Retinoblastoma

1. RETINOBLASTOMA
Dr. Pavan Naik

2. HISTORY
 First mentioned by Petras Pawius in Amsterdam -1597.
 James Wardrop- scottish surgeon first recommended
enucleation for saving lives - 1809.
 Verhoeff -origin from undifferentiated retinal cells,
named retinoblastoma in 1900’s.
 American Ophthalmology Society first adopted the term
retinoblastoma in 1926.

3. INTRODUCTION
 Primary malignant neoplasm of the retina that
arises from immature retinal cells
 It is the most common primary intraocular
malignancy of childhood in all racial groups
 Seventh MC tumor of childhood
 Unifocal/multifocal.
 Unilateral (70%) or bilateral (30%).
 Sporadic (94%) or familial (6%).
 Non hereditary (50-60%) or hereditary (40-
50%).

4. EPIDEMIOLOGY
 Cumulative lifetime incidence-1 in 15000
 Annual incidence –highest in first few months of life
 Yearly incidence decreases steadily
 Extremely low by 6 years of age.
 Rarely diagnosed congenitally or even within the first
3 months of life, except in familial cases.
 Median age at the time of diagnosis is approximately
12 months
 B/l retinoblastoma (12 months )>18m in u/l case
 Retinoblastoma affects boys and girls with equal
frequency and has no known racial predilection.

5. Frequency is shown as a function of age at diagnosis in subgroups of
unilateral versus bilateral disease.

6. INHERITANCE
 60–70% of retinoblastoma – unilateral
 30–40% are bilateral.
 In unilateral cases, only a single tumor is usually
present in the affected eye.
 In bilateral cases, multifocal tumors in both eyes are
the rule. Retinoblastoma is generally a sporadic
condition (i.e., no previously affected family members
exist).

7.  Sporadic form of retinoblastoma are affected
unilaterally.
 A small number -have a prior family history of
retinoblastoma-one of the parents is probably a
survivor of the disease.
 Transmission of the disease in such families follows
genetic rules of autosomal dominant inheritance.

9. GENETICS
 Loss or inactivation of both normal alleles of the
retinoblastoma gene
 DNA sequence localized to a small segment of the
long arm (the q14 region) of chromosome 13
 The timing of the loss or inactivation of the two
normal alleles
 germinal (i.e., can be inherited by the offspring of an
affected person)
 somatic (i.e., cannot be inherited by the offspring of
an affected person)

10.  In germinal retinoblastoma- at least one normal allele
must be lost or inactivated prior to the first mitotic
division of embryogenesis
 Sperm or the egg contains defective DNA from an affected
or carrier parent or develops that defect by means of
spontaneous mutation prior to fertilization.
 In somatic retinoblastoma, both alleles are present and
active beyond the stage of the fertilized egg- but
subsequent mutations occur to delete or inactivate
both alleles in at least one immature retinal cell
(retinoblast).

11. For retinoblastoma to occur both the allels have to be
deleted
 If only one allel is deleted it is called 13q deletion
syndrome

13.  In germinal mutaion , which is inherited ,
 First hit occurs before fertilisation & affects all types
of cell
 2nd hit occurs in somatic retinal cells leads to RB.
 2nd ry tumours like osteosarcoma are seen in familial
cases
 But in sporadic mutation both hits occurs during
development of retina , so it affects only retina , no
2nd ry tumours…

14. Individuals who inherit a mutation in the retinoblastoma gene are
heterozygous for the mutation in all cells of the body. The
“second hit” to the remaining normal copy of the gene occurs in
a developing retinal cell and leads to tumor formation

15. MOLECULAR PATHOGENESIS
 RB1 protein: cell cycle regulator, checkpoint between G1
& S-phase.
 Key factor in RB protien functioning is the
phosphorylation status.
 Normally unphosphorylated and suppresses entry into S-
phase by binding to E2F (transcription apparatus).
 Phosphorylation by cyclin/cdk’s abolishes inhibition &
causes dissociation of E2F which binds to DNA &
promotes progression through cell cycle.

18. CLINICAL MANIFESTATIONS
MANIFESTATION PERCENTAGE
LEUCOCORIA 56%
STRABISMUS 20%
RED PAINFUL EYE 7%
POOR VISION 5%
ASYMPTOMATIC 3%
ORBITAL CELLULITIS 3%
UNILATERAL MYDRIASIS 2%
HETEROCHROMIA IRIDID 1%
HYPHEMA 1%

19. CLINICAL MANIFESTATIONS
9. Proptosis of eye

20. LEUCOCORIA

21. PATTERNS OF GROWTH

23. CLINICAL MANIFESTATIONS
 Clinical presentation depends on the stage of the
disease
 Early likely to be missed- unless IDO is performed
 Translucent white fluffy retinal mass
 Strabismus- if tumor involves macula/reduced visual
acuity
 Moderately advanced-leucocoria reflection of light by
white mass in the fundus

24. THREE MANIFESTATIONS
 Endophytic: grows in to vitreous cavity. Yellow white
mass fills vitreous cavity & vitreous seeds. Retinal
vessels –not seen on the surface
 Exophytic: tumor towards subretinal space. Retinal
detachment, retinal vessels are seen over tumor
 Diffuse infiltrating tumor: diffusely involve retina
placoid thickness of the retina. Older children delay
in diagnosis

25.  Advanced- proptosis secondary to optic nerve/ orbital
extension
 Orbital extension-scleral emissary veins
 Atypical manifestations:
-pseudohypopyon
-spontaneous hyphema
-vitreous hemorrhage
-phthisis bulbli
-preseptal/orbital cellulits

26. ROUTES OF SPREAD

27. PRESENTATION
 White round oval dome shaped retinal masses
 Attract retinal BVs
 Very small tumors - Translucent thickenings
 Larger tumors- non rhegmatogenous RD
 Tumors – extend via RPE- exophytic
- into vitreous - endophytic
-generalised thickening-Infiltrating
Retinoblastoma
 Ocassionally stops progressing-Retinoma
 Severe necrosis-Phthisis

28. Typical appearance of intraretinal retinoblastoma. Opaque, yellow-white macular
tumor fed and drained by dilated, tortuous retinal blood vessels.

29. RETINOMA-spontaneously arrested retinoblastoma
Limited vascularity
Greyish-white
Speckled
Surrounding chorio-retinal atrophy
RPE hypertrophy

30. PATHOLOGY
 Malignant neuroepithelial cells (retinoblasts)- arise within the immature
retina
 The retinoblasts -large basophilic nucleus and scanty cytoplasm.
 Cellular necrosis & intralesional calcification- larger tumors.
 Tissue differentiation occurs,- producing Flexner-Wintersteiner
rosettes or Homer Wright rosettes
 Photoreceptor differentiation of individual retinoblasts (fleurettes) may
also be observed
 Retinoblastoma - tendency to invade the optic nerve and choroid -
extend out of the globe via either the optic nerve or the scleral emissary
canals.
 Retinomas show such tumors to be composed entirely of benign-
appearing neuronal cells with photoreceptor differentiation, most
notably in the form of fleurettes.
 Pseudorosettes-tumor cells around Blood vessels

31. PATHOLOGY Flexner Wintersteiner
rosettes
-columnar cells around a
central lumen
-also seen in
medulloepithelioma
Homer Wright
-rosettes around a central
neuromuscular core
-neuroblastoma,
medulloepithelioma,
medulloblastomas
Fleurettes
Tumor cells with pear
shaped eosinophilic
processes projecting through

32. DIFFERENTIAL DIAGNOSIS
Differential Diagnosis of Leukokoria
Coats’ disease
Persistent hyperplastic primary vitreous
Ocular toxocariasis
Cicatricial retinopathy of prematurity
Familial exudative vitreoretinopathy
Incontinentia pigmenti retinopathy
Norrie’s disease
Differential Diagnosis of Vitreous Seeds
Pars planitis (intermediate uveitis)
Microbial endophthalmitis or retinitis
Leukemic infiltration
Differential Diagnosis of Discrete Retinal Tumors
Astrocytoma of retina
Medulloepithelioma
Retinal capillary hemangioma

33. LEUCOCORIA

34. TO BE CONTINUED IN NEXT CLASS
STAGING
DAIGNOSIS
TREATMENT

39. DIAGNOSIS
 ULTRASONOGRAPHY
 >10-15mm, multiple foci of calcification
 Shadows the sclera & orbital soft tissue
 On reducing the gain-reflection persist
 Demonstrates a mass more echogenic than vitreous on B
scan highly reflective intrinsic echoes of fine
calcifications-Ascan
 RD in exophytic tumors
 Accuracy-80% limited by vitreous opacities & RD
 Limited evaluation of medial and lateral extension
 Colour Doppler: displays normal & tumor vasculature &
differentiates subretinal or choroidalh’he from neoplasms

40. B-scan ultrasonography of retinoblastoma. Solid,
posterior intraocular mass contains strong particulate
reflections attributable to intralesional calcification.

41. INDIRECT OPHTHALMOSCOPY
 Dilated fundus examination under anaesthesia
 IOP and anterior segment-neovascularisation,
pseudohypopyon, hyphema and signs of inflammation
 Bilateral fundus examination-360◦ scleral depression
 Ret Cam: wide angle fundus camera –documenting and
monitoring response

42. CT SCAN
 Bright on CT scan
 Infiltrating Retinoblastoma-tumor multicentricity , extensive
seeding into vitreous
MRI
 Most useful for evaluating sellar/parasellar
 Rule out- ectopic intracranial RB
 Studying optic nerve & soft tissues

43. Computed tomography of bilateral intraocular retinoblastoma.
Intraocular masses appear bright because of intralesional calcification.

45. FFA
 Not usually performed
 Rapid filling of feeder vessel-intraretinal vasculature-
draining of efferent vein
 Intralesional capillaries-leak fluoroscein

46. SYSTEMIC EVALUATON
 Germinal retinoblastoma have a strong tendency to
develop non-retinoblastoma malignancies
 Primary nonretinoblastoma intracranial malignancy -
either a pineoblastoma or an ectopic intracranial
retinoblastoma- most common neoplasm -somnolence,
headache, and other neurological symptoms.
 Central nervous system -solid tumor that involves the
suprasellar or parasellar regions of the brain
 Ophthalmoscopy frequently reveals papilledema-
referred to as trilateral retinobloma, seed the
cerebrospinal fluid and thereby spawn implantation
tumors along the spinal cord. This malignancy is
usually fatal

47. Sarcomas of bone and soft tissues- most
frequent nonretinoblastoma malignancies
Oculo-orbital external beam radiation therapy-
< age of 1 year appears-increase the
likelihood that such tumors will occur in the
field.
Syndrome of multiple congenital anomalies
attributed to a major deletion (13q deletion
syndrome by karyotype analysis.

48. BASELINE SYSTEMIC EVALUATION IN
RETINOBLASTOMA
 Complete pediatric history and physical
examination
 Blood for complete blood count (CBC)
 MRI or CT of brain, especially in bilateral or familial cases
to look for ectopic intracranial retinoblastoma
 Lumbar puncture for cerebrospinal fluid analysis[∗]
 Bone marrow aspiration or biopsy[∗]
 Bone scan[∗]

50. INTERNATIONAL CLASSIFICATION (SHIELDS)
 Group A Small tumor
Retinoblastoma <3mm in size in basal
dimension/thickness
 Group B Larger tumor
Retinoblastoma>3mm basal diameter/ thickness
Macular location<3mm to foveola
Juxtapapillary location <1.5mm to the disc
Clear subretinal fluid<3mm from the margin
 Group C Focal seeds
c1-subretinal seeds<3mm
c2 –vitreous seeds <3mm
c3-both subretinal and vitreous seeds

51.  Group D Diffuse seeds
D1-subretinal seeds>3mm
D2-vitreous seeds >3mm
D3-Both
 Group E Extensive Retinoblastoma
occupying>50% of the globe
neovascular glaucoma
opaque media-hhge-
AC/PC/Subretnal space
Invasion of postlaminar optic nerve/
choroid/sclera/orbit/AC

52. STAGING

54. PROGNOSTIC FACTORS

55. MANAGEMENT
 Primary goal-save life
 Salvage of the organ and function-secondary and tertiary
 Multidisciplinary approach
 Individualised –depends on
1. Age
2. Laterality
3. Location
4. Staging
5. Systemic condition
6. Overall progression
7. Cost effectiveness

56. CURRENT SUGGESTED PROTOCOL
 A Intraocular tumor- international classification group-A-C
U/L or B/L
1. Focal-cryotherapy/transpupillary thermotherapy
tumors<3mm in visually non crucial areas
2. Standard 6 cycle chemoreduction and focal therapy for
larger tumors and in visually crucial areas
3. Defer focal therapy for 6 cycles for tumors in macular
and juxtapapillary areas-transpupillary
thermotherapy/plaque RT in juxtapapillary and macula
4. Focal therapy small residual tumors, plaque RT, EBRT
-> 12 months.large.B/L and enucleation if U/L

57.  B. Intraocular tumor, Group D U/L or B/L
1. High dose chemotherapy/aggressive focal therapy
2. Periocular carboplatin –vitreous seeds
3. Primary enucleation-U/L- esp with no visual
prognosis

58.  C. Group E U/L or B/L
1. Primary enucleation
2. Evaluate histopathology for high risk factors

59.  D. High risk factors on HPE- Stage 2
1. Baseline systemic evaluation for metastasis
2. Standard 6 cycle adjuvant therapy
3. High dose adjuvant chemotherapy + orbital EBRT-
with scleral infiltration, extraocular extension, optic
nerve extension

60.  E. Extraocular tumor-Stage 3A
1. Baseline systemic evaluation for metastases
2. High dose chemotherapy-3-6 cycles followed by
enucleation/extended enucleation, EBRT, high
dose chemo 12 cycles

61.  F. Regional LN metastasis Stage 3B
1. Baseline evaluation for systemic metastasis
2. Neck dissection, high dose chemotherapy for 6
cycles, followed by EBRT and high dose
chemotherapy-12 cycles

62.  G. Hematogenous /CNS metastasis-Stage 4
1. Palliative therapy
2. High dose chemotherapy –BM rescue
3. High dose chemotherapy- intrathecal
chemotherapy for CNS metastases

63. TREATMENT
 TREATMENT OPTIONS FOR INTRAOCULAR
RETINOBLASTOMA
Intravenous chemotherapy
Enucleation
Radiation therapy
• External beam radiation therapy
• Plaque radiotherapy
Laser therapy
• Photocoagulation
• Transpupillary thermotherapy (TTT)
Cryotherapy
Observation (for spontaneously arrested retinoblastoma,
retinoma)

64. CHEMOTHERAPY
 Chemotherapy is currently the primary therapeutic
option -bilateral retinoblastoma.
 Initial treatment - unilateral disease -affected eye is salvageable.
 Most common chemotherapeutic regimen -a combination of
carboplatin, etoposide or a related drug, and vincristine (CEV
regimen). In some centers, cyclosporine is added to this regimen
to reduce the multidrug resistance that occurs in many
retinoblastomas.
 Chemotherapy must be supervised by a pediatric oncologist who
is familiar with the side effects and complications of the drugs
and can monitor the child closely during treatment.
 Cyclic treatment every 3–4 weeks for six or more cycles.
 Most intraocular retinoblastoma lesions (including intravitreal and

65.  Partially regressed tumors -still viable following the
second cycle of chemotherapy / any new tumors during
the course of chemotherapy must be treated by
obliterative local therapies such as cryotherapy, laser
therapy, and episcleral plaque radiation therapy.
 Periocular carboplatin injections are currently being
evaluated as an adjunct to intravenous chemotherapy in
selected cases.
 Residual or recurrent intravitreal and subretinal seeds
following chemotherapy and local treatments usually
require external beam radiation therapy if the eye is to be
salvaged.

66. Chemotherapy for
retinoblastoma. (A)
Pretreatment appearance of
macular retinoblastoma. (B)
Same lesion after two cycles of
chemotherapy using vincristine,
etoposide, and carboplatin.

67. ENUCLEATION
 Enucleation remains an important therapeutic option for this
disease.
 Children who have unilateral advanced intraocular disease.
 Enucleation is sometimes recommended for both eyes in
children who have bilateral far-advanced disease not amenable
to any eye-preserving therapy and for the more severely affected
eye in markedly asymmetrical bilateral cases.
 If enucleation is performed, the ophthalmic surgeon should
attempt to obtain a long section of the optic nerve during surgery.

68.  The principal route of exit of tumor cells from the
eye is along the optic nerve. Prior pathological
studies have shown that enucleation is usually
curative in retinoblastoma if an optic nerve section
longer than 5 mm is obtained with the globe.[15] If
possible, the ophthalmic surgeon should attempt
to obtain an optic
nerve section 10–15 mm long in every case.
 Insertion of an orbital implant at the time of
enucleation appears to be appropriate except
when there is a strong likelihood of residual tumor
in the orbit..

69. SPECIAL CONSIDERATIONS FOR
ENUCLEATION
 A Minimal manipulation
 B Avoid perforation of the eye
 C Harvest long >15 mm optic nerve stump
 D inspect the enucleated eye for macroscopic
extraocular extension & optic nerve involvement
 E Harvest fresh tissue for genetic studies
 F Place a primary implant
 G Avoid biointegrated implant if postoperative
radiotherapy is necessary

70. ORBITAL IMPLANT
 Promotes orbital growth
 Provides better cosmesis
 Enhances prosthesis motility
 Non integrated(PMMA/ silicon)
 Bio integrated(hydroxyapatite/porous polyethylene)
 Avoided if post operative adjuvant RT is necessary
 Implant vascularisation compromised by RT
 Myoconjunctival technique

71. Orbital
implants

72. EXTERNAL BEAM RADIOTHERAPY
 Most commonly employed regional eye-preserving
therapy for this disease was external beam radiation
therapy
 Using a linear accelerator in a hospital radiation therapy
department.
 Standard target doses of radiation to the eye and orbit
are in the range of 40–50 Gy given in multiple fractions
of 150–200 cGy over 4–5 weeks.
 External beam radiation therapy results in highly effective
regression of vascularized retinal tumors.
 Tumor regression have been identified.
 Type I-Calcific avascular mound Type II-prominent
calcification gray-tan fish flesh appearance

73.  One or more tumors which involve optic disc
 Diffuse vitreal/subretinal seeding
 Prior chemo/local therapy has failed
 Vitreous seeds do not respond well-relatively
hypoxic state

74.  SIDE EFFECTS OF EBRT
 Cataract-PSCC (6 months after radiation)
 Dry eye
 Radiation neuropathy
 Neovascular glaucoma
 Orbital bone growth arrest
 Non retinoblastoma malignancies

75. PLAQUE RADIATION THERAPY
 Large but localized in the presence of limited
localized vitreous seeding & does not involve optic
disc/macula
 Plaque radiation therapy -surgical implantation of a
radioactive device (eye plaque) of appropriate size
and strength on the sclera overlying the intraocular
tumor,
 Plaque in place for a sufficient period of time (usually
2–5 days) to provide a predetermined radiation dose
to the apex of the tumor, and subsequent surgical
removal of the plaque.

76.  The principal isotopes used in radioactive eye
plaques at present are iodine-125 and ruthenium-
106.
 Target dose of 40–45 Gy to the tumor apex is
generally employed. As a result of the physical
dose-distribution -,the base of the tumor always
receives a substantially >apex.
 Orbital tissue –layer of metal on outer surface shields
the emission in that direction

77.  <16mm basal diameter, < 8 mm thickness
 Notched plaque to protect optic nerve
 To apex-4000-5000cGy
 Sutured to sclera, left in situ-36-72hrs

78. A.PRETREATMENT
MACULAR
RETINOBLASTOMA
B.POST PLAQUE RT-
REGESSED

79. Ruthenium
plaque
sutured to
sclera

80. LASER THERAPY
1. PHOTOCOAGULATION
2. TRANS-PUPILLARY THERMOTHERAPY

81. PHOTOCOAGULATION
 In photocoagulation, an argon green laser-
instantaneous pronounced whitening of the target
tissues.(4mmx2mm)
 An indirect ophthalmoscope delivery system and
relatively long exposure durations (1 second or
more up to a continuous exposure).
 Ophthalmologist first creates an intense confluent
white chorioretinal coagulation approximately 1–2
mm wide entirely around the retinal tumor.
 Supplementally treats any feeding retinal blood
vessels until they appear to be occluded.
 Treats the tumor directly until it also appears
homogeneously and intensely white.

82. SIDE EFFECTS
 Transient serous RD
 Retinal vascular occlusion
 Retinal hole
 Retinal traction
 Pre retinal fibrosis
 Large xisual field defect major complication
 CI-active chemoreduction-restricts blood supply so
reduces concentration of chemotherapeutic agent

83. TRANS PUPILLARY THERMOTHERAPY
 Infrared laser beam 810nm
 Operating microscope/IDO
 Larger spot size 2-3mm
 Till dull white discolouration is produced
 Overlapping spots till homogenous
 Tumor-replaced by chorioretinal atrophy-end point
 Follow up 2-4 weeks
 Extra macular or extrapapillary tumors

84. CRYOTHERAPY
 Trans-scleral cryotherapy is an obliterative focal
treatment -destroys targeted intraocular tissues by
means of freezing
 Insulated retinal cryoprobe to indent the sclera
overlying the tumor and indirect ophthalmo-scopy to
monitor the position of the indentation in the fundus.
 Once the probe tip is positioned at the site of a
retinal tumor, the ophthalmologist activates the probe
to begin freezing.

85.  The ice ball that forms -encompass the entire tumor (if the
tumor is small) or a portion of the tumor (if the tumor is larger)
and extend into the overlying vitreous.
 The probe is then deactivated, and the ice ball is allowed to
thaw.
 This cycle is repeated once (double freeze-thaw method) or
twice (triple freeze-thaw method) at each site. If the tumor is
larger than can be encompassed entirely by a single freeze,
Repeated every 2-4 weeks
 Cryo-applied 2-3 hours prior to chemo-increases delivery of
drug across BRB

86. SIDE EFFECTS
 Transient RD
 Retinal tear

87. COURSE & OUTCOME

88. REFERENCES
1. Yanoff Textbook of Ophthalmology 3 rd edition-887-
894
2. Retinoblastoma AIOS series No 25
3. Indian journal of ophthalmology-April 2012

89.  THANK YOU