Retinoblastoma

1. Retinoblastoma
PRESENTER : DR. GOWTHAM MANIMARAN
MODERATOR : DR. VIKAS CHOUDHARY

2. • Retinoblastoma is most common intraocular malignancy in children.
• Retinoblastoma is the tenth most common pediatric cancer.
• Retinoblastoma was the first tumour to draw attention to the genetic aetiology of cancer
• The incidence of retinoblastoma is higher (6 to 10 cases per million children) in Africa,
India, and children of Native American descent in North America.
• In Developing countries, an increased incidence of retinoblastoma is associated with poverty
and low levels of maternal education, that suggests environmental factors in its etiology
INTRODUCTION

3. •RB represents a prototypical model demonstrating genetic
etiology of cancer.
•It is caused by mutation of the RB gene, a TSG on long arm of
chromosome 13 (13q14.1-q14.2).
•Normal individual inherits two copies of this gene one from each
parent.
ALFRED KNUDSON’S TWO HIT HYPOTHESIS (1971)
Two separate loss of function mutations are required to
inactivate both the homologous loci of the RB gene for
malignant phenotype to be expressed
Genetics

4. Two mutations are required for the
development of retinoblastoma.
 Sporadic retinoblastoma
• Child starts with two wild type
alleles (RB+/RB+).
• Both alleles must mutate to
produce the disease (RB/RB).
• Probability of both mutations
occurring in the same cell is low;
only one tumor forms (e.g., one
eye).
 Hereditary retinoblastoma
 Child starts with heterozygous alleles
(RB/RB+).
 Only one mutation is required to
produce disease (RB/RB).
 Mutations resulting in loss of
heterozygosity (LOH) are more
probable in rapidly dividing cells, and
multiple tumors occur (e.g., both eyes)

5. Hereditary disease
 6% of cases
 Multiple tumors in one or both
eyes.
 Closer to macula
 Child at risk for developing
second tumors
 Diagnosed by age 1 (9 months avg.)
Non-Hereditary disease
 94% of cases
 Single tumor affecting only one eye
 Diagnosed nearer age 2

6. • Leukocoria
• Most common initial sign
• Retinoblastoma remains intraocular and curable for 3–6 months after the
first sign of leucocoria
• Other signs
• Proptosis
• Swelling
• Strabismus – cross eyed/wall eyed squint
• Hypopyon
• Poor visual tracking
Clinical Presentation n
strabismus

7. TUMOR
MIXED DIFFUSE INFILTRATINGENDOPHYTIC EXOPHYTIC
•Most common
growth pattern
Pattern Of Growth
White eye reflex.
Endophytic lesion Exophytic lesion
Proptosis.
•No mass, only signs
of endophthalmitis.
•Diagnosis delayed
& most difficult.
•UL & sporadic

8. • Rapidly progressive tumor.
• Untreated fills the eye & completely destroys the globe within 6 months i.e local
extension is the rule.
• Metastasis (BM, bone, LNs and liver) is rare at presentation.
• Complete tumor regression may occur by unknown mechanism (occlusion of central
retinal artery, severe inflammatory reaction and massive necrosis leading to pthisis
bulbi).
Natural History
ROUTES OF
SPREAD
Direct local
Tumor infiltration
Choroid invasion
Scleral invasion
Orbital soft tissue,
bone & brain
invasion
Subarachnoid
Space Of
optic nerve
CSF dissemination
To brain & spine
Anterior spread to
Conjunctiva,
Eyelids &
Extra ocular tissue
Lymphatic
dissemination
Hematogenous
dissemination
From orbital, bone or
lymphatic invasion

9. • History and physical examination including examination under
anesthesia with scleral compression to evaluate the entire
retinal surface
• Imaging studies: ultrasonography, MRI of the brain and orbits, retinal
diagram, fundus photography
• Laboratory tests: complete blood count (CBC) and serum chemistry
Optional workup (Metastatc workup)
• Bone scan (if abnormal chemistries or bone pain)
• Bone marrow biopsy (if abnormal CBC)
• LP/CSF cytology (if MRI demonstrates CNS disease, or if
signs/symptoms of CNS disease are present)
Work-Up

10. OPHTHALMOSCOPIC EUA:
• Indirect ophthalmoscopy with pupillary dilation & general anesthesia.
• Number, size, location (anterior or posterior), laterality, disc diameter, subretinal
fluid or seeds noted and degree of exophthalmos measured.
• Detailed mapping done with appropriate diagrams & description (relation with
ora serrata, optic disc & macula).
• Creamy pink or snow white mass projecting into the vitreous.
• Poorly developed stroma gives way to tumor bits forming vitreal seeds, RD, vitreal
opacification & h’ge make diagnosis difficult.
Diagnostic evalution

11. Tissue biopsy confirmation not necessary: typical clinical & radiological
findings are enough.
Performance of biopsy: may result in EO seeding & misdiagnosed as uveitis.
FNAC with 30 G needle avoids vascularized conjunctiva of the limbus & the
orbit, sclera & pars plana preventing possible spread of cells through the needle
tract.
Needle tract: peripheral cornea, AC, iris, ciliary body & tumor. Overall
accuracy 95%
Indicated only in selected patients:
• diagnosis is ambiguous or
• obvious EO extension.
Role Of FNAC

12. • Calcification +++
• Necrosis ++
• Multifocality.
• Composed of uniform small round or
polygonal mitotically active cells.
• Viable tumor cells surround blood vessels
& form pseudorosettes.
• Cells are arranged in three characteristic
types:
• Flexner-Wintersteiner rosette: characteristic of
RB.
• Homer-Wright rosette.
• Fleurette
• Ultrastructurally, retinoblastoma cells
demonstrate photoreceptor differentiation
Histopathology

13. • Demonstrates a mass more echogenic than the vitreous on B mode & highly
reflective intrinsic echoes of fine calcifications on A mode.
• RD may also be seen in exophytic tumors.
• Accuracy: 80% (limited by vitreal opacities & RD).
• Limited evaluation of medial & lateral extension, extraocular disease.
• Colour doppler displays normal & tumor vasculature & differentiates
subretinal or choroidal haemorrhage from neoplasms
Ocular USG

14. • 90% show calcification
• Dense homogenous
• Extension to
choroid,vitreous & sclera
not reliable.
• Detects intracranial
disease
• Hyperintense to vitreous on T1 &
markedly hypointense on T2
• Delineation of ON, IO & EO spread
• Differentitates between tumor, RD &
subretinal fluid.
CT/MRI

15. Historically, the likelihood of tumor
response to external-beam
radiation therapy (EBRT), and
thereby the avoidance of
enucleation has been categorized
by the Reese-Ellsworth
Classification.
Limitation:
Less utility for modern approaches
that utilize
chemoreduction and local
therapies
Staging:Reese-Ellsworth Classification.

16. The new system is based
on the extent of tumor
seeding within the
vitreous cavity and
subretinal space and
seems to be a better
predictor of treatment
success
International classification of
retinoblastoma

17. staging

18. • Optic nerve invasion in the most important poor prognostic factor.
• Massive invasion of choroid, CB: increases possibility of hematogenous spread
(60% risk of mets) & extension to extrascleral tissues (6 years DFS 90% in IO
disease versus 10% for EO disease).
• Gross extraorbital extension has >90% risk of metastasis.
• Poorly differentiated tumor.
• Anterior chamber invasion, mortality 20 to 80%.
• Large tumor with vitreous seeding.
• Rubeosis iridis. Glaucoma.
• Bilateral tumors behave poorly as mortality results from second cancers &
trilateral RB.
• Trilateral RB has almost 100% fatality.-<Association of bilateral
retinoblastoma with a typically asynchronous brain tumor>
Prognostic factors

19. EXTENT OF INVASION OF
ON
MORTALITY RATE SURVIVAL (5yr)
Superficial 10% Similar to
uninvolved ON
90%Upto Lamina cribrosa 29%
Posterior to Lamina
cribrosa
42% 60%
Positive transected margin 80% 20%
Stump of ON
>5mm
better better

20. Complex issue.
• Multidisciplinary approach: Ocular oncologist, pediatric
oncologist, radiation oncologist, radiologist and child
psychologist.
•Treatment is tailored to each individual.
Goals of treatment:
• Save life.
• Preserve vision or salvage eye (i.e. avoid enucleation).
• Minimize any complications or side effects of therapy.
Choice of therapy:
• Risk of metastatic disease.
• Systemic status.
• Laterality of disease/size/location of tumor.
• Visual prognosis.
• Risk of second cancers.
Management Of Retinoblastoma

21. Treatment options
 Surgery:
• Enucleaion
• Exentration
 Focal Therapy
• Cryotherapy
• Laser PhotoCoagulation
• Thermotherapy
 Radiotherpy
• EBRT
• Brachytherapy
- Scleral Plaque Thearpy
 Chemotherapy
• Chemoreduction
• Adjuvant chemotherpay
• Periocular Chemotherapy
• Intra-arterial Chemotherapy
• Intra-vitreal chemotherapy
• Chemotherapy In Locally Advanced Disease
• HDCT & ASCT

22. Treatment: Surgery
Primary enucleation
• Enucleation is indicated in unilateral RB, where the eye is blind.
• In bilateral RB when both eyes are blind, a bilateral enucleation is done.
• If one eye is blind, a unilateral enucleation is done.
• Tumor touching the posterior surface of lens
• Raised intraocular pressures (glaucoma)
• Presence of hyphaema/ iris nodules/Vitreous hemorrhage /Phthisis bulbi/Staphyloma/Vitreous seeding
Secondary (post chemotherapy) enucleation
• Failed conservative treatment
• After neoadjuvant chemotherapy for extraocular orbital retinoblastoma
Indications for exenteration
• Extensive local tumor breaching the globe (exenteration in this situation generally is followed by
postoperative radiotherapy and chemotherapy)
• Recurrence of tumor in the socket after enucleation.
Paediatric radiation oncology –Edward C.Halperin

23. Enucleation
PROCEDURE
• Involves removal of the eye
leaving behind lids and
extraocular muscles but removing
the longest possible
segment (10 to 15mm) of optic nerve in
continuity with the globe.
• Care should be taken to avoid
perforation of the globe to prevent
seeding.
• Scleral perforation at the site of muscle
insertions.
• Traction sutures in the muscles.
• ON snares or clamps should be avoided
to prevent crush artefact which may be
misinterpreted as invasion by tumor.

25. Abramson DH, Ellsworth RM, Rozakis GW (1982) Cryotherapy for retinoblasto-ma. Arch Ophthalmol 100:1253–1256
Shields CL, Shields JA, Kiratli H et al (1995) Treatment of retinoblastoma with indi-rect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus
32:317–322
Source: Abramson DH, Schefler AC (2004) Transpupillary thermotherapy as initial
treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology 111:984–991
Treatment: Focal Therapy
Focal treatment is used for
small tumors (<3-6 mm),
classically in patients with
bilateral disease and in
combination with chemotherapy.

26. • When RB is multifocal or close to the macula or optic nerve with
preservation of vision, it has been found that cryotherapy,
photocoagulation, or plaque therapy is not adequate and that
enucleation is too drastic.
1. Extra-scleral spread
2. Cut-margin of Optic Nerve positive for tumor
3. Multifocal retinoblastoma with diffuse vitreous seeds that
fail to respond to chemotherapy
4. Microscopic residual disease after 12 cycles of chemo
5. Stage III retinoblastoma with regional lymphnodes
6. Palliative intent –at site of mets
Radiotherapy: EBRT
Indications:
Paediatric radiation oncology –Edward C.Halperin

27. Hernandez, IJROBP, 1996
a)Group I & II lesions
45Gy / 25# / 5wks (@1.8Gy / fr.) – Daily treatment
45Gy / 18# / 6wks (@2.5Gy / fr.) – Alternate day treatment
b)Group III, IV, & V lesions
50.4Gy / 28# / 6wks (@1.8Gy / fr.) – Daily treatment
50.4Gy / 20# / 7wks (@2.5Gy / fr.) – Alternate day treatment
c) Post operative
Microscopic residual disease
45Gy / 25# / 5wks (@1.8Gy / fr.) – Daily treatment
45Gy / 18# / 6wks (@2.5Gy / fr.) – Alternate day treatment
Gross residual disease
50.4Gy / 28# / 6wks (@1.8Gy / fr.) – Daily treatment
50.4Gy / 20# / 7wks (@2.5Gy / fr.) – Alternate day treatment
d) Children <1year of age, radiation dose should be reduced: Microscopic disease (post op
radiotherapy) 39.6Gy/22#/4.5wks
Gross disease (definitive radiotherapy) 45Gy/25#/ 5wks
Total dose:

28. • Retinoblastoma has been historically treated
with lateral beams to encompass the affected
retina(s), and spare the lens anteriorly, if
possible
Radiation Therapy Techniques
A single, lateral D-shaped beam.
A 4X4 cm beam ,with the anterior margin at the outer
canthus
The beam is angled posteriorly by 5° to avoid exit through
the contralateral lens.

29. CAUTION to minimize the dose to critical structures such as fellow eye, chiasm,
pituitary gland, brainstem, posterior-most upper teeth, and upper cervical spine.
The entire retina should be treated, including 5 to 8 mm of proximal optic
nerve.
The CTV should take account of likely patterns of spread: for example for
tumours invading behind the eye in the orbital cavity, the whole orbit should
be included in the CTV.
A 3mm isotropic margin is added to produce a PTV.
EBRT Techniques
SUPERIOR & INFERIOR OBLIQUE PORTALS ANTERO-LATERAL PORTALS

30. In cases where there is disease more extensive such as vitreous seeding,
it is necessary to treat a larger volume.
The prescription dose is quite conformal at the expense of low doses
delivered to a large, uninvolved area.
IMRT

31. Proton therapy
The dosimetric advantage of the
Bragg-Peak, which eliminates exit
dose,results in less low dose to
normal, uninvolved tissue.
The reduction in peripheral dose as
compared with the IMRT plan is highly
desirable in patients of this young
age, many of whom carry a germline
mutation, predisposing them to the
development of secondary cancers.
Lee et al; Int J Radiat Oncol Biol Phys 63:362–372

32. INDICATIONs:
Brachytherapy for RB
• Plaques are used for solitary 2- to 16-mm basal diameter unilateral lesions located more
than 3 mm from the optic disc or fovea, generally less than 10 mm thick,
• For two lesions that are small enough or close enough to be covered by one plaque,
• For local failure after other therapies
• Plaques can be used if there is a small amount of vitreous seeding over the tumor apex

33. Plaque Energy Half life Penetration
Co60 1.33-1.7MV 5.2 years
I125 27-25Kev 60 days upto 10mm
Ir192 295-612Kev 74 days
Ru106 3.5Mev (β) 368 days upto 6mm
Scleral Plaque Therapy
• 1929: Foster, Moore and Scott used Ra seeds
• 1948: Henry Stallard pioneered and refined the
technique, initial Ra applicator was replaced
by cobalt 60 plaque
• 1970-80’s: other radio-isotopes used e.g. I125,
Ir192, Ru106
Curved applicator to fit the eye with suture holes for
fixing.
Left in place for 3 to 7 days to deliver 40 Gy to
tumor apex and 100 to 200 Gy to tumor base.
Disadvantage: No external shielding resulting in
high radiation dose to orbital bones and the
surgeon

34. Planning: includes
• tumor size and
• location of tumor Direct visualisation (RetCam),
ocular ultrasonography, and sometimes MRI.
Target volume: Tumor base area as
projected through the sclera with a 1- to 2-mm
margin;
Tumor height is a direct measurement from the
imaging data.
The plan provides proper positioning based on the
plaque’s center and suture eyelets and the
distance from the
limbus.
Episcleral Plaque therapy

35. Brachytherapy
125I or 106Ru is used for episcleral plaque therapy. The size of the plaque is
chosen to allow a 2-mm margin on any side of the tumor. The plaque is
sutured into place under general anesthesia and left in place for
approximately 72 hours, depending on the activity of the seeds used
Dose: 30-35 Gy
to tumor apex

36. Treatment induced complications

37. GOALS OF CHEMOTHERAPY:
Reduction of tumor size→ RD dealt with focal therapy is the
standard of care in early stage disease.
1. Reduce the use of EBRT – (second malignancies and orbitofacial
growth anomalies )
2. Reduce the need of enucleation in early stage.
3. Reduce the risk of local and systemic relapse in advanced stage.
4. Improve survival in metastatic disease.
Chemotherapy

38. Indication
Chemoreduction for large intraocular tumors [2-6 cycles before consolidative therapy (can be
extended upto12 cycles)]
• Group B-D retinoblastoma
Chemoprophylaxis (6 cycles of chemotherapy)
Presence of 1 or more of the following features on HPE of the enucleated eye
• Invasion of anterior chamber, iris or ciliary body Massive choroidalinvasion
• Invasion of the sclera
• Post laminar optic nerve invasion
Adjuvant chemotherapy for microscopic residual disease (12 cycles of chemotherapy)
Presence of any 1 / both of the following features on HPE of the enucleated eye
• Extrascleral invasion
• Invasion of th optic nerve reaching the cut end
Neoadjuvant chemotherapy (2-3 cycles for tumor shrinkage) Stage
III Retinoblastoma
• Extraocular extension into orbit on imaging seen as Orbital mass or/& Optic nervethickening
• Extraocular extension on clinical examination as Anteriorly fungating mass
Treatment: Chemotherapy

39. Treatment:Chemotherapy

40. WHY??
• Recurrence of vitreous & subretinal seeds after
systemic chemotherapy
•Due to limited penetration of drugs in these avascular spaces
ADVANTAGE
• Higher effective dose of drug
• Less systemic side effect
DRUG USED- Carboplatin in Aqueous vehicle
S/E- Serious adverse events such as ocular motility changes,
orbital fat necrosis, severe pseudopreseptal celllitis, ischemic
necross with atropy of optic nerve
Periocular Chemotherapy

41. AIM:
Reduce tumor size f/b enuclation, local radiotherapy & adjuvant
chemotherapy
DRUGS: VEC X 12 cycles
RESULT:
Overall survival reported in ExtraOcular RB is 50-70%.
Indian Data show 50% survival for f/u of 18 months.
Chemotherapy for Locally Advanced
Disease

42. Secondary Cancer
Tucker MA, Tarone RE et al (2005) Risk of new cancers after radiotherapy
in long-term survivors of retinoblastoma: an extended follow-up. J Clin
Oncol 23:2272-2279

43. •RECURRENCE OCCURS USUALLY WITH IN 3 YR.
•BUT FOLLOW UP DONE FOR INDEFINITE PERIOD FOR
DIAGNOSIS OF SECOND MALIGNANCY AND TUMOR CONTROL
OPTHALMOSCOPIC
EXAMINATION :
• First year: every 2-3 months .
• Second year: every 3-4 months.
• 3-5 years: every 6 months.
• > 5 years : every one year..
FOLLOW UP

44. The main issues for consideration when selecting treatment options for a child with
retinoblastoma are as follows :
• Is the disease unilateral or bilateral?
• Does the affected eye have potential for useful vision?
• Is the tumor confined to the globe or does it extend to the optic nerve?
• Are there orbital / lymph-nodal / bony / central nervous system or hematogenous
metastasis present?
MANAGEMENT

45. Approach to IntraOcular RB

46. WHY??
• Autosomal Dominant disease with high penetration
The risk of retinoblastoma arising in the offspring of survivors of bilateral disease is 40-45%.
In patients with unilateral disease, the risk of retinoblastoma in offspring is 2.5%.
In siblings of bilaterally affected children whose parents are also affected the risk of
retinoblastoma is 45%; if the sibling is unilaterally affected the risk is 30%.
Without a family history the risk is 2% for siblings of bilateral cases and 1% for siblings of
unilateral cases.
Genetic Counselling

47. Genetic Counselling
• Parents having a child with RB (at the time of enucleation or during treatment) &
patients with family history of RB should undergo genetic counselling (blood
sample only).
• Recommendation: examination at birth & 4 monthly thereafter until 4 years of
age.
• Tumor tissue & blood required in sporadic cases while only blood sample
sufficient in inherited cases.
• Molecular tests:
• Direct analysis of the constitutional mutation of RB1 gene performed on constitutional DNA.
• Indirect analysis of the allele carrying the mutation.
• Tumor cell LOH evaluation.
• Patients should be informed about the risk of transmission and of second
primary malignant tumor development (20% at 10 years , 50% at 20 years &
90% at 30 years).

48. Thank you!