Diagnosis, Classification, and

Treatment of Retinoblastoma

Szilard Kiss, MD
Yannek I. Leiderman, MD, PhD
Shizuo Mukai, MD

Introduction

Retinoblastoma represents approximately 4% of all pediatric malignancies and is the most common primary intraocular cancer in
children.1,2 Worldwide, it is estimated that there are 5000 to 8000 newly
diagnosed cases of retinoblastoma yearly.2,3 In the United States,
approximately 250 to 350 cases are diagnosed each year.2,4 The first
description of a child successfully treated with radiation for retinoblastoma was reported in 1903.5 Since that time, improvement in survival of
retinoblastoma has been faster than any other cancer in children or
adults. In 2003, retinoblastoma was the pediatric cancer with the highest
survival.2 In the Western world, 99% of children will survive this cancer
and over 90% will retain normal vision in at least 1 eye.2,3,6 Unfortunately, primarily to late detection of advanced retinoblastoma, in
medically underdeveloped nations survival drops to approximately 50%.4
A genetic basis for the development of retinoblastoma was recognized over 70 years ago.2 In 1971, after noting differences in tumor
development in patients with unilateral versus bilateral retinoblastoma,
Knudson7 proposed his now famous two-hit model of tumorgenesis. The
retinoblastoma gene (RB1) was the first human cancer gene cloned and
was the first of a whole new class of human tumor-suppressor genes.2,3
The protein responsible for intraocular retinoblastoma is vital for
terminal differentiation of many cell lineages, including differentiation
of retinal progenitor cells.8 It is now recognized that the loss of normal
functioning RB1 is an important step in the development of many adult
nonocular cancers.2,3,9
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Epidemiology

The cumulative lifetime incidence of retinoblastoma is 1 in 18,000 to

30,000 live births worldwide.10,11 In the United States, the incidence is
estimated at 3.6 cases for each million children under the age of 15
years.6 The incidence of heritable retinoblastoma is remarkably constant
among the various populations of the world, with no sex or race
predilection and no significant environmental or socio-economic predisposing factors.12
In contrast to heritable retinoblastoma, there are marked geographic differences in the incidence of nonheritable, unilateral retinoblastoma. Sporadic, unilateral retinoblastoma seems to occur more
commonly in poorer, tropical, and subtropical regions of the world.
Preliminary evidence suggests a possible viral etiology (human papilloma virus) or perhaps a diet deficient in fruits and vegetables.13,14
Advanced paternal age has also been associated with new sporadic
retinoblastoma gene mutations and sporadic retinoblastoma.1520 New
germline RB1 mutations apparently arise more frequently during
spermatogenesis.20,21 Dryja and colleagues16 observed that the proportion of new germline RB1 gene mutations arising from a paternally
derived allele was approximately 85%. However, in cases with somatic
mutations, the initial mutation occurs on paternal or maternal chromosomes with roughly equal frequency.16,20

Clinical Features

Approximately two-thirds of all retinoblastoma cases are unilateral

and one-third of cases bilateral.4 Bilateral and familial cases of
retinoblastoma have a germline mutation and are heritable. Patients
with germline mutations are also at significant risk for developing
second and third nonocular tumors, a risk that increases throughout the
lifetime.22
Retinoblastoma is a childhood disease with most cases being
recognized by 3 years of age and 90% diagnosed by age the age of 5
years.23 The average age at presentation for germline retinoblastoma is 3
to 18 months. For sporadic, nongermline retinoblastoma, the average
age is 18 to 24 months. Patients with known family history of
retinoblastoma typically undergo early screening examinations before
developing symptoms, with a funduscopic examination at birth and then
every 2 to 3 months for the first 3 years.6 Patients are then examined at
increasing time intervals until it is safe to assume that no retinoblastoma
will develop. The oldest age at which a child with a family history of
retinoblastoma was reported to develop a tumor in a previously
documented tumor-free eye is 48 months.2,24 In the 5-10% of patients
diagnosed with retinoblastoma after the age of 5 years, the presentation

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is almost universally unilateral, sporadic retinoblastoma.25 Misdiagnosis

in these older patients is common and the prospects for globe salvage
poor.23,25
Leukocoria is the most common presenting sign in patients with
retinoblastoma.26 In the United States, nearly 60% of all cases of
retinoblastoma are diagnosed after observation of leukocoria in the
affected eye, most often by a parent or family member. In a retrospective
review by Abramson et al,26 the observation of leukocoria correlated
with the presence of advanced disease. Because a retinoblastoma in the
posterior pole has to be sufficiently large to generate a leukocoria reflex,
leukocoria is a late presenting sign with poorer prognosis for globe
salvage, but nonetheless has a good survival rate (approximately 88%
at 5 y).3,27
Strabismus is the second major presenting sign of retinoblastoma,
detected in approximately 1 in 5 retinoblastoma patients in the United
States.26 A small tumor in the fovea or foveola or tumor-associated
subretinal fluid in the macula can significantly reduce visual acuity and
result in strabismus. In contrast to leukocoria, tumors presenting with
strabismus as the initial sign are associated with a higher survival rate
and a higher chance of globe salvage.3,27
The remaining 20% of the cases of retinoblastoma present with
atypical signs and symptoms, including red, painful eye with glaucoma,
cloudy cornea, poor vision, vitreous hemorrhage, or signs of orbital
inflammation mimicking orbital cellulitis.26 These uncommon presentations are usually late signs associated with more advanced disease and
poorer survival and globe salvage prognosis.3,28
The clinical presentation of retinoblastoma is dependent on tumor
growth pattern, duration of growth, degree of tumor vascularity, and the
presence or absence of calcifications, vitreous seeding, and retinal
detachment. Endophytic retinoblastomas, accounting for nearly 60%
of cases, exhibit growth toward the vitreous cavity as a result of cell
division within the inner retinal layers.29 It presents as one or multiple
foci, isolated or coalesced, variably sized, round or oval-shaped, and
calcified creamy-white or vascularized pink retinal mass. These tumors
have a tendency for vitreous seeding. The location of endophytic
retinoblastoma is age-dependent, with the earliest tumors developing
closer to the posterior pole and more anterior tumors arising at a later
age.30 In a retrospective review by Palazzi et al,29 a disproportionately
higher percentage of patients with endophytic retinoblastoma had a
positive family history of retinoblastoma.
Approximately 39% of retinoblastomas demonstrate an exophytic
growth pattern with tumor development in the outer retinal layers and
expansion beneath the retina into the subretinal space.29 Patients with
exophytic retinoblastoma present with retinal detachment surrounding
the tumor. A disproportionately high percentage of patients with

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exophytic retinoblastoma develop glaucoma. Choroidal invasion also

occurs significantly more often in patients with exophytic retinoblastoma
than in those with endophytic retinoblastoma.29 Both exophytic and
endophytic patterns can be seen with mixed growth retinoblastoma.
The remaining 1% to 2% of cases of retinoblastoma exhibit a diffuse
infiltrating, plaquelike growth pattern. Tumor growth is diffusely within
the retina without apparent signs of a mass.31 An irregular, grayish
plaque is sometimes visible on the retinal surface. Diffuse infiltrating
retinoblastoma typically presents with signs suggestive of inflammation,
and, as a result, patients are often misdiagnosed as having uveitis.23 The
average age at presentation of this atypical form is 6 years.31 Despite an
often delayed diagnosis, the prognosis for survival is >95% after
enucleation of the affected eye.31
Any child with unexplained, atraumatic hyphema or vitreous
hemorrhage should be evaluated for retinoblastoma.4 Vitrectomy or
retinal detachment repair should be avoided until the diagnosis of
retinoblastoma is reliably ruled out.32 If vitrectomy is performed in an
eye with unsuspected retinoblastoma, enucleation combined with
adjuvant chemotherapy, radiotherapy, or both without delay is advised
to prevent systemic tumor dissemination.32

Diseases Simulating Retinoblastoma

Shields and colleagues33 retrospectively examined 500 consecutive

patients referred to the Ocular Oncology Service at Wills Eye Hospital
with the diagnosis of possible retinoblastoma. In all, 58% of patients
were found, on clinical evaluation, to have retinoblastoma and 42% had
lesions that simulated retinoblastoma. A total of 23 different conditions
accounted for these pseudoretinoblastomas. The 3 most common lesions
imitating retinoblastomas were persistent hyperplastic primary vitreous
(28%), Coats disease (16%), and presumed ocular toxocariasis (16%).33
Other less common conditions that may mimic retinoblastoma include
congenital cataract, retinopathy of prematurity, familial exudative
vitreoretinopathy, Norrie disease, and incontinentia pigmenti. Family
history, clinical examination including indirect ophthalmoscopic examination (possibly under anesthesia), fluorescein angiogram, and B-scan
ultrasonography (oftentimes demonstrating the classic shadowing of
intralesional calcification of retinoblastoma) can facilitate the diagnosis
and differentiation of retinoblastoma from pseudoretinoblastoma.

Classification

There are 4 clinical stages of retinoblastoma: intraocular, regional,

central nervous system, and hematogenous.23 Several classification
systems have been developed specifically for intraocular retinoblastoma.

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The Reese-Ellsworth Classification, developed in 1963, is based on

intraocular tumor staging and globe salvage prediction after external
beam radiation.34 This system divides eyes according to location, focality,
and size of the tumors as determined by ophthalmoscopy into 5 groups
(I to V) and 10 subgroups (a and b for each group). Group I consists
of eyes with the lowest risk of enucleation and group V with the highest
risk. At the time of the Reese-Ellsworth Classification development,
external beam radiotherapy (EBRT) was the most popular nonenucleation treatment for retinoblastoma. Peripheral retinoblastomas, multifocal tumors, and larger tumors were more difficult to treat with EBRT
than smaller, single tumors. The smaller macular tumors were presumed
to be more aggressive and earned a higher ranking in the classification.34
Over the past 10 years, the treatment approaches to retinoblastoma
have changed dramatically.2 In an effort to avoid the use of EBRT, which
can result in considerable disfigurement and increase the risk of
developing additional cancers in patients with germline mutations, most
retinoblastoma referral centers are using systemic chemotherapy (chemoreduction) and focal treatments, such as laser photocoagulation and
cryotherapy, as the primary treatment modality. The limiting variables
for successful retinoblastoma therapy with chemoreduction are considerably different than with EBRT. Tumor location, multifocality, and
size were of lesser concern than vitreous and subretinal seeding.35 The
Reese-Ellsworth Classification system does not address subretinal seeding nor does it differentiate between focal and diffuse seeding. As such,
this classification system has been found to be a poor predictor of success
(defined as salvage of the globe) with chemotherapy.4,36
In 2003, a new classification system for intraocular retinoblastoma
was finalized (Table 1). The International Classification of Retinoblastoma (ICRB) is based mainly on the extent of tumor seeding in the
vitreous and subretinal space, with consideration for tumor size and
location.37 The ICRB is based both on the natural history of retinoblastoma (early disease, group A to late disease, group E) and on the
likelihood of salvaging the eye when systemic chemotherapy and
adjuvant focal therapy is used as the primary treatment paradigm.
Group A eyes have lesions that are small and are away from critical visual
structures (Table 1). In both groups A and B, the tumor remains
confined to the retina. In groups C and D, the tumor has spread into the
subretinal space and vitreous cavity. The tumor in group E eyes is
extensive and has destroyed the eye. Group A eyes have the lowest risk
of treatment failure and enucleation, whereas group E eyes are rarely
salvageable and require enucleation as the primary treatment.36,37 The
chances of retaining useful vision decreases from groups A to E. Like the
Reese-Ellsworth Classification system, the ICRB addresses only the risk
of loss of the eye and is not a staging system for the disease in the child.
ICRB is not intended to predict life prognosis or visual outcome; rather,

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Table 1. The International Classification of Retinoblastoma*

Group
A
B

Subgroup
A
B

Quick Reference
Small tumor
Larger tumor
Macula
Juxtapapillary
Subretinal fluid

Focal seeds
C1
C2
C3

Diffuse seeds
D1
D2
D3

Extensive retinoblastoma

Specific Features
Retinoblastoma r3 mm in size
Retinoblastoma >3 mm in size or
Macular retinoblastoma location
(r3 mm to foveola)
Juxtapapillary retinoblastoma location
(r1.5 mm to disc)
Clear subretinal fluid r3 mm
from margin
Retinoblastoma with
Subretinal seeds r3 mm from
retinoblastoma
Vitreous seeds r3 mm from
retinoblastoma
Both subretinal and vitreous seeds
r3 mm from retinoblastoma
Retinoblastoma with
Subretinal seeds >3 mm
from retinoblastoma
Vitreous seeds >3 mm from
retinoblastoma
Both subretinal and vitreous seeds
>3 mm from retinoblastoma
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

*Modified from Murphree37 and Shields and Shields.4

ICRB predicts globe outcome and the probability of avoidance of

enucleation or EBRT after primary chemotherapy.36

Metastasis

There seem to be no inherent differences in the risk of metastatic

disease between patients with germline mutations and those with
sporadic retinoblastoma.2 Delay in diagnosis is the major risk factor in
affecting survival. Kopelman and colleagues38 reported that the chances
of metastasis and death were 2.5 times greater in patients in whom the
clinical diagnosis of retinoblastoma was delayed. Metastasis from

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retinoblastoma typically develops within 1 year after diagnosis of the

intraocular tumor.4
The poorly cohesive, high-mitotic-index retinoblastoma cells have a
natural propensity to invade any readily accessible space, including the
vitreous cavity, subretinal fluid, the anterior segment, and the optic
nerve.3 Retinoblastoma can spread anteriorly via the vitreous cavity or
subretinal space toward the anterior segment, invading the ciliary body
and anterior chamber and resulting in a pseudohypopyon. The tumor
can extend posteriorly toward the optic nerve with intracranial invasion.
Retinoblastoma may invade the orbit directly through the choroid and
sclera or by following the scleral emissary canals of the ciliary arteries
and nerves. Metastatic dissemination may also occur via lymphatic or
vascular pathways.4
The greatest risks for metastatic disease include histopathologic
features of retinoblastoma invasion beyond the lamina cribrosa in the
optic nerve or orbital invasion with extension outside the sclera.24,6
The mortality rate is 50% to 85% if the tumor cells have reached the
surgical resection line of the optic nerve, 13% to 69% if the tumor is
posterior to the lamina cribrosa but not at the resection line, and
insignificant if the cells are anterior to the lamina cribrosa.3,39 The
association of optic nerve invasion and massive choroidal invasion carries
the greatest risk of metastasis and requires preventative or adjuvant
chemotherapy.4,40

Secondary Nonocular Tumors

Patients with hereditary retinoblastoma are at risk for developing an

intracranial neuroblastic tumor, most often a pinealoblastoma or other
parasellar tumor, in the first 5 years of life.41 This trilateral retinoblastoma is found in approximately 3% of all children with retinoblastoma and 10% of those with bilateral or familial retinoblastoma.4
The median time from diagnosis of retinoblastoma to the diagnosis of
the neuroblastic tumor is 21 months.41 Unfortunately, pinealoblastoma
is nearly universally fatal with only a few survivors.41 A recent retrospective analysis by Shields and colleagues42 indicates that chemoreduction for retinoblastoma may prevent the development of intracranial
neuroblastic tumors. None of the 142 patients treated with chemoreduction developed pinealoblastoma. It was estimated that 5 to 15 of
these patients should have manifested the trilateral retinoblastoma.42
Carriers of mutations in the retinoblastoma gene have an increased
incidence of developing second tumors.43 Patients with bilateral or
heritable retinoblastoma have the RB1 mutation present in all cells
predisposing them to develop nonocular tumors. Second tumors
develop in 4.4% of the patients during the first 10 years of follow-up,
in 18.3% after 20 years, and in 26.1% after 30 years.44 Second cancers

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most often include osteogenic sarcoma, spindle cell sarcoma, chondrosarcoma, rhabdomyosarcoma, neuroblastoma, glioma, leukemia, sebaceous cell carcinoma, squamous cell carcinoma, and malignant
melanoma.2,4,43 Second nonocular tumors are the greatest cause of
death in these patients, rather than the primary retinoblastoma
itself.22,43 Survivors of retinoblastoma in whom second malignant
neoplasms develop are at an even higher risk for the development of
additional tumors (third, fourth, and even fifth nonocular tumors) than
they were for the development of a second tumor.45 The locations and
expected ages at which additional tumors develop are consistent with the
patterns seen in second tumors. The incidence rate for the development
of nonocular tumors is further increased in hereditary retinoblastoma
patients who have been treated with EBRT.44 In a retrospective analysis
by Abramson and colleagues,45 96% of patients in whom third tumors
developed had received radiation therapy for their intraocular retinoblastoma.

Treatment

Management of a child with retinoblastoma is individualized and is

based on the threat of metastatic disease, risks for secondary cancers,
systemic status, laterality of disease, size and location of tumors,
anticipated visual prognosis, and response to treatment.4 The most
important objective of a treatment plan is the survival of the child,
followed by salvage of the globe, and finally the preservation of the best
possible visual function.
Systemic chemotherapy (most commonly carboplatin, etoposide,
and vincristine with or without cyclosporin) has replaced EBRT as the
most commonly used primary treatment for intraocular retinoblastoma.2,6,35,46,47 Chemotherapy is used to shrink the tumor until it is
accessible to adjuvant focal treatment such as photocoagulation, thermotherapy, cryotherapy, or brachytherapy.46,48 The number and frequency
of chemotherapy cycles vary from institution to institution and are
dependent on the stage of the tumor.46,47 Chemotherapy reduces the
size of the tumor but does not usually cure the retinoblastoma; focal
therapy is necessary to consolidate the chemotherapy response. Chemoreduction, followed by focal consolidation, has reduced the frequency of
enucleation and spared the complications associated with primary EBRT
(such as the development of secondary nonocular tumors).3
In general, eyes classified as ICRB group A are treated with
cryotherapy or laser photocoagulation. Eyes classified as group B or C
usually receive chemoreduction, followed by focal consolidation. Eyes
classified as group D are treated with either chemoreduction or
enucleation depending on the laterality of the disease. Group E eyes
are treated by primarily enucleation (Table 2). Shields and colleagues36

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recently demonstrated that the ICRB is predictive of globe outcome

after chemoreduction. Treatment success was achieved in 100% of
group A, 93% of group B, 90% of group C, and 47% of group D eyes.36
Over half the patients in group D required enucleation or EBRT. All
group E eyes in this series were treated with enucleation.
Conservative treatment is possible in approximately 25% of all
unilateral retinoblastoma; enucleation is necessary in the remaining
75%.27,49 This high rate of enucleation is a result of the delay in
diagnosis of unilateral sporadic retinoblastoma, which is most often
detected by the parents or family members as leukocoria or strabismus.27 For those with less advanced unilateral tumor, chemoreduction
with focal consolidation is beneficial (Table 2).40 Unilateral group A
tumors are treated with cryotherapy or laser photocoagulation, chemoreduction or plaque or proton radiotherapy is used for group B or C,
and unilateral group D or E retinoblastoma most often requires
enulceation.4
The treatment of bilateral disease is based on the stage of the most
advanced eye (Table 2). Bilateral retinoblastoma require enucleation of
at least 1 eye in 60% of cases for dangerously advanced tumor.40
Bilateral enucleation is necessary in only about 1% of cases.49 On the
Table 2.

Treatment Strategy on the Basis of Laterality and Retinoblastoma Grouping*

International
Classification of
Retinoblastoma
A
B

Unilateral
Cryotherapy or laser
Photocoagulation
Vincristine, carboplatin plus
thermotherapy/cryotherapy,
or plaque radiotherapy
Vincristine, carboplatin,
etoposide plus thermotherapy/cryotherapy, or plaque
or proton radiotherapy
Vincristine, carboplatin,
etoposide plus thermotherapy/cryotherapy and
subconjunctival carboplatin,
or enucleation
Enucleation

*Modified from Shields and Shields.4

Bilateral (on the Basis of Most

Advanced Eye)
Cryotherapy or laser
Photocoagulation
Vincristine, carboplatin plus
thermotherapy/cryotherapy
Vincristine, carboplatin, and
etoposide plus thermotherapy/cryotherapy
Vincristine, carboplatin,
etoposide plus thermotherapy/cryotherapy, and
subconjunctival carboplatin
Enucleation, but if both eyes
equally advanced then
vincristine, carboplatin,
etoposide plus thermotherapy/cryotherapy and
subconjunctival carboplatin,
and proton radiotherapy

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basis of the worst eye, eyes with only group A disease are treated with
laser or cryotherapy; group B or C eyes receive chemoreduction
followed by focal consolidation; group D eyes receive chemoreduction,
focal consolidation and subconjunctival or subTenons carboplatin or
proton radiotherapy, or enucleation and; group E eyes are treated with
enucleation (Table 2). If both eyes are equally advanced (both group E),
the patient is treated with chemoreduction, subconjunctival or subTenons carboplatin, and proton radiotherapy.3,4
The principal complication of chemoreduction is the recurrence of
subretinal or vitreous seeds, oftentimes remote from the original
tumor.35,40,47 Tumor recurrence rate is highest for retinoblastoma
located in the macula and for retinoblastoma with greater thickness.50
In some cases, recurrent seeds can be treated with cryotherapy or plaque
radiotherapy.4
Patients with hereditary retinoblastoma can also develop new tumors
during or after chemotherapy.51 The mean interval to new tumor
development is roughly 5 months after the initiation of chemoreduction.
New tumors can be detected in 24% of patients by 5 years of follow-up.51
Children with retinoblastoma treated with chemoreduction and focal
consolidation should be followed at regular intervals for both recurrence
and new tumor development.
Most complications of the chemotherapeutic agents currently used
to treat intraocular retinoblastoma are dose related and are of short
duration. Unlike EBRT, these chemotherapeutic agents do not seem to
predispose children with heritable retinoblastoma to the same tumors
for which they are genetically at risk.24,6 However, long-term follow-up
of patients treated with primary chemoreduction is still necessary for
better understanding of primary tumor control and potential effects on
secondary tumor development.

Conclusion

Retinoblastoma is the most common primary intraocular tumor

in children. The causative gene was the first in the class of tumorsuppressor genes identified. Remarkable advances in the treatment of
this disease have been made over the past century. Chemoreduction,
followed by adjuvant focal consolidation, in combination with early
detection, has lead to a dramatic increase in overall survival and a
substantial decrease in morbidity. Patients eyes are now able to be
preserved, and oftentimes, useful visual function is also maintained.
Future directions include preimplantation diagnosis in families with a
genetic predisposition for developing retinoblastoma and targeted
molecular therapy for retinoblastoma, taking advantage of the specific
genetic defects responsible for the tumor.3

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Financial Support: None.

Conflict of Interest: No conflicting relationship exists.

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