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 Table of Contents  
Year : 2020  |  Volume : 113  |  Issue : 2  |  Page : 33-38

Clinicopathologic evaluation of primary vs secondary enucleated unilateral group D retinoblastoma eyes

1 Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria; Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Canada, Egypt

Date of Submission11-Feb-2020
Date of Acceptance15-Feb-2020
Date of Web Publication10-Jul-2020

Correspondence Address:
Ahmed M Seddeek
5 Street Abdelrahman Sedki Miami, Alexandria
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejos.ejos_2_20

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Background The risk of tumor spread is the main concern while deciding primary treatment in advanced unilateral retinoblastoma, which presents later with an intact normal eye. Enucleation was recommended as a radical treatment but with newer treatment options such as systemic and intra-arterial chemotherapy. Ocular salvage could be tried in group D eyes with smaller tumors and visual potential.
Aim The aim was to assess the histopathologic metastatic risk in primary vs secondary enucleated (trial salvage) unilateral group D eyes.
Design Retrospective, noncomparative, single-institution observational case series.
Patients and methods All primary and secondary enucleated unilateral group D eyes (June 2012 to December 2018) managed at the pediatric ocular oncology unit, Ophthalmology Department, University of Alexandria. Clinical, radiological, histopathologic, and treatment data were collected. Clinicopathologic correlation was performed to identify the frequency of high-risk histopathologic features (HRHF).
Statistical analysis All analyses were performed using Microsoft Excel 2013 software and SPSS software version 17.0.
Results Twenty-six eyes were included. Sixteen were primary enucleated and none showed HRHF while 10 were secondary enucleated after failed trial salvage. Timely enucleated secondary cases (6/10) showed no HRHF while delayed secondary enucleation (2/4) was significantly associated with HRHF (P=0.02). All cases are alive with no metastasis after a median follow-up of 5 years.
Conclusion Primary and timely secondary enucleation for unilateral group D retinoblastoma eyes are comparable in low metastatic risk and effectivity of tumor control. Controlled discussed trial ocular salvage is safe conditioned by strict timely termination, if necessary.

Keywords: cancer, enucleation, high-risk histopathologic features, unilateral retinoblastoma

How to cite this article:
Seddeek AM, Shaarawy AS, El Shakankiri NM, El Sabaa BM, Soliman SE. Clinicopathologic evaluation of primary vs secondary enucleated unilateral group D retinoblastoma eyes. J Egypt Ophthalmol Soc 2020;113:33-8

How to cite this URL:
Seddeek AM, Shaarawy AS, El Shakankiri NM, El Sabaa BM, Soliman SE. Clinicopathologic evaluation of primary vs secondary enucleated unilateral group D retinoblastoma eyes. J Egypt Ophthalmol Soc [serial online] 2020 [cited 2020 Aug 14];113:33-8. Available from: http://www.jeos.eg.net/text.asp?2020/113/2/33/289487

  Introduction Top

Retinoblastoma is the most common intraocular malignancy of the pediatric age group [1], which originates from the retinal premature cells due to the biallelic mutation in the retinoblastoma tumor suppressor gene. Unilateral retinoblastoma occurs when this mutation affects only one retinal cell in most of the cases. Rarely, a low-penetrance germline mutation might present similarly [2],[3].

Unilateral retinoblastoma usually has late presentation due to the absence of visual symptoms by the intact vision in the normal eye [2],[3],[4]. In ∼85% of cases, retinoblastoma is classified as either group E or group D by the international intraocular retinoblastoma classification [5].

Previously, enucleation of advanced unilateral retinoblastoma was recommended as a radical treatment decision to avoid cancer spread and bad cosmetic outcomes of external beam irradiation [2].

With the introduction of newer treatment options such as systemic and intra-arterial chemotherapy (IAC) [5],[6],[7], some of these group D eyes might be saved especially with smaller tumors that show visual potential. The main concern in such situation is the risk of tumor spread. Other concerns include cosmetic, psychosocial, and economic burden of trial salvage decision [8].

In this study, we retrospectively reviewed the potential risks in delaying enucleation by a trial salvage decision in unilateral group D eyes.

  Patients and methods Top


The study was approved by the Faculty of Medicine Ethics Review Board and in accordance with the Declaration of Helsinki tenets.

Study design

This is a retrospective, noncomparative, single-institute observational case series.

All files of retinoblastoma children diagnosed and treated from June 2012 to December 2018 at the Pediatric Ocular Oncology Unit, Ophthalmology Department, University of Alexandria were reviewed. Any child with an enucleated eye (either primary or secondary enucleated) staged as International Intraocular Retinoblastoma Classification unilateral group D at diagnosis (International Intraocular Retinoblastoma Classification) was included [9].

Any unilateral group D eye was assigned to either trial salvage therapy or primary enucleation. Trial salvage includes initial chemotherapy (either systemic or IAC), followed by necessary consolidation focal therapies. Trial salvage choice was offered at the presence of first, potential for acceptable vision (tumor location relative to the macula or the optic disk determined clinically or by MRI); second, small tumor size measured by the MRI; and third, parents’ consent after thorough discussion of advantages and disadvantages of both lines of treatment. Secondary enucleation was performed if the tumor is nonresponsive, progressive, or refractory.

Collected clinical data included age, family history, clinical features at diagnosis, laterality, presenting symptoms, ocular and radiologic assessment, and time to enucleation. Radiologic data included tumor largest basal diameter by MRI. Treatment data included types of primary treatment and subsequent required therapies.

Histopathology of enucleated eyes was evaluated for the presence of high-risk histopathologic features (HRHF) defined as the presence of massive (>3 mm) choroidal invasion, retrolaminar optic nerve invasion, anterior chamber involvement, iris infiltration, ciliary muscle/body infiltration, scleral/extrascleral infiltration, or extraocular disease [10]. Any child with HRHF will be assigned to additional four cycles of adjuvant chemotherapy.

Eyes were retrospectively classified both clinically and pathologically after enucleation according to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control Clinical Staging System (8th ed. cTNM and pTNM) [11].

Primary outcome is to evaluate the frequency of HRHF in primary and secondary enucleated eyes. Secondary outcome is to evaluate the impact of treatment delay on increasing risk of spread and treatment burden.


All analyses were performed using Microsoft Excel 2013 software (Microsoft Corp., Redmond, Washington, USA) and SPSS software version 17.0 (SPSS Inc., Chicago, Illinois, USA). Risk factors to develop HRHF in primary and secondary enucleated eyes were calculated using Fisher’s exact test and t-test for categorical and continuous variables, respectively. An α level of 0.05 and two-tailed P values were used to determine statistical significance.

  Results Top

Record review identified 26 children (17 females, 65%) with unilateral enucleated group D eyes that were eligible. The mean age at diagnosis was 27±11 months (range: 5–47 months) with positive parental family history in two children. Leukocoria was the main complaint in all cases. Ten children (38%) were offered trial ocular salvage while 16 eyes of 16 children were primarily enucleated. [Table 1] summarizes the clinical data of primary and secondary enucleated eyes.
Table 1 Comparison between the clinical data for the primary and secondary enucleation groups

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Primary enucleated eyes (16) showed optic nerve obscuration in 14/16 eyes (88%), foveal obscurations in 16/16 (100%), retinal detachment with subretinal fluid in 8/16 (50%), and tumor seeding in 14/16 eyes (88%, cT2b). The largest basal diameter was 17±3 mm. Time to enucleation ranged from 5 days to 21 days. Primary enucleated eyes showed no HRHF in any of them. Fifteen eyes were pathologically staged as pT1 and one eye was classified as pT2a (concomitant focal choroidal and prelaminar optic nerve invasion, 3 weeks to enucleation). None of the children developed metastasis after a median of 4.3-year follow-up.

Secondary enucleation (10 eyes) was decided after 4–6 monthly cycles of systemic chemotherapy (Vincristine, Etoposide, Carboplatin) without signs of tumor control [12]. Six families consented and enucleation was performed within 6 months from diagnosis and none showed HRHF (pT1). Four families refused to have enucleation. Two families opted for additional IAC (1–3cycles) that did not show improvement and were eventually enucleated without any HRHF (pT1). Two families disappeared for 1 and 3 months, respectively, without treatments before approving enucleation and both eyes showed HRHF in the form of massive choroidal invasion (pT3a) that required additional four cycles of systemic chemotherapy as illustrated in [Figure 1].
Figure 1 Schematic representation of the treatment timeline of eyes failing trial salvage. The associated legend demonstrates different events including systemic chemotherapy and intra-arterial chemotherapy sessions, date of decision, while termination of timeline is time of enucleation. HRHF, high-risk histopathologic features.

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None of the children developed metastasis after a median of 5.3-year follow-up.

Delay in enucleation when indicated, whether primary or secondary enucleated, was noticed in 4/26 (15.4%) eyes (all secondary enucleated) and was significantly associated with the presence of HRHF (Fisher’s exact test, P=0.018*).

  Discussion Top

There is an ongoing international debate regarding primary treatment decision for unilateral group D retinoblastoma eyes. On one side, primary enucleation will render the child cancer free especially after the histopathology confirms low risk of spread where around 20% (3–33%) of group D eyes will harbor HRHF. Furthermore, the child will avoid all the potential and local side effects of trial salvage. However, loss of any potential vision together with the parental cosmetic concerns will ensue [13].

On the contrary, primary salvage decision will try saving the eye for both vision and cosmesis given the low risk of tumor spread. This direction is currently prevailing especially with the introduction of newer salvage modalities including systemic and regional chemotherapy (intra-arterial and intravitreal) and plaque radiotherapy. However, it is not accepted to endanger children’s’ life trying to conserve globes with advanced tumors [14].

Retinoblastoma spread is anticipated when the histopathology of enucleated eyes show HRHF including massive tumor invasion to the choroid (>3 mm), retrolaminar optic nerve and/or anterior chamber invasion [10]. The presence of HRHF shows a 25% risk of metastasis and is present in around 20% of unilateral D eyes [13]. This gives an estimated metastatic risk of 5% in unilateral group D eyes [13]. Proper choice of the initial treatment strategy helps in preventing this risk.

Systemic chemotherapy in group D eyes has a 50–60% chance of globe salvage as reported from high-income countries [5]. In Alexandria, globe salvage was reported to be around 30% due to multiple socioeconomic and psychological factors that confound regularity of treatments [8].

Zhao et al. [15] reported that systemic chemotherapy masks preexisting HRHF and increase metastatic spread. They reported that greater than three cycles of chemotherapy reduces survival. Moreover, systemic complications including neutropenia, higher susceptibility to infections, and ototoxicity are frequent and were sometimes declined by parents [16].

IAC through the ophthalmic artery is an attractive treatment option as it treats intraocular tumor with minimal or no systemic side effects [7],[17]. It has reached up to 75% success of globe retention in group D eyes with few, but considerable local toxicity mainly vascular occlusions and transient nerve palsies [17],[18]. Although it seems a perfect option, it does not treat extraocular microscopic metastasis in those cases with initial high-risk features, where systemic chemotherapy is required to reduce the metastasis risk and prevent metastasis-related morbidity and mortality. Intravitreal chemotherapy has shown excellent control for vitreous seeds more than 90% without any risk of tumor spread. Vitreous seeds were a main factor of failed globe salvage previously [19],[20],[21],[22].

The primary decision is at diagnosis making any clinical sign that can predict high-risk features of tumor spread of utmost value. Most of the published literature tackled the clinical high-risk predictors of group E eyes like neovascularization of the iris, neovascular glaucoma, buphthalmos and aseptic orbital cellulits [23],[24],[25],[26],[27],[28]. Meanwhile, few publications concentrated on group D eyes’ dilemma [13],[29],[30]. Berry and colleagues identified obscured optic nerve and loss of fundus view as clinical risk predictors of HRHF [31],[32]. Fabian et al. [29] postulated that absence of vitreous seeds at presentation was the only predictive factor found for HRHF based on their analysis of 40 group D eyes (both unilateral and bilateral).

Kletke et al. [13] identified three clinical parameters in unilateral group D eyes as predictors of low metastatic risk where trial salvage is safe to execute. Those parameters are visible optic nerve, foveal noninvolvement, and presence of less than one quadrant of retinal detachment. Any parameter predicted low risk in their cohort of 38 eyes. Our criteria for trial salvage in Alexandria are similar, where we try to save eyes with visual potential with free fovea and visible nerve. Using this protocol, we did not have any eyes with HRHF at the time of primary enucleation.

Multiple other factors play an important role in decision-making besides the clinical appearance of the eye. Kaliki et al. [24] reported that prolonged duration of symptoms of more than 6 months was associated with HRHF. Parental refusal of enucleation is a well-known obstacle to timely treatment due to cultural, religious, or psychological factors [33]. Proper detailed discussion with the family is usually sufficient to overcome that barrier.After taking into consideration all the aforementioned parameters, there is no guarantee that HRHF may occur later if tumor response is not sufficient for proper control. The physician should discuss before starting trial salvage the probability of secondary enucleation and the dangers of delaying enucleation. Our data has shown significant HRHF when delay in secondary enucleation occurred.

Trial salvage provides increasing hope of cure by families especially with investment of more time, money, and emotions into different treatment modalities. This can be justified in the context of bilateral disease but not in unilateral retinoblastoma when the other eye is perfectly normal [8],[14].

Parental shopping for the desired salvage treatments is a major concern, especially when the decision for termination of trial salvage is taken by the primary care physician. This further delays proper treatment and increase the metastatic risk.

In a report from Alexandria by Soliman et al. [8], trial salvage decision in unilateral group D eyes was associated with huge social, psychological, and economic burdens that contributed around 56% of failed salvage attempts. Furthermore, there was a fivefold increase in metastatic risk than primary enucleated unilateral eyes.

Our study was limited by its retrospective nature, small sample size, and limited evaluation of the associated socioeconomic parameters.

  Conclusion Top

All primary enucleated eyes in our study showed no risk for invasion, and all cases required no postenucleation adjuvant chemotherapy. They were not exposed to chemotherapy side effects and its socioeconomic and psychological burden. However, cases who started salvage therapy had a longer treatment duration with higher risk for developing micrometastasis.

Primary enucleation is an effective treatment option for unilateral group D retinoblastoma eyes, but controlled discussed trial ocular salvage is safe, conditioned by strict timely termination if necessary.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1]


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