Expert Review of Ophthalmology

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New treatment options for pterygium

Matthias Fuest, Jodhbir S. Mehta & Minas T. Coroneo

To cite this article: Matthias Fuest, Jodhbir S. Mehta & Minas T. Coroneo (2017) New
treatment options for pterygium, Expert Review of Ophthalmology, 12:3, 193-196, DOI:
10.1080/17469899.2017.1324297

To link to this article: http://dx.doi.org/10.1080/17469899.2017.1324297

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EXPERT REVIEW OF OPHTHALMOLOGY, 2017
VOL. 12, NO. 3, 193–196
https://doi.org/10.1080/17469899.2017.1324297

EDITORIAL

New treatment options for pterygium

Matthias Fuesta,b, Jodhbir S. Mehtaa,c,d,e and Minas T. Coroneof
a
Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore; bDepartment of Ophthalmology, RWTH Aachen University,
Aachen, Germany; cSingapore National Eye Centre, Singapore; dEye-ACP, Duke-NUS Graduate Medical School, Singapore; eSchool of Material
Science and Engineering, Nanyang Technological University, Singapore; fDepartment of Ophthalmology, University of New South Wales, Sydney,
Australia

ARTICLE HISTORY Received 14 January 2017; accepted 25 April 2017

KEYWORDS Cornea; pterygium; surgery; ocular surface; inflammation

1. Introduction of 0.53 (95% confidence interval [CI]: 0.33–0.85; p = 0.009) at

6-month follow-up and recurrence rates from 3.33% to 16.7%
A pterygium is a wing-shaped corneal incursion of an aberrant
in the CAG and 2.6% to 42.3% in the AM group [6]. Therefore,
conjunctival wound healing response, characterized by the
thorough pterygium and Tenon’s tissue removal combined
centripetal growth of an altered squamous epithelium with
with a CAG transplantation is currently considered the gold
goblet cell hyperplasia and an underlying stroma of activated
standard surgical procedure.
proliferating fibroblasts, neovascularization, inflammatory
Attempts have been made to further standardize and
cells, and extracellular matrix [1]. However, the precise patho-
improve the CAG procedure.
genesis remains unclear.
An important factor for successful pterygium surgery is the
Although seen worldwide, it is commonly found in the peri-
ability to dissect a thin and accurately sized graft to cover the
equatorial latitudes, at high altitude, and in highly reflective
conjunctival defect with minimal inclusion of Tenon’s tissue [7].
environments, due to elevated levels of ultraviolet radiation, a
The resulting thin, tension-free grafts have been shown not to
known risk factor [1]. The proliferation of pterygium tissue can
subsequently retract after surgery, providing a good cosmetic
cause changes in corneal topography and refraction, occlusion
outcome with low recurrence rates [7].
of the visual axis as well as visual field loss, corneal scarring,
However, dissecting such thin grafts with minimum Tenon’s
and consequently reduction in visual acuity [1,2]. In advanced
tissue requires considerable surgical skill and is associated
cases, scarring of the ocular surface can also lead to symble-
with a substantial learning curve [7], which was also described
pharon formation, reduction of motility, and diplopia [3]. In
by Kuo et al. in a porcine cadaveric eye teaching model [8]. A
addition to these issues, pterygium can cause chronic inflam-
trainee needed approximately 50 attempts to reach desirable
mation, a dry eye state, and discomfort as well as cosmetic
CAG thicknesses of 87 ± 23 μm [8].
concerns for the patient [4].
Our group recently demonstrated a fast, accurate, and reli-
Currently, the definitive management of a patient with
able technique to achieve a thin CAG (≈70 µm) with the Z8
pterygium is surgical [2,3].
femtosecond laser (FSL) (Ziemer Ophthalmic Systems AG, Port,
Advancements in the treatment of pterygium have
Switzerland) in a porcine model [9]. The procedure proved
involved (i) the surgical procedure (ii) the use of adjuvants,
independent of surgeon experience. A clinical trial for femto-
and (iii) medication.
second laser-assisted pterygium surgery (FLAPS,
NCT02866968) has been initiated.
2. Surgical technique Preliminary results of the first six eyes have been promising
[10]. FLAPS succeeded in all patients. CAGs with a mean
For many years, a bare sclera technique, in which the ptery-
thickness of 75.6 ± 13.7 µm were dissected in 19.5 ± 1.2 s by
gium was simply excised from the cornea, leaving only bare
the FSL. No buttonholes or CAG tags occurred during surgery.
sclera exposed was the standard approach [3]. However, there
The epithelium had healed at the CAG resection site within
were unacceptably high recurrence rates of up to 88% within -
1 week in all patients. During the time of follow-up, no post-
1 year postoperatively [2,5]. Hence, alternative reconstructive
operative complication or recurrences occurred. There were
surgical procedures were sought including the use of a amnio-
minimal inflammation and no evidence of scarring at the
tic membrane (AM) or a conjunctival autograft (CAG) onto the
conjunctival graft harvest site. The results indicated that the
bare sclera. This led to a significant reduction in recurrence
FSL can assist to standardize pterygium surgery in order to
rates [2,6]. A recent Cochrane meta-analysis of 1947 eyes of
obtain a thin CAG; however, further long-term studies are
1866 patients revealed superiority of CAG over AM with a risk
needed to assess the effects on recurrence rates.
ratio (RR) for recurrence of pterygium (primary and recurrent)

CONTACT Minas T. Coroneo m.coroneo@unsw.edu.au Department of Ophthalmology, University of New South Wales, Prince of Wales Hospital, High St,
Randwick, NSW 2031, Australia
© 2017 Informa UK Limited, trading as Taylor & Francis Group
194 M. FUEST ET AL.
In an alternative approach to increasing precision, Bourcier
et al. investigated the use of robot-assisted (da Vinci surgical
system) pterygium surgery in a porcine model [11] and
recently in a patient [12]. While they found the procedure to
be feasible and no complications occurred, the surgery time
(porcine model: 36 min, patient: 60.5 min) still limits its appli-
cation in routine clinical cases. In particular, the CAG prepara-
tion time in the porcine model (7 min) took substantially
longer than our FSL-assisted grafts (19.5 ± 1.2 s [10]) or
manual dissection (126–191 s [8]).
Nevertheless, FLAPS and robotic pterygium surgery to date
are still experimental and need significantly more clinical evi-
dence before being suggested as preferred surgical techniques.
A variation to the standard CAG technique introduced by
Hirst emphasized extensive tenonectomy and pterygium
resection followed by the transplantation of a large CAG,
which led to very low recurrence rates (0.1% for 1000
patients), including primary and recurrent cases [13]. Early
indications are that this experience is reproducible in other
centers [14]. Some drawbacks include a steep learning curve,
increased pain, and transient diplopia from extensive surgery,
as well as elevated intraocular pressure (from prolonged ster-
oid usage of up to 9 weeks) and the need for an assistant and
long surgery times for up to an hour for primary pterygium
cases [13]. However, long-term complication rates are very low
with single cases (0.1%) of exotropia, granuloma, inclusion
cyst, corneal ulcer, and prolonged inflammation (0.3%) being
reported [13,14].
Limbal conjunctival autografting (LCAG) is a procedure very
similar to standard CAG surgery, where limbal tissue is
included in the transplant [15]. It is hypothesized that the
graft prevents the residual tissue from proliferating, and the
addition of limbal stem cells may promote faster healing and
reconstruct the area anatomically, creating a barrier for the
recurrence of conjunctival incursions. While controversial,
there is evidence that LCAG is more effective than CAG for
treatment of recurrent pterygium [2,15].
A recent study for patients with multi-recurrent pterygia
found that the implantation of multi-microporous expanded
polytetrafluoroethylene between AM and conjunctiva in con-
junction with mitomycin C and a conjunctival limbal autograft
led to significantly lower recurrence rates from 25% to 3.3%
(p = 0.027) and also reduced symblepharon (p = 0.024), moti-
lity restriction (p = 0.027), and hyperemia (p < 0.001) [16].
In a recent Cochrane meta-analysis, Romano et al. evalu-
ated 14 randomized controlled trials (RCTs) and found that
using the combination of fibrinogen and thrombin for CAG
fixation resulted in lower recurrence rates (RR 0.47; 95% CI:
0.27–0.82; p = 0.0076) and quicker surgery (mean difference
17.01 min, 95% CI: −20.56 to −13.46; p < 0.001), as well as less
postoperative discomfort than suturing [17]. Different types of
fibrin glue behave similarly [18]. However, fibrin glue may lead
to more complications, including graft dehiscence, graft
retraction, and granuloma compared with sutures (RR 1.92;
95% CI: 1.22–3.02; p = 0.0049) and it is more expensive than
suturing [17,18]. It is speculated that decreased inflammation
associated with the usage of glue may help to avoid recur-
rence [17,18].
The use of fibrin glue and mitomycin C in ophthalmic appli-
cations is considered an off-label use by the US FDA. Autologous
blood, containing fibrinogen and thrombin, could replace fibrin
glue in the future, reducing costs and potential infectious agent
transmission by fibrin glue. However, to date, evidence compar-
ing autologous blood to fibrin glue or sutures is sparse. Small
RCTs have shown recurrence rates between autologous blood
and fibrin glue or sutures to be equal. These studies have also
reported that autologous blood took longer time than fibrin
glue to produce adherence, but autologous blood attached
the graft faster than sutures [3]. Larger clinical trials are needed
to assess the benefits and risks of autologous blood before its
use is widely recommended.
3. Adjuvants
Adjuvant therapies have become an important part of ptery-
gium surgical management. Adjuvants studied include mito-
mycin C, 5-fluorouracil, β-irradiation, dobesilate, ranibizumab,
and bevacizumab [2,3]. Not all have been able to effectively
reduce recurrence, and several carry serious known and pos-
sible unknown side effects. The evidence for most of these
studies is of poor quality for the use of these therapies.
However, a 2013 Ophthalmic Technology Assessment by
Kaufman et al. [2] from the American Academy of
Ophthalmology evaluating 51 studies found evidence that the
intra- or postoperative application of mitomycin C could further
decrease recurrence rates in conjunctival or limbal autografting.
Increased concentrations and duration of exposure to intrao-
perative mitomycin C improved outcomes [2]. However, the use
of mitomycin C was also associated with the occurrence of
potential vision-threatening complications, including scleral
thinning and ulceration (2–19%), iritis (1–3%), as well as delayed
conjunctival epithelialization (4–5%), and there was some evi-
dence of increasing complications with increased concentra-
tions and duration of exposure [2].
The application of β-irradiation was less frequently used
than other adjuvant therapies because it is less convenient
for providers and patients. However, in a review of 16 studies
covering 6000 cases over a 30-year period, Ali et al. found a
significant reduction in recurrences when fractionated 30 Gy
doses in three fractions were given over 2 to 3 weeks follow-
ing pterygium surgery [19]. Reported complications of treat-
ment with β-irradiation include conjunctival congestion and
delayed epithelial healing, but these often spontaneously
resolve, as well as more serious complications such as scleral
ulceration, scleromalacia, necrosis, and cataract, which appear
to increase in prevalence with time [19].
Vascular endothelial growth factor (VEGF) is increased in
pterygia, and the anti-VEGF antibodies ranibizumab and bev-
acizumab have been used for treatment. Regression of pter-
ygium growth and lower recurrence rates following the
application of anti-VEGFs have been described in small case
series. However, a meta-analysis of 474 patients with 482 eyes
in nine RCTs found no beneficial effect [20]. In addition, cor-
neal defects, erosions, and melts have been reported with
their use [3,20], as well as CAG compromise [21].

4. Medication
Postoperative inflammation leads to the recurrence of ptery-
gium [4]. Consequently, different topical steroid regimens
have been suggested to control inflammation after pterygium
surgery. Hirst used topical prednisolone acetate every 2 h for
3 weeks and then four times daily for a further 6 weeks [13].
Kheirkhah et al. used prednisolone acetate every 2 h for a
longer period of 4–6 weeks [4]. In some reports, other routes
of steroid administration, such as subconjunctival injection,
were used as an additional method to halt postoperative
inflammation [22]. However, larger RCTs to evaluate an opti-
mal postoperative steroid treatment are still lacking.
Kampitak et al. recently demonstrated a reduction in recur-
rence rate by 50% (p = 0.018) through additionally applying
lubricant eye drops after steroid instillation for a postoperative
period of 3 months [22], highlighting the importance of an
adequate ocular surface management following pterygium resec-
tion. This is consistent to some extent with findings of a beneficial
effect of topical cyclosporine in reducing recurrence [23].
Recent analyses suggest the occurrence of alterations and
mutations in critical regulatory processes such as the S100
proteins, MAPK signal pathway, p53, or ras oncogenes in pter-
ygium, which are associated with neoplastic conditions [24].
Inhibition of these underlying molecular mechanisms represents
a possible approach for future medical treatments of pterygium,
which could further reduce recurrence with the use as adjuvants
or eventually even replace surgical treatment. APR-246/PRIMA-
1Met a small molecule that is capable of restoring the sequence-
specific DNA-binding and transcriptional transactivation by
mutant p53 in tumor cells, for example, reduced squamous
metaplasia in human pterygium explant cultures [24].
5. Conclusion
Conjunctival autografting represents the current gold standard
treatment for pterygium. Fibrin glue instead of suturing can
further reduce recurrence rates and surgery time. Adequate
management of the ocular surface and postoperative inflamma-
tion is important for low recurrence rates and good cosmesis.
Mitomycin C is a widely used adjuvant, particularly in recurrent
disease, although its use remains controversial. New procedures
are currently being developed to improve and standardize the
surgical procedures, possibly introducing FSLs or robots to the
surgical procedure in the future. Better understanding of the
molecular mechanism behind pterygium could bring future
medical treatments within reach.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
EXPERT REVIEW OF OPHTHALMOLOGY 195
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