Secondary prevention of retinoblastoma revisited: laser photocoagulation of

invisible new retinoblastoma.

Sameh E. Soliman, MD,1,2 * Cynthia VandenHoven, BAA, CRA,1 Leslie D. MacKeen, BSc,1 Brenda L.

Gallie, MD, FRCSC.1,3-5

Authors’ affiliations

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

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

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

Ontario, Canada.

4 Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine, University of

Toronto, Toronto, Ontario, Canada.

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

*Corresponding author: Sameh E. Soliman, 555 University Avenue, room 7265, Toronto, ON, M5G

1X8. samehelsayedsoliman@yahoo.com

Institute:

Word count:

Manuscript

Abstract

Abstract

Introduction: Invisible retinoblastoma tumors are now detected by prenatal identification of RB1 pathogenic variants inherited from affected parents, followed by early delivery with screening for retinal tumors using handheld optical coherence tomography (OCT). Laser photocoagulation is challenging, requiring exact localization of an invisible tumor. We describe an OCT-guided localization and photocoagulation technique and its preliminary outcome.

Methods: OCT revealed round homogeneous invisible tumors within the inner nuclear layer. Software calipers placed beside anatomical retinal landmarks (branched/curved vessels, fovea or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location and OCT evaluated the tumor-laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment. This technique was used to treat 11 new invisible posterior pole tumors in 7 eyes of 5 children.

Results: Localization and tumor-laser burn relationships were 100% accurate. All showed swelling and hyper-reflectiveness in post-laser OCT. A maximum of 2 photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 10/11 (91%) tumors with resulting permanent scars. Two tumors (18%) developed OCT-detected subclinical recurrences within 4 months, each treated by one laser session. No treatment scar showed migration, foveal involvement or retinal traction at 1 year follow-up.

Discussion: Precise localization avoided misapplied laser burns, preserving normal retina resulting in small treatment scars with less treatment burden and a good visual outcome (no foveal involvement by tumor/laser).

Conclusion: OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors.

Introduction

Cancer prevention occurs at three levels namely primary (prevent exposure to carcinogens),

secondary (early diagnosis and treatment) or tertiary (prevent tumor invasiveness/spread and

early rehabilitation) prevention.1 Retinoblastoma is usually prevented at the tertiary level to

prevent local/systemic tumor spread, loss of an eye or vision.2 Secondary prevention is utilized in

screening retinoblastoma survivors’ offspring to detect tumors earlier and precisely treat them to

achieve better visual outcomes with minimal scarring.2-7 Frequently, earlier tumors involve the

macular area8 and laser treatment scars would also limit the visual outcome.

Clinically, indirect ophthalmoscopy and/or wide fundus imaging can detect small tumors.

Optical coherence tomography (OCT) has improved visualization of retinal layers rendering sub-

millimeter or subclinical invisible tumor diagnosis possible.9-12 An OCT-guided posterior pole

screening technique to identify any invisible tumor that threatens vision was described.12

Laser treatment to an invisible tumor is challenging as laser delivery systems; whether

operating microscope-mount or indirect ophthalmoscopy-mount; still depend on direct

visualization of the treated area.4 In Toronto, we developed an OCT-based protocol to guide

localization and laser photocoagulation of newly discovered invisible tumors as a step further

towards better secondary prevention of retinoblastoma.

Methods

Study design

This study is a retrospective non-comparative interventional case series that was treated in

the hospital for Sick children (SickKids), Toronto, Canada. The study was approved by the

institution research ethics board and complies with guidelines of Helsinki declaration.

Eligibility

Any retinoblastoma tumor that was 1) clinically invisible or suspicious, 2) detected on OCT

posterior pole screening as a round homogenous tumors centered on the retinal inner nuclear

layer (INL) and 3) treated with OCT guided localization and photocoagulation. Data collected

included age at diagnosis and treatment of tumor, genetic status, eye staging using the

international intraocular retinoblastoma classification (IIRC)13 and the Tumor, node metastasis

and heritability staging (TNMH14), OCT assessment of tumor characters (shape, size, location,

and associated signs), laser treatment sessions, tumor recurrence, and treatment scar follow-up.

Technique description

All OCT machines software shows a red-free image of the scanned cube with a line

representing the OCT frame. Software calipers (Figure 1) when placed vertically on the OCT

frame, identifies the axial point location on the red-free image. When calipers are placed

horizontally on the OCT frame, location lateral extent on the red-free image can be identified.

Horizontal calipers provide a measurement that can reflect tumor extension but its accuracy is

questioned. Multiple calipers can be utilized on the same image.15

When OCT screening detected an invisible tumor, OCT localizing calipers (figure 2) were

used to identify the tumor extension in each frame that showed the tumor, both in vertical and

horizontal scans (12x12 mm cube). The invisible tumor location extent was mapped over the red-

free image as a rectangular area. The upper and lower boundaries of the rectangles were one

frame above and below the horizontal OCT frame(s) showing the invisible tumors respectively.

The lateral boundaries could be identified similarly in vertical scans. If a vertical scan was

insufficient or difficult to acquire, two vertical localizing calipers just outside the tumor

boundaries were placed in OCT frame(s) showing tumor and mapped over the red-free image.

Once the suspicious area was identified, nearby anatomical characteristics such as vessel curving

and branching, fovea or optic disc were noted and plotted on corresponding colour fundus

images.

On indirect ophthalmoscopy using a 22-Diopter lens, the rectangular area and its

surrounding anatomic landmarks are identified putting the upright and lateral image inversion in

perspective. Few laser (532 nm, low power, 0.5 second duration, longer interval between shots)

shots were used to flag the center of the rectangular area. Positive localization results in retinal

whitening by laser. When suspicious area is very small, within 1 or 2 frames of an OCT scan

series, performing a post laser follow-up OCT serves to validate accuracy of laser location with

indirect before applying further laser shots (to prevent inadvertent retinal damage, ensure exact

precision and identify areas of skipped treatment). Post-laser OCT (Figure 3) ensured complete

tumor treatment verified by laser extending beyond the tumor into at least two previously

uninvolved OCT frames on each side of the tumor.

Technique evaluation

Accuracy was evaluated by frequency of geographic miss and skip areas in initial post-laser

OCT. Effectiveness was evaluated by tumor recurrence rate. Burden was evaluated by final scar

size (in relation to the initial tumor size) and characters mainly migration (defined as expansion

of resultant scar > 25% over time), traction (defined as tangential pulling of the scar on the

adjacent retinal structures as optic nerve, fovea or blood vessels), gliosis (defined as superficial

white fibrous proliferation resembling tumor recurrence and verified by OCT) and pigmentary

changes.

Results

This technique was used in management of 11 invisible new tumors in seven eyes of five

children with retinoblastoma. Six eyes (4 children) had tumors discovered by OCT during

screening of a clinically free eye in a retinoblastoma prone child (H1) with family history of

retinoblastoma. One eye had a new tumor several months after control of its primary tumors with

chemoreduction and focal consolidation. Two tumors (table 1) were missed in the OCT at a

smaller stage and discovered in retrospect at 45 (figure 2) and 21 days earlier OCT scans. Eight

tumors showed rounded appearance on OCT at the level of inner nuclear layer (INL), three were

ovoid with fishtail sign. Initial vertical tumor height showed wide variation in different scans of

the same tumor owing to OCT scans inclination and vertical caliper subjective placement.

All treated tumors (100%) were accurately treated by laser without geographic misses

(initial tumor-laser burn relation) or skipped areas verified by post-laser OCT. All tumors

(100%) showed post laser OCT signs including tumor swelling, hyper-reflectiveness and

shadowing extending to the retinal pigment epithelium. all tumors were controlled with median

of 2 laser sessions (range: 1-3 sessions). One tumor (9%, Table 1) showed a subclinical

recurrence within 84 days detected by OCT (figure 2) and treated by a single laser session. We

estimated the technique effectiveness at 91%.

All tumor scars showed proportionate expansion in all directions that was less than 20% of

the initial scar dimensions at 3 months post laser completion. One scar (9%, Table 1) showed

around 50% expansion and was considered as a true scar migration, despite that the final scar

size was around 1 disc diameter.. No scar showed gliosis or traction. All scars showed

pigmentary changes. Pigmentations involved > 50% of the tumor scar size within 1 year follow-

up in 8/11 scars (73%).

Discussion

Retinoblastoma, the most common pediatric intraocular malignancy, is the prototype of

genetic cancers.16 This was well recognized when retinoblastoma became the first tumor to have

a heritability designation in its staging in the 8th edition American Joint Committee tumor, node

and metastasis (TNM) staging.14 H1 means that this individual has 50% chance of transmitting

RB1 pathogenic variant to his offspring. H1 is designated in bilateral or trilateral retinoblastoma,

positive family history when RB1 gene pathogenic variants are documented in blood via

molecular diagnosis. Family history was estimated in around 6% of newly diagnosed children

with retinoblastoma.2 Retinoblastoma showed improved survival with improved treatment

options in the last 2 decades with higher number of familial retinoblastoma children anticipated.

This highlights the necessity of improving our secondary prevention protocols to truly reflect

early diagnosis and treatment.

Secondary prevention typically starts with proper genetic counseling of survivors for

offspring screening. Postnatal screening entails examining the newborn within the first few days

of life followed by meticulous follow-up schedule to detect any tumor at the smallest size and the

lightest stage possible. Molecular diagnosis of the exact pathogenic RB1 variant in the proband

improved risk determination for each offspring, yet still not widely available. The sensitivity of

exact mutation detection is approaching 97% and this allowed even prenatal molecular diagnosis

of at-risk individuals.5 Prenatal genetic testing for the RB1 pathogenic variant can be performed

in amniocytes surrounding the fetus via amniocentesis during the second trimester of pregnancy.

Early term delivery can reduce the probability of eyes with tumor at birth to 21% compared to

50% at full term.3 Early posterior pole screening with OCT during the first six months of life can

detect the smallest tumors before they attain a size that threatens the fovea.12 This would reduce

the treatment burden in central tumors to avoid either systemic or intra-arterial chemotherapy,

which despite being effective has their own respective sets of adverse effects that would benefit

the child if avoided. Furthermore, resultant scarring would be smaller owing to the relative

smaller size of the subclinical versus clinical tumor detection requiring gentler focal laser

therapy.3

The concept of improving procedure guidance utilizing technology is very popular in

medicine as in sonographic and radiologic guided tissue biopsies, injections and endovascular

procedures.17 In Ophthalmology, OCT was reported to guide procedural managements of

complicated situations as intracameral air injection for iatrogenic Descemet’s membrane

detachment,18 complete excision of an intra-corneal epithelial cyst,19 intraoperative OCT guided

vitrectomy.20 In retinoblastoma, our group reported on utilization of hand-held OCT in guiding

laser therapy for perifoveal tumors.21 In the current study, we describe a technique of OCT

guided localization and photocoagulation of invisible subclinical retinoblastoma tumors as a step

forward towards precise controlled outcomes in retinoblastoma management. Our suggested

technique is hypothesized to further improve outcomes through precise treatment location with

minimal scarring and negligible scar migration accounting for the normal ocular growth.

Previously, detection of small tumors was performed via indirect ophthalmoscopy or wide

fundus imaging. Suspicious areas were followed to be designated as a new tumor if growth was

documented.22

OCT was reported to show small retinoblastomas (< 1 mm) arise around the inner nuclear

layer with fishtail sign and shark-fin sign.23 All invisible tumors in our cohort were detected at an

earlier stage and the fishtail sign was detected in only three tumors. This might suggest that these

signs arise later when the tumor grows and start pushing on the adjacent retinal layers and

become clinically visible. Follow-up of tumor scars using OCT can easily detect recurrences at a

subclinical level thus requiring only focal laser therapy.12,24

Vertical (axial) size measurement using calipers might be inaccurate in hand held OCT

because of probable angular inclination, subjective caliper placement and confounding individual

factors as axial length, lateral tumor location and refractive error.25 Lateral measurements are

also affected by inclination during image acquisition and might be inaccurate. Our group utilized

lateral calipers y in assessment of foveal-tumor distance in perifoveal tumors that are central and

less affected by inclination of OCT acquisition.21 For an invisible tumor, initial accurate size was

independent of the success of the technique. In 100% of tumors, the laser covered the whole

tumor regardless of its size.

Expansion of chorioretinal scars is reported to increase around 35% following diode laser

transpupillary thermotherapy within the first year of treatment.26 No reports were reported

regarding scar expansion following argon laser photocoagulation. A degree of scar expansion is

expected with rapid growth of infant’s eye. The axial length increases approximately 0.16

mm/week until full term and 1 mm/year for the first 2 years estimating around 20-25% increase

in the ocular size during the first 2 years.27,28 We estimated around 25% of scar expansion to be

accepted due to ocular growth regardless of the laser technique utilized. We noticed minimal

proportionate scar expansion in all directions that was within our accepted 25% except one scar

(9%). The pigmentary changes that occurred in all scars is a common secondary change after

laser therapy due to retinal pigment epithelium hypertrophy and hyperplasia. Progression of the

pigmentation to cover > 50% of 73 % of all scars over 1 year further supports the physiologic

scar expansion.

Hand held OCT despite its high cost, has become an important tool in evaluating

retinoblastoma and available in most tertiary level referral ocular oncology centers.22 This

technique is simple, rapid and relatively cheap as it is already built-in within every OCT machine

software and does not require specialized software planning and can be done within minutes after

OCT acquisition allowing any possible treatment to be performed in the same EUA session.

Attentive review of every frame is essential to identify very minute tumors that might appear

only in a single frame. Laser treatment is better provided by an experienced ophthalmologist to

eliminate possible geographic miss.

Retinoblastoma survival is high in developed countries owing to the shifting management

from external beam irradiation towards systemic chemotherapy in the 1990s.2 Those survivors

are currently in their reproductive years and there is a 50% chance that they have children with

retinoblastoma that can be early detected through meticulous screening.16 OCT can detect these

retinoblastoma tumors at subclinical levels and this technique would facilitate adequate treatment

at this stage.

Precise localization avoided misapplied laser burns, preserving normal retina resulting in

small treatment scars with less treatment burden and a good visual potential (no foveal

involvement by tumor growth, tumor scar or misapplied laser).

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