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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.
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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.
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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
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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.
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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
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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
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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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