Optical Coherence Tomography guided decisions in

retinoblastoma management

Sameh E. Soliman, MD,1,2 Cynthia VandenHoven,1 Leslie D. MacKeen,1 Elise Héon, MD,

FRCSC,1,3,4 Brenda L. Gallie, MD, FRCSC1,3,5,6

Authors affiliations

1Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto,

Canada.

2Department of Ophthalmology, Faculty of Medicine, University of Alexandria,

Alexandria, Egypt.

3Department of Ophthalmology & Vision Sciences, Faculty of Medicine, University of

Toronto, Toronto, Ontario, Canada.

4Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario,

Canada.

5Division of Visual Sciences, Toronto Western Research Institute, Toronto, Ontario,

Canada.

6Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine,

University of Toronto, Toronto, Ontario, Canada.

Corresponding author:

Sameh E. Soliman, 555 University Avenue, room 7265, Toronto, ON, M5G 1X8.

samehelsayedsoliman@yahoo.com

Authors’ contributions

Concept and design: Soliman, VandenHoven, MacKeen, Héon, Gallie

Data collection: Soliman, VandenHoven, MacKeen.

Figure construction: Soliman, VandenHoven.

Analysis and interpretation: Soliman, VandenHoven, MacKeen, Héon, Gallie.

Critical review: Soliman, VandenHoven, MacKeen, Héon, Gallie

Overall responsibility: Soliman, VandenHoven, MacKeen, Héon, Gallie

Concept and design: Soliman, VandenHoven, MacKeen, Heon, Gallie

Data collection: Soliman, VandenHoven, MacKeen.

Figure construction: Soliman, VandenHoven.

Analysis and interpretation: Soliman, VandenHoven, MacKeen, Heon, Gallie.

Critical review: Soliman, VandenHoven, MacKeen, Heon, Gallie

Overall responsibility: Soliman, VandenHoven, MacKeen, Heon, Gallie

Financial Support: None

Conflict of Interest: No financial conflicting relationship exists for any author.

Running head: OCT guided retinoblastoma management

Word count: 21412 / 3000 words

Numbers of figures and tables: 98 figures and 3 tables; 1 supplementary table

Key Words: retinoblastoma, Optical coherence Tomography, OCT, Cancer,

Guide.

Meeting presentation: American Academy of Ophthalmology Annual Meeting

presentation (Chicago 2016, Monday 17th October 2016)

Abstract: (29185308/350 words)

Purpose: Assess the role of handheld Optical Ccoherence Tomography (OCT) role in

guiding management decisions during guiding diagnosis, treatment and follow-up of

retinoblastoma during active treatment period.

Design: Retrospective non-comparative single institution case series.

Participants: All children newly diagnosed with retinoblastoma children from January

2011 to December 2015 thatwho had an OCT imaging session during their active

treatment at The Hospital for Sick Children in Toronto, Canada. OCT sessions for fellow

eyes of unilateral retinoblastoma without any suspicious lesion and those performed

after 6more than six months after from the last treatment were excluded.

Methods: Data collected included: age at presentation,; sex, family history, RB1

mutation status, 8th edition TNMH Cancer staging and International Intraocular

Retinoblastoma Classification 1 (IIRC), and number of OCT sessions per eye. Details of

each session were reviewedscored for indication-related details (informative or not) and

assessed for being guidanceing (directive or not), diagnosis (staging changed, new

tumors found or excluded), treatment (modified, stopped or modality shifted), or follow-

up modified.

Main outcome measures: Frequency of OCT- guided management decisions, and

stratified by indication and type of guidance (confirmatory versus influential).

Results: Sixty-three eyes of 44 children had 339 OCT sessions (median =5, range 1-

15, sessions per /eye, range 1-15). Younger Children younger at presentation and those

with positivecarrying an RB1 mutation had significantly higher number ofmore OCT

sessions. Common Indications included evaluation of post-treatment scar (55%) or fovea

(16%), and posterior pole scanning for new tumors (11%). InformativeOf all sessions

were 92% (312/339) were informative; 19/27 non-informative sessions had and the main

cause was large, or elevated lesions; of these, in 70% of non-informative sessions

(19/27); 74% of which (14/19 ) were T2a or T2b (for IIRC{Murphree, 2005 #11984}IIRC

GroupGroup CD or D)C eyes at presentation. In 94% (293/312) of informative sessions,

OCT guideddirected management decisions in 94% (293/312) of informative sessionsfor

(54%, treatment (58%), diagnosis (16 %) and follow-up (265%). , 15% guided treatment,

follow-up and diagnostic decisions respectively). Influential OCT guidance (OCT

datainfluenced and changed management fromed the pre-OCT clinical decisionplans)

was noted in 17% and 15% of directive and all OCT sessions respectively.

Conclusions: Clinical evaluation remains the gold standard for retinoblastoma

management. OCT improves accuracy of clinical evaluation gives valuable information

on tiny tumors, tumor scars and fovea improving precision in retinoblastoma

management.

AAO submitted abstract

Purpose: Assess Optical coherence Tomography (OCT)

role in management decisions guiding diagnosis,

treatment and follow-up of retinoblastoma.

Methods: Retrospective study of retinoblastoma

children (2011-2015) that had OCT. Details of each

session were reviewed and scored for indication-related

details, guided diagnosis (staging changed, new tumors

found or excluded), treatment modified, stopped or

modality shifted, or follow-up modified.

Results: Forty children (59 eyes) had 300 OCT sessions

(median=5/eye). Common indications were evaluation of

post-treatment scar (67%) or fovea (19%), and new

tumor assessment (10%). Informative sessions were

93% (286/300). OCT guided management decisions in

90% (258/286, p<0.05) of informative sessions (67%,

20%, 13% guided treatment, follow-up and diagnostic

decisions respectively).

Conclusion: OCT gives valuable information on tiny

tumors, tumor scars and fovea improving precision in

retinoblastoma management.

Précis: (2935/35 words)

Precis:

In 63 eyes of 44 patients with retinoblastoma, of 339 optical coherence tomography

sessions, 94% contributed indication-related detailsRetrospective Review of 339 OCT

sessions, 86% performed for 59 63 eyes of 40 children with retinoblastoma from 2011 to

2015 during their active treatment phase showed that in 300 sessions evaluated (median

5/eye), the most common indication was post-treatment scar evaluation in 2/3 of

eyes,OCT provideding indication-related details in 9394% and significantly guided

caretreatment, follow up and diagnosis in 9086% of sessions, and 15% influenced

important change in managementeyes.

Background sentence:

OCT guides management decisions in macular and retinal diseases. Previous reports

showed OCT signs of retinoblastoma and simulating lesions, tiny tumors, fovea and optic

disc evaluation without studying OCT impact on active management.

Optical Ccoherence Tomography (OCT) hasisis well established itself asto as playinging an

integralimportant role in ophthalmic patient assessment, improvingleading to improved diagnostic

accuracy and thus therapeutic decision making for a variety of ocular and retinal conditionshas

helped in better visualization of the retinal layers, optic disc, vitreoretinal interface and choroidal

anatomy. This improvesd the diagnostic and thus therapeutic decision makings in multiple

disorders as diabetic macular edema, macular hole and choroidal neovascular membranes.1-4

including ocular oncology. 5,6

Features of Retinoblastoma; the most common pediatric ocular malignancy; were better

appreciated Recently,in the recent years Hhandheld OCTwith the introduction of the handheld

OCT that which can be used used while the supine child is under anesthesia. during the active

management of their condition .7-10 has deepened out understanding of the features of

retinoblastoma, the most common pediatric ocular malignancy. 7-10

There are multiple published reports on the value of OCT in is shown valuable in

retinoblastoma in for detection of small invisible tumors,5,11-139- 12( Add Bremner as 9) foveal

evaluation,14,15 localization and microstructure of tumor seeds,16 and detection of optic nerve

infiltration.10,17 It is documented to help in assessment of tumor anatomy, scar edges and

simulating conditions5,18-20 (e.g. rRetinoma or aAstrocytoma). 5,18-20

Despite these various benefitsHowever, handheld OCT is still not commonly used except in

some highly rankedhighly specialized ocular oncology centers.7,21 In The current Canadian

Guidelines21 for retinoblastoma management we define the a center that has anusing handheld

OCT machine as a tertiary center and it is being updated to quaternary center in the updated

revised guidelines. Despite advances in imaging technologies, cClinical evaluation and decisions

is still the mainstay of retinoblastoma management in most situations. This raises the question of

whether OCT evaluation should be incorporated in the routine management of retinoblastoma or

that whether its use is not thatsignificantly influential on clinical decisions.

In this study, we evaluate the influence of hand held OCT in guiding the management

decisions in patientschildren with retinoblastoma children.

Methods

Study design

This study is a retrospective record review of all new children with retinoblastoma that who

presented to andwere managed in the Hhospital for Ssick Cchildren (SickKids), Toronto, Ontario,

Canada (SickKids) from January 2011 to December 2015. Ethics approval was obtained and the

study follows the guidelines of the Declaration of Helsinki.

Eligibility

The records of all children with rRetinoblastoma that who had receivedexamined with OCT

imaging during their management were reviewed. Fellow eyes of unilateral retinoblastoma

without any suspicious lesion and who had a single OCT session at presentation were excluded.

OCT sessions performed after 6 months from after the last treatment were excluded.

Data collection

The data collected included age at presentation, sex, family history, laterality, International

Iintraocular Rretinoblastoma Cclassification (IIRC)22 at presentation, genetics results, indication

for OCT, number of OCT sessions per /eye, and total active duration treatment (time from

diagnosis until last treatment).

OCT Session and Systems

An OCT session was defined as imaging a of single one eye for one or more indications, using

the OCT during an examination under anesthesia for one or more indications. During the course

of the study, two generations of handheld OCT systems were utilized: Bioptigen® Envisu C2200

andC2200 and Envisu C2300 (Bioptigen, Inc. a Leica Microsystems, Morrisville, NC USA). We

did not compare and contrast both the machines for resolution or depth. We did not receive

sponsorship or financial support to conduct this our research. At any point of time, we only had

one machine was available for both clinic and operating room. All OCT scans were captured by

one of two highly skilled mMedical imaging sSpecialists (authors CV and LM), following a

standardized methodology for improved longitudinal reproducibility.

DefinitionsTe and technical considerations and indications 23-26

OCT was performed with operator at 12 o’clock position of the supine patient. Handheld OCT

scanner was pivoted approximately 1 cm above the cornea, the optimal working distance, aiming

the scanning beam through the pupillary center.25 Manually holding the OCT probe was preferred

as it provides the greatest flexibility and ease of angling the probe towards the areas of interest.

Additionally, the operator is able to increase the probe to eye working distance in real time while

scanning over the apex of larger lesions. Image quality and scan brightness was achieved by a

combination of factors, including manual adjustment of the OCT spectrometer reference arm

settings in accordance to the patient’s axial length and optimizing the handheld probe focus for

the child’s refraction.25 and frequent application of 0.9% NaCl solution to prevents corneal

dryness.

The handheld OCT produces a variety of scan configurations of scans. For our researchWithin

this study cohort, we consistently routinely obtained volumetric scans that were composed of

non-unaveraged OCT volume scans consisting of( 1000 A-Ascans x 100 B-scans per volume)x 1

x 1. The accumulation of individual 100 B-scan produceds the associated C-scan fundus image

otherwise called the Sum Voxel Projection or (SVP). The OCT’s accompanying SVP image

provides critical information about the quality of the scan and in real-time the OCT operator can

respond with positional adjustments to improve subsequent scans. Additionally, When

clarification of pathology localization wasis frequently required; , calipers were sometimescan be

placed on the OCT B-scan image revealing the retinal position on the SVP image so that the

precise area of interest cancould be correlated to the specific retinal position. Calipers were also

used to measure tumor height in some instances . (Fig. Fig 1) . So while the Bscan OCT is of

significant value to interpreting tumour features, the SVP image is also as critical to ensure

accurate localization of lesions and interpretation of Bscan findings. It has been reported that

extensive algorithms might be applied to improve image quality via oversampling and averaging

of multiple scans.26 In our practice, we routinely captured single line volume scans as they

achieved both rapid and high quality images with ample detail to provide clinical information.

The SVP image that results when OCTs scans are averaged are unreadable. This affects the

ability to decipher the OCT tumor findings accurately.

For infants less than (≤ 6 months of age, we assessed the posterior pole) (Fig 2) to screen for a

new pre-clinical or “invisible” tumor by obtaining screening withusing the widest volumetric scan

settings available. In our center, weWe performed 9mm x 9mm scans with the( Envisu C2200

system) and 12mm x 12 mm scans with( Envisu C2300 system) of fovea, optic nerve, temporal,

superior and inferior quadrants. If a tumor is identified, the scan is repeated with the scanner

placement achieving tumor centration centered within the OCT frame. (Fig.3) (Figures 1-2)

Foveal assessment is indicated In the presence of foveal and or perifoveal tumors, to locate the

foveal center was located by obtaining a horizontal macular volumetric scan. As When needed,

this scan is followed by a vertically oriented foveal volume scan was performed whereby,with the

scanning angle is adjusted 90 degrees (within the software). The handheld scanner is held the

same physical configuration while t. The sum voxel fundus projectionSVP image is was

consequently rotated 90 degrees indicating the scan direction change. (Fig.ure Fig 34)

When For parafoveal scansning parafoveally, the handheld probe is angled towards the area of

interest. Increased resolution of the individual scans for small If the lesions is small in size, it can

be ideal towas obtained by reducinge the area of scan volume to 8 x 8 or 6 x 6, to maximize

number of A-scans per each line. of OCT B-scan, thus increasing the resolution of the individual

OCT scans. To assess the mid-periphery and beyond, a scleral depressor is was used to rotate the

eye toward the area of interest, while angling the handheld probe so that perpendicularity to the

retinal plane is achieved. (Fig.ure Fig 54)

Assessment layers

An OCT session will was be assessed as being first as being Informative if it provideds

sufficient data about the main indication for scanning; and then being as Directive if the

information provided from the OCT imaging helpedobtained guiding guided the management

decisions affecting either diagnosis, treatment or follow-up. Directive guidance can bewas

considered Confirmatory if it confirms the pre-OCT clinical decision or Influential if the

information providedit changed a pre-OCT clinical decision. Every OCT session during the active

treatment phase of each child will was be collected and assessed for all layers.

Decision guiding

Guidance is either in diagnosis, treatment or follow-up.

Guidance was provided for diagnosis, treatment or follow-up, summarized in Tables 2 and 3.

Diagnosis sessions Diagnostic cwere scored Confirmatory guidance was considered when

OCT OCT confirmeds; a) clinically suspicious tumor mass or in clinically suspicious area(s), b)

clinicalclinical eye IIRC22 grouping Group, or whenever c) the posterior pole screening was

screened in positive germ line mutationschildren known to carry an RB1 mutant allele who were

less that 6 months of age; and Influential when OCT excluded tumor in clinically suspicious

area(s), changed IIRC22 Group, or detected an invisible tumor during posterior pole screening.

up to six months of age. Diagnostic influential guidance was considered if OCT; a)

excluded tumor in clinically suspicious area(s), b) changed IIRC22 grouping or c) detected

an invisible tumor during posterior pole screening.

Treatment sessions were scored Confirmatory guidance was considered ifwhen OCT

confirmed a a) clinically suspicious new or recurrent tumor, or b) showed anatomic details (fovea,

scarring, seeds, traction…etc.) supporting the decided treatment plan;. Treatment and Influential

guidance waswhen considered if OCT a) showed revealed an unsuspected recurrent tumor within

a tumor scar, b) or showed anatomic details mandating changing or cessation of the treatment

modality or plan.

Follow-up sessions confirmatory guidance waswere considered Confirmatory if when the

OCT showed no change from the last scan in absence of active treatment;. Follow up influential

guidance was considered if and Influential when OCT showed anatomic details excluding

activity, leading to change of clinically decidedalteration in treatment plan.

Results:

Patient Demographics and numbers of OCTs

This We reviewed included 339 OCT sessions for 63 eyes of 44 children with retinoblastoma;

(26 were male, 59%). Eight children (10 eyes) are were still under active treatment from which

one child (one eye) was lost to follow up as they moved outside Canada. Demographic data are

summarized in table 1. The median number of OCT sessions per eye is was 5 sessions (range: 1-

15 sessions),. and were significantly higher for fFamilial eyes had a significantly higher median

session number of( 7) than versus 4 sessions to non-familial eyes(4) eyes (p=0.001, Mood’s

Median test). A significant negative correlation existed between the age at presentation and the

number of OCT sessions where Younger age children at presentation required significantly more

OCT sessions (r=-0.26, p=0.04). The most common indication for OCT was tumor scar

evaluation in 55% (186/339, 55%), of sessions followed by foveal assessment and posterior pole

screeningscreening (16% and 11% respectively) (. The indications for OCT imaging for each eye

are summarized in tTable 2). What are the types of the OCT machines for the duration 2011-

2016?

OCT Impact Assessmenton Care

Informative versus Non-informative OCT

Informative OCT was found Informative in 92% of evaluated sessions (312/339) (Table 2).

Large or highly elevated lesions rendered OCT technically challenging and Uninformative iIn

19/27 sessions (8%), no valuable information was acquired. The main cause of non-informative

OCT was large or elevated lesion in 70% of sessions (19/27) (Table 3, Fig 1)2,5); approximately

74% of which (14/19 ) were was IIRC22 Group D or C at first tumorpresentation. In two2

eyes/children, there was loss of thOCT became e Uniformative informative status of the OCT

after multiple previously Informative OCTs OCTs, due to progression of the central tumor (in

one) aeye and tractional retinal detachment in another eye(one).

Directive versus Non-Directive OCT

Directive OCT was Directive found in 86% (293/339) of all OCT sessions and in 94%

(293/312) of Informative sessions (Table 2), guiding . OCT directed treatment (168/312, 54%),,

diagnosis (46/312, 15%), or follow up in 54% (168/312), 15% (46/312) and 25% (79/312, 25%)

of informative sessions respectively. In 19Nineteen OCT sessions were Non-

DirectiveUninformative, mainly because the OCT, the information given was not important in

directing management decisions. The main cause was performing non-not indicated performed to

assess a clinical decision OCT (17/19) or OCT performed for academic interest (2/19). (Table 3)

Confirmatory versus Influential OCT

Of Directive OCT sessions, Confirmatory OCT was found in 83% (243/293 (83%) were)

Confirmatory: of directive sessions and guidedfor treatment 141 (58%), diagnosis 39 (16%) and

follow-up 63 (up of 58%, 16% and 26%) of confirmatory sessions respectively (Table 2)..

Influential Of Directive OCT sessions, OCT was found in 17% (50/293 (17%) were Influential:

of directive sessions and guided for treatment 27/293 (11%), diagnosis 7/293 (3%) and follow- up

16/293 (7%) (Table 2). of 54%, 14% and 32% of influential sessions. Different OCT influences

are shown in table 3The most Influential OCT sessions were for scar evaluation and foveal

evaluation (Table 3).

Discussion

The introduction of OCT in retinal imaging has been shown its effective ness in guiding

management (diagnostic and therapeutic) decisions in multiple conditions, including as macular

holes,2, macular edema1 (diabetic and vascular) and age related macular degeneration.3,4 Multiple

reports were published showinghave shown the OCT differences between ocular tumors and how

useful OCT it can be useful to differentiate ocular tumors and simulating lesions.5,6,9-12,14-16,18-20,23

At presentation, we showed that OCTs provides limited information of in eyes where the with

retinoblastoma is T224 (TNMH 8th edition27) more advanced thanequivalent to IIRC22 groupGroup

C or higher or higher and ofwith individual large tumors are usually non-informative regarding

large tumor. s, Thetumors, due to absorption of . The optical signal is absorbed through by dense

lesions and the lesion elevation is beyond the imaging capacity.as the scan cannot include them in

its focus together with associated changes as calcification and detachment.25 Eyes with T124

tumors (IIRC22 groupGroups A and B) are easily scanned even inup to the mid periphery23 (Fig

5x) (Fig. 1,2,4). OCT helps assessingassesses well the location level of the tumor whether with

respect to retina: intra-retinal, pre-retinal, vitreal or subretinal (Fig. Fig 6). This allows more

accurate TNMH24,27 or IIRC22 groupstaginging in certain eyes where a suspected tumor mass away

from the primary tumor is shown to by OCT to be a subretinal mass extension of tumor versus

and not an independent new separate tumor (Fig 6C). This changes influences the diagnosis from

a multifocal tumor (IIRC22 group B or C) to a seeding of a unifocal mass tumorwith IIRC22group

D. The verification of vitreous tumor seeds by OCT16 helps better grouping(what do you mean by

this??)helped accurate IIRC22 grouping andalso affects the choice of treatment modality (iei.e.,

intra-vitreal chemotherapy)28,29.

Detection of small and sometimes invisible tumors5,11 (Fig. Fig 2-3) has changed the visual

outcome especially in familial retinoblastoma.24 This leads to earlier detection and control with

less treatment burden (focal therapy only) and less retinal damage. In familial casesFor children at

risk of familial retinoblastoma under 3 months of age, detection of the first invisible tumor by

OCT can facilitate early, minimalized therapy.30 {Fe-Bornstein, 2002 #12863}29modify the follow

up plan to include EUA instead of clinic visits.21

In unilateral retinoblastoma, OCT helps differentiateation of suspicious lesions from

retinoblastoma (Fig. Fig 7) in the fellow normal eye. Previously, this depended on clinical

examination opinion or B-scan ultrasonography, which does not show the inner architecture of

the a lesion. Sometimes,Lacking invivoin-vivo evidence of the nature of these suspicious lesions,

presumably manyoften such lesions were treated focally, potentially and falsely changing the

diagnosis of thislabeling the child into as bilateral , heritable retinoblastoma, imposing which has

a totally different follow-up, schedule with multiple unnecessary examinations under anesthesia.21

Foveal pit detection (Fig. Fig 4) provides an important clue about visual potential in with

perifoveal tumors.14 Its Foveal localization respective to the tumor location can affect choice of

treatment modality (chemoreduction chemotherapy versus primary focal therapy with Laser), its

which laser to use subtype (532 nm versus 810 nm laser) and technique (sequential targeted laser

therapy from away inwardsfrom the tumor side opposite the fovea, shown in Figure 8). An intact

flat fovea after treatment guides the early start of amblyopia therapy even in eyes with severe

disease.31,32

It has been shown that OCT can help raise suspicionus of optic nerve invasion in with

peripapillary tumors..10,17,33 In OCT, suspected optic nerve invasion can present similarly to that of

optic nerve edema. The OCT appearance of optic nerve swelling is not necessarily pathognomic

for optic nerve invasion, but should be considered and ruled out as being highly suspicious.

Scar evaluation was the most common indication for OCT in our seriesstudy. This helpsOCT

distinguishes gliosis and scar from precise diagnosis of tumor recurrence , (isodense areas with

medium reflectivity, Fig 9) especially useful with versus gliosis. It determines the exact extent of

recurrence especially in white choroidal scars, where visualization of recurrence is challenging to

appreciate,;33 which that canand affect alter the choice of treatment modality. We have observed

that active tumor recurrence at the edge of a scar presents as isodense areas with medium

reflectivity (Fig. 9). Additionally, the lesion will present with localized thickening within several

consecutive B-scans. Medium gray, isodense, with localized retinal thickening in relation to

surrounding structures are more suspicious than areas that may be highly reflective, flat and/or

sharply demarcated.11

The current study is limited by being a single center, retrospective study, and. absence of

correlation to a quantifiable outcome. I, since it was not practical to correlate OCT sessions with

outcomes as eye salvage, vision salvage, life salvage, which are affected by many other factors

like (tumor location, number and type, stage at presentation, complications of treatments,

treatment duration, etc.). rather than a single OCT session decision. The pPresence of a single

OCT machine limited the number of sessions in some eyes due to occasional unavailability due to

maintenance or concomitant use by others.

Timeothersother surgeons. Time constraints may have affected the number of OCTs per eye

due to limited OR time. Training and academic interest may have increased the number of the

OCT sessions performed for some eyes.

In conclusion, multiple studies have reported OCT signs of retinoblastoma at presentation,

seeds, scar, fovea and optic nerve evaluation. To our Knowledgeknowledge, this is the first study

with the largest number ofto evaluate thed OCT sessions impact on to determine whether the

OCT was valuable in guiding the management decisions of active retinoblastoma. In 86% of all

studied OCT sessions, OCT imaging directed was useful in the management decisions. In 17% of

these OCT sessions, the OCT provided evidence that influencedstrongystrongly influenced

changing the clinical decisions, showing that OCT enhanceingd precision of management.

Acknowledgement

There are no conflicts of interests or disclosures. BLG is the unpaid medical director of Impact

Genetics.

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Figure Legends

Figure 1. Central tumors. (A) A perifoveal tumor mass (T1b24 or IIRC22 Group B) (is

isodense within the retinal layers; the exact foveal location is evident (*) ; maximal tumor height

of 0.75 mm (Informative, Directive and influential in guiding laser treatment) was over-estimated

on B-scan ultrasonography. (B) A peripapillary tumor (T1b24 or IIRC22 Group B) not involving

the fovea measured 1.36 mm in height on B-scan ultrasonography; OCT provided no additional

data (Non-informative). (C) A juxtafoveal tumor (T1b24 or IIRC22 Group B) measured 1.65 mm in

height on B-scan ultrasonography; OCT showed intact overlying retinal layers and minimal

surrounding subretinal fluid (arrow head) (Informative, Directive and confirmatory for diagnosis)

. (D) A larger central tumor (T1b24 or IIRC22 Group B) measuring 3.08 mm in height by B-scan

ultrasonography confirmey; OCT was Non-informative regarding both tumor internal architecture

and overlying retinal layers. In (B-D) tumors, calipers could not be accurately utilized to measure

tumor thickness, as the internal tumor boundary was ill defined.

Figure 2: OCT screening of posterior quadrants (superior, temporal, inferior, and nasal).

(A, B) An invisible lesion was seen (*) in the inferior quadrant scan; (C) reimaging centralized

the suspicious area (green 12mm x 12mm box) showing an isodense small tumor within the inner

nuclear layer (Informative, Influential for Diagnosis and Treatment).

Figure 3: First diagnosis of small tumors. (A-D):. (A - D) After detection on posterior pole

screening, small intra-retinal elevated isodense round tumors centralized on the inner nuclear

layer (T1a24 or IIRC22 Group A) were confirmed when reimaged centralized in a 12mm x 12mm

box (Informative, Influential for Diagnosis and Treatment).

Figure 4: Perifoveal tumors. The exact location of the foveal center (*) was located in

horizontal (green line) and vertical (green dotted line) scans with the foveal pit at the intersection.

The foveal center was (A) on top of tumor, (B) partially involved or (C) adjacent to the tumor

mass (Informative, Influential for Diagnosis and Treatment).

Figure 5: Pre-equatorial lesions. The eyes were deviated in the required direction with

complimentary tilting of the OCT scanner; peripheral indentation with scleral depressor was

helpful. (A) OCT of a peripheral nasal elevated isodense lesion. (B) OCT to evaluate a tumor tag

(*) vs vitreous seed revealed an unsuspected nearby edge recurrence (arrowhead)  (Informative,

Directive, Influential for Diagnosis and Treatment). (C) Two months after both active tumors

were treated clinical exam and OCT showed that the tumor tag extending into vitreous had

increased in size, while the edge recurrence had completely disappeared (Informative, Directive,

Confirmatory). (Further laser and cryotherapy resolved the tag.)

Figure 6: Suspected tumor seeds. (A) Multiple white small masses in the macular area of an

eye harboring a large nasal tumor were shown by OCT to be preretinal vitreous seeds

(Informative/ Directive/ Influential for Diagnosis and Treatment). (B) Multiple yellowish spots in

an eye with treated retinoblastoma, were shown on OCT to be retinal calcified tumors in the

retina; an isodense inner nuclear layer lesion (*) was considered an active new tumor, thereby

treated with laser (Informative/ Directive/ Influential for Diagnosis and Treatment). Multiple

vitrouus seeds cast shadowing on the OCT (arrowheads). (C) A large white lesion (arrowhead)

inferior to large central tumor with inferior shallow retinal detachment in unilateral

retinoblastoma; due to its rounded appearance, it was considered as a separate primary tumor and

the eye was staged T2a24 or IIRC22 Group C; OCT showed a subretinal seed within the shallow

retinal detachment, upgrading the staging to T2b24 or IIRC22 Group D eye changing treatment 

(Informative/ Directive/ Influential for Diagnosis and Treatment).

Figure 7. Exclusion of retinoblastoma in second eyes of unilateral retinoblastoma. (A)

Coloboma (arrowhead), (B) peripapillary thickening, and (C) a kinked vessel (*) could have been

misdiagnosed or mistreated, but were verified by OCT to be not retinoblastoma (Informative/

Directive/ Confirmatory (Influential) for Diagnosis and Treatment).

Figure 8. Sequential targeted Laser therapy (STLT) in juxtafoveal retinoblastoma. The

child presented with T2b24 or IIRC22 Group D eye with two large tumors; the central tumor was

juxtafoveal. (A) After six cycles of systemic chemotherapy, the fovea was visible on OCT; STLT

was initiated using 532 nm laser starting from the edge farthest from the fovea sequentially

moving inwards (direction of the arrows) avoiding the tumor nearest to the fovea (*). (B)

Appearance 6 months after starting STLT. (C) Appearance 12 months after starting STLT; the

fovea is further away from the tumor edge that can be treated. (D) 18 months after starting STLT

OCT showed a flattened lesion with preserved foveal pit; 18 months after last treatment the tumor

remains the same.  (Informative/ Directive/ Confirmatory (Influential) for Diagnosis, Treatment,

Follow-up)

Figure 9 (A-C): Evaluation of tumor scars. (A) A clinically suspected recurrence in scar

(arrowhead) showed on OCT an isodense elevation of indicating active tumor, which was treated

with laser. The adjacent unsuspected scar showed a similar edge recurrence and was also treated.

(B) OCT detected tumor activity (arrow) hidden within areas of calcification (star).  (C) OCT of 2

clinically suspicious white areas showed that the upper white area (*) was a flat scar (gliosis) and

the lower white area (arrow) was an elevated lesion. (Informative/ Directive/ Influential

(Confirmatory) for Diagnosis, Follow-up).

Figure 3: Foveal assessment

Figure 4: Peripheral lesions

Figure 5: Optic nerve head assessment

Figure 6: Exclusion of RB.

Figure 7: Level of tumor

Figure 8: Sequential targeted laser therapy

Figure 9: Scar evaluation

Table legends

Table 1: Demographic characteristics of the studied groupGroup.

Character

Patient

s Eyes‍

Laterality

Bilateral 36 53

Unilateral 8 10

Total 44 63‍

Genetics

Germline

Familia

l 11 20

Sporadi

c 25 34

Total 36 54

Mosaic 2 3

Non‍Germline 6 6‍

Tumour

status

RB 44 58

Stable 36

Salvage

d 37

Enucleated 9

Active 8* 10

No

RB 0 5‍

*‍one‍child‍is‍lost‍follow‍up,‍RB:‍Retinoblastoma

Table 2: layers of Assessment for the OCT sessions based on its indication

Treatment complication 0 0 0 0 0 0 1 4 1 3 0 0 1 2 0 0

Suscpicious lesion 0 0 0 0 0 0 0 0 1 3 11

4 0 0 0 0‍

Total (n)2

7 1001

91

001

411

002

71

003

91

00 71

006

31

001

61

00 43

Table 2……

Table 3: Causes of different OCT assessment layers.

OCT

Assessment Causes N %

Non informative

Large‍tumor/elevated‍lesion¶

1

9 70

Peripheral‍lesion 4 15

Retinal‍detachment 2 7

Media‍Opacity 1 4

Awake‍child 1 4

Total

2

7

10

0

Non Directive

Doubtful‍indication

1

7 89

Academic‍interest 2 11

Total

1

9

10

0

Directive

Influential

Diagnosis

Exclude‍RB* 1 2

Upstage‍Clinical‍grouping‍§ 2 4

Invisible‍tumors‍£ 1 2

Modify‍treatment‍plan‍# 2 4

Recurrence‍versus‍Gliosis‍¥ 1 2