RETINOBLASTOMA

DR.CHRISTINA SAMUEL

Overview

•Retinoblastoma is the most common primary intraocular malignancy of childhood and infancy with a cumulative life time incidence of 1 in 3,300 to 1 in 20,000 live births world wide.

• Indian studies have shown the incidence of the tumor in 1:15000 live births. • Retinoblastoma is a highly malignant tumor that arises from an

accumulation of proliferating embryonic retinal cells.• Early diagnosis and treatment of the tumor is essential for child survival

and salvaging the eye to give useful vision.

GeneticsRetinoblastoma represents the phenotypic expression of an abnormal tumor suppressor gene known as retinoblastoma gene RB1.Normally a gene will cause expression of a cell proliferation, but RB1 gene acts by suppressing the phenotypic characteristics.The gene is activated in hypophosphorylated state, (pRB)4, which is responsible for the inhibition of cell proliferation.After the mutation, the gene is not converted to pRB form which leadsto uncontrolled cell growth.In order for retinoblastoma to develop; both copies of the gene at the 13q14 locus must be lost, deleted, mutated, or inactivated.

‘two hit’ hypothesis

• Alfred Knudson in 1971, stated that two complementary chromosomal mutations are required in the same retinal cell to develop retinoblastoma.

• The “first hit” is a germ line mutation that is found in all or most of the cells of the body and hence inherited.

• The second hit occurs sometime during development, and if it occurs in a somatic cell such as a retinal cell then retinoblastoma develops.

• The likely retinoblastomas which are heritable are: • All familial tumors • 15- 20 % of sporadic tumors caused by germ line mutation • Bilateral tumors • Unilateral tumors with multi-focal lesions

HISTOLOGY• Retinoblasts- Basophilic cells, Increases N:C ratio

• Flexner Wintersteiner rosettes

• Homer Wright Pseudo rosettes

• Fleurettes

Age at diagnosis

• Average age at diagnosis – 18 months

• Unilateral – a 23 months

• Bilateral – 12 months

• 90% of cases – diagnosed before 5yrs

PRESENTATION

-Leukocoria (Amaurotic cat’s eye) -Strabismus ( convergent) - Secondary glaucoma ( Buphthalmos)-Pseudohypopyon, hyphema-Tumour seedings on Iris, tumor induced uveitis-Iris neovascularisation-Orbital inflammation, Orbital invasion with proptosis - Bony involvement, metastasis in regional lymph nodes and brain

--- Thorough slit lamp examinationIDO under sedation- with 360 degree scleral depression –mandatory (diagnostic in 90% of RB)

GROWTH PATTERN:-

• ENDOPHYTIC- seeds into the vitreous as a white mass

• EXOPHYTIC- subretinal, multilobular white mass causing RD

- O.N invasion

- Choroidal invasion

Special presentation• Spontaneous hyphema

posterior segment ischemia- causes new vessels to develop in iris- bleed.

any child with spontaneous hyphema, without trauma

- B scan to rule out RB

• Phthisis bulbiundergo severe inflammation-spontaneous regress-phthisis

RB to considered in any child with phthisical eye of uncertain origin

Exophytic lesions

CUT SECTION

Investigations

• TC,DC,ESR-to exclude inflammatory/other causes simulating RB• Aqueous humor-assay of LDH

aqueous:blood LDH ratio >1 – in RB

<1 – in other causes• X-rays of orbit – not help in diagnosis, but can show

calcifications• Genetic analysis – blood samples from patient and

parents

B - ScanRound irregular intraocular mass, V-Y pattern.

Numerous highly reflective echoes-representing typical intralesional calcification.

A-Scan- high internal echoes with tumor & rapid attenuation of orbital pattern

Irregular soft tissue density with Heavy calcification- CT ORBIT

• Calcific mass

• Posterior wall of the globe

TRILATERAL RETINOBLASTOMARetinoblastoma + Pinealoblastoma

QUADRILATERAL RETINOBLASTOMA

• Bilateral Retinoblastoma

• Pinealoblastoma

• Suprasellar mass

FFA-Large tumors-dilated feeding vessels & veinsSmall tumors-minimally dilated feeding vessels in the arterial phase, mild hypervascularity in venous phase& late staining of mass

METASTATIC WORK UP:-

Only if evidence of local/systemic extensionBone marrow aspiration/biopsyCSF analysis

Reese – Ellsworth Classification Of Retinoblastoma

OlderGr I A. Solitary tumours < 4D B. Multiple tumour < 4DGr II A. Solitary tumour 4-10 D B. Multiple tumour 4-10DGr III A. tumour anterior to equator B. Solitary tumour larger than 10d.Gr IV A. Multiple tumours > than 10d B. Lesion extending to oraGr V Massive tumours involving half retina Vitreous seeding

Newer Classification

Group A

• 3 mm or less – in greatest diameter

• Not touching optic nerve or foveal avascular zone

• no vitreous seeding

Rx-

• Local treatment only

• Cryotherapy for peripheral ds

• Laser photocoagulation for posterior ds

Group B

• Multiple smaller tumour not larger than 10 mm

• Solitary tumour not larger than 10 mm

• No vitreous seeding ; no RD

Rx

Primary brachytherapy – single site. If multiple sites are needed, to treat like C

Group C

• Tumours less than 15 mm

• No vitreous seeding or RD

• Small tumours < 3mm touching optic nerve or involving fovea

Rx

-Three drug chemoreduction

Local consolidation – cryotherapy laser or plaque

Lens sparing External Beam Radiotherapy for tumours not responding to chemo

< 1 yr – consider plaque therapy

Group D

• Dispersed, disseminated or diffuse

• Vitreous seeding or RD or both

• Volume of tumour does not exceed half the volume of the eye

Rx

Four drug chemoreduction with prechemotherapy cryo

Whole Eye EBR – Intensified chemo

Enucleation for unilateral lesions

Group E

Extra retinal

• Volume of tumour greater than half the volume of eye

• Antr. seg - glaucoma, hyphaema

• total detachment

• Fixed retinal folds

Rx

Enucleation

Group F

Metastatic ds –

Massive choroidal involvement/ involvement of Optic Nerve

Posterior to lamina cribrosa

Rx

Adjuvant. Chemotherapy before and after enucleation

Orbital radiation therapy if

- orbit

- optic nerve is involved

Treatment Methods and Techniques

Focal treatment

• Direct tumour Hyperthermia and Photocoagulation

• Argon Laser – frequency doubled YAG –

• Diode laser (532mm or 810mm)

TechniqueHyperthermia using Iris medical 810nm diode laserSpot size upto 2mmDuration – 9 secTumour is covered over 10-15 mts.Hyperthermia – given on same day as IV carboplatinHyperthermia useful in smaller tumour not responding to chemotherapy

Photocoagulation

In darkly pigmented eye - long wavelength laserLightly pigmented - shorter wavelengthPower 250-300 mwDuration 400-600 msec increased till blanching of tumour

occurs

Cryotherapy

Destruction by cryo – (ice crystals directly destroy tumour cells rupturing cellular memb)

Done in Gr. A Ds – anterior to equatorIn lesion – 2.5mm in diameter and 1mm thickness in

sensory retinaIf 3.5mm in diameter and 2mm thickness, more than

one treatment is necessary.Contraindication – vitreous seeding and Tumour greater

than 5mm

Radioactive Plaque (Brachytherapy)

•Primary brachytherapy – is the treatment in Group B• Iodine 125 Isotope is used•Other radioactive plaques are – Cobalt 60, Ruthenium 106, Iridium 192 and Palladium 103

Chemotherapy

1)Primary Neoadjuvant chemotherapy2)Adjuvant chemotherapy3)Thermo chemotherapy

New Drugs used are – Carboplatin VP-16 (Etoposide) VM-26 teniposide Cyclosporin A Older Drugs used Cyclophoshamide – (Cytoxan) Vincristin and Adriamycin – do not penetrate

into eye

Group C and D – have been treated by initially by Chemoreduction (Neoadjuvant therapy) followed by focal therapy

Day Chemotherapeutic agent 0 C E V 1 E 2 E 7 V 14 V

i. Carboplastin 560 mg/m2/close or 18.7mg/kg

IV over 1 hr in 100 ml of NSii.Etoposide 150m/m2/dose or 5mg/kg/IV

in 1 hr in 100 ml of NSiii.Vincristine 1.5mg/m2/dose

or .05mg/kg/dose

•Group C - 3 - 4 cycles of CT•Group D - 7 - 9 cycles

Adjuvant chemotherapy – given to 1) Prevent metastasis in patients with risk for - extra ocular spread - tumour extension to optic nerve past

lamina cribrosa - massive choroidal invasionDose – 6-12 cycles of 3 drugsCarboplatin, etoposide and vincristine

Thermochemotherapy

•Done for group C tumour – with 3 drugs•Smaller than 8mm in diameter & 5mm in thickness•Cured with TCT – continuous heat for 20-30mins after 2-3 hrs after chemotherapy infusion

Hyperthermia due

1.Continuous wave diode laser – small & portable. Power 110v

2.Argon laser

External Beam Radiotherapy

EBR – Retinoblastoma – radiosensitive tumourHowever, incidence of second malignant neoplasm (SMN)

following EBR has increased35% of patient 40 yrs after treatmemt – pt died –SMNOnly 6% of not treated – patient died

Complications

•Radiation – Cataract •Radiation retinopathy•Dry eye syndrome & loss of eye lash

Dose – 15 Gy given by Antr approach

30 by – Lateral approachTotal dose 45 Gy – or daily 2Gy or alt. day 4Gy.

Wedge is used to block lens

Lens sparing Electron beam approach

•Done under sedation or short anesthesia•Eye fixed with beam defining collimater•Using low – vacuum contact lens – held in place by magnetic slide.

Enucleation

1.Major treatment since 100 years2.Initial treatment for advanced

I.O.Retinoblastoma3.In massive tumours where no vision is

salvageable4.Diffuse vitreous seeding – Enucleation done

FOLLOW UP

• Every 4 months- 3-4yrs• 6 months - 6yrs• Every year • Examine under GA• Unilateral 20% risk• Rpt CT• Secondary tumours in hereditary cases