Diagnosis and Management of Retinobastoma Thanks to Dr. Rupal for the presentation.

1. Retinoblastoma
Dr. Rupal

2. Introduction
 Retinoblastoma is most common intraocular
malignancy in children
 Incidence 1:15000 to 1:18000 livebirth
 Second to uveal melanoma
 No racial or gender predisposition

3. History
 The first description : Peter Pawius of
Amsterdam
 In 1805, William Hey : coined the term fungus
haematodes.
 In 1809,Scottish surgeon James Wardrop:
described metastasis to optic nerve, brain
and different parts of body.
 In 1864, Virchow:named glioma of the retina.In 1864, Virchow:named glioma of the retina.
 In 1891, Flexner of Johns Hopkins : first toIn 1891, Flexner of Johns Hopkins : first to
notice rosettes within the tumor.notice rosettes within the tumor.

4.  In 1897, Wintersteiner : proposed the nameIn 1897, Wintersteiner : proposed the name
neuroepithelioma.neuroepithelioma.
 Veorhoff : coined the term retinoblastomaVeorhoff : coined the term retinoblastoma

5.  It is bilateral in 25% to 35% cases
 Average age at diagnosis 18mth
 Unilateral cases being diagnosed at around
24mth
 Bilateral cases being diagnosed before 12mth

6. Genetics of Rb
 Rb gene is tumor suppressor gene located on
long arm of 13th
chromosome 13q14.
 Produces Rb protein that binds to cellular
protein & suppresses cell growth
 The gene is recessive oncogene at cellular
level
 Primitive retinal cells disappear within first few
yrs of life.So Rb is usually is not seen after 3-
4yrs of age.

7. Hereditary Rb(40% of cases)
 Patients inherits abnormal allele from parents
and 1normal allele which undergoes a
subsequent mutation after conception
 The risk of 2nd
hit is very high hence Rb is
inherited as Autosomal Dominant
 Risk of bilateral Rb is high as all cells have
inherited 1 mutant allele
 Risk of nonocular malignancies is also high
for same reasons
 Early age of presentation -1yr

8. Nonhereditary Rb(60% of cases)
 Both alleles are normal after fertilization but
subsequent mutations inactivate both
alleles.This are somatic mutation in same
retinal cells
 No risk of bilateral Rb. In fact most of them
are unilateral
 No risk of nonocular malignancies

9. Two hit hypothesis
 Proposed by Knudson in 1971
 He stated that for retinoblastoma to
develop,two chromosomal mutations are
needed.
 In hereditary cases the initial hit is a germinal
mutation,inherited and found in all cells
 Therefore hereditary cases are predisposed
to development of nonocular tumors.
 Second hit develops in somatic retinal cells

10.  In unilateral sporadic cases,both hits occurs
during retina development and are somatic
mutations.
 Therefore there is no risk of second
nonocular tumors.

11. Clinical manifestations
 Leukocoria (56.1%)
 Strabismus
 Secondary changes : includes glaucoma, retinal
detachment, and inflammation secondary to tumor
necrosis.
 Pseudouveitis : characteristic of an infiltrating type
of retinoblastoma
 Orbital inflammation mimicking orbital cellulitis
 Proptosis

13. Diagnosis
 Ultrasonography :
useful in distinguishing
retinoblastomas from
non-neoplastic
conditions. It is also
useful in detecting
calcifications.

14. MRI
 beneficial in estimating the degree of

15.  CT scan:
 delineates
extraocular extension
and can detect
associated
pinealoblastoma

16.  On FFA smaller tumors shows minimally
dilated feeding vessels in arterial
phase,blotchy hyperflourescence in venous
phase and late staining
 X-ray studies: identifying intraocular calcium
in patients with opaque media.

17. Histopathology
 Poorly differentiated tumors shows small to
medium sized round cells with large
hyperchromatic nuclei and scanty cytoplasm
with mitotic figures
 Well differenciated tumors show rosettes and
fleurettes.

18. Flexer Wintersteiner rosettes
consist of columnar cells arranged around central
lumen,highly characteristic of retinoblastoma

19. Homer Wright rosettes
consist of cells arranged around central neuromuscular tangle

20. Fleurettes are eosinophilic structures composed of tumor
cells with pear shaped eosinophilic processes through
fenestrating membrane

21. areas of necrosis and calcifications

22. Endophytic growth
Tumor breaks through the internal limiting membrane and has an
ophthalmic appearance of a white-to-cream mass showing either no
surface vessels or small irregular tumor vessels.

23. Exophytic growth
Exophytic growth occurs in the subretinal space.
This growth pattern often is associated with subretinal fluid
accumulation and retinal detachment.

24. Diffuse infiltrating growth
This is a rare subtype comprising 1.5% of all retinoblastoma.
It is characterized by a relatively flat infiltration of the retina by tumor
cells but without a discrete tumor mass.
It grows slowly compared with typical retinoblastoma.

25. Differential Diagnosis
 Congenital cataract
 Coats disease
 PHPV
 ROP
 Retinal detachment
 Coloboma
 Retinal dysplasia
 Norries disease
 FEVR
 Toxocariasis

27. International Classification Of Intraocular
Retinoblastoma

34. Management of Retinoblastoma
 Primary goal is to save life
 Salvage of organ and function
 Needs team approach including an ocular
oncologist,pediatric oncologist,radiation
oncologist and physicist,genetic and
ophthalmic oncopathologist.
 Management strategy depends on the stage
of disease.

35.  Management of Rb is highly individualised
 Based on following considerations:
1. age at presentation
2. Laterality
3. Tumor location
4. Tumor staging
5. Visual prognosis
6. Systemic condition
7. Family and societal perception
8. Cost effectiveness of treatment

36. Methods to Manage Intraocular Rb
1. Focal—
 Cryotherapy
 Laser
photocoagulation
 Transpupillary
thermotherapy
 Transcleral
thermotherapy
 Plaque
brachytherapy
2. Local—
 External beam
radiotherapy
 Enucleation
3. Systemic—
 Chemotherapy

37. Cryotherapy
 Performed for small and
peripheral tumors
measuring upto 4mmin
basal diameter and
2mm in thickness
 Triple freeze thaw
cryotherapy applied at
4-6wk interval until
complete tumor
regression
 It produces scar larger
than tumor

38.  Complications:
 Transient serous retinal detachment
 Retinal tear
 Rhegmatogenous retinal detachment
 Cryotherapy administered 2-3hrs prior to
chemotherapy increase the drug delivery across
the blood retinal barrier and thus has synergistic
effect.

39. Laser Photocoagulation
 Used for small posterior tumors 4mm in basal
diameter and 2mm in thickness
 Delimits the tumor and coagulate the blood
supply to tumor by surrounding it with two
rows of overlapping laser burns.
 It is contraindicated while patient is on active
chemoreduction protocol.

40. Complications:
 Transient serous retinal detachment
 Retinal vascular occlusion
 Retinal hole
 Retinal traction
 Preretinal fibrosis
Less often employed now with advent of
thermotherapy

41. Thermotherapy
 Mechanism: focused heat generated by
infrared radiation is applied to tissues at
subphotocoagulation levels to induce tumor
necrosis
 Goal is to achieve slow and sustained
temperature range from 40-60degC within
tumor,thus sparing damage to retinal blood
vessels

42.  Performed for small
tumors-4mm in basal
diam and 2mm
thickness
 Complete tumor
regression achieved in
85% tumors using 3-4
sessions

43.  TTT done using infrared radiation from a
semiconductor diode laser delivered with
1300micron large spot indirect
ophthalmoscope delivery system
 Can be applied transpupillary through
operating microscope or by transcleral route
with diopexy probe
 Tumor is heated until it turns subtle gray

44.  Complications:
Focal iris atrophy
Focal paraxial lens opacity
Retinal traction and serous detachment
 Major application :as an adjunct to
chemoreduction
 This synergistic combination is termed
chemothermotherapy.

45. Plaque Brachytherapy
 Involves placing
radioactive implant on
sclera corrosponding to
base of tumor to
transclerally irradiate
tumor
 Ruthenium 106 and
Iodine125 commonly
used

46. Contd
Advantages:
 Focal delivery of radiation and minimal
damage to normal tissue
 Minimal periorbital tissue damage
 Absence of cosmetic abnormality because of
retarded bone growth
 Reduced risk of second malignant neoplasm
 Shorter duration of treatment

47. Contd.
 Indication: tumors less than 16mm in basl diam and
less than 8mm thickness
 It could be primary or secondary modality of
treatment
 Currently performed only in cases where
chemotherapy is contraindicated
 Most usefull in eyes that fail to respond to
chemoreduction and external beam radiotherapy or
for tumor recurrences
 Complications: radiation papillopathy and retinopathy

48. Contd.
 Plaque brachytherapy requires precise tumor
localisation and measurement of its basal
dimensions
 Thickness is measured on USG
 Dose to tomor apex ranges from 4000-
5000cGy
 Plaque is sutured to sclera after confirming
tumor centration and left for 36-72hrs
 Results in 90% tumor control

49. External beam radiotherapy
Indication:
 In eyes where primary chemotherapy and local
therapy has failed
 When chemotherapy is contraindicated
Problems with EBT:
 Stunting of orbital growth
 Dry eye
 Cataract
 Radiation retinopathy
 Optic neuropathy

50. Contd
 EBT can induce second
malignant neoplasm
esp in patients with
hereditary form of Rb
 The risk of second
malignant neoplasm is
greater in children
under 12 mth of age.

51. Enucleation
 Most common method for managing advanced Rb
Treatment of choice for:
 Advanced intraocular Rb with NVI
 Secondary glaucoma
 Anterior chamber tumor invasion
 Tumor occupying >75% vitreous volume
 Necrotic tumor with secondary orbital inflammation
 Tumors associated with hyphema or vitreous
hemorrhage

52. Special Considerations for Enucleation
in Rb
 Minimal manipulation
 Avoid perforation of eye
 Harvest long (>15mm)optic
nerve stump
 Inspect the enucleated eye
for macroscopic
extraocular extension and
optic nerve involvement
 Harvest fresh tissue for
genetic studies
 Avoid biointegrated
implant if postoperative
radiotherapy is necessary

53. Chemotherapy
 Chemoreduction, defined as the process of
reduction in tumor volume with chemotherapy
 Chemotherapy alone is not curative and must
be associated with intensive local therapy
 This can minimize the need for enucleation or
EBT without significant systemic toxicity

54. Commonly used drugs are
 Vincristine
 Etoposide
 Carboplatin

55.  Chemoreduction is most usefull for tumors
without associated subretinal fluid or vitreous
seeding

56.  Vincristine (Vincasar, OncovinPFS)
 Mechanism: Cycle specific and phase
specific, which blocks mitosis in metaphase.
Blocks ability of tubulin to polymerize to form
microtubules, which leads to rapid cytotoxic
effects and cell destruction.
 Pediatric Dose: For retinoblastoma: 1.5
mg/m2 (0.05 mg/kg for children younger than
or = 36 mo and maximum dose, or = 2 mg)
Intravenous administration q3wk for 9 cycles
 Contraindications: Documented
hypersensitivity to vinca alkaloids; pregnancy

57.  Carboplatin (Paraplatin)
 Mechanism: Inhibits both DNA and RNA
synthesis. Binds to protein and other
compounds containing SH group.
 Pediatric Dose: For retinoblastoma: 560
mg/m2 (18.6 mg/kg for children, or = 36 mo) IV
q3wk for 9 cycles
 Contraindications: Documented
hypersensitivity; preexisting severe renal
impairment and myelosuppression; severe
allergy to platinum components

58.  Etoposide (Toposar, VePesid)
 Mechanism: Blocks cells in the late S-G2 phase of
the cell cycle.
 Pediatric Dose: For retinoblastoma: 150 mg/m2 (5
mg/kg for children younger than or = 36 mo) IV
q3wk for 9 cycles
 Contraindications: Documented hypersensitivity;
myelosuppression; liver impairment; IT
administration may cause death

59. Contd
 Favourable signs to chemotherapy:
1.Considerable shrinkage after 2 cycle
2.Reduce vascularization
3.Calcification : cottage cheese appearance
4.Clearing of vitreous seeds
5.Resolution of RD

60. Contd
 Adverse effects :
1.Myelosuppression
2.Febrile episodes
3.Neurotoxicity
4.Nonspecific gastrointestinal toxicity

61. Periocular chemotherapy
 Carboplatin delivered deep posterior
subtenon has been demonstrated to be
efficacious in management of advanced
intraocular retinoblastoma with vitreous seed
 It can penetrate sclera & achieve effective
concentration in vitreous
 This modality is under trial
 It achieves 70% eye salvage in patients with
RB with diffuse vitreous seeds

62. Follow up schedule
 Chemoreduction therapy: every 3 weeks with
each cycle of chemotherapy
 Focal therapy: every 4-8 weeks until complete
tumor regression
 Following tumor regression : 3 mnthly for 1st
yr
, 6mthly for 3yrs or until child is 6yrs age &
yrly there after

63. Histopathologic high risk factors predictive
of metastasis
1.Anterior chamber seeding
2.Iris infiltration
3.Ciliary body infiltration
4.Massive choroidal infiltration
5.Invasion of optic nerve lamina cribrosa
6.Retrolaminar optic nerve invasion
7.Invasion of optic nerve transection
8.Scleral infiltration
9.Extra scleral extension

64. Orbital Retinoblastoma
Clinical manifestation:
1. Primary
2. Secondary
3. Accidental
4. Overt
5. Microscopic

65. Orbital retinoblastoma
Clinical manifestation:
1.Primary orbital Rb:
 Refers to clinically or radiologically detected
orbital extension of intraocular Rb at initial
clinical presentation with/without proptosis or
fungating mass.

66. 2.Secondary orbital Rb :
 Orbital recurrence following uncomplicated
enucleation for intraocular Rb
 Unexplained displacement , bulge or
extrusion of previously well fitting conformer
or prosthesis is an omnious finding
suggestive of orbital recurrence

67. 3.Accidental orbital Rb:
 Inadvertent perforation , FNAB or intraocular
surgery in eye with unsuspected intraocular
Rb

68. 4.Overt orbital Rb:
 Previously unrecognized extrascleral or optic
nerve extension discovered during
enucleation
 Enlarged & inelastic optic nerve with/without
nodular optic nerve sheath are clinical
indicators of optic nerve extension of Rb that
should be recognized during enucleation

69. 5.Microscopic orbital Rb:
 Orbital extension may not be clinically evident
& may only be miocroscopic
 Detection of full thickness scleral infiltration ,
extra scleral extension & invasion of optic
nerve transection on histopathologic
evaluation are unequivocal features of orbital
Rb

70. Management of orbital Rb
Primary orbital Rb:
 High dose chemotherapy(3-6cycles) followed
by surgery (enucleation , extended
enucleation or exenteration as appropriate) ,
orbital radiotherapy & additional 12 cycle std
dose chemotherapy
Accidental , Overt or Microscopic orbital Rb:
 Orbital EBT (fractionated 45-50 Gy) &12 cycle
of dose chemotherapy

71. Metastatic Rb
 Metastatic disease at the time Rb diagnosis is
very rare
 Common sites for local spread & metastasis
include orbital & regional lymph node
extension, CNS, bone & bone marrow ,
liver,spleen, pleura
 After the diagnosis of metastasis , the period
of survival varies from 6-12 mths

72. Treatment of metastatic disease:
1.Chemotherapy intense:
cyclophophamide 20mg/kg IV,
vincristine 50mg/kg IV
doxorubicin
2.Palliative local radiotherapy
3.Craniospinal radition
4.Intrathecal methotrexate(0.5mg/kg) & intrathecal
diazoquone help to induce remissions

73. Follow up schedule
 Include fundoscopy & IDO under full dilatation
under GA
 FFA in cases with
radio/cryo/photocoagulation is done to detect
vascularity
6 wks after therapy
every 3mnths for 1st
yr
every 4mnths for 2nd
yr
every 6mnth till 6 yrs of age
once a yr upto 20 yrs of age

74. Second cancers / non Rb malignancies
 Incidence:hereditary: 6% over lifetime
 Hereditary Rb with EBT : 1% / yr in field of
radiation
 Avg. age of diagnosis is 13 yrs
Tumors:
 Osteogenic sarcoma-most common
 Pineoloblastoma-2yrs after diagnosis of Rb

75.  Beyond 2 yrs:
1.Bony and soft tissue tumors:Ewings
sarcoma,chondrosarcoma &
rhabdomyosarcoma
2.Skin tumors: malignant melanoma , SCC ,
sebaceous cell CA
3.Neurobalstoma , medulloblastoma , leukemia

76. Prognosis
Overall survival rate is 90%
5 yr mortality rate of Rb cases :
1.Optic nerve involvement :
not involved 8%
upto lamina cribrosa 15%
beyond lamina cribrosa 44%
surgical end of section 65%
2.Choroidal invasion 25%
3.Orbital invasion 91%

77. Newer modalities
1.Thermotherapy:
 entire eye sparing the anterior segment – u
wave strip line applicator
 Inducing focal hyperthermia- using
ultrasonically induced hyperthermia
2.Radiosensitisers :
 SR 2508 & SZR 2555 better absorption with
lesser toxicity. Misionidazole-hypoxic cell
sensitiser but is toxic for clinical use
3.Local chemotherapy:
Serial Aggressive Local Therapy (SALT ):
fluorouracil, methotrexate, cytosine
arabinoside, azoquinone
4.Monoclonal antibodies
5.PDT

78. Thank you