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.
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
Unilateral (70%) or bilateral (30%).
Sporadic (94%) or familial (6%).
Non hereditary (50-60%) or hereditary (40-
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
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.
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
Sporadic form of retinoblastoma are affected
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.
Loss or inactivation of both normal alleles of the
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
germinal (i.e., can be inherited by the offspring of an
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
For retinoblastoma to occur both the allels have to be
If only one allel is deleted it is called 13q deletion
In germinal mutaion , which is inherited ,
First hit occurs before fertilisation & affects all types
2nd hit occurs in somatic retinal cells leads to RB.
2nd ry tumours like osteosarcoma are seen in familial
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
RB1 protein: cell cycle regulator, checkpoint between G1
Key factor in RB protien functioning is the
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.
Clinical presentation depends on the stage of the
Early likely to be missed- unless IDO is performed
Translucent white fluffy retinal mass
Strabismus- if tumor involves macula/reduced visual
Moderately advanced-leucocoria reflection of light by
white mass in the fundus
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
Advanced- proptosis secondary to optic nerve/ orbital
Orbital extension-scleral emissary veins
Malignant neuroepithelial cells (retinoblasts)- arise within the immature
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
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
-columnar cells around a
-also seen in
-rosettes around a central
Tumor cells with pear
processes projecting through
Differential Diagnosis of Leukokoria
Persistent hyperplastic primary vitreous
Cicatricial retinopathy of prematurity
Familial exudative vitreoretinopathy
Incontinentia pigmenti retinopathy
Differential Diagnosis of Vitreous Seeds
Pars planitis (intermediate uveitis)
Microbial endophthalmitis or retinitis
Differential Diagnosis of Discrete Retinal Tumors
Astrocytoma of retina
Retinal capillary hemangioma
TO BE CONTINUED IN NEXT CLASS
>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
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
B-scan ultrasonography of retinoblastoma. Solid,
posterior intraocular mass contains strong particulate
reflections attributable to intralesional calcification.
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
Bright on CT scan
Infiltrating Retinoblastoma-tumor multicentricity , extensive
seeding into vitreous
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.
Not usually performed
Rapid filling of feeder vessel-intraretinal vasculature-
draining of efferent vein
Intralesional capillaries-leak fluoroscein
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
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
Syndrome of multiple congenital anomalies
attributed to a major deletion (13q deletion
syndrome by karyotype analysis.
BASELINE SYSTEMIC EVALUATION IN
Complete pediatric history and physical
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[∗]
INTERNATIONAL CLASSIFICATION (SHIELDS)
Group A Small tumor
Retinoblastoma <3mm in size in basal
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
c2 –vitreous seeds <3mm
c3-both subretinal and vitreous seeds
Group D Diffuse seeds
D2-vitreous seeds >3mm
Group E Extensive Retinoblastoma
occupying>50% of the globe
Invasion of postlaminar optic nerve/
Primary goal-save life
Salvage of the organ and function-secondary and tertiary
Individualised –depends on
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
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
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
G. Hematogenous /CNS metastasis-Stage 4
1. Palliative therapy
2. High dose chemotherapy –BM rescue
3. High dose chemotherapy- intrathecal
chemotherapy for CNS metastases
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
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
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
Residual or recurrent intravitreal and subretinal seeds
following chemotherapy and local treatments usually
require external beam radiation therapy if the eye is to be
Pretreatment appearance of
macular retinoblastoma. (B)
Same lesion after two cycles of
chemotherapy using vincristine,
etoposide, and carboplatin.
Enucleation remains an important therapeutic option for this
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. 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..
SPECIAL CONSIDERATIONS FOR
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
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
EXTERNAL BEAM RADIOTHERAPY
Most commonly employed regional eye-preserving
therapy for this disease was external beam radiation
Using a linear accelerator in a hospital radiation therapy
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
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
SIDE EFFECTS OF EBRT
Cataract-PSCC (6 months after radiation)
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
Plaque radiation therapy -surgical implantation of a
radioactive device (eye plaque) of appropriate size
and strength on the sclera overlying the intraocular
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.
The principal isotopes used in radioactive eye
plaques at present are iodine-125 and ruthenium-
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
<16mm basal diameter, < 8 mm thickness
Notched plaque to protect optic nerve
Sutured to sclera, left in situ-36-72hrs
In photocoagulation, an argon green laser-
instantaneous pronounced whitening of the target
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.
Transient serous RD
Retinal vascular occlusion
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
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
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
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