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Experimental Eye Research 175 (2018) 199–206
Contents lists available at ScienceDirect
Experimental Eye Research
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Epithelial dysplasia in pterygium postoperative granuloma
Guoliang Wang
, Nuo Dong
, Yanzi Wang , Jing Li , Fei Dong , Vimalin Jeyalatha ,
Jingwen Wua,b, Mei Shena,b, Qichen Yanga,b, Pei Chena,b, Yuhua Xuec, Zuguo Liua,b, Cheng Lia,b,∗
Eye Institute & Affiliated Xiamen Eye Center, Xiamen University Medical College, Xiamen, Fujian, China
Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
Pterygium postoperative granuloma
Epithelial cell
Epithelial mesenchymal transition (EMT)
Collagen Ⅳ
Pterygium postoperative granuloma (PPG) is one of the common complications of pterygium surgery. In order to
provide the structural features of PPG, and to further explore its pathogenetic mechanism, we analyzed clinical
and pathological characteristics of 12 PPG cases. New blood vessels were observed under a slit lamp in PPG and
peripheral conjunctival tissues. In vivo confocal imaging showed that there was extensive neovascularization in
the stroma, accompanied by infiltration of dendritic cells and inflammatory cells. Dense fibrous structures were
observed in some PPG tissues. H&E staining results confirmed neovascularization and inflammatory cells in PPG
tissues. In addition, H&E staining exhibited epithelioid tissue covering some PPG tissues. The immunofluorescence results demonstrated that the PPG epithelium was negative for K19, K10 and Muc5AC. Compared
with the normal conjunctiva and pterygium, the expression of collagen IV in PPG basement membrane decreased, the expression of pan-cytokeratin (PCK), claudin 4 and E-cadherin in PPG epithelium was significantly
lower, while the expression of vimentin, α-SMA and Snail was significantly increased. Therefore, our results
suggest that the expression of epithelial keratin markers and goblet cell specific mucin marker is downregulated
in the PPG tissues, and it likely is associated with the occurrence of EMT in granulomatous tissues.
1. Introduction
Granuloma formation after conjunctival surgery is pink tissue hyperplasia with large individual differences, potentially caused by
chronic inflammation of the conjunctiva. Ophthalmic surgeries in
treating pterygium, strabismus, eye trauma and eye reshaping are the
major cause of conjunctival granulomas (Agraval et al., 2017; Espinoza
and Lueder, 2005; Kokubo et al., 2016; Romano et al., 2016). Conjunctival granulomas can lead to obvious discomfort or even vision
impairment in patients, and usually require further surgical interventions for resection. The incidence of PPG in patients with pterygium is
much higher. The granuloma may propagate at the excision loci of the
nasal pterygium and the conjunctival flaps. Up until now, there have
been few studies on the formation and histological characteristics of
During or after the pterygium surgery, the intrusion of foreign
bodies such as synthetic fiber (Farooq et al., 2011), surgical sutures and
talc (Lyon and Taylor, 2007) into conjunctiva may lead to nodular
conjunctival granuloma, bacterial and fungal infections at the surgical
sites. Microbial infection may also cause purulent lesions in the conjunctival tissues, which results in pyogenic granuloma (Knox et al.,
2003). Wu D et al. proposed that there is a correlation between the
clinical features and the histological characteristics of granuloma (Wu
et al., 2017). However, previous studies only focused on its observed
clinical features and histomorphology. In the current study, we used in
vivo confocal imaging and immunofluorescent staining to study the
structural characteristics and biomarkers of the PPG tissue.
2. Material and methods
2.1. Patients
The study was performed in accordance with the ethical standards
included in the Declaration of Helsinki. The study protocol was reviewed and approved by an independent ethics committee of the institution with written informed consent. Demographic and clinical data
were obtained, including date of birth, gender, operation and medication information. Patients with ocular infections, trauma, contact lens
Corresponding author. Eye Institute & Affiliated Xiamen Eye Center, Xiamen University Medical College, Xiamen, Fujian, China.
E-mail address: (C. Li).
These authors contributed equally to this work and should be considered as co-first authors.
Received 17 January 2018; Received in revised form 10 August 2018; Accepted 15 August 2018
Available online 17 August 2018
0014-4835/ © 2018 Elsevier Ltd. All rights reserved.
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
Table 1
Profile of PPG patients.
Pterygium size
in cornea (mm)
methods of
Source of
medical therapy
Interval from
pterygium surgery to
appearance of PPG
Interval from
appearance of PPG
to excision (days)
diameter of
PPG (mm)
medical therapy
Tob, AT
Tob, AT
Tob, AT
Pra, AT
Vid, AT
Tob, Pra
Tob, Vid
Vid, AT
Tob, AT
Pra, AT
Vid, AT
Tob, Pra
Tob, AT
Vid, AT
Tob, Pra
Notes M, Male; F, Female; PE, Pterygium excision; CT, Conjunctiva Transplantation; Tob, Tobradex eyedrops; AT, artificial tears; Vid, Vidisic eyedrops; Pra,
Pranoprofen eyedrops.
parallel to the cutting plane, and 6 μm thick frozen sections were prepared using a cryostat microtome (Leica, NuBloch, Germany).
Continuous sections were cut for each specimen.
wear, diabetes, autoimmune disorders or allergy were excluded from
the study. All examinations were carried out on the operated eye, using
the same room at each visit and maintaining a constant environment.
2.2. Ophthalmologic examination
2.5. Hematoxylin & eosin staining
Every patient recruited in the study underwent a normative ophthalmologic examination involving slit lamp microscope and confocal
laser-scanning microscopic evaluation. HRT Ⅲ Confocal laser-scanning
microscope was purchased from Heidelberg Engineering Inc (BadenWurttemberg, Germany), pre-installed with a built-in Heidelberg Eye
Explorer version software.
Before each examination, 0.5% proparacaine hydrochloride eye
drops (Alcon. Inc, Puurs, Belgium) were dripped into the conjunctival
fornix. A fixation light was used for the contralateral eye to keep good
control over the eye to be examined. A disposable plastic cap was used
to maintain a stable distance from the cornea to the microscope lens,
and Carbomer gel as a coupling medium. The positioning and constant
contact of the eye relative to the plastic cap was monitored by an accessory digital camera, set perpendicular to the eye being examined.
Then the granulomas were imaged and recorded using the model of
Frozen sections stored in −80 °C were dried at room temperature
for about 5–10 min and fixed in ice cold acetone for 5 min, then rinsed
in running water for 3 min. Slides were hematoxylin stained for 5 min
and washed several times in running tap water. Then the slides were
stained in eosin for 30 s, followed by immersion in 75% alcohol + 2 ml
hydrochloric acid for 1 s and rinsed in running tap water for 5 min. The
slides were dehydrated by placing them consecutively in 80%, 95%,
100% alcohol for 2 min each time and finally immersed in xylene for
2 min. The air-dried slides were mounted using neutral resin and
overlaid with a coverslip.
2.6. Immunofluorescent staining
The frozen sections were thawed and fixed in cold acetone for
10 min at −20 °C. The tissue was rehydrated with phosphate butter
solution (PBS) for 5 min and blocked with 2% BSA to prevent nonspecific binding. Then the specimens were incubated with the primary
antibody or an isotype control (Sigma Chemical Co.) overnight at 4 °C.
The sections were incubated with secondary antibody for 1 h at room
temperature followed by 3 washes in PBS for 10 min. Again, the sections were washed 3 times and covered with VECTASHIELD (H-1200).
Images were captured and stored using a fluorescence microscope
(Leica, Wetzlar, Germany) equipped with corresponding software.
2.3. Materials and reagents
Antibodies used in this study: Mouse anti-cytokeratin 19 antibody
(K19, M0888), cytokeratin 10 antibody (K10, M7002) and cytokeratin
antibody (PCK, M3515) were obtained from Dako Cytomation
(Copenhagen, CPH, DEN). Rabbit anti-collagen IV antibody (ab6586,
Abcam), MUC5AC antibody (ab3649, Abcam) and alpha smooth muscle
actin (α-SMA, ab5694, Abcam) were from Abcam (Los Angeles, CA,
USA). Rabbit anti-vimentin antibody (HPA001762) was from SigmaAldrich Corp (St. Louis, MA, USA). Rabbit anti-E-cadherin (sc7870)
antibody and mouse anti-claudin 4 (sc376643) were from Santa Cruz
Biotechnology (Santa Cruz, CA, USA). Rabbit anti-Snail (A5243) antibody was purchased from Abclonal Technology (Wuhan, China).
Fluorescein Alexa-Fluor 488 and 594 conjugated secondary antibodies
(goat anti-mouse or rabbit immunoglobulin [IgG]) were from Thermo
Fisher Scientific (Waltham, MA, USA). Immunofluorescence mounting
medium VECTASHIELD with DAPI (4,6-diamino-2-phenyl indole) was
from Vector Laboratories (Vectorlabs, CA, USA).
3. Results
3.1. Clinical evaluation
A total of 12 PPG patients from the Xiamen Eye Center of Xiamen
University were recruited for this study. Their specifics are shown in
Table 1. Patient average age was 43.3 ± 10.4 years, and the distance
of the head of the pterygium extending onto the cornea was 0.5–4 mm.
All the pterygium patients were subjected to surgical resection combined with conjunctival autograft transplantation. Granuloma occurred
within one week after surgery (4.75 ± 1.81 days). The time interval
between the granuloma occurrence and its resection was quite different
(15.3 ± 6.7 days), and the granulomatous base diameter was
2.6 ± 1.0 mm before resection.
2.4. Tissue sectioning
The PPG tissues were embedded in optimal cutting temperature
compound (Sakura, CA, USA) after adjustment of their vertical planes
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
Fig. 1. Resection of PPG. A. Slit lamp photography of
pterygium; B. Granuloma 3 W after pterygium surgery; C. 1d
after granulomatous resection.
c'), inflammatory cell infiltration (Fig. 3C a and c) and partial tissue
fibrosis (Fig. 3D-b') in PPG, which was consistent with the confocal
microscopy results (Fig. 2). In addition, H&E staining revealed multiple
layers (more than 10 layers) of epithelial-like cells covering the PPG
tissue in 8 out of 12 patients (Fig. 3D-a').
3.2. Histomorphology of PPG tissue
Most of the PPG patients in this study have the head of the pterygium extending to the cornea preoperatively, with a pterygium activity score (PAS) of 3–7. Slit lamp observation showed rich neovascularization in the pterygium body and clear boundary invasion
from the head of the pterygium to the cornea (Fig. 1A). After pterygium
surgery, visible hyperplasia appeared in some patients. The PPG at the
surgical site was reddish under slit lamp observation and surrounded by
a large number of blood vessels (Fig. 1B). The general treatment of PPG
was a local surgical resection, usually without postoperative stitching
(Fig. 1C).
The confocal imaging after the pterygium surgery showed scar tissues in the proximal corneal stroma, with numerous dendritic cells
(Fig. 2C and D), which were rare in the normal corneal and conjunctival
stroma (Fig. 2A and B). Compared with the normal conjunctiva, the
postoperative granulomatous stroma exhibited significant neovascularization (Fig. 2E), and many dendritic cells which had branch-like
extensions, accompanied by inflammatory cell infiltration (Fig. 2F and
G). This phenomenon was more pronounced in the granuloma stroma
(Fig. 2H). In addition, confocal imaging also revealed numerous dense
fibrous tissues (Fig. 2E).
Pterygium is a growth of the mucous membrane that covers the
sclera. For some patients, pterygium causes no symptoms other than
appearance. In our study, tissue fibrosis and inflammatory cells were
not seen in normal conjunctiva and pterygium (Fig. 3A and B). H&E
staining showed the presence of neovascularization (Fig. 3C–b and 3D-
3.3. Epithelial phenotype of PPG tissue
Keratin is one of the major structural proteins of the epithelial cells,
exhibiting high tissue specificity, the expression of which is closely
related to the proliferation and differentiation of epithelial cells. K19 is
a marker of differentiated conjunctival epithelial cells and is highly
expressed in normal conjunctival epithelium (Pitz and Moll, 2002). K10
is a keratinized epithelial cell marker. In this study, the expression of
K19 and K10 in PPG tissue, the normal conjunctiva and pterygium were
examined by immunofluorescent staining. As shown in Fig. 4, K19 was
expressed in both normal conjunctiva and pterygium tissue, but not in
PPG tissues. K10 was not detected in normal conjunctiva or PPG tissues,
but sporadically expressed in pterygium tissues.
Conjunctival goblet cells can secrete a variety of mucins, among
which Muc5AC is the major glycoprotein, therefore it is often considered as the conjunctival goblet cell specific protein. The immunofluorescence results showed that Muc5AC was expressed in normal
conjunctiva and pterygium epithelium which appeared as dots and
flakes in the immunofluorescent staining pattern. The PPG tissue was
Muc5AC negative (Fig. 5).
Fig. 2. In vivo confocal microscopy of PPG and its surrounding cornea. A. Normal corneal stroma; B. Normal conjunctival stroma; C. Cornea (c) scar tissue (st)
proximal to PPG; D. Cornea proximal to PPG, with dendritic cells (DC) shown; E. PPG stroma, red label represents neovascularization (NV); F. PPG stroma, with some
dendritic cells shown; G. PPG stroma, with round and bright inflammatory cells (IC) shown; H. Granuloma base, with dendritic cells and inflammatory cells shown,
accompanied by neovascularization (conjunctiva, cj; granuloma, g). (For interpretation of the references to colour in this figure legend, the reader is referred to the
Web version of this article.)
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
Fig. 3. HE staining of postoperative granuloma, normal conjunctiva and pterygium. A, B. Normal conjunctiva and pterygium. C, D two different granulomatous
tissues, showing a large number of neovascularization (C-b and D-c'), inflammatory cell infiltration (C-a, c and D-c') and partial tissue fibrosis (D-b') in stroma; C.
Without epithelium-like structure covered; D. Epithelium-like structure covered, with multiple layers of epithelial-like cells (D-a').
The basement membrane is formed by the extracellular matrix secreted by basal epithelial cells, which is mainly composed of collagen IV
and laminin. The immunofluorescence showed that collagen IV was
significantly expressed in the basement membranes of normal conjunctiva and pterygium tissue. In this location, it was continuous and
showed an uniform thickness. Collagen IV was also significantly expressed in the vascular endothelium, which is similar to that in the PPG
tissues. However, the expression of collagen IV was significantly decreased in the sub-epithelial basement membrane of PPG tissues. The
thickness of the basement membrane varied and in some regions there
were large segments of broken basement membrane or it was absent
(Fig. 6).
and pterygial epithelium, whereas it was widely expressed in PPG
epithelium. In contrast, PCK expression was present in nearly all the
epithelial cell layers of conjunctiva and pterygium, while was totally
absent in PPG tissue. Only the sporadic suprabasal cells both expressed
PCK and vimentin (Fig. 7C). At the same time, α-SMA was highly expressed in PPG tissue, but not in the normal conjunctiva and pterygium,
which implies a transition of the phenotype (Fig. 7D). To verify the
above results, we tested the expression of Snail, a master regulatory
transcription factor for EMT. We observed that, Snail was rarely found
in the normal conjunctiva and the pterygium tissue, but was expressed
in the nucleus of basal epithelial cells in PPG tissue (Fig. 7E). Thus,
combining the changes in epithelial basement membrane in PPG tissue,
these results are consistent with the concept that epithelial dysplasia of
PPG can be associated with EMT.
3.5. Epithelial mesenchymal transition in PPG tissue
4. Discussion
EMT plays a vital role in the embryonic development, tumor cell
invasion and the repair of damaged tissue. This process involves the
variation in the expression of E-cadherin, PCK and vimentin. As shown
in Fig. 7A and B, E-cadherin and claudin 4 were highly expressed in the
normal conjunctiva and pterygium epithelium tissue, but were significantly reduced in PPG tissue. Double immunofluorescent staining
(Fig. 7C) revealed that vimentin was not detected in the conjunctival
Until now, surgical resection is the treatment of choice and autologous conjunctival grafting has minimized the challenge of pterygium
recurrence. Thus, all the patients included in this study were subjected
to conjunctival autograft transplantation after resection of the pterygium. However, our study did not find any significant correlation
between postoperative care methods and the occurrence of PPG tissues.
Numerous studies have reported an epithelial-like structure in
3.4. Changes in epithelial basement membrane in PPG tissue
Fig. 4. Expression of K19 and K10 in PPG tissues. K19 is evenly distributed in all epithelial layers of conjunctiva and pterygium and is not expressed in PPG-5 and
PPG-8 tissues; K10 is expressed in superficial epithelial cells of pterygium tissue but not in conjunctiva and PPG tissues.
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
Fig. 5. Expression of Muc5AC in PPG. Muc5AC is present in the superficial epithelium of conjunctiva and pterygium shaped like dots and flakes, and is low in
pterygium tissues, but not in PPG epithelium.
Fig. 6. Expression of collagen IV in the epithelial basement membrane of PPG tissue. Collagen IV is primarily highly expressed in the conjunctival epithelial
basal layer (red arrows) and vascular endothelium in normal conjunctiva, and it is continuous and the thickness is uniform. The expression of collagen IV in
pterygium is not different from that in conjunctiva. The expression of collagen IV in PPG vascular endothelium is similar to that in conjunctiva, with weak expression
in epithelial basement membrane and large segments of broken or absent in some PPG tissues (white arrows). (For interpretation of the references to colour in this
figure legend, the reader is referred to the Web version of this article.)
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
Fig. 7. Expression of E-cadherin, claudin 4, PCK and
vimentin, α-SMA in PPG tissues. A, B. E-cadherin and
claudin 4 were highly expressed in normal conjunctiva
and pterygium epithelium, but were found to be reduced
in PPG tissues. C. Vimentin was not expressed in normal
conjunctiva and pterygium epithelium, but significantly
increased in PPG superficial epithelial cells. In contrast,
PCK was expressed in all epithelial layers of conjunctiva
and pterygium, but was almost absent in PPG tissues, a
few PPG epithelial cells expressed both PCK and vimentin. D. α-SMA was highly expressed in PPG tissue,
but not in normal conjunctiva and pterygium. E. Snail
staining showed that most of the epithelial cells in the
normal conjunctiva and the pterygium rarely expressed
Snail, while Snail nuclear staining showed that the expression was markedly increased in the basal epithelial
cells of PPG tissue.
Experimental Eye Research 175 (2018) 199–206
G. Wang et al.
conjunctival granuloma tissues. Wu D et al. observed that fibrous pattern granulomas have a complete intact, attenuated epithelial structure
(Wu et al., 2017). Dayanir V found that PPG tissues have a significant
multi-layer epithelial structure by H&E staining (Dayanir et al., 2009).
Consistent with the previous studies, we also observed marked multi
layered epithelial structures in some PPG tissue (8/12). However, a
small portion of PPG tissues (4/12) did not have this epithelial-like
Since the PPG tissues emerge at the conjunctival site following the
pterygium surgery, it can be hypothesized that PPG originate from
conjunctiva or pterygium. Cytokeratin has distinct tissue specificity,
which is closely related to the proliferation and differentiation of epithelial cells. K19 is highly expressed in normal conjunctival epithelium
(Pitz and Moll, 2002). We found significant K19 expression in conjunctiva and pterygium, but not in PPG tissues. In the squamous metaplastic diseases represented by pterygium, epithelial cells undergo
transdifferentiation and express skin epithelial K10 (Li et al., 2016).
However, we did not find K10 expression in PPG tissues. Our further
study found that PCK is highly expressed in conjunctiva and pterygium
but not in PPG tissues. There are various amounts of goblet cells in
normal conjunctival epithelium (Colorado et al., 2016), which secrete a
variety of mucins, with the majority being Muc5AC (Paulsen and Berry,
2006). Our results confirmed Muc5AC expression in conjunctiva and
pterygium, with a slightly reduced expression in pterygium, consistent
with the results of Dong N et al. (Dong et al., 2013). However, no expression of Muc5AC was observed in PPG tissues, suggesting no goblet
cells based on the lack of mucin secretion in the epithelium-like
structure of PPG tissue. Therefore, the above results demonstrated that
the PPG epithelium-like structure was significantly different from the
conjunctival and pterygium epithelial tissues. This epithelium-like
tissue might have arisen as a consequence of differentiation.
EMT is a biological process in which the epithelial cells are transformed into cells with interstitial phenotypes through a specific
pathway, and they lose their epithelial cell function and properties.
EMT is a key step during the embryonic development, malignant
transformation of a non-malignant tumor, and tissue injury repair
(Thiery, 2003). The process of EMT ends when the inflammatory response caused by trauma resolves itself. However, in a prolonged activation of the inflammatory response, the process of EMT persists and
eventually leads to tissue fibrosis (Kalluri and Weinberg, 2009). Numerous studies have found that EMT plays a role in the fibrosis of
limbus, lens, and pterygium (Engelsvold et al., 2013; Kawakita et al.,
2005; Taiyab et al., 2016). E-cadherin is an important protein which is
known to aid in the adhesion of epithelial cells, while vimentin is primarily expressed in the various mesenchymal cells and they are important biomarkers of epithelial and stromal cells, respectively (De
Wever et al., 2008; Ivaska, 2011). Upon the occurrence of EMT, the
expression of E-cadherin and vimentin may change significantly
(Zeisberg and Neilson, 2009). Our study shows that the expression of Ecadherin in PPG epithelium-like tissue was significantly lower than that
in conjunctiva and pterygium, whereas the expression of vimentin was
significantly increased in both, which implies an EMT process in PPG
tissues. This interpretation was further supported by the up-regulated
EMT marker proteins, α-SMA and Snail. In addition, the expression of
collagen IV in PPG tissues was found to be abnormal. Collagen IV is one
of the major component of the basement membrane (Timpl and Brown,
1996), primarily secreted by the epithelial basal cells, which aids in the
cell adhesion and maintains the integrity of tissue structures (Kalluri
and Cosgrove, 2000). The basement membrane regulates the polarity of
the epithelial cells. The disruption of the basement membrane can lead
to loss of cell polarity, which enhances the process of EMT (Burns et al.,
2007; Fujiwara et al., 2007). In this context, Shintani Y et al. found that
an interaction between the extracellular matrix and the collagen damaged the basement membrane which triggered EMT (Shintani et al.,
2008). The evidence of an incomplete and abnormal basement membrane expression in the PPG tissue, in our study, indirectly proves that
the cells in the PPG tissue underwent EMT.
In conclusion, as far as we know this is the first study demonstrating
that PPG epithelial tissue differentiated into an abnormal phenotype
which occurs as consequence of the EMT phenomenon. At present, the
cause of EMT in PPG remains unknown, and further study will be of
great significance in reducing the occurrence of postoperative complications of pterygium and improve the prognosis of patients with pterygium.
Conflicts of interest
The authors declare no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.
This study was supported in part by grants from the National Key R
&D Program of China (2018YFA0107301), the National Natural Science
Foundation of China (NSFC No. 81470601, 81770891, 81330002,
81470600), Fujian Natural Science Foundation of Fujian Province (No.
2016J01416, 2016D013, 2015-ZQN-ZD-34), Fundamental Research
Funds for Xiamen University (No. 20720160055), Huaxia Translational
Medicine Fund (No. 2017-A-001, 2017-A-002), Xiamen Science and
Technology Planning Project (No. 3502Z20159017).
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