Journal of Population Therapeutics

& Clinical Pharmacology

REVIEW ARTICLE
DOI: 10.47750/jptcp.2022.968

Update on overview of pterygium and its surgical management

Mitra Akbari
Eye Research Center, Eye Department, Amiralmomenin Hospital, School of Medicine, Guilan University
of Medical Sciences, Rasht, Iran

Corresponding author: Mitra Akbari, Eye Research Center, Eye Department, Amiralmomenin Hospital,
School of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Email: mitra.akbari20@gmail.com

Submitted: 8 August 2022; Accepted: 22 September 2022; Published: 9 November 2022

ABSTRACT
Pterygium is a bulbar conjunctival fibrovascular growth that crosses the limbus and extends onto the
­peripheral cornea, and in some cases leads to significant visual complications. The prevalence of this
disease has been reported to be from 1.2% to about 40% in different parts of the world. Although there
are various risk factors for pterygium, which include ultraviolet (UV) radiation, viral infection, hereditary
factors, immune factors, aseptic inflammation, and environmental irritation, the pathogenesis of pteryg-
ium is mainly related to exposure to UV light. In addition to cosmetic problems, pterygium can lead to eye
irritation, disrupt the transparency of cornea on the pupil area, and cause disorders such as corneal astig-
matism and damage to the visual axis leading to vision impairment. In the last few years, the treatment of
pterygium has been developed and various new solutions have been used. Surgery is the main treatment
for pterygium. Various techniques such as Bare Sclera, Rotational Conjunctival Flap, Limbal Conjunctival
Autograft, Amniotic Membrane Graft, and Free Conjunctival Autograft are used for the removal of pte-
rygium. It also seems that the worrisome problem of recurrence has been significantly reduced with newer
treatment methods. On the contrary, the use of auxiliary treatments such as mitomycin C, b-radiation,
5-fluorouracil, topical use of interferons, and Avastin are also effective in reducing the recurrence rate.
Keywords: Pterygium; risk factors; UV radiation; surgery; recurrence

J Popul Ther Clin Pharmacol Vol 29(4):e30–e45; 09 November 2022.

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Update on pterygium and its surgical management

INTRODUCTION of PubMed, Embase, Web of Science, Scopus, and

Cochrane using the keywords of pterygium, compli-
Pterygium is a common eye disorder, which is
cations, causes, pathophysiology, classification, and
clinically described as a wing-shaped, fleshy, trian-
treatment. Studies published in English that were
gular fibrovascular conjunctival growth that extends
conducted from 1953 to 2022 were analyzed and
over the cornea of the eye and is mostly located on
included in this review.
the nasal side of the conjunctiva.1–4 The pterygium
consists of a body part that is located on the sclera, a
head-like part that attacks the cornea, and a neck part MATERIALS AND METHODS
that includes the superficial limbus. Stocker’s line, A comprehensive search in the online databases,
an epithelial iron deposit at the leading edge of the including PubMed, MEDLINE, Science Direct,
pterygium, is a common clinical feature of pteryg- Scopus, Scielo, and Google Scholar, was performed
ium.1,5 The main components of pterygium include using different keywords, including “pterygium” or
proliferative clusters of limbal stem cells (LSCs), “pterygium surgery” combined with “eye” or “ocu-
epithelial metaplasia, active fibrovascular tissue, lar” or “ophthalmology.” Considering the rapidly
and inflammation and disruption of Bowman’s layer growing body of the literature, only peer-reviewed
along the invasive apex of pterygium.6 Although the reviews and original research articles were included
exact cause of pterygium is unknown, there appears in this study, and case reports, letters, poster pre-
to be an association between outdoor work and the sentations, and editorials were not. Human studies
formation of pterygium, particularly with ultravio- were of priority, but when needed, animal studies
let (UV) radiation.7 Also, various factors, such as were also included. Articles with English full text
viruses, oxidative stress, DNA methylation, apop- published since 1st January 2021 was evaluated for
totic and oncogene proteins, loss of heterozygosity, their appropriateness. Because of the high number
microsatellite instability, inflammatory mediators, of articles on this issue, we attempted to include the
extracellular matrix modifiers, lymphangiogenesis, most important and unique articles in this review.
epithelial-mesenchymal cell transition, and changes
in cholesterol metabolism, play a role in the devel-
PREVALENCE
opment of pterygium.8 In addition to cosmetic prob-
lems, pterygium can lead to eye irritation, disrupt The prevalence of pterygium varies widely
the transparency of the pupil area, and cause dis- according to geography, age, and gender in dif-
orders such as corneal astigmatism; in addition, it ferent populations.7 Although this disease occurs
may rarely lead to visual impairment due to damage worldwide, its prevalence is higher in the “pteryg-
to the visual axis, which in severe cases requires ium belt,” which is between 30 degrees north and
surgery.6,9–11 Due to the importance of this disease, 30 degrees south of the equator.3 In countries near
this review provides a major review on etiologies, the equator, the prevalence of this disease is higher,
risk factors, complications, and surgical manage- which is probably due to exposure to a higher level
ment of pterygium, focusing on the updates and the of UV radiation outdoors.11 It usually occurs in peo-
new features of the literature. Since new methods ple who live in hot and dry climates and may be
and medications are constantly developed to fur- a response to chronic dryness, tear film abnormal-
ther reduce the recurrence of the pterygium after ities, and exposure to sunlight.12 Numerous studies
excision, different methods of pterygium surgery have mentioned pterygium as one of the most com-
and recent adjuvant therapies are discussed in this mon chronic eye diseases in Asia and other coun-
review article. Articles were searched in databases tries located in the pterygium belt.10 The prevalence

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Update on pterygium and its surgical management

of pterygium has been reported from 1.2% to about features of chronic inflammation are also observed
40% in different parts of the world.10 The preva- in pterygium. The presence of chronic inflamma-
lence of pterygium has been reported to be 3% in tion in the pterygium is also caused by factors such
Australians, 23% in African-Americans, 15% in as the presence of lymphocyte purification consist-
Tibetans, 18% in Mongolia, 30% in Japan, and 7% ing of T lymphocytes, plasma cells, and mast cells;
in Chinese and Indian Singaporeans.3 The differ- the increase of newly formed blood vessels and
ence in prevalence could be due to the age differ- fibroblasts; the presence of degenerative collagen
ence in the studied populations.10 On the contrary, fibers; and the presence of abnormal elastic fibers.14
the prevalence of this disease is higher in people The destructive effect of UV rays leads to the reduc-
living in villages, which can be due to differences tion of corneal LSCs, and subsequently causes lim-
in employment conditions, lifestyles of urban and bal failure and activates tissue growth factors that
rural people, seasonal conditions, poverty, and lim- cause angiogenesis and cell proliferation. The pte-
ited access to health services.10 rygium consists of fibrovascular tissue and its col-
lagen fibers often show elastosis. Except for the top
of the pterygium, the rest of its parts are covered
HISTOLOGICAL FEATURES
by conjunctival epithelium. Above the pterygium,
Understanding the histopathological changes a wedge-like extension of fibrous tissue is visible
and clinical features of pterygium may lead to a microscopically, and the head of the pterygium pen-
better understanding of its pathogenesis and pro- etrates the cornea, thus the Bowman’s membrane is
vide more clues for its management strategies (sur- invaded and fragmented.19,20
gical or nonsurgical) in order to reduce recurrence, Although the pathogenesis of pterygium is not
severity of inflammation, tissue invasion, and pro- fully understood, it is believed that in the develop-
liferation.13 The pterygium consists of three sepa- ment of pterygium, corneal epithelial cells acquire
rate parts including cap, head, and body/tail.14 The an altered balance between proliferation and apop-
cap or front edge is a smooth area on the cornea tosis.21,22 The cellular origin of fibroblasts is not only
that is mainly composed of fibroblasts that attack remnants of embryonic origin but may arise from
and destroy Bowman’s membrane. The head is tissue-specific epithelial cells.23 The phenomenon in
a vascular area located behind the cap and firmly which epithelial cells change their phenotype to fibro-
attached to the cornea. The body and tail are mobile blastic cells following morphogenic pressure from
areas of bulbar conjunctiva that are easily separated damaged tissue is called Epithelial-Mesenchymal
from the underlying tissue. Stocker’s line, which Transition (EMT), and it is a common feature of
is iron deposition in the basal layer of the corneal cancer cells.8 EMT is a well-known mechanism that
epithelium in front of the cap, indicates the chro- plays a role in the dispersion of cells during verte-
nicity of pterygium.1,14 Squamous metaplasia has brate embryogenesis and is also observed in adults
also been observed in samples obtained from pte- during the repair of damaged tissue and also in the
rygium.14 Histopathologically, pterygium is a col- early stages of cancer metastasis.23 EMT plays an
lection of altered LSCs with centripetal growth, important role in the pathogenesis of several eye
which is associated with metaplastic and hyper- diseases and is probably involved in cataracts in
plastic epithelium, squamous goblet cells, disrup- humans and mice and subretinal fibrosis after retinal
tion of Bowman’s membrane with abundant active detachment. On the contrary, it has been found that
fibroblasts, stromal inflammation, neovasculariza- limbal epithelial corneal cells (LECs) also undergo
tion, and extracellular matrix metalloproteinases EMT following exposure to air in vitro.21 Also,
(MMPs) activities.15–18 Many histopathological there is a significant difference in the epithelium

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Update on pterygium and its surgical management

and stroma of the connective tissue compared to UV RADIATION

the pterygium in the normal bulbar conjunctiva.
Pterygium occurs due to a wide range of fac-
Pterygium has similarities with tumors due to cell
tors such as sunlight and UV rays, which is why
proliferation, corneal invasion, and recurrence after
pterygium is more common in tropical regions.10
removal. Epithelial proliferation is also important in
The prevalence of pterygium in these areas is esti-
pterygium growth and development. This excessive
mated to be 22% and outside of them, this rate is
cell proliferation occurs in the fibrovascular layer
less than 2%, which indicates that UV rays may
of the pterygium. Fractalkine (CX3CL1) is a mem-
be related to the pathogenesis of pterygium.26,27
ber of chemokines that consists of low molecular
Ultraviolet-A (UVA) and Ultraviolet-B (UVB) are
weight proteins and has two isoforms, a soluble form
the primary subtypes of UV rays that reach the sur-
(related to the cytoplasm) and a form bound to the
face of the eye.6 UVA is an important driver of pig-
cell membrane (CX3CL1 bound to the membrane).
mentation and contributes to premature skin aging,
In many inflammatory conditions, such as athero-
immune system suppression, and carcinogenesis.
sclerosis, rheumatoid arthritis, asthma, osteoarthri-
Unlike UVA, UVB is absorbed by the ozone layer
tis, diabetes and pterygium, fractalkine expression is
and makes up about 1–10% of the total UV radia-
increased. Fractalkine is involved in the transfer of T
tion that reaches the earth’s surface. UVB acts as
cells, natural killer cells, leukocytes, and monocytes
an erythema stimulant and, like UVA, is respon-
from the blood to inflammatory sites in the presence
sible for various biological events, including sun-
of inflammation. It also plays a role in controlling
burn, immunosuppression, and carcinogenesis.25,28
angiogenesis. Through the interaction of a specific
Although early studies focused on the role of UVB
receptor (CX3CR1), fractalkine increases the migra-
in DNA damage and altered intracellular signaling
tion of inflammatory cells and tissue destruction by
in ocular surface diseases, epidemiological studies
increasing the secretion of tumor necrosis factor-­
have shown that both UVB and UVA play a role
alpha (TNF-α), MMPs, and interferon-gamma
in the development of pterygium.6 One of the cru-
(IFN-γ).24 Solar basophilic elastoid degeneration has
cial components of pterygium is abnormal synthesis
also been observed in the pterygium stroma. The
and secondary degeneration of elastic fibers. This
presence of stromal vessels is both a cosmetic and
response has similarities with skin changes caused
a therapeutic goal in the management of pterygium.
by the sun. It is believed that the changes caused by
These vessels are associated with stromal fibrosis, in
Ultraviolet radiation (UVR) in the corneal epithelial
which the vessels are usually more prominent than
stem cells are the driving force for the subsequent
the fibrosis. A mild chronic inflammatory response,
destruction of Bowman’s membrane and elasto-
either in the stroma or in the epithelium, has been
sis.29 The transformation of LSCs is recognized as
present in most cases of pterygium.6
the first biological event in pterygium formation.25
On the other hand, UV radiation can damage LSCs,
RISK FACTORS
change the function of stromal fibroblasts, or induce
Studies have shown that pterygium is associ- inflammatory responses.6 It reaches the LSCs in the
ated with several risk factors, including UV radi- basal layer of the limbus through a transit pathway
ation, viral infection, hereditary factors, immune and can render them ineffective or degenerate. As a
factors, aseptic inflammation, and environmental result of chronic UV light radiation, initially, focal
irritation caused by wind, dust or impact, smoke, LSCs are gradually changed by this radiation. Then,
and dry eye.25 In this section, we examine some of progressive corneal “conjunctivitis” occurs due to
the most important factors. focal limbal barrier dysfunction.25 Light entering

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Update on pterygium and its surgical management

tangentially at the temporal limbus travels across DNA changes in pterygium fibroblasts and may
the anterior chamber of the eye and is focused on the therefore be responsible for their abnormal bio-
contralateral cornea near the nasal limbus.29 Theses logical behavior.25 UV-altered LSCs may activate
rays damage the LSCs and fibroblasts residing in underlying fibroblasts through transforming growth
the nasal limbus, and these changed LSCs (pte- factor-β (TGF-β) and a fibroblast growth factor-­
rygium cells) migrate centrally toward the cornea dependent mechanism (b-FGF), or the injury of
to form a migratory limbus, and a certain number conjunctival epithelial cells may result in changes
of these cells infiltrate the epithelium surrounding in the metabolism of stromal fibroblasts, which is
the limbal and local conjunctiva.25 In addition to revealed by changing the expression of elastin and
interfering with the onset of pterygium, UV radi- collagen fibers.6
ation plays a role in the development of pterygium
through the positive regulation of numerous proin-
INHERITANCE
flammatory cytokines, growth factors, and MMPs.
These factors are involved in inflammation, fibro- Pterygium has previously been considered a
sis, angiogenesis, and ECM regeneration, which degenerative disease. However, this hypothesis has
are the characteristics of pterygium.25 Exposure of been challenged in recent years by the detection of
cells to UVR induces the activation of epidermal critical genetic alterations in pterygium, including
growth factor receptors and subsequent signaling loss of DNA heterozygosity, microsatellites, or over-
through mitogen-activated protein kinase pathways, expression of mutant versions of poorly functioning
which are partially responsible for the expression p53, which can promote tumor growth.30 The role of
of proinflammatory cytokines and MMPs in pte- family history can indicate the association of inheri-
rygium cells. Expression of MMP-2 and MMP-9 tance with the incidence of pterygium.5 The familial
by pterygium fibroblasts is significantly increased occurrence of pterygium was first reported in 1893
after pterygium progression, suggesting their role by Gutierrez-Ponce, who identified five affected men
in disease progression.29 In addition, UVR induces in three generations of the same family.6 Therefore,
mutations in p53 tumor suppressor genes. These it seems that there is a hereditary potential for pte-
genes are involved in DNA repair or apoptosis of rygium. Some pedigrees have shown clear trans-
cells that have a lot of DNA damage. Therefore, mission over several generations, indicating a
if the p53 genes are mutated, they can no longer probable autosomal dominant mode of inheritance.31
contribute to the DNA repair process.29 It has been However, the exact mode of inheritance of pteryg-
found that UV-induced p53 gene mutations may ium and its genetic basis are not fully understood.
also be involved in the development of pterygium Identifying the genetic basis of familial pterygium
cells. Therefore, p53 mutations occur in primary facilitates knowledge about the pathological mecha-
basal LSCs under the influence of chronic focal UV nisms of pterygium development.25 There are various
radiation. Due to the lack of p53-dependent pro- reports of familial occurrence of pterygium.32,33 It is
grammed cell death, mutations in other genes are reported that genetic factors probably lead to abnor-
gradually acquired by altered LSCs, which eventu- malities in the control of proliferation of fibrovas-
ally transform into pterygium cells.25 On the other cular vessels, and UV light also causes the growth
hand, exposure to UV rays is also responsible for of pterygium by inducing growth factors that stim-
the abnormal behavior of pterygium fibroblasts. It ulate fibrovascular proliferation in susceptible indi-
has been found that these fibroblasts have a higher viduals.32 Reproduction between cousins increases
proliferative capacity compared to normal conjunc- the risk of hereditary diseases in a large family. The
tival stromal cells.6 UV radiation induces multiple ratio between pterygium-affected and nonafflicted

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Update on pterygium and its surgical management

individuals in the combined family of pterygium neoplastic disease. Oncogenic viruses or additional
probands is 9:7, which indicates double inheritance UVR exposure that adds further damage to a sus-
(the simplest form of multifactorial inheritance).34 ceptible genetic material may trigger the develop-
Several genes and familial pathways have been pro- ment or recurrence of pterygium30.
posed for pterygium inheritance, and one of the pro-
posed genes is MMP-1. It is believed that a certain
TREATMENT OF PTERYGIUM
polymorphism of the MMP-1 promoter can predis-
pose the carriers to develop pterygium through the The treatment of pterygium is still a controver-
loss of heterozygosity process.6 In a certain number sial issue. In the past, different materials, such as
of families, there may be a dominant mode of pte- romania, akebia, licorice, ginseng, acacia gum, vin-
rygium inheritance. However, this assumption does egar, sweet wood, aloe extract, and salt, have been
not mean that every pterygium occurs as a result of used to remove pterygium.38 Another safe and effec-
hereditary factors. Pterygium can also develop as an tive treatment in the past was to use a material such
acquired pathological condition that is provoked by as thread or horse hair as a Gigli saw to remove the
external factors. It seems that the hereditary poten- pterygium. Later, agents, such as lead-acid, mercury
tial of pterygium is revealed only if exogenous con- lanolin, radiotherapy, thiotepa, 5-fluorouracil, and,
ditions exist and contribute to its growth.26 recently, mitomycin C, have been used for its treat-
ment. The Food and Drug Administration (FDA)2
also considers the administration of mitomycin C in
VIRAL INFECTION
pterygium surgery. The Greeks believed that when
Some reports show the presence of the herpes the pterygium is small, it should be treated with pur-
simplex virus and human papillomavirus (HPV) in gatives, but when it is advanced or hardened, surgery
pterygium samples.35,36 Viruses encode proteins that is needed.38 Nonsurgical treatment of pterygium
inactivate p53, leading to chromosomal instability includes the use of topical lubricating solutions, occa-
and increasing the likelihood of cell progression sional use of vasoconstrictors or mild anti-inflamma-
to malignancy. HPV is often found in the pteryg- tory agents for flare-ups, and protection from UV
ium with different rates of prevalence. Although its rays with sunglasses.2 Nonsurgical treatments may
involvement as a cofactor in the pathogenesis of pte- provide relief, foreign body sensations, and reduction
rygium has been suggested, there are debates in this of inflammation.39 On the other hand, pterygium sur-
field. If HPV is indeed involved in the pathogene- gery is one of the most common eye surgeries per-
sis or recurrence of pterygium, antiviral drugs or formed. However, the reality is that the procedures
vaccination may be new options in the treatment of differ widely. Several techniques have been proposed
pterygium.37 HPV types 16 and 18, which are con- with significant variations among them in terms of
sidered high-risk strains for causing cancer, are the recurrence rate, required surgical time, and patient
most common genotypes reported to be associated comfort. This review shows that the current prefer-
with pterygium.6 These strains encode E6 and E7 ence of ophthalmologists is to completely remove the
proteins and interfere with p53 function.30 A multi- pterygium, including its base, along with removing
stage pathogenetic process, involving genetic inher- the mid-posterior Tenon’s capsule.40
itance, UV radiation, and oncogenic viral infection
has been proposed for the pathogenesis of pteryg-
PTERYGIUM SURGERY AND RECURRENCE
ium. Based on this hypothesis, inherited genetic
changes or exposure to environmental factors such Surgery is the main treatment for pterygium
as UVR can predispose individuals to this benign disease.3 The first documentation of surgical removal

J Popul Ther Clin Pharmacol Vol 29(4):e30–e45; 09 November 2022.

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Update on pterygium and its surgical management

dates back to about 500–1000 BC (by Susruta), like an arrowhead toward the limbus, usually indi-
which is similar to today’s bare sclera technique.41 cate conjunctival recurrence.45 Fibroblast prolifer-
By the 1930s, several surgical techniques were pro- ation and invasion adequately explain the clinical
posed, but none had significant success or efficacy. appearance and behavior of pterygium with his-
These techniques included resection, incision, cau- tological support.34 Most recurrences occur in the
terization, grafting, surgical division, inversion, first 6 months after surgery and are attributed to the
radiation, coagulation, rotation, and chemother- positive regulation of the inflammatory process.46
apy.42 The incision method with simple conjuncti- Surgical trauma and postoperative inflammation
val closure was the most common. The pterygium cause the activation of subconjunctival fibroblasts,
was shaved from the cornea, the damaged conjunc- the proliferation of fibroblast and vascular cells,
tiva was removed from the limbus to the carun- and the deposition of extracellular matrix proteins,
cle, and the defect was closed with sutures. By the which in turn contributes to the recurrence of pte-
mid-1900s, the bare sclera technique had evolved. rygium.47 The reported recurrence rate ranges from
In this method, the head of the pterygium, along 2% for removal with conjunctival autograft tech-
with some abnormal bulbar conjunctiva adjacent nique to 89% for bare sclera technique. Differences
to the nose and Tenon’s tissue that is located under in study methodology, patient characteristics, nature
the abnormal bulbar conjunctiva, was cut entirely.42 of pterygium, geographic region, definition of recur-
Depending on the preference of the patient and the rence, length of follow-up, and loss to follow-up are
surgeon and the complexity of the case, pterygium some of the factors responsible for the widely vary-
surgery can be performed in an operating room ing rates of recurrence.48 Also, recurrence is affected
using local anesthesia.2 An ideal surgical procedure by various factors, which include geographic loca-
for pterygium should be a simple technique with the tion, race, age, and pterygium morphology.42,48 Also,
aim of optimizing aesthetics as much as possible pre-existing lacrimal caruncle deformity, ocular
and minimizing adverse consequences.43 There is motility restriction, concurrent inflammation of the
still no consensus on the ideal way to remove the ocular surface, fibrogenic structure, and family his-
pterygium with the lowest rate of recurrence.3 When tory are among the patient characteristics associated
the pterygium is removed, astigmatism and topo- with recurrence.49 Pterygium recurrence cannot be
graphical irregularity are often reversed and visual successfully predicted based on histological or
acuity improves. While surgical removal can often immunohistological parameters alone, and several
effectively reduce or eliminate symptoms, there are biological characteristics are associated with recur-
complications in achieving safe, aesthetically pleas- rence; thus, related biomarkers should be further
ing, and permanent removal of the pterygium. The evaluated as predictors of recurrence.42 Recurrence
possibility of recurrence of pterygium after surgical after pterygium surgery can occur in the cornea
removal is frustrating for both patients and surgeons. or conjunctiva. Corneal relapses, such as primary
In this regard, many studies have evaluated the risk pterygium, manifest as fibrovascular tissue growth
factors of recurrence.44 Recurrence of pterygium is across the limbus and on the cornea, and conjunc-
defined as the primary complication of surgery, with tival relapses manifest as conjunctival retraction.50
the regrowth of fibrovascular tissue throughout the Kamiya et al. also suggested that a significant myo-
limbus and on the cornea.3 This usually excludes the pic shift can occur postoperatively, postulating cor-
continuation of deeper corneal vessels and corneal neal thickening after pterygium removal as the cause
scarring that may remain even after adequate pte- and the degree of myopic shift is related to pteryg-
rygium resection. Conjunctivochalasis and the for- ium size.51 Gulani and Dastur reported that 63% of
mation of parallel rings of vessels, pointing almost the studied patients achieved a distance-corrected

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Update on pterygium and its surgical management

visual acuity of 6.12 postoperatively, but both astig- CONJUNCTIVAL AUTOGRAFT

matism (ATR and with-the-rule) was greater than 1 TECHNIQUE
diopter (D) in 6 months.52 Kamiya et al. reported tar-
Kenyon et al. first described conjunctival auto-
get correction in only 48% of patient eyes examined
graft as a treatment for pterygium in 1985.55,56 They
at G0.5 D (82% at G1.0 D).51,52 Several surgical tech-
reported a recurrence rate of 5.3% with rare and rel-
niques have been described since the early 1960s,
atively minor complications.47 Since then, this tech-
including the Bare Sclera technique, Rotational
nique has gradually become a popular treatment for
Conjunctival Flap, Limbal Conjunctival Autograft
pterygium.54 Conjunctival transplantation is based
(LCAG), Amniotic Membrane (AM) Graft, and
on the theory of differentiation of conjunctival epi-
Conjunctival Autograft.2,44,53
thelium into corneal epithelium.57 This technique
involves covering the scleral bed with a free graft
BARE SCLERA TECHNIQUE
taken from the adjacent conjunctiva after remov-
Complete removal of the pterygium from the ing the pterygium.6 The conjunctival autograft
cornea and sclera and subsequent exposure of the technique enables the reconstruction of the natu-
corneal scleral surface is a classic surgical pro- ral limbus structure.58 The graft can be fixed to the
cedure. This method, which is also known as the adjacent tissue with sutures or adhesive products.6
bare sclera technique, was first fully described by Compared to bare sclera alone, this method is asso-
D’Ombrain in 1948.54 This technique, which is the ciated with a lower recurrence rate and has greater
first technique used to remove the pterygium, is char- long-term effectiveness. Even if the recurrence rate
acterized by a simple incision, and allows the scleral after conjunctival autograft varies in different clini-
bed to re-epithelialize.49 In general, this technique cal studies, this method is often considered the most
involves removing a part of the bulbar conjunctiva effective method for the treatment of pterygium.49
through the nose, which causes this defect to heal Although conjunctival autograft is effective in pre-
from the surrounding conjunctiva.38 In the bare venting pterygium recurrence, due to fixation, this
sclera technique, the pterygium is removed from technique requires technical expertise and longer
the cornea, conjunctiva, and underlying Tenon’s tis- surgical time, especially when sutures are used. In
sue.2 Sometimes, the conjunctiva is actually sutured fact, due to the need to stabilize the graft, the sur-
to the sclera, leaving a defect, and sometimes the gical time required can be longer than that required
conjunctiva is left free to adhere to the underlying for simple removal of the bare sclera. Also, the cost
sclera.38 For a long time, this treatment method was of the operation and the discomfort of the patients
the method of choice for the treatment of pteryg- are among the disadvantages of this technique.47,49,59
ium, but the high frequency of its recurrence led to However, despite the need for more time and exper-
the search for adjuvant treatment options.54 These tise, this method is associated with a lower recur-
adjuvant therapies included intraoperative mitomy- rence rate compared to the bare sclera technique
cin, postoperative mitomycin, beta radiation, 5-FU, alone.6 Tenon’s tissue associated with the graft
anti-VEGF agents, and cyclosporine.6,38 The advan- may act as a new reservoir for further proliferation
tages of this technique are that it is by far the fastest of fibroblasts and inhibition of pterygium recur-
removal method with the least surgical interven- rence.6 Also, complications caused by conjunctival
tion, and theoretically, it seems to be the easiest and autograft are rare and do not threaten vision.55 The
cleanest removal method. However, this method is main side effects of this method are discomfort and
the least satisfactory for treatment due to the recur- burning of the eye after the operation, granuloma
rence rate, which may vary up to 80%.38 formation, and rarely displacement or rejection of

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Update on pterygium and its surgical management

the transplant.6 However, this method avoids the technique has less twisting effects on the tissues and
unacceptable serious side effects of a single dose has better aesthetic results compared to the conjunc-
of mitomycin C, such as melting of the sclera and tival autograft in the early and late postoperative
the destruction of corneal endothelial cells, and pro- periods. This method can be used as an acceptable
vides a lower recurrence rate and a better aesthetic method for pterygium surgery, especially in patients
result than AM transplantation.60 This technique with insufficient conjunctiva.49 The rotational con-
can be fixed on the level of the scleral bed by differ- junctival flap has been performed since the 1940s
ent methods. Fibrin glue is an alternative synthetic with varying recurrence rates.55,64 Reported recur-
glue (made from donor plasma) that is used for this rence rates range from less than 1% to more than 5%
purpose. Although fixation with fibrin glue requires for this technique. Also, this technique has minimal
a shorter operation time, it has a possible risk of complications; although complications such as flap
infection, hypersensitivity reactions, potential risk retraction and cyst formation have been reported.55
of graft tissue loss, and higher costs.49 In the study The key feature of this technique is that by exten-
conducted by Wanzeler, the results showed that sive resection of Tenon’s capsule beyond the bor-
removal of pterygium using conjunctival autograft der of the conjunctival resection (up to 2 mm at the
and fibrin glue improves symptoms with a high nasal margin), the source of fibrovascular tissue for
satisfaction rate.61 Covering the bare sclera using future recurrence can be reduced. Also, the partial
autologous conjunctival tissue can be done with preservation of the vascular network in the limbal
primary direct closure, sliding conjunctival flap, or anchoring area may play a role in increasing the
free conjunctival autograft. The free graft is usu- survival of the flap and reducing its contraction.63
ally removed from the upper bulbar conjunctiva and In general, this technique is a more challenging
sutured, or after cutting the pterygium, it is attached surgical procedure than the conjunctival autograft,
to the bare scleral defect. It seems that sliding and but once mastered, it requires less surgical time
free grafts are equally effective, but direct conjunc- compared to the conjunctival autograft. The reason
tival closure alone is not as effective as sliding or for this is the difficulty of separating the fibrovas-
free grafts.54 cular tissue from a small graft, the smaller size of
the graft in relation to the bare sclera, and the need
for more sutures to hold the graft in the rotational
ROTATIONAL CONJUNCTIVAL FLAP
method.49 Although there is a consensus that flap
TECHNIQUE
is better than grafting for reconstructive surgery,65
Recently, rotational flaps have been proposed more clinical trials are needed to confirm the supe-
as an alternative to conjunctival autograft in pteryg- riority of flap methods over conjunctival autograft
ium surgery. They are also used to treat tube erosion treatment.44 In a study conducted by Hassanen et
with glaucoma drainage devices.62 In the conjuncti- al., the results showed that after a long period of
val flap technique, instead of completely removing follow-up for autograft and conjunctival flap sur-
the conjunctiva at the donor site, a part of the con- gery, there was no statistically significant difference
junctiva remains attached and the surgeon rotates in terms of the recurrence rate, but the flap tech-
or slides the flap in its position.44 In this technique, nique was associated with less postoperative edema
a rectangular conjunctival flap, related to the bare and was a faster and easier technique.66 A study by
scleral area, is removed from the upper conjunctiva BİLGİN and ŞİMŞEK also showed that autograft
and then rotated through the nose around a limbal and conjunctival flap have advantages and disad-
anchor point and sutured to the bare scleral area vantages and both are effective in preventing recur-
using polyglactin sutures.63 The conjunctival flap rence.67 Also, a study by Abul Naga et al. on the two

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Update on pterygium and its surgical management

techniques of free conjunctival autograft and rota- recurrence rate of pterygium after LCAG shows a
tional conjunctival flap showed comparable results statistically significant advantage compared to AM
in terms of reducing the recurrence rate. These grafts and bare sclera.44 The recurrence rate in this
researchers stated that these two methods are safe treatment method has been reported to be less than
and effective methods for pterygium surgery and 7%.69 Also, in this treatment technique, fibrin glue
have few complications.68 The flap technique can be is used to maintain the limbal conjunctival graft,
safely performed when conjunctival characteristics and this creates a statistically significant reduction
do not allow conjunctival autograft, with similar in recurrence and operation time. Possible compli-
recurrence rates and significantly shorter opera- cations of this technique include hematoma, Tenon’s
tive time. In addition, conjunctival autograft may granuloma, pannus formation, and pseudopteryg-
require peribulbar anesthesia and traction sutures, ium.44 In a meta-analysis performed to compare the
while they are almost unnecessary for the flap tech- rate of pterygium recurrence after LCAG and other
nique. Also, there is no risk of loss and inversion of techniques, the results showed that the rate of recur-
the graft in the flap technique, and the structure of rence after LCAG was lower compared to the bare
the vessels is preserved with a better healing pro- sclera technique, conjunctival autograft, or intra-
cess and a reduction in the risk of graft necrosis. operative mitomycin C. There was no statistically
However, the flap cannot be considered in the case significant difference in the recurrence rate after
of large pterygium where a wider graft is needed.49 LCAG and AM transplantation.71 Fayez conducted
a study to compare the safety and effectiveness of
limbal conjunctival transplantation versus conjunc-
LIMBAL CONJUNCTIVAL AUTOGRAFT
tival autograft for the treatment of pterygium and
TECHNIQUE
reported that with an average follow-up of 62 (with
Another method related to the conjunctival a range of 36–96) months, 10 patients (10%) of the
autograft is the method of LCAG, in which the lim- conjunctival autograft group and 1 patient (1%) of
bal tissue is placed in the source of the transplant the limbal conjunctival group experienced the recur-
and then transferred to the desired site.44 This treat- rence of pterygium. No signs of LSC deficiency were
ment technique was presented by Kenyon et al.69 observed during follow-up. Based on their findings,
The limbal area of the edge of the cornea is approx- the limbal conjunctival technique is safer and more
imately 0.5 mm wide, which is in front of the sclera. effective than the conjunctival autograft technique
In order to understand ocular surface disorders, in preventing recurrence after pterygium removal.60
Noel Rice emphasized the importance of LSCs,
which are vital for normal corneal epithelial regen-
AMNIOTIC MEMBRANE GRAFT
eration. LSCs have been found to play an import-
TECHNIQUE
ant role in the pathogenesis of pterygium.70 In this
technique, the grafts prevent the proliferation of AM grafts were first described by Davis et al.
the remaining tissue, and the addition of LSCs may for use as a surgical material in skin grafts and,
cause faster healing and anatomical reconstruction since 1995, have been increasingly used for the
of the area.44 The added limbal epithelium acts as treatment of a variety of ocular surface conditions
a barrier between the conjunctiva and the cornea, including persistent corneal epithelial defects, acute
and since the lack of LSCs plays an important role chemical burns, and cicatricial conditions such as
in the pathogenesis of pterygium, transplantation Stevens-Johnson syndrome and ocular cicatricial
of these stem cells may restore the barrier and pre- pemphigoid.72 The AM is the innermost layer of the
vent pterygium recurrence.71 In the long term, the placenta (consisting of a thick base membrane and

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Update on pterygium and its surgical management

an avascular stromal matrix) that can be used as a greatly improved the recurrence rate after pteryg-
graft with anti-inflammatory and anti-fibrotic prop- ium surgery, they are not without complications.
erties, and it is also able to provide multiple growth Reported complications include wound dehiscence,
factors and differentiation of epithelial cells with- Tenon’s granuloma, conjunctival cyst, necrotizing
out the risk of immune reactions.42,49 Due to these scleritis, and donor-site subconjunctival fibrosis.72
features, the human AM has been considered use-
ful in several ocular surgeries including pterygium
OTHER ADJUVANT TECHNIQUES AND
and other conjunctival diseases. Typically, it should
TREATMENTS
be placed on the bare sclera, with the basement
membrane facing up and the stroma facing down. Despite advances in surgical instruments,
Fibrin glue may also be used to stabilize the graft microscopes, suture materials, and drugs, as well as
of the AM to the underlying sclera.49 An AM graft techniques developed, studied, and tested in clini-
is usually used to cover the bare sclera. These grafts cal research worldwide, recurrence of pterygium is
may help prevent recurrence through anti-inflam- still considered a serious problem.41 Since the rate of
matory properties, promotion of epithelial growth, recurrence of pterygium after surgery is high, several
suppression of TGF-β signaling, and suppression of adjuvant treatments have been proposed to reduce
fibroblasts, as well as direct contact with fibroblasts the recurrence rate. Among them, mitomycin-C
associated with Tenon’s fascia.44,73 AM grafting is (MMC) and 5-fluorouracil (5-FU) are commonly
also useful for patients with scarred conjunctival used. 5-FU was first synthesized by Dushinski et al.
donor sites, cases that need large grafts, or patients in 1957. This compound is a fluorinated pyrimidine
that need to preserve the conjunctiva for possi- antimetabolite that, when exposed to the cornea,
ble future glaucoma surgery.44 This technique can inhibits the proliferation of conjunctival fibroblasts
be useful during the surgical reconstruction of the and Tenon’s capsule, and also inhibits the prolif-
cutting the pterygium area through a number of eration of corneal epithelial cells. This preventive
mechanisms. The stromal component and the basal action is thought to reduce the rate of recurrence, but
layer covering AM are similar to the structure of the the related recurrence rates have been reported to be
natural human conjunctiva, and they can provide a between 11.4 and 60%.42 Mitomycin (MMC) is an
platform for the growth of the conjunctival epithelial alkylating agent with cytotoxic effects that inhibits
layer and the cornea. The coating property of AM DNA synthesis and is widely used in ophthalmol-
reduces postoperative pain by protecting the scleral ogy. MMC leads to the death of cells caused by the
nerve endings. Probably, the presence of AM may inability to repair the genotoxic damage caused by
create an obstacle to the abnormal growth of con- alkylation. It acts against all cells regardless of the
junctival stem cells in the lower limbus and facilitate cell cycle and even in cells that do not synthesize
the proliferation of normal LSCs.6 It is also poten- DNA.34 Mitomycin C has direct secondary effects
tially a simpler and shorter method than alternative on tissues and is associated with persistent epithe-
methods because this method eliminates the need to lial defects and ischemic necrosis of the sclera.75
prepare a conjunctival graft with the proper thick- Bevacizumab (Avastin) is a human monoclonal
ness and quality for optimal grafting after removing antibody to VEGF that is used intravenously and is
the Tenon’s layer.74 Both conjunctival autograft and mainly approved for the treatment of colorectal can-
AM techniques can be effective in preventing recur- cer. Various clinical studies worldwide have used
rence.73 The recurrence rate of pterygium following bevacizumab for intravitreal injection and have con-
amniotic membrane graft (AMG) has been reported firmed its safety and efficacy in macular degenera-
to be between 14.5 and 27.3%. While grafts have tion and macular edema.34,38 Alsmman et al. reported

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Update on pterygium and its surgical management

that preoperative combined injection of Avastin and factor for the development and progression of this
MMC is safe and effective in reducing postoperative disorder is exposure to UV rays. In many cases, this
recurrence of pterygium. Histological and immuno- disease is treated through surgery and removal of
histological changes were observed in the form of the lesion. One of the important issues related to
decreased fibrovascular activity and degeneration the surgical methods is the recurrence of pterygium
of extracellular matrix and nerve axons.34 Teng et after surgery. Newer treatment and surgical meth-
al. also reported the effectiveness of Bevacizumab ods, such as conjunctival autograft and AM tech-
in the treatment of primary pterygium with a short- niques, have a lower recurrence rate. On the other
term reduction of irritation.76 There are also reports hand, the use of adjuvant treatments such as mito-
of the effect of local use of IFN-α-2b in the treatment mycin C, 5-FU, local use of interferons alpha-2b,
of pterygium.75,77,78 Interferons (IFNs) are cytokinins and Avastin are also effective in reducing the recur-
that are secreted by cells in response to a variety of rence rate.
stressful factors, including infection and tumors.77
They are glycoproteins that have anti-proliferative
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