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Page 1: At a glance (32/35) - sharedocs.ca file · Web viewLow-risk Histopathology in Unilateral cT2b Retinoblastoma. Word count: 2691/3000 ... Unilateral retinoblastoma staged Group D by

Clinical predictors of low histopathologic risk features in unilateral cT2b (Group D) retinoblastoma at

diagnosis

Stephanie N. Kletke, MD1, Zhao Xun Feng, BSc2, Lili-Naz Hazrati, MD, PhD, FRCPC3, Brenda L. Gallie,

MD, FRCSC1,2,4, Sameh E. Soliman, MD2,5

Authors’ Affiliations

1 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada;

2 Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Canada;

3 Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada;

4 Departments of Molecular Genetics and Medical Biophysics, University of Toronto, Toronto, Canada;

5 Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Corresponding Author: Sameh E. Soliman, 555 University Avenue, Room 7265, Toronto, Canada,

M5G 1X8. [email protected]

Running Head: Low-risk Histopathology in Unilateral cT2b Retinoblastoma

Word count: 2691/3000 words

Number of Figures and Tables: 1 figure, 3 tables and 2 supplementary files.

Keywords: unilateral retinoblastoma; Group D; histopathology; cancer; primary enucleation; vitreous

seeds.

Sameh Soliman, 12/16/18,
Word Count for Original Clinical Science Research: (Excluding title page, abstract, tables, references, acknowledgements, contributions) max 3000; Abstract max 250 words; References max 35
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At a glance (32/35)

Retrospective review of 38 primarily enucleated unilateral cT2b/Group D retinoblastoma eyes showed

that visible optic nerve, macular sparing and <1 quadrant of retinal detachment predicted 100% low-risk

histopathology supporting trial ocular salvage.

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Abstract (247/250)

Background/Aims: Attempted eye salvage for unilateral cT2b (Group D) retinoblastoma may

increase risk of tumor spread compared to primary enucleation. Identification of clinical features

predictive of low histopathologic risk would guide potentially safe trial salvage.

Methods: A retrospective review of eyes primarily enucleated for unilateral cT2b retinoblastoma

(2008-2018) was conducted. Clinical features (intraocular pressure, optic nerve obscuration, macular

involvement, tumor seeding and serous retinal detachment (RD) >1 quadrant), histopathological findings,

and dates of metastasis and death were reviewed. Primary outcome was high-risk (HR) (pT3/pT4) versus

low-risk (LR) (pT1/pT2) (8th Edition American Joint Committee on Cancer) histopathology. Clinico-

pathologic correlations were evaluated.

Results: Histopathology diagnosed 4/38–10.5% HR and 34/38–89.5% LR eyes. HR eyes demonstrated

massive choroidal invasion (4/38–10.5%), or trans-scleral, extraocular and retrolaminar optic nerve

invasion (1/38–2.6%). Clinical findings included macular involvement (31/38–82%), optic nerve

obscuration (28/38–74%), and RD (28/38–74%). The probability that an eye had HR histopathology was

13% with macular involvement, 14% with optic nerve obscuration, and 14% with RD. The probability

that an eye had LR histopathology was 100% with macular sparing, optic nerve visibility and/or <1

quadrant of RD. One child who lacked all 3 clinical LR predictive features and had HR histopathology

(pT3a) developed metastases and died; other children are alive and well (mean follow-up 65 months).

Conclusion: All unilateral cT2b eyes with macular sparing, optic-nerve visibility and <1 quadrant of

RD had LR histopathology when enucleated at diagnosis, suggesting that eye salvage could be safely

attempted.

Gallie Brenda, 12/16/18,
Put in the actual numbers
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Introduction

Unilateral retinoblastoma staged Group D by the International Intraocular Retinoblastoma

Classification (IIRC)1 and cT2a or cT2b by the 8th Edition American Joint Committee on Cancer (AJCC)

TNMH (tumor, node, metastasis and heritable trait) staging,2 poses a management challenge of

international debate. Attempted eye salvage using primary intra-arterial (IAC)3-7 or systemic

chemotherapy,8 both with focal consolidation, has been suggested. However, primary enucleation is an

effective and safe option to minimize risk of extraocular extension and metastasis. The Canadian National

Retinoblastoma Strategy Guidelines for Care published in 2009 recommend enucleation of affected

unilateral Group D eyes.9

Recently, multiple treatment modalities are suggested to improve success of eye salvage, including

intravitreal chemotherapy (IVC),10-12 IAC,3-7 periocular chemotherapy,13 and tumor endoresection via pars

plana vitrectomy (PPV).14 The primary concern is whether attempted eye salvage increases the risk of

extraocular tumor dissemination. Our aim was to identify clinical features of primarily enucleated

unilateral cT2a/cT2b (Group D) eyes that predict low histopathologic risk at diagnosis, in order to guide

“safe” trial eye salvage.

Methods

Study Design

A retrospective, non-comparative, single institutional observational study was conducted in

accordance with the guidelines of the Declaration of Helsinki. Institutional Research Ethics Board

approval was obtained.

Eligibility

Children diagnosed with unilateral Group D (cT2a or cT2b) retinoblastoma managed with primary

enucleation of the affected eye at the Hospital for Sick Children (SickKids), Toronto, Canada between

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January 2008 (following submission and implementation of the Canadian guidelines9) through February

2018 were evaluated. Exclusion criteria included unilateral retinoblastoma of any other clinical stage,

primarily enucleated cT2a/cT2b eyes in bilateral cases, and cT2a/cT2b eyes that were secondarily

enucleated following trial salvage.

Data Collection

Clinical and Radiological Features

Medical records, including fundus photographs from examinations under anesthesia (EUA), were

reviewed for age at diagnosis and enucleation, laterality, clinical features at presentation (intraocular

pressure (IOP), tumor seeding, optic nerve obscuration, macular involvement and serous retinal

detachment (RD) either > or <1 quadrant, parental consent to the proposed treatment, eye staging by

IIRC, molecular genetic analysis, follow-up duration, adjuvant treatments received, metastasis and death.

Eyes were retrospectively staged by the 8th Ed. AJCC TNMH.2 Baseline magnetic resonance imaging

(MRI) or computed tomography (CT) of the brain and orbit were reviewed.

Histopathologic Features

Histopathology reports and representative slides were reviewed for all children. Presence of choroidal

invasion was documented as “none”, “focal [<3 mm]” or “massive [>3 mm in maximum diameter]”,

based on consensus definitions from the International Retinoblastoma Staging Working Group.15 Invasion

of the sub-retinal pigment epithelial (sub-RPE) space but not through Bruch’s membrane was identified.

Optic nerve invasion was categorized as “none”, “prelaminar”, “retrolaminar but not to the optic nerve

resection margin” and “tumor at the transected end”.15 Scleral invasion, anterior segment involvement and

extraocular disease were identified. Enucleated eyes were retrospectively staged by the 8th Ed. AJCC

pTNM.2 Table 1 summarizes the 8th Ed. AJCC pathological staging.

Outcome Measures

Gallie Brenda, 12/16/18,
Do you mean the treatment consent, or consent for study of the health record????
Gallie Brenda, 12/16/18,
Definition in abstract is different
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The primary outcome was the presence of high-risk (HR) histopathology, defined as pT3 or pT4,

versus low-risk (LR) histopathology, defined as pT1 or pT2.2 High-risk histopathologic features included

massive choroidal invasion, retrolaminar invasion of the optic nerve head, scleral invasion and

extraocular extension.

Clinicopathologic correlation was evaluated. Positive predictive value was defined as the probability

that an eye with high-risk clinical features to have HR histopathology. Negative predictive value was

defined as the probability that an eye with low-risk clinical features to have LR histopathology.

Statistical Analysis

Results were summarized using frequency/percentage for categorical variables and mean, median and

standard deviation for continuous variables. Groups were compared using Fisher’s exact test for

categorical variables and Student’s t-test for continuous variables. All P-values reported were two-sided

and significance was judged at the 5% level. All analyses were performed using SPSS Version 25 (IBM

Corp).

Results

Demographic and Clinical Features

Thirty-eight primarily enucleated Group D eyes of 38 children (presenting age mean 21 months, range

2–48) with unilateral retinoblastoma were included (63% right, 37% left). All eyes were staged cT2b (8 th

Edition AJCC).2

At presentation, all eyes had normal IOP. Vitreous seeding was present in all eyes. Tumor involved the

macula in 31/38–82%. Children with macular involvement tended to be younger at diagnosis than

children with macular sparing (mean 20 vs 28 months, respectively) (p=0.09). The optic nerve was

obscured in 28/38–74% and RD (>1 quadrant) was present in 28/38–74%. Retinal detachment impaired

accurate assessment of subretinal seeding in some eyes. The presence of macular involvement, optic

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nerve obscuration and RD were positively correlated [macula and optic nerve (p=0.01), macula and RD

(p< 0.001), optic nerve and RD (p=0.002)]. Four of 28 eyes with optic nerve obscuration demonstrated

possible optic nerve enhancement on baseline imaging of the brain/orbit. There were no radiological cases

of extraocular or intracranial involvement.

The median interval from diagnosis to enucleation was 4 days (range, 0–14). Primary enucleation

occurred during the staging EUA for all children, with the exception of one child for whom enucleation

was delayed due to low partial thromboplastin time. All parents consented to enucleation as the primary

treatment.

Histopathologic Features

Choroidal involvement included “none” (26/38–68.4%), “focal” (8/38–21.1%), and “massive” (4/38–

10.5%). Six eyes (15.8%) demonstrated tumour cells in the sub-RPE space without invasion of Bruch’s

membrane. Optic nerve involvement included “none” (10/38–26.3%), “prelaminar invasion” (27/38–

71.1%), and “retrolaminar invasion but not to the optic nerve resection margin” (1/38–2.6%). There were

no cases of tumor involvement of the resected margin. One eye (2.6%) demonstrated histopathologic

evidence of anterior segment involvement (pT2b). There was one eye (2.6%) with trans-scleral and

extraocular extension (pT4). Table 2 summarizes the histopathologic features of the studied population.

Summary of Eyes with High-Risk Pathology (Figure 1)

Histopathology review identified 4/38–10.5% HR eyes and 34/38–89.5% LR eyes. HR eyes

demonstrated massive choroidal invasion (4/38–10.5%), and trans-scleral, extraocular and retrolaminar

optic nerve invasion (1/38–2.6%). Mean age at diagnosis was not significantly different for children with

HR versus LR eyes (p>0.05). Presenting signs included leukocoria (3/4–75%) and strabismus (1/4–25%).

Baseline MRI brain and orbits showed no evidence of optic nerve, extraocular or intracranial involvement

in children with HR eyes. There was no evidence of metastases at presentation.

Sameh Soliman, 12/16/18,
Is it better to be put as supplemental? The aim is not to teach about high risk
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Clinico-pathologic Correlation

Optic nerve obscuration was not significantly associated with retrolaminar optic nerve invasion in this

cohort (p=1.000). Macular involvement was not significantly associated with massive choroidal invasion

(p=0.557) or scleral invasion (p=1.000). Serous RD was not significantly associated with massive

choroidal invasion (p=0.287) or scleral invasion (p=1.000, Supplementary Table 1). None of the eyes

showing enhanced optic nerve on the MRI scanning at presentation had retrolaminar nerve invasion

(p=1). The probability that an eye had HR histopathology was 13% with macular involvement, 14% with

optic nerve obscuration, and 14% with RD. The probability that an eye had LR histopathology was 100%

with macular sparing, 100% with optic nerve visibility and 100% with <1 quadrant of RD. (Table 3)

Molecular analysis

Molecular genetic testing was performed on tumor samples from 37 enucleated eyes while one eye

(Hx) was yet untested due to economic causes. The two tumor RB1 pathogenic variants were identified in

34/37 eyes [H0 (27/38–71%) and H1 (7/38–18%)] and 3 eyes were Hx (heritability cannot be verified).

H1 children showed mosaicism for the RB1 pathogenic variant (3/7), low penetrance RB1 pathogenic

variant (3/7) and 13q deletion syndrome (1/7). The children that showed high risk pathology were H1 (1

extraocular, pT4, Figure 1A), HX (2 eyes, pT3a, one died, Figure 1C and 1D) and H0 (pT3a, Figure 1B).

Follow-up, Metastasis and Death

At mean follow-up of 65 months, one child (2.6%) with all three clinical HR predictive features and

HR histopathology (pT3a) developed metastases and died. Bony metastases were found 1 year following

retinoblastoma diagnosis.16 The child received six cycles of systemic chemotherapy, autologous bone

marrow transplant and focal radiation. While ocular pathology was initially interpreted as LR, internal

retrospective review identified an area of massive choroidal invasion. Metastatic surveillance remained

negative until 1 year later, when intracranial dural-based metastases were identified on MRI. The child

Gallie Brenda, 12/16/18,
What is this???
Sameh Soliman, 12/16/18,
Brenda, How to write this?
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died 18 months after metastasis diagnosis, despite focal radiotherapy. The other children in this cohort are

alive and well. None of the children were lost to follow-up.

Discussion

The International Intraocular Retinoblastoma Classification (IIRC) introduced in 2005 staged eyes

clinically as Group A (very low risk) through E (very high risk) to predict outcomes following systemic

chemoreduction and focal therapy.1 The 8th Edition TNMH was recently updated based on evidence-based

data,2 and serves as the current gold standard for retinoblastoma staging. IIRC Group E eyes show

advanced intraocular tumors as phthisis bulbi (cT3a), anterior segment tumor invasion (cT3b), rubeosis

irides with neovascular glaucoma (cT3c), hyphema and/or massive vitreous hemorrhage (cT3d) and or

aseptic orbital cellulitis (cT3e). IIRC Group D eyes have intraocular tumor with significant RD (cT2a)

and/or any vitreous and/or subretinal seeding (cT2b). High-risk histopathologic features predictive of

increased metastatic risk are defined as pT3/pT4 following enucleation, and include massive choroidal

invasion,17,18 retrolaminar invasion of the optic nerve head with or without a positive margin,17,19 scleral

invasion and extraocular extension (Table 1).2

The main goal of treatment for advanced unilateral retinoblastoma is to save the child’s life and

prevent extraocular tumour dissemination followed by saving a seeing eye. The concept of salvage of a

blind eye for cosmesis is no longer justified, given the improved implant and prosthesis movement with

myoconjunctival enucleation.20. Multiple modalities, including systemic chemotherapy, IAC, IVC,

periocular chemotherapy and PPV have been suggested for eye salvage. However, primary enucleation is

a safe option, allowing an early return to normal life,21 fewer interventions and EUAs,22 less

socioeconomic impacts,23 as well as histopathologic review. This is the accepted practice in many centers

for cT3 (IIRC Group E) eyes and probably most cT2b eyes (IIRC Group D). The dilemma of justifying

salvage treatment for advanced eyes on parental refusal of enucleation depends on the treating physician

and how the parents are counselled. In our cohort we did not face parental refusal in any of our enucleated

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eyes. Prolonged attempts at globe salvage could lead to delayed diagnosis of metastasis if HR features are

not identified timely. Systemic chemoreduction should also be considered cautiously, as pre-enucleation

chemotherapy may downstage pathological findings of extraocular disease.24 With no evidence from

randomized controlled trials to guide management of cT2a/cT2b eyes, the clinician must consider the

impact of years of trial salvage for an eye with limited visual potential on quality of life for the child and

family.

The success of intravitreal chemotherapy in controlling vitreous disease,10-12 a main clinical feature of

cT2b (IIRC Group D) eyes, together with the availability of more literature on IAC,5 that previously

posed a dilemma, as chemotherapy delivered focally that is ineffective against escaped tumor cells 5 made

the trial salvage attempt for a unilateral cT2b justified as long as the tumor is less likely to spread beyond

the eye. Clinical features at presentation predictive of HR histopathology include older age, symptoms >6

months, hyphema, pseudohypopyon, orbital cellulitis, secondary glaucoma and buphthalmos.25-27

Furthermore, exophytic growth pattern, tumor thickness >15 mm and vitreous hemorrhage predict optic

nerve invasion,19 and iris neovascularization is associated with choroidal invasion.18,28 However, these

characteristics predominantly describe cT3 (Group E) eyes and are not relevant when considering the

treatment of cT2b eyes. Yousef et al29 concluded that clinical staging alone (TNM 7th ed., IIRC or Reese

Ellsworth classification) is insufficient to predict HR histopathology. This encouraged us to study the

individual clinical findings as predictors rather than the whole eye staging.

The ideal predictive clinical finding need to be a reproducible objective finding easily picked at the

staging EUA, the time of the decision of trial salvage. Furthermore, it needs to be picked clinically and

not based on an investigation that might be unavailable as MRI or genetic testing. In our analysis we

excluded subjective findings as presenting complain or duration of symptoms, debatable findings as

pattern of tumor growth (endophytic, exophytic or mixed) and presence of subretinal seeding under

detached retina, together with unavailable findings at diagnosis as RB1 pathogenic variant status.

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Approximately 2–33% of Group D eyes are expected to harbor HR histopathologic features following

primary enucleation.21,27,29-33 However, the literature is heterogeneous and limited by non-consensus in

defining HR histopathology features, variable classifications, and inclusion of primarily and secondarily

enucleated eyes, children with unilateral and bilateral disease, as well as eyes with no indication of

staging. In our cohort of primarily enucleated unilateral cT2b eyes, 10.5% had HR histopathology.

Macular involvement, optic nerve obscuration and >1 quadrant of RD had low predictive value for HR

histopathology (13%, 14%, and 14%, respectively). However, macular sparing, visibility of the optic

nerve and <1 quadrant of RD had 100% predictive value for the presence of LR histopathology,

suggesting that an eye with these three clinical features may undergo cautious trial salvage.

Fabian et al32 reported on 40 primarily enucleated IIRC Group D eyes (all cT2b, 37 unilateral). At

presentation, 95% (38/40) had macular involvement, 95% (38/40) had optic disc obscuration and 97%

had RD, compared to 82%, 74% and 74%, respectively in our cohort. They report absence of vitreous

seeds as a sole significant predictor of HR based on p=0.42.32 Small sample sizes renders tests of

significance inaccurate as one extra entry can shift the p-value significantly which lead us to use the

predictive values rather than then tests of significance to interpret our data. We ran significance test for

our collective samples (78 eyes, table 3), absence of vitreous seeds lost its significance (p=0.05) other

factors showed a lower p-value than reported yet insignificant. When we applied predictive values, we

had the same results of 100% predictive of LR histopathology if the optic nerve is seen and the fovea is

not involved. Absence of vitreous seeds showed 71% probability of having LR histopathology (Table 3).

Jesse et al33 reported a retrospective review of IIRC Group D/E eyes and found that 15% of eyes with

optic nerve obscuration at presentation (69/102) had postlaminar invasion, while 0% with visible optic

nerve at diagnosis (33/102) had postlaminar invasion following primary enucleation, suggesting a

possible clinico-pathologic association. This goes in accordance with our 100% probability for LR with

visible optic nerve in our cohort.

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The decision of trial ocular salvage is taken at time of diagnosis making any clinical predictors of

histopathologic risk features valuable in the process of decision making. However, tumor response to

therapies might change or downstage the initial histopathology risk.24 Our proposed clinical predictors are

to be used at initial diagnosis and no evidence is available suggesting their usefulness in recurrent or

refractory cases decision-making. These predictors are not used to predict outcomes but only predict

histopathology risk at diagnosis. Eyes with LR at diagnosis are not guaranteed to remain LR if

unresponsive to initial treatment and the decision of further trying salvage should be based on an interplay

of intended outcomes, metastatic risks, treatment morbidity, socioeconomic impacts and visual potential

taking into consideration that the other eye is perfectly normal. Early detection of HR histopathologic

features is important and when present, warrants metastatic surveillance and adjuvant therapy.

Postenucleation adjuvant treatments, including systemic chemotherapy, significantly reduce metastatic

events from 24% to 4%, particularly in the presence of massive choroidal and retrolaminar invasion.34

Furthermore, post-enucleation adjuvant VEC was associated with no metastatic events for 51 high-risk 35

Group E eyes (mean 66 month follow-up).36 However, the specific indications for adjuvant therapy are

debated,37 with some groups suggesting good prognosis for isolated choroidal or retrolaminar optic nerve

invasion and negative margins without adjuvant treatment.38,39 In our cohort, the child who developed

metastasis did not receive post-enucleation adjuvant therapy, as massive choroidal invasion was only

identified following retrospective review. The other three children with HR histopathology received

adjuvant treatments and are alive and well at last follow-up.

The limitations of this study include its retrospective design and relatively small sample size.

However, our inclusion criteria of only unilateral, primarily enucleated Group D eyes were stringent,

achieving a homogenous study population. Another limitation is the low rate of positive events, which

limits statistical analysis of associations between clinical findings and histopathologic features of the

included eyes. Furthermore, our analysis is at the point of diagnosis and does not offer any data on

progress of the histopathologic risk with different treatments

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Conclusion

In summary, 10.5% of primarily enucleated unilateral cT2b (Group D) eyes had HR

histopathology. Macular sparing, optic nerve visibility and <1 quadrant of RD at presentation were highly

predictive of low-risk in unilateral cT2b eyes, and may predict which advanced eyes are suitable for trial

salvage decision. Given the widespread management debate of unilateral cT2a/cT2b eyes, there is a need

for robust, multicentre collaborative studies involving a larger group of children to further assess these

clinico-pathologic correlations.

References

Tables

Table 1. Summary of American Joint Committee on Cancer (AJCC) pathological staging 8th Edition.

Table 2. Histopathologic features of the studied eyes.

Table 3. Combined analysis of Fabian et al 32 and current sample showing significance versus

probability assessment.

Supplementary Table 1. Significance of association between clinical findings and histopathologic

features of enucleated eyes.

Figure Legend

Figure 1. (A) Left, RetCam fundus photograph of child 1 showing a right multilobulated tumor with

overlying serous retinal detachment (RD) and subretinal seeding. Middle left, Histopathological section

Kletke, Stephanie, 12/16/18,
Over the limit of 35
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under low magnification through the optic nerve demonstrating extra-scleral and post-lamina cribrosa

invasion (arrows), but not to the optic nerve resection margin (pT4). Middle right, high magnification of

trans-scleral and extra-scleral invasion (arrow). Right, High magnification showing retrolaminar invasion

(arrow). Whole-body MRI (WBMRI), lumbar puncture (LP) and bilateral bone marrow aspirate (BMA)

were negative for malignancy. He underwent six cycles of vincristine, etoposide, carboplatin (VEC) and

cyclophosphamide, followed by orbital irradiation.

(B) Left, RetCam fundus photograph of child 2 demonstrating a large inferior tumor with overlying

RD, vitreous and subretinal seeds. The optic nerve was obscured. Middle and right, Histopathological

sections under low and intermediate magnification showing massive choroidal invasion (asterisk) beyond

the confines of the retinal pigment epithelium (arrow), with no evidence of scleral invasion (pT3a). There

was prelaminar optic nerve invasion. LP and BMA were negative for malignancy and she received four

cycles of VEC.

(C) Left, RetCam fundus photograph of child 4 demonstrating a large tumor obscuring the nerve and

macula, with associated hemorrhage, RD and diffuse vitreous seeding. There was no anterior segment

extension evident on ultrasound biomicroscopy. Histopathology was confirmed to be massive (pT3a). The

child received systemic adjuvant chemotherapy.

(D) Left, RetCam fundus image of child 3 demonstrating a large tumor with associated RD, subretinal

and focal vitreous seeding. There was no visualization of the optic nerve and the macula was involved.

Initial review was consistent with low-risk histopathology. One year later the child presented with fever

and pain, and WBMRI identified a paraspinal tumor. Molecular analysis confirmed metastasis.16tumor

cells. MRI showed no orbital or intracranial disease and LP was negative. Internal review of the ocular

pathology, including further choroidal sections, showed an area of massive choroidal invasion (pT3a).

The child received 6 cycles of VEC and cyclosporine, followed by autologous bone marrow transplant

and focal irradiation. He was diagnosed with dural-based metastases 1 year later. Despite radiotherapy,

the child died 18 months after presentation with metastases.

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1. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology clinics of North America. 2005;18:41-53.

2. Mallipatna A, Gallie BL, Chévez-Barrios P, et al. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, eds. AJCC Cancer Staging Manual. Vol 8th Edition. New York, NY: Springer; 2017:819-831.

3. Munier FL, Mosimann P, Puccinelli F, et al. First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20 years of treatment. Br J Ophthalmol. 2016.

4. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology. 2014;121(7):1453-1460.

5. Yousef YA, Soliman SE, Astudillo PP, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA ophthalmology. 2016;134(6):584-591.

6. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011;129(6):732-737.

7. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081-2087.

8. Chan HS, Gallie BL, Munier FL, Beck Popovic M. Chemotherapy for retinoblastoma. Ophthalmology clinics of North America. 2005;18(1):55-63, viii.

9. Canadian Retinoblastoma S. National Retinoblastoma Strategy Canadian Guidelines for Care: Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44 Suppl 2:S1-88.

10. Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96(8):1078-1083.

11. Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A, Beck-Popovic M. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012;96(8):1084-1087.

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