AIOS, CME SERIES

(No. 25)

Retinoblastoma
They Live and See!
 This CME Material has been supported by the
funds of the AIOS, but the views expressed therein
do not reflect the official opinion of the AIOS.

(As part of the AIOS CME Programme) Authors : Santosh G. Honavar, MD, FACS
Published July 2012 Fairooz PM, MD
Mohd Javed Ali, MD, FRCS
Geeta K Vemuganti, MD
Vijay Anand P Reddy, MD

Reviewer : Dr E Ravindra Mohan

Trinethra Eye Clinic
Chennai 600034
Phone: 91 98404 13336
Published by: email: [email protected]
ALL INDIA OPHTHALMOLOGICAL SOCIETY
For any suggestion, please write to:
Dr. Lalit Verma
(Director, Vitreo-Retina Services, Centre for Sight)
Honorary General Secretary, AIOS
Room No. 111 (OPD Block), 1st Floor
Dr. R.P. Centre, A.I.I.M.S., Ansari Nagar
New Delhi 110029 (India)
Tel : 011-26588327; 011-26593135
Email : [email protected]; [email protected]
Website : www.aios.in
 All India Ophthalmological Society

Office Bearers (2012-13)

President : Dr NSD Raju

President Elect : Dr Anita Panda
Vice President : Dr Quresh B Maskati
Hon General Secretary : Dr Lalit Verma
Joint Secretary : Dr Sambasiva Rao
Hon Treasurer : Dr Harbansh Lal
Joint Treasurer : Dr Ruchi Goel
Editor IJO : Dr S Natarajan
Editor Proceedings : Dr Samar Kumar Basak
Chairman Scientific Committee : Dr D Ramamurthy
Chairman ARC : Dr Ajit Babu Majji
Immediate Past President : Dr AK Grover
 Foreward

R
etinoblastoma is the most common intraocular malignancy of
infancy and childhood. Till a century ago Retinoblastoma was
uniformly a fatal disease. Thanks to advances in surgical techniques
external beam radiation, focal treatment and chemotherapy, the
survival rate and preservation of vision have greatly improved.

AIOS is bringing out this CME publication as a comprehensive

treatise on Retinoblastoma. It gives an excellent overview on the history
of the diseases, its genetic predisposition and epidemiology, clinical
features and classification, and the current management strategy.
Great emphasis has been placed on the enucleation technique for
advanced unilateral retinoblastoma with excellent graphics and photo
documentation. The section on radiotherapy encompasses all modern
concepts of external beam radiation with or without chemo reduction
and all of these has significantly contributed to preservation of vision
and increased survival rate. In fact all specifics relating to retinoblastoma
have been exhaustively covered in this publication. The authors have
done an admirable job by bringing out this outstanding treatise on
Retinoblastoma.

NSD Raju Team AIOS Lalit Verma

President Hon. General Secretary
 All India Ophthalmological Society

Academic Research Committee

Chairman : Dr Ajit Babu Majji
[email protected]
(M) 09391026292

Members

North Zone : Dr Amit Khosla

[email protected]
[email protected]
(M) 09811060501

East Zone : Dr Ashis K Bhattacharya

[email protected]
(M) 09831019779, 09331016045

West Zone : Dr Anant Deshpande

[email protected]
[email protected]
(M) 09850086491

South Zone : Dr Sharat Babu Chilukuri

[email protected]
(M) 09849058355

Central Zone : Dr Gaurav Luthra

[email protected]
[email protected]
(M) 09997978479
 Preface

A
mong intraocular malignancies of infancy and childhood,
retinoblastoma is the most common. Until recently, retiblastoma
outcomes remained uniformly poor unless diagnosed at an
early stage. But with the advent of chemo reduction and external
beam radiotherapy, in addition to focal treatments like direct
photocoagulation, cryotherapy and trans papillary thermo therapy, the
survival rates have improved considerably even at advanced stages.
However, I would like to emphasize that screening of children for white
reflex should be taken up along the lines of a public campaign, and
dilated fundus screening for children should become a standard clinical
practice. The impact of a child going blind is enormous as it corresponds
to the loss of number of man years of productivity.

The Academic and Research committee has brought out a CME

on Retinoblastoma with an intention to increase awareness among
Ophthalmologists. This CME gives an excellent overview of clinical
features, diagnosis and classification of retinoblastoma. It can serve as a
good guide to accurately stage the disease and prognosis. In this CME,
the authors have demonstrated good outcomes in India, comparable
to any series in the world. The outcomes can be even better if the
disease is diagnosed at an early stage. The reviewer has done good job
in pointing out the relevent lacunae, so that the CME series can aim to
be as useful as possible to all Ophthalmologists.

In expect all members of All India Ophthalmological Society go

through this CME series, imbibe the knowledge and help in saving lives
as well as in preventing blindness in children due to retinoblastoma.

Dr. Ajit Babu Majji

Chairman Academic & Research Committee
All India Ophthalmological Society
Senior Consultant,
Smt. Kanuri Santhamma Center for Vitreo Retina Diseases
Kallam Anji Reddy Campus
LV Prasad Marg, Banjara Hill, Hyderabad
 Contents

Introduction 1

Genetics of Retinoblastoma 3

Histopathology of Retinoblastoma 5

Clinical Manifestations of Retinoblastoma 6

Diagnosis of Retinoblastoma 9

Classification of Retinoblastoma 11

Management of Retinoblastoma 18
1. Management of Intraocular Retinoblastoma
2. Management of High Risk Retinoblastoma
3. Orbital Retinoblastoma
4. Metastatic Retinoblastoma

Conclusion 41

Reference 42
 Introduction

R
etinoblastoma is the most common intraocular malignancy in
children, with a reported incidence ranging from 1 in 15,000 to 1
in 18,000 live births.1 It is second only to uveal melanoma in the
frequency of occurrence of malignant intraocular tumors. There is no
racial or gender predisposition in the incidence of retinoblastoma.
Retinoblastoma is bilateral in about 25 to 35% of cases.2 The average
age at diagnosis is 18 months, unilateral cases being diagnosed at
around 24 months and bilateral cases before 12 months.2

Pawius described retinoblastoma as early as in 1597.3 In 1809,

Wardrop referred to the tumor as fungus haematodes and suggested
enucleation as the primary mode of management.3 The discovery of
ophthalmoloscope in 1851 facilitated recognition of specific clinical
features of retinoblastoma. Initially thought to be derived from the glial
cells, it was called a glioma of the retina by Virchow (1864).3 Flexner
(1891) and Wintersteiner (1897) believed it to be a neuroepithelioma
because of the presence of rosettes.3 Later, there was a consensus
that the tumor originated from the retinoblasts and the American
Ophthalmological Society officially accepted the term retinoblastoma
in 1926.4

Retinoblastoma was associated with near certain death just over a

century ago. Early tumor recognition aided by indirect ophthalmoscopy
and refined enucleation techniques contributed to an improved
survival from 5% in 1896 to 81% in 1967.2 Advances in external beam
radiotherapy in the 1960s and 1970s and further progress in planning
and delivery provided an excellent alternative to enucleation and
resulted in substantial eye salvage.2 Focal therapeutic measures such
as cryotherapy, photocoagulation and plaque brachytherapy allowed
targeted treatment of smaller tumors entailing vision salvage.2
Parallel advancements in ophthalmic diagnostics and introduction of
ultrasonography, computed tomography, and magnetic resonance
imaging contributed to improved diagnostic accuracy and early
detection of extraocular retinoblastoma.

Despite all the advances that took place between 1960 and 1990,
the overall management of retinoblastoma stood at cross roads in the

1
 1990s. The outstanding issues related to identification of a child at
risk of developing retinoblastoma by genetic testing, optimization of
vision salvage by minimization of the size of the tumor regression scar,
reduction in the incidence of second malignant neoplasm following
external beam radiotherapy by exploring for alternative therapeutic
modalities, reduction in the incidence of systemic metastasis
following enucleation, and improvement in the prognosis of orbital
retinoblastoma and metastatic retinoblastoma.

The recent advances such as identification of genetic mutations,5,6

replacement of external beam radiotherapy by chemoreduction
as the primary management modality, use of chemoreduction to
minimize the size of regression scar with consequent optimization of
visual potential,7-11 identification of histopathologic high-risk factors
following enucleation12 and provision of adjuvant therapy to reduce
the incidence of systemic metastasis,13 protocol-based management
of retinoblastoma with accidental perforation or intraocular surgery14-16
and aggressive multimodal therapy in the management of orbital
retinoblastoma17,18 have contributed to improved outcome in terms of
better survival, improved eye salvage and potential for optimal visual
recovery.

2
 Genetics of Retinoblastoma

O
ut of the newly diagnosed cases of retinoblastoma only 6% are
familial while 94% are sporadic.2,19 Bilateral retinoblastomas
involve germinal mutations in all cases. Approximately 15% of
unilateral sporadic retinoblastoma is caused by germinal mutations
affecting only one eye while the 85% are sporadic.2

In 1971, Knudson proposed the two hit hypothesis.20 He stated

that for retinoblastoma to develop, two chromosomal mutations
are needed. In hereditary retinoblastoma, the initial hit is a germinal
mutation, which is inherited and is found in all the cells. The second
hit develops in the somatic retinal cells leading to the development
of retinoblastoma. Therefore, hereditary cases are predisposed to the
development of nonocular tumors such as osteosarcoma. In unilateral
sporadic retinoblastoma, both the hits occur during the development
of the retina and are somatic mutations. Therefore, there is no risk of
second nonocular tumors.

Genetic counseling is an important aspect in the management of

retinoblastoma. In patients with a positive family history, 40% of the
siblings would be at risk of developing retinoblastoma and 40% of
the offspring of the affected patient may develop retinoblastoma.
In patients with no family history of retinoblastoma, if the affected
child has unilateral retinoblastoma, 1% of the siblings are at risk and
8% of the offspring may develop retinoblastoma. In cases of bilateral
retinoblastoma with no positive family history, 6% of the siblings and
40% of the offspring have a chance of developing retinoblastoma.2

Apart from empiric genetic counseling as described above,

the current trend is to identify the mutation and compute specific
antenatal risk. We screened twenty-one probands, twelve with bilateral
retinoblastoma and 9 with unilateral retinoblastoma, for mutations in
the RB1 gene using genomic DNA from peripheral blood leukocytes as
well as tumors. Amplification of individual exons and flanking regions
of the RB1 gene were carried out, followed by direct sequencing of the
amplified products. Sequences of affected individuals were compared
with those of controls. Mutations were identified in seven patients, five
with bilateral and two with unilateral retinoblastoma. Analysis of the

3
 peripheral blood of seven patients with unilateral disease also showed
no mutations.5

Subsequently, we carried out mutational screening of the exons

and promoter of the RB1 gene in Indian patients with retinoblastoma
in order to determine the range of mutations giving rise to the disease.
Eight novel mutations were identified, including 4 single base changes,
2 small deletions and 1 duplication. These were g.64365T>G (Tyr325Ter),
g.78131G>A (Trp515Ter), g.150061G>T (Glu587Ter), g.170383C>G
(S834X), g.41924A>C (IVS3-2A>C), g.150064ins4, g.160792del22, and
g.76940del14 (IVS15 del +20-33). All mutations produced nonsense
codons or frameshifts. Detectable mutations in exons were found in
46% of patients tested. Knowledge of the full range of mutations can
aid in the design of screening tests for individuals at risk.6

4
 Histopathology of Retinoblastoma

O
n low magnification, basophilic areas of tumor are seen along
with eosinophilic areas of necrosis and more basophilic areas
of calcification within the tumor. Poorly differentiated tumors
consist of small to medium sized round cells with large hyperchromatic
nuclei and scanty cytoplasm with mitotic figures. Well-differentiated
tumors show the presence of rosettes and fleurettes. These can be
of various types. Flexner-Wintersteiner rosettes consist of columnar
cells arranged around a central lumen. This is highly characteristic of
retinoblastoma and is also seen in medulloepithelioma. Homer Wright
rosettes consist of cells arranged around a central neuromuscular
tangle. This is also found in neuroblastomas, medulloblastomas and
medulloepitheliomas. Pseudorosette refers to the arrangement of tumor
cells around blood vessels. They are not signs of good differentiation.
Fleurettes are eosinophilic structures composed of tumor cells with
pear shaped eosinophilic processes projecting through a fenestrated
membrane. Rosettes and fleurettes indicate that the tumor cells show
photoreceptor differentiation. In addition basophilic deposits, which
are, precipitated DNA (released after tumor necrosis) can be found in
the walls of the lumen of blood vessels.2

5
 Clinical Manifestations of
Retinoblastoma

L
eucocoria is the most common presenting feature of
retinoblastoma, followed by strabismus, painful blind eye and
loss of vision. Table 1 lists the common presenting features of
retinoblastoma.21

Table 1. Common presenting features of retinoblastoma

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%

The clinical presentation of retinoblastoma depends on the stage

of the disease.10 Early lesions are likely to be missed, unless an indirect
ophthalmoscopy is performed. The tumor appears as a translucent
or white fluffy retinal mass (Figure 1). The child may present with
strabismus if the tumor involves the macula, or with reduced visual
acuity.

Moderately advanced lesions usually present with leucocoria due to

the reflection of light by the white mass in the fundus (Figure 2). As the
tumor grows further, three patterns are usually seen:10

l Endophytic, in which the tumor grows into the vitreous cavity

(Figure 3). A yellow white mass progressively fills the entire vitreous
cavity and vitreous seeds occur. The retinal vessels are not seen on
the tumor surface.
l Exophytic, in which the tumor grows towards the subretinal space
(Figure 4). Retinal detachment usually occurs and retinal vessels are
seen over the tumor.

6
 Figure 1 Figure 2

Figure 3 Figure 4

Figure 5 Figure 6

Figure 7 Figure 8
Figure 1. Early manifestation of retinoblastoma with a localized tumor at the posterior
pole
Figure 2. Lecocoria is the most common clinical presentation of retinoblastoma.
Figure 3. Endophytic tumor with vitreous seeds.
Figure 4. Exophytic retinal tumor with exudative retinal detachment.
Figure 5. Diffuse infiltrative retinoblastoma with placoid retinal thickening seen on
gross examination of the enucleated eye in a 7-year-old child.
Figure 6. Retinoblastoma with orbital extension in a 3-year-old child.
Figure 7. A 5-year-old child with retinoblastoma with anterior segment seeding
manifesting with tumor hypopyon.
Figure 8. A 4-year-old with spontaneous hyphema in the left eye. Ultrasonography
confirmed the diagnosis of retinoblastoma.

7
 l Diffuse infiltrating tumor, in which the tumor diffusely involves the
retina causing just a placoid thickness of the retina and not a mass.
This is generally seen in older children and usually there is a delay in
the diagnosis (Figure 5).

Advanced tumors manifest with proptosis secondary to optic nerve

extension or orbital extension (Figure 6) and systemic metastasis.10
Retinoblastoma can spread through the optic nerve with relative ease
especially once the lamina cribrosa is breached. Orbital extension may
present with proptosis and is most likely to occur at the site of the scleral
emissary veins. Systemic metastasis occurs to the brain, skull, distant
bones and the lymph nodes.

Some of the atypical manifestations of retinoblastoma include

pseudohypopyon (Figure 7), spontaneous hyphema (Figure 8), vitreous
hemorrhage (Figure 9), phthisis bulbi (Figure 10) and preseptal or orbital
cellulites (Figure 11).10

Figure 9 Figure 10
Figure 9. Spontaneous vitreous
hemorrhage as the presenting feature of
retinoblastoma in a 4-year-old child
Figure 10. An 18-month-old child with
bilateral retinoblastoma. The right eye has
secondary glaucoma and enlarged cornea
while the left eye is phthisical.
Figure 11. A 3-year-old child with
retinoblastoma presenting with orbital
cellulites

Figure 11

8
 Diagnosis of Retinoblastoma

A
thorough clinical evaluation with careful attention to details,
aided by ultrasonography B-scan helps in the diagnosis.10
Computed tomography and magnetic resonance imaging are
generally reserved for cases with atypical manifestations and diagnostic
dilemma and where extraocular or intracranial tumor extension is
suspected.10

A child with suspected retinoblastoma necessarily needs complete

ophthalmic evaluation including a dilated fundus examination under
anaesthesia.10 The intraocular pressure is measured and the anterior
segment is examined for neovascularization, pseudohypopyon,
hyphema, and signs of inflammation.10 Bilateral fundus examination with
360 degree scleral depression is mandatory. Direct visualization of the
tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma
in over 90% of cases.21 RetCam is a wide-angle fundus camera, useful
in accurately documenting retinoblastoma and monitoring response to
therapy (Figure 12).

Ultrasonography B-scan shows a rounded or irregular intraocular

mass with high internal reflectivity representing typical intralesional
calcification (Figure 13).10 Computed tomography delineates extraocular
extension and can detect an associated pinealoblastoma (Figure
14).10 Magnetic resonance imaging is specifically indicated if optic
nerve invasion or intracranial extension is suspected.10 On fluorescein
angiography, smaller retinoblastoma shows minimally dilated feeding
vessels in the arterial phase, blotchy hyperfluorescence in the venous
phase and late staining (Figure 15).10

9
 Figure 12 Figure 13

Figure 14 Figure 15

Figure 12. RetCam, a wide-angle digital fundus camera and image archival system helps
in documentation and assessment of tumor regression on follow-up
Figure 13. Ultrasonography B-scan showing multifocal retinal tumors
Figure 14. Computed tomography scan shows pinealoblastoma
Figure 15. Fundus fluorescein angiography in retinoblastoma in the early phase shows
blotchy hyperfluorescence

10
 Classification of Retinoblastoma

A
n ideal classification system for retinoblastoma should include two
components: grouping and staging. Grouping is a clinical system
of prognosticating organ salvage while staging prognosticates
survival.

The Reese Ellsworth classification was introduced to prognosticate

patients treated with methods other than enucleation.22 This classification
was devised prior to the widespread use of indirect ophthalmoscopy
and focal measures of management of retinoblastoma and mainly
pertained to eye salvage with external beam radiotherapy. Although
the Essen classification addressed some of the shortcomings of Reese
Ellsworth classification, it is considered too complex. Further, none of
the older systems of classification had been designed to prognosticate
chemoreduction, the current favored method of retinoblastoma
management. The new International Classification of Intraocular
Retinoblastoma is a logical flow of sequential tumor grading that
linearly correlates with the outcome of newer therapeutic modalities.
There are two versions of this classification (Table 2, 3).23,24 The recent
TNM classification by the American Joint Committee on Cancer and the
Union Internationale Contre le Cancer (AJCC/UICC) is comprehensive
and includes both clinical and histopathological aspects (Table 4).

The new International Staging system is the first such for

retinoblastoma and incorporates five distinct stages (Table 5).25 Staging
is based on collective information gathered by the clinical evaluation,
imaging, systemic survey and histopathology.

11
 Table 2. International Classification of Intraocular Retinoblastoma
(Murphree)
Group A: Small intraretinal tumours away from foveola and disc.
• All tumours are 3 mm or smaller in greatest dimension, confined to the
retina
• All tumours are located further than 3 mm from the foveola and 1.5 mm
from the optic disc
Group B: All remaining discrete tumours confined to the retina.
• All other tumours confined to the retina not in Group A.
• Tumour-associated subretinal fluid less than 3 mm from the tumour
with no subretinal seeding.
Group C: Discrete local disease with minimal subretinal or vitreous
seeding.
• Tumour(s) are discrete.
• Subretinal fluid, present or past, without seeding involving up to one-
fourth of the retina.
• Local fine vitreous seeding may be present close to discrete tumour.
• Local subretinal seeding less than 3 mm (2 DD) from the tumour.
Group D: Diffuse disease with significant vitreous or subretinal
seeding.
• Tumour(s) may be massive or diffuse.
• Subretinal fluid present or past without seeding, involving up to total
retinal detachment.
• Diffuse or massive vitreous disease may include “greasy” seeds or
avascular tumour masses.
• Diffuse subretinal seeding may include subretinal plaques or tumour
nodules.
Group E: Presence of any one or more of these poor prognosis features.
• Tumour touching the lens.
• Tumour anterior to anterior vitreous face involving ciliary body or
anterior segment.
• Diffuse infiltrating retinoblastoma.
• Neovascular glaucoma.
• Opaque media from hemorrhage.
• Tumour necrosis with aseptic orbital cellulites.
• Phthisis bulbi.

12
 Table 3. International Classification of Retinoblastoma (Shields)
Group A Small tumor
• Retinoblastoma <3 mm in size in basal dimension/thickness
Group B Larger tumor
• Retinoblastoma >3 mm in basal dimension/thickness
• Macular location (<3 mm to foveola)
• Juxtapapillary location (<1.5 mm to disc)
• Clear subretinal fluid <3 mm from margin
Group C Focal seeds
• C1 Subretinal seeds <3 mm from retinoblastoma
• C2 Vitreous seeds <3 mm from retinoblastoma
• C3 Both subretinal and vitreous seeds <3 mm from
retinoblastoma
Group D Diffuse seeds
• D1 Subretinal seeds >3 mm from retinoblastoma
• D2 Vitreous seeds >3 mm from retinoblastoma
• D3 Both subretinal and vitreous seeds >3 mm from
retinoblastoma
Group E Extensive retinoblastoma
• Occupying >50% globe or
• Neovascular glaucoma
• Opaque media from hemorrhage in anterior chamber,
vitreous, or subretinal space
• Invasion of postlaminar optic nerve, choroid (>2 mm), sclera,
orbit, anterior chamber

13
 Table 4. TNM Classification for Retinoblastoma

The TNM (Tumour, Node, Metastesis) classification is developed, monitored

and enforced by the American Joint Commission on Cancer and the Union
Internationale Control Cancer (AJCC/UICC).

When both eyes are affected, each eye is staged independently. When only
one stage is stated in patient reports for a bilateral child, this refers to the stage
of the worst eye, as an indicator of risk to the child’s life.

Clinical Classification (cTNM)

Primary Tumour (T)
cTX: Primary Tumour cannot be assessed.
cT0: No evidence of primary tumour.
cT1: Tumours no more than 2/3 the volume of the eye, with no viteous or
subretinal seeding:
cT1a: No tumour in either eye is greater than 3mm in largest dimension,
or located closer than 1.5mm to the optic nerve of fovea.
cT1b: At least one tumour is greater than 3mm in largest dimension, or
located closer than 1.5mm to the optic nerve or fovea. No retinal
detachment or subretinal fluid beyond 5mm from the base of the
tumour.
cT1c: At least one tumour is greater than 3mm in largest dimension, or
located closer than 1.5mm to the optic nerve or fovea, with retinal
detachment or subretinal fluid beyond 5mm from the base of the
tumour.
cT2: Tumours no more than 2/3 the volume of the eye with vitreous or subretinal
seeding. Can have retinal detachment:
cT2a: Focal vitreous and/or subretinal seeding of fine aggregates of
tumour is present, but no large clumps or “snowballs” of tumour
cells.
cT2b: Massive vitreous and/or subretinal seeding is present, defined as
diffuse clumps or “snowballs” of tumour cells.
cT3: Severe Intraocular Disease:
cT3a: Tumour fills more than 2/3 of the eye.
cT3b: One or more complications present which may include tumour-
associated neovascular or angle closure glaucoma, tumour extension into
the anterior segment, hyphema, vitreous hemorrhage or orbital cellulitis.
cT4: Extra-ocular disease detected by imaging studies:
cT4a: Invasion of optic nerve.
cT4b: Invasion into the orbit.
cT4c: Intracranial extension not past the chiasm.
cT4d: Intracranial extension past chiasm.

14
Note: The following suffixes may be added to the appropriate T categories:
“m" indicates multiple tumours (eg, T2 [m2]).
"f" indicates cases with a known family history.
"d" indicates diffuse retinal involvement without the formation of discrete
masses.

Regional Lymph Nodes (N)

cNX: Regional lymph nodes cannot be assessed.
cN0: No regional lymph node metastasis.
cN1: Regional lymph node metastasis involvement (preauricular, cervical,
submandibular).
cN2: Distant lymph node involvement.

Distant Metastasis (M)

cMX: Presence of distant metastasis cannot be assessed
cM0: No distant metastasis
cM1: Systemic metastasis:
cM1a: Single lesion to sites other than Central Nervous System.
cM1b: Multiple lesions to sites other than Central Nervous System.
cM1c: Prechiasmatic Central Nervous System lesion(s).
cM1d: Postchiasmatic Central Nervous System lesion(s).
cM1e: Leptomeningeal or Cerebro Spinal Fluid involvement.

Pathologic Classification (pTNM)

Primary Tumour (pT)
pTX: Primary Tumour cannot be assessed.
pT0: No evidence of primary tumour.
pT1: Tumour confined to the eye with no optic nerve or choroidal invasion.
pT2: Tumour with minimal optic nerve and / or choroidal invasion:
pT2a: Tumour superficially invades optic nerve head but does not extend
past lamina cribrosa, or tumour exhibits focal choroidal invasion.
pT2b: Tumour superficially invades optic nerve head but does not extend
past lamina cribrosa and tumour exhibits focal choroidal invasion.
pT3: Tumour with significant optic nerve and / or choroidal invasion:
pT3a: Tumour invades optic nerve past lamina cribrosa but not to surgical
resection line, or tumour exhibits massive choroidal invasion.
pT3b: Tumour invades optic nerve past lamina cribrosa but not to
surgical resection line and exhibits massive choroidal invasion.
pT4: Tumour invades optic nerve to surgical resection line or exhibits extra-
ocular extension elsewhere.
pT4a: Tumour invades optic nerve to resection line, but no extra-ocular
extension identified.
pT4b: Tumour invades optic nerve to resection line, and extra-ocular
extension identified.
15
 Regional Lymph Nodes (pN)
pNX: Regional lymph nodes cannot be assessed.
pN0: No regional lymph node metastasis.
pN1: Regional lymph node involvement (preauricular, cervical).
pN2: Distant lymph node involvement.

Metastasis (pM)
pMX: Presence of metastasis cannot be assessed.
pM0: No distant metastasis.
pM1: Metastasis to sites other than Central Nervous System
pM1a: Single lesion
pM1b: Multiple lesions
pM1c: CNS metastasis
pM1d: Discrete masses without leptomeningeal and/or CSF involvement
pM1e: Leptomeningeal and/or CSF involvement

TNM Descriptors:
For identification of special cases of cTNM or pTNM classifications, the “m”
suffix and “y,”“r,” and “a” prefixes are used. Although they do not affect the
stage grouping, they indicate cases needing separate analysis.
“m” (suffix) indicates the presence of multiple primary tumours in a single site
and is recorded in parentheses: pT(m)NM.
“y” (prefix) indicates those cases in which classification is performed during
or following initial multimodality therapy (ie, neoadjuvant chemotherapy,
radiation therapy, or both chemotherapy and radiation therapy).
The cTNM (clinical) or pTNM (pathological) category is identified by a “y” prefix.
The ycTNM or ypTNM categorizes the extent of tumour actually present at the
time of that examination. The “y” categorization is not an estimate of tumour
prior to multimodality therapy (ie, before initiation of neoadjuvant therapy).
“r” (prefix) indicates a recurrent tumour when staged after a documented
disease-free interval, and is identified by the “r” prefix: rTNM.
“a” (prefix) designates the stage determined at autopsy: aTNM.

Additional Descriptors
Residual Tumour (R)
Tumour remaining in a patient after therapy with curative intent (eg, surgical
resection for cure) is categorized by a system known as R classification, shown
below.
RX: Presence of residual tumour cannot be assessed.
R0: No residual tumour.
R1: Microscopic residual tumour.
R2: Macroscopic residual tumour.

16
For the surgeon, the R classification may be useful to indicate the known or
assumed status of the completeness of a surgical excision. For the pathologist,
the R classification is relevant to the status of the margins of a surgical resection
specimen. That is, tumour involving the resection margin on pathologic
examination may be assumed to correspond to residual tumour in the patient,
and may be classified as macroscopic or microscopic according to the findings
at the specimen margin(s).

Vessel Invasion
Vessel invasion (lymphatic or venous) does not affect the T: category indicating
local extent of tumour, unless specifically included in the definition of a T
category. In all other cases, lymphatic and venous invasion by tumour are
coded separately as follows.
Lymphatic Vessel Invasion (L)
LX: Lymphatic vessel invasion cannot be assessed.
L0: No lymphatic vessel invasion.
L1: Lymphatic vessel invasion.
Venous Invasion (V)
VX: Venous invasion cannot be assessed.
V0: No venous invasion.
V1: Microscopic venous invasion.
V2: Macroscopic venous invasion.

Table 5. International Staging System for Retinoblastoma

Stage 0 No enucleation (one or both eyes may have intraocular disease)
Stage I Enucleation, tumor completely resected
Stage II Enucleation with microscopic residual tumor
Stage III Regional extension
A. Overt orbital disease
B. Preauricular or cervical lymph node extension
Stage IV Metastatic disease
A. Hematogenous metastasis
1. Single lesion
2. Multiple lesions
B. CNS Extension
1. Prechiasmatic lesion
2. CNS mass
3. Leptomeningeal disease

17
 Management of Retinoblastoma

T
he primary goal of management of retinoblastoma is to save life.
Salvage of the organ (eye) and function (vision) are the secondary
and tertiary goals respectively. The management of retinoblastoma
needs a multidisciplinary team approach including an ocular oncologist,
pediatric oncologist, radiation oncologist, radiation physicist, and an
ophthalmic oncopathologist. The management strategy depends on
the stage of the disease – intraocular retinoblastoma, retinoblastoma
with high-risk characteristics, orbital retinoblastoma and metastatic
retinoblastoma.

Management of retinoblastoma is highly individualized and is

based on several considerations - age at presentation, laterality, tumor
location, tumor staging, visual prognosis, systemic condition, family and
societal perception, and, to a certain extent, the overall prognosis and
cost-effectiveness of treatment in a given economic situation (Table 6).

Table 6. Current Suggested Protocol

A. Intraocular tumor, International Classification Group A to C, Unilateral or
Bilateral
1. Focal therapy (cryotherapy or transpupillary thermotherapy) alone
for smaller tumors (< 3mm in diameter and height) located in visually
noncrucial areas
2. Standard 6 cycle chemoreduction and sequential aggressive focal
therapy for larger tumors and those located in visually crucial areas
3. Defer focal therapy until 6 cycles for tumors located in the macular
and juxtapapillary areas. Transpupillary thermotherapy or plaque
brachytherapy for residual tumor in the macular and juxtapapillary
areas >6 cycles.
4. Focal therapy for small residual tumor, and plaque brachytherapy/
external beam radiotherapy (>12 months age) for large residual tumor
if bilateral, and enucleation if unilateral.

B. Intraocular tumor, International Classification Group D, Unilateral or

Bilateral
1. High dose chemotherapy and sequential aggressive focal therapy
2. Periocular carboplatin for vitreous seeds

18
 3. Consider primary enucleation if unilateral, specially in eyes with no
visual prognosis

C. Intraocular tumor, International Classification Group E, Unilateral or Bilateral

1. Primary enucleation
2. Evaluate histopathology for high risk factors

D. High risk factors on histopathology, International Staging, Stage 2

1. Baseline systemic evaluation for metastasis
2. Standard 6 cycle adjuvant chemotherapy
3. High dose adjuvant chemotherapy and orbital external beam
radiotherapy in patients with scleral infiltration, extraocular extension,
and optic nerve extension to transection.

E. Extraocular tumor, International Staging, Stage 3A

1. Baseline systemic evaluation for metastasis
2. High dose chemotherapy for 3-6 cycles, followed by enucleation or
extended enucleation, external beam radiotherapy, and continued high
dose chemotherapy for 12 cycles

F. Regional Lymph Node Metastasis, International Staging, Stage 3B

1. Baseline evaluation for systemic metastasis
2. Neck dissection, high dose chemotherapy for 6 cycles, followed by
external beam radiotherapy, and continued high dose chemotherapy
for 12 cycles

G. Hematogenous or Central Nervous System Metastasis, International

Staging, Stage 4
1. Palliative therapy in discussion with the family
2. High dose chemotherapy with bone marrow rescue for hematogenous
metastasis
3. High dose chemotherapy with intrathecal chemotherapy for central
nervous system metastasis

19
 1. Management of Intraocular Retinoblastoma
A majority of children with retinoblastoma manifest at a stage when the
tumor is confined to the eye. About 90-95% of children in developed
countries present with intraocular retinoblastoma while 60-70% present
at this stage in the developing world.10 Diagnosis of retinoblastoma
at this stage and appropriate management are crucial in life, eye and
possible vision salvage.

There are several methods to manage intraocular retinoblastoma

– focal (cryotherapy, laser photocoagulation, transpupillary
thermotherapy, transcleral thermotherapy, plaque brachytherapy),
local (external beam radiotherapy, enucleation), and systemic
(chemotherapy). While primary focal measures are mainly reserved for
small tumors, local and systemic modalities are used to treat advanced
retinoblastoma.

Cryotherapy
Cryotherapy is performed for small equatorial and peripheral retinal
tumors measuring up to 4 mm in basal diameter and 2 mm in thickness.2,10
Triple freeze thaw cryotherapy is applied at 4-6 week intervals until
complete tumor regression. Cryotherapy produces a scar much larger
than the tumor (Figure 16). Complications of cryotherapy include
transient serous retinal detachment, retinal tear and rhegmatogenous
retinal detachment. Cryotherapy administered 2-3 hours prior to
chemotherapy can increase the delivery of chemotherapeutic agents
across the blood retinal barrier and thus has synergistic effect.10

Figure 16. A peripheral retinal tumor that underwent Cryotherapy (left). The tumor has
completely regressed but the scar is much larger than the tumor itself (right)

20
Laser photocoagulation
Laser photcoagulation is used for small posterior tumors 4 mm in basal
diameter and 2 mm in thickness.2,10 The treatment is directed to delimit
the tumor and restrict the blood supply to the tumor by surrounding
it with two rows of overlapping laser burns. Complications include
transient serous retinal detachment, retinal vascular occlusion, retinal
hole, retinal traction, and preretinal fibrosis. A large visual field defect is
a major complication of laser photocoagulation if the tumor is located
in the juxtapapillary area. It is less often employed now with the advent
of thermotherapy. In fact, laser photocoagulation is contraindicated
while the patient is on active chemoreduction protocol because it
restricts the blood supply to the tumor and consequently reduces the
intra-tumor concentration of the chemotherapeutic agent.10

Thermotherapy
In thermotherapy, focused heat generated by infrared radiation is
applied to tissues at subphotocoagulation levels to induce tumor cell
apoptosis.26 The goal is to achieve a slow and sustained temperature
range of 40 to 60 degree C within the tumor, thus sparing damage
to the retinal vessels (Figure 17). Transpupillary thermotherapy using
infrared radiation from a semiconductor diode laser delivered with a
1300-micron large spot indirect ophthalmoscope delivery system has
become the standard practice. It can also be applied transpupillary
through an operating microscope or by the transscleral route with a
diopexy probe. The tumor is
heated until it turns a subtle
gray. Thermotherapy provides
satisfactory control for small
tumors - 4 mm in basal diameter
and 2 mm in thickness.
Complete tumor regression
can be achieved in over 85%
of tumors using 3-4 sessions of
thermotherapy.26 The common
complications such as focal
iris atrophy and focal paraxial Figure 17. Three focal tumors treated with
transpupillary thermotherapy: Note flat scars
lens opacity can be minimized with patent blood vessels coursing through
by using 1300-micron indirect the scars. Transpupillary thermotherapy
ophthalmoscope delivery classically spares the blood vessels from
system and duration of occlusion and produces a compact scar.
21
 treatment limited to 5 minutes in one session. Retinal traction and serous
retinal detachment may occur following heavy 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 of thermotherapy with chemoreduction
protocol is termed chemothermotherapy or thermochemotherapy
depending on the sequence in which the treatments are delivered.

Plaque Brachytherapy
Plaque brachytherapy involves
placement of a radioactive
implant on the sclera
corresponding to the base of the
tumor to transsclerally irradiate
the tumor.27 Commonly used
radioactive materials include
Ruthenium 106 (Figure 18) and
Iodine 125. The advantages
of plaque brachytherapy are
Figure 18. Ruthenium 106 plaque focal delivery of radiation
with minimal damage to the
surrounding normal structures, minimal periorbital tissue damage,
absence of cosmetic abnormality because of retarded bone growth
in the field of irradiation as occurs with external beam radiotherapy,
reduced risk of second malignant neoplasm and shorter duration of
treatment.

Plaque brachytherapy is indicated in tumors < 16 mm in basal

diameter and < 8 mm thickness. It could be the primary or secondary
modality of management. Primary plaque brachytherapy is currently
performed only in situations where chemotherapy is contraindicated.
It is most useful as secondary treatment in eyes that fail to respond
to chemoreduction and external beam radiotherapy or for tumor
recurrences.

Plaque brachytherapy requires precise tumor localization and

measurement of its basal dimensions. The tumor thickness is measured
by ultrasonography. The data is used for dosimetry on a three-
dimensional computerized tumor modeling system. The plaque design
is chosen depending on the basal tumor dimensions, its location, and
22
configuration – for example, a notched plaque is used to protect the
optic nerve when used for tumors which are peripapillary in location.
The dose to the tumor apex ranges from 4000-5000 cGy. The plaque is
sutured to the sclera after confirming tumor centration and is left in situ
for the duration of exposure, generally ranging from 36 to 72 hours. The
results of plaque brachytherapy are gratifying, with about 90% tumor
control. The common complications are radiation papillopathy and
radiation retinopathy.

External Beam Radiotherapy

External beam radiotherapy was the preferred form of management
of moderately advanced retinoblastoma in late 1900s.28,29 However
with the advent of newer chemotherapy protocols, external beam
radiotherapy is being used less often. Presently it is indicated in eyes
where primary chemotherapy and local therapy has failed, or rarely
when chemotherapy is contraindicated.10

External beam radiotherapy is delivered using Cobalt 60 (gamma

rays) or linear accelerator (X-rays). Linear accelerator with multi-
beam technique (intensity-modulated radiotherapy), image-guided
radiotherapy and stereotactic radiotherapy have better treatment
accuracy, minimal damage to normal structures and least complications.

The major problems with external beam radiotherapy are the

stunting of the orbital growth, dry eye, cataract, radiation retinopathy
and optic neuropathy. External beam radiotherapy can induce second
malignant neoplasm especially in
patients with the hereditary form of
retinoblastoma (Figure 19). There
is a high 30% chance of developing
another malignancy by the age of
30 years in such patients if they are
given external beam radiotherapy,
compared to a less than 6% chance
in those who do not receive external
beam radiotherapy.30 The risk of Figure 19. Osteosarcoma of the
second malignant neoplasm is greater frontal bone in a 20-year-old patient
in children under 12 months of age.30 with bilateral retinoblastoma who
had undergone external beam
radiotherapy at 1-year age

23
 Enucleation
Enucleation is a common method of managing advanced
retinoblastoma. Just about 3 decades ago, a majority of patients with
unilateral retinoblastoma and the worse eye in bilateral retinoblastoma
underwent primary enucleation. A substantial reduction in the
frequency of enucleation has occurred in the late last century.31
Concurrently, there has been an increase in the use of alternative eye-
and vision-conserving methods of treatment.9,32

Primary enucleation continues to be the treatment of choice for

advanced intraocular retinoblastoma with neovascularization of
iris, secondary glaucoma, anterior chamber tumor invasion, tumors
occupying >75% of the vitreous volume, necrotic tumors with secondary
orbital inflammation, and tumors associated with hyphema or vitreous
hemorrhage where the tumor characteristics can not be visualized,
especially when only one eye is involved.10

There are specific considerations while enucleating an eye with

retinoblastoma (Table 7). Minimum-manipulation surgical technique
should be necessarily practiced.11 It is important to take due precautions
not to accidentally perforate the eye. The sclera is thin at the site of
muscle insertions and the rectus muscles have to be hooked delicately.
It is mandatory to obtain a long optic nerve stump, ideally more than 15
mm, but never less than 10 mm (Figure 20).11 Certain steps can be taken
to obtain about 15 mm long optic nerve stump in all cases of advanced
retinoblastoma.11 Gentle traction can be applied by the traction sutures
applied to recti muscle stumps prior to transecting the optic nerve. As
an alternative to the traction sutures, medial or lateral rectus muscle

Table 7. Special considerations for enucleation in retinoblastoma

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 and
optic nerve involvement
e. Harvest fresh tissue for genetic studies
f. Place a primary implant
g. Avoid biointegrated implant if postoperative radiotherapy is necessary

24
stumps may be kept long and traction exerted with an artery clamp. It
is best to prolapse the eyeball through the blades of the wire speculum.
A 15-degree curved and blunt-tipped tenotomy scissors is introduced
from the lateral aspect (or a straight scissors from the medial aspect)
and the optic nerve is palpated with the closed tip of the scissors while
maintaining gentle anteroposterior traction on the eyeball. The scissors
is moved posteriorly to touch the orbital apex while gently “strumming”
the optic nerve. The scissors is lifted by 2 or 3 millimeters off the orbital
apex (to prevent accidental damage to the contents of the superior
orbital fissure), the blades of the scissors are opened to engage the optic
nerve, and the nerve is transected with one bold cut. This maneuver
easily provides at least 15 mm long optic nerve stump.11 Enucleation
spoon and heavy enucleation scissors limit space for maneuverability
and may result in a shorter optic nerve stump. In addition, one should
be careful not to accidentally perforate the eye during enucleation. The
enucleated eyeball is thoroughly inspected for optic nerve (Figure 20)
or extraocular extension (Figure 21) of the tumor and suspicious areas
(sclera thinning, induration, discoloration, vascuarilty, and nodularity
and, dilated vortex veins) are marked for histoapthogic examination to
evaluate scleral or extrascleral extension of the tumor.

Eyes manifesting tumor necrosis with aseptic orbital cellulitis pose a

specific problem. These patients should be imaged to rule out extraocular
extension. Enucleation is best performed when the inflammation has
resolved.11 A brief course of preoperative oral and topical corticosteroids
help control inflammation. Patients with retinoblastoma presenting as
phthisis bulbi, specifically phthisical eyes that show disproportionately

Figure 20. Enucleated eyeball showing 18 Figure 21. Enucleated eyeball showing
mm optic nerve stump. Note the proximal extrascleral tumor extension.
portion of the optic nerve is thickened
indicating tumor infiltration

25
 less enophthalmos need imaging to exclude extraocular and optic nerve
extension.11 Phthisis generally results following spontaneous tumor
necrosis and an episode of aseptic intraocular and orbital inflammation.
Enucleation in these cases is often complicated by excessive peribulbar
fibrosis and intraoperative bleeding.11

Placement of a primary orbital implant following enucleation for

retinoblastoma is the current standard of care. The orbital implant
promotes orbital growth, provides better cosmesis and enhances
prosthesis motility. The implant could be non-integrated (polymethyl
methacrylate or silicon) or bio-integrated (hydroxyapatite or porous
polyethylene). Placement of a biointegrated implant is generally avoided
if post-operative adjuvant radiotherapy is considered necessary.11
Although most implants structurally tolerate radiotherapy well, implant
vascularization may be compromised by radiotherapy thus increasing
the risk of implant exposure. Use of myoconjunctival technique and
custom ocular prosthesis have optimized prosthesis motility and static
cosmesis (Figure 22).

Figure 22. Retinoblastoma in the right eye following enucleation with orbital implant by
the myoconjunctival technique (left). Excellent cosmesis following fitting of a custom
ocular prosthesis (right).

Systemic Chemotherapy
Chemoreduction, defined as the process of reduction in the tumor
volume with chemotherapy, has become an integral part of the current
management of retinoblastoma.32 Chemotherapy alone is not curative
and must be synergistically combined with sequential and well-timed
intensive focal therapy. Chemoreduction coupled with focal therapy
can minimize the need for enucleation or external beam radiotherapy
without significant systemic toxicity.

26
 Chemoreduction in combination with focal therapy is now
extensively used in the primary management of retinoblastoma.33-36
There are different protocols in chemotherapy. The commonly used
drugs are vincristine, etoposide and carboplatin in combination, for
6 cycles.7-10 (Table 8) Standard dose chemoreduction is provided in
Reese Ellsworth groups I-IV (or international classification Group C).10
In high dose chemoreduction, the dose of etoposide and carboplatin is
increased. This is indicated in Reese Ellsworth group V (or international
classification Group D or higher) tumors.10

Table 8. Chemoreduction regimen and doses for intraocular

retinoblastoma
Day 1: Vincristine + Etoposide + Carboplatin
Day 2: Etoposide
Standard dose: (3 weekly, 6 cycles): Vincristine 1.5 mg/m2 (0.05 mg/kg for
children < 36 months of age and maximum dose < 2mg), Etoposide 150
mg/m2 (5 mg/kg for children < 36 months of age), Carboplatin 560 mg/m2
(18.6 mg/kg for children < 36 months of age)
High-dose (3 weekly, 6-12 cycles): Vincristine 0.025 mg/Kg, Etoposide 12
mg/Kg, Carboplatin 28 mg/Kg

With chemoreduction and sequential local therapy, it is now possible

to salvage an eye and maximize residual vision. Chemoreduction
is most successful for tumors without associated subretinal fluid or
vitreous seeding.7,8 Risk factors for tumor, subretinal seed and vitreous
seed recurrence, and failure of chemoreduction leading to external
beam radiotherapy and/or enucleation have been identified.7,8
Chemoreduction offers satisfactory tumor control for Reese Ellsworth
groups I-IV eyes, with treatment failure necessitating additional
external beam radiotherapy in only 10% and enucleation in 15% at
5-year follow-up. Patients with Reese Ellsworth group V eyes require
external beam radiotherapy in 47% and enucleation in 53% at 5
years.7,8 Chemoreduction is an option for selected eyes with unilateral
retinoblastoma.9

Figure 23 shows a tumor involving the macula at presentation. With

chemoreduction and transpupillary thermotherapy, there was complete
tumor regression. Figures 24, 25 and 26 show that the resulting scar
with chemoreduction was much smaller than the original tumor with

27
 Figure 23. Macular retinoblastoma in a 6-month-old child (left), completely regressed
with 6 cycles of chemoreduction alone (right).

Figure 24. Multifocal retinoblastoma (left) following chemoreduction and transpupillary

thermotherapy (right). Note flat scars that are much smaller than the original tumor.

Figure 25. A juxtapapillary retinal tumor in a 9-month-old child (left) partially regressed
with 3 cycles of chemoreduction (middle) and completely regressed with 6 cycles
of chemoreduction and transpupillary thermotherapy (right). Note the completely
exposed fovea following treatment, thus maximizing visual potential.

28
Figure 26. Multifocal retinoblastoma (top) regressed following chemoreduction and
transpupillary thermotherapy (bottom).

the foveola fully exposed, thus maximizing visual potential. With the
modified protocol that we use specifically for advanced retinoblastoma,
our eye salvage rates are 100% for Reese Ellsworth groups 1-3, 90% for
group D and 75% for group E (Table 9).

Table 9. Eye Salvage Rates with External Beam Radiotherapy Vs

Chemoreduction

Reese Ellsworth, Hungerford,

Shields, 2003 LVPEI, 2005
Ellsworth 1977 1995
Chemoreduction Chemoreduction*
Group EBRT EBRT
I 91% 100% 100% 100%
II 83% 84% 100% 100%
III 82% 82% 100% 100%
IV 62% 43% 75% 90%
V 29% 66% 50% 75%

* High dose chemotherapy for group V, periocular chemotherapy for VB

29
 It is important to be aware of the adverse effects and interactions
of chemotherapeutic agents, which include myelosuppression, febrile
episodes, neurotoxicity and non-specific gastrointestinal toxicity.
Chemotherapy should be given only under the supervision of an
experienced pediatric oncologist.

Periocular chemotherapy
Carboplatin delivered deep posterior subtenons has been
demonstrated to be efficacious in the management of retinoblastoma
with vitreous seeds because it can penetrate the sclera and achieve
effective concentrations in the vitreous cavity. This modality is currently
under trial. Our early results have shown that periocular chemotherapy
achieves 70% eye salvage in patients with Reese Ellsworth group VB
retinoblastoma (Figure 27).37

Figure 27. Retinoblastoma with massive vitreous seeds (Figure 27 top left). Following 3
cycles of high-dose chemoreduction (Figure 27 top right) the tumor is partially regressed
but the vitreous seeds persist. With periocular carboplatin injection in addition to high
dose chemoreduction, the vitreous seeds show complete regression (Figure 27 bottom,
left and right).

30
Intraarterial chemotherapy
Although chemotherapy protocols used in retinoblastoma are
generally considered safe, there are concerns about the increased
risk of secondary acute myelogenous leukemia. Techniques that offer
concentrated delivery of chemotherapy to the eye, while avoiding high
systemic concentrations seems ideal. Although there have been few
case reports of intravitreal injection of chemotherapy, such approach has
not gained wide acceptance because of concerns regarding extraocular
dissemination of retinoblastoma. Injection of a chemotherapeutic
agent into the carotid artery was first attempted by Reese in 1957.
More recently, Japanese investigators have employed interventional
radiology to catheterise the carotid artery, and inject melphalan. A
balloon catheter was then passed into the internal carotid artery and
inflated to occlude the artery and allow the medication to perfuse the
eye without reaching the brain. However, this technique was combined
with hyperthermia and EBRT, making it difficult to assess the effects
of the isolated intraarterial chemotherapy. A Recent phase I/II clinical
trial has evaluated intraarterial melphalan in unilateral Reese Ellsworth
Group V eyes, which would otherwise have undergone enucleation.62

Nine of 10 patients could be successfully cannulated and a total

of 27 injections were given. There was dramatic regression of tumors,
vitreous seeds and subretinal seeds in nine patients. None of the nine
children had a tumor recurrence. Two children underwent enucleation
because of concerns regarding persistent retinal detachment and
suspected tumor recurrence; however, histopathological examination
found no viable tumor. There were no severe systemic side effects,
although one child did develop neutropenia. After a mean follow-up
of 8.8 months, the researchers found little toxicity associated with the
treatment. Three patients developed conjunctival and lid edema that
resolved without treatment. One previously irradiated eye developed
retinal ischemia, and another eye developed radiation-like retinopathy
after subsequent brachytherapy. Although generally poor, vision did
stabilize or improve in all but one patient after treatment. Although
the early results seem exciting, the outstanding concerns that need to
be addressed are the potential for vascular complications (ischeamic
events, vascular spasms, vascular stenosis or complete occlusion) and
drug toxicity.63,64

31
 Follow-up Schedule
The usual protocol is to schedule the first examination 3–6 weeks after the
initial therapy. In cases where chemoreduction has been administered,
the examination should be done every 3 weeks along with each cycle of
chemotherapy. Patients under focal therapy are evaluated and treated
every 4-8 weeks until complete tumor regression. Following tumor
regression, subsequent examination should be 3 monthly for the first
year, 6 monthly for three years or until the child attains 6 years of age,
and yearly thereafter.

2. Management of High Risk Retinoblastoma

Systemic metastasis is the main cause for mortality in patients
with retinoblastoma. Although the life prognosis of patients with
retinoblastoma has dramatically improved in the last three decades,
with a reported survival of more than 90% in developed countries,38
mortality is still as high as 50% in the developing nations.39,40 Reduction
in the rate of systemic metastasis by identification of high-risk factors
and appropriate adjuvant therapy may help improve survival.

High–Risk Factors
None of the clinical high-risk factors seem to strongly correlate with
mortality. Recent studies have evaluated the role of histopathologic
high-risk factors identified following enucleation. The identification of
frequency and significance of high-risk histopathologic factors (Figures
28-31) that can reliably predict metastasis is vital for patient selection
for adjuvant therapy. Several studies have addressed this issue.39,41-49 It
is now generally agreed that massive choroidal infiltration, retrolaminar
optic nerve invasion, invasion of the optic nerve to transection, scleral
infiltration, and extrascleral extension are the risk factors that are
predictive of metastasis (Table 10).39,41-49

The reported occurrence of anterior chamber seeding (7%),45

massive choroidal infiltration (12-23%),43-49 invasion of optic nerve
lamina cribrosa (6-7%),43-49 retrolaminar optic nerve invasion (6-12%),43-49
invasion of optic nerve transection (1-25%),43-49 scleral infiltration (1-8%),43-49
and extrascleral extension (2-13%),43-49 widely vary even in developed
countries. Vemuganti and associates have reported that 21% of the
76 eyes enucleated for advanced retinoblastoma in India had anterior
chamber seeding, 54% had massive choroidal infiltration, 46% had optic

32
Figure 28 Figure 29

Figure 30 Figure 31

Figure 28. Histopathology of retinoblastoma showing anterior chamber seeding, iris

infiltration, trabecular meshwork infiltration and ciliary body invasion.
Figure 29. Histopathology of retinoblastoma showing massive choroidal infiltration,
scleral infiltration and extrascleral extension.
Figure 30. Histopathology of retinoblastoma showing infiltration of the optic nerve
beyond the lamina cribrosa.
Figure 31. Histopathology of retinoblastoma showing optic nerve infiltration to the
level of transection.

Table 10. Histopathologic high-risk factors predictive of metastasis

• Anterior chamber seeding
• Iris infiltration
• Ciliary body infiltration
• Massive choroidal infiltration
• Invasion of the optic nerve lamina cribrosa
• Retrolaminar optic nerve invasion
• Invasion of optic nerve transection
• Scleral infiltration
• Extrascleral extension

33
 nerve invasion at or beyond the lamina cribrosa and 7% had scleral
infiltration or extrascleral extension.12 It is apparent that the incidence
of histopathologic risk factors is strikingly high in developing countries
compared to the published data from developed countries.

Adjuvant Therapy
Studies on the efficacy of adjuvant therapy to minimize the risk of
metastasis initiated in the 1970s were marked by variable results and
provided no firm recommendation.18 A recent study with a long-term
follow-up provides useful information.13,50 It included a subset of patients
with unilateral sporadic retinoblastoma who underwent primary
enucleation. The study used specific predetermined histopathologic
characteristics for patient selection. A minimum follow-up of 1 year was
allowed to include metastatic events that generally occur at a mean of
9 months following enucleation.13,50 The incidence of metastasis was
4% in those who received adjuvant therapy compared to 24% in those
who did not. The study found that administration of adjuvant therapy
significantly reduced the risk of metastasis in patients with high-risk
histopathologic characteristics.

Our current practice is to administer 6 cycles of a combination of

carboplatin, etoposide and vincristine (identical to the protocol used
for chemoreduction of intraocular retinoblastoma) in patients with
histopathologic high-risk characteristics. All patients with extension
of retinoblastoma up to the level of optic nerve transection, scleral
infiltration, and extrascleral extension receive high dose chemotherapy
for 12 cycles and fractionated 4500 to 5000 cGy orbital external beam
radiotherapy.

3. Orbital Retinoblastoma
Orbital retinoblastoma is rare in developed countries. Ellsworth observed
a steady decline in the incidence of orbital retinoblastoma in his large
series of 1160 patients collected over 50 years.51 Orbital retinoblastoma
is relatively more common in the developing countries. In a recent large
multi-center study from Mexico, 18% of 500 patients presented with
an orbital retinoblastoma.52 A Taiwanese group reported that 36% (42
of 116) of their patients manifested with orbital retinoblastoma.53 The
incidence is higher (40%, 19 of 43) in Nepal, with proptosis being the
most common clinical manifestation of retinoblastoma.54

34
Clinical Manifestations
There are several clinical presentations of orbital retinoblastoma.

a. Primary Orbital Retinoblastoma

Primary orbital retinoblastoma refers to clinical or radiologically
detected orbital extension of an intraocular retinoblastoma at the
initial clinical presentation, with or without proptosis or a fungating
mass (Figure 32). Silent proptosis without significant orbital and
periocular inflammation in a patient with manifest intraocular tumor
is the characteristic presentation. Proptosis with inflammation
generally indicates reactive sterile orbital cellulitis secondary to
intraocular tumor necrosis.

b. Secondary Orbital Retinoblastoma

Orbital recurrence following uncomplicated enucleation
for intraocular retinoblastoma is termed secondary orbital
retinoblastoma (Figure 33). Unexplained displacement, bulge or
extrusion of a previously well-fitting conformer or a prosthesis is an
ominous finding suggestive of orbital recurrence.

Figure 32. Primary orbital retinoblastoma manifesting with proptosis (left). Computed
tomography scan shows massive orbital tumor (right).

Figure 33. Secondary orbital retinoblastoma following enucleation, manifesting with

extrusion of the prosthetic eye (left). CT can shows an orbital tumor (right).

35
 c. Accidental Orbital Retinoblastoma
Inadvertent perforation, fine-needle aspiration biopsy or intraocular
surgery in an eye with unsuspected intraocular retinoblastoma
should be considered as accidental orbital retinoblastoma and
managed as such (Figure 34).

Figure 34. A child with retinoblastoma misdiagnosed as traumatic hyphema in the left
eye and treated with hyphema drainage without a baseline ultrasonograpy evaluation
presents after 1 year with extraocular extension (left) and regional lymph node
metastasis (right).

d. Overt Orbital Retinoblastoma

Previously unrecognized extrascleral or optic nerve extension
discovered during enucleation qualifies as overt orbital
retinoblastoma. Pale pink to cherry red episcleral nodule, generally
in juxtapapillary location or at the site of vortex veins, may be
visualized during enucleation. An enlarged and inelastic optic nerve
with or without nodular optic nerve sheath are clinical indicators of
optic nerve extension of retinoblastoma that should be recognized
during enucleation.

e. Microscopic Orbital Retinoblastoma

In several instances, orbital extension of retinoblastoma may not
be clinically evident and may only be microscopic. Detection of full-
thickness scleral infiltration, extrascleral extension and invasion of
the optic nerve on histopathologic evaluation of an eye enucleated
for intraocular retinoblastoma are unequivocal features of orbital
retinoblastoma. Tumor cells in choroidal and scleral emissaria and
optic nerve sheath indicate possible orbital extension mandating
further serial sections and detailed histopathologic analysis.

36
Diagnostic Evaluation
A thorough clinical evaluation paying attention to the subtle signs
of orbital retinoblastoma is necessary. Magnetic resonance imaging
preferably, or computed tomography scan of the orbit and brain in axial
and coronal orientation with 2-mm slice thickness helps confirm the
presence of orbital retinoblastoma and determine its extent. Systemic
evaluation, including a detailed physical examination, palpation of the
regional lymph nodes and fine needle aspiration biopsy if involved,
imaging of the orbit and brain, chest X-ray, ultrasonography of the
abdomen, bone marrow biopsy and cerebrospinal fluid cytology
are necessary to stage the disease. Technetium-99 bone scan and
positron-emission tomography coupled with computed tomography
may be useful modalities of the early detection of subclinical systemic
metastases. Orbital biopsy is rarely required, and should be considered
specifically when a child presents with an orbital mass following
enucleation or evisceration where the primary histopathology is
unavailable.

Management of Orbital Retinoblastoma

Primary orbital retinoblastoma has been managed in the past with
orbital exenteration, chemotherapy or external beam radiotherapy
in isolation or in sequential combination with variable results.55-60 It is
well known that local treatments have a limited effect on the course of
this advanced disease. Orbital exenteration alone is unlikely to achieve
complete surgical clearance and preclude secondary relapses; external
beam radiotherapy does not generally prevent systemic metastasis;
and chemotherapy alone may not eradicate residual orbital disease.55-60
Therefore, a combination therapy is considered to be more effective.
We have developed a treatment protocol comprising of initial three
drug (Vincristine, Etoposide, Carboplatin) high dose chemotherapy
(3-6 cycles) followed by surgery (enucleation, extended enucleation or
orbital exenteration as appropriate) after radiological confirmation of
complete resolution of the extraocular component of the tumor, orbital
radiotherapy, and extended high-dose chemotherapy for 12 cycles.17 In
6 carefully selected cases without intracranial extension and systemic
metastasis, there was dramatic resolution of orbital involvement.
All the involved eyes became phthisical after 3 cycles of high dose
chemotherapy. No clinically apparent orbital tumor was found
during enucleation. All patients completed the treatment protocol of
orbital external beam radiotherapy, and additional 12 cycle standard
37
 chemotherapy. All the patients were free of local recurrence or systemic
metastasis at a mean follow-up of 36 months (range 12-102 months)
and achieved acceptable cosmetic outcome (Figure 35).17

Our treatment protocol outlined for primary orbital retinoblastoma

is currently under evaluation for secondary orbital retinoblastoma and
early results have been very encouraging. Surgical intervention in such
cases may be limited to excision of the residual orbital mass or an orbital
exenteration depending on the extent of the residual tumor after the
initial 3-6 cycles of high-dose chemotherapy.

All eyes that have undergone an intraocular surgery for unsuspected

retinoblastoma should be promptly enucleated.16 Conjunctiva

Figure 35. A child with primary orbital retinoblastoma (top left), showing massive orbital
tumor on computed tomography scan (top right). Following 12 cycles of high-dose
chemotherapy, extended enucleation and orbital external beam radiotherapy (bottom
left). The child is alive and well and wears a custom ocular prosthesis 3 years following
completion of treatment (bottom right).

38
overlying the ports with about 4 mm clear margins should be included
en-bloc with enucleation. Random orbital biopsy may be also obtained,
but there is no data to support its utility. If immediate enucleation is
not logistically possible, then the vitrectomy ports or the surgical
incision should be subjected to triple-freeze-thaw cryotherapy and
enucleation should be performed at the earliest possible convenience.
Histopathologic evaluation of such eyes may include specific analysis of
the sites of sclerotomy ports or the cataract wound for tumor cells.

If an extraocular extension is macroscopically visualized during

enucleation, special precaution is taken to excise it completely along
with the eyeball, preferably along with the layer of Tenon's capsule
intact in the involved area.11

All patients with accidental, overt or microscopic orbital

retinoblastoma undergo baseline systemic evaluation to rule out
metastasis. Orbital external beam radiotherapy (fractionated 45-50 Gy)
and 12 cycles of high dose chemotherapy are recommended.16

4. Metastatic Retinoblastoma
Metastatic disease at the time of retinoblastoma diagnosis is very
rare. Therefore, staging procedures such as bone scans, lumbar
puncture, and bone marrow aspiration at the initial presentation are
generally not recommended. The common sites for local spread and
metastasis include orbital and regional lymph node extension, central
nervous system metastasis, and systemic metastasis to bone and bone
marrow. Metastasis usually occurs within one year of diagnosis of
the retinoblastoma. If there is no metastatic disease within 5 years of
retinoblastoma diagnosis, the child is usually considered cured.

Metastatic retinoblastoma is reported to develop in fewer than 5%

of patients in developed countries. However, it is a major contributor to
retinoblastoma related mortality in developing nations. Until recently,
the prognosis with metastatic retinoblastoma was poor. Conventional
dose chemotherapy using vincristine, doxorubicin, cyclophosphamide,
cisplatin, and etoposide combined with radiation therapy has yielded
only a few survivors. Dismal results with conventional therapy has
prompted the use of high dose chemotherapy with hematopoietic stem
cell rescue. Twenty-five patients with extraocular disease or invasion of

39
 the cut end of optic nerve received high-dose chemotherapy including
carboplatin, etoposide, and cyclophosphamide followed by autologous
hematopoietic stem cell rescue. The three year disease-free survival was
67%.60,61 All except one patient with central nervous system disease,
however, died. The main side effects were hematological, mucositis,
diarrhoea, ototoxicity, and cardiac toxicity. Overall the response rate
suggested that the treatment regimen was promising in patients with
bone or bone marrow involvement, but not in patients with central
nervous system disease.

Children’s Oncology Group is conducting a trial for the treatment

of metastasis retinoblastoma. In this trial, the patients will be stratified
into 3 groups: orbital/nodal disease, central nervous system disease,
and systemic disease. Each patient will undergo induction therapy with
cisplatin, cyclophosphamide, vincristine, and etoposide. Those with
systemic metastasis or central nervous system disease will then receive
high dose therapy with etoposide, carboplatin and thiotepa.

40
 Conclusion

T
here has been a dramatic change in the overall management
of retinoblastoma in the last decade. Specific genetic protocols
have been able to make prenatal diagnosis of retinoblastoma.
Early diagnosis and advancements in focal therapy have resulted
in improved eye and vision salvage. Chemoreduction has become
the standard of care for the management of moderately advanced
intraocular retinoblastoma. Periocular chemotherapy is now an
additional useful tool in salvaging eyes with vitreous seeds. Efficacy
and complications of intraarterial chemotherapy and safety of direct
intravitreal chemotherapy are being explored. Enucleation continues
to be the preferred primary treatment approach in unilateral advanced
retinoblastoma. Post-enucelation protocol, including identification
of histopathologic high-risk characteristics and provision of adjuvant
therapy has resulted in substantial reduction in the incidence of systemic
metastasis. The vexing orbital retinoblastoma now seems to have a cure
finally with the aggressive multimodal approach. Future holds promise
for further advancement in focal therapy and targeted drug delivery.

41
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48
 This CME Material has been supported by the
funds of the AIOS, but the views expressed therein
do not reflect the official opinion of the AIOS.

(As part of the AIOS CME Programme) Authors : Santosh G. Honavar, MD, FACS
Published July 2012 Fairooz PM, MD
Mohd Javed Ali, MD, FRCS
Geeta K Vemuganti, MD
Vijay Anand P Reddy, MD

Reviewer : Dr E Ravindra Mohan

Trinethra Eye Clinic
Chennai 600034
Phone: 91 98404 13336
Published by: email: [email protected]
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 AIOS, CME SERIES
(No. 25)

Retinoblastoma
They Live and See!