Rard 17 02 Okfinal

See discussions, stats, and author profiles for this publication at: https://www.researchgate.
net/publication/325542537
Pterygium: A Complex and Multifactorial Ocular Surface Disease. A Review on

its Pathogenic Aspects
Chapter · May 2018

DOI: 10.29290/RARD.1.2.2018.2-37
CITATIONS READS
0 518
5 authors, including:
Horacio M Serra Maria Fernanda Suarez

National University of Cordoba, Argentina Tufts Medical Center
100 PUBLICATIONS 1,964 CITATIONS 25 PUBLICATIONS 69 CITATIONS
SEE PROFILE SEE PROFILE
Juan Pablo Maccio Evangelina Espósito

Clínica Universitaria Reina Fabiola McGill University
6 PUBLICATIONS 66 CITATIONS 37 PUBLICATIONS 68 CITATIONS
SEE PROFILE SEE PROFILE
Some of the authors of this publication are also working on these related projects:
HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target? View project
Epithelium and connective tissues involved diseases View project
All content following this page was uploaded by Horacio M Serra on 17 April 2019.
The user has requested enhancement of the downloaded file.

Rare Diseases
Chapter 02
Pterygium: A Complex and Multifactorial
Ocular Surface Disease. A Review on its
Pathogenic Aspects
Horacio M Serra1#*, Maria F Suarez1#, Juan P Maccio2, Evangelina
Esposito2 and Julio A Urrets-Zavalia2
#Both authors equally contributed
1
CIBICI, Department of Clinical Biochemistry, Faculty of Chemical Sci-
ences, Universidad Nacional de Córdoba, Argentina
2
Department of Ophthalmology, University Clinic Reina Fabiola, Universi-
dad Católica de Córdoba, Argentina
*
Corresponding Author: Horacio Marcelo Serra, CIBICI, Faculty of
Chemical Sciences, Universidad Nacional de Córdoba, Haya de la Torre
esquina Medina Allende, 5000 Córdoba, Argentina, Tel: 54 351 4344973;
Fax: 54 351 4333048; Email: hserra@fcq.unc.edu.ar
First Published April 23, 2018
Copyright: © 2018 Horacio Marcelo Serra, et al.
This article is distributed under the terms of the Creative Commons Attribu-
tion 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give ap-
propriate credit to the original author(s) and the source.
2 www.avidscience.com
Rare Diseases
Summary
Pterygium is an abnormal overgrowth of epithelial and fibrovas-
cular tissue of the bulbar conjunctiva onto the corneoscleral limbus
that may progress invading the superficial corneal layers. Usually, it
develops horizontally on the nasal area of the interpalpebral fissure,
but it may also affect the temporal side, and rarely both areas in a
same eye. Its prevalence rate varies from 0.7 to 31% in different geo-
graphical regions around the world, being especially common in the
tropics. Although many factors, such as ultraviolet radiation expo-
sure, may contribute to the development and progression of pterygia,
its pathogenesis remains elusive.
In this chapter, we review the anatomy and histology of the
normal conjunctiva, the molecular characterization of conjunctival
epithelial cells and the expression of different types of cytokeratins,
clinical aspects, presentation and treatment of pterygium, and possi-
ble pathogenetic factors influencing its development, such as expres-
sion of cytokeratins and matrix metalloproteinases, dysregulation of
the elastin metabolism, inflammatory mediators and growth factors,
alterations in gene expression, and lipid metabolism and peroxidation
in pterygium.
Keywords
Pterygium; Conjunctiva; Cytokeratins; Collagenases; Pax6 Gene;
Actinic Elastosis; Ultraviolet Radiation; Ophthalmoeliosis
Anatomy and Histology of the Normal

Conjunctiva
The conjunctiva is the transparent mucous membrane lining the
inner surfaces of the eyelids; it is reflected through the upper and low-
er fornices over the anterior episclera and sclera before terminating at
the limbus, where it is continuous with the corneal epithelium. Two
aspects of the conjunctiva are described: the palpebral and the bulbar
www.avidscience.com 3
Rare Diseases
conjunctiva. The palpebral conjunctiva lines the posterior surface of

the eyelids, extends from the fornices to the mucocutaneous junction
at the eyelid margins. The bulbar conjunctiva begins at the limbus, at
which point the corneal epithelium gradually becomes replaced by
conjunctival epithelium and continues over the sclera to the superior
and inferior fornices [1].
The blood supply of the conjunctiva is derived mainly from that
of the eyelids, with some contribution from the anterior ciliary ves-
sels in its bulbar portion through the limbal plexus and vessels may
extend a short distance on to the cornea but in so doing terminates
in an even border on the clear cornea. The nerve supply is mainly
from the ophthalmic division of the trigeminal nerve but a variable
proportion of the inferior conjunctiva is supplied by branches of the
maxillary division [1].
The conjunctival epithelium consists of non-keratinized strati-
fied squamous epithelium that rests upon a basal lamina overlying the
substantia propria. Within the conjunctival epithelium are goblet cells
(mucus-secreting) cells, especially in the fornices, and melanocytes in
the basal epithelial layers. Lymphoid follicles with germinal centers
reside in the conjunctiva, particularly in the fornices; scattered lym-
phocytes are not unusual within the conjunctiva [2].
The fibrovascular subepithelial connective tissue of the conjunc-
tival stroma normally contains nerve cells and melanocytes. Both the
caruncle and plicasemilunaris represent specialized segments of the
conjunctiva. The caruncle resembles skin and may normally contain
skin adnexa [3].
The identification of markers that are expressed in the conjunc-
tival epithelium but not in the corneal epithelium has been studied
since 1994. Good candidates are cytokeratins (K), since they form
filaments responsible for the integrity of the epithelial cell structure,
and because of their different expression patterns [4].
On the same year Chen et al. demonstrated that corneal epithe-
lium, unlike the conjunctival epithelium, expresses cytokeratin K12
Rare Diseases
[5]. Although Donisi et al. proposed initially that K19 was a specific
marker of conjunctival epithelial cells [6], other groups found that
this cytokeratin is not specific to conjunctival epithelial cells because
it is also expressed in corneal epithelial cells as well [7,8].
More recently, Barbaro et al. compared expression of K3, K12,
K19 and mucin 1 in both sclerocorneal tissues and impression cytol-
ogy specimens by immunofluorescence and their results confirmed
the previous finding that K19 is not specific to conjunctival epithelial
cells [9].
In 2007 Turner et al. and later on in 2011 Ramirez-Miranda et al.
searched for a more specific marker of limbal and conjunctival epithe-
lia. They performed preferential gene profiling in the conjunctiva in
direct comparison to that in the cornea using microarray technique,
qRT–PCR, and immunohistochemistry. K13 at both the mRNA and
protein levels was expressed only in the posterior limbal and conjunc-
tival epithelia and completely absent on the cornea, and it expression
pattern was mutually exclusive of the K12 [10,11].
Paired box homeotic gene 6 (Pax6) functions as an early ecto-
dermal gene expressed during optic vesicle formation for eye develop-
ment. Since this DNA-binding transcription factor PAX6 was cloned
25 years ago numerous genetic, cellular, molecular and evolutionary
studies have been made and it is currently considered the universal
master control gene for eye morphogenesis. It has been shown that
Pax6 is expressed by different types of retina cells, iris, ciliary body
and in the epithelially-derived lens and cornea cells from early gesta-
tion until the postnatal stage. Postnatally, Pax6 expression is restricted
to corneal, conjunctival, lens and iris epithelia and amacrine cells of
the retina. Pax6 expression is linked with the control of EGF-induced
cultured corneal epithelial cell proliferation, and K12 gene expres-
sion; it also regulates cell differentiation, and mediates apoptosis [12].
As have been reviewed by Li et al., cumulative evidence indicates
that limbal epithelial stem cells (LSC) are regulated by their surround-
ing micro-environment, the so-called limbal stem cell niche where
cornea epithelial cells undergo continuous renewal from LSC [13].
Rare Diseases
LSC which are positive for p63, K5/K14/K19, migrate centrip-

etally for several millimeters to the central cornea during which it un-
dergoes differentiation and K5/K14 are replaced by corneal-specific
K3 and K12. These processes of LSC differentiation are controlled by
the WNT7A–PAX6 axis [14].
Pterygium
The term “pterygium” is a Latinized version of the Greek term
“pterygion” meaning “small wing” [15]. Pterygium is an abnormal
growth of epithelial and fibrovascular tissue from the corneoscleral
limbus that centripetally invades the cornea, causing ocular surface
inflammation and potential vision impairment. It is characterized by
an altered basal epithelial cell proliferation, vascularization, and inva-
sion of the adjacent corneal epithelium. Its usually develops nasally,
rarely temporally, and very infrequently both sectors simultaneously.
Clinically, initial signs of disease progression are represented by the
presence of circumscribed superficial gray dots in the prelimbal cor-
nea, taut conjunctiva opposite to the area of corneal affection, and
displacement of the plica. Later, a wing-shaped extension of the fleshy
growth of the bulbar conjunctiva onto the cornea takes place. A fully
developed pterygium presents a well formed “apex” or “head” (apical
aspect present on the cornea), a “body” (conjunctival aspect extend-
ing between the limbus and the canthus), and a “neck” (limbal aspect)
[16,17].
The pathogenesis of pterygia remains partly understood [18].
Histologically, pterygia show basophilic degeneration (actinic or
senile elastosis) of the subepithelial substantia propria. The epithe-
lium overlying a pterygium may show a variety of secondary changes
such as orthokeratosis, acanthosis, and dyskeratosis, and mast cells
can be found in several pterygia [19]. Deep corneal changes at the
level of Descemet’s membrane and the endothelium, such as reduced
endothelial cell density, may be seen in association with long-stand-
ing nasal pterygia in elderly individuals [20].
Rare Diseases
The control of elastogenesis is seriously defective in pterygia

so that the elastic fibers are not immature, but are abnormal in their
biochemical organization. A marked reduction of elastic microfibrils,
rather than an overproduction, appears to prevent normal assembly
of elastic fibers.
It is especially common in the tropics, leading Cameron to refer
this region as the pterygium belt [21]. Pterygium prevalence rate var-
ies from 0.7 to 31% in different geographical regions around the world
[22-33].
In some regions, like South India, the prevalence of pterygium
and pinguecula has been found to be similar (9.5% and 11.3%, respec-
tively [34]. Whereas Rezvan F, et al. studied 40 to 64 year old citizens
of Shahroud city, which is located 410 kilometers to the east of Tehran
and has a cold desert climate. They reported a pterygium prevalence
of 9.4% in at least one eye and 2.9% had bilateral pterygium. The prev-
alence of pterygium in this study was lower than reported rates in the
world but higher than Tehran [35]. Contrary to the Indian population
study, they found a very high prevalence of pinguecula (61.0% in at
least one eye and 49.0% in both eyes).
Our group has previously described Climatic Droplet Keratopa-
thy (CDK), a degenerative corneal disease, in individuals living in a
remote rural region of the Argentine Patagonia [36]. More recently,
we carried out a comparative study between CDK, pinguecula and
pterygium in this cold arid climate region of Argentina, in order to
determine the prevalence of these ocular surface ophthalmoheliosis
and the correlation, if any, among these diseases. Non-probabilistic
consecutive patients who live in this region of Argentina were includ-
ed in this study. From a total of 159 individuals (52.83% men and
47.17% women), 28.9%, 32.1%, and 13.2%, had CDK, pinguecula, and
pterygium, respectively. We have studied patients that only present
one of these ophthalmoheliosis (CDK, or pinguecula or pterygium).
Twenty-five/46 individuals with CDK, (54.35%) only presented this
pathology; 31/51 (62%) patients with pinguecula only had this dis-
ease; and 10/21 (47.62%) individuals with pterygium only had this
Rare Diseases
disease. There were not significant association between CDK and

pinguecula, or CDK and pterygium, and there were only four pa-
tients presenting both pinguecula and pterygium at the same time.
Although pinguecula could be a precursor or trigger for pterygium
[37], we studied some patients who presented only pinguecula and
we followed them up for approximately 10 years, by annual ophthal-
mological examination, and no pinguecula evolved to pterygium.
(Manuscript in preparation).
Classifications of Pterygium
Pterygium was firstly classified histologically and divided into
three morphological types: angiomatous, fibrous and mixed [19]. In
the angiomatous pterygium, the stroma contains a significant num-
ber of vascular vessels with edema in the intervascular space; in the
fibrous form the stroma is predominantly fibrous with a few scattered
vascular elements; in the mixed pterygium the stroma contains both
vascular vessels and thin bundles of collagenous tissue (Figure 1).
Figure 1: Pterygium histological classification. (A) Normal conjunctiva, composed by

five layers of epitelial cells and few vessels underneath. (B) Fibrous pterygium, observe
the fibrotic band below the basal membrane (arrowhead) and the solar elastosis (aster-
isks). (C)Angiomatous pterygium, with a deorganized and thickened epithelium and
clusters of vessels in the conjunctival stroma. (D) Mixed pterygium, with vascular and
fibrotic proliferation at the stroma. H&E 20X.
Rare Diseases
Tan et al. classified pterygium according to the morphology

into three grades [38] Grade T1 (atrophic) refers to a pterygium in
which episcleral vessels underlying the body of the pterygium are un-
obscured and clearly distinguished. Grade T3 (fleshy) shows a thick
pterygium in which episcleral vessels underlying the body of the
pterygium are totally obscured. Grade T2 (intermediate) groups all
other pterygia that do not fit any other category (Figure 2). Pterygium
usually develops nasally, rarely temporally, and very infrequently both
sectors simultaneously. (Figure 2C)
Figure 2: Pterygium morphological classification. (A) Pterygium grade T1. (B) Pteryg-
ium grade T2 and (C) temporal pterygium grade T3 (*).
Another classification has taken into account the degree of pro-

gression of pterygium on the cornea [39]. These authors have divided
pterygium into 5 stages (Table 1). Also, each stage has been subdivid-
ed into subgroups taking into account the vascularization, the thick-
ness of the tissue at the level of the conjunctiva, the thickness of the
tissue at the level of the cornea and the pigmentation or line of Ferry
(Table 2). This semi quantitative approach has provided an overall rat-
ing based upon the progression (or in the case of therapy, regression)
of the pterygium as well as a more detailed description of important
characteristics of each pterygium.
Rare Diseases
Table 1: Clinical Stages of Pinguecula and Pterigyum.
Stage 0 Pingeoculum, posterior to the limbus

Stage 1 Tissue involvement to the limbus
Stage 2 Tissue just to the limbus
Stage 3 Tissue between the limbus and pupillary margin
Stage 4 Tissue central to the pupillary margin
Table 2: Pterygium subgroups according to vascularization, thickness of the tissue at

conjunctival or corneal levels, and pigmentation or line of Ferry.
Conjunctival / corneal Conjunctival tissue thick- Corneal tissue thick- Pigmentation / Ferry
vascularization(V) ness (C) ness (K) Line (P)
V0 - No discernible C0 - Conjunctival ectasia or K0 - Conjunctival ectasia P0 - No discernible
thinning or thinning
V1 - Minimal papillary C1 - Flat tissue K1 - Flat tissue P1 - Faint
response without visible
vessels
V2 - Normal vascularity C2–Minimally elevated-tissue K2–Minimally eleva- P2 - Minimal pigmented line
ted-tissue
V3 - Moderate vascularity C3 - Tissue elevation up K3 - Tissue elevation up P3 - Moderate pigmen-
and vessel congestion to 1mm to 1mm ted line
V4 - Severe vasculari- C4 - Tissue elevation over K4 - Tissue elevation P4 - Dense pigmented line
ty,vessel congestion and 1mm over 1mm
dilatation
Pterygium Etiopathogenesis
Although pterygium has been studied for many years, its patho-
genesis still remains uncertain. It is thought to be an ophthalmohe-
liosis because of its possible relationship with high exposure to ul-
traviolet radiation (UVR). A wide range of other pathogenic factors
have been proposed, including epithelial-mesenchymal transition,
deregulation of extracellular matrix (ECM) modulators and growth
factors, viral infections, epigenetic aberrations, immunologic and
anti-apoptotic mechanisms, angiogenic and lymphangiogenic stimu-
lation, inflammation cascades, recruitment of bone-marrow-derived
stem- and progenitor cells, and modifications in the cholesterol me-
tabolism. Most of these factors are thought to be more related to the
development and maintenance of the disease than to its origin [40].
Rare Diseases
Abnormal Phenotypes of Pterygial Cells

The pathogenesis of primary pterygium is complex. Controversy
between limbal stem cell failure versus proliferation still remains. It
has been considered as a limbal failure permitting the advancement of
conjunctival epithelium on the cornea. This fibrovascular lesion over-
growth of conjunctiva on the corneal surface often associates with
dissolution of Bowman’s membrane, connective tissue remodeling,
chronic inflammation and angiogenesis [41].
Epithelial cells from vascularized corneal pannus in patients
with pterygium showed a decline of Pax6 expression, accompanied by
a decline or absence of K12 but an increase of K10 and filaggrin ex-
pression. Pannus basal epithelial cells maintained nuclear p63 expres-
sion and showed activated proliferation, evidenced by positive Ki67
and K16 staining indicative of an alternative pathway of keratinocyte
proliferation. These results indicated that the pannus epithelium ex-
hibited abnormal epidermal differentiation, squamous metaplasia
with hyper-proliferation [42].
More recently Bai et al. have reported the expression of stem cell
markers such as ATP-binding cassette transporter glycoprotein fam-
ily member-2 (ABCG2), CK15, p63, Pax6, as well as matrix metal-
loproteinase-2 and 9, in different regions of primary pterygia (such
as the head, the neck, and the body. They also explored the migratory
pattern of pterygial epithelial cells. More proliferating stem-like cells
(p63+) were present in the head region, which have higher colony-
forming efficiency and they might act as a proliferation force for the
growth of pterygium. ABCG2 and K15 were found mainly in the body
basal epithelia, similar to that in normal conjunctiva. Much fewer
proliferating stem-like cells in the neck region supported the limbal
failure as a cause of pterygium formation. Pax6 was more expressed
in the head than in the other two regions. Matrix metalloproteinases
(MMP)-2 and 9 were detected in the pterygium head margin, but not
in the body part. By colony-forming assay, epithelial cells from the
head region had higher proliferative ability than those from the body.
Rare Diseases
The authors also demonstrated that the head epithelial cells grew and
migrated faster than body cells and the efficiency was influenced by
expression of active MMP-2 and 9 proteins. Results from this study
clearly showed a spatial expression pattern of markers for stem cells,
cell growth, and matrix metalloproteinases in the primary pterygium
tissue [43].
Josifovska et al. have very recently developed an ex vivo model
of tissue engineered pterygium in which cells were adherently cul-
tivated and grown out of the abnormal conjunctival tissue explants
using gravitational force from viscoelastic material for more than
three months. After that the authors used multiple antibodies specific
for hematopoietic- and mesenchymal stem cell markers, for pluri-
potency and stemness, oxidative stress, migration and proliferation,
cytokeratin, and secretory markers to determine the phenotype and
possible origin of these cells. Cells showed high expression of mi-
gration- (CXCR4), secretory- (MUC1, MUC4) and oxidative dam-
age- (8-OHdG) markers, and low expression of proliferation- (Ki-67)
marker. Moderate and low expression of the pluripotency markers
(Vimentin and ΔNp63) was present, respectively, while the putative
markers of stemness (Sox2, Oct4, ABCG-2) and epithelial cell mark-
ers- (CK19, CK8-18) were weak. The surface marker profile of the
outgrowing cells revealed high expression of the hematopoietic mark-
er CD47, mesenchymal markers CD90 and CD73, and minor or less
positivity for the hematopoietic marker CD34, mesenchymal marker
CD105, progenitor marker CD117. The authors concluded that hu-
man pterygium explants can give rise to 3-dimensional outgrowing
cells which could proliferate and migrate out of the grafts and form
a stratified structure very much like the one in vivo. The expanding
cells carried markers related to an undifferentiated state, but also a
commitment towards epithelial lineage. Stemness markers suggest a
flexible cell phenotype in the long-term cultures [44].
Pterygium is also characterized by highly vascularized mass of
hypertrophic and elastotic degenerated connective tissue. The sub-
epithelial tissue of the pterygium shows elastodysplasia (immature
Rare Diseases
formation of elastic fibers) as well as elastodystrophy (degenerative

changes in elastic fibers and formation of electrodense inclusions).
Pterygium pathogenesis involves dysregulation of the elastin metabo-
lism, since tropoelastin, fibulin (FBLN)-2, and FBLN-3 are over ex-
pressed in subepithelial connective tissue [45].
Collagen and elastin fiber formation are complex processes
which result in molding these two major components of the extra-
cellular matrix (ECM). Elastin is formed through the reticulation of
tropoelastin monomers over a fibulin/fibrillin-rich microfibril tem-
plate. Lysyl oxidases (LOXs) are extracellular amine oxidase copper
enzymes whose primary function is to catalyze the covalent cross-
linking of collagen and elastin fibers in the ECM. The major substrate
for LOX is collagen I. However, LOXL-1, but not LOX, is specifically
targeted to sites of elastogenesis, showing that LOXL-1 is closely re-
lated with the elastic lamina, whereas LOX is broadly distributed [46].
It already has been shown that high exposure to UV irradiation
(UVR) causes increased elastin levels in different tissues as well as in-
creased elastin mRNA levels and enhanced elastin promoter activity
in sun-damaged skin [47].
Pérez-Rico et al. evaluated the expression of several extracellular
matrix constituents on pterygial tissues subjected to immunohisto-
chemical staining with anti-lysyl oxidase (LOX), lyxyl oxidase-like 1
(LOXL-1), FBLN-5 and FBLN-4, and fibrillin-1 (FBN1) antibodies.
Specific primers for the same constituents were used in a quantita-
tive real time PCR (qRT-PCR) analysis to determine gene expression.
They found that in the subepithelial connective tissue of human
pterygium, LOXL-1/FBLN5, and FBN1 mRNA expression was sig-
nificantly increased in respect to levels in healthy conjunctiva, while
the expression of LOX and FBLN-4 is comparable to levels in controls.
The pathology results in an increased protein expression of the same
constituents (LOX/LOXL-1 and FBLN-5) that is more pronounced in
the older patients. These data support the hypothesis of a dysregula-
tion in the synthesis and reticulation of the elastic components in this
type of pathology [48].
Rare Diseases
Role of Viruses
Many studies have been conducted to investigate the involve-
ment of a variety of oncogenic viruses, including human papillomavi-
rus (HPV), cytomegalovirus (CMV), and herpes simplex virus (HSV)
or Epstein barr virus (EBV), in the development and recurrence of
pterygium, and as it has been reviewed by Chalkia et al. [49] the re-
sults are not irrefutable. Such a disparity in the prevalence of onco-
genic virus detection in pterygium may partly be explained by ethnic
or geographical factors or by laboratory techniques. However, it may
also reflect the heterogeneous nature of pterygium pathogenesis and
the possibility that oncogenic viruses affect only a sub-group of oph-
thalmic pterygia.
Inflammatory Mediators and Growth Fac-

tors Involved in Pterygium Development
A large set of pro-inflammatory cytokines, lipid mediators,
growth factors and their receptors has been described as involved in
the development of pterygium. Also, Tetsushi et al. and García Car-
mona et al. have demonstrated more abundant number of mast cell in
the pterygium than in normal conjunctiva, using antibodies against
tryptase or CD117, respectively. They also showed lack of correlation
between morphologic types of pterigia or relapse pterygium and pres-
ence of mast cells [50,51].
It has been shown that UVR-B can induce cytokine secretion
from ocular surface cells and increased release into the tear film [52-
55].
Our research group have shown that in human corneal epithe-
lial cells, UVR-B increased pro-inflammatory cytokine release, gelati-
nases secretion with a striking effect on MMP-9, demonstrating that
corneal epithelium could participate in other opthalmoheliosis such
as CDK development as a source of cytokines and gelatinases [56].
Rare Diseases
Di Girolamo et al. have demonstrated that pterygium epithelium

expressed abundantly IL-6 and IL-8 proteins, having additional ex-
pression of IL-8 associated with vascular endothelium; compared to
normal conjunctiva, cornea and limbus. Additionally, pterygium epi-
thelial cells exposed to increasing UVR-B doses have shown induced
expression of IL-6 and IL-8 in a time and dose dependent manner.
Also, pterygium tissues in organ culture have shown increased level of
these two cytokines compared to non irradiated tissues. The authors
stated that this was the first study evidencing the direct relation be-
tween UVR-B and pterygia pathogenesis [57]. IL-1 and TNF-α have
also been described over expressed in pterigyum as a result of UVR-B
[58,59].
Cyclooxygenases (COX), LOX and cytochrome P450 monooxy-
genases (CYP) derived eicosanoids are also increased in tissue and
tears from pterygium patients. A comparative study has shown a
shift in favor of pro-inflammatory versus anti-inflammatory lipid
autacoids, being the most abundant the LOX derived 12-hydroxyei-
cosatetraenoic acid (12-HETE), a potent pro-inflammatory and pro-
angiogenic lipid mediator. On the other hand, the anti-inflammatory
LOX-derived lipid, 15-HETE was lower in pterygium. Also, COX-
derived lipids PGE2 and TxB2 were increased in pterygium, thus sup-
porting previous studies [60,61].
The role of the nuclear factor κB was also described in pterygi-
um. It was demonstrated that NF- κB is activated in pterygium tissue
and both canonical and non canonical pathways can be activated in
fibroblasts from primary pterygium in response to TNF-α, with con-
comitant upregulation of NF-κB target genes [62]. It was previously
described in skin cells that UV-B can induce activation of mitogen
activated protein kinase (MAPK) pathways, leading to NF-κB induc-
tion and consequent release of IL-1, IL-6 and TNF-α [63]. Later on,
Torres et al. have investigated the activation of MAPK and NF-κB
pathways in pterygium. They have shown that pathologic tissues have
decreased levels of c-jun N-terminal (JNK) and IκΒ-α and increased
phospho-IκΒ-α levels and phospho/total ratio of JNK and IκΒ-α were
present in pterygium tissue compared with healthy conjunctivas [64].
Rare Diseases
Di Girolamo et al. have also demonstrated that ERK1/2, JNK, and p38
mitogen-activated protein kinases are involved in pterygium patho-
genesis and using inhibitors for these pathways significantly abolished
the UVR-B-mediated increase in IL-6, IL-8, and vascular endothelial
growth factor (VEGF) [65].
It has been postulated that increased proliferation and angiogen-
esis in pterygium resembles tumor characteristics [40,66]. The expres-
sion of VEGF, TGF-β and PGE2 using inmmunohistochemical assays
was studied by Bianchi et al. [67], comparing primary pterygium sam-
ples with normal conjuctiva. The first one was significantly increased
in the epithelium, vascular endothelium and stromal cells, TGF-β
showed a moderate expression in the epihelium and stroma, while
PGE2 was markedly expressed in the epithelial cells from primary
pterygium in comparison with healthy conjunctiva. The authors have
suggested that these growth factors may contribute to the progres-
sion of pterygium by means of angiogenesis, leading to the formation
of new vessels, thus these factors could be potential therapeutic tar-
gets for the treatment of this pathology. Pterygium tissue also shows
elevated levels of cell signaling and adhesion molecules, including
VCAM-1 and ICAM-1 [68]. Lee et al. have studied the effect of chon-
drocyte-derived extracellular matrix (CDECM) on human primary
pterygium epithelial cells (hPECs), showing that CDECM signifi-
cantly downregulated MMP-9 and fibronectin and upregulated tissue
inhibitor of metalloproteinase 1 (TIMP-1) and -2. Angiogenic factors
such as VEGF, VCAM-1, CD31, pro-inflammatory factors such as
TNF-α, COX-2, IL-6 and PGE2 were significantly reduced in hPECs.
CDECM also inhibited expression of NADPH oxidase subunits Nox2
and p47phox, with the subsequently inhibition of the generation of
intracellular reactive oxygen species (ROS). CDECM also suppressed
NF-κB activation and the phosphorylation of p38 MAPK, protein ki-
nase C alpha (PKCα), and PKCθ [69].
Kim et al. have studied the effect of stromal cell-derived factor 1
(SDF-1) and the interaction with its chemokine receptor 4 (CXCR4),
since SDF-1-CXCR4 increased signaling contributes to hypertrophic
Rare Diseases
scarring [70]. They cultured fibroblasts from excised pterygium grade

T1 to T3, and determined levels of SDF-1, CXCR4, and α-smooth
muscle actin (α –SMA) as a marker of myofibroblast transformation.
SDF-1 expression was upregulated in severe pterygium (T3) and SDF-
1 and CXCR4 interaction contribute to the myofibroblast transfor-
mation. Bamdad et al. have corroborated those results investigating
not only the expression of SDF-1 and CXCR4, but also CXCR7 levels.
They found that SDF-1 and both receptors transcripts have increased
expression in pterygium compared to controls, supporting the idea
that the SDF-1/CXCR4/CXCR7 axis may participate in pterygium de-
velopment [66].
The ErbB family of four receptor tyrosine kinases: epidermal
growth factor (EGF) receptor ErbB-1 (or EGFR) and three family
members (ErbB-2, ErbB-3 and ErbB-4) mediate a variety of cellular
responses to the environment, participating in a wide variety of bio-
logical processes from neuronal development to breast cancer [71,72].
ErbB 1, 2 and 3 can recognize 11 different, but structurally related
growth factors, such as epidermal growth factor (EGF), TGF-α, and
heparin binding EGF (HB-EGF), among others. ErbB-2 does not bind
to a known ligand but instead functions as a co-receptor for each of
the other three [72]. The expression pattern and quantity of EGFR,
ErbB2 and ErbB3 proteins were studied in pterygium tissue com-
pared to healthy conjuctiva. In normal conjunctiva, EGFR were pre-
sent in the basal cells while ErbB2 and 3 were present in superficial
layers of the epithelium, but all three proteins were highly expressed
in the whole epithelium from pterygium samples. These results were
corroborated by western blot. According to the authors, the increased
expression of the studied receptors supports the idea that pterygium
is a disorder with abnormal proliferation [73].
The S100 proteins are a family of small calcium-binding proteins,
only expressed in vertebrates, with high structural homology and
pleiotropic functions, such as cell migration, proliferation, and differ-
entiation [74]. They have been implicated in the regulation of neutro-
phil chemotaxis and inflammation related to ocular surface diseases
Rare Diseases
such as dry eye, meibomian gland dysfunction, pterygium, and cor-

neal neovascularization [75-77]. Riau et al. have studied the expres-
sion and tissue distribution of S100A4, S100A6, S100A8, S100A9 and
S100A11 proteins in pterygium specimens. They have found higher
levels of S100A6, S100A8, and S100A9 expression in pterygium tissue
compared to normal conjunctiva. S100A11 was expressed in the basal
cells of conjunctival epithelium, but it was found in the suprabasal
layers of pterygium epithelium, hence they have associated these S100
proteins with the formation of pterygium [77].
Epigenetic Factors
Epigenetics refers to the study of the heritable alterations in gene
expression that do not involve the underlying DNA sequence. Epige-
netic mechanisms include DNA methylation, histone modifications,
and micro RNAs [78]. There is only one publication about epigenetic
changes in pterygium. In this article, authors described altered meth-
ylation patterns at CpG loci near the genes encoding transglutami-
nase 2 (TGM2), MMP-2, and CD24 [79]. Hyper methylation at the
promoter region of TGM2 led to decreased transcript and protein
levels, and hypo methylation of intergenic regions of MMP2 and the
promoter region of CD24 led to increased transcript and protein lev-
els. These changes could have implication in pterygium development
since they play key roles in extracellular matrix remodeling and cell
adhesion [80,81].
Lipids Metabolism in Pterygium

As far as we know there are scarce information about lipid me-
tabolism and lipid peroxidation in pterygium. In fact, by using prima-
ry pterygia fibroblast cells one article described increased cholesterol
metabolism activity [82], and other article showed increased mRNA
levels of hydroxyl methylglutaryl coenzyme A reductase (rate limiting
enzyme of cholesterol biosynthesis) [83].
We have studied the phospholipid profile in conjunctival tissues
from affected and non affected areas of the conjunctiva in patients
Rare Diseases
who underwent pterygium surgery. We have found that total amount

of phospholipids is higher in pterygium tissue than in healthy con-
junctiva. This fact is the opposite to what we have described in EPCD
[84]. Also, phosphatidylcholine and phosphatidylserine concentra-
tion were higher in affected than in non affected conjunctiva. In addi-
tion, we have described a subset of phospholipids uniquely present in
pterygium tissue or in healthy conjunctiva, and other phospholipids
common to both regions of the patientes’ conjunctiva (data not pub-
lished).
Ancient, Traditional and Novel Treatments

for Pterygium
Ancient writers who described medical and surgical manage-
ment of pterygium included Hippocrates, Celsus, Pallus, Sushruta,
and Aetius. They all recognized that treatment was difficult and that
recurrences were almost inevitable.
The first reported surgical approach to pterygium management
was described by Celsus, in which a needle and thread were passed
under the pterygium. The thread was then elevated, the pterygium
was completely lifted from the cornea to the canthus using a sawing
motion, and the pterygium was excised. Later, in the 16th century,
it was noted that this operation should rarely be performed due to
its dangers and the risk of recurrence. From the 1800s to the 1930s,
various techniques were developed, but none proved to be particu-
larly successful. Though good short-term results and few complica-
tions have been gotten with excision and simple conjunctival closure.
In the first half of the 20th century, transplantation of the pterygium
head away from the cornea, or redirection, was the most commonly
used approach. However, though a relatively simple procedure with
few complications, it failed to solve the major problem, that of recur-
rence, and was eventually replaced [85].
Pterygium is generally asymptomatic at early stages. When the
disease progresses the lesions increase in size and may encroach on
the visual axis and reduce vision, and also can induce major against-
Rare Diseases
the-rule (ATR) astigmatism. It can lead to a diplopia by restricting

extra ocular movement [86]. At this point, pterygium excision is nec-
essary.
There are several surgical techniques for the treatment of pteryg-
ium. Among them we can mention simple excision or bare sclera
technique, conjunctival autograft and amniotic membrane graft.
Bare sclera technique involved the excision of the pterygium
head and removal of some of the adjacent normal nasal bulbar con-
junctiva along with excision of the underlying Tenon’s capsule tissue,
which then resulted in a bare sclera. Following suture of the sur-
rounding normal bulbar conjunctiva to the sclera, several millimeters
of the sclera next to the limbus are left bare [87]. Initially, the bare
sclera procedure was simple and had few or no complications, but
literature showed that this technique had high recurrence rate [38].
Nowadays, the technique is still in use, but usually combined with
adjunctive therapies to reduce recurrence rate.
Conjunctival autograft have been used previously for the treat-
ment of several ocular surface disorders [88]. In 1985, Kenyon et al.
adapted this technique to perform surgery in cases of advanced pri-
mary and recurrent secondary pterygium [89]. The procedure con-
sists in obtaining free conjunctival grafts from the superotemporal
bulbar conjunctiva of the same eye to resurface scleral bed once the
pterygium has been removed [89].
Conjunctival autografts can be placed using sutures or fibrin
glue. Since suture is associated with inflammation and discomfort,
fibrin glue can replace sutures when attaching conjunctival grafts (or
amniotic membrane), significantly shortening operating times and
decreasing postoperative discomfort, as well as decreasing recurrence
rates [87]. Since fibrin adhesives are prepared from pooled donor
sources, there is a small but finite risk of infection, such as hepatitis
and HIV, as well as of anaphylactic reaction [90].
Rare Diseases
There has been proposed that conjunctival autograft can be en-

riched with LSC (limbal- conjunctival graft), suggesting that these
cells can act as a barrier to stop the advanced of conjunctival cells
migrating to the corneal surface, but recurrence rates after using this
technique are similar to those obtained after conjunctival autograft for
recurrent pterygium [91]. In a study comparing bare sclera excision
and conjunctival autograft, Tan et al. have shown that in 38 (61%) of
62 cases of bare sclera surgery presented recurrence in contrast with 1
(2%) of 61 cases of conjunctival autograft [38]. In consequence, con-
junctival autograft results in long-term efficacy [92-94].
Amniotic membrane grafts for ocular surgery has been used
since first decades of 1900. Since results were not encouraging, it has
been disused until last part of the XX century [95]. Several character-
istics of amniotic membrane appear to make it suitable for treating
pterygium, including its anti-inflammatory, anti-scarring, and anti-
angiogenic properties. Once harvested, amniotic membrane can be
used fresh or preserved (either freeze-dried or cryopreserved). Dur-
ing this type of surgery, fibrin glue is also used to attach the mem-
brane graft to the episcleral tissue. Although some clinical trials of
amniotic membrane grafts for the treatment of pterygium reported
a lower rate of recurrence compared to bare sclera technique, other
studies have shown an unacceptably high recurrence rate compared
with conjunctival autograft. Thus, it may provide a superior alterna-
tive for selected cases [87,96-98].
After pterygium surgery, various adjunctive therapies have been
used in an attempt to reduce the high risk of postoperative recurrence
[85]. Adjuvants commonly used are: Mitomycin C (MMC), ß-radia-
tion, and 5-fluoruroacil (5-Fu).
MMC is an antibiotic and an anti-mitotic agent that induces
the apoptosis of keratocytes and myofibroblasts [99]. The combined
treatment with conjunctival autograft significantly reduced the recur-
rence of primary and recurrent pterygium compare with bare sclera
Rare Diseases
excision surgery alone. This adjuvant can be applied as postoperative

topical eye drops and in an intraoperative way using MMC- soaked
sponges, both with similar recurrence rates [100]. Adjunctive mito-
mycin C treatment has presented some risks and has been associated
with rare but severe long-term complications, including persistent
epithelial defects of both the cornea and sclera, endophthalmitis, in-
fectious scleritis, perforation, and scleral necrosis [101].
ß-radiation is a particulate radiation consisting of high-speed
electrons, which are rapidly attenuated by biological tissues, absorbed
in the outer layers of the ocular tissue, inhibiting fibroblast prolifera-
tion [102]. It was used in the 1970s, employing strontium-90, for the
treatment of pterygium after bare sclera excision. Recurrence rate us-
ing this adjuvant ranged from 0.5 to 62% and patients presented com-
plications as conjunctivitis, punctate keratitis, cataract, scleromalacia,
infectious scleritis and endophthalmitis [85].
5-Fu is a fluorinated pyrimidine analogue that inhibits DNA
synthesis on the S-phase of the cell cycle, in consequence affecting
rapidly proliferating cells, like fibroblast attachment and migration
[103]. The use of 5-FU as an adjuvant to conjunctival autograft post
pterygium excision has had a rate of recurrence compared with low-
dose mitomycin-C (0.01%) [104].
Bevacizumab is a recombinant humanized monoclonal antibody
that inhibits the VEGF induced proliferation of endothelial cells. Sub-
conjunctival injections with anti-VEGF provide another strategy to
manage neovascularization and preventing the pterygium recurrence
[105]. Repeated injections in the first year after surgery may help pre-
vent the high recurrence rate; but side-effects of multiple or increased
doses must be addressed. Subconjuctival injections of bevacizumab
can be complemented with argon laser phototherapy to obliterate spe-
cific conjunctival feeder vessels or intrastromal corneal vessels. The
laser is usually set to repeat mode, 0.1 second duration, 100 microns
spot size, and anywhere between 200 and 900 mW [106-107]. Topi-
cal bevacizumab drops have also been applied to control corneal and
Rare Diseases
conjunctival neovascularization. A 1% solution is administrated once

or twice a day for a period of several weeks to several months [108].
Using only argon laser after pterygium surgery, it was reported
that in 36 patients and 42 eyes the success rate was 92.8% when laser
therapy was employed in recurrent pterygia which were excised once,
while it was 64.2% in cases where excisions were done repeatedly
times, in follow up period of 912 months [109].
Cyclosporine A (CsA) is an immunosuppressive systemic drug
showing a selective effect in preventing T-helper cells activation,
hence avoiding the synthesis and secretion of ILs and also blocking
angiogenic factors. It has been used, as eye drops, in the treatment of
ocular surface disorders such as dry eye syndrome, vernal keratocon-
junctivitis, corneal ulcers, herpetic stromal keratitis. Recently, CsA
have been used in the treatment of pterygium to prevent recurrence,
showing good results using doses as low as 0.05% [110-112].
Fonseca et al. have recently published a network meta-analysis
comparing most use adjuvant treatments in combination with bare
sclera excision, conjunctival autograft or amniotic membrane graft.
They presented a ranked from best to worse treatment to prevent the
recurrence, and they have postulated that the best adjuvant treatment
to prevent recurrence after primary pterygium surgery is the associa-
tion of conjunctival autograft and ciclosporin 0.05% eye drops. Bare
sclera technique alone should be discontinued since it is associated
with high recurrence rates [113].
Patient management after pterygium surgery also includes an an-
tibiotic, a steroid and nonsteroidal anti-inflammatory drug (NSAID).
Doses administrated depend on the commercial product, and it has
been suggested that antibiotic and NSAID should be discontinued af-
ter 1 week [89].
Doxycycline, a broad spectrum antibiotic, can be a useful ad-
junct in oral administration, due to its beneficial non antimicrobial ef-
fects, including anti-inflammatory, anticollagenase, meibomian lipid
Rare Diseases
viscosity reduction, vascular stabilization, and anti-MMP 9 activities.

Doxycycline is preferred over tetracycline or minocycline because
of its superior efficacy, more versatile dosing, and a somewhat more
favorable side effect profile [114]. Also, it has been recently demon-
strated in a pterygium murine model that doxycycline can inhibit the
pterygium anterior segment growth, suggesting that this antiobiotic
may be successful in the disease treatment [115]. Topical azithromy-
cin has proven useful, for the same menu of non-antimicrobial ben-
efits offered by oral doxycycline. It is particularly useful for patients
who are intolerant to oral doxycycline. Prolonged therapy can be use-
ful but is often impractical due to cost. Many chronic patients benefit
from 1 week per month of topical azithromycin during a year round
[116-117].
Intraoperative or post operative subconjunctival steroid injec-
tions provide excellent inflammation control in addition to topical
therapy, allowing a significant reduction in the intensity of the post-
operative steroid regimen [118-119].
Conclusions
Although the pathogenesis of pterygium has been studied for
many years, its still remains uncertain. A wide range of pathogenic
factors have been proposed, including high exposure to ultraviolet
radiation (UVR), viral infections, epigenetic aberrations, epithelial-
mesenchymal transition, deregulation of extracellular matrix (ECM)
modulators and growth factors, immunologic and anti-apoptotic
mechanisms, angiogenic and lymphangiogenic stimulation, inflam-
mation cascades, recruitment of bone-marrow-derived stem- and
progenitor cells, and modifications in the cholesterol metabolism.
Since there are some discrepancies among the involvement of diverse
factors it is possible that there could be different pterigia with various
geneses.
Rare Diseases
References
1. Spalton DJ, Hitchings RA, Hunter PA. Atlas of Clinical Oph-
thalmology. Kidlington: Mosby/Elsevier. 2015.
2. Dzunic B, Jovanovic P, Veselinovic D, Petrovic A, Stefanovic
I, et al. Analysis of pathohistological characteristics of
pterygium. Bosn J Basic Med Sci. 2010; 10: 307-313.
3. Mills SE. Histology for Pathologists. 3rd edn. Philadelphia,
PA: LW Wilkins. 2007.
4. Krenzer KL, Freddo TF. Patterns of cytokeratin expression
in impression cytology specimens from normal human con-
junctival epithelium. Adv Exp Med Biol. 1994; 350: 289-292.
5. Chen WY, Mui MM, Kao WW, Liu CY, Tseng SC. Conjunc-
tival epithelial cells do not transdifferentiate in organotypic
cultures: expression of K12 keratin is restricted to corneal
epithelium. Curr Eye Res. 1994; 13: 14.
6. Donisi PM, Rama P, Fasolo A, Ponzin D. Analysis of limbal
stem cell deficiency by corneal impression cytology. Cornea.
2003; 22: 533-538.
7. Chen Z, de Paiva CS, Luo L, Kretzer FL, Pflugfelder SC, et al.
Characterization of putative stem cell phenotype in human
limbal epithelia. Stem Cells. 2004; 22: 355-366.
8. Yoshida S, Shimmura S, Kawakita T, Miyashita H, Den S, et
al. Cytokeratin 15 can be used to identify the limbal pheno-
type in normal and diseased ocular surfaces. Invest Oph-
thalmol Vis Sci. 2006; 47: 4780-4786.
9. Barbaro V, Ferrari S, Fasolo A, Pedrotti E, Marchini G, et al.
Evaluation of ocular surface disorders: a new diagnostic tool
based on impression cytology and confocal laser scanning
microscopy. Br J Ophthalmol. 2010; 94: 926-932.
Rare Diseases
10. Ramirez-Miranda A, Nakatsu MN, Zarei-Ghanavati S,

Nguyen CV, Deng SX. Keratin 13 is a more specific marker
of conjunctival epithelium than keratin 19. Mol Vis. 2011;
17: 1652-1661.
11. Turner HC, Budak MT, Akinci MA, Wolosin JM. Compara-
tive analysis of human conjunctival and corneal epithelial
gene expression with oligonucleotide microarrays. Invest
Ophthalmol Vis Sci. 2007; 48: 2050-2061.
12. Cvekl A, Callaerts P. PAX6: 25th anniversary and more to
learn. Exp Eye Res. 2017; 156: 10-21.
13. Li W, Hayashida Y, Chen YT, Tseng SC. Niche regulation of
corneal epithelial stem cells at the limbus. Cell Res. 2001;
17: 26-37.
14. Ouyang H, Xue Y, Lin Y, Zhang X, Xi L, et al. WNT7A and
PAX6 define corneal epithelium homeostasis and pathogen-
esis. Nature. 2014; 511: 358-361.
15. Dorland’s illustrated medical dictionary. In: Illustrated
medical dictionary. Philadelphia, PA : Saunders. 2007.
16. Hecht F, Shoptaugh M. Winglets of the eye: dominant trans-
mission of early adult pterygium of the conjunctiva. Journal
of Medical Genetics. 1990; 27: 392-394.
17. Ozgurhan EB, Kara N, Bozkurt E, Gencer B, Agca A, et al.
Effect of fluorometholone/tetrahydrozoline fixed combina-
tion on conjunctival autograft morphology after primary
pterygium excision. Biomed Res Int. 2013; 481843.
18. Bradley JC, Yang W, Bradley RH, Reid TW, Schwab IR. The
science of pterygia. Br J Ophthalmol. 2010; 94: 815-820.
19. Ratnakar KS, Goswamy V, Agarwal LP. Mast cells and
pterygium. Acta Ophthalmol (Copenh). 1976; 54: 363-368.
20. Yanoff M, Sassani JW. Ocular pathology. London: Elsevier
Saunders. 2015.
Rare Diseases
21. Cameron ME. Pterygium Throughout the World. Spring-

field: The Charles C Thomas Publishers. 1965.
22. Cajucom-Uy H, Tong L, Wong TY, Tay W T, Saw SM. The
prevalence of and risk factors for pterygium in an urban
Malay population: the Singapore Malay Eye Study (SiMES).
Br J Ophthalmol. 2010; 94: 977-1781.
23. Huang TL, Hsu SY, Tsai RK, Sheu MM. Etiology of ocular
diseases in elderly Amis aborigines in Eastern Taiwan (The
Amis Eye Study). Jpn J Ophthalmol. 2010; 54: 266-271.
24. Hussain A, Awan H, Khan MD. Prevalence of non-vision-
impairing conditions in a village in Chakwal district, Pun-
jab, Pakistan. Ophthalmic Epidemiol. 2004; 11: 413-426.
25. Liang QF, Xu L, Jin XY, You QS, Yang X H, et al. Epidemiol-
ogy of pterygium in aged rural population of Beijing, China.
Chin Med J (Engl). 2010; 123: 1699-1701.
26. Luthra R, Nemesure BB, Wu SY, Xie SH, Leske MC, et
al.Frequency and risk factors for pterygium in the Barbados
Eye Study. Arch Ophthalmol. 2001; 119: 1827-1832.
27. McCarty CA, Fu CL, Taylor HR. Epidemiology of pterygium
in Victoria, Australia. Br J Ophthalmol. 2000; 84: 289-292.
28. Panchapakesan J, Hourihan F, Mitchell P. Prevalence of
pterygium and pinguecula: the Blue Mountains Eye Study.
Aust N Z J Ophthalmol. 1998; 26: S2-5.
29. Saw SM, Tan. Pterygium: prevalence, demography and risk
factors. Ophthalmic Epidemiol. 1999; 6: 219-228.
30. Singh MM, Murthy GV, Venkatraman R, Rao SP, Nayar S.
A study of ocular morbidity among elderly population in a
rural area of central India. Indian J Ophthalmol. 1997; 45:
61-65.
31. Viso E, Gude F, Rodriguez-Ares MT.Prevalence of pinguec-
ula and pterygium in a general population in Spain. Eye
(Lond). 2011; 25: 350-357.
Rare Diseases
32. Wong TY, Foster PJ, Johnson GJ, Seah SK, Tan DT. The prev-
alence and risk factors for pterygium in an adult Chinese
population in Singapore: The Tanjong Pagar survey. Am J
Ophthalmol. 2001; 131: 176-183.
33. Wu K, He M, Xu J, Li S. The epidemiological characteris-
tic of pterygium in middle aged and the elderly in Doumen
County. J Clin Ophthalmol. 1999; 7: 17-18.
34. Asokan R, Venkatasubbu RS, Velumuri L, Lingam V, George
R. Prevalence and associated factors for pterygium and
pinguecula in a South Indian population. Ophthalmic Phys-
iol Opt. 2012; 32: 39-44.
35. Rezvan F, Hashemi H, Emamian MH, Kheirkhah A, Shariati
M, et al., The prevalence and determinants of pterygium and
pinguecula in an urban population in Shahroud, Iran. Acta
Med Iran. 2012; 50: 689-696.
36. Urrets-Zavalia JA, Knoll EG, Maccio JP, Urrets-Zavalia EA,
Saad JA, et al.Climatic droplet keratopathy in the Argentine
Patagonia. Am J Ophthalmol. 2006; 141: 744-746.
37. Hilgers JH. Pterygium: its incidence, heredity and etiology.
Am J Ophthalmol. 1960; 50: 635-644.
38. Tan DT, Chee SP, Dear KB, Lim AS. Effect of pterygium
morphology on pterygium recurrence in a controlled trial
comparing conjunctival autografting with bare sclera exci-
sion. Arch Ophthalmol. 1997; 115: 1235-1240.
39. Sheppard JD, Mansur A, Comstock TL, Hovanesian JA. A
Comprehensive System for Pterygium Classification. Invest.
Ophthalmol. Vis. Sci. 2004; 45: 2940.
40. Cardenas-Cantu E, Zavala J, Valenzuela J, Valdez-Garcia
JE.Molecular Basis of Pterygium Development. Semin Oph-
thalmol. 2016; 31: 567-583.
Rare Diseases
41. Kwok LS, Coroneo MT. A model for pterygium formation.

Cornea. 1994; 13: 219-224.
42. Li W, Chen YT, Hayashida Y, Blanco G, Kheirkah A, et al.
Down-regulation of Pax6 is associated with abnormal dif-
ferentiation of corneal epithelial cells in severe ocular sur-
face diseases. J Pathol. 2008; 214: 114-120.
43. Bai H, Teng Y, Wong L, Jhanji V, Pang CP, et al. Proliferative
and migratory aptitude in pterygium. Histochem Cell Biol.
2010; 134: 527-535.
44. Josifovska N, Szabo DJ, Nagymihaly R, Vereb Z, Facsko A,
et al. Cultivation and characterization of pterygium as an ex
vivo study model for disease and therapy. Cont Lens Ante-
rior Eye. 2017; 40: 283-292.
45. Perez-Rico C, Pascual G, Sotomayor S, Montes-Mollon MA,
Trejo C, et al. Tropoelastin and fibulin overexpression in the
subepithelial connective tissue of human pterygium. Am J
Ophthalmol. 2011; 151: 44-52.
46. Finney J, Moon HJ, Ronnebaum T, Lantz M, Mure M. Hu-
man copper-dependent amine oxidases. Arch Biochem Bio-
phys. 2014; 546: 19-32.
47. Wang IJ, Hu FR, Chen PJ, Lin CT. Mechanism of abnormal
elastin gene expression in the pinguecular part of pterygia.
Am J Pathol. 2000; 157: 1269-1276.
48. Perez-Rico C, Pascual G, Sotomayor S, Asunsolo A, Ci-
fuentes A, et al. Elastin development-associated extracel-
lular matrix constituents of subepithelial connective tissue
in human pterygium. Invest Ophthalmol Vis Sci. 2014; 55:
6309-6318.
49. Chalkia AK, Spandidos DA, Detorakis ET. Viral involve-
ment in the pathogenesis and clinical features of ophthalmic
pterygium (Review). Int J Mol Med. 2013; 32: 539-543.
Rare Diseases
50. García Carmona KP, Romero Guadarrama MB, Rodríguez

Florido MA, Tenorio G. Correlación morfológica del pter-
igión y su evolución clínica. Hosp Gral de México. 2006; 69:
205-211.
51. Nakagami T, Murakami A, Okisaka S, Ebihara N. Mast cells
in pterygium: number and phenotype. Jpn J Ophthalmol.
1999; 43: 75-79.
52. Acera A, Rocha G, Vecino E, Lema I, Duran JA. Inflamma-
tory markers in the tears of patients with ocular surface dis-
ease. Ophthalmic Res. 2008; 40: 315-321.
53. Black AT, Gordon MK, Heck DE, Gallo MA, Laskin DL, et
al. UVB light regulates expression of antioxidants and in-
flammatory mediators in human corneal epithelial cells.
Biochem Pharmacol. 2011; 81: 873-880.
54. Thakur A, Willcox MD, Stapleton F. The pro inflamma-
tory cytokines and arachidonic acid metabolites in human
overnight tears: homeostatic mechanisms. J Clin Immunol.
1998; 18: 61-70.
55. Yoshizumi M, Nakamura T, Kato M, Ishioka T, Kozawa K.
Release of cytokines/chemokines and cell death in UVB-
irradiated human keratinocytes, HaCaT. Cell Biol Int. 2008;
32: 1405-1411.
56. Holopainen JM, Robciuc A, Cafaro TA, Suarez MF, Kont-
tinen YT, et al. Pro-inflammatory cytokines and gelatinases
in climatic droplet keratopathy. Invest Ophthalmol Vis Sci.
2012; 53: 3527-3535.
57. Di Girolamo N, Kumar RK, Coroneo MT, Wakefield D.
UVB-mediated induction of interleukin-6 and -8 in ptery-
gia and cultured human pterygium epithelial cells. Invest
58. Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Patho-
genesis of pterygia: role of cytokines, growth factors, and
Rare Diseases
matrix metalloproteinases. Prog Retin Eye Res. 2004; 23:

195-228.
59. Kria L, Ohira A, Amemiya T. Immunohistochemical lo-
calization of basic fibroblast growth factor, platelet derived
growth factor, transforming growth factor-beta and tumor
necrosis factor-alpha in the pterygium. Acta Histochem.
1996; 98: 195-201.
60. Chiang CC, Cheng YW, Lin CL, Lee H, Tsai FJ, et al. Cy-
clooxygenase 2 expression in pterygium. Mol Vis. 2007; 13:
635-638.
61. Fox T, Gotlinger KH, Dunn MW, Lee OL, Milman T, et al.
Dysregulated heme oxygenase-ferritin system in pterygium
pathogenesis. Cornea. 2013; 32: 1276-1282.
62. Siak JJ, Ng SL, Seet LF, Beuerman RW, Tong L. The nuclear-
factor kappa B pathway is activated in pterygium. Invest
63. Abeyama K, Eng W, Jester JV, Vink AA, Edelbaum D, et al. A
role for NF-kappaB-dependent gene transactivation in sun-
burn. J Clin Invest. 2000; 105: 1751-1759.
64. Torres J, Enriquez-de-Salamanca A, Fernandez I, Rodri-
guez-Ares MT, Quadrado MJ, et al. Activation of MAPK
signaling pathway and NF-kappaB activation in pterygium
and ipsilateral pterygium-free conjunctival specimens. In-
vest Ophthalmol Vis Sci. 2011; 52: 5842-5852.
65. Di Girolamo N, Wakefield D, Coroneo MT. UVB-mediated
induction of cytokines and growth factors in pterygium epi-
thelial cells involves cell surface receptors and intracellular
signaling. Invest Ophthalmol Vis Sci. 2006; 47: 2430-2437.
66. Bamdad S, Khademi B, Chenari N, Taseh A, Razmkhah
M. Stromal cell derived factor-1, CXCR4 and CXCR7 gene
transcripts in pterygia. J Curr Ophthalmol. 2017; 29: 28-32.
Rare Diseases
67. Bianchi E, Scarinci F, Grande C, Plateroti R, Plateroti P, et

al. Immunohistochemical profile of VEGF, TGF-beta and
PGE(2) in human pterygium and normal conjunctiva: ex-
perimental study and review of the literature. Int J Immuno-
pathol Pharmacol. 2012; 25: 607-615.
68. Beden U, Irkec M, Orhan D, Orhan M. The roles of T-lym-
phocyte subpopulations (CD4 and CD8), intercellular ad-
hesion molecule-1 (ICAM-1), HLA-DR receptor, and mast
cells in etiopathogenesis of pterygium. Ocul Immunol In-
flamm. 2003; 11: 115-122.
69. Lee H, Lee M, Lee Y, Choi S, Yang J. Chondrocyte-derived
extracellular matrix suppresses pathogenesis of human
pterygium epithelial cells by blocking the NF-kappaB sign-
aling pathways. Mol Vis. 2016; 22: 1490-1502.
70. Kim KW, Park SH, Lee SH, Kim JC. Upregulated stromal
cell-derived factor 1 (SDF-1) expression and its interaction
with CXCR4 contribute to the pathogenesis of severe ptery-
gia. Invest Ophthalmol Vis Sci. 2013; 54: 7198-7206.
71. Hynes NE, MacDonald G. ErbB receptors and signaling
pathways in cancer. Curr Opin Cell Biol. 2009; 21: 177-184.
72. Linggi B, Carpenter G. ErbB receptors: new insights on
mechanisms and biology. Trends Cell Biol. 2006; 16: 649-
656.
73. Liu, Z, Xie Y, Zhang M. Overexpression of type I growth
factor receptors in pterygium. Chin Med J (Engl). 2002; 115:
418-421.
74. Heizmann CW, Fritz G, Schafer BW. S100 proteins: struc-
ture, functions and pathology. Front Biosci. 2002; 7: 1356-
1368.
75. Chui J, Di Girolamo N, Wakefield D, Coroneo MT. The
pathogenesis of pterygium: current concepts and their ther-
apeutic implications. Ocul Surf. 2008; 6: 24-43.
Rare Diseases
76. Grimbaldeston MA, Geczy CL, Tedla N, Finlay-Jones JJ,

Hart PH. S100A8 induction in keratinocytes by ultraviolet
A irradiation is dependent on reactive oxygen intermedi-
ates. J Invest Dermatol. 2003; 121: 1168-1174.
77. Riau AK, Wong TT, Beuerman RW, Tong L. Calcium-bind-
ing S100 protein expression in pterygium. Mol Vis. 2009;
15: 335-342.
78. Jirtle RL, Skinner MK. Environmental epigenomics and dis-
ease susceptibility. Nat Rev Genet. 2007; 8: 253-262.
79. Riau AK, Wong TT, Lan W, Finger SN, Chaurasia SS, et al.
Aberrant DNA methylation of matrix remodeling and cell
adhesion related genes in pterygium. PLoS One. 2011; 6:
e14687.
80. Li W, Liu J, Galvin JA. Epigenetics and Common Ophthal-
mic Diseases. Yale J Biol Med. 2016; 89: 597-600.
81. Liu MM, Chan CC, Tuo J. Epigenetics in ocular diseases.
Curr Genomics. 2013; 14: 166-172.
82. Peiretti E, Dessi S, Mulas MF, Abete C, Galantuomo MS, et
al. Fibroblasts isolated from human pterygia exhibit altered
lipid metabolism characteristics. Exp Eye Res. 2006; 83: 536-
542.
83. Peiretti E, Dessi S, Putzolu M, Fossarello M. Hyperexpres-
sion of low-density lipoprotein receptors and hydroxy-
methylglutaryl-coenzyme A-reductase in human pinguecu-
la and primary pterygium. Invest Ophthalmol Vis Sci. 2004.
45: 3982-3985.
84. Suarez MF, Piqueras MC, Correa L, Esposito E, Barros MF,
et al. Phospholipidomic Studies in Human Cornea From
Climatic Droplet Keratopathy. J Cell Biochem. 2017; 118:
3920-3931.
Rare Diseases
85. Johnson RD, Pai VC, Hoft RH. Historical approaches to

pterygium surgery, including bare sclera and adjunctive beta
radiation techniques. In: Hovanesian JA, editor. Pterygium:
Techniques and Technologies for Surgical Success. Thoro-
fare: Slack Incorporated. 2012; 27–36.
86. Maheshwari S. Effect of pterygium excision on pterygium
induced astigmatism. Indian J Ophthalmol. 2003; 51: 187–
188.
87. Ang LP, Chua JL, Tan DT. Current concepts and techniques
in pterygium treatment. Curr Opin Ophthalmol. 2007; 18:
308-313.
88. Herman WK, Doughman OJ, Lindstrom RL. Conjunctival
autograft transplantation for unilateral ocular surface dis-
eases. Ophthalmology. 1983; 90: 1121-1126.
89. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival au-
tograft transplantation for advanced and recurrent pterygi-
um. Ophthalmology. 1985; 92: 1461-1470.
90. Hardten DR. Fibrin tissue adhesive. In: H JA, Editor. Pteryg-
ium: Techniques and Technologies for Surgical Success.
Thorofare: SlackIncorporated. 2012; 6.
91. Du Z, Jiang D, Nie A. Limbal epithelial autograft transplan-
tation in treatment of pterygium. Chin J Ophth. 2002; 38:
351–354.
92. Yang Y, Pi M, Xu F. Observation of long-term efficacy of
corneal limbal conjunctival autografts in microscopy treat-
ments of pterygium. Eye Sci. 2013; 28: 73–78.
93. Salagar KM, Biradar KG. Conjunctival autograft in primary
and recurrent pterygium: a study. J Clin Diagn Res. 2013; 7:
2825–2827.
Rare Diseases
94. Kocamis O, Bilgec M. Evaluation of the recurrence rate for

pterygium treated with conjunctival autograft. Graefes Arch
Clin Exp Ophthalmol. 2014; 252: 817–820.
95. Batlle JF. History of amniotic membranes in pterygium
surgery. In: Hovanesian JA, ed, Pterygium: Techniques and
Technologies for Surgical Success. Thorofare: Slack Inc.
2012; 65–78.
96. Kaufman SC, Jacobs DS, Lee WB, Deng SX, Rosenblatt MI,
et al. Options and adjuvants in surgery for pterygium: a re-
port by the American Academy of Ophthalmology. Oph-
thalmology. 2013; 120: 201-208.
97. Arain MA, Yaqub MA, Ameen SS, Iqbal Z, Naqvi AH, et al.
Amniotic membrane transplantation in primary pterygium
compared with bare sclera technique. J Coll Physicians Surg
Pak. 2012; 22: 440–443.
98. Liang W, Li R, Deng X. Comparison of the efficacy of
pterygium resection combined with conjunctival autograft
versus pterygium resection combined with amniotic mem-
brane transplantation. Eye Sci. 2012; 27: 102–105.
99. Netto MV, Mohan RR, Sinha S, Sharma A, Gupta PC, et
al. Effect of prophylactic and therapeutic mitomycin C on
corneal apoptosis, cellular proliferation, haze, and long-
term keratocyte density in rabbits. J Refract Surg. 2006; 22:
562–574.
100. Mastropasqua L, Carpineto P, Ciancaglini M, Enrico Gal-
lenga P. Long term results of intraoperative mitomycin C
in the treatment of recurrent pterygium. Br J Ophthalmol.
1996; 80: 288-291.
101. Rubinfeld RS, Pfister RR, Stein RM, Foster CS, Martin NF,
et al. Serious complications of topical mitomycin-C after
pterygium surgery. Ophthalmology. 1992; 99: 1647-1654.
Rare Diseases
102. Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irra-
diation: new uses for an old treatment: a review. Eye (Lond).
2003; 17: 207-215.
103. Yamamoto T, Varani J, Soong HK, Lichter PR. Effects of
5-fluorouracil and mitomycin C on cultured rabbit subcon-
junctival fibroblasts. Ophthalmology. 1990; 97: 1204-1210.
104. Bekibele CO, Ashaye A, Olusanya B, Baiyeroju A, Fasina O.
5-Fluorouracil versus mitomycin C as adjuncts to conjunc-
tival autograft in preventing pterygium recurrence. Int Oph-
thalmol Clin. 2012; 32: 3-8.
105. Nuzzi R, Tridico F. Efficacy of subconjunctival bevacizumab
injections before and after surgical excision in preventing
pterygium recurrence. J Ophthalmol. 2017.
106. Sourdille P. Pterygoid and pterygium. Treatment using an
argon laser. Bull Soc Ophtalmol Fr. 1974; 74: 189-191.
107. Sheppard JD, Mansur A, Comstock TL, Hovanesian JA. An
update on the surgical management of pterygium and the
role of loteprednol etabonate ointment. Clin Ophthalmol.
2014; 8: 1105-1118.
108. Kim SW, Ha BJ, Kim EK, Tchah H, Kim TI. The effect of
topical bevacizumab on corneal neovascularization. Oph-
thalmology. 2008; 115: e33-38.
109. Saifuddin S, Baum KL. Recurrent pterygia--laser therapy: a
preliminary report. Indian J Ophthalmol. 1993; 41: 17-19.
110. Strong B, Farley W, Stern ME, Pflugfelder SC. Topical cyclo-
sporine inhibits conjunctival epithelial apoptosis in experi-
mental murine keratoconjunctivitis sicca. Cornea. 2005; 24:
80–85.
111. Yalcin Tok O, Burcu Nurozler A, Ergun G, Akbas Kocao-
glu F, Duman S. Topical cyclosporine A in the prevention
of pterygium recurrence. Ophthalmologica. 2008; 222: 391–
396.
Rare Diseases
112. Turan-Vural E, Torun-Acar B, Kivanc SA, Acar S. The ef-

fect of topical 0.05% cyclosporine on recurrence following
pterygium surgery. Clin Ophthalmol. 2011; 5: 881-885.
113. Fonseca EC, Rocha EM, Arruda GV. Comparison among
adjuvant treatments for primary pterygium: a network
meta-analysis. Br J Ophthalmol. 2017. pii: bjophthal-
mol-2017-310288.
114. Rua O, Larrayoz IM, Barajas MT, Velilla S, Martinez A.
Oral doxycycline reduces pterygium lesions; results from a
double blind, randomized, placebo controlled clinical trial.
PLoS One. 2012; 7: e52696.
115. Cox CA, Amaral J, Salloum R, Guedez L, Reid TW, et al.
Doxycycline’s effect on ocular angiogenesis: an in vivo anal-
ysis. Ophthalmology. 2010; 117: 1782-1791.
116. Opitz DL, Tyler KF. Efficacy of azithromycin 1% ophthalmic
solution for treatment of ocular surface disease from poste-
rior blepharitis. Clin Exp Optom. 2011; 94: 200-206.
117. Veldman P, Colby K. Current evidence for topical azithro-
mycin 1% ophthalmic solution in the treatment of blephari-
tis and blepharitis-associated ocular dryness. Int Ophthal-
mol Clin. 2011; 51: 43-52.
118. Kheirkhah A, Nazari R, Safi H, Ghassemi H, Behrouz MJ, et
al. Effects of intraoperative steroid injection on the outcome
of pterygium surgery. Eye (Lond). 2013; 27: 906-914.
119. Paris Fdos S, de Farias CC, Melo GB, Dos Santos MS, Ba-
tista JL, et al.Postoperative subconjunctival corticosteroid
injection to prevent pterygium recurrence. Cornea. 2008;
27: 406-410.
View publication stats

Rard 17 02 Okfinal

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Rard 17 02 Okfinal

Transféré par

Droits d'auteur :

Formats disponibles

See discussions, stats, and author profiles for this publication at: https://www.researchgate.

Pterygium: A Complex and Multifactorial Ocular Surface Disease. A Review on

Chapter · May 2018

Horacio M Serra Maria Fernanda Suarez

SEE PROFILE SEE PROFILE

Juan Pablo Maccio Evangelina Espósito

SEE PROFILE SEE PROFILE

HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target? View project

Epithelium and connective tissues involved diseases View project

The user has requested enhancement of the downloaded file.

#Both authors equally contributed

First Published April 23, 2018

Copyright: © 2018 Horacio Marcelo Serra, et al.

Anatomy and Histology of the Normal

conjunctiva. The palpebral conjunctiva lines the posterior surface of

LSC which are positive for p63, K5/K14/K19, migrate centrip-

The control of elastogenesis is seriously defective in pterygia

disease. There were not significant association between CDK and

Figure 1: Pterygium histological classification. (A) Normal conjunctiva, composed by

Tan et al. classified pterygium according to the morphology

Another classification has taken into account the degree of pro-

Table 1: Clinical Stages of Pinguecula and Pterigyum.

Stage 0 Pingeoculum, posterior to the limbus

Table 2: Pterygium subgroups according to vascularization, thickness of the tissue at

Abnormal Phenotypes of Pterygial Cells

formation of elastic fibers) as well as elastodystrophy (degenerative

Inflammatory Mediators and Growth Fac-

Di Girolamo et al. have demonstrated that pterygium epithelium

scarring [70]. They cultured fibroblasts from excised pterygium grade

such as dry eye, meibomian gland dysfunction, pterygium, and cor-

Lipids Metabolism in Pterygium

who underwent pterygium surgery. We have found that total amount

Ancient, Traditional and Novel Treatments

the-rule (ATR) astigmatism. It can lead to a diplopia by restricting

There has been proposed that conjunctival autograft can be en-

excision surgery alone. This adjuvant can be applied as postoperative

conjunctival neovascularization. A 1% solution is administrated once

viscosity reduction, vascular stabilization, and anti-MMP 9 activities.

10. Ramirez-Miranda A, Nakatsu MN, Zarei-Ghanavati S,

21. Cameron ME. Pterygium Throughout the World. Spring-

41. Kwok LS, Coroneo MT. A model for pterygium formation.

50. García Carmona KP, Romero Guadarrama MB, Rodríguez

matrix metalloproteinases. Prog Retin Eye Res. 2004; 23:

67. Bianchi E, Scarinci F, Grande C, Plateroti R, Plateroti P, et

76. Grimbaldeston MA, Geczy CL, Tedla N, Finlay-Jones JJ,

85. Johnson RD, Pai VC, Hoft RH. Historical approaches to

94. Kocamis O, Bilgec M. Evaluation of the recurrence rate for

112. Turan-Vural E, Torun-Acar B, Kivanc SA, Acar S. The ef-

Vous aimerez peut-être aussi