Retinoblastoma

1. RETINOBLASTOMA
DR.KIRAN KUMAR BR

2. Clinical Anatomy
 The eye is composed of three
layers.
 Outer fibrous layer formed by
the sclera posteriorly and the
cornea anteriorly.
 Inner layer , sensory retina with
vision concentrated at the fovea
which is lateral to the optic
nerve and directly posterior to
the lens.
 In between these vascular layer –
the uvea or choroid –which
supplies the retina. The iris is
the outer continuation of the
vascular layer
 Lens sits just behind iris,
suspended from the ciliary body.
 No lymphatic drainage

3. Retinoblastoma
 Mid 18th century: 1st clinical report of RB was recognized
 1920-“ Vernoff” coined the term retinoblastoma
 2.5-4% of paediatric malignancies
 Most common intraocular malignancy of childhood
 2nd most common primary intraocular malignancy in any age group
 Tumor is of neuroepithelial origin & arises from unidentified
progenitor cell in nucleated layers of one or both eyes
 Accounts for 1:17,000-34,000 live births worldwide

4. Epidemiology
 Slight male preponderance 1.15:1.0
 More than 90% of cases occur before age of 5 year
 Most common among blacks & Africans
 Age: average age in hereditary cases: 12-14 months, sporadic cases 24-30
months
 Unilateral: 65-80%
 Bilateral: 20-35%
Aetiology: unknown

6. Genetics
 Deletion of long arm of chromosome 13, 13q14, which is a tumor
suppressor gene termed as RB gene.
 ‘Alfred Knudson’ hypothesis: 2 types
Hereditary Non-hereditary
Familial Sporadic
Germline mutations 2 hits
Bilateral, multifocal Unilateral, unifocal
Young age older age

7. First Hit
First Hit
First Hit
Second Hit

8. 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

9. Clinical features
 Family history: 10%
 Leukocoria (white pupillary reflex): 50% ,
commonest
 Strabismus [esotropia]: 20%
 Ocular inflammation: due to necrosis of tumor
or tumor cells may enter AC resembling
hyphema [pseudohypopyon]
 Secondary glaucoma: angle-closure
 Loss of vision
 Proptosis: extra ocular invasion
 Trilateral retinoblastoma; bil RB+
pineoblastoma
 Distant metastases

12. Routes of spread
 Local spread; anteriorly- seeding of vitreous & aqueous; posteriorly, sub
retinal space and choroids
 May spread through optic nerve
 Along the central retinal vessels: tumor cells pass through the lamina
cribrosa and enter subarachnoid space
 Distant metastases: CNS, skull, bones, lymph nodes, spinal cord, bone
marrow
 Orbital involvement

13. Staging

14. Reese-Ellsworth Classification

15. International Classification of Retinoblastoma
Group Features
A Small tumor: ≤3 mm
B Large tumor: >3 mm
Macular: ≤3 mm to foveola
Juxtapapillary: ≤1.5 mm to disc
Subretinal fluid: ≤3 mm from the margin
C Focal seeds
Subretinal seeds: ≤3 mm
Vitreous seeds: ≤3 mm
Both subretinal and vitreous seeds: ≤3 mm
D Diffused seeds
Subretinal seeds: >3 mm
Vitreous seeds: >3 mm
Both subretinal and vitreous seeds: >3 mm
E Extensive retinoblastoma occupying more than 50% or
neovascular glaucoma
or opaque media from hemorrhage in anterior chamber, vitreous or subretinal space
Invasion of postlaminar optic nerve, choroid (> 2mm), sclera, orbit, anterior chamber

16. AJCC Tumour Staging System for RB
T1/p1 <25% of retina
T2/pT2 >25 to 50% of retina
T3/Pt3 >50% of retina and/or intraocular beyond retina
T3a/pT3a >50% of retina and/or cells in vitreous
T3b Optic disk
pT3b Optic nerve up to lamina cribrosa
T3c Anterior chamber and/or uvea
pT3c Anterior chamber and/or uvea and/or intrascleral
T4/pT4 Extraocular
T4a Optic nerve
pT4a Beyond lamina cribrosa, not at resection line
T4b Other extraocular
pT4b Other extraocular and/or at resection line
N1/pN1 Regional
MI Distant metastases

17. St. Jude’s Tumor Staging System
Stage I: Tumor (unifocal or multifocal) confined to retina
a. Occupying one quadrant or less
b. Occupying two quadrants or less
c. Occupying more than 50% of retinal surface
Stage II: Tumor (unifocal or multifocal) confined to globe
a. With vitreous seeding
b. Extending to optic nerve head
c. Extending to choroid
d. Extending to choroid and optic nerve head
e. Extending to emissaries
Stage III: Extraocular extension of tumor
a. Extending beyond cut end of optic nerve (including subarachnoid extension)
b. Extending through sclera into orbital contents
c. Extending to choroid and beyond cut end of optic nerve (including subarachnoid extension)
d. Extending through sclera into orbital contents and beyond cut end of optic nerve (including subarachnoid extension)
Stage IV: Distant metastases
a. Extending through optic nerve to brain
b. Blood-borne metastases to soft tissue(s) and bone(s)
c. Bone marrow metastases

18. Diagnostic workup
 Diagnosis of retinoblastoma is made without pathologic
confirmation and is based on a clinical examination.
 Clinical history
 Physical examination: EUA
 Direct ophthalmoscopy: white reflex
 Indirect ophthalmoscopy:
 RB seen as projecting into vitreous, creamy white in color, neovascularisation seen on
surface, calcification gives cottage cheese appearance (glistening white)
 RB diagnosed owing to vitreous hemorrhage, RD, severe inflammatory reaction
(A) A fundus photograph of an eye with
retinoblastoma
(B) The corresponding sketch of the disease in
the eye diagram.

19. Ophthalmic USG: Non-invasive, safe, repeatable, and immediately interpretable.
 B-scan USG reveals a 2D cross-sectional view, confirms presence and the
relationship, the size and shape of the tumors. Orbital involvement, optic
nerve invasion can be seen, extrascleral extension, and calcification.
.
B-scan of an eye with retinoblastoma

20. CT scan, dense heterogenous lesion with hyper dense foci corresponding to
calcification.
 for assessing extraocular extension and invasion of the optic nerve.
A computed tomography scan of a
large calcified retinoblastoma in the
right eye.

21.  Instead, as part of an extent-of-disease work-up, MRI is routinely performed.
 Involvement of the optic nerve, extraocular extension, and intracranial midline
neoplasm in trilateral retinoblastoma are best detected.
 Used in differentiating retinoblastoma from simulating lesions.
MRI

22. Other tests
 Anterior chamber para-centesis: to assay LDH. Elevated ratio of aqueous
LDH5/LDH1 iso-enzymes, elevated ratio of aqueous LDH/ serum LDH
 Fluorescein angiography: tumor blush
 CSF cytology
 Bone marrow biopsy &aspiration
 Bone scan
 Lab tests: Hemogram, Blood chemistries, KFT, LFT

23. Flexner-Wintersteiner Rosettes
 Spoke and wheel cell clusters surrounding a distinct
lumen containing small cytoplasmic extentions of
encircling cells

24. Homer Wright Rosettes
 Clusters of cells surrounding a tangle of cytoplasmic
filaments without a lumen
 Also seen in Neuroblastoma

25. Treatment of Retinoblastoma
 Primary goal
 to ensure the survival of children.
 retention of eyes and vision.
 Avoidance of side effects- second malignancies, facial bony
deformities, or other physical changes that can affect functional
well-being.
 Treatment approaches are guided by the presence of
intraocular or extraocular disease.
 5 yr. DFS > 90% for intraocular disease pts., but < 10% for
extra-ocular disease.

26. Treatment Modalities
Surgery
• enucleation, exenteration
Local therapy
• cryotherapy, photocoagulation, laser
hyperthermia, radioactive plaque
applications
Radiotherapy
• EBRT, radioactive plaque, Particle
treatment
Chemotherapy
• Systemic Chemotherapy, intra-arterial

27. Surgery

28. Enucleation
 Procedure: removal of globe after severing the rectus muscles, optic nerve is cut
(10-20mm) near its exit from the socket
 Indications:
 Unilateral RB with blind eye
 Bilateral RB with both eyes blind- bilateral enucleation
 Uni/bilateral RB with glaucoma (rubeosis iridis) with visual loss
 Local recurrence after conservative measures fail
 bilateral retinoblastoma in which the previously mentioned conditions exist in only one
eye
 a tumor present in the anterior chamber
 retinoblastoma unresponsive to other forms of local therapy
 cases with permanent vision loss in which intraocular tumor is suspected.

29. Exenteration
 Procedure: removal of globe, extra ocular muscles, lids , nerves and orbital fat
 Indications:
 Extensive local tumor breaching the globe
 Recurrence of tumor in socket after enucleation

30. Local therapies
 Used for small tumors < 3 – 6 mm
 Usually in patients with bi-lateral disease and
 In combination with Chemo- Radiation.

31. Cryotherapy
Procedure: tumor is localized (by indirect ophthalmoscope), indented trans-
sclerally with nitrous oxide cryoprobe, freeze is applied (-80°c),
Indications:
 Small tumor anterior to equator (4-7 mm in size)
 Small recurrence or tumor persisting after radiotherapy
 In conjunction with chemotherapy (may increase the intravitreal penetration
of carboplatin)
Side effects:
 Can induce acute retinal edema
 Accumulation of sub retinal fluid → retinal detachment

32. Photocoagulation
Procedure: obliteration of retinal vessels by creating retinal burn with laser beam
Indications:
 Tumor ≤4.5mm at base and ≤2.5mm thick
 Away from macula or disc
 Small tumor recurrence after prior irradiation
 Contraindication: vitreous seeding
Laser hyperthermia
Procedure: generated by Diode laser (810 nm) on continuous mode
 Single spot 0.8-2 mm placed on center of tumor
 Tumor is heated for 10-30 min per session. Central tumor temperature 460c and
decreases by 20c for each mm outside the temperature spot

33. Radioactive plaque application
 Isotopes used: Co-60, Ir-192, I-125, 106Rh (ß
emitter)
 Co-60: circular, crescentic to fit around optic
nerve
 I-125: seeds glued within a carrier and gold shield,
circular or notched configuration
 Procedure: 1st USG of eye done: for tumor
dimensions: maximum basal diameter, max
height → surgical exploration → applicators are
applied over sclera overlying the tumor → 1.5-2
mm margin on either side of basal diameter →
retention sutures → Rx → Re-exploration for
removal of plaques

34. Iodine 125 plaques
 Indications:
 Solitary lesion 2-16 mm
basal diameter
 Unifocal lesions
 Located greater than 3
mm from optic nerve or
fovea
 Thickness <10 mm
 Two lesions, small or
close enough to be
covered by one plaque
 Local recurrence (small)
following radiotherapy
[EBRT]

35. Cont…
 treatment volume covers the tumor + 2mm margin.
 Dose
 dose to the tumor apex is 40 Gy (while the base receives 100–200 Gy).
 dose rate is 0.7–1.0 Gy/h, and ~2–4 days of treatment are required.
 Advantages: high tumor control rates with preservation of vision
 Procedure time is short.
 High dose of radiation to area of interest.
 Disadvantages: increased dose to orbital bone and to operator
 Complications: vascular necrosis, hemorrhage, cataract formation,
optic neuritis

36. Radiotherapy

37. External beam radiotherapy
 Indications
 Multi-focal retinoblastoma
 RB close to macula or optic nerve
 Large tumor with vitreous seeding
 Positioning
 Proper immobilization is important
 thermoplastic or Perspex shell with the
patient supine and the chin in a neutral
position
 Treatment is done under anesthesia:
Ketamine
 Energy: Co-60 or 4-6 MV photons

38. Technique
Lateral field technique
 Started in 1930’s
 D – shaped lateral field with anterior border
kept at bony orbit
 Disadvantage: tumor recurrence at or near ora
serrata
Modified lateral beam technique
 Two lateral opposed D-shaped fields are used

39. Direct anterior field [Hungerford et al ]
 Whole eye is treated
 Disadvantage:
 Cataract formation
 Dose exits through brain
 Lacrimal gland irradiation-impaired tear production
 Advantages:
 Simple, easy to setup
 Reproducible
 Homogenously irradiates entire retina
Anterior lens sparing technique (ALD) [Abramson et al ]
 Lateral D-shaped field: Day1-Day 4 by photons
 Anterior electron beam field with central circular contact lens as lens shaped shield: on
Day 5

40.  Unilateral disease:
 one lateral field or
 2 oblique portals [superior and inferior]
 Bilateral disease:
 parallel opposed lateral fields
The anterior beam edge is placed at the bony
canthus and the beam is angled 1.5 degrees
posteriorly if the contralateral eye remains in
place.

41. Dose
 Ideal: 40-45 Gy, 1.8-2 Gy per fraction, 5 days a week
 For large tumor /vitreous seeding: 48-50 Gy
 Palliative radiotherapy:
 Extra-ocular involvement: 20-25 Gy
 Metastatic disease: CNS, bones: 5 Gy/1#, 15 Gy/3#
 Unilateral : single lateral field
 With anterior extension: anterior field + lateral field tilted 5-15° posteriorly
 Bilateral disease: parallel opposed lateral fields

42. 3D conformal radiotherapy
technique
 based on 3D CT scan planning
 In unilateral RB, 4 non-coplanar fields are used.
 fields are anterior oblique: superior, inferior, medial, and lateral.
 0.5-cm bolus can be used.
 entire retina should be treated, including 5 to 8 mm of the proximal optic
nerve.
 critical structures such as the opposite eye, optic chiasm, pituitary gland,
brainstem, posteriormost upper teeth, and upper cervical spine.
 the tumor volume is treated to the 98% or 95% line,with the aforementioned
organs and tissues receiving significantly less dose.

43.  bilateral disease, six
noncoplanar fields are used:
 two lateral opposing, and
 two anterior oblique fields
to each eye following the
same criteria described
previously.
3D CT scan reconstruction image showing beam arrangement for unilateral RB : anterior medial and lateral fields
(A), anterior superior and inferior fields (B), sagittal view of composite isodose distribution (C), and axial
transverse view of isodose distribution (D)

44. Side effects of RT
 Cataract formation: lens
 Lacrimal gland: decreased tear film production
 Vascular: retinal vasculitis → hemorrhage, and vitreous opacity
 Bone & soft tissue: temporal bone hypoplasia, molar tooth abnormalities
 Mid-facial hypoplasia: hypotelorism, enophthalmos, atrophy of temporalis
muscle, narrow and deep orbits, depressed nasion.
 Second malignancies: overall incidence: 3-5%
 Most common are osteosarcoma, fibrosarcoma, other spindle cell sarcomas

45. Chemotherapy

46.  “Chemoreduction” (using chemotherapy to reduce the size of tumors)
 area of active clinical and basic science research,
 avoid enucleation and external beam radiation
 Indications
 for patients who have visual potential in eyes containing tumors that are too large to
treat with focal methods.
 In patient with extra-ocular disease
 Subgroup of patient with introcular disease with high risk histologic features.
 Patient with bilateral disease in conjunction with Aggressive local therapy.
 Currently, six cycles of vincristine, carboplatin and etoposide are employed as
the standard starting regimen.

47. Treatment recommendations
Unilateral
intraocular
Laser therapy alone, or chemoreduction×6c → focal therapy.
Focal therapy options include:
EBRT (35–46 Gy) for small tumors located within macula, diffuse
vitreous seeding, or multifocal tumors
Cryotherapy for lesions <4 DD in the anterior Retina
Photocoagulation for posteriorly located tumors <4 DD distinct
from the optic nerve head and macula
Episcleral plaque brachytherapy is used for either focal
unilateral disease or recurrent disease following prior EBRT
Enucleation if the tumor is massive or if the eye is unlikely to have
useful vision after treatment

48. Bilateral
Each eye is assessed individually. The worse eye is no longer
routinely enucleated. If there is potential vision preservation
in both eyes, bilateral chemoreduction ± EBRT
with close follow-up for focal treatment may be used
Extraocular Orbital EBRT + chemo for palliation.
Trilateral
Retinoblastoma
Treat eyes as above. Neurosurgical resection, chemo,
with cranial RT or CSI. MS is only 11 months, but as
high as 24 months if caught early

49. Follow up
 1st 6 months: 4-6 week intervals
 Upto 3 years: at 4-6 month intervals
 Later, yearly
 Family history positive: all family members [other children at birth]
should be examined yearly