Retinoblastoma (Rb)

The first description: was by Peter Pawius of
Amsterdam.
In 1805, William Hey coined the term fungus
haematodes
In 1809, the Scottish surgeon James Wardrop
concluded that: tumor arose from the retina
In 1836, Langenbech, Robin, and Nystin of Paris
confirmed by microscopic studies.
In 1864, Virchow named it a glioma of the retina

In 1891, Flexner of Johns Hopkins was first to notice
rosettes within the tumor
in 1897, Wintersteiner proposed the name
neuroepithelioma
Veorhoff : coin the term retinoblastoma
In 1970, Tso and colleagues established: tumor
arises from photoreceptor precursors

Retinoblastoma is a rare childhood cancer.
third most common cancer overall affecting
children
3% of all cancers in children younger than 15
years of age
National Cancer Institute [NCI], 2007
most common intraocular malignant neoplasm
in children (Castillo and Kaufman, 2003).

BEFORE 50 YRS:-
- 1 in 34,000 live births
RECENTLY
- 11 cases per million children < 5 yrs of age
- affects 1 in every 15,000 to 20,000 live births.
- About 5000 new cases worldwide yrly
- Incidence of heritable retinoblastoma: constant
- striking geographic differences in the incidence of
the nonheritable dz

The increased incidence in the poorer, tropical
and subtropical regions of the world is due to
- Viral etiology : human papilloma virus
- Diet deficient in fruits and vegetables in
pregnant mothers
- Advanced paternal age.

Poor prognosis
Mortality >50%
Delayed detection
Advanced dz
High risk cases

arises from a multipotential precursor cell that
could develop into almost any type of inner or
outer retinal cell

changes in or absence of a gene called RB1.
located on chromosome 13
RB1 produces a tumor suppressor protein
prevents a retinal cell from becoming
cancerous

Only one functioning RB1 gene in a retinal cell
is necessary to prevent the cell from becoming
cancerous.
If both RB1 genes in a retinal cell become non-
functional, then a retinal cell can become
cancerous and retinoblastoma can result

In 1971, Knudson proposed the two hit
hypothesis.
Two chromosomal mutations are needed for
development of retinoblastoma

Autosomal dominant with incomplete penetrance
and variable expressivity

Refers to the frequency that a heritable dz is
manifest in offspring of affected individuals
Inheritance of single inactive allele of rb1 gene-
predisposition to cancer- dominant trait
Second inactivating mutation must occur in at
least one retinoblast for RB to occur(recessive
trait)

in pedigrees, the tumor appears to be
dominant:
 probability that at least one will get the
required mutation to develop a tumor is at least
90%.
Rest 10% are carriers
90%

Refers to the variability of clinical
manifestations in affected individuals
E.g. patients with heritable RB who develop
only unilateral eye dz manifest reduced
expressivity.
Reduced penetrance and expressivity tend to
segregate in same families

very early in life (>90% before 5 yrs)
RB in the adult is not observed except
- when it arises from a related, benign lesion
termed retinoma
- rare persistence of embryonal retinal cell
Non-heritable dz: average 24 months
Heritable dz: presents between newborn to
1 yr

Genetically-related second cancers can
occur in survivors of bilateral or heritable
RB
5% chance in first 10 years of follow-up,
18% during the first 20 years, and
26% within 30 years.5
51% cumulative risk over 50 years
75% of all SMNs occur in radiated areas

osteogenic sarcoma,
spindle cell sarcoma,
chondrosarcoma,
rhabdomyosarcoma
neuroblastoma,
glioma,
leukemia,
sebaceous cell
carcinoma,
squamous cell
carcinoma, and
malignant
melanoma.

Shortcomings:
Anterior tumors were classified in a more
advanced group
Doesn’t take into account RD and SR
seeding
Vitreous seeding places the eye in the last
5b group

In 2003, the ABC classification proposed by
the European Congress of Ophthalmology
was accepted by the xth International RB
symposium
The International classification is based
both on
- the natural history of retinoblastoma
- the likelihood of salvaging the eye when
systemic chemotherapy is used as the
primary treatment

3 mm or smaller in greatest dimension confined
to retina
> 3mm from fovea and > 1.5 mm from disc.

Any tumor size and location with no vitreous or
subretinal seeding

Discrete tumor
SRF, past or present, upto one quadrant of retina
Local SR seeding, past or present, less than 5 mm
from the tumor

Massive or diffuse tumor
SRF upto total RD
Diffuse SR seeding, may include SR plaques or tumor
nodules.
Diffuse or massive viteous seedings, greasy seeds or
avascular tumor masses.

Tumor touching the lens
Neovascular glaucoma
Tumor anterior to anterior vitreous face
involving ciliary body or anterior segment
Diffuse infiltrating RB
Opaque media from hemorrhage
Tumor necrosis with aseptic orbital cellulitis
Phthisis bulbi

Stage 1: intraocular RB
Stage 2: stage of glaucoma
Stage 3: orbital dz
Stage 4: stage of metastasis

1. Leucocoria 56%
2. Strabismus 20%
3. Red painful eye 7%
4. Poor vision 5%
5. Asymptomatic 3%
6. Orbital Cellulitis 3%
7. Unilateral Mydriasis 2%
8. Heterochromia Iridis 1%
9. Hyphema 1%
56%
20%
7%
5%
3%
3%
2%1%3%
I II III IV V VI VII VIII Slice 9

EUA: complete ophthalmic evaluation
including a dilated fundus examination
360 degree scleral depression is mandatory.
visualization of the tumor by an IO is
diagnostic in over 90% of cases.

The intraocular pressure is measured
Corneal diameter measured
anterior segment is examined for
neovascularization, pseudohypopyon, hyphema,
and signs of inflammation using hand held slit
lamp examination
Staging of the tumor is done.
Careful retinal drawing with colored pencils

G/E: to r/o 13 q deletion RB syndrome
low set and posteriorly rotated ears,
simian crease in the palms,
broad thumbs,
hypertelorism,
telecanthus

As good as CT in its ability to detect
calcification
Measures the height of each discrete tumor in
millimeters
rounded or irregular intraocular mass with high
internal reflectivity

To know
Extraocular extension
optic nerve invasion
extent of recurrent dz
Trilateral RB syndrome
Subarachnoid seeding
Involvement of brain

• MRI is not as
specific because of
its lack of
sensitivity in
detecting
calcification
• CT scan
involves
exposing the
child to a low
dose of
radiation

useful in documenting the size and location
of tumors
Helps the family accept the reality of a
tumor.
Comparison images are useful in follow-up
examinations

minimally dilated feeding vessels in the arterial
phase, blotchy hyperfluorescence in the venous
phase and late staining
To confirm a questionable area of recurrent RB
in a previously treated lesion or scar
Differentiates from presumed retinoma

Carried out only if the treating physician
suspects extraocular or metastatic
retinoblastoma
Lumbar puncture for CSF analysis
Bone marrow aspiration and biopsy
(aspiration from more than one site because
bone marrow involvement can be uneven)
typically taken from illiac crest
Bone scan if clear evidence of metastasis.

FNAB:
Limited to exceptional cases in which
- diagnosis cannot be achieved by any other
means
- If pt. demands pathological verification of
diagnosis before consenting for surgery
Specular microscopy:
- helps in differentiating Kps from RB cells

Flexner-Wintersteiner
rosettes-the cells
surround the central
lumen
characterized by a single
row of columnar cells
with eosinophilic
cytoplasm and
peripherally situated
nuclei

Homer Wright
rosette –without
features of retinal
differentiation.
Lumen is filled with
eosinophilic
cytoplasmic processes
Fleurette- represent
photoreceptor diff
Flower like str
They are curvilinear
clusters of cells
composed of rod and
cone segments

Treat the child and not only the eye.
primary goal: save life.
secondary goal: Salvage of the organ (eye)
Tertiary goal: function (vision)

Pediatric ophthalmologist
Pediatric surgeon
Pediatric hematologist
Radiation oncologist
Neurologist
Pediatric nurse specialist
Rehabilitation specialist
Psychologist
Social workers
Geneticist

- focal
 Cryotherapy
 laser photocoagulation,
 transpupillary thermotherapy,
 transcleral thermotherapy,
 plaque brachytherapy,
- Local
 external beam radiotherapy,
 enucleation, and
- systemic
 Chemotherapy

small equatorial and peripheral retinal
tumors
Upto 4 mm in basal diameter and 2 mm in
thickness
Triple freeze thaw cryotherapy is applied at
4-6 week intervals
Cryotherapy produces a scar much larger
than the tumor

small posterior tumors: 4 mm in basal
diameter and 2 mm in thickness.
delimit the tumor and coagulate the blood
supply to the tumor
less often employed now with the advent of
thermotherapy.

Green laser better absorbed by the nonpigmented
RB
Starts concurrently with beginning of 2nd
or 3rd
cycle
of chemoreduction
First burns are placed at the edge of the lesion with
half spot on and half off the tumor
Once outlined entire lesion is covered with burns
Goal: 30% overlap
Three different sessions

focused heat generated by infrared radiation is
applied to tissues at subphotocoagulation levels
to induce tumor necrosis.
Goal: achieve a slow and sustained temperature
range of 40 to 60 degree C within the tumor

The tumor is heated until it turns a subtle gray.
Penetration upto 3.9mm in the tissue
M/A
- Cytolysis
- Mitochondrial damage
- Vascular occlusion
Complete tumor regression can be achieved in over
85% of tumors using 3-4 sessions of thermotherapy

The major application of thermotherapy is as
an adjunct to chemoreduction.
The application of heat amplifies the cytotoxic
effect of platinum analogues.
This synergistic combination with
chemoreduction protocol is termed
chemothermotherapy.

4500 cGy
4-6 weeks( daily doses of 200 cGy or altenate doses of
400 cGY
A wedge is used to block the posterior surface of the
lens
Anterior + lateral portals
Experienced centre

Dry eye
Cilia loss
Retinopathy
Papillopathy
Cataract
Neurocognitive
deficits
Phthisis
Secondary sarcoma
Bony hypoplasia of the
midface

No EBRT: 6%
Prior EBRT : 35%
Hence avoided in bilateral and familial cases

Indications
Primary or secondary treatment
Solitary tumors height < 6mm
Local/over the surface seedings
CI
Diffuse seedings
Dense VH
Infiltration of optic disc/ant. Segment
Functional blindness

Isotopes
Iodine
ruthenium
Success
90% of eyes when used as a primary treatment.
In recurrence after chemoreduction, complete
control of the tumor is achieved in 96% of
cases.

protons cause little damage to tissues they pass
through
able to deliver more radiation to the tumor and
damage nearby normal tissues less.
The machines needed to make protons are
expensive

A type of 3-D radiation therapy
uses a computer to make pictures of the size
and shape of the tumor.
Thin beams of radiation of different intensities
(strengths) are aimed at the tumor from many
angles.
causes less damage to healthy tissue near the
tumor.

uses a rigid head frame attached to the skull to
aim high-dose radiation beams directly at the
tumors
causing less damage to nearby healthy tissue.
also called stereotactic external-beam radiation
and stereotaxic radiation therapy

Chemoreduction: defined as the process of reduction in
the tumor volume with chemotherapy
Goals
- Reduce tumor size
- Allow focal methods
photocoagulation
cryotherapy
plaque brachytherapy
- Avoid enucleation
- Avoid EBRT
.

Gallie and colleagues added cyclosporin A to the
regimen in an effort to competitively inhibit the
multiple drug resistance

Myelosuppression, even AML known with
etoposide (hence few centres have dropped
etoposide from the regimen)
febrile episodes,
Hepatic toxicity
Neurotoxicity (vincristine) and
non-specific gastrointestinal toxicity.

Group A: excellent visual acuity 100% eyes
salvaged
Group B: 95% visual acuity ranged from 6/60 to
6/6 depending upon the location of the tumor.
Group C: 90% of the eyes salvaged
Group D: 47 % without the use of external
beam radiotherapy
Group E: only 2 %salvaged

Carboplatin: retinoblastoma with vitreous
seeds ( group C and D)
penetrate the sclera and achieve effective
concentrations in the vitreous cavity.
2ml containing 20mg of the drug.
Avoid systemic toxicity
This modality is currently under trial.
Long term results awaited
Adr: extensive orbital soft tissue scarring

chemotherapy directly into the ophthalmic
artery.
delivery of high concentrations of
chemotherapy to the eye (and to the cancer)
with far lower concentrations to the patient
than systemic administration
Melphalan with/without carboplatin

require treatment with cryotherapy,
thermotherapy, plaque radiotherapy, external
beam radiotherapy, or enucleation.
24% of patients.
in those who present as infants and with family
history of retinoblastoma.

type description consolidation
0 Completely disappears without RPE changes no
I Entire lesion calcifies
‘Rock salt’ look with RPE changes
Probably yes
II Homogenous semi-translucent, gray ‘fish
flesh’ lesion
yes
III Combination of I and II, most common yes
IV Flat scar with significant RPE changes Yes, three
complete laser
coverages

1st
container
of fixative
2nd
container
of formalin Petri dish

Following enucleation, an orbital implant is
placed to provide
a more natural cosmetic appearance of the
patient's artificial eye
to enable motility of the prosthesis.
growth of the socket

MRI done yrly
If heritable dz diagnosed before 1 yr then MRI done 6
monthly to look for midline PNET

Anterior chamber infiltration
Ciliary body infiltration
Trabecular meshwork infiltration
Massive choroidal infiltration
Retrolaminar optic nerve invasion
Optic nerve invasion upto transection
Scleral infiltration
Extrascleral extension
Orbital invasion

Anterior chamber infiltration
Ciliary body infiltration
Trabecular meshwork infiltration
Massive choroidal infiltration
Retrolaminar optic nerve invasion
Optic nerve invasion upto transection
Scleral infiltration
Extrascleral extension
Orbital invasion
Adjuvant chemo
6 cycles ?
Adjuvant chemo
12 cycles and
radiotherapy

If the chance of salvaging useful vision is not good,
heroic treatment approaches are unwarranted.

Group A: local therapy, photo or cryo.
Group B: three to four cycles of chemotherapy
of 2 or 3 drugs plus local consolidation therapy
Group C: 6 cycles of chemotherapy plus focal
consolidation

Unilateral: if the child and not the eye is taken
into consideration: enucleation
Bilateral RB:
6 cycles of chemotherapy
+
three cycles of local subtenon carboplatin
+
local consolidation therapy.
Local treatment may be delayed until the
chemoreduction aimed at the fellow eye has its
effect
Group D
eye
other
eye

Local chemotherapy
Brachytherapy for local seedings
EBRT for diffuse seeds
Intravitreal chemotherapy
thiopeta, melphalan

Unilateral
Bilateral
optic nerve
invasion:
enucleation
chemotherapy( 6
cycles) f/by
enucleation
enucleation f/by
chemotherapy
for other eye
stage.
CT /MRI
No optic
nerve
invasion

a. Primary Orbital Retinoblastoma
b. Secondary Orbital Retinoblastoma
c. Accidental Orbital Retinoblastoma
d. Overt Orbital Retinoblastoma
e. Microscopic Orbital RB

High dose chemotherapy(neoadjuvant chemo)
Enucleation after >3 cycles
Orbital EBRT
Continued chemo for 12 cycles

develop in fewer than 10% of patients in advanced
countries.
major contributor to retinoblastoma related mortality
in developing nations.

Bones or bone
marrows
Meninges
Central nervous
tissue
Paranasal sinuses
Salivary glands
Lymph node
Subcu tissue
liver
Spleen
Pleura
testes

High dose chemotherapy
Bone marrow transplant
Total body irradiation
Intrathecal chemotherapy
The three year disease-free survival was 67% with this
therapy
if required

Presence was first recognized by Jacobiec et al
in 1977
Recogized as one of the group of primitive
neural ectodermal tumor(PNET)
2-3% of heritable dz
Fever, meningeal irritation, seizures, headache,
papilloedema

MRI 6 monthly for 3 yrs in patients diagnosed
having bilateral RB
Chemo: vincristine, cyclophospamide
Sxcal resection

Genetic counseling is the process of providing
individuals and families with information on the
nature, inheritance, and implications of genetic
disorders to help them make informed medical and
personal decisions

It is also recommended that siblings
continue to undergo periodic retinal
examinations under anesthetic until they
are three years of age.
The retinal examinations can be avoided if
DNA testing indicates that the patient has a
non-inherited form of retinoblastoma or if
the sibling has not inherited the RB1 gene
change/deletion

Apoptosis: way body gets rid of abnormal cells
that might become cancerous or cause other
problems.

In combination with topotecan, the
topoisomerase I inhibitor (also induces p53)
exert a synergistic response
Tried successfully in mouse and testtubes
Local delivery of this two-drug targeted
treatment was even more effective.

Rational: prevent the growth of tumors by
blocking the formation of new blood
vessels that feed the tumors
bevacizumab induced a 75% reduction in
the growth of the retinoblastomas
without producing significant systemic
toxicity (animal study)
Lee SY, Kim DK, Cho JH, Koh JY, Yoon
YH

technique for correcting defective genes
responsible for disease development
normal" gene is inserted into the genome to replace
an "abnormal,"
A carrier molecule called a vector is used

5% in 1896, 81% in 1967
95% in developed countries
Only 50% worldwide
Success story
From 95% mortality to 95% survival
Attributed to
Early diagnosis
Correct diagnosis
Newer treatment modalities

Metastasis
Pineoloblastoma
Second cancers

Local surgical techniques including laser
photocaogulation or cryotherapy applied directly to
the residual tumor mass following tumor volume
reduction by primary systemic chemotherapy

Tumor confined to retina
Mutations (perhaps loss of suppressor gene
PNET)
Cells grow without extracellular matrix
dependence
Enough cells divisions and mutations occur
to acquire task of cancer cell

No mutational hotspots
10-15% large deletions
5% chromosomal aberrations
80% small mutations in exons and spice sites
Promoter mutations very rare
Epigenetic changes in tumor

 vitamin D receptors in retinoblastoma
 The mechanism of action : increased p53-related
gene expression resulting in increased apoptosis.
Conclusion : 16,23-D 3 and 1a-OH-D2 are effective
in tumor reduction in two mouse models of RB
with low toxicity
Albert D.M.; Nickells R.W.; Gamm D.M.; Zimbric
M.L.; Schlamp C.L.; Lindstrom M.J.; Audo I.
Source: Ophthalmic Genetics, Volume 23, Number 3,
September 2002 , pp. 137-156(20)

- Time period examined: 5,10 yrs
- Survival from RB alone or from both RB and
second primary neoplasms
- If EBR had been used in the treatment
- Whether or not there was a delay in
receiving medical attention
- Multiple episodes of recurrent disease is a
bad prognostic sign
More cell divisions; achieve enabling
mutations that allow clone of cells to
survive outside the eye.

 Age at diagnosis
 Delay in diagnosis
 Massive tumor
 Neovascular
glaucoma
 Orbital extension
Adjuvant chemo doesn’t
help
Aggressive management
may improve the
prognosis

Indications:
Unilateral: group D and group E
Bilateral: group E
In case the disease is symmetrical or almost so, then it
is reasonable to delay enucleation until response to
primary chemotherapy is evaluated in both eyes.

Retinoblastoma (Rb)

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