Indian J Pediatr

DOI 10.1007/s12098-017-2395-0

REVIEW ARTICLE

Retinoblastoma
Raksha Rao1 & Santosh G. Honavar2

Received: 15 March 2017 / Accepted: 18 May 2017

# Dr. K C Chaudhuri Foundation 2017

Abstract Retinoblastoma represents 3% of all childhood can-cers, Introduction

and is the most common intraocular malignancy of child-hood. It
is fatal, if untreated. White eye reflex, also known as leukocoria, Retinoblastoma was first described by Pawius in the sixteenth
is the commonest sign, followed by strabismus. The pediatricians century [1]. But it was not until 1809 that retinoblastoma was
have a very important role to play in the diagnosis of this discovered to originate from the retina, when Wardrop per-
relatively rare, but easily detectable tumor. Early diagnosis yields formed meticulous dissection on eyes with retinoblastoma,
better results. The management of reti-noblastoma has gradually and called it fungus hematodes [1]. The incidence of retino-
evolved over the past few decades, with an aim to not only blastoma is 1 in every 15,000 to 18,000 live births [2]. There
preserve life and eye, but also optimize residual vision. The is no variation among different races and gender. There are an
treatment of retinoblastoma is multimodal, with chemotherapy, estimated 5000 new cases worldwide annually, with India
focal treatment including trans-pupillary thermotherapy, alone contributing to 1500–2000 cases. A review of
cryotherapy and laser photocoagulation, radia-tion therapy and population-based cancer registries survey reported that the
surgery, all playing a vital role. Intravenous chemotherapy has age-adjusted incidence of retinoblastoma in India is 1.3–12.3
been the mainstay of treatment for the past two decades, and still per million children aged 0–14 y [3]. In countries of Asia and
continues to be the most extensively used eye-saving modality of Africa, not only is the incidence higher, but the mortality rates
treatment. Periocular and intravitreal chemotherapy have specific for retinoblastoma is also higher, owing to the delay in diag-
indications in the management of retinoblastoma. Intra-arterial nosis, advanced disease at presentation, lack of access to ad-
chemotherapy has emerged as a promising alternative for vanced medical facilities, and absence of standard manage-
advanced and refractory retinoblasto-ma, both as a primary and ment protocols.
secondary therapy. Recent advances in genetics of retinoblastoma
have also helped in improving the overall clinical management of
this malignancy. Genetics of Retinoblastoma
. . . .
Keywords Eye Retina Malignant tumor Retinoblastoma Retinoblastoma is a malignancy associated with somatic mu-
. tation or germline mutation [2, 4]. Knudson proposed the two-hit
Chemotherapy Radiotherapy
hypothesis where he described the occurrence of two con-
secutive mutations for the conversion of a normal retinal cell into
a malignant cell (Fig. 1). In heritable retinoblastoma, the first
* Santosh G. Honavar
mutation is in the germ cell, and this ‘first hit’ is carried in every
[email protected]
cell in the body, making them prone not only to retino-blastoma,
1 but also to other second cancers (most commonly
Orbit, Oculoplasty and Ocular Oncology, Chaithanya Eye
Hospital and Research Institute, Trivandrum, India pinealoblastoma, osteosarcoma and soft tissue sarcomas) [4]. The
2 ‘second hit’ occurring in the retinal cells during retinal
Ocular Oncology Service, National Retinoblastoma
Foundation, Centre for Sight, Ashoka Capitol, Road No 2, development causes retinoblastoma. In non-heritable retino-
Banjara Hills, Hyderabad 500034, India blastoma, both hits occur in the retinal cell, and thus the
 Indian J Pediatr

Fig. 1 Genetics of
retinoblastoma

mutation is confined to one single cell in the retina. subretinal seeds. In contrast, an endophytic retinoblastoma
Heritable retinoblastoma constitutes 30–40% of all arises from the inner retinal layers, progressively fills the vit-
retinoblastomas, while the rest 60–70% are non-heritable. reous cavity, and causes vitreous seeding (Fig. 2b). At times,
One-fourths of the germline mutations are familial with the tumor may be a combination of these two growth patterns.
autosomal dominant in-heritance pattern, and the others are Diffuse infiltrating retinoblastoma is a rare pattern of presen-
de-novo non-familial germline mutations [4]. tation where there is no obvious mass, only a flat retinal infil-
RB1 is a tumor suppressor gene that was identified in asso- tration, and is acalcific. It is generally seen in older children,
ciation with retinoblastoma and it validated the two hit and the incidence is less than 2%. Diffuse anterior retinoblas-
hypoth-esis. RB1 gene is located in the long arm of toma, a recent entity, is considered as an anterior variant of
chromosome 13 (13q), and most of the mutations are diffuse infiltrating retinoblastoma [5].
nonsense codons or frame shifts. Sometimes retinoblastomas Patients with anterior extension of the tumor can present
are caused by genomic de-letion of chromosome 13q, a with white fluffy exudates in the anterior chamber resembling
syndrome known as RB1 gene deletion syndrome, where the a hypopyon, called pseudohypopyon [2]. Neovascularization
affected individual has varying degrees of dysmorphic of iris and glaucoma are other clinical presentations seen in
features and neurodevelopmental de-lays [2]. patients with advanced tumor (Fig. 2c). Orbital cellulitis-like
picture occurs when a large tumor undergoes necrosis and
induces inflammation in and around the eye (Fig. 2d).
Clinical Features Retinoblastoma which has extended outside the confines of
the eye is known as orbital retinoblastoma when the patient
Retinoblastoma is usually diagnosed at an average age of 18 generally presents with proptosis.
mo, with 95% of children diagnosed by 5 y of age. Germline
retinoblastomas can present as early as first month and spo-
radic retinoblastomas are detected at an average age of 24 mo Differential Diagnosis
[2]. Retinoblastoma can be unilateral or bilateral. All bilateral
cases are positive for germline mutation, whereas only 10– The most important differential diagnosis is Coats’ disease
15% patients with unilateral retinoblastoma carry a germline [6]. There are several other lesions that can simulate
mutation. The most common presenting symptom and sign is
leukocoria. Strabismus is the second most common sign. The
other common clinical features are as listed in Table 1.
Retinoblastoma typically manifests as a unifocal or multi- Table 1 Clinical features of retinoblastoma
focal, well-circumscribed, dome-shaped retinal mass with di- Leukocoria
lated retinal vessels. Although initially transparent and diffi- Strabismus
cult to visualize, it grows to become opaque and white. When Poor vision
small, the tumor is entirely intraretinal. As it enlarges, it Red painful eye
grows in a three-dimensional plane, extending away from the Vitreous hemorrhage
vitre-ous cavity (exophytic) or towards it (endophytic) [2]. Phthisis bulbi
In the exophytic growth pattern, the tumor arises from the Sterile orbital cellulitis
outer retinal layers and causes diffuse retinal detachment (Fig. Proptosis
2a). It is most often associated with numerous small
Indian J Pediatr

Fig. 2 Clinical presentation of

retinoblastoma (a) Exophytic
growth pattern with diffuse
subretinal fluid (b) Endophytic
growth pattern with diffuse
vitreous seeds (c) Advanced
retinoblastoma with neovascular
glaucoma (d) Advanced
retinoblastoma presenting as
sterile orbital cellulitis

retinoblastoma and are known as pseudoretinoblastomas. Grouping and Staging

The important differential diagnoses are listed in Table 2.
The grouping system is for retinoblastomas confined to the eye,
where eye salvage is the end point, whereas the staging system is
Imaging for predicting survival in patients with retinoblasto-ma.
International Classification of Retinoblastoma (ICRB) was
While the diagnosis of retinoblastoma is mostly clinical, an- devised in 2003 and includes both grouping and staging [9]. The
cillary tests like ultrasonography, fluorescein angiography grouping is based on the tumor size, location, severity and
(FA), optical coherence tomography (OCT), computed to- presence of subretinal and vitreous seeds (Table 3).
mography (CT) and magnetic resonance imaging (MRI) aid in
the documentation of the disease and differentiation of
pseudoretinoblastomas from retinoblastoma [7, 8]. CT scan Management
also helps diagnose extraocular extension, while MRI is most
appropriate to detect optic nerve invasion and to screen for Management of a child with retinoblastoma is aimed at
pinealoblastoma in heritable retinoblastoma. achieving the three sequential goals of life salvage, eye sal-
vage and optimal vision. It involves identification of the
tumor group and stage, decision-making regarding the
Table 2 Pseudoretinoblastoma
appropriate therapeutic measure (Table 4), and meticulous
Coats’ disease follow-up for monitoring the treatment progress and
Persistent fetal vasculature detection of any recurrence.
Vitreous hemorrhage
Toxocariasis Intravenous Chemotherapy
Familial exudative vitreoretinopathy
Retinal detachment Currently, intravenous chemotherapy (IVC) is the most wide-ly
Congenital cataract used treatment in India. Used as a combination triple drug
Coloboma therapy of vincristine, etoposide and carboplatin, and typically for
Astrocytic hamartoma 6 cycles, chemotherapy with focal consolidation achieves
Combined hamartoma excellent success rates in the primary management of retino-
Endogenous endophthalmitis blastoma. Chemotherapy alone can achieve an impressive tu-mor
Retinopathy of prematurity
control in less advanced cases, with success rates of 100%, 93%
and 90% in ICRB groups A, B and C, respectively (Fig. 3a and b)
Medulloepithelioma
[10–12]. Rates of regression of retinoblastoma and eye salvage
X-linked retinoschisis
with standard triple-drug chemotherapy have been suboptimal for
Incontinentia pigmenti
ICRB group D and E tumors. In group D eyes, approximately
Juvenile xanthogranuloma
half of the eyes require either external beam radiation therapy
Norrie’s disease
(EBRT) or enucleation for tumor
 Indian J Pediatr

Table 3 International classification of retinoblastoma Periocular Chemotherapy

Grouping:
Group A: Small tumor Retinoblastoma ≤3 mm in size Periocular topotecan or carboplatin achieves rapid levels within
Group B: Larger tumor Rb > 3 mm, the vitreous in 30 min which lasts for hours, and attains doses that
Macular location (≤3 mm to foveola), are six to ten times higher than that achieved by IVC. Periocular
Juxtapapillary location (≤1.5 mm to disc)
chemotherapy (POC) is used for advanced groups D or E with
Clear subretinal fluid ≤3 mm from margin
Group C: Focal seeds Subretinal seeds ≤3 mm from retinal tumor diffuse vitreous seeds in which a higher local dose of chemother-
Vitreous seeds ≤3 mm from retinal tumor apy is desired. It is administered by posterior sub-tenon injection
Subretinal & Vitreous seeds ≤3 mm from in the quadrant closest to the location of the vitreous seeds. High-
retinal tumor dose chemotherapy with concurrent periocular carboplatin has
Group D: Diffuse Subretinal seeds >3 mm from retinal tumor
seeds Vitreous seeds >3 mm from retinal tumor been tried as a primary management strategy, specifically in eyes
Subretinal & Vitreous seeds >3 mm from with diffuse vitreous seeds [14]. This has led to better tumor
retinal tumor control in advanced cases, with 95% eye salvage rate in eyes with
Group E: Extensive Rb occupying 50% globe focal vitreous seeds and a 70% eye salvage rate in those with
retinoblastoma Neovascular glaucoma
diffuse vitreous seeds (Fig. 3c and d) [14].
Opaque media (from hemorrhage in anterior
chamber, vitreous, or subretinal space)
Invasion of postlaminar optic nerve, choroid Intra-Arterial Chemotherapy
(2 mm), sclera, orbit, anterior chamber
Staging:
Suzuki & Kaneko described the technique of ‘selective oph-
Stage 0 Unilateral or bilateral retinoblastoma
and no enucleation thalmic artery infusion’ in 2004 by the balloon technique,
Stage I Enucleation with complete histological where a micro-balloon catheter positioned just distal to the
resection orifice for the ophthalmic artery, by a transfemoral artery ap-
Stage II Enucleation with microscopic tumor residual proach, is inflated and chemotherapy is injected with flow
(anterior chamber, choroid, optic nerve, sclera)
Stage III Regional extension
directed into the ophthalmic artery [15].
A. Overt orbital disease In 2006, Abramson and Gobin pioneered direct intra-
B. Preauricular or cervical lymph arterial (ophthalmic artery) infusion or superselective intra-
node extension arterial chemotherapy (IAC) or Bchemosurgery^ [16]. The
Stage IV Metastatic disease
procedure is performed under general anesthesia using a ster-
A. Hematogenous metastasis
1. Single lesion ile technique (Fig. 4a and b). Through a transfemoral ap-
2. Multiple lesions proach, the ipsilateral internal carotid artery is catheterized,
B. CNS extension and the arterial anatomy visualized with serial angiography
1. Prechiasmatic lesion runs. The ostium of the ophthalmic artery is superselectively
2. CNS mass
3. Leptomeningeal disease
catheterized, and chemotherapeutic drugs injected [16].
IAC has emerged as an effective treatment for advanced
Rb Retinoblastoma retinoblastoma (Fig. 4c and d). It can be used as a primary
therapy in advanced cases, or as a secondary therapy in
control [10]. A combination of chemotherapy and radiation recur-rent cases. Shields et al. observed 94% globe salvage
in eyes with vitreous seeds has yielded globe salvage rates in group D eyes, and 91% vitreous seed regression, when
vary-ing from 22 to 70% [13]. IAC was used as a primary therapy [17–19].

Table 4 Decision-making in the

management of retinoblastoma: Primary tumor: Options for treatment
treatment options Unilateral advanced (Groups D and E) IAC, IVC, Enucleation
Unilateral less advanced (Groups A, B and C) IAC, IVC, Focal therapy
Bilateral advanced (Groups D and E) IVC + POC
Bilateral less advanced (Groups A, B and C) IVC
Recurrent tumor: Options for treatment
Solid tumor IVC, IAC, Plaque radiation, Enucleation
Subretinal seeds IVC, IAC
Vitreous seeds IVitC

IAC Intra-arterial chemotherapy; IVC Intravenous chemotherapy; POC Periocular chemotherapy; IVitC
Intravitreal chemotherapy
Indian J Pediatr

Fig. 3 Intravenous chemotherapy

in retinoblastoma (a) A group C
eye (b) After
6 cycles of standard-dose chemo-
therapy (c) A group D eye with
fine diffuse vitreous seeds (d)
Complete regression after 6 cy-
cles of high-dose chemotherapy
with 2 doses of concurrent
periocular carboplatin

Intravitreal Chemotherapy a potentially safe technique to perform intravitreal

injections to prevent extraocular extension of the tumor
Vitreous seeds are aggregates of tumor cells found in the [21]. They ad-vocated the application of triple freeze-thaw
avas-cular vitreous, which are relatively resistant to the cryotherapy at the injection site to prevent egress of the
effect of intravenous chemotherapy due to lack of blood tumor cells in the needle track (Fig. 5a and b).
supply. These appear due to the disruption of the apical With melphalan, vitreous seed regression ranging from 85
tumor either spontaneously (primary) or treatment-induced to 100% of eyes and globe salvage in 80–100% of eyes have
necrosis (sec-ondary). Suboptimal concentration of been reported [22–24]. Intravitreal melphalan is given as a
chemotherapeutic agents in the vitreous results in weekly injection until regression. A combination of intravit-
persistence of vitreous seeds [20]. Intravitreal real melphalan and topotecan has also been used to achieve
chemotherapy (IVitC) achieves higher drug concentration excellent regression in refractory vitreous seeds. The authors
within the vitreous and effectively causes re-gression of have used topotecan as monotherapy in achieving vitreous
vitreous seeds, without associated systemic side effects. seed regression in 36 eyes (Fig. 5c and d). Topotecan is a very
Melphalan is now the most extensively used drug to control safe drug for intraocular use, is stable in solution and can be
the vitreous disease in retinoblastoma. Munier et al. discussed given as a 3-weekly injection.

Fig. 4 Intra-arterial
chemotherapy: Procedure in the
cath lab (a) Patient under
general anesthesia with a
transfemoral cathether (b) An
angiography performed with the
microcatheter at the ostium of
the ophthalmic artery, showing
a patent ophthalmic artery (c) A
group E eye with a very large
tumor and diffuse subretinal
fluid (d) After 3 cycles of intra-
arterial chemotherapy
 Indian J Pediatr

Enucleation

Enucleation is the oldest form of treatment for retinoblas-

toma, and is still indicated in advanced cases [11].
Unilateral disease with no salvageable vision is best treat-
ed by enucleation and the patient can be rid of the disease
for life. Enucleation is a simple procedure, although extra
care needs to be taken when handling an eye with retino-
blastoma to avoid accidental perforation that can potential-
ly cause orbital seeding of the tumor. A primary orbital
implant (silicone, polymethylmethacrylate, porous poly-
ethylene, or hydroxyapatite) placed in the socket provides
adequate static and dynamic cosmesis.
An enucleated eyeball is always submitted for patholo-
Fig. 5 Intravitreal chemotherapy (a) Pars plana intravitreal injection gy to assess for high risk factors (HRF). HRF include
of topotecan at a dose of 30 μg in 0.15 ml with a 30-gauge needle (b) significant invasion of the uvea, anterior segment, or optic
Triple freeze-thaw cryotherapy at the injection site (c) Before and (d) nerve. In a landmark paper by Honavar et al., the need for
after 2 doses of intravitreal topotecan injections in an eye with
recurrent diffuse vitreous seeds after 6 cycles of chemotherapy
adjuvant chemotherapy has been emphasized to reduce the
risk of secondary orbital recurrence and systemic metasta-
sis [29]. The incidence of metastasis was 4% in those who
Radiation Therapy received adjuvant therapy, compared with 24% in those
who did not. Hence when HRF is positive, adjuvant treat-
Retinoblastoma is a highly radiosensitive tumor, and radiation ment with chemotherapy and/or EBRT is indicated.
therapy can be curative. Radiation in the form of external Adjuvant chemotherapy consists of a combination of vin-
beam radiation therapy was the most popular globe-salvage cristine, etoposide and carboplatin given 4-weekly for 6
therapy in retinoblastoma before the introduction of chemo- cycles [29].
therapy in 1990s. Although it is no longer the primary modal-
ity of treatment for retinoblastoma due to the associated com-
plications, it has its own therapeutic indications including re- Orbital Retinoblastoma
calcitrant cases, and as a part of multimodal treatment in or-
bital retinoblastoma. Episcleral plaque radiotherapy is a form Orbital retinoblastoma is an advanced form of retinoblastoma
of brachytherapy wherein the source of radiation is placed on seen mostly in developing countries of Asia and Africa. The
the episclera adjacent to the tumor, and the tumor absorbs incidence varies among different countries, and is in the range
radiation, sparing other healthy ocular tissues from the ill- of 18–40% [30]. Primary orbital retinoblastoma is the orbital
effects of radiation [25]. It is now used as a secondary therapy extension of the disease which is evident at presentation ei-
for recurrent cases in tumors not amenable to focal therapy. ther clinically or radiologically. Most of the patients present
with proptosis, or a large fungating mass which bleeds on
Focal Therapy touch. Secondary orbital retinoblastoma occurs in an enucle-
ated socket after an uncomplicated surgery. It may present as
Focal therapy in retinoblastoma includes cryotherapy, an orbital mass with an unexplained displacement of the im-
transpupillary thermotherapy, and laser therapy. These are plant, or a palpable orbital mass. Accidental retinoblastoma
used for consolidation once the tumor has attained a occurs in the event of an inadvertent perforation of the eye
consid-erably lower volume with chemoreduction, usually harboring retinoblastoma. This can occur due to improper
after 2 or 3 cycles, or for the treatment of small recurrent enucleation technique, or various intraocular surgeries in an
tumors or subretinal seeds [26–28]. However, they can eye with unsuspected intraocular retinoblastoma. Overt orbit-
also be used as the sole therapy for small retinoblastomas al retinoblastoma refers to previously unrecognized
(Group A or B). Transscleral cryotherapy involves freezing extrascleral or optic nerve extension discovered during enu-
the tumor under v i s u a l i z a t i o n u s i n g i n d i r e c t cleation as an episcleral nodule, or an enlarged and inelastic
o p h t h a l m o s c o p y. I n thermotherapy, hyperthermia optic nerve with or without nodular optic nerve sheath.
generated by infrared radiation at subphotocoagulation Microscopic orbital retinoblastoma is identified on histopath-
levels destroys the tumor. Photocoagulation using argon ological examination of the enucleated eyeball as full thick-
green laser (532 nm) is deliv-ered with an indirect laser ness scleral infiltration, extrascleral extension or invasion of
delivery system which causes tumor apoptosis. the optic nerve.
Indian J Pediatr

The presence of orbital disease is generally known to Prenatal Genetics

carry a poor prognosis. Orbital disease increases the risk of
systemic metastasis by 10–27 times and the mortality rates To prevent transmission of the disease from parents to off-
range from 25 to 100% [30]. However, with an intensive spring, genetic testing for germline mutations can be done at
multimodal management and careful monitoring, patients specialized laboratories. RB1 is the only gene that is implicat-
with orbital dis-ease are known to do well (Fig. 6a–d). ed in retinoblastoma. However, there are different types of
mutations affecting this gene. Direct DNA sequencing detects
75% of the mutations, and PCR amplification detects yet an-
Metastatic Retinoblastoma other 20% of the mutations. Peripheral blood lymphocytes or
tumor tissue, when available, are sampled for the detection of
With an incidence of less than 5% of all retinoblastoma cases, the mutation [32].
metastatic retinoblastoma is most often seen in developing In heritable retinoblastoma, once the mutation is identified
countries. It usually occurs as a relapse following enucleation in the lymphocytes, the presence of the same mutation is test-
for intraocular retinoblastoma, especially in those who had ed in the fetus (sibling or offspring) by chorionic villus biopsy
high risk pathologic features [31]. Most commonly, metastasis or amniocentesis. If the mutation is found, a decision to ter-
occurs to the central nervous system (CNS), bone and bone minate the pregnancy can be made [32].
marrow. The metastasis occurs in one of the three ways – by In non-heritable retinoblastoma, if the tumor tissue is avail-
direct dissemination into the CNS via the optic nerve, choroi- able from an affected individual, it can be sampled to detect
dal invasion and hematogenous spread, or orbital extension the type of mutation. If the same mutation is also found in the
with lymph node involvement and hematogenous spread. blood of the patient, the individual is positive for germline
Bony metastasis, usually involving the long bones or the cra- mutation and the offspring can be tested for the same muta-
niofacial bones, causes non-tender palpable mass. tion. However, if no mutation is found in the blood, the tumor
Cerebrospinal fluid cytology, bone marrow evaluation and is nongermline (sporadic), without any risk of transmission of
whole body imaging are done in all cases of metastatic retino- the disease to the offspring. In case no tumor tissue is avail-
blastoma for staging the disease. Use of high-dose chemothera-py able, lymphocytes are sampled for the type of RB1 mutation,
with autologous stem cell rescue (ASCR) has offered some but the interpretation of a negative result in these cases is
encouraging results. However, most of the experience is in stage difficult. Either the patient has a sporadic retinoblastoma, or a
4a disease that does not involve the CNS. The use of radiother- germline mutation that escaped detection by the currently
apy and intrathecal chemotherapy for CNS lesions have been available techniques.
recommended, although the prognosis for such advanced meta- Preimplantation genetic testing for carriers of mutation
static retinoblastoma continues to remain grim [31]. involves the identification of RB1 mutation in a blasto-
mere (8-cell embryo) which is obtained by in vitro fertil-
ization (IVF) technique. The small material is amplified by
polymerase chain reaction (PCR) and the blastomere
without the RB1 mutation maybe implanted for a success-
ful pregnancy [3, 32].

Conclusions

The management of retinoblastoma revolves around having a

sound knowledge of the disease, choosing the best treatment for
the patient among the various available options and careful
monitoring for recurrences. A pediatrician plays a vital role in the
diagnosis of the disease, and any case of leukocoria and strabis-
mus must be referred urgently to an ophthalmologist for a thor-
ough evaluation to rule out retinoblastoma. Retinoblastoma has a
Fig. 6 Multimodal management in orbital retinoblastoma (a) External very high cure rate, and is best managed in an integrated retino-
photograph of primary orbital retinoblastoma left eye taken during blastoma clinic under the watchful monitoring of an expert ocu-
examination under anesthesia (b) Axial computed tomography image lar oncologist. The recent advances in the management of reti-
displaying extraocular extension of the intraocular tumor left eye (c)
noblastoma and a holistic approach have rendered it eminently
After 12 cycles of doses of high-dose chemotherapy, external beam
ra-diotherapy and enucleation (d) Healthy child cured of orbital curable - prognosis for life salvage is now around 98%, with 90%
retinoblas-toma, with a well-fitting prosthesis eye salvage and 80% vision salvage.
 Indian J Pediatr

Contributions RR: Drafting of the manuscript and figure compilation; 16. Abramson DH, Marr BP, Dunkel IJ, et al. Intra-arterial chemo-
SGH: Concept, critical revision and will act as guarantor for the paper. therapy for retinoblastoma in eyes with vitreous and/or
subretinal seeding: 2-year results. Br J Ophthalmol. 2012;96:
Compliance with Ethical Standards 499–502.
17. Shields CL, Manjandavida FP, Lally SE. Intra-arterial
Conflict of Interest None. chemothera-py for retinoblastoma in 70 eyes: outcomes based
on the interna-tional classification of retinoblastoma.
Ophthalmology. 2014;121: 1453–60.
Source of Funding None.
18. Shields CL, Jorge R, Say EA, et al. Unilateral retinoblasto-ma
managed with intravenous chemotherapy versus intra-arterial
chemotherapy: outcomes based on the international
References classification of retinoblastoma. Asia Pac J Ophthalmol.
2016;5:97–103.
19. Shields CL, Kaliki S, Al-Dahmash S, et al. Management of ad-
1. Albert DM. Historic review of retinoblastoma. Ophthalmology. vanced retinoblastoma with intravenous chemotherapy then
1987;94:654–62. intra-arterial chemotherapy as alternative to enucleation. Retina.
2. Shields J, Shields C. Retinoblastoma: introduction, genetics, 2013;33:2103–9.
clini-cal features, classification. In: Shields J, Shields C, editors. 20. Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemothera-
Atlas of Intraocular Tumors, 3rd ed. Philadelphia: Lippinocott, py for vitreous disease in retinoblastoma revisited: from prohibition
Wolters Kluwer; 2016. p. 311–4. to conditional indications. Br J Ophthalmol. 2012;96:1078–83.
3. Satyanarayana L, Asthana S, Labani SP. Childhood cancer inci- 21. Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A,
dence in India: a review of population-based cancer registries. Beck-Popovic M. Profiling safety of intravitreal injections for
Indian Pediatr. 2014;51:218–20. retinoblas-toma using an anti-reflux procedure and sterilisation
4. Nichols KE, Walther S, Chao E, Shields C, Ganguly A. Recent of the needle track. Br J Ophthalmol. 2012;96:1084–7.
advances in retinoblastoma genetic research. Curr Opin
22. Ghassemi F, Shields CL. Intravitreal melphalan for refractory
Ophthalmol. 2009;20:351–5. or recurrent vitreous seeding from retinoblastoma. Arch
5. Jijelava KP, Grossniklaus HE. Diffuse anterior retinoblastoma: Ophthalmol. 2012;130:1268–71.
a review. Saudi J Ophthalmol. 2013;27:135–9.
23. Francis JH, Abramson DH, Gaillard MC, Marr BP, Beck-
6. Shields CL, Schoenberg E, Kocher K, et al. Lesions simulating
Popovic M, Munier FL. The classification of vitreous seeds in
retinoblastoma (pseudoretinoblastoma) in 604 cases: results
retinoblasto-ma and response to intravitreal melphalan.
based on age at presentation. Ophthalmology. 2013;120:311–6.
Ophthalmology. 2015;122:1173–9.
7. Rootman DB, Gonzalez E, Mallipatna A, et al. Hand-held high-
24. Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melpha-
resolution spectral domain optical coherence tomography in
lan for persistent or recurrent retinoblastoma vitreous seeds: prelim-
retino-blastoma: clinical and morphologic considerations. Br J
inary results. JAMA Ophthalmol. 2014;132:319–25.
Ophthalmol. 2013;97:59–65.
25. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for ret-
8. Shields J, Shields C. Retinoblastoma: diagnostic approaches. In:
inoblastoma: long-term tumor control and treatment complications
Shields J, Shields C, editors. Atlas of Intraocular Tumors, 3rd
in 208 tumors. Ophthalmology. 2001;108:2116–21.
ed. Philadelphia: Lippinoctt, Wolters Kluwer; 2016. p. 335–42.
9. Chantada G, Doz F, Antoneli CB, et al. A proposal for an 26. Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H,
interna-tional retinoblastoma staging system. Pediatr Blood Naduvilath TJ. Chemoreduction for unilateral retinoblastoma.
Cancer. 2006;47:801–5. Arch Ophthalmol. 2002;120:1653–8.
10. Shields CL, Mashayekhi A, Au AK, et al. The international 27. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction
classi-fication of retinoblastoma predicts chemoreduction plus focal therapy for retinoblastoma: factors predictive of need
success. Ophthalmology. 2006;113:2276–80. for treat-ment with external beam radiotherapy or enucleation.
11. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers Am J Ophthalmol. 2002;133:657–64.
with intravenous, intra-arterial, periocular, and intravitreal 28. Murphree AL, Villablanca JG, Deegan WF 3rd, et al.
chemo-therapy. Eye. 2012;27:253–64. Chemotherapy plus local treatment in the management of intraoc-
12. Shields CL, Shields JA. Retinoblastoma management: advances ular retinoblastoma. Arch Ophthalmol. 1996;114:1348–56.
in enucleation, intravenous chemoreduction, and intra-arterial 29. Honavar SG, Singh AD, Shields CL, Demirci H, Smith AF,
chemo-therapy. Curr Opin Ophthalmol. 2010;21:203–12. Shields JA. Post-enucleation prophylactic chemotherapy in
13. Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results high-risk reti-noblastoma. Arch Ophthalmol. 2002;120:923–31.
of combined chemotherapy and radiotherapy for advanced 30. Honavar SG. Orbital retinoblastoma. In: Singh AD, Murphee
intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1339–43. LA, Damato BE, editors. Clinical ophthalmic Oncology-
14. Manjandavida FP, Honavar SG, Reddy V, Khanna R. retinoblastoma. 2nd ed. NY: Springer; 2015. p. 185–94.
Management a n d o u t c o m e o f r e t i n o b l a s t om a w i t 31. Dunkel IJ, Khakoo Y, Kernan NA, et al. Intensive
h v i t r e o u s s e e d s . Ophthalmology. 2014;121:517–24. multimodality therapy for patients with stage 4a metastatic
15. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic retinoblastoma. Pediatr Blood Cancer. 2010;55:55–9.
arterial injection therapy for intraocular retinoblastoma: the long- 32. Rao R, Honavar SG. Recent developments in retinoblastoma.
term prognosis. Ophthalmology. 2011;118:2081–7. Delhi J Ophthalmol. 2016;27:50–61.