Abstract
In this retrospective study, we evaluated loss of fundus view as an indication for secondary enucleation and associated histopathologic findings. Of 64 secondarily enucleated eyes, 24 were enucleated for loss of fundus view. Average time from loss of fundus view to enucleation was 4.7 months. Of these eyes, 22 had viable tumor cells on histopathology, but none had high-risk features. Loss of fundus view was a common indication for secondary enucleation after chemoreduction. Given the high prevalence of viable histopathologic tumor cells, enucleation for loss of fundus view should not be significantly delayed to decrease risk of high-risk tumor progression.
Keywords: high-risk histopathology, loss of fundus view, retinoblastoma, secondary enucleation
1 |. INTRODUCTION
The International Intraocular Retinoblastoma Classification (IIRC)1 is used to classify stage and prognosis of retinoblastoma treated with chemotherapy. Any eye with retinoblastoma that undergoes attempted salvage has risk for tumor recurrence requiring secondary enucleation, particularly advanced Group D/E eyes. Several studies report rates of chemoreduction failure in advanced stages ranging from 30.5 to 63.9%.2,3
Secondary enucleation is often required when there is inability to monitor for tumor recurrence due to loss of fundus view from cataracts, retinal detachment, and/or vitreous hemorrhage.4 However, the validity of loss of fundus view as an indication for enucleation has not been previously analyzed. Rates of high-risk histopathologic features after secondary enucleation range from 0 to 21%5,6 and indicate either persistent or progressive disease, with the latter category indicating a lack of sufficient monitoring in some cases. Both the rate of active disease and high-risk histopathology in eyes enucleated with loss of fundus view would encourage a short period of monitoring before enucleation.
We hypothesized loss of fundus view, due to cataract, significant synechiae formation, vitreous hemorrhage, and/or retinal detachment, is a risk factor for the presence of viable retinoblastoma tumor and high-risk histopathology features in secondarily enucleated eyes.
2 |. METHODS
We reviewed the records of 61 patients who were diagnosed at Children’s Hospital Los Angeles (CHLA) with any stage of retinoblastoma based on the IIRC (A-E) classification in at least one eye between 1995 and 2015 and required subsequent enucleation. Infants with extraocular disease at diagnosis and requiring chemotherapy for central nervous system disease based on the Children’s Oncology Group protocol were excluded.
Sixty-one patients were initially treated with chemoreduction with systemic chemotherapy and subsequently required enucleation. At every examination under anesthesia, patients were monitored for tumor response, tumor persistence, and development of ocular complications preventing appropriate view of the tumor. The indication for enucleation, including loss of fundus view, was recorded. Regarding loss of view, patients were recommended to have secondary enucleation if monitoring of tumors that were active within the last 6 months was no longer adequate with fundoscopy or B-scan ultrasonography.
Based on clinical factors, chemoreduction to salvage the globe is offered in patients with unilateral/bilateral Group A–D eyes or patients with Group E disease in bilateral cases. The CHLA chemoreduction protocol has been previously published7 and consists of systemic chemotherapy and local consolidation therapies. Prior to 2012, some patients received external beam radiation therapy (EBRT) as salvage treatment if the patient exhibited tumor persistence or recurrence following chemoreduction. Total EBRT of 36 Gy was administered as intensity-modulated radiotherapy with 18 fractions of a 2 Gy daily dose. Some patients in our cohort received local chemotherapy for vitreous seeding, including subtenon carboplatin injections (prior to 2012) and intravitreal melphalan (after 2012).
3 |. RESULTS
Sixty-four eyes in 61 patients required secondary enucleation. The indications for secondary enucleation included recurrent tumors (45.3%), persistently viable tumors during or after treatment (12.5%), loss of fundus view (37.5%), and blind painful eye (4.7%). Two of 64 eyes (3.1%) with no loss of fundus view demonstrated high-risk histopathologic features. The treatment modalities received by all the eyes undergoing secondary enucleation compared to just those with loss of fundus view are shown in Table 1. All eyes were treated with systemic chemotherapy; 16.7% of eyes with loss of view were subsequently treated with EBRT.
TABLE 1.
Treatment modalities received by eyes requiring secondary enucleation
| Treatment | All secondary enucleations (n = 64) | Eyes with loss of fundus view (n = 24) |
|---|---|---|
| Systemic chemotherapy | 64 (100%) | 24 (100%) |
| Intra-arterial chemotherapy | 2 (3.1%) | 0 |
| Brachytherapy | 2 (3.1%) | 0 |
| External beam radiation therapy | 11 (17.2%) | 4 (16.7%) |
| Subtenon carboplatin | 27 (42.2%) | 7 (29.2%) |
| Intravitreal melphalan | 9 (14.1%) | 5 (20.8%) |
3.1 |. Eyes with loss of fundus view
Of the 64 secondarily enucleated eyes, 24 eyes (37.5%) had loss of fundus view. The average time from diagnosis to loss of view was 8.1 months (SD 12.9 months); the average time from loss of view to enucleation was 4.7 months (SD, 6.1 months). Nine eyes (37.5%) had loss of view with inability to monitor the tumor cited as the primary reason for enucleation; 15 eyes (62.5%) had additional indications (Figure 1). Reasons for loss of fundus view included retinal detachment (50%), vitreous hemorrhage (12.5%), cataract (20.8%), hyphema (12.5%), and a blood-stained cornea secondary to persistent hyphema (4.2%). Twenty-two of the 24 globes (91.7%) demonstrated persistently active tumor on histopathology; none demonstrated high-risk histopathologic features.
FIGURE 1.
A Consolidated Standards of Reporting Trials (CONSORT) diagram illustrating the total number of eyes undergoing secondary enucleation for loss of fundus view. The number of eyes and associated percentages are included
4 |. DISCUSSION
Loss of fundus view was a common indication for secondary enucleation at our center. Without an adequate view into the fundus, the risk of unrecognized tumor growth leading to high-risk pathologic features and extraocular tumor spread may be significant, particularly in advanced eyes. Previous studies demonstrated the risk of tumor regrowth following chemoreduction for advanced eyes ranges from 30 to 80%.7,8 At our center, eyes were enucleated at an average of 4.7 months following loss of fundus view, demonstrating our strict protocol to enucleate eyes with a loss of fundus view due to an inability to adequately monitor for tumor recurrence; none of the eyes had high-risk pathologic features and no patient developed metastasis.
In our cohort, 91.7% of eyes with loss of fundus view had viable tumor cells on histopathology. Massive ocular tumor recurrence and extraocular spread may have occurred if enucleation had not been performed. The loss of fundus view in eyes with retinoblastoma likely demonstrates an advanced state of disease, reflected by massive involvement of the retina resulting in vitreous hemorrhage or complete retinal detachment. The loss of fundus view can also occur from treatment effect following systemic or intra-arterial chemotherapy, intravitreal melphalan injection, or radiation therapy. These eyes likely have poor visual prognosis, and intervention to improve vision, such as cataract surgery and/or vitrectomy typically, cannot be considered until the tumor has been stable for >12 months due to risk of tumor spread. Our data indicate that the presence of persistently viable cells is likely in eyes with active or recently active disease and loss of view. To decrease the risk of tumor progression, these eyes likely require immediate enucleation or monitoring for a few months only to determine if immediate improvement in the view will occur, while the parents and child are prepared for likely enucleation.
Two of 64 eyes demonstrated high-risk pathologic features. Both eyes were noted to have active tumor recurrence and not loss of view. Zhao et al. demonstrated a higher rate of metastasis in patients with Group E eyes undergoing enucleations if they were treated first for more than 3 months with chemoreduction, likely due to downgrading of high-risk pathologic features.9 Fabian et al. showed a 21% rate of high-risk histopathologic features in secondary enucleations with 80% of eyes demonstrating anterior segment invasion following intra-arterial chemotherapy.5 The reason for the low rate of high-risk pathologic features in eyes undergoing secondary enucleations at our institution is unclear,5 although differences in treated patient populations and a short time to enucleation after loss of view may explain this discrepancy. It is unknown what percentage in the Zhao and Fabian series had loss of fundus view, although based on our experience, this is not an uncommon indication for secondary enucleations.
In patients with retinoblastoma, the presence of active tumor following secondary enucleation for loss of fundus view likely represents tumor regrowth during active monitoring. Although our analysis is retrospective, our results suggest a strict protocol of enucleating eyes with a loss of fundus view can minimize this risk and improve overall patient outcomes.
ACKNOWLEDGMENTS
This study was supported by an Unrestricted Departmental Grant from Research to Prevent Blindness and The Institute for Families, Inc, Children’s Hospital Los Angeles.
Funding information
Grant sponsor: Research to Prevent Blindness; Grant sponsor: The Institute for Families, Inc, Children’s Hospital Los Angeles.
Abbreviations:
- CHLA
Children’s Hospital Los Angeles
- EBRT
external beam radiation therapy
- IIRC
International Intraocular Retinoblastoma Classification
Footnotes
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
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