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1. Retinoblastoma
Dr Shylesh B Dabke
Resident, Dept of Ophthalmology, KMC Mangalore

2. Introduction
 1st clinical report of RB : Mid 18th Century.
 “ Vernoff” coined the term retinoblastoma : 1920
 Most common intraocular malignancy of childhood.*
 Untreated children typically die within 2-4years.

3. Epidemiology
 More than 90% of cases occur before age of 5 year.
 3% of paediatric malignancies.
 Accounts for 1:17,000-34,000 live births worldwide.
 Age of presentation : 12months - Bilateral(30-40%)
24months - Unilateral(60-70%)
 Similar incidence in males and females.

4. Genetics
 Retinoblastoma gene, Rb1 – Tumor suppressor gene - long arm of chromosome 13
 Loss or inactivation of both normal alleles of the Rb gene(Knudson two-hit
Hypothesis).
 Retinoblastoma inherited as an autosomal recessive trait(cellular level), however
behaves clinically as if it has an autosomal dominant pattern with 90% penetrance.
 Timing of this loss or inactivation determines whether disease is
- Somatic or Sporadic(60%)
- Germinal or Hereditary(40%)

5. Sporadic Retinoblastoma
 First hit occurs after conception in utero or in early infancy.
 All cells in body are not affected as germ cells are not involved.
 Second somatic mutation results in loss of other normal allele.

6. Hereditary Retinoblastoma
 Child starts with heterozygous alleles.
 Only one mutation is required to produce disease.
 First hit occurs in utero in germ cells before conception
or is inherited from a parent.
 All cells of body affected.

7. Sporadic Vs Hereditary
Sporadic Hereditary
Unilateral, Unifocal Bilateral, Multifocal
Early presentation Late presentation
Low risk of Rb development in relatives High risk or Rb development in relatives
Increased risk of second malignancy
- Osteoscarcoma, pinealoblstoma,
melanoma etc.

8. Genetics
All new
patients
Positive
family
history
7% 93%
bilateral unilateral
Negative
family
history
bilateral
67% 33% 25% 75% Unilateral
Hereditary probabilities & laterality

9. Screening
 Parents and siblings of retinoblastoma patients should be screened.
 Parents may have undetected regressed retinoblastoma and new onset of
disease in siblings may be detected at an early age.
 Siblings at risk of Rb should be screened by ophthalmoscopy soon after
birth and then regularly until the age of 4-5years.
Retinoblastoma
Unilateral
Affected Parents 30%
Unaffected
Parents
Less than 1%
Bilateral
Affected Parents 45%
Unaffected
Parents
5%

10. Clinical presentation
 Leucocoria(60%) : white reflex in pupillary area.
 Strabismus(20%) : Esotropia(11%), Exotropia (9%)
 Painful eye with Secondary Glaucoma(7%) & buphthalmos.
 Pseudohypopyon : Anterior chamber involvement.
 Orbital cellulitis(3%)
 Proptosis and fungating orbital extension
 Unexplained hyphema or onset of phthisis bulbi

11. Signs
E
x
o
 Early tumor presents as a small white or almost translucent intra retinal
lesion.
 Endophytic tumor grows towards vitreous and projects as white mass
from retina.*
 An exophytic tumor grows as sub retinal mass and can present with retinal
detachment.

12. Pattern of tumor spread
 Growth pattern may be endophytic(into the vitreous), with seeding of
tumor cells throughout the eye or exophytic(into sub retinal space)
causing retinal detachment.
 Optic nerve invasion, with spread of tumor along the subarachnoid space
to brain.
 Diffuse infiltration of the retina, without exophytic or endophytic growth.
 Metastatic spread is to regional nodes, bone, lung, brain and bone.
Child with bilateral RB may present with second intra cranial tumor (Trilateral Rb) commonly Pinealoblastoma.

13. Staging
 Reese-Ellsworth staging system
- Predicts chance of visual preservation well but not of survival.
 The International Classification (“ABCDE”) system for Rb is under
modification and is used in recent clinical protocols.
 The AJCC TNM system.

14. Reese-Ellsworth staging system

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
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. Histology
 Tumor is composed of small basophilic cells(retinoblasts) with large
hyperchromatic nuclei and scanty cytoplasm.
 Shows areas of high mitotic activity and areas of necrosis and calcifications.
 Most Retinoblastomas are undifferentiated but varying degree of differentiation
results in formation of rosettes. Characteristically,
- Flexner-Wintersteiner rosettes
- Homer-Wright rosettes
- Fleurettes

18. Investigations
 CBC, urinalysis and liver function tests.*
 Aqueous humor to serum LDH ratio : more then 1.0
Examination under anesthesia :
- Indirect ophthalmoscopy with scleral indentation must be performed on both eye after
full mydriasis.
- General examination of congenital abnormalities of face and hands.
- Tonometry.
- Measurement of corneal diameter.
- Anterior chamber examination with hand held slit lamp.

19. Ultrasound
 Demonstrates a mass more echogenic than the vitreous on B mode.
 Highly reflective intrinsic echoes of fine calcifications on A mode.
 Detect size and extent of tumor.
 Accuracy 80 %.

20. Computed Tomography
 Detect dense heterogenous lesion with hyper dense foci (Calcifications).
 Detect extraocular extension in proptotic eye.
 Detect optic nerve and intracranial extension.

21. Magnetic resonance imaging
 Tumor size.
 Optic nerve involvement.
 Detect presence of associated intracranial lesion - Tri-lateral RB.
 preferred in children less then 1year of age - avoid cancer risk that
increase with CT.

22.  Bone marrow biopsy, cerebrospinal fluid cytology & Bone scan.
Risk factors for metastasis are present such as tumor involving anterior
segment, choroid or optic nerve or extending extrasclerally.
 FNAC from tumor should be avoided - increase risk of vitreous seeding.

23. Differential Diagnosis
PHPV Congenital Cataract Inflammatory cyclitic membrane
Posterior polar toxocara granuloma Coats Disease Advanced retinopathy of prematurity

24. Other DD’s
 Exudative Retinal detachment.
 Vitreoretinal dysplasia.
 Incontinentia pigmenti
 Retinocytoma(Retinoma).
 Retinal Astrocytoma.

25. Treatment
 Primary goal
- Ensure the survival.
- Retention of eyes and vision.
- Avoidance of side effects of therapy.
Treatment approach depends on tumor size, extent, intraocular or
extraocular extension.

26. Treatment Modalities
Surgery
• Enucleation
• Exenteration
Local therapy
• Cryotherapy
• Photocoagulation
• Laser hyperthermia
• Radioactive
plaque applications
Radiotherapy
• EBRT
• Radioactive plaque
Chemotherapy
• Systemic
• Local
• Intra-arterial

27. Treatment of small tumors - <3mm diameter
<2mm thick
 Chemotherapy
- Without other treatment can be attempted for macular tumors.*
 Photocoagulation
- Focal consolidation after chemotherapy.
 Cryotherapy(triple freeze-thaw technique)
- Pre equatorial tumors without deep invasion or vitreous seeding.

28. Treatment of medium size tumors – Upto 12mm wide
6mm thick
 Primary Chemotherapy
- IV Carboplatin, Etoposide &Vincristine.
- Sub Tenons Carboplatin injections.
- Followed by local cryotherapy.
 Brachytherapy(Iodine-125 or Ruthenium-106)

29. Treatment of large tumors
 Chemotherapy
- Shrinks tumor – subsequent local therapy – avoiding enucleation or
EBRT.
- Beneficial for smaller tumors in fellow eye and incase of
Pinealoblastoma.
 Enucleation, Exenteration.

30. Treatment of extraocular extension
 Adjuvant chemotherapy
- 6months course of CEV after enucleation if there is retrolaminar or massive
choroidal spread.
 External Beam Radiotherapy
- Tumor extending to the cut end of Optic nerve at enucleation.
- Extension through sclera.

31. Chemotherapy
 Most retinoblastomas are large at the time of presentation - reduce tumor
volume - enhances the success of local therapies.
 As initial treatment of retinoblastoma - improves the ocular salvage rate.
 Currently, 6 cycles of Vincristine, Carboplatin and Etoposide are employed as the
standard starting regimen.
 Standard dose: (3 weekly, 6 cycles)
Vincristine (0.05 mg/kg for children < 3yrs & maximum dose < 2 mg)
Etoposide (5 mg/kg for children < 3yrs )
Carboplatin (18.6 mg/kg for children < 3yrs)

32. Chemotherapy Statistics
 Numerous studies suggests chemotherapy to be effective in globe salvage
in R-E Group I–IV eyes with success rate 85%.
 chemoreduction is generally considered for group A, B, and C eyes, and is
less effective for more advanced disease.
 Ocular salvage in a series of patients in Group E, at the 2 year follow-up:
Chemoreduction + EBRTx : 91%
Chemoreduction alone : 53%
 Following chemoreduction, tumor respond well to thermotherapy and
rarely require EBRT or enucleation.

33. Local Chemotherapy
 Sub-Tenon’s carboplatin though associated with
a higher failure rate, is currently considered for
possible use as a “boost” with chemoreduction
for groups C, D, and E tumors
 Intra-arterial chemotherapy:
- Catheterization of the ophthalmic artery and
injection of chemotherapy, usually Melphalan
(with or without Topotecan(.

34. Macular Rb showing complete regression with 6
cycles of Chemoreduction alone

35. Juxtapupillary Rb – Partially regressed with 3
cycles Chemoreduction – complete regression with
6 cycles

36. Laser Photocoagulation(Argon/Diode laser/Xenon arc)
 Small post. tumors 4 mm basal diameter & 2 mm in thickness.
 Restrict blood supply to tumor by surrounding it with 2 rows of overlapping laser
burns.
 Most tumors require 2 to 3 sessions to be cured.
 Contraindications:
- Tumor located at or near macula or pupillary area.
- Tumors arising from a vitreous base.
- Patient on active chemoreduction protocol.*
- Presence of vitreous seeding.

37. Thermotherapy
 Focused heat - Infrared Radiation(wavelength 810nm) - applied to tissues
at sub-photocoagulation levels to induce tumor cell apoptosis.
 Achieve slow & sustained temperature ( 40 to 60 degree C) within tumor,
sparing retinal vessels.
 Transpupillary thermotherapy using infrared radiation from semiconductor
diode laser is most commonly used.

38. - 3 Focal Rb treated with Transpupillary
Thermotherapy
- Flat scar with patent vessels coursing through

39. Multifocal Rb following Chemoreduction and
Transpupillary thermotherapy.

40. Cryotherapy
 Equatorial & Peripheral retinal tumors upto 4 mm in diameter & 2 mm in
thickness.
 Under GA, pencil like probe is placed precisely on the sclera directly
behind the intraocular focus of RB.
 Rapid freezing forms intracellular crystals which ruptures tumor cells and
causes vascular occlusion.
 Triple freeze thaw cryotherapy at 4-6 week interval until complete tumor
regression.

41. Plaque Brachytherapy
 Placement of radioactive implant on sclera corresponding to base of
tumor, transsclerally irradiate tumor.
 Tumors < 16mm basal diameter & < 8 mm thickness
 Tumor thickness measured by ultrasonography
 Plaque design depending on basal tumor dimensions, its location &
configuration.
 Plaque sutured to sclera & left for duration of exposure (ranging 36 to 72
hrs)
 90% tumor control

42. - Ruthenium 106 & Iodine 125
- Dose – 4000 – 5000 cGy

43.  Advantages
- Focal delivering of radiation.*
- Absence of cosmetic abnormality due to retarded bone growth(EBRT)
- Shorter duration of treatment
 Disadvantage - Placement of plaques can be technically difficult and
requires a second surgical procedure for removal.
 Complications
- Radiation papillopathy
- Radiation retinopathy

44. External Beam Radiotherapy(EBRT)
 It is currently rarely utilized
 Indications
- Large bilateral tumors.
- Vitreous seeding.
- Thick tumors near the optic nerve or fovea in the eye with visual potential.
- Multiple tumors that are too large for cryotherapy or laser photocoagulation.
- Recurrent or no response from chemoreduction.
 Delivered using Cobalt 60 (gamma rays) or linear accelerator ( X-rays)

45.  Complications
- Second cancers, particularly in patients with hereditary RB.
- Damage to the retina, optic nerve, lacrimal gland, lens and loss of
eyelashes.
- Midface hypoplasia.
- Dry eye
- Cataract
- Radiation retinopathy
- Optic neuropathy
 The risk of tumor recurrence following EBRTx is 7 % within 40 months.

46. - Osteosarcoma of frontal bone in patient who
underwent EBRT for Bilateral Rb at 1yr of age

47. Enucleation
 Indications
1. Rubeosis, vitreous haemorrhage or optic nerve invasion.
2. Chemotherapy fails or normal fellow eye makes aggressive
chemotherapy inappropriate.
3. Diffuse retinoblastomas.
4. Blind painfull eye.
 Enucleation should be performed with minimal manipulation and it is
imperative to obtain long piece of optic nerve(15mm)
 Orbital implant should be as large as possible, implanted at the time of
operation. Tenons and conjunctiva should be sutured separately.

48. Post-enucleation follow-up:
 Child must be monitored closely for orbital relapse in the two years
after surgery. *
 the incidence of orbital recurrence after enucleation is 4.2%.
 The majority of patients (85 %) with orbital recurrence also developed
metastatic disease.

49. 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.

50. Followup
 After radio or chemotherapy tumor regress to a “Cottage-cheese” calcified mass
or a translucent “Fish-flesh” mass or a mixture of both or as a flat atrophic scar.
 If Rb has been treated conservatively EUA should be performed every 2-8weeks
until 3years of age after this time examination without anesthesia is performed
every 6months until 5years of age, then annually until 10years of age.

51. References
 Ophthalmology – Myron Yanoff & Jay Duker
 Clinical Ophthalmolgy – Jack J Kanski
 Clinical Eye Atlas – Daniel Gold & Richard Lewis
 Post Graduate Ophthalmology
 Internet