Professional Documents
Culture Documents
Association of
human papilloma
virus with
pterygia and
ocular-surface
squamous neoplasia
N Di Girolamo
Abstract
Introduction
When the Human Microbiome Project is
complete, a comprehensive assessment of the
human microbiota and its role in health and
disease will be appreciated.1 The human skin2
and oral cavity3 microbiome was recently
characterized, with each study identifing over
200 species-level phylotypes. Most recently,
Dong et al4 disclosed a similar profile of
microbes on the healthy human conjunctiva;
some were characterized whereas others (31%)
were novel or unclassified. Approximately
18% of all cancers can be attributed to
microorganisms, the most common being
Helicobacter pylori, Human Papilloma virus
(HPV), Hepatitis B and C virus, Epstein-Barr
virus and Human Herpes virus.5 Although
these microbes are known to target specific
tissues, such as the stomach, liver, and cervix,
some are associated with tumors that arise on
the ocular surface.6
203
Eye
100
80
60
40
20
0
18.6%
7)
(2
(3
0)
Br
az
il1
(3
3
U
U K )
ga (2
nd 9
Po a ( )
la 31
G nd )
re (
Ta ec 35)
iw e (
a 2
Ec n- 8)
ua 1 (
do 36
)
Ja r (3
0
p
D
en an )
m (
Ta ar 34)
iw k (
Ta an- 32)
iw 2 (
an 37
Br -3 )
az (4
0
i
U l-2 )
SA (4
Tu -1 1)
rk (3
G ey- 9)
er 2
m (4
an 2)
U y(
SA 43
Ta )
iw 2 (
an 38
-4 )
(4
4)
HPV Prevalence
(%) in Pterygia
204
HPV Prevalence
Ta
(%) in OSSN
iw
an
-1
U
SA (44
)
U 1 (5
SA 7
U -2 )
ga (3
nd 8)
Sa
a
U
ud
SA (3
1
iA
ra 3 ( )
bi
53
Sa A a-1 )
ud ust (5
i A ral 5)
ra ia
G bia (54
er
)
m -2
an (5
6
H y-1 )
u
G ng (58
er ar
)
m y
an (5
y- 6)
In 2 (
di 43
a)
U 1 (6
SA 3
Ta -4 )
iw
an (39
Th -2 )
(
ai
la 60)
nd
(6
1)
Fi
nl
an
d
(5
9)
Ita
ly
1
yke
r
Tu
100
80
60
40
20
0
33.8%
2)
a-
di
(6
In
Figure 1 Prevalence of HPV in Ocular-Surface Diseases. Data from the literature were collated on the prevalence of HPV in pterygia
(a) and OSSN (b), which ranged from 0 to 100% in both disease groups. HPV was more common (1.8-fold) in OSSN than in pterygia.
Asterisks (*) in panels (a and b) denote data from the same investigation but from a different ethnic source. The numbers in parenthesis
along the x-axis denote respective references.
Piras et al (Italy)
Varinli et al (Turkey)27
Rodrigues et al (Brazil)33
Gallagher et al (UK)29
Ateenyi-Agaba et al (Uganda)31
Piecyk-Sidor et al (Poland)35
Detorakis et al (Greece)28
Tsai et al (Taiwan)36
Piras et al (Ecuador)30
Takamura et al (Japan)34
Sjo et al (Denmark)32
Hsiao et al (Taiwan)37
Chen et al (Taiwan)40
Schellini et al (Brazil)41
Dushku et al (USA)39
Otlu et al (Turkey)42
Guthoff et al (Germany)43
McDonnell et al (USA)38
Kuo et al (Taiwan)44
Sample size
17
25
36
10
10
58 (51 primary,
50
129
24
42 (40 primary,
90 primary
65 (35 primary,
65
36 primary
13 (12 primary,
40 (30 primary,
11
6
4
Prevalence (%)
7 recurrent)
2 recurrent)
30 recurrent)
1 recurrent)
10 recurrent)
100
64
58.3
50
50
27.6
24
24
21
4.8
4.4
3
0
0
0
0
0
0
0
HPV subtypes
Method
PCR/sequencing
IHC
PCR
PCR
PCR/Southern
PCR
PCR
PCR/IHC
PCR/sequencing
PCR/HC-II
PCR/ISH
PCR/ISH
PCR
PCR
PCR
PCR
PCR/IHC
PCR
PCR
Abbreviations: HC-II, hybrid capture; IHC, immunohistochemistry; ISH, in situ hybridization; PCR, polymerase chain reaction.
Eye
205
Kuo et al (Taiwan)44
Scott et al (USA)57
McDonnell et al (USA)38
Ateenyi-Agaba et al (Uganda)31
Lauer et al (USA)53
Karcioglu et al (Saudi Arabia)55
Tabrizi et al (Australia)54
Toth et al (Saudi Arabia)56
Auw-Haedrich et al (Germany)58
Toth et al (Hungary)56
Guthoff et al (Germany)43
Manderwad et al (India)63
Dushku et al (USA)39
Eng et al (Taiwan)60
Tulvatana et al (Thailand)61
Sen et al (India)62
Tuppurainen et al (Finland)59
9 (Dysplasia)
10 (Dysplasia)
42 (OSSN)
21 (SCC)
5 (OSSN)
45 (CIS/SCC)
88 (OSSN)
16 (SCC)
12 (Dysplasia)
7 (SCC)
31 (OSSN)
48 (OSSN)
8 (OSSN)
20 (OSSN)
30 (OSSN)
30 (OSSN)
4 (CIS/SCC)
Prevalence (%)
100
100
88.1
86
80
55.6
39
25
16.7
14.3
0
0
0
0
0
0
0
HPV subtypes
Method
PCR
PCR
PCR/DB
PCR
PCR
PCR
PCR
PCR
PCR
PCR
PCR/IHC
PCR/ISH-CARD
PCR
PCR
PCR/DB
IHC
PCR/ISH
Abbreviations: CIS, carcinoma in situ; DB, dot blot; dysplasia, mild, moderate, and severe dysplasia; IHC, immunohistochemistry; ISH-CARD, in situ
hybridization-catalyzed reporter deposition; OSSN, ocular surface squamous neoplasia; PCR, polymerase chain reaction.
Eye
206
Eye
207
Conclusions
The current study reports the prevalence of HPV in
ophthalmic pterygia and OSSN as 18% and 33%,
respectively. This contrasts with stronger associations
(B80%) for conjunctival papilloma. Overall, these data
suggest that the involvement of HPV in pterygia and
OSSN is inconclusive. Moreover, the International
Agency for Research on Cancer (IARC) regarded the
evidence as weak105 and in 2011 the IARCs report did
not mention HPV as a carcinogenic mediator of ocularsurface disease.106 As seen from the evidence presented
in Figure 1 and Tables 1 and 2, the field is divided and
conclusions made have often been based on sub-optimal
study designs and techniques used to identify HPVs in
biological specimens. The ocular field is in desperate
need of a gold-standard detection and tissue-collection
protocol for assessing HPV infection. A multiplex
approach to identify all known HPV within a single
specimen and larger case-control studies are warranted.
HPV genotypes most represented in pterygia and
OSSN include types 6, 11, 16, and 18 (Tables 1 and 2).
Infection with these genotypes is preventable by the
quadrivalent vaccine Gardacil (Merck Sharp & Dohme
Corp., Whitehouse Station, NJ, USA). Hence, if effective,
the vaccine may reduce the incidence or may potentially
eradicate ocular disease attributable to HPV infection.
The global immunization program for HPV began in
2007 and currently 60 million individuals (mainly young
women) have been vaccinated. Unfortunately, immediate
benefits (if any) for patients with eye disease will not be
apparent for years as pterygia can require decades to
develop, and OSSN is generally a disease of elderly men.
Alternative treatments that do not involve surgery
or a vaccine are being trialed. Immunotherapy with
interferon-alpha 2b has been used in patients with HPV16/18-positive conjunctival neoplasia. This naturally
occurring cytokine has anti-viral, anti-neoplastic, and
anti-proliferative actions, which involve immuneenhancing properties. However, local and systemic
discomforts, as well as recurrences have been noted.107
Precisely how HPV infects the ocular surface is
unknown, however infection from mother to newborn
during birth has been speculated.108 Moreover, digital
self-inoculation is possible as HPV DNA was noted on
the fingers of males and females positive for genital
HPV.109 Although none of the studies highlighted in this
review screened for HPV-related genital disease, good
personal hygiene is a reasonable starting point to
minimize the risk of ocular infection.
Conflict of interest
The author declares no conflict of interest.
Eye
208
Acknowledgements
N Di Girolamo is supported by a Career Development
Award (no. 455358) from the National Health and Medial
Research Council of Australia.
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