Clinicopathological Review of 547 Bulbar Enucleations in Hungary (2006–2017)

Purpose To analyse current clinicopathological enucleation indications in a large third-referral centre in a developed country (Hungary) over a period of 12 years. Methods Retrospective review was performed on 547 enucleated eyes of 543 patients (48.6% males, age 52.7 ± 24.5 years) who were operated on between 2006 and 2017 at the Department of Ophthalmology of Semmelweis University, in Budapest, Hungary. For each subject, clinicopathological data, including patient demographics, indications for enucleation, B-scan ultrasound reports, operative details, and histopathological analyses, were reviewed. Primary enucleation indications were classified into trauma, tumours, systemic diseases, surgical diseases, infections or inflammations, miscellaneous diseases, and unclassifiable groups. Clinical immediate enucleation indications were classified as tumours, atrophia or phthisis bulbi, infection or inflammation, painful blind eye due to glaucoma, acute trauma, threatening or spontaneous perforation, cosmetic causes, and expulsive bleeding. Results The most common primary enucleation indications were tumours (47.3%), trauma (16.8%), surgical diseases (15.7%), infection or inflammation (11.6%), systemic diseases (5.1%), miscellaneous diseases (2.0%), and unclassifiable diseases (1.5%). Clinical immediate enucleation indications were tumours (46.1%), atrophia or phthisis bulbi (18.5%), infection or inflammation (18.5%), painful blind eye due to glaucoma (11.2%), acute trauma (3.7%), threatening or spontaneous perforation (1.3%), cosmetic reasons (0.5%), and expulsive bleeding (0.4%). Conclusions Intraocular tumours represent the most common clinicopathological indication for ocular enucleation in our study population. Following ocular trauma and systemic diseases, the rate of enucleation decreased in the last decade, compared to those previously reported in other developed countries. However, changes were not observed for surgical diseases, infectious and inflammatory causes, or for miscellaneous and unclassified diseases. Orbital implant financing should be increased to ensure better postoperative aesthetic rehabilitation, following enucleation in Hungary.


Introduction
Enucleation is the removal of the entire globe and a section of the optic nerve. It is sometimes an unavoidable end-stage solution for several ophthalmic diseases. is procedure may be required after severe ocular trauma, tumours, infections, or painful blind eye [1]. Indications for enucleation-since the first description of the surgery in 1583 by Bartisch-may differ over time, with changing incidences of different ophthalmic conditions (e.g., diabetes mellitus, secondary glaucoma, and tumours) and therapeutic regimens (e.g., panretinal photocoagulation, intravitreal injections, and chemotherapies) [2]. ere have been several clinicopathological studies on indications for enucleation, but these surveys are not current or were published in developing countries [3][4][5][6][7]. e order of primary clinical enucleation indications varies among different countries.
Since there is almost no up-to-date information about enucleation in European countries, the primary aim of this study was to analyse current enucleation indications in a developed country (Hungary) over a period of 12 years.

Materials and Methods
is retrospective study was undertaken at a tertiary eye care centre, to analyse the current indications for enucleation in Hungary. e study was performed in accordance with the Declaration of Helsinki Guidelines for Human Research.
is retrospective review was conducted on 547 eyes of 543 patients who underwent enucleation at the Department of Ophthalmology of Semmelweis University, between January 2006 and December 2017. For each subject, clinicopathological data were reviewed, which included patient demographics, indications for enucleation, B-scan ultrasound reports, operative details, and histopathological analyses. Final diagnosis was based on clinical history and histopathological findings. Paraffin sections stained with haematoxylin-eosin and histopathological charts were available for 535 (97.8%) globes.
Primary enucleation indications (classification of de Gottrau et al. [3]; based on clinical history and histological reports) were divided into seven groups: trauma, tumours (intraocular, periocular, or intraorbital), systemic diseases, surgical diseases (treated or untreated), infectious and inflammatory diseases, miscellaneous diseases, and unclassifiable diseases due to incomplete case history. Second, immediate clinical enucleation indications were categorised using the classification of de Gottrau et al. [3], modified with three additional diagnosis groups, such as threatening or spontaneous perforation, expulsive bleeding, and cosmetic reasons. erefore, the immediate clinical enucleation indications were (last diagnosis before anophthalmia surgery) tumour, atrophia or phthisis bulbi, infection or inflammation, painful blind eye due to glaucoma, acute trauma (within the first month after trauma because of unrepairable blind eye and fear of sympathetic ophthalmia), threatening or spontaneous perforation, cosmetic causes, and expulsive bleeding.
Statistical analysis was performed with Statistica 8.0 (StatSoft Inc., Tulsa, OK, USA). Data were expressed as median with standard deviation (SD). e chi-squared test was used to evaluate differences among groups. A p value lower than 0.05 was considered statistically significant.
In the trauma group, the number of male patients was significantly higher than the number of female patients (n � 62/30, p < 0.0001); moreover, in the infection/ inflammation group, the number of female subjects was significantly higher than the number of male subjects (n � 18/45, p � 0.0007). ere was no sex predominance in the systemic disease group (n � 9/19, p � 0.0731), tumour group (n � 127/132, p � 0.8570), or surgical disease group (n � 44/42, p � 0.6085) ( Figure 2). Because of small sample sizes, the miscellaneous and not classified groups were not analysed regarding age or gender distribution.
Seven eyes (2.7%) were enucleated with clinical misdiagnosis of tumour.
Systemic diseases that were enucleation indications are shown in Table 2.

Discussion
To our knowledge, this is the first study regarding ocular enucleations in Hungary and the first comprehensive study in Europe in the last 20 years. Enucleation is regarded as the last resort for many hopeless eye diseases, in which no other eye-preserving therapy is available; these include untreatable ocular malignancies, infections, inflammations, or painful blind eye. Due to differences in methodologies and definitions, comparisons between studies and results are not easy.
Regarding primary indications, patients with trauma were the youngest (48.6 years) and subjects with inflammatory or infectious diseases were the oldest (64.7 years) among enucleated persons. de Gottrau et al. [3] reported higher mean age (66.1 years) for surgical diseases, compared to our study (50.1 years); however, his mean ages for trauma (44.2 years) and inflammatory or infectious disease (67.6 years) groups were similar to those of our study (48.6 and 64.7 years). e peak incidence of enucleation in Hungary (between 0-5 and 51-85 years) occurred in a similar age group among pediatric patients to that reported in China (between 0-10 and 31-40 years) [4] or in India (between 0 and 10 years) [6,7] and in a similar age group among adult patients to that   [3]. In Hungary, in more than 82% of cases, enucleations were performed in subjects older than 30 years, while in India [6,7] and Turkey [8], 82-84% and 54% of enucleations, respectively, were performed in subjects below 30 years of age.
In the present study, the most common primary enucleation indications were tumours (47.3%), trauma (16.8%), surgical diseases (15.7%) and infectious/inflammatory diseases (11.6%). In our study, there is an interesting inversion in the distribution of eyes with trauma and tumours, compared to previous studies. Previously, trauma was reportedly the most common primary enucleation indication (62.5% between 2003 and 2006 in China [4]; 37.4% between 1980 and 1990 in Germany [3]; 36.0% between 1982 and 2002 in Poland [11]), and tumours were the second most common indication (28.5% in China [4]; 20.7% in Poland [11]; 19.6% in Germany [3]). However, trauma is still considered the primary cause of enucleation in some developing countries [5]. is changing trend is well known [2,9,[11][12][13][14], due to the improved management of eye traumas and better surgical tools, which help to prevent eye loss after severe ocular injuries. erefore, trauma is not the most common indication for enucleation in developed countries anymore.
Furthermore, the number of enucleations with tumours did not decrease over time in the literature [9,12]; a similar result was observed in our series ( Figure 4) [15,16]. Similar to the findings of our study, tumours were also reported as the leading causes of enucleation in France [17], Turkey [8], and India [7] in 1996, 1997, and 2018, respectively.
In contrast to the results of studies from Western countries and similar to the findings from China [4], lung cancer was the most common primary tumour with ocular metastasis in enucleated globes. is is consistent with the fact that lung cancer is a leading cause of death in our country [20] because smoking is a serious public health problem in Hungary, compared to its frequency in other developed countries [21].
Sigurdsson et al. [9] found that work accidents were more common than those happening at home (34.7% vs. 26.4%). In contrast, we observed that home accidents (54.3%) were more common than work accidents (7.6%). e location of the primary wound in our series was similar to that reported by Cheng (mostly corneal/corneoscleral) [4], although strictly corneal injuries were slightly more common than corneoscleral wounds in our survey.
Systemic diseases were more common enucleation indications in the report by de Gottreau (17.1%) [3], than in our study (5.1%). Currently, through introduction of improved conservative and surgical treatment methods, we may prevent the most serious eye complications of systemic diseases. Diabetes mellitus (DM) is one of the most common causes of blindness and severe visual impairment in middleaged people. e most dangerous and common complications of DM leading to enucleation are proliferative diabetic retinopathy and retinal vein occlusion [22,23]. Enucleation due to systemic diseases has decreased remarkably in recent decades [12]. e proportions of retinal vein occlusion and diabetic retinopathy, as systemic disease causes of enucleation, were 57.7% and 32.7% in the study by de Gottrau et al. [3], whereas they were 14.3% and 17.9% in our study. Explanations are readily available: regular control and wellorganized screening for DM, modern antidiabetic agents, introduction of panretinal photocoagulation, and vitreoretinal surgery can prevent and treat severe eye complications of DM [13].
Similar to the findings in the study by Cheng (5.3%) [4], we found iris rubeosis in 4.1% of the globes. is value is remarkably lower than that reported by de Gottrau et al. (48.0%) [3] and seems to refute the concept that most secondary angle closures follow rubeosis iridis [24]. e order of other primary enucleation indications in our study was similar to earlier reports. Tumour, trauma, and systemic diseases were followed by surgical (15.7% vs. 5.7-14.1%) and inflammatory/infectious diseases (11.6% vs. 1.7-7.0%) [3,4]. Despite the development of microsurgical instruments and modern antibiotics, the frequency of surgical-related enucleations has not changed over time [3]. Anterior staphyloma (1.0%) was a rare primary enucleation indication, in contrast to the rate reported by Vemuganti from India [6] (49.0%), where anterior staphyloma was the most common primary cause of enucleation. Reportedly, anterior staphyloma is a rarity in Western countries but is a common condition in Asia [25]. e main clinical immediate indications for enucleation were tumours (46.1%), followed by atrophy or phthisis bulbi (18.5%) (similar to the new reports from India [7]), infection or inflammation (18.5%), painful blind eye secondary to glaucoma (11.2%), and acute trauma (3.7%). In China [4], 64.9% of all enucleations were performed in patients with atrophia or phthisis bulbi (36.4%) and tumours (28.5%), Journal of Ophthalmology which is almost the same as our 64.6%, but in the reverse order. de Gottrau et al. [3] also reported similar results with one exception, almost 25 years ago. In his study, secondary glaucoma was the most common (34.9%) clinical indication for enucleation, whereas tumours were the second most common indication (21.7%). Most studies reported nearly similar proportions for glaucoma in enucleated eyes (USA: 8.0% [12]; China: 10.1% [4]; Denmark: 15.0% [13]; Turkey: 16.0% [8]; France: 16.0% [17]) to those found in our present work (11.2%). Worldwide, enucleation due to glaucoma has shown a decreasing trend over multiple decades. Setlur et al. found that, from the 1960s to the 2000s, there was a decreasing tendency, from 31% to 8.4% [12,26]. e main explanation for this decrease may be introduction of modern therapeutic (antiglaucoma and antidiabetic agents) and surgical methods, which help to rescue many glaucomatous eyes and prevent serious eye complications [9,13].
After excluding globes with tumour and acute trauma-similar to the method used by Cheng [4]-retinal detachment was most frequently associated with atrophia or phthisis bulbi (71.0%) in our series.
Approximately every fourth patient received an orbital implant following enucleation. e reason for this low proportion is that, in Hungary, financing of orbital implants is generally not covered by health insurance, nor is it included in the surgical costs of enucleation. Other studies have reported much higher rates of orbital implants (92-100%) [5,27]. In the literature, hydroxyapatite implants were most frequently used (67.2%) [5,18,28].

Conclusions
In summary, intraocular tumours represent the most common clinicopathological indication for ocular enucleation in our study population. Following ocular trauma and systemic diseases, the rate of enucleation decreased in the last decade, compared to those previously reported in other developed countries. However, changes were not observed for surgical diseases, infectious and inflammatory causes, or miscellaneous and unclassified diseases. Orbital implant financing in Hungary should be increased to achieve better postoperative aesthetic rehabilitation following enucleation.

Data Availability
e data used to support the findings of this study are included within the article. Disclosure e funding organization had no role in the design or conduct of this research.