Bilateral enucleation for retinoblastoma: A study of 14 patients.

PURPOSE: To study the clinical profile of patients who underwent bilateral enucleation for retinoblastoma (RB).
METHODS: Retrospective study of 14 cases.
RESULTS: Of >3000 RB cases, 14 (<1%) underwent bilateral enucleation for treatment of RB. The mean age at diagnosis of RB was 26 months (median, 24 months; range, 5-72 months). All patients had bilateral RB at presentation. Intraocular RB was evident in 23 (82%) eyes and orbital tumor extension was noted in 5 (18%) eyes. Based on the International Classification of Intraocular RB, tumors were classified as Group B (n = 1; 4%), D (n = 4; 14%), or E (n = 14; 50%) at presentation. Based on the International RB Staging System, tumors were classified as Stage 1 (n = 23; 82%) or Stage 3 (n = 5; 18%). Two patients (four eyes with intraocular RB) had undergone prior treatment before presenting to us and thus could not be classified. Primary treatment included systemic chemotherapy (n = 27; 96%) or enucleation (n = 1; 4%). Five patients were lost to follow-up for a mean duration of 15 months (median, 12 months; range, 7-24 months) during treatment and presented with the orbital extension of RB in one (n = 4; 29%) or both (n = 1; 7%) eyes. Secondary enucleation was performed in 27 (96%) eyes. Over a mean follow-up period of 49 months (median, 29 months; range, 3-340 months), there was no evidence of metastasis and 1 (7%) child died due to pneumonia.
CONCLUSION: Bilateral enucleation is rare in the treatment of RB. Advanced tumor presentation or noncompliance to treatment necessitates bilateral enucleation. Copyright:

Introduction

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. If left untreated, it puts the child's vision, eye, and life at risk. Despite advances in therapeutic strategies for RB, enucleation remains an essential therapeutic modality in the management of advanced tumors. RB can present as an unilateral or bilateral disease. It originates in the retina and can subsequently involve the optic nerve and choroid. After invading these structures, the disease often metastasizes to the central nervous system.[1] If the disease is left untreated, it can metastasize to the brain within 1 or 2 years of diagnosis.

Outcomes for RB are assessed in terms of patient survival, globe, and vision salvage. In developed countries, early detection of intraocular disease and easy access to care have resulted in a patient survival rate of more than 90%. This success is encouraging to both treating physicians and even parents. The current main modalities of treatment of intraocular RB comprise transpupillary thermotherapy, cryotherapy, plaque radiotherapy, intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, subtenon's chemotherapy, external-beam radiotherapy (rarely used currently), and enucleation.[12345678910] Intravenous chemoreduction has been popular for nearly three decades and continues to provide favorable tumor control for most eyes classified as Groups A, B, or C and some D eyes, using the International Classification of RB. Intra-arterial chemotherapy involves the injection of chemotherapeutic agent into the ophthalmic artery under neurointerventional guidance. Multidisciplinary approaches that incorporate systemic chemotherapy and focal consolidation remain the main modality of treatment in majority of the cases. Availability of resources and the resultant costs have further widened the divide in the management of RB between developed and developing countries. This becomes important when one realizes that approximately 85% of the world's 8000 annual cases of RB occur in developing countries.

Enucleation is generally reserved for eyes with advanced RB, in which there is no hope for useful vision. Enucleation with implant placement and customized prosthesis allows excellent cosmetic outcome. Enucleation especially in a child will have physiological and psychosocial sequelae and distress on parents. Convincing families to accept enucleation is one of the important aspects of managing advanced RB cases. Convincing parents to accept bilateral enucleation is really a tough job for the treating physicians.[5]

Methods

This is a retrospective study which included patients with RB who presented to an ocular oncology referral center from August 1995 to January 2021. The center's institutional review board approved this study. All cases who underwent bilateral enucleation for the treatment of RB were included in this study. Patients who were lost to follow-up before completion of treatment with unknown globe status were excluded from the study.

The details of patient characteristics, treatment modalities, and pathologic features of the enucleated eyes were gathered. The International Classification of RB system was used to describe the intraocular tumor and the International RB Staging System was used for tumors extending beyond the eye. Treatment (intravenous chemotherapy, focal treatment in the form of transpupillary thermotherapy, cryotherapy, intra-arterial chemotherapy, and intravitreal chemotherapy) before the patient underwent enucleation were documented. Postenucleation treatment details were also recorded. Indications for primary and secondary enucleation were recorded. In view of advanced disease at presentation, bone marrow and cerebrospinal fluid (CSF) analysis was performed in all cases. All patients underwent orbital imaging.

As an institutional protocol, unilateral advanced RB undergo primary enucleation. However, in cases of bilateral advanced RB, primary enucleation is avoided unless the patient presents with a painful blind eye or the eye is beyond the chances of salvage. All patients with intraocular RB received intravenous systemic chemotherapy (six cycles of 3 weekly vincristine, etoposide, and carboplatin). Further treatment was planned based on the response to treatment. Chemotherapy was combined with appropriate focal and adjuvant treatment during or after intravenous chemotherapy. Enucleation was performed only if the globe could not be salvage with maximal treatment. All patients with extraocular tumor extension (optic nerve or extrascleral tumor extension) received six cycles of high-dose intravenous chemotherapy followed by enucleation, orbital external-beam radiotherapy, and another six cycles of high-dose chemotherapy.

Results

Over the 25-year study period, a total of >3000 cases of RB were treated at the institute. Of these, 14 (<1%) cases had to undergo bilateral enucleation for complete tumor control. These 14 cases were included for further analysis [Table 1]. The mean age at diagnosis of RB was 26 months (median, 24 months; range, 5–72 months). There were 5 (35%) males and 9 (65%) females. The mean duration of symptoms was 10 months (median, 3 months; range, <1–72 months). There was no family history of RB in any case. All patients had bilateral RB at presentation.

Table 1

Bilateral enucleation for retinoblastoma

Patient number	Age (months)	Gender	Eye	Tumor location	Primary treatment	Enucleation	Time interval between enucleation of both eyes (months)	Loss to follow-up (months)	Total follow-up duration	Outcome
1	22	Female	OD	I (Group E)	IVC	S	17	0	47	Alive
			OS	I (Group D)	IVC	S
2	12	Female	OD	I (Group D)	IVC	S	0	7	20	Dead
			OS	I (Group D)	IVC	S
3	5	Female	OD	I (Group E)	IVC	S	29	0	69	Alive
			OS	I (Group E)	IVC	S
4	60	Female	OD	NA*	IVC	S	39	0	340	Alive
			OS	NA*	IVC	S
5	24	Female	OD	NA*	IVC	S	12	0	15	Alive
			OS	NA*	IVC	S
6	9	Female	OD	I (Group B)	IVC	S	39	12	40	Alive
			OS	0 (Stage 3)	IVC	S
7	9	Male	OD	I (Group E)	IVC	S	31	18	40	Alive
			OS	I (Group E)	IVC	S
8	12	Female	OD	I (Group E)	IVC	S	27	12	40	Alive
			OS	I (Group D)	IVC	S
9	32	Male	OD	I (Group E)	Enucleation	P	3	0	3	Alive
			OS	I (Group E)	IVC	S
10	24	Male	OD	I (Group E)	IVC	S	12	0	5	Alive
			OS	I (Group E)	IVC	S
11	24	Male	OD	0 (Stage 3)	IVC	S	14	0	7	Alive
			OS	I (Group E)	IVC	S
12	72	Female	OD	0 (Stage 3)	IVC	S	16	0	17	Alive
			OS	I (Group E)	IVC	S
13	24	Female	OD	0 (Stage 3)	IVC	S	9	24	38	Alive
			OS	0 (Stage 3)	IVC	S
14	36	Male	OD	I (Group E)	IVC	S	10	0	8	Alive
			OS	I (Group E)	IVC	S

*Treated elsewhere before presenting to us. OD=Right eye, OS=Left eye, I=Intraocular retinoblastoma, O=Extraocular tumor extension, IVC=Intravenous chemotherapy, P=Primary, S=Secondary, NA=Not applicable

At presentation, intraocular RB was evident in 23 (82%) eyes and orbital tumor extension was noted in 5 (18%) eyes. Significant anterior segment findings included pseudohypopyon (n = 1), iris neovascularization (n = 5), ectropion uveae (n = 1), and cataract (n = 5). Based on the International Classification of Intraocular RB, tumors were classified as Group B (n = 1; 4%), D (n = 4; 14%), or E (n = 14; 50%) at presentation. Associated features included retinal detachment (n = 6), vitreous seeds (n = 8), subretinal seeds (n = 8), and vitreous hemorrhage (n = 11). Based on the International RB Staging System, tumors were classified as Stage 1 (n = 23; 82%) or Stage 3 (n = 5; 18%). Of these patients with Stage 3 disease, optic nerve tumor extension (n = 2) or extrascleral tumor extension (n = 4) was noted. Two patients (4 eyes with intraocular RB) had undergone prior treatment before presenting to us and thus could not be classified. None of the patients had bone marrow or CSF tumor spread at presentation.

Primary treatment included systemic chemotherapy (n = 27; 96%) or enucleation (n = 1; 4%). The only patient who underwent primary enucleation of one eye had pseudohypopyon at presentation with very advanced intraocular RB. Five patients were lost to follow-up for a mean duration of 15 months (median, 12 months; range, 7–24 months) during treatment and presented with orbital extension of RB in one (n = 4; 29%) or both (n = 1; 7%) eyes. Additional globe salvage treatments included transpupillary thermotherapy and/or cryotherapy (n = 6), intravitreal chemotherapy (n = 1), intra-arterial chemotherapy (n = 2), plaque radiotherapy (n = 2), and external-beam radiotherapy to the orbit (n = 6). Two patients also underwent cataract extraction and anterior vitrectomy to clear the media for tumor visualization. Secondary enucleation was done in 27 (96%) eyes due to progressive disease (n = 14; 52%), or as part of protocol-based treatment for orbital tumor extension (n = 11; 41%), or media opacity due to vitreous hemorrhage (n = 2; 7%). Six (43%) patients underwent bilateral secondary enucleation at the same time, while 8 (57%) underwent sequential enucleation. The mean interval between enucleation of both eyes was 14 months (median, 8 months; range, 0–39 months).

On histopathology, the tumors were well differentiated (n = 10), moderately differentiated (n = 2), or poorly differentiated (n = 14). Two eyes had nonviable tumor. Other histopathology features included anterior segment invasion (n = 1), massive choroidal invasion (n = 3), prelaminar optic nerve invasion (n = 2), and scleral infiltration (n = 3).

Over a mean follow-up period of 49 months (median, 29 months; range, 3–340 months), death occurred in 1 (7%) patient. This child had bilateral advanced intraocular RB at presentation for which the child received six cycles of chemotherapy. At the end of chemotherapy, the child had dense vitreous hemorrhage in both eyes precluding the visualization of tumor. Bilateral enucleation was advised, but the child was lost to follow-up for 7 months during which the tumor progressed to extraocular disease in one eye. The child received six more cycles of chemotherapy and underwent enucleation of both eyes. Postenucleation, the child was undergoing protocol-based treatment of 6 more cycles of chemotherapy, during which the child developed severe pneumonia and died during treatment of the same.

Discussion

With a population of approximately 1.2 billion, India is a densely populated country of Asia second only to China, and thus the burden of RB is much more compared to less populated regions.[11] The reported incidence of RB is 1 in 15,000–1 in 18,000 live births. It is second only to uveal melanoma in the frequency of occurrence of malignant intraocular tumors. There is no racial or gender predisposition in the incidence of RB. RB is bilateral in about 25%–35% of cases. The average age at diagnosis was 18 months, unilateral cases being diagnosed at around 24 months and bilateral cases before 12 months.[4] In our study, the age at diagnosis of bilateral RB was 26 months, indicating a delayed diagnosis. Delayed diagnosis may be responsible for advanced disease at presentation, thus resulting in poor chances of globe salvage.

The primary goal of the management of RB is to save life. Salvage of the eye and vision are the secondary and tertiary goals, respectively. The management of RB needs a multidisciplinary team approach, including an ocular oncologist, pediatric oncologist, radiation oncologist, radiation physicist, and ophthalmic oncopathologist. The management strategy depends on the stage of the disease: intraocular RB, RB with high-risk characteristics, orbital RB, and metastatic RB. Enucleation is a common method of managing advanced RB. Before 1990, a majority of patients with unilateral RB and the worse eye in bilateral RB underwent primary enucleation. A significant reduction in the frequency of enucleation has occurred in the late last century. Concurrently, there has been an increase in the use of alternative eye and vision-conserving methods of treatment. Primary enucleation continues to be the treatment of choice for advanced intraocular RB with neovascularization of iris, secondary glaucoma, anterior chamber tumor invasion, tumors associated with hyphema, or vitreous hemorrhage where the tumor cannot be monitored.[89] In our study, primary enucleation was performed in one eye with pseudohypopyon. An attempt for globe salvage was done in the remaining 23 eyes, though all cases required enucleation due to poor tumor control.

The globe salvage rates are poor in eyes with Group D and E RB. In the era of intravenous chemotherapy, all Group E eyes were enucleated and globe salvage was 47% for Group D eyes.[7] The success rate of Group D eyes improved to 67% with a combination of intravenous chemotherapy and external-beam radiotherapy.[12] Similarly, for Group E eyes, intravenous chemotherapy alone results in globe salvage in 53% of eyes, and a combination of intravenous chemotherapy and external-beam radiotherapy can improve the globe salvage to 91%.[13] In the intra-arterial and intravitreal chemotherapy era, the globe salvage rates have become better, with a globe salvage rate of 30%–100% in Group D eyes and 9%–90% in Group E eyes.[14151617] In our study, all but one eye with intraocular RB belonged to Group D or E. In spite of multimodal treatment strategies, all eyes required enucleation. Only one eye belonged to Group B, which also became an advanced RB due to poor treatment compliance. Tumors presenting with extraocular tumor extension are beyond the stage of globe salvage and require enucleation during the treatment course.[18]

While enucleation may be the best form of treatment for the patient when everything else fails, it is not easy to convince parents, especially if it involves bilateral enucleation. This trend was seen in our study since five children were lost to follow-up when enucleation was required for the second eye, resulting in the progression of RB. Extensive counseling is required in such cases with emphasis on life salvage. Discussion along with display of photographs of other children with a good customized ocular prosthesis is also helpful in convincing the parents.

Conclusion

Bilateral enucleation is rarely (<1%) performed in cases with bilateral advanced RB. While all efforts are made to salvage both eyes in all patients, life salvage should always remain our primary goal. Early diagnosis of RB and compliance to treatment are of paramount importance to achieve life, globe, and vision salvage. In those requiring bilateral enucleation simultaneously or sequentially, extensive counseling is needed to avoid treatment abandonment. In children who have the potential to lose both eyes in view of advanced disease at presentation, vision rehabilitation activities should be initiated at the earliest to allow easy adaptation for the child and parents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.