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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 27  |  Issue : 2  |  Page : 386-394

Clinical, pathological, and molecular aspects of recurrent versus primary pterygium


1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
2 Department of Pathology, National Liver Institute, Menoufia University, Shebin El-Kom, Menoufia, Egypt

Date of Submission14-Jul-2013
Date of Acceptance13-Sep-2014
Date of Web Publication26-Sep-2014

Correspondence Address:
Ahmed M Shebl
MBBCh, Department of Ophthalmology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.141713

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  Abstract 

Objectives
The objective of this study was to evaluate the clinical aspects of primary and recurrent pterygia and correlate them with the histopathological, immunohistochemical, and molecular characteristics of the pterygial sections.
Background
Pterygium is a fibrovascular, usually triangular membrane that begins growing from limbal epithelium and advances on the corneal surface, characterized by degenerative and hyperplastic changes in the conjunctival epithelium, proliferative and inflammatory characteristics, and a rich vasculature. The pathogenesis of pterygium is still incompletely understood. Ultraviolet irradiation is believed to be the most important factor in its development.
Materials and methods
This study included 44 pterygium patients who underwent pterygium excision by the bare sclera procedure. The tissues obtained were subjected to a histopathological examination as well as an immunohistochemical analysis for phospho-P53 and ki-67 and PCR for the human papillomavirus (HPV).
Results
Histopathological findings included epithelial and stromal inflammation, vascular proliferation, fibrosis, and solar elastosis. Epithelial dysplasia was detected in 43.6% of the specimens. The phospho-P53-positive rate was 96.2% and the ki-67-positive rate was 96.3%. HPV DNA was not detected in any of the pterygial specimens.
Conclusion
The high frequency of epithelial dysplasia supports the neoplastic theory of pterygium pathogenesis. Phospho-p53 expression is increased in pterygial epithelium as well as ki-67, which indicates the high proliferative activity. The absence of HPV suggests that it is not an etiological factor for pterygium pathogenesis in Egypt.

Keywords: Histopathology, human papillomavirus, immunohistochemistry, ki-67, p53, polymerase chain reaction, pterygium


How to cite this article:
Nassar MK, El-Sebaey AR, Abdel-Rahman MH, El-Ghonemy K, Shebl AM. Clinical, pathological, and molecular aspects of recurrent versus primary pterygium. Menoufia Med J 2014;27:386-94

How to cite this URL:
Nassar MK, El-Sebaey AR, Abdel-Rahman MH, El-Ghonemy K, Shebl AM. Clinical, pathological, and molecular aspects of recurrent versus primary pterygium. Menoufia Med J [serial online] 2014 [cited 2024 Mar 28];27:386-94. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/386/141713


  Introduction Top


Pterygium can be described as a fibrovascular, usually triangular membrane that begins growing from the limbal epithelium and advances on the corneal surface, with its apex toward the center of the cornea, characterized by degenerative and hyperplastic changes in the conjunctival epithelium, as well as proliferative and inflammatory characteristics and a rich vasculature [1]. Sometimes, it may be bilateral and usually originates from the nasal bulbar conjunctiva, but also occasionally from the temporal conjunctiva [2].

Histologically, pterygium is characterized by hyaloid degeneration of conjunctival stroma, with accumulation of eosinophilic deposits together with intense fibroblastic proliferation and a rich vascular supply. Degenerated type I and type IV collagen fibers have also been described [3]. Distorted fibrillar structures stained with elastic tissue pigments, such as Weigert or Verlhof, are commonly observed. They were initially considered to be derived from elastic fibers, hence the term 'elastotic degeneration'. However, the fact that incubation with elastose does not disrupt them led to the suggestion that they may represent a form of degenerated collagen [4]. Epithelial changes are variable and usually include hyperkeratosis, parakeratosis, or akanthosis [5].

To date, the pathogenesis of pterygium is still incompletely understood [2]. Several theories have been proposed to describe its pathogenesis [6]. Epidemiological studies indicate that chronic exposure to sunlight, including most probably ultraviolet (UV) irradiation, is an important factor in the development of pterygium [7],[8]. During the last decades, several potential mechanisms for the development of pterygium have been examined including immunological mechanisms [9], increased oxidative stress with formation of reactive oxygen species [8], hereditary factors [10], chronic ocular surface inflammation with tear film abnormalities [11], altered expression of various growth factors and cytokines [6], molecular genetic alterations including altered expression of tumor suppressor genes, particularly the p53 gene [12], and viral infection particularly herpes simplex virus and human papillomavirus (HPV) [13],[14],[15].

The p53 gene encodes the p53 protein, which plays an important role in preventing uncontrolled proliferation and tumor formation [16]. However, its action depends on various factors, such as the levels of acetylation or phosphorylation [17]. Several studies have detected increased levels of p53 protein in pterygia; however, other studies have not confirmed such findings [6],[18],[19],[20]. The p53 protein has a short half-life in normal cells so that its level often remains undetectable. It is believed that the increased exposure to UVR can cause mutation in the p53 gene, which may lead to increased stability of the p53 protein, allowing its detection by immunohistochemical methods [12].

Several studies point toward the involvement of HPV in pterygium, although large regional and racial differences have been reported [14],[15]. Many authors have reported increased expression of abnormal p53 associated with HPV In pterygia [21],[22], suggesting that viral oncoproteins may play a role in suppressing p53 activity. However, others detected increased p53 in pterygium without evidence of HPV infection [23].


  Materials and methods Top


Pterygial samples were obtained from 44 primary and recurrent pterygium patients subjected to excision of pterygia at the Ophthalmology Department, Menoufia University Hospital between January 2011 and June 2012. Eighteen men and 26 women were recruited ranging in age from 25 to 77 years.

Preoperative examination

This included assessment of history (age, sex, occupation, degree of sun exposure, history of other medical conditions including hypertension and diabetes, history of other surgeries, history of excessive scaring and pattern of wound healing, previous ocular surgery, and time from previous pterygium excision in recurrent cases), general examination (weight, height, cutaneous features suggestive of chronic sun exposure, especially on the back of the neck and face), and detailed slit lamp ocular examination. Patients who had undergone previous pterygium surgery with antimetabolites application were excluded from this study.

Surgical procedure

All pterygia were excised in total using the bare sclera technique.

Histological examination

All lesions were collected on a piece of filter paper with the outer surface of the conjunctiva facing up and immediately fixed in 10% buffered formalin. Samples were processed routinely using ascending grades of ethanol and xylene, and were embedded in paraffin. Five micrometer sections were cut from each specimen using a microtome and mounted on glass slides. All sections were then deparaffinized in xylene, rehydrated through descending grades of ethanol, and then stained with hematoxylin and eosin and examined microscopically. Histological assessment of specimens included whether the cornea was included, degree of dysplastic changes in the conjunctival or conjunctival/corneal junctional epithelium, degree of inflammation in the epithelium and stroma, degree of stromal fibrosis, degree of stromal angiogenesis, and presence and degree of solar elastosis. Histological changes were classified into three categories (minimal, moderate, and marked).

For epithelial dysplasia, minimal dysplastic changes were defined as nuclear and cellular polymorphism involving one-third of the epithelial thickness with an intact basement membrane, moderate dysplasia was defined as nuclear and cellular polymorphism involving more than one-third and less than two-third of the epithelium with loss of cellular polarity, and marked dysplastic changes/carcinoma in situ were defined as nuclear and cellular polymorphism involving more than two-third of the epithelial thickness with loss of cellular polarity and an intact basement membrane.

Immunohistochemistry for p53 and ki-67

Immunohistochemistry was carried out on 5-mm-cut sections of each sample that were mounted on positive charged glass slides. All sections were deparaffinized in xylene, sequentially rehydrated in a graded series of ethanol, and washed in PBS. Immunohistochemistry detection of p53 was performed using the streptavidin-biotin-peroxidase method and incubation with mouse anti-phospho-P53 monoclonal antibody (at a dilution of 1 : 100; Santa Cruz Biotechnology) and anti-ki-67 monoclonal antibody (prediluted; Invitrogen). For both ki-67 and phospho-P53 (pP53), the percentage of positive nuclei in the epithelium was assessed by a pathologist blinded to the clinical status of the samples. The masking process of the samples included labeling each with a random laboratory number.

Polymerase chain reaction for human papillomavirus

DNA isolation

The genomic DNA was extracted from whole excised tissue of each sample. Five to 10 of 5-mm-thick sections were processed for each sample. DNA extraction was carried out using the Qiagen, DNA micro kit according to the manufacturer's protocol. Briefly, cut sections were collected in 1.5 ml sterile, DNAse, RNAse-free propylene tubes, sections were deparaffinized in xylene, briefly washed in absolute ethanol, dried, and then incubated overnight at 55°C with tissue lysis buffer and proteinase K solution (200 mg/ml). DNA was extracted using the Qiagen silica-membrane-based nucleic acid purification system. After extraction, the quantity and quality of DNA was assessed using a spectrophotometer at 260/280. Samples with at least 200 ng of DNA were used for the assessment of HPV.

Analysis for the human papillomavirus

A qualitative multiplex PCR was carried out to assess the presence or absence of HPV DNA in the excised tissues of different patients. The PCR for HPV was performed according to a published protocol. Primers for the HPV were nonspecific, amplifying all different subtypes of HPV. Primers for the globin gene were used as controls for assessment of the PCR efficiency and quality of DNA. Samples with no amplification of the globin gene were considered to have degraded DNA and were excluded from the analysis. The PCR product was analyzed on a 3% agarose gel stained with ethidium bromide. DNA samples extracted from HeLa cell cultures that are positive for HPV were used as a positive control.


  Results Top


The study included 44 patients; one of them was found, by histopathological examination, to have a conjunctival cyst and not a pterygium and was therefore excluded. Of the remaining 43 patients, 18 (41.9%) were men and 25 (58.1%) were women. Their ages ranged from 26 to 77 years, mean 45.49 ± 12.24 SD. Thirty-five cases were primary pterygium and eight cases were recurrent pterygium.

Histopathological findings

Out of 43 cases, only 39 cases were available for a histopathological examination. Epithelial dysplasia was detected in 43.6% (17 of 39) of pterygium specimens. This included 45.2% (14/31) of primary pterygium specimens and 37.5% (3/8) of recurrent pterygium specimens, with no significant difference between the two groups. Dysplasia was classified as minimal in 28.2% (11 cases), moderate in 10.2% (four cases), marked in 2.6% (one case), and carcinoma in situ in 2.6% (one case).

Other histopathological findings included epithelial inflammation, which was minimal focal in 84.2% of the specimens and moderate in 15.8% of the specimens. Stromal inflammation was detected in 36 cases (92.2%), which was minimal in 71.8%, moderate in 15.3%, and marked in 5.1% of the cases. Vascular proliferation was minimal in 48.7%, moderate in 38.5%, and marked in 12.8% of the samples. Stromal fibrosis was detected in 37 specimens (94.9%), which was minimal in 23.1%, moderate in 48.7%, and marked in 23.1% of the samples. Solar elastosis was detected in 30 specimens (76.9%), which was minimal in 23.1%, moderate in 28.2%, and marked in 25.6% of the specimens. There was no significant difference between primary and recurrent pterygia in terms of all histopathological findings [Table 1],[Table 2],[Table 3],[Table 4] and [Table 5].
Table 1: Histopathological findings of the studied group

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Table 2: Comparison between primary and recurrent pterygium in histopathological findings of the studied group

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Table 3: Phospho-P53 and Ki-67 expression in the studied group

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Table 4: Comparison between primary and recurrent pterygium in phospho-P53 and Ki-67

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Table 5: Comparison between primary and recurrent pterygium in phospo-P53 and Ki-67 (mean percentage of positive cells ± SD)

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Immunohistochemistry for phospho-P53 and ki-67

In our study, sufficient tissue was available for immunohistochemistry for pP53 in only 26 cases (20 primary and six recurrent pterygium cases). Specimens with immunostaining of more than 1% of cells were considered positive for pP53 expression. Twenty-five pterygium specimens (96.2%) were positive for pP53 expression, including 19 (95%) of primary pterygia and all six recurrent pterygia (100%), whereas only one case (3.8%) was negative. There was no significant difference between primary and recurrent pterygium in pP53 expression.

For immunohistochemistry for ki-67, tissue was available in only 27 cases (21 primary and six recurrent pterygium cases). Specimens with immunostaining of more than 1% of cells were considered positive for ki-67 expression. Twenty-six pterygium specimens (96.3%) were positive for ki-67 expression, including 20 (95.2%) of primary pterygia and all six recurrent pterygia (100%), whereas only one case (3.7%) was negative for ki-67 expression. The ki-67 labeling index (LI) was 41.4 ± 15.6% (mean ± SD) in primary pterygia and 45.00 ± 27.4% in recurrent pterygia. There was no significant difference between primary and recurrent pterygia in ki-67 expression.

Polymerase chain reaction for human papillomavirus

In our study, sufficient tissue with high-quality DNA was available for PCR for HPV only for 18 cases (15 primary and three recurrent pterygia). All the 18 specimens (100%) were negative for HPV DNA, with no significant difference between primary and recurrent pterygia [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7] and [Figure 8].
Figure 1:

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Figure 2:

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Figure 3:

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Figure 4:

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Figure 5:

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Figure 6:

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Figure 7:

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Figure 8:

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  Discussion Top


Histopathological features

In this study, several histopathological features were identified in pterygium specimens. These included epithelial dysplasia, epithelial and stromal inflammation, vascular proliferation, fibrosis, and solar elastosis.

Epithelial dysplasia was detected in 43.6% (17/39) of pterygium specimens, which is significantly higher than that detected by other authors. Gaton et al. [24] detected mild dysplasia in only 6.6% (3/45) of pterygium specimens. This high frequency of dysplastic changes in pterygium samples in our study shows the major importance of histopathological examination of all specimens removed as pterygium. Such cases with marked dysplasia and CIS carry the risk of progression into invasive carcinoma. Pathological examination is also important to avoid a misdiagnosis. One case in our study was initially diagnosed as pterygium and was then found out be a conjunctival cyst.

In our study, there was no significant difference between primary and recurrent pterygium in all histopathological findings. This could be attributed to the small number of cases with recurrent pterygium. This is similar to Nuhoglu et al. [25], who compared 90 cases with primary pterygium with 11 cases with recurrent pterygium. Histopathological changes were classified in terms of inflammation intensity, degree of vascularization, and fibrinoid change, with no significant difference between the two groups [25].

P53 expression

In our study, we utilized antibodies for the activated (phosphorylated) P53. Activation of P53 is observed in cases with DNA-induced injury. Specimens with immunostaining of more than 1% of cells were considered positive for pP53 expression. Twenty-five pterygium specimens (96.2%) were positive for pP53 expression. These data are consistent with other studies that detected increased expression of p53 in primary and recurrent pterygium in up to 100% of the studied specimens in some instances [18],[23],[26].

Other studies showed a considerable variability in the rate of p53 expression in pterygium, which was 37.5% [27], 60% [28], 36.8% [29], 38.1% [29], 50% [30], 22.8% [31], 35.48% [32], 60.4% [33], 74.5% [33], 45.45% [34], and 47.5% [35] in different studies.

This marked variation in the rate of p53 overexpression in pterygium specimens ranging from 7.9 up to 100% could be attributed to several factors. One is the different types of p53 antibodies used in the different studies. DO7 is the most commonly used antibody and it is the one used in our study. Dushku et al. [18] used DO1 and the prevalence was 100% (14/14), and the same antibody was used by Dushku et al. [23], where the prevalence rate was also 100% (9/9). Ueda et al. [29] used the CM-1 polyclonal p53 antibody and the prevalence rate was 38.1 and 36.8%. Chowers et al. [30] used bp53.12 and obtained 50% positive p53 staining. Tan et al. [27] used pAb 240 and obtained a 37.5% p53 positive rate compared with 60% obtained by Tan et al. [28] using DO7.

Another factor may be the different cutoff level for the percentage of cells stained positively for p53. In our study, we set the cutoff level at 1% and obtained a 96.2% p53-positive rate. Tsai et al. [31] used a cutoff level of 10% and obtained a 22.8% prevalence rate whereas if the cutoff level had been set at 1%, the positive rate would then have doubled to 47.2%. Chowers et al. [30] detected a 50% prevalence rate; however, all p53-positive pterygia had fewer than 10% p53-positive cells.

The rate of p53 overexpression also varies among different races and with different environmental factors such as UVR exposure. Ueda et al. [29] compared pterygia of Japanese and Tunisian patients, suggesting that the difference in p53 positivity between the two groups may be attributed to the different race and environmental factors, although they reported that the difference between them was statistically insignificant. Pelit et al. [33] examined p53 expression in patients from two Turkish cities with different climatic conditions, one of them with a sunnier and warmer climate than the other and therefore with higher levels of UVR exposure; however, the difference between the two groups was also insignificant.

In our study, there was no statistically significant difference between primary and recurrent pterygium in p53 overexpression. This could be attributed partly to the small number of cases with recurrent pterygia. However, this result is consistent with other studies including Chowers et al. [30] and Zhang et al. [35]. Chowers et al. [30] concluded that p53 immunoreactivity in the pterygium epithelium is not associated with recurrence of pterygium. In contrast, Khalfaoui et al. [26] reported that active primary and recurrent pterygia have different patterns of expression. In primary pterygium, an important variability of p53 expression was observed. However, in recurrent pterygium, p53 immunoreactivity was weak to moderate [26].

Immunohistochemistry for ki-67

The expression of the human ki-67 protein is associated with cell proliferation and it can be used as a good marker for the proliferative activity of a given cell population [36]. The detection of ki-67 overexpression in pterygium epithelium suggests that the disease could be a result of uncontrolled cell proliferation [37].

In our study, specimens with immunostaining of more than 1% of cells were considered positive for ki-67 expression. Twenty-six pterygium specimens (96.3%) were positive for ki-67 expression. The ki-67 LI was 41.4 ± 15.6% (mean ± SD) in primary pterygia and 45.00 ± 27.4% in recurrent pterygia. There was no significant difference between primary and recurrent pterygium in ki-67 expression. Our results are consistent with those obtained by other authors [30],[34],[37],[38].

Chowers et al. [30] reported that proliferative activity was found in the epithelium overlying the pterygia and the mean ki-67-positive cell count/grid ± SE was 2.84 ± 1.07 in primary pterygia that did not recur, 1.74 ± 0.82 in primary pterygia that recurred, and 3.83 ± 1.35 in the recurrent pterygial tissue that was excised from patients in the second group, and there was no significant difference between the three groups.

Ohara et al. [38] carried out ki-67 immunohistochemical analysis on four pterygium cases in Japan and the ki-67 LI was 9.0 ± 2.2% [38]. Liang et al. [34] observed ki-67 protein expression in all pterygium cases and all normal conjunctiva cases. However, the number of immune-positive cells in the epithelial layer of pterygia (14.27 ± 4.43) was significantly higher than that in normal conjunctivas (4.26 ± 2.42, P < 0.01).

Sebastiα et al. [37] detected ki-67 overexpression in 60% of pterygium samples. Pterygium epithelium showed a higher percentage of cells that stained for ki-67 (10.1 ± 9.5) than for normal conjunctiva (2.1 ± 1.9). The difference was statistically significant (P < 0.01) [37].

Polymerase chain reaction for human papillomavirus

To the best of our knowledge, this is the first study to describe the status of HPV in pterygium in Egypt. In our study, all the specimens were negative for HPV DNA, with no significant difference between primary and recurrent pterygia. These findings are consistent with other studies in other parts of the world that reported the absence of HPV from pterygium [23],[39],[40],[41],[42]. Other studies reported the presence of HPV in a small insignificant percentage of pterygial specimens of only 4.4% [43], 4.8% [44], and 3% [45] in these studies.

However, other studies reported the presence of HPV in pterygium, suggesting its possible synergistic role in disease pathogenesis. The prevalence of HPV in pterygial specimens was variable in these studies, being 24% [13], 50% [14], 54% [15], 58.3% [21], 24% [22], and 27.6% [46].

The considerable difference in the reported rates of HPV detection in pterygium could be attributed to the variation in the prevalence of the virus in geographically distant populations. HPV was absent or detected in a small insignificant percentage of pterygium specimens in studies carried out in Asia (Taiwan [39],[45] and Japan [44]), USA [23], some studies in Brazil [40], and some European countries including Germany [42], Denmark [43], and Turkey [41], whereas the virus was detected in a moderate to high percentage of pterygia in studies carried out in some European countries (Greece [13], UK [14], Italy [15], and Poland [46]) and South America (Ecuador [15] and Brazil [21]). Our study suggests that HPV is not an etiological factor for pterygium pathogenesis in Egypt.


  Conclusion Top


The histopathological characteristics of pterygium include epithelial and stromal inflammation, stromal vascular proliferation, fibrosis, and solar elastosis, in addition to the high frequency of epithelial dysplasia, which supports the neoplastic theory of pterygium pathogenesis. There was no significant difference between primary and recurrent pterygia in histopathological features. It was found that p53 expression is increased in pterygial epithelium as well as ki-67, which indicates the high proliferative activity. The absence of HPV suggests that it is not an etiological factor for pterygium pathogenesis in Egypt.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interests.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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