Acta Ophthalmologica 2009

Occurrence of human
papillomavirus in pterygia
Marta Piecyk-Sidor,1 Magorzata Polz-Dacewicz,2
1
_
Zbigniew Zagorski1 and Tomasz Zarnowski
1

Tadeusz Krwawicz Chair of Ophthalmology and First Eye Hospital, Medical

University of Lublin, Poland
2
Department of Virology, Medical University of Lublin, Poland

ABSTRACT.
Purpose: The aim of the study was to assess the occurrence of human papillomavirus (HPV) DNA in pterygium.
Methods: The study involved 89 patients undergoing surgical procedures at the
Department of Ophthalmology, Medical University of Lublin, Poland. Group
1 included 58 patients with clinically diagnosed pterygium. Group 2 consisted
of 31 individuals with normal conjunctiva. The material was collected during
elective surgical procedures. The presence of HPV genome was determined
using polymerase chain reaction (PCR). Once the presence of HPV DNA was
conrmed, 28 HPV genotypes were determined using reverse hybridization.
Results: The determinations conrmed the presence of HPV DNA in pterygium. In the material collected from 58 cases of pterygium (group 1), HPV
DNA was identied in 16 patients (27.6%). In the material from 31 diagnostic
specimens of normal conjunctiva (group 2), the presence of HPV was demonstrated in three cases (9.7%). A statistically signicant difference was found
in the presence of HPV DNA between the patients from groups 1 and 2
(p = 0.041). HPV type 16 was most common and was demonstrated in 56%
of HPV-positive cases of pterygium. HPV 16 and HPV 6 co-infections were
found in 19% of cases, while HPV 18 and HPV 6 co-infections were observed
in 13%. In group 2, all three patients with HPV showed HPV 18.
Conclusion: It seems that HPV is not necessary to induce pterygium; however,
it might play a synergistic role in the multi-stage process of its development.
Key words: human papillomavirus occurrence PCR pterygium

Acta Ophthalmol. 2009: 87: 890895

2009 The Authors
Journal compilation 2009 Acta Ophthalmol

doi: 10.1111/j.1755-3768.2008.01372.x

Introduction
Pterygium is a brovascular lesion of
the eye surface that tends to increase in
size and recur after surgical removal.
The Bowman membrane and supercial layers of the cornea beneath the
lesion are damaged. Visual acuity is
likely to decrease in advanced stages

890

because of the involvement of the

visual axis or astigmatism (Gallagher
et al. 2001; Chan et al. 2002).
Despite the fact that pterygium was
rst observed some 3000 years ago
and has been dealt with in numerous
studies, its pathogenesis has not been
explained fully. It is believed that the

formation of pterygium is a multistage process in which the genetic and

environmental factors (mainly solar
radiation) as well as infections with
oncogenic viruses [human papillomavirus (HPV), herpes simplex virus
(HSV)] are likely to be involved
(Dushku et al. 1999; Detorakis et al.
2000, 2001; Di Girolamo et al. 2004).
Although pterygium belongs to the
eld of degenerative changes, a neoplastic aetiology has been suggested
recently. This is related to the occurrence of histological changes such as
local dysplasia, additional blood supply and recurrence following surgical
removal of the lesion (Chen et al.
1994; Detorakis et al. 2000; Di Girolamo et al. 2004). HPV is implicated as
a causal factor in benign and malignant neoplasms of the cervix, airways,
skin and oral mucosa (Bernard 2005;
Cason & Mant 2005; Chen et al. 2005;
Nair & Pillai 2005). HPV DNA was
detected in squamous cell carcinoma
of the conjunctiva (Saegusa et al. 1995;
Karcioglu & Issa 1997; Ateenyi-Agaba
et al. 2004), epithelial lacrimal sac neoplasia (Sjo et al. 2007a), conjunctival
dysplasia (McDonnell et al. 1992;
Saegusa et al. 1995), conjunctival papilloma (Michel et al. 1996; Dushku
et al. 1999; Buggage et al. 2002; Sjo
et al 2000, 2007b), pterygium and pinguecula (Spandidos et al. 1994; Detorakis et al. 2001; Gallagher et al. 2001;
Piras et al. 2003; Sjo et al 2007c).
No studies concerning the presence
of HPV in ocular lesions have been
carried out in Poland. The group
examined in the present study is one

Acta Ophthalmologica 2009

of the largest populations of patients

with pterygium studied for the presence of the HPV genome worldwide.
The aim of this study was to assess
the incidence of HPV DNA in pterygium and to determine the genotypes
of HPV.

Materials and Methods

The study involved 89 patients undergoing surgical procedures at the I
Department of Ophthalmology, Medical University of Lublin. Group 1
consisted of 58 patients with clinically
diagnosed pterygium [38 male, 20
female; mean age 60.1 years; standard
deviation (SD) 13.1]. In all cases, the
location of pterygium was nasal. Primary pterygium was found in 51 cases
whereas recurrences in seven cases.
Pterygium was divided into three clinical stages according to Donaldson et
al. (2003) [stage I 0 (non-surgical
stage), stage II 30, stage III 28].
Group 2 consisted of 31 individuals with no detectable clinical lesions of the conjunctiva who
underwent surgery because of posttraumatic retinal detachment, macular
hole and strabismus [20 male,
11 female; mean age 55.3 years; SD
15.4]. The normal conjunctiva was
obtained from the region anatomically
corresponding to the occurrence of
pterygium (nasal location, near the
limbus).
No statistically signicant intergroup differences were found between

the presence of pterygium and selected

parameters such as age, sex and place
of residence (Table 1).
The material was collected during
elective surgical procedures. After surgery, tissue specimens (either pterygia
or conjunctiva) were stored at )70C
until isolation. DNA was isolated
using the Sherlock AX kit (DNA
Gdansk, A&A Biotechnology, Gdynia, Poland). The presence of HPV
genome was determined using the
human papillomavirus polymerase
chain reaction (PCR) DEIA kit
according to the manufacturers
instructions (Labo Bio-Medical Products, Rijswijk, Netherlands). The
PCR product was analysed by electrophoresis on 2% agarose gel stained
with ethidinum bromide and viewed
in ultraviolet (UV) transillumination.
Once the presence of HPV DNA
was conrmed, the HPV genotypes
were determined using the INNOLiPA HPV Genotyping v 2Amp kit
(Innogenetics NV, Gent, Belgium),
which allows the detection of the following HPV genotypes: 6, 11, 16, 18,
31, 40, 58, 33, 54, 34, 35, 39, 40, 42,
43, 44, 4, 51, 52, 53, 56, 58, 59, 66,
68, 39, 70 and 74. This test is based
on the reverse hybridization principle.
The results were statistically analysed using the statistica software
(Polska, Krakow, Poland). Statistical
comparisons between groups were performed using v2 Pearson and Fishers
exact test. p < 0.05 was considered
statistically signicant.

Table 1. Comparison of the examined parameters in the pterygium patients (group 1) and in
pterygium-free patients (group 2).
Parameter
Sex
Female
Male
Age (years)
Mean
Age groups (years)
< 40
4049
5059
6069
> 70
Median test Median = 56.0
6
>
Place of residence
Town with > 30 000 inhabitants
Town with < 30 000 inhabitants
Countryside
Number of cases

Group 1

Group 2

20
38
3483
60.1 13.1

11
20
2481
55.3 15.4

v2 = 0.01; p = 0.908

1
17
13
8
19

3
9
8
2
9

v2 = 5.64; p = 0.227

25
33

20
11

v2 = 3.70; p = 0.054

10
14
34
58

8
11
12
31

v2 = 4.78; p = 0.091

Results
The determinations conrmed the
presence of HPV DNA in pterygium.
In the material collected from 58 clinically conrmed cases of pterygium
(group 1), HPV DNA was detected in
16 patients (27.6%). In the material
from 31 diagnostic specimens of the
clinically unchanged conjunctiva (group
2), the presence of HPV was
demonstrated in three cases (9.7%)
(Fig. 1). Analysis of the results
showed statistically signicant differences between the incidence of HPV
DNA in both groups examined (v2
Pearson: 3.859, p = 0.049; Fishers
exact test: p = 0.041).
Amongst seven cases of recurrent
pterygium, HPV 16 was detected in
two cases.
The group of 58 patients with
pterygium
included
20
women
(34.48%) and 38 men (65.52%). The
majority of patients with detected
HPV DNA were male 81.25%
(13 16); female patients constituted
18.75% (3 16). The group with negative results contained 25 (59.52%)
male and 17 (40.48%) female patients
(Table 4) There were no statistically
signicant differences found between
the presence of HPV DNA and sex
(p = 0.12).
Statistically signicant differences in
the presence of HPV DNA were
found between patients living in the
country and those from big towns.
(Chi2 = 4.85,
p = 0.028,
exact
Fischer test p = 0.026). In the
remaining cases, there were signicant
differences between the presence of
HPV DNA and the place of residence
(p = 0.089) (Table 5).
The majority of patients with pterygium and positive as well as negative
HPV DNA results were farmers (56.25%
and 45.24%). White-collar workers constituted the smallest group - 6.25% in
HPV positive group and 11.9% in HPV
negative group (Table 5).
The occurrence of HPV DNA versus to the place of work and versus
UV radiation exposure in patients
undergoing surgery due to pterygium
is presented in table 5.
There were no statistically signicant
differences found between the presence
of HPV DNA and the selected parameters such as age, type and place of
work, length of exposure to UV radiation or rst symptoms of pterygium.

891

Acta Ophthalmologica 2009

100%

80%

60%
HPV ()
HPV (+)

40%

20%

27.60%
9.70%

0%
Patients without
pterygium

Patients with pterygium

Fig. 1. Incidence of human papillomavirus (HPV) DNA in the material from patients with
pterygium (group 1) and without pterygium (group 2). (v2 Pearson: 3.859, p = 0.049; Fishers
exact test: p = 0.041).

In the population studied, HPV

infections of high oncogenic risk were
found in 56.0% (9/16) and mixed
HPV infections of low and high oncogenic potential in 37.5% (6/16) of the
cases; in one case, the HPV co-infection of medium and high oncogenic
potential was observed. The genotype
16 of HPV was most common and
was demonstrated in nine cases of
pterygium. HPV 16 and HPV six
co-infections were observed in three
while HPV 18 and HPV six co-infections in two cases (Fig. 2).
In group 2, all three patients with
HPV showed only HPV type 18.
In the pterygium patients with the
HPV genome, the incidence of genotype 16 was twice as high in clinical
stage III compared to stage II of
pterygium (Table 2).

Discussion
In our study, the presence of HPV
DNA in pterygium was conrmed in

27.6% of cases. Moreover, there was a

statistically signicant difference in the
presence of HPV genome in pterygium
patients compared to those with no
clinical lesions of the conjunctiva.
Many authors reported oncogenic
viruses in pterygium (Table 3). In the
majority of studies, HPV was determined by PCR and its incidence ranged
from 4.4% to 100% (Detorakis et al.
2001; Gallagher et al. 2001; Piras et al.
2003; Ateenyi-Agaba et al. 2004;
Rodriguez-Cabrera et al. 2004; Sjo
et al. 2007c). Detorakis et al. (2001)
demonstrated HPV in 24% and HSV
in 22% of pterygium cases; the presence of both was detected in 6% of
cases.
Generally, in most studies HPV was
detected only in primary pterygium
(Chen et al. 2003, Schellini et al. 2005,
Sjo et al. 2007c) and data on recurrent
pterygium is scanty and inconclusive.
In our small subgroup, the HPV genome was found in two out of seven
cases (28.6%) of recurrent pterygium,
HPV 16
HPV 6 and HPV 16
HPV 6 and HPV 18
HPV 16 and HPV 31
HPV 11,16,18,52,5,59

6%

6%

13%

56%
19%
Fig. 2. Human papillomavirus (HPV) genotypes identied in patients with pterygium.

892

thus the incidence is similar to overall

group. According to Rodriguez-Cabrera et al. (2004) the HPV genome
was detected in one of recurrent pterygium. Moreover, Gallagher et al.
(2001) in their study did not identify
HPV DNA in recurrent pterygium. In
fact, the correlation of postoperative
recurrences and the history of conjunctivitis in the simultaneous detection of HPV and HSV has been
described by Detorakis et al. 2001.
Hypothetically, the presence of
HPV and HSV is likely to impair the
p-53 dependent apoptotic pathway as
p53 and pRb may be inactivated by
proteins of E6 and E7 viruses (Nair &
Pillai 2005). The viral proteins may
also contribute to potentially higher
number of abnormalities in the cell
genetic material (Nair & Pillai 2005).
Detorakis et al. (2000) proposed a
model of pterygium formation,
according to which oncogenic viruses
(HPV and HSV) are likely to be
involved in the development of pterygium by inducing additional changes
in the genome (besides changes caused
by UV exposure and hereditary factors).
The analysis of our ndings did not
reveal statistically signicant relations
between the occurrence of HPV DNA
and UV exposure in patients undergoing surgery due to pterygium. It
should be stressed, however, that 32
out of 58 examined patients had the
history of UV radiation exposure
longer than 8 hours a day. Many
studies evaluated the effects of excessive UV exposure on the development
of pterygium (Detorakis et al. 2000,
Saw et al. 2000, Gazzard et al. 2002).
Some authors have reported that in
tropical regions the incidence of pterygium is higher and progression of
lesions is quicker (Luthra et al. 2001,
Paula et al. 2006).
The present study did not demonstrate signicant relations between the
occurrence of HPV DNA and sex as
well as age of patients with pterygium.
However, it should be emphasized
that the majority of patients with
pterygium were male (65.2%). Our
ndings are similar to those reported
by other authors (Khoo et al. 1998,
McCarty et al. 2000, Panchapakesan
et al. 1998, Saw et al. 2000, Wong
et al. 2001). On the other hand, there
are some reports demonstrating higher
occurrence of pterygium in females

Acta Ophthalmologica 2009

Table 2. Human papillomavirus (HPV) genotypes versus clinical stage of pterygium.

Clinical stage of pterygium
Stage II

Stage III

HPV genotype detected

HPV
HPV
HPV
HPV
HPV

3
2
1
1
1

18.75
12.50
6.25
6.25
6.25

6
1
1
0
0

37.50
6.25
6.25
0.00
0.00

50.00

50.00

16
6 and 16
6 and 18
16 and 31
11, 16, 18, 52, 53, 59

Total

Table 3. Human papillomavirus (HPV) DNA in pterygia. Comparison of published data.

Number of
cases, n

HPV (+)
lesions, n (%)

100
36
10
32
17
24
65
10
50
3

4
0
5
4
17
5
0
5
12
0

HPV type

Study

HPV 6

Sjo et al. (2007c)

Schellini et al. (2006)
Ateenyi-Agaba et al. (2004)
Rodriguez-Cabrera et al. (2004)
Piras et al. (2003)

(50%)
(12.5%)
(100%)
(21%)

HPV 38, HPV 11

*
HPV 52, 54, 90

(50%)
(24%)

HPV 6, 11, 16
HPV 18

Chen et al. (2003)

Gallagher et al.(2001)
Detorakis et al. (2001)
Assadoulina et al. (1999); Piras et al. (2003)

*No genotype identied.

Table 4. Occurrence of human papillomavirus (HPV) DNA in patients with pterygium

according to sex.
Examined groups
DNA
HPV (+)

DNA
HPV ())

Total

Sex

Females
Males

3
13

18.75
81.25

17
25

40.48
59.52

20
38

34.48
65.52

(Paula et al. 2006, Schellini et al.

2005). This relation is likely to be
associated with the specicity of life
of South American Indians described
by Paula and colleagues. They
observed that pterygium was seven
times more common among shing
tribes and those living near rivers
(36.6%) compared to hunting tribes
and those living in Amazonian tropical forests (6%) (Paula et al. 2006).
Higher occurrence of pterygium in
men may be related to the fact that
they more often work outdoors, thus,
they are more exposed to UV radiation and other irritants. RodrigezCabrera and colleagues detected the
presence of HPV genome in 12.5%

(4 32) of patients with pterygium. In

all cases, patients worked outdoors
(Rodrigez-Cabrera et al. 2004). In our
study, similarly to other reports
(Khoo et al. 1998, McCarty et al.
2000), the majority of patients with
pterygium worked outdoors (farmers).
Statistically signicant differences in
the presence of HPV genome were
found between patients living in the
country and those from big towns.
Amongst 16 patients with pterygium
and positive HPV results, 14 individuals worked outdoors. Khoo and
co-workers demonstrated a statistically signicant relation between outdoor activities (drivers, builders,
airport workers) and the development
of pterygium, which in such cases may
be related to higher exposure to solar
radiation and other irritants (dust,
wind) (Khoo et al. 1998).
Chen et al. (2003), in their study
conducted in Taiwan, did not identify
HPV DNA in pterygium patients
by PCR. Similar results were reported
by Dushku et al. (1999), who examined populations in the USA, and
Schellini et al. (2006), who conducted
their study in Brazil. The differences
between these observations and our

ndings may result from geographical

differences in the incidence of HPV.
The studies carried out in Greece
showed the presence of HPV DNA in
12 out of 50 pterygium cases (24%).
The presence of HPV 18 was demonstrated in all 12 patients (Detorakis
et al. 2001). In Denmark, amongst
100 examined pterygia, HPV 4 was
found in only four cases (Sjo et al.
2007c). HPV type 6 was identied in
all HPV-positive pterygia (Sjo et al.
2007c). In studies performed in the
UK, 50% of pterygium cases (5 10)
were HPV-positive and dot-blot genotyping demonstrated HPV types 6, 11
and 16 (Gallagher et al. 2001). In the
German study, HPV was not identied in any of three pterygium cases
(Assadoulina et al. 1999). Piras et al.
(2003) detected the presence of HPV
in 100% of pterygium cases in Italian
patients (17 17) and in 21% (5 24) of
cases from Ecuador. According to
some other studies carried out by
Dolmetsch et al. (1996) in Canada,
HPV 16 was present in 100% of
pterygia (immunohistochemical method).
Different results were reported by
McDonnell et al. (1992), who detected
HPV 16 in 88.1% (37 42) of their
patients with conjunctival intraepithelial neoplasia (CIN) but in none of six
pterygium cases.
There are literature reports demonstrating the presence of HPV DNA in
the clinically intact conjunctiva.
According to them, the HPV genome
was detected in 1.632% of healthy
conjunctiva cases (Karcioglu & Issa
1997; Tabrizi et al. 1997; Detorakis
et al. 2001; Tornesello et al. 2006). In
our study, the HPV genome was
found in 9.7% of normal conjunctivae. However, it should be stressed
that similarly to the ndings reported
by Detorakis et al. (2001), only HPV
18 was observed. Other authors report
the presence of HPV 6 (Tornesello
et al. 2006), HPV 6 11 and HPV 16
(Tabrizi et al. 1997). Contrary to the
results presented above, the study of
Chen et al. (2003) conducted in 88
normal conjunctivae did not demonstrate HPV DNA. Similar results were
described by Scott et al. (2002).
The literature differences in the incidence of HPV in pterygia may be
related
not
only
to
different
geographical distribution of HPV
infections but also to different study
methods used, lack of control groups

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Acta Ophthalmologica 2009

Table 5. Occurrence of human papillomavirus (HPV) DNA in patients with pterygium according to the type of work, place of work, place of residence and UV exposure.
Examined groups

Type of work
Farmer
white-collar worker
manual worker
Place of work
indoors
outdoors
Place of residence
Town > 30 0001
Town < 30 0002
Country3
Length of exposure to
<6 h
48 h
>8 h

DNA HPV(+)

DNA HPV())

n = 16

n = 42

Total
n = 58

9
1
6

56.25
6.25
37.50

19
5
18

45.24
11.90
42.86

28
6
24

p = 0.527

2
14

12.50
87.50

16
26

38.10
61.90

18
40

p = 0.059

0
0
10
4
25.0
10
12
75.0
22
UV radiation (h day)
2
12.50
12
4
25.00
8
10
62.50
22

23.81
23.81
52.38

10
14
34

For 1,2,3 p = 0,089

For1 and 3 p = 0.028

28.57
19.00
52.40

14
12
32

p = 0.437

or small populations examined

(1050). In the past, HPV was detected
using anti-HPV polyclonal antibodies
(Lass et al. 1983; Varinli et al. 1994;
Dolmetsch et al. 1996). According to
the literature available, Hybrid Capture II Assay seems to be a useful,
highly sensitive method for the detection of HPV infections in pterygia
(Kumamoto et al. 2002). The in situ
hybridisation technique is less sensitive
to detect HPV than the PCR technique. (Herrington et al. 1995; Sjo et
al. 2007a). At present, it seems that the
PCR method used in our study, based
on amplication of HPV DNA fragments, is the most sensitive method for
the diagnosis of viral infections.
Moreover, it should be stressed that
the method of transmission of the
virus to the eye tissues has not been
explained fully. HPV is spread mainly
by sexual contact (Bosch et al. 1995;
Baseman & Koutsky 2005). One of
the possible transmission modes is
infection when the foetus passes
through the birth canal (Buggage
et al. 2002; Cason & Mant 2005).
According to one of the reports published (Bodaghi et al. 2005), HPV
may also spread via blood. It has also
been suggested that in eye surface
lesions, HPV is acquired by autoinfection from the focus already present in
the organism. This hypothesis is supported by the fact that HPV 16 was
found in conjunctivae of asymptomatic patients with the diagnosis of
cervical HPV and was identied

894

bilaterally in patients with unilateral

conjunctival changes (Buggage et al.
1999). McDonnell et al. (1991) demonstrated HPV (76.5% of cases) in
the samples collected from clinically
healthy eyes of patients with condyloma acuminatum. According to one
report, HPV is likely to be transmitted
by aerosol produced by lasers (Garden
et al. 2002).
The HPV types can be divided
according to their potential ability to
cause neoplastic lesions. Those rarely
found in neoplasms are called low-risk
oncogenes (6, 11, 42, 43, 44), while
those often detected are called highrisk oncogenes (16, 18, 31, 45, 56) (Di
Girlamo et al. 2004; Baseman &
Koutsky 2005). The high oncogenic
potential types are capable of immortalizing human keratinocytes. The
neoplastic transformation of the cell
infected with a low-risk virus is probably conditioned by additional physical
or chemical carcinogenic factors. In
our study, HPV infections of high
oncogenic risk were found in 56.0%
(9 16) of cases; infections with mixed
HPV of low and high oncogenic
potential were found in 37.5% (6 16)
of cases.
The identication of HPV and
determination of its oncogenic potential may be relevant for prognosis.
High oncogenic potential infections
found in poorly clinically advanced
lesions require careful and regular
observations while pterygium cases
related to carcinogenesis should be

treated appropriately. Moreover, it

should be remembered that new types
of HPV are being discovered, thus the
range of genotypes is incomplete (Bernard 2005). Some new, unclassied
HPV types might be involved in the
development of pterygium.
Analysis of the literature data
shows that ndings differ depending
on the diagnostic research tool used
and the type of diseased tissues examined. Nevertheless, the majority of
opinions seem to conrm the relationship between HPV infection and
pterygium. HPV is not necessary to
induce pterygium; however, it may
play a synergistic role in the multistage process of its development. Considering all the information discussed
here, it is evident that studies on the
pathogenesis of pterygium from a
virological aspect are of theoretical as
well as practical relevance.

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Received on September 15th, 2007.

Accepted on April 10th, 2008.
Correspondence:
Marta Piecyk-Sidor
Tadeusz Krwawicz Chair of Ophthalmology
and First Eye Hospital
Chmielna 1
20-079 Lublin
Poland
Tel: +48 0815324827
Fax: +48 0815324827
Email: psmarta@wp.pl

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