Optical Coherence Tomography guided decisions in

retinoblastoma management

Sameh E. Soliman, MD,1,2 Cynthia VandenHoven,1 Leslie 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, 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: 2142 / 3000 words

Numbers of figures and tables: 8 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)

Abstract: (285/350 words)

Purpose: Assess the role of Optical Coherence Tomography (OCT) in guiding

management decisions during diagnosis, treatment and follow-up of retinoblastoma.

Design: Retrospective non-comparative single institution case series.

Participants: All children newly diagnosed with retinoblastoma from January 2011 to

December 2015 who had an OCT imaging session during their active treatment at

SickKids hospital in Toronto. OCT sessions for fellow eyes of unilateral retinoblastoma

without any suspicious lesion and those performed more than six months after 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 excluded), treatment (modified, stopped or modality

shifted), or follow-up modified.

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

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

Results: Forty-four children (63 eyes) had 339 OCT sessions (median 5, range 1-15,

sessions per eye). Children younger at presentation and those carrying an RB1 mutation

had significantly more OCT sessions. Indications included evaluation of post-treatment

scar (55%) or fovea (16%), and posterior pole scanning for new tumors (11%). Of all

sessions 92% (312/339) were informative; 19/27 non-informative sessions had large,

elevated lesions; of these, 14/19 were T2a or T2b (IIRC Group C or D) eyes. In 94%

(293/312) of informative sessions, OCT directed management decisions for treatment

(58%), diagnosis (16 %) and follow-up (26%). OCT influenced and changed

management from pre-OCT clinical plans in 15% of all OCT sessions.

Conclusions: OCT improves accuracy of clinical evaluation in retinoblastoma

management.

Précis: (29/35 words)

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

sessions, 94% contributed indication-related details, 86% significantly guided care, and

15% influenced important change in management.

Optical Coherence Tomography (OCT) is established to play an important role in ophthalmic

patient assessment, improving diagnostic accuracy and thus therapeutic decision making for a

variety of ocular and retinal conditions1-4 including ocular oncology.5,6 Handheld OCT used while

the supine child is under anesthesia7-10

OCT is shown valuable in retinoblastoma for detection of small invisible tumors,5,11-1314,15

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 conditions (e.g.

retinoma or astrocytoma).5,18-20

However, handheld OCT is still not commonly used except in highly specialized ocular

oncology centers.7,21 The current Canadian Guidelines21 for retinoblastoma management define a

center using handheld OCT as a tertiary center.

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

decisions in children with retinoblastoma.

Methods

Study design

This study is a retrospective review of children with retinoblastoma who were managed in the

Hospital for Sick Children (SickKids), Toronto, Ontario, Canada 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 retinoblastoma examined with OCT imaging during their

management were reviewed. Fellow eyes of unilateral retinoblastoma without any suspicious

lesion who had a single OCT session at presentation were excluded. OCT sessions performed 6

months after the last treatment were excluded.

Data collection

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

Intraocular Retinoblastoma Classification (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 of one eye for one or more indications, during an

examination under anesthesia. During the course of the study, two generations of handheld OCT

systems were utilized: Bioptigen® Envisu C2200 and Envisu C2300 (Bioptigen, Inc. a Leica

Microsystems, Morrisville, NC USA). We did not compare the machines. We did not receive

sponsorship or financial support to conduct our research. At any point of time, one machine was

available for both clinic and operating room. All scans were captured by one of two highly skilled

medical imaging specialists (authors CV and LM), following a standardized methodology for

improved longitudinal reproducibility.

Technical considerations and indications23-26

The handheld OCT produces a variety of scan configurations. Within this study cohort, we

routinely obtained volumetric scans composed of non-averaged OCT scans (1000 A-scans x 100

B-scans per volume). The accumulation of individual 100 B-scan produced the associated C-scan

fundus image otherwise called the Sum Voxel Projection (SVP). Calipers were sometimes placed

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

interest could be correlated to the specific retinal position. Calipers were used to measure tumor

height in some instances (Fig 1).

Ideally, OCT is performed prior to other contact imaging that may inadvertently impair the

corneal clarity providing clear view of fundus. Operator sits at 12 o’clock position of the supine

patient with the OCT monitor placed so that an optimal view of the patient and screen can be

achieved. Handheld OCT scanner is 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 is the preferred method of the authors as it provides the greatest flexibility and ease of

use to angle the probe towards the areas of interest. Additionally by handholding the probe, 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 is 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 prevents corneal dryness.

The production of averaged OCT scans allowed for thorough assessment across a large retinal

area without large gaps between OCT B-scans. In our practice, single line volume scans produced

both rapid and high quality images with ample detail to provide information. 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, the production of averaged OCT images to achieve

higher quality images rarely yielded increased information. Additionally, the SVP image provides

information about the quality of the scan and in real-time the OCT operator can respond with

positional adjustments to improve subsequent scans.

For infants less than 6 months of age, we assessed the posterior pole (Fig 2) for pre-clinical or

“invisible” tumor using the widest volumetric scan settings available. We performed 9mm x 9mm

scans (Envisu C2200 system) and 12mm x 12mm scans (Envisu C2300 system) of fovea, optic

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

the tumor centered within the OCT frame. (Fig.3)

In the presence of foveal or perifoveal tumors, the foveal center was located by a horizontal

macular volumetric scan. When needed, a vertically oriented scan was performed with the

scanning angle adjusted 90 degrees. The handheld scanner is held the same physical configuration

while the SVP image was rotated 90 degrees indicating the scan direction change. (Fig 4)

For parafoveal scans, the handheld probe is angled towards the area of interest. Increased

resolution of the individual scans for small lesions was obtained by reducing the area of scan

volume to 8 x 8 or 6 x 6, to maximize number of A-scans per each line. To assess the mid-

periphery and beyond, a scleral depressor was used to rotate the eye, while angling the handheld

probe perpendicular to the retinal plane. (Fig 5)

Assessment

An OCT session was assessed Informative if it provided sufficient data about the main indication;

then as Directive if the information obtained guided management decisions affecting diagnosis,

treatment or follow-up. Directive guidance was considered Confirmatory if it confirms the pre-

OCT clinical decision or Influential if it changed a pre-OCT clinical decision. Every OCT session

during the active treatment phase of each child was assessed.

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

Diagnosis sessions were scored Confirmatory when OCT confirmed a clinically suspicious tumor

mass or clinical eye IIRC22 Group, or whenever the posterior pole was screened in children

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. sessions were scored Confirmatory when OCT

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

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

revealed an unsuspected recurrent tumor within a tumor scar or showed anatomic details

mandating changing the treatment modality or plan. Follow-up sessions were considered

Confirmatory when the OCT showed no change from the last scan in absence of active treatment;

and Influential when OCT showed anatomic details excluding activity, leading to alteration in

treatment plan.

Results:

Patient Demographics and numbers of OCTs

We reviewed 339 OCT sessions for 63 eyes of 44 children with retinoblastoma; 26 were male.

Eight children (10 eyes) were still under active treatment from which one child (one eye) was

lost to follow up. The median number of OCT sessions per eye was 5 sessions (range: 1-15

sessions), and were significantly higher for familial (7) than non-familial (4) eyes (p=0.001,

Mood’s Median test). Younger children at presentation required significantly more OCT sessions

(r=-0.26, p=0.04). The most common indication for OCT was tumor scar evaluation (186/339,

55%), followed by foveal assessment and posterior pole screening (16% and 11% respectively)

(Table 2).

OCT Impact on Care

Informative versus Non-informative

OCT was Informative in 92% of sessions (312/339) (Table 2). Large or highly elevated lesions

rendered OCT technically challenging and Uninformative in 19/27 sessions (Table 3, Fig 1);

14/19 were IIRC22 Group D or C at presentation. In two eyes/children, OCT became Uniformative

after multiple previously Informative OCTs, due to progression of central tumor (one) and

tractional retinal detachment (one).

Directive versus Non-Directive OCT

OCT was Directive in 86% (293/339) of all OCT sessions and 94% (293/312) of Informative

sessions (Table 2), guiding treatment (168/312, 54%), diagnosis (46/312, 15%), or follow up

(79/312, 25%). Nineteen OCT sessions were Uninformative, mainly because the OCT was not

indicated (17/19) or performed for academic interest (2/19). (Table 3)

Confirmatory versus Influential OCT

Of Directive OCT sessions, 243/293 (83%) were Confirmatory: for treatment 141 (58%),

diagnosis 39 (16%) and follow-up 63 (26%) (Table 2). Of Directive OCT sessions, 50/293 (17%)

were Influential: for treatment 27/293 (11%), diagnosis 7/293 (3%) and follow-up 16/293 (7%)

(Table 2). The most Influential OCT sessions were for scar evaluation and foveal evaluation

(Table 3).

Discussion

OCT in retinal imaging has been shown effective in guiding management (diagnostic and

therapeutic) decisions in multiple conditions, including macular holes,21 (diabetic and vascular)

and age related macular degeneration.3,4 Multiple reports have shown how useful OCT can be to

differentiate ocular tumors and simulating lesions.5,6,9-12,14-16,18-20,23

We observed that 22 Group C and with large tumors, due to absorption of optical signal by

dense lesions and lesion elevation beyond the imaging capacity.25 Eyes with IIRC22 Groups A and

B are easily scanned up to the mid periphery23 (Fig x). OCT assesses well the location of tumor

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

accurate IIRC22 staging in eyes where a suspected tumor mass away from the primary tumor is

shown by OCT to be a subretinal extension of tumor and not an independent new tumor (Fig 6C).

This influences the diagnosis from multifocal tumor16 27,28.

Detection of small and sometimes invisible tumors5,11 (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. For children at risk of familial

retinoblastoma under 3 months of age, detection of the first invisible tumor by OCT can facilitate

early, minimalized therapy.29

In unilateral retinoblastoma, OCT helps differentiate suspicious lesions from retinoblastoma

(Fig 7) in the normal eye. Previously, this depended on clinical opinion or B-scan

ultrasonography, which does not show the inner architecture of a lesion. Lacking in-vivo

evidence of the nature of these suspicious lesions, often such lesions were focally, potentially

falsely labeling the child as bilateral, heritable retinoblastoma, imposing multiple unnecessary

examinations under anesthesia.21

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

tumors.14 Foveal localization respective to the tumor can affect choice of treatment modality

(chemotherapy versus primary focal therapy), which laser to use (532 nm versus 810 nm laser)

and technique (sequential targeted laser therapy from the tumor side opposite the fovea, shown in

Fig 8). An intact fovea after treatment guides early start of amblyopia therapy even in eyes with

severe disease.30,31

OCT can raise suspicion of optic nerve invasion with peripapillary tumors.10,17,32athognomic

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 study. OCT distinguishes

gliosis and scar from tumor recurrence, (isodense areas with medium reflectivity, Fig 9)

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

appreciate,32

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

correlation to a quantifiable outcome. It was not practical to correlate OCT sessions with

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

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

duration, etc.). The presence of a single OCT machine limited the number of sessions in some

eyes due to unavailability due to maintenance or concomitant use by other surgeons. Training and

academic interest may have increased the number of OCT sessions performed for some eyes.

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

our knowledge, this is the first study to evaluate the OCT sessions impact on guiding

management decisions of active retinoblastoma. In 86% of all OCT sessions, OCT imaging was

useful in management decisions. In 17% of OCT sessions, the OCT evidence strongy influenced

clinical decisions, enhancing 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 (A-D): OCT assessment of central tumors. (A) A perifoveal tumor mass (IIRC22

Group B) (colored fundus image) appears as an isodense tumor within the retinal layers; the exact

location of the foveal pit can be appreciated (*). A caliper was used to measure the maximal

tumor height of 0.75 mm which was not appreciated on B-scan ultrasonography. (B) A

peripapillary tumor mass (IIRC22 Group B) not involving the foveal center is seen in the colored

fundus image and measuring 1.36 mm in height on B-scan ultrasonography. OCT provide

minimal information (non-informative) regarding the tumor internal architecture. (C) A

juxtafoveal tumor mass (IIRC22 Group B) is seen in the colored fundus image and measuring 1.65

mm in height on B-scan ultrasonography with OCT showing intact overlying retinal layers and

minimal fluid collection on its sides (arrow head). (D) A larger central tumor mass (IIRC22 Group

B) measuring 3.08 mm in height by B-scan ultrasonography and non-informative OCT regarding

both tumor internal architecture and overlying retinal layers. In (B-D) tumors, calipers cannot be

accurately utilized to measure tumor thickness, as the internal tumor boundary is ill defined.

Figure 2: Posterior pole assessment. OCT imaging along the four quadrants (superior (S),

temporal (T), inferior (I) and nasal (N)). An invisible suspicious lesion was seen (*) in the inferior

quadrant and reimaged with suspicious area centralized in the green (12mm x 12mm) box

showing an isodense small tumor within the retinal layers to be treated by focal laser therapy

under OCT guidance.

Figure 3 (A-D): OCT appearance of small tumors. After posterior pole assessment, the lesion

is centralized in a 12mm x 12mm box and reimaged. A-D scans show different eyes that

presented with a small tumor (IIRC22 Group A). All tumors appear as an elevated isodense

rounded lesion within the retinal layers with intact retinal pigment epithelium (RPE) line.

Figure 4 (A-C): Foveal assessment. In perifoveal tumors, the exact location of the foveal

center (*) is located by having 2 scans (one horizontal and one vertical), the fovea is identified by

the two intersecting approximately perpendicular scans containing the foveal pit. This foveal

center can be overlying tumor (A), partially involved (B) or non-involved by the tumor mass.

Figure 5 (A-C): OCT imaging in pre-equatorial lesions. OCT can verify elevated tumor

masses in the pre-equatorial region by deviating the globe in the required direction with

complimentary tilting of the OCT scanner. A peripheral indentation using scleral depressor may

be helpful. (A) A peripheral nasal tumor can be OCT scanned showing an elevated isodense

lesion. (B) A suspicious tumor tag (*) was OCT scanned to show a nearby edge recurrence

(arrowhead) that was not clinically suspected (influential treatment guidance) while the tag can be

seen. (C) After 2 months the vitreous tumor tag can be clinically noted to be increasing in size.

The OCT confirmed growth by increasing tag size from previous scan with complete

disappearance of the edge recurrence.

Figure 6: OCT appearance of suspected tumor seeds. (A) Multiple white small masses can be

seen in the macular area of an eye harboring a large nasal tumor, proven by OCT to be preretinal

vitreous seeds. (B) Multiple yellowish white masses in an eye with treated retinoblastoma, proven

by OCT to be retinal calcified lesions with an isodense lesion (*) that might be active and need

treatment. (C) A large white lesion (arrowhead) inferior to large central tumor in an eye of a

unilateral retinoblastoma with inferior shallow retinal detachment. Clinically and due to its

rounded appearance, it was initially considered as a separate tumor and the eye was Grouped as

IIRC22 Group C. OCT showed that the mass is a subretinal seed within the shallow retinal

detachment. That upgraded the Grouping to IIRC22 Group D eye with different treatment

chemotherapy protocol (Influential diagnostic guidance).

Figure 7. Exclusion of Retinoblastoma by OCT in fellow eyes of unilateral retinoblastoma.

Fellow eyes might have a suspicious lesion as (A) a coloboma (arrowhead), (B) peripapillary

thickenng and (C) a kinked vessel (*) that may be misdiagnosed or mistreated as a retinoblastoma

and can be verified by OCT imaging to be not retinoblastoma.

Figure 8 (A-D): Sequential targeted Laser therapy (STLT) in juxtafoveal retinoblastoma.

The child presented with IIRC22 Group D eye with two large tumors. The central tumor was

juxtafoveal. (A) Appearance after six cycles of systemic chemotherapy. The fovea can be

appreciated by OCT. the decision of STLT using 532 nm Laser starting from the farthest edge

from the fovea and converging inwards (direction of the arrows) avoiding the tumor nearest to the

fovea (*). (B) Appearance after 6 months from starting STLT. (C) Appearance after 12 months

from starting STLT and the fovea is now away from the tumor edge that can be treated. (D) 18

months after starting STLT showing a flattened inactive lesion with preserved foveal pit. The

child show the same appearance as D now after 18 months from last treatment session.

Figure 9 (A-C): OCT evaluation of tumor scars. (A) OCT evaluation of a clinically suspected

edge recurrence (arrowhead) showed an isodense elevation of moderate reflectively showing

active tumor. Another adjacent unsuspected scar showed a similar appearance (Influential

treatment guidance). (B) OCT can identify areas of suspected activity (arrow) from areas of

calcification (star). (C) OCT of 2 clinically suspicious white area showed that the upper white

area (*) is a flat scar (gliosis) and the lower white area (arrow) to be an elevated lesion.

Table legends

Table 1: Demographic characteristics of the studied Group.

Character Patients

Laterality

Table 2……

Table 3: Causes of different OCT assessment layers.