RETINOBLASTOMA

Dr. Pavan Naik

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 1900s.
American Ophthalmology Society first adopted the
term retinoblastoma in 1926.
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%).
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.
Frequency is shown as a function of age at diagnosis in subgroups
of unilateral versus bilateral disease.
INHERITANCE
6070% of retinoblastoma unilateral
3040% 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).
 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.
 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)
 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).
 For retinoblastoma to occur both the allels have to
be deleted
If only one allel is deleted it is called 13q deletion
syndrome
 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
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
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/cdks abolishes inhibition &

causes dissociation of E2F which binds to DNA &
promotes progression through cell cycle.
 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%
CLINICAL MANIFESTATIONS

9. Proptosis of eye
LEUCOCORIA
PATTERNS OF GROWTH
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
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
 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
ROUTES OF SPREAD
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
Typical appearance of intraretinal retinoblastoma. Opaque, yellow-white
macular tumor fed and drained by dilated, tortuous retinal blood vessels.
RETINOMA-spontaneously arrested retinoblastoma
Limited vascularity
Greyish-white
Speckled
Surrounding chorio-retinal atrophy
RPE hypertrophy
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
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
DIFFERENTIAL DIAGNOSIS
Differential Diagnosis of Leukokoria
Coats disease
Persistent hyperplastic primary vitreous
Ocular toxocariasis
Cicatricial retinopathy of prematurity
Familial exudative vitreoretinopathy
Incontinentia pigmenti retinopathy
Norries 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
LEUCOCORIA
TO BE CONTINUED IN NEXT CLASS

STAGING
DAIGNOSIS
TREATMENT
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
choroidalhhe from neoplasms
B-scan ultrasonography of retinoblastoma. Solid,
posterior intraocular mass contains strong particulate
reflections attributable to intralesional calcification.
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
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

Computed tomography of bilateral intraocular retinoblastoma.
Intraocular masses appear bright because of intralesional calcification.
FFA
Not usually performed

Rapid filling of feeder vessel-intraretinal vasculature-

draining of efferent vein
Intralesional capillaries-leak fluoroscein
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
 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.
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[]
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
 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
STAGING
PROGNOSTIC FACTORS
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
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
 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
 C. Group E U/L or B/L
1. Primary enucleation
2. Evaluate histopathology for high risk factors
 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
 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
 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
 G. Hematogenous /CNS metastasis-Stage 4
1. Palliative therapy
2. High dose chemotherapy BM rescue
3. High dose chemotherapy- intrathecal
chemotherapy for CNS metastases
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)
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 34 weeks for six or more cycles.

 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.
 Chemotherapy for
retinoblastoma. (A)
Pretreatment appearance of
macular retinoblastoma. (B)
Same lesion after two cycles
of chemotherapy using
vincristine, etoposide, and
carboplatin.
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.
 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 1015 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..
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
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
Orbital
implants
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 4050 Gy given in multiple
fractions of 150200 cGy over 45 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
 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
 SIDE EFFECTS OF EBRT
Cataract-PSCC (6 months after radiation)

Dry eye

Radiation neuropathy

Neovascular glaucoma

Orbital bone growth arrest

Non retinoblastoma malignancies

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 25 days) to provide a predetermined
radiation dose to the apex of the tumor, and
subsequent surgical removal of the plaque.
 The principal isotopes used in radioactive eye
plaques at present are iodine-125 and ruthenium-
106.
Target dose of 4045 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
 <16mm basal diameter, < 8 mm thickness
Notched plaque to protect optic nerve

To apex-4000-5000cGy

Sutured to sclera, left in situ-36-72hrs

A.PRETREATMENT
MACULAR
RETINOBLASTOMA

B.POST PLAQUE
RT-REGESSED
Ruthenium
plaque
sutured to
sclera
LASER THERAPY

1. PHOTOCOAGULATION
2. TRANS-PUPILLARY THERMOTHERAPY
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
12 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.
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
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

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.
 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
SIDE EFFECTS
Transient RD

Retinal tear
COURSE & OUTCOME
REFERENCES

1. Yanoff Textbook of Ophthalmology 3 rd edition-

887-894
2. Retinoblastoma AIOS series No 25
3. Indian journal of ophthalmology-April 2012
 THANK YOU