Clinical characterization and long-term postoperative outcomes of retinoblastoma patients receiving enucleation and primary orbital implantation in early infancy: an observational study

Abstract

Objectives

To retrospectively investigate clinical characterization and the long-term postoperative outcomes of retinoblastoma (RB) patients receiving enucleation with primary orbital implantation in early infancy (0–6 months old).

Methods

The clinical and follow-up data of 42 RB patients receiving enucleation with primary orbital implantation in early infancy at Beijing Tongren Hospital from December 2009 to January 2020 were analysed. The average follow-up time was 83 months. The patient group included 24 males and 18 females, 30 unilateral and 12 bilateral cases. A total of 44 eyes with 10 in stage D and 34 in stage E underwent 40 unilateral and 2 bilateral surgeries. 17 RB eyes received hydrogel and 27 RB eyes received hydroxyapatite implants. This study was performed by following the guideline of STROBE.

Results

Enucleation combined with primary orbital implantation promoted survival and was safe with few and minor complications such as increased secretion, upper eyelid ptosis, and sunken eye sockets which were not affected by stages, lateralities, or implant materials. 55-80% RB patients exhibited satisfactory appearance and obvious or moderate motility of orbital implants according to the evaluation by doctors and family members. Family members were likely more optimistic about the appearance and more pessimistic about motility of the orbital implantation than doctors did.The quality of life was high as indicated by PedsQL3.0 or PedsQL4.0 scores ( ≧ 90 for > 75% patients). It was not affected by the stages, laterality, and implant materials, nor affected by the appearance and motility of the implants.

Conclusions

The outcomes of the combination of enucleation and primary orbital implantation for pertinent RB patients in early infancy are generally satisfactory with few and minor complications, high safety, appearance, and overall quality of life. Enucleation combined with primary orbital implantation in early infancy benefits pertinent RB patients in appearance, survival, and quality of life.

Introduction

Retinoblastoma (RB) is a malignancy mostly found in children under 4 years old [1,2,3,4,5,6]. RB may occur in the perinatal period, and its symptoms may exhibit at birth [7,8,9,10]. RB may metastasize throughout the body in the late stage and be life-threatening.

RB is generally diagnosed through imaging and ophthalmic examination, and confirmed through postoperative pathological examination. RB is mainly treated with local and/or systematic chemotherapy, surgery, and radiation therapy based on the diagnosis and the guidelines such as the International Intraocular Retinoblastoma Classification (IIRC) [11] or the TNM staging system 8th edition (TNM8) [12,13,14,15].

The primary purpose of RB treatment is to promote survival. The secondary is to preserve the eyes and vision, and then improve the quality of life. For RB with IIRC stages D and E, enucleation surgery combined with chemotherapy or radiation therapy is an optional approach to promote survival [8, 14, 16, 17]. The eye preservation rate of patients in Group D or Group E is 19% [9]. The combination of chemotherapy, intra-arterial chemotherapy (IAC), enucleation, and vitrectomy may promote survival time of infants [10].

The most common sequelae of enucleation in children with RB are orbital deformation caused by bone atrophy and neurocognitive impairment after surgery [18], although enucleation surgery typically involves an orbital implant [19, 20]. Children are in the physical growth and development stage, and their orbits are also rapidly growing and developing. The orbit volumes of both sides are similar and positively and linearly correlated with ages for children aged 0–6 years old [21]. Even in late adolescence (ages 6–18), the orbit volumes of children increase at a rate of 1–2% per year [22]. Delayed orbital growth is related to the age of surgery, and is more prominent in children receiving treatment in the first year of life [23]. In addition, enucleation and orbital implantation may affect the cosmetic outcomes of patients. The presence of orbital implants is associated with higher objective evaluation scores for upper sulcus symmetry, implant mobility, and eyelid position and alignment [24].

Although active treatment for tumors is usually completed in childhood, survivors and their families often suffer from long-term effects, including visual impairment, facial deformities, and fear of recurrence or secondary cancer, which have a certain impact on growth, development, and quality of life [9, 10, 25, 26]. In addition, vision weakening or even loss greatly affects behavioral and cognitive development, bringing huge mental and economic burden to the patients and their families.

The occurrence, progression, and diagnosis and treatment of RB not only affect the physical health of children, but also have a huge impact on their subsequent social development, especially for the early stages of infant development (defined by World Health Organization as 0–6 months). There have been no systematic reports on the clinical characteristics and physical and mental development status of RB patients receiving enucleation and primary obital implantation. In this study, clinical characterization and long-term postoperative outcomes and their potential affecting factors of RB patients receiving enucleation and primary orbital implantation in early infancy were investigated.

Materials and methods

Patients and data collection

The RB patients who visited the ophthalmology department of Tongren Hospital in Beijing from December 2009 to January 2020 were included in this study. Inclusion criteria: (1) The patient whose surgery was performed at the age less than 6 months; (2) The patient with complete medical history and pathological examination data; (3) No evidence of distant tumor metastasis before surgery; (4) The patient with enucleation and primary orbital implantation; (5) The diagnose of RB was confirmed by histopathology and immunohistochemistry after surgery; (6) The patient who signed a written informed consent form with the guardian before surgery and received follow-up. Exclusion criteria: (1) There was concomitant other familial hereditary diseases; (2) There was evidence of intraorbital or systemic metastasis prior to surgery; (3) Trilateral retinoblastoma; (4) Failure to provide standardized treatment and follow-up according to the diagnosis and treatment plans; (5) The patients with incomplete medical history, and histopathological examination data. The demographic and clinical data were collected according to the items in Supplemental Table 1.

The diagnosis of retinoblastoma in all cases was performed by both ophthalmologists and pathologists based on clinical manifestations, combined with ocular ultrasonic imaging, CT (computed tomography) scan, and magnetic resonance imaging (MRI), Retcam fundus examination results under general anesthesia, and postsurgery histopathological examination. According to the International Retinoblastoma Intraocular Classification (IIRC) and the International Retinoblastoma Staging System (IRSS), intraocular diseases are grouped and staged. Two ophthalmologists independently evaluated the staging to determine the treatment options for each patient.

This study was approved by the ethics committee or institutional review board in Beijing Tongren Hospital, Capital Medical University. Written informed consents were obtained from the legal representatives for all patients. This study was performed by following the guideline of STROBE.

Treatment of patients

Treatment information of RB patients in this study was summarized in Supplemental Table 2.

Enucleation and orbital implantation procedures: (1) After general anesthesia, disinfection, and towel laying, cut open the conjunctiva along the corneal edge to expose the eyeball. (2) Identify the four rectus muscles, place double loop sutures on the rectus muscle tendons and tie the tendons, then detach and transection the tendons. Separate the tissues around the eyeball, cut off the posterior optic nerve of the eyeball, and remove the eyeball. (3) Use a metal ball mold to compress and stop bleeding, open the cavity, and confirm the diameter of the implant. (4) The hydroxyapatite orbital implant (18–20 mm) (Bio Eye OH Patite Orbital Implant, Beijing Yihuajian Science and Trade Co., Ltd., Beijing, China) or the self expanding hydrogel orbital implant (3 or 4 ml) (Tissue Expander, osmed gmbh, Ehrenbergstraße 29, 98693 Ilmenau, Germany), which has been pre-soaked in the normal saline containing dexamethasone hydrochloride and tobramycin, is implanted into the muscle cone. (5) Cover and fix the allogeneic sclera in front of the artificial eye. Trim the allogeneic sclera (Eye Bank of Beijing Tongren Hospital affiliated to Capital Medical University) and lay it on the anterior surface of the artificial eye. Suture and fix the four rectus muscles to the allogeneic sclera. (6) Use 6 − 0 suture to suture the fascia, subconjunctival, and conjunctival tissue incisions layer by layer, and conclude the surgery.

Determination of the size of the candidate orbital implant: (1) Estimation of the size of the candidate orbital implant. The size of the candidate orbital implant is determined based on the age of the patient, orbital development, ocular axis, and intraoperative conditions. The mean eye axis of a person is approximately 16 mm in the first year after birth. Preoperative ultrasound imaging examination is used to determine the specific axial diameter of each child. According to the aforementioned information, the size of the candidate orbital implant is then estimated. (2) Confirmation of the size of the candidate orbital implant. Before placing the artificial eye implant, a metal ball mold pre-adjusted based on the estimated size is used to compress and stop bleeding, open the cavity, and confirm the size of the implant. In addition, a small amount of polishing of the front part of the implant is often performed to reduce the tension on the sutured fascia and conjunctiva.

Repair of implant exposure: The implant exposue was found during examination at the hospital visit for eye redness, increased secretion, mild pain, and discomfort. To manage the implant exposure, anti-inflammatory treatment was first applied, and then the repair surgery was performed. Two cases of artificial eye exposure were found and repaired with surgery. One exposed implant exhibited a small exposure range and a small amount of connective tissue (thinning conjunctival tissue) in front of the implant. During the operation, the conjunctiva and subconjunctival fascia were separated along the exposed edge of the conjunctiva with more separation in the horizontal direction. A one-centimeter incision was made in the conjunctiva of the fornix to reduce conjunctival tension, and then the released fascia and conjunctiva were pulled up and sutured. Another exposed implant exhibited large exposure range, and no obvious connective tissue was found in front of the implant. To repair, the conjunctiva and subconjunctival fascia were released and separated, and the allogeneic sclera was used to cover the exposed artificial eye implant. Then, the surrounding conjunctiva and fascia were separated and released and sutured in alignment. During and after surgery, antibiotics were applied to prevent infection. After multiple follow-up visits, the conjunctival injury was found healing well and smoothly, and there was no more exposure of the repaired implants.

Chemotherapy and radiation therapy. The VCE regimen (vincristine, carboplatin, etoposide) was applied in preoperative and postopeartive chemotherapy for the RB patients in this study. There was no radiation therapy applied to the RB patients in this study.

Follow up

Follow up was performed once every 3–6 months after surgery, once every 6–12 months after 6–7 years old, every 1–2 years for lifelong follow-up. All follow-ups were performed by telephone, WeChat, or in-person visit. The latest follow-up in this study was conducted at the outpatient clinic. The follow-up was and will be ended on death from any cause. Follow-ups include examinations for eyelid morphology, appearance, depth of conjunctival sac, presence of implant exposure, infection, gross eye swelling, visual acuity, anterior segment condition, and fundus examination.

The latest follow-up included motility of the implant, postoperative chemotherapy (frequency), other postoperative treatments, complications (symptoms and timing), postoperative treatment time, treatment methods, appearance, and the quality of life. The appearance and quality of life questionnaire was completed through face-to-face interviews, and prognostic information was collected and summarized.

Evaluation of facial appearance

The facial appearances of the subjects were evaluated by both doctors and family members. The outcomes were divided into satisfaction and dissatisfaction. For doctor’s evaluation: Two doctors simultaneously determined the degree of satisfaction. Unsatisfied aspects included: (1) Eye depression: the protrusion of the eyeballs exceeds 2 mm when wearing eye lenses in both eyes. (2) Asymmetric size: The size of palpebral fissures in both eyes is different. Ptosis of the upper eyelid is found in the surgical eye. When look horizontally, the upper eyelid margin is more than 2 mm lower than the contralateral side. (3) Asymmetric appearance of both eyes: Surgical eye abnormalities, facial fullness, etc. were evaluated through taking photos. Two doctors checked eyes and/or photos twice. When there was inconsistency in the inspection or evaluation, the inspection and evaluation were repeated, and the result was obtained upon the agreement was achieved. Family assessment: Family members made subjective judgments based on the condition of the contralateral eyes and/or the normal healthy controls.

Evaluation of orbital implant motility

The orbital implant motility was evaluated by both doctors and family members according to the comparison between the surgical eyes and the contralateral eyes and/or the normal healthy controls. The degree of motility of the orbital implants was divided into four levels: obvious (satisfactory), moderately obvious (able to exercise, but the amplitude is not large, relatively satisfactory), poor (slight motility, not satisfactory), and no motility.

Assessment of quality of life

The Pediatric Quality of Life Cancer Module Scale (PedsQL 3.0) and Pediatric Quality of Life Universal Core Scale (PedsQL 4.0) were used to assess the quality of life. PedsQL 3.0 was pecifically designed to assess quality of life in pediatric cancer patients. It focused on cancer-related symptoms, treatment, worry, and communication and included 27 items in 8 categories: pain and hurt (2 items), nausea (5 items), procedural anxiety (3 items), treatment anxiety (3 items), worry (3 items), cognitive problems (5 items), perceived physical appearance (3 items), and communication (3 items). The PedsQL4.0 was pecifically designed to measure overall health-related quality of life in children and adolescents. It focused on overall health-related quality of life across conditions and included physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items). The frequency of an event occurring within the past month was investigated for each item. The answer options for each entry have five levels from 0 to 4 with corresponding scores: 0 = “never” (100 points), 1 = “almost never“(75 points), 2= “sometimes” (50 points), 3 = “often” (25 points), and 4 = “always” (0 points). The total scores for each entry were calculated. The higher the score, the better the quality of life [27].

Data processing and statistical analysis

The comparison of continuous variables between two groups was conducted using t-test or Pearson correlation analysis. Non continuous variables were analyzed using chi square test, Fisher’s exact test, or Spearman correlation analysis. P < 0.05 was considered statistically significant.

Results

Basic characterization of the study cohort

A total of 45 eligible RB cases were collected. After excluding 2 deaths due to brain metastasis and 1 death due to an accident, a total of 42 cases were included in this study, 24 males and 18 females (ratio 3:2). More cases came from rural areas than from the non-rural areas (29:13). A total of 54 RB eyes were affected, including 16 left and 14 right, and 12 bilateral RB cases. A total of 44 RB eyes underwent surgery, with 10 in D-stage and 34 in E-stage.

The ages on admittance and surgery, admission-surgery intervals, lengths of hospital stay, follow-up durations, ages at the latest follow-up, time intervals from presentation to chemotherapy, delayed time, time intervals from presentation to surgery, and time intervals from diagnosis to surgery were summarized in Table 1. The follow-up period of this study is 30–157 months, with median and mean values of 83 and 87 months, respectively (Table 1), indicating a long survival period for RB patients receiving enucleation and primary orbital implantation in early infancy.

Table 1 Time and intervals related to diagnosis, reatment, and follow-up of RB patients undergone enucleation and primary orbital implantation in early infancy

Treatment and postoperative conditions

Treatment information of the RB patients included in this study was summrized in Supplemental Table 2. A total of 66% (29/44) RB eyes did not receive preoperative chemotherapy, and 34% eyes received preoperative chemotherapy 1–5 rounds. Subgroup analysis showed that the D-stage group and the bilaterally affected eyes received more preoperative chemotherapy than the E-stage group and unilateral affected eyes did, respectively. There were no differences in the the preoperative chemotherapy frequency between the hydroxyapatite and hydrogel groups (Table 2).

Table 2 The preopreative and postoperative chemotherapy received by RB patients undergone enucleation and primary orbital implantation in early infancy

A total of 61% (27/44) RB eyes underwent 1–12 rounds of postoperative chemotherapy. Subgroup analysis showed that the bilaterally affected eyes received more postoperative chemotherapy than the unilaterally affected eyes did. There was no difference in the frequencies of postoperative chemotherapy between stages, and between the hydroxyapatite and hydrogel groups (Table 2).

A total of 39% (17/44) eyes were implanted with hydrogel and 61% (27/44) eyes with hydroxyapatite. There was no difference in the size of the orbital implants (Supplemental Table 3) or the ratio of materials (hydroxyapatite and hydrogel) used in the orbital implantation (Supplemental Table 4) between the stages and between lateralities. The optic nerve resection ranged 11–20 mm. There was no significant difference in the length of the resected nerve between stages, and between lateralities (Supplemental Table 5).

While 32% (14/44) eyes had no complications, 68% (30/44) exhibited complications. 4.5% (2/44) eyes had exposed implants caused by infections. Two cases of artificial eye exposure were found and repaired with surgery. One exposed artificial eye exhibited a small exposure range and a small amount of connective tissue (thinning conjunctival tissue) in front of the implant. Another exposed artificial eye exhibited large the exposure range and no obvious connective tissue in front of the implant. There was no more exposure of the repaired artificial eye implants. A total of 41% (18/44) eyes had misalignment of eyelids, including 36% (16/44) upper eyelid ptosis and 4.5% (2/44) entropion of the lower eyelids. No lower eyelid retraction was observed. 2% (1/44) eyes had orbital cellulitis, 4.5% (2/44) eyes had conjunctival cysts. 18% (8/44) eyes had sunken eye sockets, and 45% (20/44) eyes had intermittent secretions that were accompanied with colds or significant weather changes. 14% (6/44) eyes had other abnormalities. No granuloma or implant displacement or misalignment was found in any RB eye. There were no differences in the ratio of postoperative complications between stages, between the unilateral and bilateral affected eyes, and between the hydroxyapatite and hydrogel groups (Supplemental Table 6).

Evaluation of facial appearance

Facial appearances of patients were evaluated by both doctors and family members. According to the doctor’s evaluation, 73% (32/44) eyes exhibited satisfactory appearance and 27% (12/44) exhibited unsatisfactory appearance. The unsatisfactory appearance included asymmetry in the appearance of both eyes (27%, 12/44), asymmetry in size (23%, 10/44), and sunken eyeballs (11%, 5/44). 9% (4/44) eyes had all three features. 14% (6/44) had the asymmetrical size and appearance, and 2% (1/44) had the sunken eyeball and asymmetrical eye appearance. According to the evaluation by family members, the appearance of 80% (35/44) eyes were satisfactory, and 20% (9/44) eyes exhibited unsatisfactory features. Subgroup analysis showed that there was no difference in appearance evaluated by either doctors or family members between stages, between the unilateral and bilateral groups, and between the hydroxyapatite and hydrogel groups (Table 3). The results of evaluation of facial appearance by the doctors were silimar to those by the family members (Spearman correlation test r = 0.70, P < 0.0001).

Table 3 Doctor and famile-evaluated facial appearance of orbital implants of RB patients receiving enucleation and primary orbital implantation in early infancy

Evaluation of motility of orbital implants

Motility of orbital implants was evaluated by both doctors and family members. According to the doctor’s evaluation, all orbital implants were movable, with 30% (13/44) eyes showing obvious motility, 43% (19/44) eyes showing moderate motility, and 27% (12/44) eyes showing poor motility. There were significant differences between stages, between unilateral and bilateral affected eyes, and between the hydroxyapatite and hydrogel groups in the rate of orbital implantation motion evaluation (Table 4).

Table 4 Doctor and famile-evaluated motility of orbital implants of RB patients receiving enucleation and primary orbital implantation in early infancy

According to the evaluation by family members, 25% (11/44) orbital implants showed significant motility, 30% (13/44) eyes showed moderate motility, 32% (14/44) eyes showed poor motility, and 14% (6/44) eyes showed no motility. There were differences in the rate of motility of orbital implants between stages, and between the hydroxyapatite and hydrogel groups (Table 4).

The results of evaluation of motility of orbital implants by the doctors were silimar to those by the family members (Spearman correlation test r = 0.36, P = 0.017). Subgroup analysis showed that there were significant differences in the results of evaluation of motility of orbital implants in all subgroups except the bilateral affected groups between the doctors and family members (Table 4).

Quality of life assessment

A total of 43% (18/42) patients got a full PedsQL 3.0 total score (100), 33% (14/42) got ≧ 90, 19% (8/42) got ≧ 80, and 5% (2/42) got ≧ 70. Two entries, pain and hurt and worry, scored higher than the total score, while other entries showed no statistically significant difference compared to the total score (Fig. 1A). A total of 36% (15/42) patients got a full PedQL4.0 score (100), 45% (19/42) got ≧ 90, 12% (5/42) got ≧ 80, 7% (3/42) got < 80. The mean score of social function dimension was significantly higher than the total score. The mean score of emotional function was lower compared to the total score (Fig. 1B). There was no significant difference between the case groups at different stages, between the unilateral and bilateral eye case groups, and between the hydroxyapatite and hydrogel case groups in both PedsQL 3.0 and (PedsQL 4.0 scores (Table 5).

Fig. 1

PedsQL3.0 score and PedsQL4.0 score for RB patients. (A) Total PedsQL3.0 scores and dimension scores. (B) Total PedsQL4.0 scores and dimension scores. *, P < 0.05; **, P < 0.01; ***, P < 0.001

Table 5 PedsQL3.0 and PedsQL4.0 scores of RB patients receiving enucleation and primary orbital implantation in early infancy

There was a significant correlation between the total scores of PedsQL3.0 and PedsQL4.0 (Pearson correlation test r = 0.4, P = 0.0080). There was no correlation between the total score of PedsQL3.0 and PedsQL4.0 in the case group of D-stage, the bilateral affected eyes, and the hydrogel implants (P > 0.05). There was a significant correlation (P < 0.05) between the total scores of PedsQL3.0 and PedsQL4.0 in the groups of E-stage, the unilateral affected eyes, and hydroxyapatite implants (Table 5).

The initial treatment was negatively correlated with PedsQL3.0 full score (R=-0.32, P = 0.03). There are no treatment factors related to the PedsQL4.0 full score. There was a significant correlation between initial treatment and implant material (R = 0.40, P = 0.01) and preoperative chemotherapy frequency (R=-0.75, P = 0.00, negative correlation) (Fig. 2). There was no correlation between the motility and appearance of the orbital implantation. There was a correlation between family appearance satisfaction and PedsQL3.0 full score (R = 0.35, P = 0.02), while there was no correlation with the rest. There was no significant correlation between the appearance and motility of the orbital implantation and the PedsQL4.0 full score (Fig. 2).

Fig. 2

Correlation analysis of the factors of the treatment, appearance, and motility of the implant in RB patients with the PedsQL3.0 and PedsQL4.0 full scores. Left panel: Correlation coefficient R values. Right panel: P values

Disscussion

RB may occur in the perinatal period, and the youngest clinical RB patients may have RB symptoms at birth [7,8,9,10]. The occurrence, progression, and diagnosis and treatment of RB not only affect the physical health of children, but also have a huge impact on their subsequent social development. Studies have been conducted to investigate the clinical characteristics of RB patients with an average age of initial diagnosis of 2.2 ± 1.7 years, populations with a median age of 1.91 years [7], mean age 22.87 ± 18.99 months [28], age range 1-167 months and a median onset age of 16 months in the D and E groups of RB patients [9], around 1 year old [29], and age range 10 days to 11.93 months and a median age of 6.22 months [10]. In this study, we have investigated the clinical and prognostic characteristics and quality of life of RB patients receiving enucleation and primary orbital implantation in early infancy for the first time.

Our study shows that there is no difference in the number of preoperative and postoperative chemotherapy between the patient group with hydroxyapatite implants and the patient group with hydrogel implants. Increased secretion, upper eyelid ptosis, and sunken eye sockets are main postoperative complications. There is no difference in the rates of postoperative complications between D and E stages, the bilateral and unilateral groups, and between the hydroxyapatite and hydrogel groups. These findings suggest that enucleation combined with primary orbital implantation is safe with few and minor complications which are not affected by stages, literalities, or implant materials.

Facial appearance of patients and motility of orbital implants are among factors to affect physical and social development. In the current study, facial appearance of patients and motility of orbital implants are evaluated by both doctors and family members. According to the doctor’s evaluation, most (73%, 32/44) eyes exhibit satisfactory appearance and the rest exhibit unsatisfactory appearance. Most (73%, 32/44) eyes exhibit obvious or moderate motility of orbital implants and the rest exhibited poor motility of orbital implants. According to the family member’s evaluation, the appearance of 80% (35/44) eyes are satisfactory, and 20% (9/44) eyes exhibit unsatisfactory features. 55% orbital implants show obvious or moderate motility and 32% (14/44) eyes show poor motility, and 14% (6/44) eyes show no motility. There is no correlation between the motility and appearance of the orbital implantation. Although the results of evaluation of appearance and motility of orbital implants by the doctors are silimar to those by the family members, subgroup analysis reveal that there are no differences in appearance between D and E stages, the bilateral and unilateral groups, and between the hydroxyapatite and hydrogel groups while there are significant differences in the results of evaluation of appearance in the D-stage group, and the hydrogel group between the results by the doctors and by family members. There are significant differences in the results of evaluation of motility of orbital implants in all subgroups except the bilateral affected groups between the doctors and family members. Family members are likely more optimistic about the appearance and more pessimistic about motility of the orbital implantation than doctors do.

In our study, 43% (18/42) cases achieve full score and 33% (14/42) cases achieve ≧ 90 in PedsQL 3.0 evaluation. Two entries, pain and hurt and worry, score higher than the total score. 36% (15/42) cases achieve full score and 45% (19/42) cases achieve ≧ 90 in PedsQL 4.0 evaluation. The mean score of social function dimension is significantly higher than the total score. The mean score of emotional function is lower compared to the total score. There is a significant correlation between the total scores of PedsQL3.0 and PedsQL4.0. Therefore, the quality of life of more than 80% RB patients receiving enucleation and primary orbital implantation in early infancy is generally satisfactory, especially in pain and hurt, worry, and social function dimensions. The subgroup analysis shows that there are no significant differences in PedsQL3.0 and PedsQL4.0 scores between the case groups at different stages, between the unilateral and bilateral eye case groups, and between the hydroxyapatite and hydrogel case groups. There is no significant correlation between the appearance and motility of the implant and the overall score of PedsQL3.0 or PedsQL4.0. It is likely that the quality of life of RB patients receiving enucleation and primary orbital implantation in early infancy is not affected by the stages, laterality, and implant materials, nor affected by the appearance and motility of the implant, and excel in pain and hurt and worry control and social function.

PedsQL 3.0 is specifically designed to assess quality of life in pediatric cancer patients and focuses on cancer-related symptoms, treatment, worry, and communication [27]. The PedsQL4.0 is specifically designed to measure overall health-related quality of life in children and adolescents and focuses on overall health-related quality of life across conditions [27]. Our study shows that there is a significant correlation between the total scores of PedsQL3.0 and PedsQL4.0, and a significant correlation (P < 0.05) between the total scores of PedsQL3.0 and PedsQL4.0 in the groups of E-stage, and hydroxyapatite implant cases. However, there is no correlation between the total score of PedsQL3.0 and PedsQL4.0 in the case group of D-stage, the bilateral affected eyes, and the case group with hydrogel implants. Therefore, both PedsQL3.0 and PedsQL4.0 scores may complemenatrily contribute to assessment of quality of life of RB patients receiving enucleation and primary orbital implantation in early infancy, especially those in D-stage, with the bilateral affected eyes, and/or with the hydrogel implants.

It is still controversial whether orbital implantation is performed right after enucleation for RB children. Orbital implants do not evolve to match the needs of orbital development. However, lack of eyeball stimulation after enucleation leads to delayed orbital development on the affected side, and then causes problems such as asymmetric facial development and deepening of upper palpebral sulci on the affected side, which seriously affects the facial appearance of children. In addition, clinical studies have shown that even for RB patients with optic nerve invasion, primary orbital implantation is still safe. Long-term follow-up shows that it does not increase the risk of recurrence and death [30]. The current study reveals that it is safe and the clinical outcome and quality of life are satisfactory for RB patients receiving enucleation with primary orbital implantation in early infancy. Compared with the secondary orbital implantation, the primary implantation has some advantages: (1) There is no postoperative tissue hyperplasia and contracture that results in difficult implantation and unsatisfactory implantation outcome. (2) Primary orbital implants stimulate orbital and craniofacial development earlier, timely and fully. (3) The appearance of the child recovers well and it is easy for him/her to be integrated into society. (4) The suffering of pains from multiple operations is avoided. (5) The financial burden for the affected family is reduced. Therefore, it might be a better choice for RB patients to receive primary orbital implanation combined with enucleation in early infancy.

There are three main limitations of the current study. The first is that the number of cases included in the study is small. The second one, the data is collected in a single center but not multiple centers. The third one, there is no control cohort of RB patients that undergo enulceation without combining with primary orbital implanation in the early infancy. Therefore, there is potenial bias in the conclusions. More cases, multi-center, and properly-controlled studies may be warranted to test and corroborate the conclusions based on the current study.

Conclusions

In summary, the outcomes of the combination of enucleation and primary orbital implantation in early infancy for RB patients are generally satisfactory with few and curable complications. The overall satisfaction with the postoperative appearance is high. The vast majority of patients have good postoperative quality of life. Therefore, for children with retinoblastoma, as long as there is no extraocular metastasis detected during preoperative examination and surgery, it is recommended to apply enucleation combined with primary orbital implantation to survive and promote quality of life.