Eur J Ophthalmol 2013; 23 ( 3 ): 303-308

DOI: 10.5301/ejo.5000231

ORIGINAL ARTICLE

Is there a relation between histopathologic characteristics of pterygium and recurrence rates?

Fadime Nuhoglu1, Fatma Turna1, Meral Uyar2, Fatma Esin Ozdemir1, Kadir Eltutar1
1 2

Department of Ophthalmology, Istanbul Training and Research Hospital, Istanbul - Turkey Department of Ophthalmology, Istanbul Training and Research Hospital, Istanbul - Turkey Department of Ophthalmology, Istanbul Training and Research Hospital, Istanbul - Turkey

Department of Ophthalmology, Istanbul Training and Research Hospital, Istanbul - Turkey Department of Pathology, Bagcilar Training and Research Hospital, Istanbul - Turkey

PURpOSE. To explore the interrelationships of histopathologic characteristics of pterygium and postoperative recurrence. METHODS. Consecutive patients with primary pterygium or recurrent pterygium treated in our tertiary center between January 2007 and January 2010 were included in the study. All the patients were surgically treated by limbal-conjunctival autograft transplantation and postoperatively followed up for at least 1 year. Histopathologic changes were classified as inflammation intensity, degree of vascularization, and fibrinoid change. The results of examination of histopathologic and clinical characteristics of pterygium were comparatively analyzed. A total of 101 consecutive patients were included in the study. Ninety eyes of 90 patients who had primary pterygium (PP group) were compared with 11 eyes of 11 patients who had recurrent pterygium (RP group). In the PP group, 7 of the 90 (7.8%) patients had evidence of recurrence, while in the RP group, 2 of the 11 (18.2%) patients had evidence of recurrence (p=0.254). RESULTS. No significant difference was found in inflammation intensity, degree of vascularization, and fibrinoid change between PP and RP groups (p>0.05). In the PP group, no significant difference was found for inflammation intensity, degree of vascularization, and fibrinoid change between patients with (7/90) and without recurrences (83/90) (p>0.05). In the RP group, no significant difference was detected for inflammation intensity, degree of vascularization, and fibrinoid change between patients with (2/11) and without recurrences (9/11) (p>0.05). CONcLUSIONS. No significant correlation between the histology of pterygium and recurrence rate could be established. KEY WORDS. Histopathologic, Morphology, Primary, Pterygium, Recurrence
Accepted: November 12, 2012

INTRODUCTION
Pterygium is a degenerative lesion presenting as a fibrovascular conjunctival growth in the palpebral aperture of the eye with corneal extension. The incidence is higher geographically toward the equator or in certain climates and environments (1). The etiology of pterygium has been linked to exposure to ultraviolet irradiation, chronic irritation by dust, wind, and other environmental factors (2). Pterygium may be responsible for disturbance of vision by

its astigmatic effect or by growing so large as to occlude the visual axis. It could also be a cause of much ocular irritation as well as being cosmetically unacceptable for many people, especially when fleshy or inflamed. Surgical removal is usually recommended in symptomatic patients. Recurrence after pterygium excision represents a challenge for ophthalmologists and is considered the most common postoperative complication (3). Recurrence rates range from 24% to 89%, mainly dependent on the preferred surgical technique (3, 4). Recurrences typically occur within the first year, and frequently, recurrent pterygium 303

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tends to be more aggressive than primary pterygium (4). Histologic studies have shown multiplication and degeneration of elastic and collagenous fibers and inflammatory changes in the body of the pterygium (5). As a result of hyperplasia occurring in the damaged limbal stem cells in individuals exposed to UV, limbal tissue is perceived as a foreign substance, and chronic inflammation develops as a form of hypersensitivity reaction. Chronic inflammation leads to vascularization (6, 7). Mast cell mediators, and especially heparin, and histamine with their vasoactive properties contribute to angiogenesis. Mast cells rank third after chemical and immunologic agents as important factors contributing to tissue fibrosis, and angiogenesis by taking part in the development of inflammation (8). The condition defined as elastodysplasia because of the presence of significant amount of elastic fibers and excess quantities of fibroblast in the pterygium together with thickening of the pterygium tissue has been blamed in the pathogenesis of pterygium. These were defined as precursors of elastic fibers, an abnormal maturation form of degeneration (1). The aim of the present study is to explore the interrelationships of histopathologic characteristics of pterygium and on the basis of their analysis test the possibility of predicting its evolution and the recurrence. The secondary aim of the study was to investigate the clinical characteristics of pterygium.

Outcome measures
Excised pterygium tissue was fixed in 10% buffered formalin and processed routinely for paraffin-embedded sections. In order to observe general composition and topohistologic characteristics of the pterygia, 3- to 5-m-thick samples were stained by classic histochemical methods: hematoxylin & eosin, Mason trichrome staining, Gomori reticulin staining, and Periodic acid-Schiff technique. Histopathologic changes were classified into 5 groups. Inflammation intensity: group 0 = no inflammatory infiltrate; group 1 = sporadic, perivascular presence of lymphocytes; group 2 = multifocal chronic inflammatory infiltrate (mostly lymphocytes); group 3 = multifocal chronic inflammatory infiltrate (domination of plasmocytes); group 4 = diffusive chronic inflammatory infiltrate. Degree of vascularization: group 0 = vascularization of pterygium resembles normal conjunctiva; group 1 = arteriole blood vessels presence is dominant in the region of the vascular stalk; group 2 = presence of arterial blood vessels in the center of pterygium; group 3 = a stronger presence of capillary blood vessels subepithelially and in the advanced region; group 4 = more expressed presence of arteriole blood vessels subepithelially and in advanced region. Fibrinoid change: group 0 = without presence; group 1 = rare focal, perivascular fibrinoid changes; group 2 = a greater number of focal perivascular changes; group 3 = a greater number of focal changes and sporadically subepithelial; group 4 = a greater number of focal and diffusively subepithelial and/or massive change in the progressive part. The results of examination of histopathologic and clinical characteristics of pterygium were comparatively analyzed.

MATERIALS AND METHODS Study design

Institutional review board/ethics committee approval was obtained for this study, and all work was consistent with Good Clinical Practices and the Declaration of Helsinki, 1996. Consecutive patients with primary pterygium or recurrent pterygium treated in our tertiary center between January 2007 and January 2010 were included in the study. All patients had a complete preoperative ophthalmic examination performed. Patients were surgically treated by limbal-conjunctival autograft transplantation and postoperatively followed up for at least 1 year. All patients had pterygium excision by either of the 2 experienced surgeons. Steroid drops were commenced after 2448 hours when epithelium over the corneal wound would have healed. Patients with a history of keratoconus, corneal trauma, corneal scarring, ocular surgery, malignancy, or contact lens wear were excluded. 304

Statistical analysis
Data were analyzed using the Statistical Package for Social Sciences (SPSS) software (version 11.0 for Windows). All differences associated with a chance probability of 0.05 or less were considered statistically significant. Student t and MannWhitney U tests were performed on nominal data.

RESULTS
A total of 101 consecutive patients were included in the study. Ninety eyes of 90 patients (46 female and 44 male) who had primary pterygium (PP group) were compared with 11 eyes of 11 patients (4 female and 7 male) who had recurrent pterygi-

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Fig. 1 - Diffuse degeneration of collagen fibers in the subepithelial tissue (hematoxylin & eosin, 20).

Fig. 2 - Intense lymphoplasmacytic inflammation in the subepithelial connective tissue (hematoxylin & eosin, 20).

Fig. 3 - Diffuse capillary proliferation, and alteration in collagen fibrils (reticulin, 20).

Fig. 4 - Dense lymphocytic inflammation and capillary proliferation in the hilum of the pterygium (hematoxylin & eosin, 20).

um (RP group). The mean age of the PP group was 48.715.3 years while that of the RP group was 43.216.9 years. No significant difference in gender or age was found between PP group and RP group (p0.05). Mean follow-up for the study group was 16.73.1 (range 12-24) months. In the PP group, 7 of the 90 (7.8%) patients had evidence of recurrence; while in the RP group, 2 of the 11 (18.2%) patients had evidence of recurrence. There was no statistically significant difference between groups with respect to recurrence rate (p=0.254, chi-square test). Recurrence rate was found to be 2.635 times greater in the RP group than the PP group.
Fig. 5 - Hypervascularity in the vicinity of the hilum of the subepithe- lial pterygium (hematoxylin & eosin, 20).
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There was no statistically significant difference between sexes with respect to recurrence rate (p=0.513, chi-square test). In women, 4 of the 500 (8%) patients had evidence of recurrence; in men, 5 of the 51 (9.8%) patients had evidence of recurrence. Recurrence rate was found to be 1.250 times greater in men than women. No significant difference was found in inflammation intensity, degree of vascularization, or fibrinoid change between PP group and RP group (p>0.05) (Figs. 1 and 2). As for the PP group, no significant difference was found in inflammation intensity, degree of vascularization, or fibrinoid change between patients with recurrence (7 of 90) and those without recurrence (83 of 90) (p>0.05). As for the RP group, no significant difference was found in inflammation intensity, degree of vascularization, or fibrinoid change between patients with recurrence (2 of 11) and those without recurrence (9 of 11) (p>0.05) (Figs. 3-5). Histopathologic scoring revealed positive correlation between inflammation intensity and degree of vascularization (p=0.022). Fibrinoid change correlated with neither inflammation intensity (p=0.211) nor degree of vascularization (p=0.879).

DISCUSSION
The primary measure of a successful pterygium excision surgery is recurrence. In this report, we aimed to explore the interrelationships of histopathologic characteristics of pterygium and recurrence; however, no relation between the histology of pterygium and recurrence rate could be established. Although pterygium recurrence has been reported to occur as far as 1 year after surgery, most recurrences occur within the first 3-6 months after surgery (9, 10). In the present study, the patients were followed up for at least 1 year. In the present study, the mean time to recurrence was 4.32.1 months in the PP group compared to 4.12.2 months in the RP group. Different factors have been implicated to influence recurrence. The demographic and ethnic factors are well known. Race has been suggested to have a significant correlation with recurrence, and fibrin tissue adhesive may behave differently in higher risk populations. In the present study, all patients were Caucasian. Although Lewallen (11) and Chen et al (12) found a significant relationship between patient age and pterygium recurrence, Tan et al (13), Kkerdn306

mez et al (15), Essex et al (16), and Farrah et al (14) did not find any relationship, similar to our study. Tan et al (13) explained that the pterygia that develop in young people are mostly type 3 (inflamed), and this is related to the high postoperative recurrence rates seen in this age group. In our study, we did not document the pterygium types, so we could not evaluate this assumption. Increasing age has previously been shown to be a protective factor for pterygium recurrence (17). The present study also found an overall higher recurrence rate in younger patients. This may be due to a more robust and vigorous inflammatory response in younger patients. Furthermore, younger patients may not be as compliant with postoperative drops and may tend to have greater exposure to UV radiation as a result of variable lifestyle activities. Similar to other studies in the literature, we also did not find any relationship between the sex of the patient and recurrence rate (14, 16). Ti et al (18) and Farrah et al (14) showed that recurrence depends on the individual technique and surgical experience. Barraquer (19) reported that the amount of fibrovascular tissue that is removed during surgery is an important factor in reducing recurrence rates. In the present study, all patients were operated by the same surgical technique and by the same group of experienced surgeons. There is also evidence to suggest that there is a transformation of the phenotypic characteristics of the conjunctival fibroblasts that may be triggered by UV radiation and/or inflammation (20). Absorbable sutures are inflammatory and may be drawing in those same inflammatory cytokines and metalloproteinases that have been linked to pterygium recurrence (21). Further studies looking at the exact inflammatory response cascade will clarify the variability at a molecular level. Despite proposal of different theories, the reason why pterygium arises from only certain locations of conjunctiva, and why recurrence rates vary among individuals with similar environmental conditions who have undergone the same surgical method, are debatable. Therefore, recently attention has been concentrated on histopathologic characteristics. We hypothesized that histopathologic analysis of morphologic characteristics of pterygium along with clinical parameters may be used in assuming the probability of recurrence. Histomorphologically, pterygium can be defined as fibrovascular proliferations, mostly covered by conjunctival epithelium. The epithelium of pterygium mainly exhibits the morphology of modified stratified squamous epithelium of the cornea, in accordance with the data of

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Cilova-Atanasova (22) and Seifert et al (22, 23). Weinstein et al (24) found abnormal expression of p53 in pterygium epithelium, suggesting that pterygium can be the result of uncontrolled cell proliferation, but not degenerative lesion. There is no connection regarding abnormal expression of p53 among the groups with or without recurrences. The main part of the pterygium is composed of connective tissue that undergoes pathologic changes that are accompanied by the increase of the mass of the pterygium itself. The newly formed structure is located subepithelially and progresses towards the cornea. In the corneal part of pterygium, this newly formed and well-vascularized conjunctiva is positioned between the epithelium and the rough original layers of stroma (25). Mechanical stress cannot be absorbed anymore, so the tissue is bulged above the eyeball surface. For these reasons, during surgical procedures not only should this surface loose tissue in the region of cornea and sclera be removed, but the tissue underneath and around lateral margins as well, to prevent recurrences of residual pathologically changed cells. In the study of Markovich et al (26), pterygia specimens had a greater number of blood vessels positive for von Willebrand growth factor (vWF) and vascular endothelial growth factor (VEGF), and stronger staining intensity to VEGF in epithelial, stromal, and endothelial cells, and greater number of VEGF-positive cells than in normal conjunctiva. Overexpression of VEGF in pterygium tissue, along with abundance of vWFstained blood vessels, can support previous hypotheses that angiogenesis plays an important role in formation of

pterygium. Patients with Fuchs patches had higher inflammation in pterygium tissue in comparison to the group of patients without progression zones. Fuchs patches are a significant, primarily clinical indicator of progressiveness or activity of the pterygium tissue (23). Since the presence of Fuchs patches represents a potential risk of recurrence, patients with recurrence are expected to have higher inflammation in comparison to those without recurrence. In the present study, despite the above mentioned studies, no significant difference was found in inflammation intensity, degree of vascularization, or fibrinoid change between the PP group and the RP group. As for the PP group, no significant difference was found in histologic parameters between patients with recurrence (7/90) and those without recurrence (83/90). Similarly, for the RP group, no significant difference was found in histologic parameters between patients with recurrence (2/11) and those without recurrence (9/11). In conclusion, we have shown that the histology of pterygium does not influence the recurrence rate.
The authors report no proprietary interest or financial support. Address for correspondence: Fadime Nuhoglu, MD Department of Ophthalmology Istanbul Training and Research Hospital PK: 34098 Istanbul Turkey drbnuhoglu@gmail.com

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