Clinical predictors at diagnosis 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: /51 figure, 3 tables and 2 supplementary files.
Keywords: unilateral retinoblastoma; Group D; histopathology; cancer; primary enucleation;, vitreous
seeds.
Word Count for Original Clinical Science Research: (Excluding title page, abstract, tables, references,
acknowledgements, contributions) max 3000; Abstract max 250 words; References max 35
At a glance (324/35)
Retrospective review of 38 primarily enucleated unilateral cT2b/Group -D retinoblastoma eyes
showed that visible optic nerve, macular sparing and/or <1 quadrant of retinal detachment predicted 100%
probability of low-risk histopathology, with visible optic-nerve, macular sparing and <1-quadrant of
retinal detachment rendering them safer forsupporting trial ocular salvage decision.
2
Abstract (25047/250)
Background/Aims: Whether Attempted eye salvage for unilateral cT2b (Group D) retinoblastoma
may increases risk of tumor spread compared to primary enucleation is debated. Identification of clinical
features predictive of low histopathologic risk may would guide potentially safe trial salvage decision.
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 (RD)), histopathological
findings, and dates of metastasis and death were reviewed. Primary outcome was high-risk (HR)
histopathology (pT3/pT4) versus low-risk (LR) (pT1/pT2) (8th Edition American Joint Committee on
Cancer). histopathology. Clinico-pathologic correlations was 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%), and or trans-scleral, extraocular and retrolaminar optic nerve
invasion (1/38–2.6%). Clinical findings included macular involvement (31/38–82%), optic nerve
obscuration (278/38–714%), and RD (28/38–74%). The probability that an eye had HR histopathology
was 13% (4/28) with macular involvement, 1114% (4/31) with optic nerve obscuration, and 14% (4/28)
with RD. The probability that an eye hadof LR histopathology was 100% with macular sparing (7/7),
91% with optic nerve visibility (10/10) and 100% with <1 quadrant of RD (10/10). One child (who with
lacked all 3 clinical LHR predictive features) and had HR histopathology (pT3a) developed metastases
and died; other children are alive and well (mean follow-up 65 months).
Conclusion: Trial salvage decision is suitablepotentially just for All uUnilateral cT2b eyes that
showseyes thatwith show mMacular sparing, optic- nerve visibility and <1 quadrant of RD were highly
predictive of LR . These clinical signs does not predict had LR histopathology when enucleated at
diagnosisoutcomes but only LR histopathology at diagnosis, suggesting that eye salvage could be safely
attempted. . in unilateral cT2b eyes, enabling identification of eyes suitable for likely safe trial salvage.
3
Introduction
Unilateral retinoblastoma staged as Group D by the International Intraocular Retinoblastoma
Classification (IIRC)1 and as 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
chemotherapy8 (both with focal consolidation) has beenis now commonly suggested. However, primary
enucleation is an effective and safe option to minimize risk of extraocular extension and metastasis. In
Canada, The Canadian National Retinoblastoma Strategy Guidelines for Care published in 2009
recommend enucleation of affected unilateral Group D eyes.9
Recently, multiple treatment modalities have beenare suggested to improve success of eye salvage,
including intravitreal chemotherapy (IVitC),10-12 IAC, , 3-7 periocular chemotherapy,13 and tumor
endoresection via pars plana vitrectomy (PPV).14 The primary concern with such modalities is whether
attempted eye salvage increases the risk of extraocular tumor dissemination. Our aim was to identify
potential clinical features of primarily enucleated unilateral cT2a/cT2b (Group D) eyes predictive ofthat
can predict at diagnosis low histopathologic risk at diagnosis, in an attemptorder to guide “potentially
safe” trial eye salvage decision.
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
4
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
January 2008 (following submission and implementation of the Canadian guidelines9) through February
2018 were evaluated. Exclusion criteria included unilateral retinoblastoma of any other clinical stageing,
primarily enucleated cT2a/cT2b eyes in bilaterally affect children cases, or and cT2a/cT2bcT2 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 >1 quadrant of serous
retinal detachment (RD) , either > or) <1 quadrant), parental agreement consent with 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 under 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 also identified. Enucleated eyes were retrospectively staged by
the 8th Ed. AJCC pTNM.2 Table 1 summarizes the 8th Ed. AJCC pathological staging.
5
Outcome Measures
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) (8th Ed. AJCC).2 High-risk histopathologic
features included massive choroidal invasion, retrolaminar invasion of the optic nerve head, scleral
invasion and extraocular extension.
Clinico-pathologic correlation was evaluated. Positive predictive value was defined as the probability
that an eye with high-risk certain clinical features (macular involvement, optic nerve obscuration or
RD)features towould havedpredict HR histopathology (i.e. HR clinical features predicting HR
histopathology). Negative predictive value was defined as the probability that an eye with low-risk certain
clinical featuress (macular sparing, optic nerve visibility and <1 quadrant of RD) had to havewould
predict LR histopathology (i.e. LR clinical features predicting LR histopathology).
Secondary outcomes included the proportion of eyes for which salvage therapy may have been
considered as an alternative to enucleation based on standard of care in 2018, as determined by senior
author review (B.L.G., S.E.S.).
Statistical Analysis
Results were summarized using frequency/percentage for categorical variables and mean, median, and
standard deviation and range 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
6
Thirty-eight (Supplementary table 1) primarily enucleated Group D eyes ofeyes of 38 children (mean
presenting age mean 21 months, range 2 – 48) with unilateral retinoblastoma were included (63% right,
37% left). All eyes were staged cT2b (8th Edition AJCC).2 Based on high-quality molecular genetic
analysis, heritable trait was HX (4/38–11%), H0 (27/38–71%) and H1 (7/38–18%). H1 children showed
mosaicism for the RB1 pathogenic variant (3/7), low penetrance RB1 pathogenic variant (3/7) and13-q
deletion syndrome (1/7).
At presentation, all eyes had within normal IOP. Vitreous seeding was seen present in all eyes. Tumor
involved the macula in 31/38–82%. Children with macular involvement were tended to be younger at
diagnosisdiagnosed earlier than children with macular sparing (mean 20 vs 28 months, respectively),
though this difference was not significant (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 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 was performed 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 under the 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–
7
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 case eye (2.6%) of had
trans-scleral and extraocular extension (pT4). study eyes
Summary of High-Risk Pathology Eyes High-Risk Eyes (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 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.
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 Ttable 2). 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/or 100% with <1 quadrant of RD. (Table 2)
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 RB1 pathogenic variants were
identified in 34/37 eyes [H0* (27/38–71%) and H1 (7/38–18%)]. andThe three3 eyes were designated
8
(Hx () as the germline statushHeritability cannot be verified). and one had hypermethylation of the RB1
premotor in blood cells. In retrospective designation by the 8th ed. AJCC, heritable trait was HX (4/38–
11%), H0 (27/38–71%) and H1 (7/38–18%). H1 children showed mosaicism for the RB1 RB1 pathogenic
variant (3/7), low penetrance RB1 RB1 pathogenic variant (3/7) and 13-q deletion syndrome (1/7). The
children that showed high riskhigh-risk pathology were H1 (1 extraocular, pT4 eye, Figure 1A), HXx (2
pT3a 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. The child was diagnosed with Bony
metastases were found 1 year following retinoblastoma diagnosis.16 He 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. He The child died 18 months after metastasis diagnosis, despite focal
radiotherapy. The other children in this cohort are alive and well. None of theNo children were was( lost
to follow-up.
Discussion
The International Intraocular Retinoblastoma Classification (IIRC) (2005) 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 A modification was proposed in 2006 (International
Classification of Retinoblastoma, ICRB). In 2010, the 7th Edition AJCC defined clinical and pathological
staging for overall prognosis. The 8th Edition TNMH was recently updated based on evidence-based data
from an international survey,2 and now serves as the current gold standard for retinoblastoma staging.
Advanced intraocular disease includes IIRC Group E [withfeatures such phthisis bulbi (cT3a), anterior
9
segment tumor invasion (cT3b), rubeosis irides with neovascular glaucoma (cT3c), hyphema and/or
massive vitreous hemorrhage (cT3d) and or aseptic orbital cellulitis (cT3e)] and IIRC Group D eyes [with
significant RD (cT2a) and/or seeding (any vitreous and/or subretinal, seeding (cT2b)]. High-risk
histopathologic features of the enucleated eye predictive of increased metastatic risk are defined as
pT3/pT4 following enucleation, andwhich 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
(T8th Edition AJCC, Table 1).2
The mainfirst goal of treatment for advanced unilateral retinoblastoma is to save the child’s life and
prevent extraocular tumour dissemination; secondary goal is to followed by save 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 the a safest and lest costly option, allowing an early return to normal
life,20 fewer interventions and EUAs,21 lessless socioeconomic impacts,22 as well asand histopathological
review of disease extent to guide further therapy. This is the accepted practice in many centersPrimary
enucleation is current practice for cT3 (IIRC Group E) eyes and probably mostmany cT2b eyes (IIRC
Ggroup D). In our cohort all parents accepted our recommendation for primary enucleation. Parental
acceptance of enucleation depends on the treating physician and how the parents are counselled.
Potential for useful vision is important but salvage of a unilateral blind eye for cosmesis may not be
justified, given good prosthesis movement with myoconjunctival enucleation.23 The dilemma of parental
refusal of enucleation justifying treatment for these advanced eyes dependdilemma 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 eyes.
Prolonged attempts at globe salvage could may lead to delayeddelay diagnosis of HR features pointing to
potential subclinical metastasis. metastasis if HR features are not identified timely.24 Systemic
10
chemoreduction should also be considered cautiously, as Pre-enucleation chemotherapy may downstage
pathological findings, delay enucleation and block recognition of HR diseaseextraocular disease.24 With
no randomized controlled trial evidence from randomized controlled trials to guide management of
cT2a/cT2b eyes, the clinician and family must can consider balance the impact of potential years of trial
salvage with hidden risks,24 for against an eye with limited visionual potential and on quality of life for
the child and family. Systemic chemotherapy, IAC, IVitC, periocular chemotherapy and PPV are
available for attempted eye salvage. The success of IVitC to control vitreous disease10-12 justifies trial
salvage for a unilateral cT2b as long as metastatic risk is minimal. The literature on IAC lacks definitive
research5 and IAC chemotherapy delivered only to the eye is unlikely to treat hidden escaped tumour.
Systemic chemotherapy, IAC, IVitC, periocular chemotherapy and PPV are available for attempted
eye salvage. IVitCto (cT2b, Group D)10-12 justifies trial salvage for a unilateral cT2b as long as risk
metastatic risk is minimal. cThe lacks definitive research5andIAC only to the eyeisis unlikely
ineffectiveto treathidden escaped tumour.5
Clinical features at presentation reported to predictive of HR histopathology predominantly describe
cT3 (Group E) eyes, not cT2b eyes and 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, theseThese characteristics
predominantly describe cT3 (Group E) eyes, and are not relevant when considering the treatment ofnot
cT2b eyes.Yousef et al29 concluded that clinical staging alone (TNM 7th ed., IIRC or Reese Ellseworth
classification) is insufficient to predict HR histopathology. This encouraged us to study the individual
clinical findings as predictors of HR histopathology. rather than the whole eye staging. A useful
predictive reproducible clinical finding would be easily identified at intital staging EUA, the time of
decision of trial salvage vs primary enucleation. We excluded subjective findings such as presenting
11
complaint, duration of symptoms, pattern of growth (endophytic, exophytic or mixed) and presence of
subretinal seeding under detached retina.
The Auseful reproducible would beidentifiedintital vs primary enucleation.needsbasedsuch t,
subjective eyesuch .
Approximately 2–33% of Group D eyes are expected to harborharbour HR histopathologic features
following in primary enucleationenucleated eyes.20,27,29-33 However, the heterogeneous literature is
heterogeneous and limited by non-consensus in defining HR histopathology features, variable
classifications, and inclusion of primarily and secondarily enucleated eyes and, children with unilateral
and bilateral disease, as well asand eyes with no staging indication ofrecorded staging. In our cohort of
primarily enucleated unilateral cT2b eyes, 10.5% had HR histopathology. Macular involvement, optic
nerve obscuration or >1 quadrant of RD had low predictive value for HR histopathology (13%, 14%, or
14%, respectively). However, the combination of macular sparing, visibility of the optic nerve and/or <1
quadrant of RD had 100% predictive value for the presence of LR histopathology, suggesting that such an
eye with these three clinical features may undergois appropriate for 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 reported absence of vitreous
seeds as athe 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. We used the predictive
values rather than then significance tests to interpret our data. We ran significance test forIn our study of
our collectiveall samples (78 eyes, table 3), absence of vitreous seeds lost itswas not significantcance
(p=0.05) and other factors showed a lower p-value than reported yet insignificantby others. 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 X3). Berry et al 33 reported that 15% of eyes with optic nerve obscuration
12
(69/102), while 0% with visible optic nerve (33/102) at diagnosis had post-laminar invasion following
primary enucleation, suggesting a possible clinico-pathologic association 33. This goes in accordance with
our 100% probability for LR with visible optic nerve in our cohort.
Our proposed clinical predictors are to be used at initial diagnosis and no evidence is available to
suggest their usefulness in recurrent or refractory cases decision makingdecision-making. These
predictors do not predict outcomes as LR eyes at diagnosis are not guaranteed to remain LR if
unresponsive to initial treatment and the decision of further trial 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.
Post-enucleation 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 ICRB35 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
13
histopathologicalhistopathologic 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
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-riskLR in unilateral cT2b eyes, and may predict which advanced eyes are suitable for
trial salvage decision. HR histopathology was found in10.5% of primarily enucleated unilateral cT2b
(Group D) eyes. Given The widespread management debate of on management of unilateral cT2a/cT2b
eyes, there is a need forwould be solved by robust, multicentre collaborative studies involving a larger
group ofmany children to further assessestablish 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. Clinicopathologic features of the whole studied sample (n=38)
14
Supplementary Table 2: Significance of association between clinical findings and histopathologic
features of enucleated eyes.
Figure Legend
Figure 1. (A) Left, wide-angle RetCam fundus photograph of child 1 showing a right multilobulated
tumor with overlying serous retinal detachment (RD) and subretinal seeding. Middle left,
Histopathological section 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. HeThe child underwent six cycles of
vincristine, etoposide, carboplatin (VEC) and cyclophosphamide, followed by orbital irradiation.
(B) Left, wide-angle 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 shethe child received four cycles of VEC.
(C) Left, RetCamwide-angle 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, wide-angle 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
15
presented with fever and pain, and WBMRI identified a paraspinal tumor. Molecular analysis confirmed
metastasis.16s (Racher 2016). Bilateral BMA were involved with tumor 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. HeThe
child was diagnosed with dural-based metastases 1 year later. Despite radiotherapy, the child died 18
months after presentation with metastases.
1. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology clinics of North America. 2005;18:41-53.
2. Mallipatna A, Gallie BL, Chévez-Barrios P, et al. Retinoblastoma. In: Amin MB, Edge SB, Greene FL, eds. AJCC Cancer Staging Manual. Vol 8th Edition. New York, NY: Springer; 2017:819-831.
3. Munier FL, Mosimann P, Puccinelli F, et al. First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20 years of treatment. Br J Ophthalmol. 2016.
4. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology. 2014;121(7):1453-1460.
5. Yousef YA, Soliman SE, Astudillo PP, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA ophthalmology. 2016;134(6):584-591.
6. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011;129(6):732-737.
7. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081-2087.
8. Chan HS, Gallie BL, Munier FL, Beck Popovic M. Chemotherapy for retinoblastoma. Ophthalmology clinics of North America. 2005;18(1):55-63, viii.
9. Canadian Retinoblastoma S. National Retinoblastoma Strategy Canadian Guidelines for Care: Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44 Suppl 2:S1-88.
10. Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96(8):1078-1083.
16
11. Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A, Beck-Popovic M. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012;96(8):1084-1087.
12. Berry JL, Shah S, Bechtold M, Zolfaghari E, Jubran R, Kim JW. Long-term outcomes of Group D retinoblastoma eyes during the intravitreal melphalan era. Pediatr Blood Cancer. 2017.
13. Mallipatna AC, Dimaras H, Chan HS, Heon E, Gallie BL. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol. 2011;129(6):738-745.
14. Zhao J, Li Q, Wu S, et al. Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology. 2018;125(2):320-322.
15. Sastre X, Chantada GL, Doz F, et al. Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Archives of pathology & laboratory medicine. 2009;133(8):1199-1202.
16. Racher H, Soliman S, Argiropoulos B, et al. Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma. Cancer Genet. 2016;209(7-8):359-363.
17. Khelfaoui F, Validire P, Auperin A, et al. Histopathologic risk factors in retinoblastoma: a retrospective study of 172 patients treated in a single institution. Cancer. 1996;77(6):1206-1213.
18. Shields CL, Shields JA, Baez KA, Cater J, De Potter PV. Choroidal invasion of retinoblastoma: metastatic potential and clinical risk factors [see comments]. British Journal of Ophthalmology. 1993;77(9):544-548.
19. Shields CL, Shields JA, Baez K, Cater JR, De-Potter P. Optic nerve invasion of retinoblastoma. Metastatic potential and clinical risk factors. Cancer. 1994;73(3):692-698.
20. Mallipatna AC, Sutherland JE, Gallie BL, Chan H, Heon E. Management and outcome of unilateral retinoblastoma. J AAPOS. 2009;13(6):546-550.
21. Fabian ID, Stacey AW, Johnson KC, et al. Primary enucleation for group D retinoblastoma in the era of systemic and targeted chemotherapy: the price of retaining an eye. Br J Ophthalmol. 2017.
22. Soliman SE, Dimaras H, Souka AA, Ashry MH, Gallie BL. Socioeconomic and psychological impact of treatment for unilateral intraocular retinoblastoma. Journal Francais D Ophtalmologie. 2015;38:550—558.
23. Shome D, Honavar SG, Raizada K, Raizada D. Implant and prosthesis movement after enucleation: a randomized controlled trial. Ophthalmology. 2010;117(8):1638-1644.
24. Zhao J, Dimaras H, Massey C, et al. Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(7):845-851.
25. Kashyap S, Meel R, Pushker N, et al. Clinical predictors of high risk histopathology in retinoblastoma. Pediatr Blood Cancer. 2012;58(3):356-361.
26. Chantada GL, Gonzalez A, Fandino A, et al. Some clinical findings at presentation can predict high-risk pathology features in unilateral retinoblastoma. J Pediatr Hematol Oncol. 2009;31(5):325-329.
17
27. Kaliki S, Srinivasan V, Gupta A, Mishra DK, Naik MN. Clinical Features Predictive of High-Risk Retinoblastoma in 403 Asian Indian Patients: A Case-Control Study. Ophthalmology. 2015.
28. Chawla B, Sharma S, Sen S, et al. Correlation between clinical features, magnetic resonance imaging, and histopathologic findings in retinoblastoma: a prospective study. Ophthalmology. 2012;119(4):850-856.
29. Yousef YA, Al-Hussaini M, Mehyar M, et al. Predictive Value of Tnm Classification, International Classification, and Reese-Ellsworth Staging of Retinoblastoma for the Likelihood of High-Risk Pathologic Features. Retina. 2015.
30. Wilson MW, Qaddoumi I, Billups C, Haik BG, Rodriguez-Galindo C. A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma. The British journal of ophthalmology. 2011;95(4):553-558.
31. Kaliki S, Tahiliani P, Mishra DK, Srinivasan V, Ali MH, Reddy VA. OPTIC NERVE INFILTRATION BY RETINOBLASTOMA: Predictive Clinical Features and Outcome. Retina. 2016;36(6):1177-1183.
32. Fabian ID, Stacey AW, Chowdhury T, et al. High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes. Ophthalmology. 2017;124(6):851-858.
33. Berry JL, Kogachi K, Jubran R, Kim JW. Loss of fundus view as an indication for secondary enucleation in retinoblastoma. Pediatr Blood Cancer. 2017.
34. Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol. 2002;120(7):923-931.
35. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113(12):2276-2280.
36. Kaliki S, Shields CL, Shah SU, Eagle RC, Jr., Shields JA, Leahey A. Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol. 2011;129(11):1422-1427.
37. Kim JW. Retinoblastoma: evidence for postenucleation adjuvant chemotherapy. Int Ophthalmol Clin. 2015;55(1):77-96.
38. Chantada GL, Dunkel IJ, de Davila MT, Abramson DH. Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol. 2004;88(8):1069-1073.
39. Bosaleh A, Sampor C, Solernou V, et al. Outcome of children with retinoblastoma and isolated choroidal invasion. Arch Ophthalmol. 2012;130(6):724-729.
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