REVIEW ARTICLE
Retinoblastoma for Pediatric Ophthalmologists
Alaa AlAli, MD, FRCSC,* Stephanie Kletke, MD,*
Brenda Gallie, MD, FRCSC,*†‡§ and Wai-Ching Lam, MD, FRCSC†¶
Abstract: Retinoblastoma can present in 1 or both eyes and is the most
common intraocular malignancy in childhood. It is typically initiated by
biallelic mutation of the RB1 tumor suppressor gene, leading to malignant
transformation of primitive retinal cells. The most common presentation
is leukocoria, followed by strabismus. Heritable retinoblastoma accounts
for 45% of all cases, with 80% being bilateral. Treatment and prognosis
of retinoblastoma is dictated by the disease stage at initial presentation.
The 8th Edition American Joint Committee on Cancer (AJCC) TNMH
Downloaded from http://journals.lww.com/apjoo by BhDMf5ePHKbH4TTImqenVD7nNEO3Od0IK7zXffF07KoCI626PX2hbNB5FUQQCFK/fUCIbOgmav8= on 12/08/2019
(tumor, node, metastasis, heritable trait) staging system defines evidence-
based clinical and pathological staging for overall prognosis for eye(s)
and child. Multiple treatment options are available in 2018 for retino-
blastoma management with a multidisciplinary team, including pediatric
ocular oncology, medical oncology, radiation oncology, genetics, nurs-
ing, and social work. Survival exceeds 95% when disease is diagnosed
early and treated in centers specializing in retinoblastoma. However,
survival rates are less than 50% with extraocular tumor dissemination.
We summarize the epidemiology, genetics, prenatal screening, diagnosis,
classification, investigations, and current therapeutic options in the man-
agement of retinoblastoma.
Key Words: retinoblastoma, TNMH classification, RB1 mutation
(Asia-Pac J Ophthalmol 2018;7:160–168)
R etinoblastoma can present in 1 or both eyes and is considered
the most common intraocular malignancy in childhood. The
main therapeutic priority for retinoblastoma is to first save the
child’s life through early tumor detection and prevention of meta-
static spread. Secondary goals are globe salvage and maximizing
visual potential. With timely intervention while tumors remain
small, the survival rate for affected children is nearly 100%.1
Globally, mortality is considerably higher due to delayed diag-
nosis, poor access to multidisciplinary retinoblastoma-specific
health care and pathology, lack of genetic testing and counsel-
ing, and socioeconomic factors.2‒4 Advanced retinoblastoma can
directly invade the orbit, spread via the optic nerve to the central
nervous system, or metastasize hematogenously to bone marrow,
From the *Department of Ophthalmology & Vision Sciences, University of Toronto,
Toronto; †Department of Ophthalmology & Vision Sciences, The Hospital
for Sick Children, Toronto; ‡Techna Institute, University Health Network,
Toronto; §Departments of Molecular Genetics and Medical Biophysics,
University of Toronto, Toronto, Canada; and ¶Department of Ophthalmology,
The University of Hong Kong, Hong Kong.
Received for publication February 28, 2018; accepted April 23, 2018.
A.A. and S.K. contributed equally to this review as co-first authors.
B.L.G. is unpaid Medical Director at Impact Genetics.
The authors have no other funding or conflicts of interest to declare.
Reprints: Wai-Ching Lam, MD, FRCSC, Room 301, Level 3, Block B, Cyberport
4, 100 Cyberport Road, Hong Kong. E‑mail: waichlam@hku.hk.
Copyright © 2018 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.201870
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and later to visceral organs. Late diagnosis is therefore associated
with high morbidity and mortality. We predict that improved un-
derstanding of retinoblastoma among primary care providers, pe-
diatric ophthalmologists, and parents will enable early diagnosis
and timely intervention. With safe, evidence-based new therapeu-
tic approaches to clearly define disease stage, collaborative care
with Internet communication specific to retinoblastoma care3,5
(http://depictrb.technainstitute.com/), and location of nearby cen-
ters for retinoblastoma care worldwide (http://map.1rbw.org/), we
would hope that no child should die from retinoblastoma.3 The
yet unaddressed major cause of later death of these children is
second primary malignancy.
EPIDEMIOLOGY
Retinoblastoma occurs worldwide at an estimated rate of 1
in 16,000–18,000 live births, with approximately 8000 new cases
predicted annually.3 Mean age at diagnosis is 27 months for uni-
lateral and 15 months for bilateral retinoblastoma in Canada but
36 and 25 months, respectively, in Kenya, where many children
present with extraocular disease.4 There are no ethnic or sexual
predilections and no geographic or environmental associations
with retinoblastoma.
GENETICS
Retinoblastoma is the prototypic genetic cancer.1 The tumors
have mutation of both copies of the RB1 tumor suppressor gene
located on the long arm of chromosome 13 (13q14), which en-
codes the retinoblastoma protein (pRB). The cellular origin of ret-
inoblastoma is likely a uniquely susceptible cone photoreceptor
precursor cell in the infant retina, which remains within the inner
nuclear layer after losing both alleles of the RB1 tumor suppressor
gene.3,6 This initiates a benign precursor, “retinoma,” which usu-
ally progresses to retinoblastoma with accumulation of increasing
genomic changes and uncontrolled cellular proliferation.7,8
There are 2 major genetic forms of retinoblastoma: heritable
(also known as germline) and nonheritable. Heritable retinoblas-
toma accounts for 45% of all cases; 80% are bilateral, 15% unilat-
eral, and 5% trilateral (bilateral retinoblastoma with pineal/mid-
line neuroectodermal tumor).1 One RB1 allele is mutated in all
cells and a second somatic mutagenic event affects the remaining
allele in a primitive retinal cell (known as the “2-hit model”),
thus initiating tumorigenesis.9 A mutated RB1 allele is inherited
in only 5% of children with heritable retinoblastoma.1 Children of
a parent with heritable retinoblastoma have a 45% chance of be-
ing affected (50% risk of inheritance and 90% penetrance). How-
ever, most heritable retinoblastoma arises de novo and the RB1
mutation may be present in all cells (preconception mutation) or
only a subset of cells, termed “mosaicism” (postconception muta-
tion) (Fig. 1).1,10,11 Most children with retinoblastoma are the first
© 2018 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018 Retinoblastoma for Pediatric Ophthalmologists

A B

C D

FIGURE 1. A, Pedigree of a family with a unilaterally affected father discovered to be mosaic (H1) for a high penetrance RB1 mutation when his second
child was found to have bilateral retinoblastoma (H1).11 The child had late diagnosis requiring intensive therapy, with suboptimal visual prognosis.
B, DePICTRB visualization3,5 demonstrating the child’s follow-up and treatment timeline. C, At presentation, the right eye was staged TNMH29 cT2b and
IIRC25 Group D and the left eye TNMH29 cT1b and IIRC25 Group B. D, After extensive treatments, there was tumor regression with inactive scars bilaterally.
Visual acuity was fix and follow (F&F) in the right eye and 0.2 logarithm of the minimum angle of resolution (logMAR) by Cardiff in the left eye.

family member (proband) with the disease. Children with herita- villus sampling (between 11‒14 weeks’ gestation) or amniocen-
ble retinoblastoma are usually diagnosed earlier and present with tesis (after 16 weeks’ gestation) may be considered so parents
bilateral, multifocal tumors. Frequent examinations under anes- have choices of how to manage the pregnancy if the fetus has the
thesia (EUA) for retinal examination with scleral indentation are RB1 mutation. Amniocentesis can also be offered at 33 weeks’
recommended up to at least 3 years of age to treat tumors when gestation when the risks of miscarriage are lower and manage-
they are as small as possible with minimally invasive therapies.12 able.1 Examination for tumors as soon as possible after birth, fol-
Persons with RB1 germline predisposition also have a high life- lowed by repeated EUA for the first few years of life, facilitates
time risk of developing second primary malignancies, especially early detection of tumors that can be managed with less invasive
osteosarcomas, soft-tissue sarcomas, and melanomas.13‒15
Approximately 55% of cases have nonheritable retinoblasto-
ma that is always unilateral. Of nonheritable retinoblastoma, 98%
result from somatic loss of both RB1 alleles in a susceptible reti-
nal precursor cell, but 2% have normal RB1 alleles (RB1+/+) and
are initiated by somatic amplification of the MYCN oncogene.16
These tumors are always unilateral, nonheritable, and diagnosed
at median 4.5 months.
Genetic testing and counseling are extremely important in
the management of retinoblastoma, involving a laboratory with
high sensitivity to detect RB1 mutations.12 RB1 genetic testing of
the proband may identify heritability, and at-risk family members
may then undergo testing for the specific mutation. Children of a
proband with bilateral retinoblastoma have a 50% risk of carrying
the RB1 mutation, whereas children of an untested unilateral pro-
band have a 7.5% risk (50% × 15%), which can be accurately up-
dated to either 100% or 0% by genetic testing of the proband and FIGURE 2. The Internet and public media now help with awareness
then the fetus if the proband is found to carry an RB1 mutation.11 of retinoblastoma. This mother noticed photoleukorcoria when
The frequency of follow-up for children at risk of retinoblastoma she downloaded pictures from her camera and took her son to the
is informed by the results of genetic testing and counseling. emergency department the next day when Internet searches revealed
that it could be something sinister, like retinoblastoma. Once their son
was diagnosed, the family wanted to spread the word by contacting
PRENATAL SCREENING media outlets. This Finnish newspaper featured the photoleukocoria
Children with a family history of retinoblastoma who car- photographs of the child in July, which directly resulted in another child
ry the RB1 mutation are at risk of tumors at birth. Chorionic being diagnosed with retinoblastoma in September.

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AlAli et al Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018

interventions.17 Infants who had prenatal RB1 mutation detection
followed by early full-term delivery (36‒38 weeks’ gestation) and
coordinated retinal examination had smaller tumors at birth and
improved visual outcomes.
DIAGNOSIS
Retinoblastoma most commonly presents with leukocoria
(white pupillary reflex), resulting from light reflecting off the tu-
mor causing a “glint,” “cat’s eye reflex,” or other similar descrip-
tions by parents and other people caring for the baby (Fig. 2).4,18‒20
Retinoblastoma must be the key differential diagnosis suspected
by the primary care physician or pediatric ophthalmologist when
parents report an abnormal “glow” or “squint.” Too commonly,
the primary physician has forgotten about retinoblastoma and
does not react with immediate concern to the observation of the
parent, leading to significant delay in diagnosis, despite the strong
guidelines for “red reflex” testing as part of routine care.21
Leukocoria is now commonly detected as a white reflection
by flash photography, termed “photoleukocoria” (Fig. 2).22,23 Stra-
bismus is the second most common presentation, which occurs
with vision loss secondary to central macular involvement.4,18,19
Retinoblastoma may be diagnosed during an office eye ex-
amination by a general doctor or pediatrician. All children with
high suspicion for retinoblastoma should immediately be re-
ferred to a retinoblastoma center for diagnostic confirmation and
a staging EUA.24 This also includes a detailed fundus diagram
during dilated indirect ophthalmoscopy with scleral indentation
360 degrees to view the entire retina, documenting the location
and size of all tumors relative to the fovea and optic nerve, pres-
ence of calcification, subretinal fluid, and vitreous and/or subreti-
nal seeding.
CLASSIFICATION
Treatment and prognosis of retinoblastoma depend on the
staging at initial presentation. Tumor size, location, presence of
subretinal fluid and/or seeding, and histopathological features are
all predictors of overall outcome. A multitude of different classifi-
cation systems for retinoblastoma has led to significant confusion
in the literature, preventing proper comparison among studies and
confounding patient care. The International Intraocular Retino-
blastoma Classification (IIRC) staged eyes as Group A (very low
risk) through E (very high risk).25 A subsequent modification of

B C D

E F G

FIGURE 3. Presentation and staging of eyes with retinoblastoma. A, Fundus photograph of a clinically invisible solitary tumor (TNMH29 cT1a, IIRC25 Group
A) detected by OCT at 38 weeks’ gestation, 15 days of age; the child was diagnosed in utero to be H1, her mother’s RB1 mutation. B, As the tumor grows,
it gains blood supply and becomes globular. This fundus photo demonstrates a large central perifoveal tumor and multiple smaller tumors; yellow luteal
pigment at the inferior edge of the central tumor indicates the foveal location. There was less than 5 mm associated subretinal fluid and no evidence of
seeding (TNMH29 cT1b, IIRC25 Group B). C, D, Tumor extends beyond the inner limiting membrane giving rise to vitreous seeding and into the subretinal
space with seeding (TNMH29 cT2b, IIRC25 Group D). E, Fundus photograph of a total exudative retinal detachment overlying a large inferior tumor
(TNMH29 cT2a, IIRC25 Group D). F, Ultrasound biomicroscopy demonstrating an anteriorly situated tumor adjacent to the ciliary body (TNMH29 cT3, IIRC25
Group E); histopathology after enucleation confirmed invasion into the ciliary muscle. G, Unilateral retinoblastoma can mimic advanced Coats disease,
particularly in the presence of retinal detachment. This child was initially diagnosed with Coats disease based on total exudative retinal detachment
without calcification, but vitreous and subretinal seeding were evident during EUA and retinoblastoma diagnosis was confirmed after enucleation.43

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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018 Retinoblastoma for Pediatric Ophthalmologists

this classification26 resulted in severely advanced eyes being clas-
sified with less-affected eyes, so that “Group E” no longer was
understood to designate eyes in danger of extraocular disease that
should be promptly enucleated.3,27,28
The 2017 American Joint Committee on Cancer (AJCC) 8th
edition TNMH (tumor, node, metastasis, heritable trait) clinical
and pathological staging system is the first evidence-based sys-
tem for predicting overall prognosis of both eye(s) and patients
(Fig. 3, Table 1).29 It is informed by an international survey of
1728 eyes with retinoblastoma comparing all the previous clas-
sifications and best separates severity of eye disease and the like-
lihood to save the eye without use of external beam irradiation;
the TNMH has become the gold standard to define the extent of
retinoblastoma at diagnosis in 2018.
Small retinoblastoma tumors initially present as round,
gray intraretinal lesions (Fig. 3A).25 With further growth and ex-
pansion of blood supply, the tumor assumes an irregular lobu-
lated shape, opaque white or pink color, and may have areas of
calcification (Fig. 3B). More advanced tumors may have asso-
ciated vitreous seeding (tumor cells extending beyond the inner
limiting membrane into the vitreous cavity) (Fig. 3C) and subreti-
nal seeding (tumor extension into the subretinal space) (Fig. 3D),
along with exudative retinal detachment (Fig. 3E).
Advanced retinoblastoma may present with anterior chamber
invasion, elevated intraocular pressure with neovascularization,
hyphema, vitreous hemorrhage, cataract, or aseptic orbital celluli-
tis. The most dangerous presentation is aseptic orbital cellulitis,30
often due to central retinal arterial occlusion at the optic nerve
head, causing massive acute tumor and ophthalmic necrosis.31
Retinoblastoma is importantly the first cancer to recognize
the role of germline predisposition by incorporating stage cat-
egory “H” into the AJCC classification. H1 is supported by the
presence of bilateral disease (Fig. 1, Table 1), a family history
of retinoblastoma, a concomitant central nervous system midline
embryonic tumor (trilateral disease), or the presence of high-qual-
ity molecular evidence of an RB1 mutation.29 Those at unknown

TABLE 1. TNMH Clinical Staging in Comparison With IIRC Group Classification of Eyes With Intraocular Retinoblastoma

AJCC 8th Edition TNMH Staging29 IIRC Group25

cTX Unknown evidence of intraocular tumor

cT0 No evidence of intraocular tumor
cT1 Intraretinal tumor(s) with subretinal fluid <5 mm from the tumor base. No vitreous or subretinal seeding
cT1a Tumors ≤3 mm in size and >1.5 mm away from the optic disc and fovea A
cT1b Tumors >3 mm in size and <1.5 mm away from the optic disc and fovea B
cT2 Tumors with retinal detachment/subretinal seeding/vitreous seeding
cT2a Subretinal fluid >5 mm from the tumor base C/D
cT2b Tumors with vitreous seeding and/or subretinal seeding C/D/E
cT3 Advanced intraocular tumor(s) E
cT3a Phthisis or prephthisis bulbi
cT3b Tumor invasion of choroid, pars plana, ciliary body, lens, zonules, iris, or anterior chamber
cT3c Raised intraocular pressure with neovascularization and/or buphthalmos
cT3d Hyphema and/or massive vitreous hemorrhage
cT3e Aseptic orbital cellulitis
cT4 Extraocular tumor(s) involving orbit, including optic nerve
HX Unknown or insufficient evidence of RB1 constitutional mutation
H0 Normal RB1 alleles in blood
H0* Normal RB1 in blood with <1% residual risk mosaicism
H1 Bilateral retinoblastoma, trilateral retinoblastoma, family history of retinoblastoma, or molecular definition of constitutional
RB1 gene mutation
pTX Unknown evidence of intraocular tumor
pT0 No evidence of intraocular tumor
pT1 Intraocular tumor(s) without any local invasion, focal choroidal invasion, or pre- or intralaminar involvement of the optic
nerve head
pT2 Intraocular tumor(s) with local invasion
pT2a Concomitant focal choroidal invasion and pre- or intralaminar involvement of the optic nerve head
pT2b Tumor invasion of stroma of iris and/or trabecular meshwork and/or Schlemm canal
pT3 Intraocular tumor(s) with significant local invasion
pT3a Massive choroidal invasion (>3 mm in largest diameter, or multiple foci of focal choroidal involvement totaling >3 mm, or
any full-thickness choroidal involvement)
pT3b Retrolaminar invasion of the optic nerve head, not involving the transected end of the optic nerve
pT3c Any partial-thickness involvement of the sclera within the inner two thirds
pT3d Full-thickness invasion into the outer third of the sclera and/or invasion into or around emissary channels
pT4 Evidence of extraocular tumor: tumor at the transected end of the optic nerve, tumor in the meningeal spaces around the
optic nerve, full-thickness invasion of the sclera with invasion of the episclera, adjacent adipose tissue, extraocular
muscle, bone, conjunctiva, or eyelids

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AlAli et al Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018

risk or who have variants of unknown significance are catego-
rized HX. A family member who tests negative for the known
RB1 mutation of the proband is considered at population risk
(0.007%) and may be assigned H0. If no mutation is found in a
proband or an unaffected parent of a proband in a lab with sensi-
tivity exceeding 97% for bilaterally affected patients, the residual
risk for undetectable mosaicism is less than 1% and the designa-
tion H0* is suggested.1
Pathological staging (pTNM) can only be performed after
enucleation of the affected eye. Features such as massive cho-
roidal invasion (more than 3 mm in largest diameter, or multiple
foci of focal choroidal involvement totaling more than 3 mm, or
any full-thickness choroidal involvement) (Fig. 4), retrolaminar
invasion of the optic nerve head, scleral invasion, or evidence
of extraocular tumor confer high risk for metastases.29 The pres-
ence of such high-risk features (pT3, pT4) warrants metastatic
surveillance with cerebrospinal fluid and bone marrow analyses
and prophylactic adjuvant systemic chemotherapy.32,33
changing (17%) clinical decisions.35 Additionally, OCT is ex-
tremely helpful in the detection of small invisible tumors that
cannot be identified by indirect ophthalmoscopy alone (Fig.
3A).3,35‒38
For advanced retinoblastoma, ultrasound biomicroscopy
(UBM) is valuable in the precise evaluation of anterior segment
and ciliary body extension (Fig. 3F). In these cases, UBM may
provide useful clinical information for management, such as indi-
cation for enucleation.39
Magnetic resonance imaging (MRI) of the brain and orbit
is preferred over computed tomography (CT) to evaluate optic
nerve and orbital extension and intracranial involvement and to
rule out trilateral disease at initial presentation. The use of MRI
offers better soft-tissue resolution and avoids the radiation of CT,
which increases the risk of second primary malignancy in patients
with germline predisposition to cancer because of their RB1 mu-
tation. The diagnostic sensitivity of MRI to detect high-risk fea-
tures, including postlaminar optic nerve, choroidal, and scleral
invasion, is reportedly 59%, 74%, and 88%, respectively.40

INVESTIGATIONS
Diagnosis of retinoblastoma is made clinically and does not
rely on histopathology; diagnostic fine needle aspiration biopsy
would impose risk of systemic tumor dissemination.7 B-scan ul-
trasonography can assess tumor size and calcification, help to
distinguish retinoblastoma from other pathologies such as Coats
disease and persistent fetal vasculature (PFV), and can be per-
formed with the child awake in the office or at the staging EUA.
Wide-field fundus photography with scleral depression to view
the entire retina during the staging EUA will document the ex-
tent and location of the tumor(s); accurate fundus drawings aid in
monitoring response of tumors to treatment that may alter future
management.
Handheld optical coherence tomography (OCT) performed
on the supine child is valuable in the diagnosis and management
of retinoblastoma for localization of the tumor, detection of optic
nerve infiltration, evaluation of scars and retinal structure after
treatment, and assessment of foveal integrity, which is impor-
tant to assess visual potential.34 In a study of 339 OCT sessions,
OCT was found to play an important role in confirming (83%) or
DIFFERENTIAL DIAGNOSIS
Multiple ocular conditions that present with leukocoria or
strabismus may mimic retinoblastoma and may be differenti-
ated by a comprehensive history, clinical exam, and appropriate
testing.
Generally, PFV and Coats disease are considered the most
common differential diagnoses for unilateral retinoblastoma.19
Of these, PFV is a sporadic developmental ocular disorder re-
sulting from failure of normal hyaloid vasculature regression.41
It often presents with leukocoria in the first days to weeks of life.
Two thirds of cases are unilateral and may be associated with mi-
crophthalmos, retrolenticular fibrovascular mass, elongated cili-
ary processes, cataract, and a funnel-shaped retinal detachment
in advanced cases. A characteristic vascular stalk extending from
the optic nerve to the posterior lens capsule is usually noted on
clinical exam and/or B-scan ultrasonography.
Coats disease is a rare, unilateral, idiopathic nonhereditary
exudative retinopathy presenting most commonly in males dur-
ing the first or second decade of life.42 It presents with a “yellow”

A B C

FIGURE 4. High-risk histopathological features predictive of increased metastatic risk. A, Low magnification histopathological section of a TNMH29 cT2b
(IIRC25 Group D) eye demonstrating massive choroidal invasion, transscleral and extrascleral invasion, and tumor extending beyond the lamina cribrosa.
Clinically, the tumor was multilobulated with overlying exudative retinal detachment and extensive subretinal seeding; optic nerve and fovea were
not visualized at presentation. B, Histopathological section under high magnification demonstrating full thickness tumor invasion of sclera, adjacent
episclera, and adipose tissue (TNMH29 pT4). C, Histopathological section under high magnification showing post‒lamina cribrosa invasion; the tumor did
not extend to the resection margin of the optic nerve.

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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
pupillary reflex due to intraretinal and/or subretinal exudation
secondary to retinal telangiectasia, often associated with serous
retinal detachment (Fig. 3G). Subretinal lipid deposits can be
seen on ultrasonography, and fluorescein angiography shows the
classic telangiectatic vessels. Clinically distinguishing Coats dis-
ease from retinoblastoma can be challenging in advanced cases
with little potential for useful vision. Enucleation is a reasonable
diagnostic/treatment option given the life-threatening potential of
undiagnosed retinoblastoma.43
Congenital cataracts may present with leukocoria but the re-
mainder of the ocular exam is usually normal, and B-scan ultra-
sonography shows no posterior abnormalities. Severe retinopathy
of prematurity, incontinentia pigmenti, and Norrie disease may
progress to retinal detachment and leukocoria. Infectious causes
of leukocoria that can mimic retinoblastoma include ocular toxo-
cariasis and toxoplasmosis, typically in older children with histo-
ry of soil or contaminated food ingestion or exposure to animals.
They typically present with uveitis and posterior or peripheral
subretinal granulomas.17
Other benign tumors such as astrocytic hamartoma and me-
dulloepithelioma are included in the differential diagnosis of
retinoblastoma. Myelinated nerve fiber layer, morning glory syn-
drome, traumatic vitreous hemorrhage, coloboma of the choroid
or optic disc, along with photographic artifact from light hitting
the optic nerve may also present with leukocoria. However, as
retinoblastoma is a potentially life-threatening diagnosis, leuko-
coria requires urgent referral for full expert fundus examination
and diagnosis.19
Retinoma is not a differential diagnosis for retinoblastoma,
as it is on a continuous spectrum of malignancy from benign pre-
malignant to malignant retinoblastoma, and most retinomas in-
deed progress to malignancy.7,8
2018 MANAGEMENT OPTIONS
FOR RETINOBLASTOMA
The primary goal of retinoblastoma management is to save
the child’s life, followed by salvage of the eye and optimization of
FIGURE 5. The multimodal therapeutic options for intraocular retinoblastoma in 2018 include chemotherapy combined with focal therapies and surgical
approaches. A relative “weighting” of value of each therapy for the eye and patient is suggested by font size and box width. Therapies highlighted in
gray are today reserved for salvage of tumors refractory to other modalities.
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Retinoblastoma for Pediatric Ophthalmologists
visual function. Many treatment options are available and depend
on the laterality and extent of disease (Fig. 5). A multidisciplinary
team approach, including 1 or more ophthalmologists focused on
care for children with retinoblastoma, pediatric medical oncolo-
gist, pediatric radiation oncologist, geneticist, social worker, and
others, facilitates optimized care. Retinoblastoma only leads to
death when the disease escapes the confines of the eye; delayed
diagnosis and treatment and excessive focus on saving a blind eye
with advanced disease put the child at risk for extraocular exten-
sion, metastases, and death.
Primary enucleation remains the definitive treatment for ad-
vanced unilateral retinoblastoma (TNMH29 cT3 and IIRC25 Group
E eyes), allowing the child to return to normal life and enabling
histopathological analysis.44 For unilateral retinoblastoma, enu-
cleation is the definitive treatment when the optic nerve is not
visible and in the presence of retinal detachment (TNMH29 cT2a
and IIRC25 Group D eyes) or extensive vitreous seeds (TNMH29
cT2b and IIRC25 Group D eyes) that otherwise require invasive
treatments over several years that are costly to the child and fam-
ily to save an eye with poor vision. Enucleation is strongly rec-
ommended when orbital or optic nerve involvement is suspected,
when there is anterior segment invasion, neovascular glaucoma,
intraocular hemorrhage, orbital cellulitis, and no potential for
useful vision.
The enucleation technique for retinoblastoma minimizes
the potential for globe penetration while obtaining 8–12 mm of
the optic nerve. Postoperative movement of the prosthesis is bet-
ter with the myoconjunctival technique of a simple polymethyl
methacrylate implant and rectus muscles sutured to the conjunc-
tival fornices than with integrated implants with muscles imbri-
cated to the implant.45
Attempts to salvage an eye require consideration of stag-
ing, visual potential, and considerable discussion with the child’s
family. Although small tumors may be managed with focal thera-
pies alone, chemotherapy with focal consolidation is required for
eyes with tumors too large for primary focal therapy or too close
to the optic nerve and macula (TNMH29 cT1b, cT2 and IIRC25
Group B, C, D eyes). Chemotherapy can be systemic or, recently,
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AlAli et al
intra-arterial in specific situations. Systemic chemotherapy (most
commonly intravenous carboplatin, etoposide, and vincristine)
is given over 4 to 6 cycles (every 3‒4 weeks) depending on the
extent of disease. Chemotherapy reduces tumor size, and focal
therapy on repeated follow-up EUAs destroys remnants of tumor
(Fig. 6A). Handheld OCT is excellent to accurately assess tumor
activity related to focal therapy scars.35
Intra-arterial chemotherapy (IAC) has an important role in
unilateral cT1b and cT2 (IIRC C/D) eyes, but important long-term
outcomes, such as visual acuity, extraocular disease, and death,
have not yet been scientifically compared.46 Characteristically the
choroid shows changes after IAC (Fig. 6C), so the lifelong vision
outcome will not be known until there is long-term follow-up and
will best be determined by prospective studies. Intra-arterial che-
motherapy is excellent for children with unilateral retinoblastoma
[cT1b/cT2 (IIRC Groups B/C/D) eyes (Fig. 6B)] when the optic
nerve and fovea are visualized at presentation so there is no risk
of masking high-risk features for extraocular extension. The most
commonly used intra-arterial chemotherapeutic agent is melpha-
lan, sometimes combined with topotecan and/or carboplatin. Al-
though IAC reportedly has high rates of globe salvage (66% of
all eyes and 57% with advanced disease), the literature is limited
by variable staging schemes, absence of defined drug protocols,
and lack of long-term follow-up data.46 For well-selected patients,
A Vitreous seeds are generally resistant to systemic and intra-
B cryotherapy at the injection site after needle removal. Intravit-
C ment centers worldwide found no extraocular extension of tumor
FIGURE 6. Chemotherapy reduces tumor volume so that focal therapy,
such as laser photocoagulation, can be used to physically eradicate
any remaining live tumor cells. A, Tumor regression after systemic
chemotherapy and laser treatment to obtain long-term regression and
inactive scar (TNMH29 cT1b and IIRC25 Group B). B, Tumor regression
after IAC and laser treatment in unilateral retinoblastoma (TNMH29
cT1b and IIRC25 Group B) to obtain long-term regression and inactive
scar. C, Note the peripheral choroidal pigmentary disturbance
characteristic of treatment with IAC, which is not seen in the untreated
normal right eye. In contrast, this choroidal pigmentary change is not
evident after treatment with systemic chemotherapy.
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
the outcomes of IAC to eradicate the cancer efficiently are im-
pressive.47 Systemic and ocular complications are uncommon.
Systemic complications include unsuccessful catheterization,
stroke or a neurological complication (rare), groin hematoma,
fever, neutropenia, bronchospasm, nausea, and vomiting. Ocular
complications include central retinal artery occlusion, optic atro-
phy, extraocular muscle dysfunction, retinal detachment, vitreous
hemorrhage, ptosis, enophthalmos, and phthisis bulbi. Transient
periorbital edema and loss of eyelashes may also be observed.
Incompletely reported are extraocular tumor and metastasis.
Focal therapies include laser photocoagulation (Fig. 6) and
cryotherapy.48 Laser photocoagulation involves argon laser in-
direct (532 nm) and transpupillary indirect or transcleral diode
(810 nm) laser to first destroy the tumor blood supply, then di-
rect treatment on the regressing tumor. Laser treatment is best
given after chemotherapy is completed, as it cuts off the access
of chemotherapy to the tumor. Optical coherence tomography has
greatly improved the accuracy of laser treatment and minimized
local complications, by both discovering tiny tumors invisible to
direct viewing with indirect ophthalmoscopy or cameras (Fig.
3A) and accurately identifying residual or recurrent tumor.34‒36
Cryotherapy with a triple freeze-thaw technique for small and re-
current peripheral tumors directly kills tumor cells. A single cryo-
therapy freeze in peripheral retina 24‒48 hours before systemic
chemotherapy (prechemo cryotherapy) disrupts the blood-retina
barrier and increases penetration of chemotherapy.49
arterial chemotherapy mainly due to the avascular nature of the
vitreous. Intravitreal chemotherapy (melphalan and/or topotecan)
is used to control vitreous seeds, previously the most difficult
form of intraocular retinoblastoma to cure.50,51 The technique
involves an anterior chamber paracentesis or ocular massage to
reduce intraocular pressure, followed by intravitreal injection
under microscopic visualization, with 3 cycles of freeze-thaw
real melphalan injection can be repeated monthly depending on
the clinical response. The main complications include vitreous
hemorrhage, retinal tears/detachment, damage to the lens leading
to cataract, and endophthalmitis. Focal retinal pigment epithelial
changes reflect direct retinal toxicity when the drug is not well
dispersed through the vitreous.52,53 A recent retrospective study of
intravitreal chemotherapy injections in 10 retinoblastoma treat-
when used with precautions, such as selection of eyes where the
source of seeds is controlled, preinjection lowering of intraocular
pressure, and postinjection cryotherapy to the needle and needle
track.50,51,54
External beam radiotherapy is now only considered as a last
resort salvage option for eyes with tumors refractory to all other
therapies. Radiation increases the risk of second primary malig-
nancy with standardized incidence ratio of 20.4 for radiotherapy,
increasing to 26.4 when radiation was combined with alkylating
chemotherapy55 in H129 patients. Although proton beam radia-
tion56 and stereotactic radiation57,58 intend to reduce radiation dos-
es to normal tissues, they still may carry risk for second primary
malignancy.59 Other local long-term adverse effects of radiation
include health of soft tissues and bone around the eye, cataract
formation, and keratoconjunctivitis sicca.60,61
Brachytherapy is focal therapy using a radioactive source
(iodine-125, ruthenium-106) applied externally to the eye to
© 2018 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
treat specific localized intraocular tumors.58,62,63 The radioactive
plaques are shielded to minimize radiation exposure to bone, and
there is no evidence of risk to increase second primary malignan-
cy.64 The adverse effects of plaque radiotherapy are local, includ-
ing cataract, glaucoma, and radiation retinopathy.
The most recent addition to the treatment choices through
the long course of therapies to save an eye from retinoblastoma
is pars plana vitrectomy (PPV). Previously, opening an eye with
active tumor was considered heresy! Now, after vitreous seeds
are uncontrolled by main-line therapies, PPV with melphalan in
the irrigation fluid is shown to be an effective option without evi-
dence of extraocular disease.65 However, PPV is reserved for eyes
with no evidence of optic nerve involvement both clinically and
on neuroimaging, in which case enucleation is the safest option.
In patients who are candidates for PPV, a laser barrier around the
solid tumor source of seeds can be applied before the planned
PPV, with endolaser reinforcement and silicone oil tamponade at
the time of PPV to stabilize the retina.
CONCLUSIONS
Our current effort should aim to achieve a near to zero-
death cancer in retinoblastoma within the next 10 years. This
can be potentially achieved through improved understanding of
retinoblastoma among primary care providers, pediatric ophthal-
mologists, parents, and the public. Early diagnosis and timely
intervention is key to improved overall survival of patients with
retinoblastoma. Optimal management of retinoblastoma is multi-
disciplinary, including the ophthalmologist(s) focused on retino-
blastoma, medical and radiation oncologists, geneticists, nurses,
social workers, psychologists, and so on. Initiatives such as na-
tional tumor board rounds and DePICTRB visualization (demo at
http://depictrb.technainstitute.com/)3,5 to support communication
across the whole management team, including parents, aim to max-
imize the understanding of retinoblastoma from both clinical and
research perspectives and maximize opportunities for patients.
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