size confined to retina ICRB A• Away from OD or macula• Local recurrence after RT so re irradiation is avoided• No seeding / retinal detachment• Posterior tumors are better treated by lasers

Laser Hyperthermia• Generated by diode lasers of wavelength 810nm• Beam directed at center of tumor creates a single spot of

0.8 – 2mm• Heating for 10-30min up to 42-45 degrees, per session• Hyperthermia around the coagulation spot increases the

effect of chemo and RT

Indications • Primary treatment of ICRB group A tumors• Consolidation after chemo and RT• Local recurrence• Retinal pigment epithelium beneath the tumor should be

intact• No retinal detachment

Thermochemotherapy: hyperthermia just before giving chemo increase tumor killing effect of chemo

Local Ablative Therapy

• The end point of each of these therapies is the formation of a flat scar

• If there is residual elevation, it indicates persistent tumor

RADIOTHERAPY

Radiotherapy

•Brachytherapy

•External Beam Radiotherapy

Episcleral Plaque Radiotherapy

Indications :• Unilateral • Small 2-16mm basal diameter ICRB Gp B• >3mm from OD/fovea• <10mm high• Single lesion or 2 lesions small enough or close enough to

be covered by one plaque• For local recurrence too large for other local therapy• Small amount of vitreous seeding over tumor apex• Tumors anterior to equator

Episcleral Plaque Brachytherapy

Not indicated in :

Tumors in the peripapillary area or near macula

Tumors at the insertion of extraoccular muscles

Anatomically difficult sites posterior to eye


Radiation Source• Cobalt 60 (1.17 & 1.33 MeV, t1/2 5.2 yrs)• Iodine 125 (27-35 keV, t1/2 60 days)• Iridium 192 (295 keV- 612keV, t1/2 74.5 days)

In Gold Plaque

directs radiation to tumor, shielded in other directions




Procedure :

Measure the max basal diameter and maximum height of the tumor using US

Peritomy : open the conjunctiva

Rotate the eyeball

Trans illuminate over pupil : shadow cast by the tumor is marked

Place a dummy plaque

Place the live plaque, rotate the eyeball back into place, close sutures

Remove after dose delivery




Dose :

Single application 30-40 Gy to tumor apex

If after chemo, dose reduced to 25-30Gy


Side effects:

Non proliferative retinopathy

Maculopathy

Glaucoma

Cataract

External Beam Radiotherapy

• Goal of EBRT :To provide a homogenous and tumoricidal dose to the entire retina and vitreous

1. All retinal cells may have a genetic neoplastic potential

2. Vitreous seeding may occur

3. Multiple tumors may arise from a primary RB

4. Tumor may spread via the subretinal space

5. Retinal differentiation progresses from posterior to anterior and from superior to inferior, so subclinical disease in immature retina may be treated


Whole Eye Radiotherapy

Lens Sparing Technique

IMRT

Proton Therapy


Indications• Unsuitable for focal treatment • <5mm to Optic Disc/Macula• Too large >10mm for plaque• Too numerous > 2 tumors for plaque

Whole Eye TechniqueJ L Hungerford, N M Toma et al,British Journal of Ophthalmology 1995;79:109-111

Used until 1985

1. In B/L RB :

If one eye enucleated, exit beam passes through the enucleated socket

2. B/L RB

If both to be irradiated, parallel opposed lateral beam were used

3. U/L RB

If C/L eye to be protected, direct anterior or superior/inferior oblique beams were used

Whole eye technique• Results

80% of eyes in RE gr I – V were preserved after RT alone or f/b salvage local therapy

That is 20% required enucleation

All retained eyes developed Radiation induced Cataract

Complications of Whole Eye Technique

• Severe ocular morbidity, painful photobic eye• Eyelid damage, eyelash loss• Decreased tear production, dry eye• Corneal toxicity• Cataract• Conjunctival telangiectasia• Corneal vascularization and opacification

Lens Sparing TechniqueRadiotherapy and Oncology, I (1983) 31-41Schipper et al

• 6 MV/8 MV Linear Accelerator• A simple but highly accurate irradiation method based on

the temporal approach ensuring precise delivery of uniform radiation dose to the entire retina and vitreous, sparing the lens


Immobilisation :

• Plaster of Paris mold over the entire head and neck region• Vacuum Pillow (Vac-Pac, NF-1) for positioning the head

during treatment• For children under 3 yrs, anesthesia with a mixture of

Nitrous oxide and Oxygen with Halothane is given, preceded by administration of atropine


Lasers are projected onto the patient for accurate alignment

Measure the axial intraocular dimensions by ultrasonic biometry


• Single Lateral D shaped field• Includes

Entire Retina ( up to ora serrata) and vitreous

10mm of optic N as it exits the globe

Ant edge of the beam is tangent to the post pole of lens

2.6 X 3.2cm2 (20 X 26 cm2 for babies <1y)

D shaped Field• Sharply and accurately defined field in all directions

1. Precision machined 11cm thick lead beam defining blocks is used to define the entire beam

2. Short collimator to eye distance of 17 cm

3. Independent Jaws

4. Decrease side scatter inherent to high MeV energy beams

Lens Sparing Technique• Centre of tumorous eye is exactly in the isocentre,

100 cm from source• Accurately align and position the eye in the radiation

beam by indirect fixation of eye to the beam defining collimator

• A contact lens fixes the eye by creating a low vacuum• Iron pin on the lens is magnetically coupled to a scale on

the collimator holder : measure distance between the cornea and the anterior edge of the beam

External Beam Radiotherapy• Centre of tumorous eye exactly in isocentre, 100 cm from

source• Accurately align and position the eye in the radiation

beam by indirect fixation of eye to beam defining collimator

• A contact lens fixes the eye by creating a low vacuum• Iron pin on the lens is magnetically coupled to a scale on

the collimator holder : measure distance between the cornea and the anterior edge of the beam

Lens Sparing Technique• Radiation beam is directed at any angle by simply rotating

the gantry without changing the position of the eye• Beam is angled at 90 degrees if the other eye is

enucleated• If the C/L eye is to be spared, the beam is directed in the

superior oblique/ inferior oblique direction at 35-45 degrees

• In B/L RB simultaneous irradiation by parallel opposed fields is done by fixing both eyes

• In B/L treatment the eye nearest to the collimator is positioned in the isocenter of the treatment unit

For ensuring Dose Homogeneity

• Center of the beam is directed 2-3 mm post to posterior pole of lens using split beam or independent Jaws

• Requires a scatter of Perspex of thickness 8 mm interposed in the beam for decreasing depth for dose build up of 6MV beams to prevent under dosage of the temporal retina which is superficial, just below the skin edge.

Scatterer to skin distance 4 cm 6 MV

2 cm 8 MV

Beam Profile

• Distance from the back of lens to ora serrata is 1-1.5mm, so to treat entire retina and simultaneously avoid the lens is difficult

• A very narrow penumbra is obtained, the dose falling from 85% - 15% of the central axis dose in 2mm at a depth of 2 cm

“an almost penumbra free, non divergent beam”

Contraindications of Lens sparing RT

• Untreated tumor anterior to equator• Retinal detachment extending to Ora Serrata• Vitreous seeding

Radiation Dosage

• Dose 40-45 Gy in 2 Gy/ fraction, 5 days per week

• If after chemo, dose is 26 Gy

Results of Lens Sparing RT• 92 % eye preservation rate• But there was a higher incidence of new anterior tumor • Whole Eye RT reduced the incidence of new anterior

tumors as it had a prophylactic effect on tumors too small to be detected or new RB lesions that developed from malignant transformation of undifferentiated cells harboring the mutated gene.

• Also more undifferentiated cells were located anteriorly• But fortunately anterior recurrences are detected earlier

and easier to treat by local salvage therapy

Intensity Modulated Radiotherapy

• Better dose distribution than 3DCRT• Helps in greater sparing of

Surrounding bony orbit

Lacrimal gland

Lens

Cornea• While delivering therapeutic dose to the entire retina

Dose Constraints

• Lacrimal Gland 30 Gy dry Eye Syndrome• Optic Nerve 54 Gy Radiation optic neuropathy • Cornea 50 Gy • Lens 12 Gy , most radiosensitive Cataract

Proton Therapy• Better dosage distribution with sparing of the other eye

can be obtained using Proton therapy in the lateral approach

• This is due to the deposition of energy via the Bragg peak

CHEMOTHERAPY

CHEMOTHERAPY

Radiotherapy pitfalls :• Poor outcome in advanced RB• Orbital/ midfacial deformity• Lacrimal gland dysfunction• Increased risk of second malignancies in Hereditary RB

Chemotherapy has become a reasonable safer alternative

Indications of Chemotherapy

• To shrink tumors so that they may be amenable to local ablative therapy

• Prophylaxis in children following enucleation with histopathological features of high risk disease

• Extra ocular disease should be treated first with chemo• Localized bulky disease or large orbital recurrence• Treatment of metastases to bone, meninges or bone

marrow involvement

Chemotherapy in ICRB Group B• Foveal or peripapillary disease• Or > 3 mm in size• Chemoreduction with 2 drug regime with Vincristine and

Carboplatin• f/b Plaque RT

Chemotherapy in ICRB Group C

• 6 courses of chemo with Vincristine, Etoposide and Carboplatin

• Local ablative therapy or Plaque RT

Chemotherapy for Group D• Chemo with VEC to consolidate tumor• f/b

One of the following :

1. EBRT

2. Sub tenon / sub conjuctival carboplatin

1mL of 10mg/mL at each of 2 sites in 2 quadrants, total of 20mg

3. Add 4th drug Cyclosporin

4. Enucleation

Chemo for Regional Extra Ocular Disease

• Without treatment, mortality of 20%• Induction chemo with 4 cycles of Vincristine, Cisplatin,

Cyclophosphamide with mesna and Etoposide• f/b Orbital RT at 6 weeks

Extra Ocular Tumor with metastases• 100% mortality in the absence of aggressive management• Induction chemo with 4 courses of vincristine, cisplatin,

cyclophosphamide and etoposide• Consolidative chemo with myeloablative therapy :

carboplatin, thiotepa, etoposide f/b autologous stem cell rescue

• EBRT to site of bulky disease 42 days after stem cell rescue

• 67% disease free survival at 3 years

Complications of Chemotherapy

• Febrile Neutropenia

• Risk of Second Malignancy esp AML due to Etoposide

SURGERY

ENUCLEATION

Indications:

1.U/L or B/L Blind Eye

2. Local recurrence not amenable to local therapy and not responding to chemotherapy

3. Reasonable expectation of vision after local therapy is nil.• Anterior traction placed on globe• Rectus muscles are severed• Optic nerve is cut

EXENTERATION• Removal of globe, Extra ocular muscles, lids, nerves and

orbital fat

Indications:

1. Local tumor breaching the globe

2. Local recurrence after enucleation

Should be followed by systemic chemo and RT

Survival Rates

Follow Up

• Patients should be monitored under anesthesia every 3-4 months until age 3-4yrs

• Thereafter every 6 months until 5-6 yrs• At about 8 yrs, a dilated fundus exam without anesthesia

annually• Should be examined for and warned about second

malignancies, the incidence of which increases with time

References

1. Pediatric Radiation Oncology, Edward C. Halperin

2. Oncology of Infancy and Childhood, Stuart H. Orkin

3. Textbook of Radiation Oncology, Leibel & Phillips

4. External Beam Radiotherapy for retinoblastoma, British Journal of Ophthalmology 1995; 79: 112-117

5. An accurate and simple method for megavoltage radiation therapy of RB, J. Schipper et al, Radiotherapy and Oncology, I (1983) 31-41

The End

Education

Retinoblastoma