Supplementary information. Figure 1. Systematic review flowchart.
1391 publications
(728, 360 and 242 identified through PubMedTM, ScopusTM, and EMBASETM searches, respectively, and 61
identified from the bibliographic references of the eligible studies and related reviews)
PubMedTM search expression: (SCCC OR OSSN OR ((scc OR cancer OR neoplasia OR carcinoma OR CIN OR dysplasia) AND (conjunctiva OR
conjunctival OR eye OR ocular))) AND (HIV Infections [MeSH] OR HIV [MeSH] OR hiv [tw] OR hiv-1* [tw] OR hiv-2* [tw] OR hiv1 [tw] OR hiv2
[tw] OR hiv infect* [tw] OR human immunodeficiency virus [tw] OR human immunedeficiency virus [tw] OR human immuno-deficiency virus
[tw] OR human immune-deficiency virus [tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome
[tw] OR acquired immunedeficiency syndrome [tw] OR acquired immuno-deficiency syndrome [tw] OR acquired immune-deficiency syndrome [tw]
OR ((acquired immun*) AND (deficiency syndrome [tw])) OR “sexually transmitted diseases, viral” [MeSH:NoExp] OR AIDS OR (papillomaviridae
[MeSH] OR Papillomavirus Infections [MeSH Terms] OR HPV [tw] OR papillomavirus [tw] OR papillomaviridae [tw])) NOT (animals[mh] NOT
humans[mh])
ScopusTM search expression: TITLE-ABS-KEY(((sccc OR ossn OR ((scc OR cancer OR neoplasia OR carcinoma OR cin OR dysplasia) AND
(conjunctiva OR conjunctival OR eye OR ocular)))) AND (((papillomaviridae OR hpv OR papillomavirus)) OR (("HIV Infections" OR hiv OR hiv OR
hiv-1 OR hiv-2 OR hiv1 OR hiv2 OR "human immunodeficiency virus" OR "human immunedeficiency virus" OR "human immuno-deficiency virus"
OR "human immune-deficiency virus" OR "deficiency virus" OR "acquired immunodeficiency syndrome" OR "acquired immunedeficiency syndrome"
OR "acquired immuno-deficiency syndrome" OR "acquired immune-deficiency syndrome" OR "deficiency syndrome" OR aids))))
EMBASETM (OVID) search expression: (SCCC OR OSSN OR ((scc OR cancer OR neoplasia OR carcinoma OR CIN OR dysplasia) AND
(conjunctiva OR conjunctival OR eye OR ocular))) AND (HIV Infections OR HIV OR hiv OR hiv-1* OR hiv-2* OR hiv1 OR hiv2 OR hiv infect* OR
human immunodeficiency virus OR human immunedeficiency virus OR human immuno-deficiency virus OR human immune-deficiency virus OR
((human immun*) AND (deficiency virus)) OR acquired immunodeficiency syndrome OR acquired immunedeficiency syndrome OR acquired
immuno-deficiency syndrome OR acquired immune-deficiency syndrome OR ((acquired immun*) AND (deficiency syndrome)) OR AIDS OR
(papillomaviridae OR papillomavirus OR HPV))
1117 articles excluded based on title and abstract assessment:
103 not involving humans
349 reviews on unrelated topics, guidelines or comments without original data
275 case reports or case series
390 studies evaluating the association between HIV and/or HPV infection and
outcomes other than OSSN
274 publications
193 articles excluded based on full text assessment:
45
reviews, guidelines or comments
70
case reports or case series
52
not providing a relative risk estimate for the association between HIV
and/or HPV infection and OSSN, or the necessary information to
compute it
26
data already described in other included study
81 publications
52 articles excluded during data extraction:
37
reviews on related topics
6
data already described in other included study
1
study with increased probability of HIV finding
5
data in a non eligible format for data extraction
1
study whose outcome was ocular cancers other than retinoblastoma and
melanoma
1
study in which the excess of risk was computed dividing the observed
number of ocular cancers (all were SCCC) by the expected number of all
ocular cancers
1
control group only includes patients with AIDS-defining malignancies
29 studies eligible for systematic review
4 not considered for meta-analysis, as they did not
detected HPV neither among cases nor among
controls
25 studies eligible for meta-analyses
12 studies with data on the
association between HIV infection
and OSSN
5 studies with data on the
association between cutaneous
subtypes of HPV and OSSN
16 studies with data on the
association between mucosal
subtypes of HPV and OSSN
3 studies with data on the
association between HPV
infection and OSSN by HIV status
3 studies with data on the
association between HPV
infection and OSSN by HIV status
1
2
Table 1. Main characteristics of the studies included in the systematic review that assessed the association between human immunodeficiency
virus (HIV) and/or human papillomavirus (HPV) and ocular surface squamous neoplasia (OSSN).
1st author,
year of
publication
Country,
region
Carrilho et al,
2013 (Carrilho et
al, 2013)
Mozambique
, Maputo
Description of the participants
Cases:
“low-grade intraepithelial neoplasia (n=4), highgrade intraepithelial neoplasia (n=16), invasive
squamous cell carcinomas (n=13)”
Outcome
OSSN
India,
New Delhi
Cases:
“Sixty-four patients with OSSN (44 SCC, 20 CIN)”
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
Broad spectrum of mucosal and
cutaneous HPV subtypes were tested
NA
HPV were detected in 11 cases (9 for
cutaneous subtypes, 1 for HPV 18 and
2 for HPV 16)
Controls:
“clinically and histologically benign conjunctival
conditions in patients with no other cancer
diagnosis (n=5, namely three pingueculae, one
melanosis, and one conjunctivitis).”
Chauhan, 2012
(Chauhan et al,
2012)
HPV infection
Controls:
“15 controls (conjunctival epithelialectomy tissues
from limbal stem cell deficiency patients)”
Broad spectrum of mucosal HPV
subtypes were tested
Control
of
confounding
Mucosal HPV+
vs
Mucosal HPVOR=1.40 (0.09-22.16)
*
No
Cutaneous HPV+ vs
cutaneous HPVOR=3.80 (0.27-52.90)
*
Method: PCR
SCCC and
CIN
Relative
risk
estimate (95%CI)
NA
Positive samples were genotyped, and
only HPV subtype 16 was detected in
the seven HPV-positive OSSN
Mucosal HPV+
mucosal HPV-
vs.
No
vs.
No
OR=3.69
(0.22-61.36) * ‖¶
Method: PCR
Asadi-Amoli,
2011
(Asadi-Amoli
al, 2011)
Iran, Tehran
Cases:
“50 SCC cases”
SCCC
Broad spectrum of mucosal HPV
subtypes were tested
NA
Mucosal HPV+
mucosal HPV-
et
Controls:
“50 age frequency-matched control patients with
lesion-free, normal conjunctival biopsies”
HPV detected of subtypes not
specified, though HPV 16, 18, 31 and
33 were ruled out
OR=107.59
(6.80-1702.19)* ‖ ¶ ‡
Method: nested PCR
3
1st author,
year of
publication
Country,
region
Ateenyi-Agaba,
2010
(Ateenyi-Agaba
et al, 2010)
Uganda,
Kampala
Description of the participants
Cases:
“patients admitted to the Departments of
Ophthalmology (…) for eye lesions suspected to
be SCCC (…) A consensus was achieved on the
presence of SCCC in 100 patients”
Controls:
“Eligible controls were patients who had been
admitted to the same hospitals as cases for eye
conditions other than SCCC or dysplasia, and
required surgical intervention. (…) The most
frequent diagnosis were cataract (37%), chalazia
(12%), corneal tears (10%), and eye trauma (9%).
Patients presenting with pterygium or pingueculum
were not included (…)”
Outcome
SCCC/
Dysplasia
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
Broad spectrum of mucosal HPV
subtypes tested, and positive samples
were tested for 25 mucosal HPV types
(high-risk: HPV 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, 66, 68, and 70;
low-risk: HPV 6, 11, 34, 40, 42, 43, 44,
53, 54, and 74), plus 17 additional
HPV subtypes (HPV 26, 30, 55, 61,
62, 64, 67, 69, 71, 82, 83, 84, 85, 87,
89, 90, and 91)
NA
Relative
risk
estimate (95%CI)
Control
of
confounding
Mucosal HPV+
mucosal HPV-
vs.
Adjusted for
age, sex and HIV
status
Cutaneous HPV+ vs.
cutaneous HPV-
Adjusted for
age, sex and HIV
status
OR=1.0 (0.4-2.7)
HPV of subtypes 16, 45, 52, 53, 83,
plus 14 cases unclassified were
detected
Method: PCR
25 cutaneous HPV subtypes (HPV 5,
8, 9, 12, 14, 15, 17, 19–25, 36–38, 47,
49, 75, 76, 80, 92, 93, and 96) were
tested
NA
Single infection:
OR=2.3 (1.2-4.4)
HPV of subtypes 5, 8, 9, 12, 14, 15,
17, 19, 20, 21, 22, 23, 24, 25, 36, 37,
38, 49, 75, 76, 80, 92, 93, 86, plus 5
cases unclassified, were detected
Method: PCR reverse hybridization
NA
Multiple infection:
OR=18.3 (6.2-54.4)
HIV
of
specified
subtype
not
HIV+ vs. HIV-
Adjusted for
age, sex
OR=7.3 (4.2-12.4)
Method:
ELISA
Western blot
NA
and
Exposure: AIDS
AIDS+ vs. AIDS-
AIDS’s assessment: “The
diagnosis of AIDS was
based on the presence of
cytomegalovirus retinitis,
cryptococcal meningitis, or
skin rash with weight loss.”
OR=5.6 (1.5-20.3)
Adjusted for
age, sex
4
1st author,
year of
publication
Country,
region
Ateenyi-Agaba,
2010
(Ateenyi-Agaba
et al, 2010)
Uganda,
Kampala
Simbiri et al,
2010 (Simbiri et
al, 2010)
Botswana,
Gaborone
Description of the participants
Cases:
“patients admitted to the Departments of
Ophthalmology (…) for eye lesions suspected to
be SCCC (…) A consensus was achieved on the
presence of SCCC in 100 patients”
Controls:
“Eligible controls were patients who had been
admitted to the same hospitals as cases for eye
conditions other than SCCC or dysplasia, and
required surgical intervention. (…) The most
frequent diagnosis were cataract (37%), chalazia
(12%), corneal tears (10%), and eye trauma (9%).
Patients presenting with pterygium or pingueculum
were not included (…)”
Cases:
“HIV-1 infected patients with conjunctival lesions
(…) 28 whose clinical diagnosis was OSSN”
Outcome
SCCC/
Dysplasia
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
25 cutaneous HPV subtypes (HPV 5,
8, 9, 12, 14, 15, 17, 19–25, 36–38, 47,
49, 75, 76, 80, 92, 93, and 96) were
tested
HIV
of
specified
Method:
ELISA
Western blot
Cases:
“Seven cases were considered CIN I and II; 17
cases were considered CIN III (…) Seven
additional cases were conjunctival invasive
squamous cell carcinomas (…)”
Controls:
“Five conjunctival specimens of 3 female and 2
male patients for primary retinal detachment
surgery and with a mean age of 70 (range 65-76)
years without any clinically identifiable conjunctival
disease served as controls.”
and
Method: PCR
OSSN
Broad spectrum of mucosal subtypes
and HPV type specific 16 and 18
tested
HIV -1 positive patients
Broad spectrum of mucosal subtypes
tested; genotyping of 15 different HPV
subtypes (6, 11, 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, and 68) was
attempted
Method: multiplex fluorescent PCR
Mucosal HPV subtypes 16, 18, 33, 35,
39, 45, 56, 58 were tested
HIV+ and cutaneous
HPV+
(single
infection)
vs. HIV+
and cutaneous HPV-:
OR=2.7 (1.3-5.6)
Adjusted for
age, sex
Mucosal HPV+
mucosal HPV-
vs
No
Method: ELISA
Considering
the
samples that were
positive by at least one
of the three methods
applied:
OR=1.02 (0.45-2.31) *
HPV 1, 3, 7, 11, 13, 16, 18, 39, 40, 43,
45, 59, 61, 68, 70, 77, 85, 89, 91, 97
found
OSSN
Control
of
confounding
HIV+ and cutaneous
HPV+
(multiple
infection)
vs. HIV+
and cutaneous HPV-:
OR=15.4 (5.2-45.5)
Method: PCR; ISH; IHC
Germany,
Wuerzburg
not
HPV of subtypes 5, 8, 9, 12, 14, 15,
17, 19, 20, 21, 22, 23, 24, 25, 36, 37,
38, 49, 75, 76, 80, 92, 93, 86, plus 5
cases unclassified, were detected
Controls:
“8 pterygia”
Guthoff, 2009
(Guthoff et al,
2009)
subtype
Relative
risk
estimate (95%CI)
NA
Considering only the
samples that were
positive using PCR:
OR=2.5 (0.50-12.51) *
HPV infection was not
detected among cases
or controls with both
methods,
and
therefore a relative risk
estimate
was
not
computed
NA
NA
Method: immunohistochemistry
5
1st author,
year of
publication
Country,
region
Auw-Haedrich,
2008
(Auw-Haedrich
et al, 2008)
Germany,
ND
de Koning, 2008
(de Koning et al,
2008)
Uganda,
country-wide
Description of the participants
Cases:
“12 conjunctival specimens (…) excised from the
bulbar conjunctiva with the suspicion of
conjunctival intra-epithelial neoplasia (CIN) (…)
The (…) patients slides were diagnosed (…) as
follows: 2 CIN grade I (…), 3 CIN grade II (…), 5
CIN grade III (…), and 2 CIN with beginning
invasion”
Controls:
“14
macroscopically
normal
postmortem
conjunctival specimens and 1 conjunctival
specimen with slight inflammatory changes”
Cases:
"anyone with a suspect corneo-conjunctival lesion
was offered removal and histology, and enrolment
in a follow-up study with home visits."
Controls:
"Those who subsequently turned out to have
lesions other than ocular surface squamous
neoplasia were used as a control group in the
analyses of HPV."
Outcome
CIN
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
Broad spectrum of mucosal subtypes
tested
NA
Detected HPV of subtype 16
Relative
risk
estimate (95%CI)
Control
of
confounding
Mucosal HPV+
mucosal HPV-
No
vs.
OR=2.06
(1.04-4.11) * ‖ ¶
Method: nested PCR
CIN
NA
HIV
of
specified
subtype
not
Method:
two
enzyme
immunoassay tests in
parallel, with Western blot
if required
Broad spectrum of mucosal HPV
subtypes tested, and positive samples
were genotyped for HPV subtypes
(high risk: 16, 18, 31, 33, 35, 39, 45,
51, 52, 56, 58, 59, 66, 68, 70, and lowrisk 6, 11, 34, 40, 42, 43, 44, 53, 54,
74)
HPV of subtypes 6, 11, 16, 18, 31, 33,
35, 44, 51, 52, 66, plus 2 cases
unclassified were detected
Method: PCR
NA
Not infected with HIV
Method:
two
enzyme
immunoassay tests in
parallel, with Western blot
if required
HIV
of subtype
not
specified
Method:
two
enzyme
immunoassay tests in
parallel, with Western blot
if required
HIV+ vs. HIV-
No
OR=4.49
(1.80-11.20) *
Mucosal HPV+
mucosal HPV-
vs.
OR=1.0 (0.4-2.7)
HIV- and mucosal
HPV+ vs HIV- and
mucosal HPV-
No
No
OR=1.2 (0.3-5.5)
HIV+ and mucosal
HPV+ vs. HIV+ and
mucosal HPV-
No
OR=0.9 (0.2-4.3)
6
1st author,
year of
publication
Country,
region
de Koning, 2008
(de Koning et al,
2008)
Uganda,
country-wide
Description of the participants
Cases:
"anyone with a suspect corneo-conjunctival lesion
was offered removal and histology, and enrolment
in a follow-up study with home visits."
Outcome
CIN
Controls:
"Those who subsequently turned out to have
lesions other than ocular surface squamous
neoplasia were used as a control group in the
analyses of HPV."
Guech-Ongey,
2008
(Guech-Ongey
et al, 2008)
USA,
9
states and 5
metropolitan
areas
Sen, 2007
(Sen et al, 2007)
India, ND
Chinogurei et al,
2006
(Chinogurei
et
al, 2006)
Zimbabwe,
Harare
Description of the cohort:
“We investigated eye cancers among adults (aged
>15 or older) in the U.S. HACM Study diagnosed
with AIDS from 1980 to 2004. The U.S. HACM
Study links population-based HIV/AIDS registry
and cancer registry databases in 9 U.S. states (…)
The expected number of cancers was calculated
using general population age-, race-, sex-,
calendar year- and registry-specific incidence rates
applied to the person time distribution of PWA
[persons with AIDS]”
Cases:
“Biopsies obtained from (…) 30 cases of ocular
surface squamous neoplasia (OSSN)”
Controls:
“30 age and sex-matched controls of normal
conjunctivas were also obtained from the eye
bank”
Cases:
“[16] invasive squamous cell carcinoma of
conjunctiva (…) [10] all forms of dysplasias and
carcinoma in situ”
Controls:
“[15] Pterygium”
SCCC
OSSN
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
NA
Not infected with HIV
Cutaneous
HPV+
cutaneous HPV-
Method: two enzyme immunoassay
tests in parallel, with Western blot if
required
HIV of subtype not specified
OR=8.0 (1.0-169)
HIV- and cutaneous HPV+
vs. HIV- and cutaneous
HPV-
Method: two enzyme immunoassay
tests in parallel, with Western blot if
required
OR=11.30
(0.68-188.39)* ‖ ¶ ‡
HIV+
and
cutaneous
HPV+ vs. HIV+ and
cutaneous HPV-
OSSN
OR=0.8 (0.2-3.8)
Exposure: AIDS
NA
Mucosal HPV subtypes 6, 18, 31, 33,
42, 51, 52, 56, 58 were tested
Methods: immunohistochemistry
situ HPV antigen detection)
NA
vs.
Relative
risk
estimate (95%CI)
Control
of
confounding
No
No
No
No
No
No
AIDS+ vs. AIDS-
Adjusted for:
age, race, sex,
calendar year and
registry
AIDS’s
assessment:
previous diagnosis
SIR=12.2 (6.8-20.2)
NA
HPV infection was not
detected among cases
or
controls,
and
therefore a relative risk
estimate
was
not
computed
NA
HIV+ vs. HIV-
No
(in
HIV
of
specified
subtype
not
Method:
ELISA,
and
Western blot confirmation
of doubtful cases
OR=22.00
115.01)
(4.21-
7
1st author,
year of
publication
Country,
region
Tornesello, 2006
(Tornesello et al,
2006)
Uganda,
south
Description of the participants
Cases:
“125 consecutive patients clinically diagnosed with
conjunctival neoplasia”
Controls:
“The 125 cancer-free controls, frequency matched
to the cases by sex and age (…) were
consecutively randomly enrolled from a pool of
patients treated for benign eye lesions (i.e.
pterygium) or eye injuries (…) The control group
included two pinguecula, one pterygium and one
papilloma of the conjunctiva”
Outcome
Conjunctival
neoplasia
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
NA
Broad spectrum of mucosal HPV
subtypes tested, in addition to
targeting HPV subtype 16
Only mucosal HPV of subtypes 6 and
18 were detected
Method: PCR
HIV
of
specified
subtype
not
Method: ELISA, followed
by
Western
blot
confirmation
NA
HIV of subtype not defined
Method: ELISA, followed
by
Western
blot
confirmation
Not infected with HIV
Method: ELISA, followed
by
Western
blot
confirmation
Broad spectrum of cutaneous HPV
subtypes tested, in addition to
targeting HPV subtype 38
HPV of subtypes 14, 20, 38 were
detected
Method: PCR
NA
HIV
of
specified
subtype
not
Method:
ELISA,
and
followed by Western blot
confirmation
Not infected with HIV
Method: ELISA, followed
by
Western
blot
confirmation
Relative
risk
estimate (95%CI)
Control
of
confounding
HIV+ vs. HIV-
No
OR=2.99
(1.36-6.53) *
Mucosal HPV+
mucosal HPV-
vs.
No
OR=2.24
(0.11-45.6) * ‖ ¶ ‡ ***
HIV+ and mucosal
HPV+ vs. HIV+ and
mucosal HPV-
No
OR=0.86
(0.04-20.04) * † ¶ ‡
HIV- and mucosal
HPV+ vs. HIV- and
mucosal HPV-
No
OR=2.34
(0.10-55.11) * ‡
Cutaneous HPV+ vs.
cutaneous HPV-
No
OR=4.93
(0.28-87.00) * ‖ ¶ ‡
HIV+ and cutaneous
HPV+ vs. HIV+ and
cutaneous HPV-
No
OR=2.57
(0.15-45.28) * † ¶ ‡
HIV- and cutaneous
HPV+ vs. HIV- and
cutaneous HPV-
No
OR=2.34
(0.10-55.11) * ‡
8
1st author,
year of
publication
Country,
region
Ateenyi-Agaba
et al, 2004
(Ateenyi-Agaba
et al, 2004)
Uganda,
Kampala
Timm,
(Timm
2004)
2004
et al,
Description of the participants
Cases:
“21 SCC cases”
Outcome
SCC of the
conjunctiva
Controls:
“22 age frequency-matched control patients with
benign conjunctival lesions (…) In total, 10 controls
had pterygium, seven pingueculum, four solar
keratosis and 1 pigmented naevus”
Democratic
Republic of
Congo
Cases:
“CIN I and II, CIN III and squamous cell
carcinoma”
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
Broad spectrum of mucosal and
cutaneous subtypes, including EV
HPV types were tested. Type specific
HPV probes for HPV 16, 18, 45 and
EV HPV 38 were also tested.
NA
EV HPV types 8, 12, 14, 24, 36, 37, 38
and RTRX7 detected
OSSN
Method: PCR and southern blotting
NA
Relative
risk
estimate (95%CI)
Control
of
confounding
Cutaneous HPV+ vs
cutaneous HPV-
Adjusted for age
and gender
OR=12.0 (1.7-84.9)
Cutaneous HPV+ vs
cutaneous HPV-
Adjusted for sun
exposure
OR=22.7 (1.7-312)
ELISA, with confirmation
by a second ELISA test
HIV+ vs. HIV-
No
OR=0.6
(0.11-3.04) *
Controls:
“benign lesions [6 pingueculae, 1 papilloma, 1
sebaceous carcinoma]”
Porges, 2003
(Porges
&
Groisman, 2003)
Zimbabwe,
Mashonalad
Cases:
"a group of 23 African black patients underwent
excisional biopsy for conjunctival lesions."
SCCC and
carcinoma in
situ
NA
Thailand,
ND
Cases:
“thirty cases were retrieved from the most recent
pathological tissue diagnosed to be conjunctival
squamous cell neoplasia.”
Conjunctival
squamous
cell
neoplasia
Mucosal HPV subtypes were tested
Controls:
“Controls were disease-free conjunctiva from age
and sex matched patients who underwent planned
extracapsular cataract extraction.”
subtype
not
Method: ELISA, followed
by
confirmation
with
immunofluorescence
or
Western blot
Controls:
"The control group with benign conjunctival lesions
(benign/HIV control group) consisted of seven
patients (…) This group was part of a larger group
of patients with conjunctival lesions who had been
operated in our unit during the study period"
Tulvatana, 2003
(Tulvatana et al,
2003)
HIV
of
specified
Method: PCR and dot hybridization
NA
HIV+ vs. HIV-
No
OR=30.0
(2.19-411.0) *
HPV infection was not
detected among cases
or
controls,
and
therefore a relative risk
estimate
was
not
computed
NA
9
1st author,
year of
publication
Country,
region
Scott, 2002
(Scott et
2002)
USA, Miami
al,
Description of the participants
Cases:
“10 consecutive patients who underwent CIN
excision by one surgeon”
Outcome
CIN
Uganda,
Kampala
Cases:
"60 cases of conjunctival cancer (…) Thirty-two
people with eye cancers that were not specifically
diagnosed clinically as being squamous cell
carcinomas, or had a pathological diagnosis of
malignancy of uncertain morphology were
excluded."
SCCC
Brazil,
Paulo
São
Cases:
“in a sample of patients referred to the
Ophthalmology Service of the Cancer Hospital –
Antonio Prudente Foundation”
Controls:
“Swabs of the conjunctiva (…) as well as in sixty
matched controls.”
Exposure assessed
Method
Exposure assessed
Method
Mucosal HPV subtypes 16, 18 were
tested
NA
Mucosal HPV subtypes 16, 18, 45
tested, and all subtypes were detected
Controls:
"The control group included (…) cancers of the
oral cavity (57), oesophagus (150), stomach (74),
liver (103), breast (178), ovary (67), prostate (56),
and other cancer sites or types (405). In addition,
124 patients with a provisional diagnosis of cancer,
but who subsequently turned out to have benign
tumours, were also included in the control group."
Palazzi, 2000
(Palazzi et al,
2000)
HIV infection/AIDS
NA
Method: in situ hybridization and
reverse transcriptase in situ PCR
Controls:
“conjunctival specimens from five control patients
(age-matched to five of the cases) who had no
clinically identifiable conjunctival disease and who
underwent retinal detachment repair”
Newton,
2002(Newton et
al, 2002)
HPV infection
and
dot
HPV 16 and/or 18+ vs.
HPV 16 and/or 18-
No
HIV subtype HIV-1
HIV+ vs. HIV-
Method: ELISA
OR=10.1 (5.2-19.4)
NA
HPV 16, 18, 45+ vs.
HPV 16, 18, 45OR=1.3 (0.5-3.2)
Mucosal HPV subtypes 11 and 16
tested; both subtypes were detected
Method:
PCR
hybridization
Control
of
confounding
OR=11.46
(0.80-163.26) * ‖ ¶ ‡
Method: serological analysis
Carcinoma
in
situ,
invasive
SCCC,
severe
dysplasia
and
mild
dysplasia
(OSSN) §
Relative
risk
estimate (95%CI)
blot
NA
HPV 11, 16+ vs. HPV
11, 16-
Adjusted for
age group, sex,
current region of
residence
and
personal income
Adjusted for
age, sex, address,
personal income
and HIV-1 serostatus
No
OR=5.90
(0.51-68.61) * ‡
10
1st author,
year of
publication
Country,
region
Dushku et al,
1999 (Dushku et
al, 1999)
Description of the participants
Cases:
“limbal tumors (n=10: 2 with actinic keratosis
dysplasia, 1 with conjunctival intraepithelial
neoplasia, 3 with carcinoma in situ, and 4 with
squamous cell carcinoma)”
Outcome
OSSN
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
Broad spectrum of mucosal HPV
subtypes tested
Relative
risk
estimate (95%CI)
Control
of
confounding
NA
“We were unable to
detect the 450-bp or
the nested 139-bp L1
region
HPV
DNA
fragments
in
all
specimen tested
NA
NA
HPV 16, 18+ vs. HPV
16, 18-
No
Method:
PCR
Controls:
“specimens of pinguecula (n=1), pterygia (n=13: 7
with primary, 1 with recurrent, 1 with dysplasia,
and 4 primary (…)”
Karcioglu, 1997
(Karcioglu
&
Issa, 1997)
Saudi Arabia
Cases:
"Specimens from 115 patients, 69 males (60%)
and 46 females (40%) were included in this study."
Invasive
SCCC and
in situ SCCC
Mucosal HPV subtypes 16, 18 tested;
both subtypes were detected
Method: nested PCR
OR=2.7
(0.87-8.40) *
Controls:
"19 specimens of normal appearing conjunctiva
were included"
Tabrizi et al,
1997) (Tabrizi et
al, 1997)
Australia,
ND
Cases:
“all cases reported as corneal or conjunctival
carcinoma or severe dysplasia” (88 cases)
Corneal or
conjunctival
carcinoma
Broad spectrum of mucosal HPV
subtypes tested
HPV 6, 11, 16 and 18 found
Controls:
“control specimens (n=66) were selected from
conjunctival and corneal specimens with no or
minimal dysplasia and were matched by year of
biopsy, gender and age (…) Pterygia was present
(…) in 48 (74%) controls”
NA
Mucosal HPV+
Mucosal HPV-
vs
No
OR=7.68 (2.80-21.04)
*
Method:
PCR
11
1st author,
year of
publication
Country,
region
Waddell, 1996
(Waddell et al,
1996)
Uganda,
Kampala
Description of the participants
Cases:
“all patients in seven countywide eye clinics who
had suspicious conjunctival lesions had excision
biopsy of the lesion (…). In September to October
1994 at New Malugo Hospital, Kampala, the same
procedure was followed." (In total, 12 CIN and 20
SCCC from Malawi; 11 CIN and 27 SCCC from
Uganda)
Outcome
CIN
SCCC
and
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
NA
HIV
of
specified
subtype
not
Method: serology
Western blot
NA
and
Relative
risk
estimate (95%CI)
Control
of
confounding
HIV+ vs. HIV-
No
OR=13.1 (4.7-37.6)
Mucosal HPV of subtype 16 was
tested
HPV 16+ vs. HPV 16-
No
OR=1.08
(0.16-7.42) *
Method: PCR
Controls:
"The controls came from the same unit or lived in
the same district. Sixteen controls were patients in
the eye clinic without neoplasia or clinical features
of HIV disease; the remaining 54 were general
(non-eye clinic) anonymous outpatients ate the
same health units"
Adachi, 1995
(Adachi et al,
1995)
Japan, not
further
specified
Cases:
“We tried to identify human papilloma virus (HPV)
in ocular surface diseases characterized by
abnormal epithelial proliferation”
SCCC
Uganda,
Kampala
Cases:
"all patients with conjunctival growths who
presented to the ophthalmology clinic had an
excision biopsy"
USA,
not
further
specified
Description of the cohort:
“We investigated the relation of this disease and of
malignant melanoma of the conjunctiva to AIDS
(…) In 50050 people with AIDS”
HPV 16 and/or 18+ vs.
HPV 16 and/or 18-
No
OR=10.00
(0.53-187.10) * ¶
Method: PCR
SCCC
NA
HIV
of
specified
subtype
not
HIV+ vs. HIV-
No
OR=13.0 (4.5-39.4)
Method: ELISA, followed
by
Western
blot
confirmation
Controls:
"Age-matched and sex-matched controls were
chosen from patients attending the same clinic
with other eye diseases."
Goedert, 1995
(Goedert
&
Cote, 1995)
NA
Only HPV subtype 16 was detected
Controls:
“9 normal eyes”
Ateenyi-Agaba,
1995
(Ateenyi-Agaba,
1995)
Mucosal HPV subtypes 16 and 18
were tested
SCCC
NA
HIV
of
specified
subtype
not
HIV+ vs. HIV-
ND
SIR=13 (4-34)
HIV assessment: previous
diagnosis
12
1st author,
year of
publication
Country,
region
Saegusa, 1995
(Saegusa et al,
1995)
Japan,
Kanagawa
Kestelyn, 1990
(Kestelyn et al,
1990)
Rwanda,
Kigali
Description of the participants
Cases:
“four [cases] of dysplasia, and four of squamous
cell carcinomas surgically removed from the eyelid
area (…)”
Controls:
“12 [cases] of basal cell epithelioma”
Cases:
"all patients with clinical evidence of conjunctival
dysplasia or malignancy" (5 CIN and 6 SCCC)
Controls:
"To select controls from the same outpatient
department we took blood from all patients on two
consecutive days at the end of the study period.
(…) Patients referred from elsewhere and patients
with ocular malignancies were excluded from the
control group. We randomly selected two controls,
matched on sex and age within five years, for each
case and tested their blood for HIV antibody."
McDonnell et al,
1989
(McDonnell et al,
1989)
United
States
of
America,
Los Angeles
Cases:
“six patients with dysplastic or malignant lesions of
the conjunctiva”
Controls:
“one specimen each of conjunctival nevus,
melanoma, pterygium and cutaneous seborrheic
keratosis.”
Outcome
Dysplasia
and SCCC
HPV infection
HIV infection/AIDS
Exposure assessed
Method
Exposure assessed
Method
HPV mucosal subtypes 6, 11, 16, 18,
31, 33, 42, 52, 58 were tested
NA
Only HPV subtype 16 was detected
Method: PCR and in situ hybridization
OSSN
(dysplasia,
in
situ
epitelioma
and SCCC)
NA
OSSN
HPV subtypes
searched
Relative
risk
estimate (95%CI)
Control
of
confounding
HPV 16+ vs. HPV 5,
11, 16, 18, 31, 33, 42,
52, 58-
No
OR=10.11
(0.59-172.83) *
HIV
of
specified
subtype
not
HIV+ vs HIV-
No
OR=13 (2.2-76.9)
Method: ELISA, followed
by
immunofluorescence
and
Western
blot
confirmation
Method:
PCR
16
and
18
were
NA
Mucosal HPV+
mucosal HPV-
vs
No
OR=13.00
(0.89-189.39) *
95%CI – 95% confidence interval;
NA – not applicable;
ND – not defined;
13
PCR – polymerase chain reaction;
IHC – immunohistochemistry
ISH – in situ hydridization
SCC – squamous cell carcinoma;
SCCC – squamous cell carcinoma of the conjunctiva;
AIDS – acquired immune deficiency syndrome;
CIN- conjunctival intraepithelial neoplasia;
EV - epidermodysplasia verruciformis
* OR estimates and corresponding 95% confidence intervals computed by the authors of the present review using Epi Info 7® with the
information presented in the original study;
‖ None of the controls were infected with HPV;
† None of the HIV infected subjects were HPV infected;
¶ Odds ratio and respective confidence intervals were estimated using the metan command of the STATA®, which adds by default 0.5 to all
cells of the 2x2 table of the study;(Harris et al, 2008)
*** We computed odds ratios after excluding the papilloma included in the control group;
**** Putative new HPV type identified;
14
‡ OR estimates computed by the authors of the present study, though sample recruitment procedures involved matched controls. (Palazzi et al,
2000; Scott et al, 2002; Tornesello et al, 2006)
§ When the proportion of exposed subjects was provided separately for two or more of the conditions jointly referred as OSSN (mild-dysplasia,
severe dysplasia, carcinoma in situ, invasive squamous cell carcinoma (SCC), we computed an overall RR estimate considering OSSN as the
outcome.
15
16
References
Adachi W, Nishida K, Shimizu A, Soma H, Yokoi N, Kinoshita S (1995) Human papilloma
virus in the conjunctiva in ocular surface diseases. Japanese Journal of Clinical
Ophthalmology 49(3): 439-442
Asadi-Amoli F, Heidari AB, Jahanzad I, Jabbarvand M (2011) Detection of human
papillomavirus in squamous cell carcinoma of conjunctiva by nested PCR: a case control
study in Iran. Acta Med Iran 49(11): 707-14
Ateenyi-Agaba C (1995) Conjunctival squamous-cell carcinoma associated with HIV
infection in Kampala, Uganda. Lancet 345(8951): 695-6
Ateenyi-Agaba C, Franceschi S, Wabwire-Mangen F, Arslan A, Othieno E, Binta-Kahwa
J, van Doorn LJ, Kleter B, Quint W, Weiderpass E (2010) Human papillomavirus
infection and squamous cell carcinoma of the conjunctiva. Br J Cancer 102(2): 262-7
Ateenyi-Agaba C, Weiderpass E, Smet A, Dong W, Dai M, Kahwa B, Wabinga H,
Katongole-Mbidde E, Franceschi S, Tommasino M (2004) Epidermodysplasia
verruciformis human papillomavirus types and carcinoma of the conjunctiva: a pilot
study. Br J Cancer 90(9): 1777-9
Auw-Haedrich C, Martin G, Spelsberg H, Sundmacher R, Freudenberg N, Maier P,
Reinhard T (2008) Expression of p16 in Conjunctival Intraepithelial Neoplasia Does Not
Correlate with HPV-Infection. Open Ophthalmol J 2: 48-56
Carrilho C, Gouveia P, Yokohama H, Lopes JM, Lunet N, Ferro J, Ismail M, Walboomers
J, Sobrinho-Simoes M, David L (2013) Human papillomaviruses in intraepithelial
neoplasia and squamous cell carcinoma of the conjunctiva: a study from Mozambique.
Eur J Cancer Prev
Chauhan S, Sen S, Sharma A, Dar L, Kashyap S, Kumar P, Bajaj MS, Tandon R (2012)
Human papillomavirus: a predictor of better survival in ocular surface squamous
neoplasia patients. Br J Ophthalmol
Chinogurei TS, Masanganise R, Rusakaniko S, Sibanda E (2006) Ocular surface
squamous neoplasia (OSSN) and human immunodeficiency virus at Sekuru Kaguvi Eye
Unit in Zimbabwe: the role of operational research studies in a resource poor
environment? Cent Afr J Med 52(5-6): 56-8
de Koning MN, Waddell K, Magyezi J, Purdie K, Proby C, Harwood C, Lucas S, Downing
R, Quint WG, Newton R (2008) Genital and cutaneous human papillomavirus (HPV)
types in relation to conjunctival squamous cell neoplasia: a case-control study in
Uganda. Infect Agent Cancer 3: 12
17
Dushku N, Hatcher SL, Albert DM, Reid TW (1999) p53 expression and relation to
human papillomavirus infection in pingueculae, pterygia, and limbal tumors. Arch
Ophthalmol 117(12): 1593-9
Goedert JJ, Cote TR (1995) Conjunctival malignant disease with AIDS in USA. Lancet
346(8969): 257-8
Guech-Ongey M, Engels EA, Goedert JJ, Biggar RJ, Mbulaiteye SM (2008) Elevated risk
for squamous cell carcinoma of the conjunctiva among adults with AIDS in the United
States. Int J Cancer 122(11): 2590-3
Guthoff R, Marx A, Stroebel P (2009) No evidence for a pathogenic role of human
papillomavirus infection in ocular surface squamous neoplasia in Germany. Curr Eye
Res 34(8): 666-71
Harris RJ, Bradburn MJ, Deeks JJ, Harbord RM, Altman DG, Sterne JAC (2008) metan:
fixed- and random-effects meta-analysis. The Stata Journal 8(1): 3-28
Karcioglu ZA, Issa TM (1997) Human papilloma virus in neoplastic and non-neoplastic
conditions of the external eye. Br J Ophthalmol 81(7): 595-8
Kestelyn P, Stevens AM, Ndayambaje A, Hanssens M, van de Perre P (1990) HIV and
conjunctival malignancies. Lancet 336(8706): 51-2
McDonnell JM, Mayr AJ, Martin WJ (1989) DNA of human papillomavirus type 16 in
dysplastic and malignant lesions of the conjunctiva and cornea. N Engl J Med 320(22):
1442-6
Newton R, Ziegler J, Ateenyi-Agaba C, Bousarghin L, Casabonne D, Beral V, Mbidde E,
Carpenter L, Reeves G, Parkin DM, Wabinga H, Mbulaiteye S, Jaffe H, Bourboulia D,
Boshoff C, Touze A, Coursaget P (2002) The epidemiology of conjunctival squamous
cell carcinoma in Uganda. Br J Cancer 87(3): 301-8
Palazzi MA, Erwenne CM, Villa LL (2000) Detection of human papillomavirus in epithelial
lesions of the conjunctiva. Sao Paulo Med J 118(5): 125-30
Porges Y, Groisman GM (2003) Prevalence of HIV with conjunctival squamous cell
neoplasia in an African provincial hospital. Cornea 22(1): 1-4
Saegusa M, Takano Y, Hashimura M, Okayasu I, Shiga J (1995) HPV type 16 in
conjunctival and junctional papilloma, dysplasia, and squamous cell carcinoma. J Clin
Pathol 48(12): 1106-10
Scott IU, Karp CL, Nuovo GJ (2002) Human papillomavirus 16 and 18 expression in
conjunctival intraepithelial neoplasia. Ophthalmology 109(3): 542-7
18
Sen S, Sharma A, Panda A (2007) Immunohistochemical localization of human
papilloma virus in conjunctival neoplasias: a retrospective study. Indian J Ophthalmol
55(5): 361-3
Simbiri KO, Murakami M, Feldman M, Steenhoff AP, Nkomazana O, Bisson G,
Robertson ES (2010) Multiple oncogenic viruses identified in Ocular surface squamous
neoplasia in HIV-1 patients. Infect Agent Cancer 5: 6
Tabrizi SN, McCurrach FE, Drewe RH, Borg AJ, Garland SM, Taylor HR (1997) Human
papillomavirus in corneal and conjunctival carcinoma. Aust N Z J Ophthalmol 25(3): 2115
Timm A, Stropahl G, Schittkowski M, Sinzidi C, Kayembe D, Guthoff R (2004)
[Association of malignant tumors of the conjunctiva and HIV infection in Kinshasa (D. R.
Congo). First results]. Ophthalmologe 101(10): 1011-6
Tornesello ML, Duraturo ML, Waddell KM, Biryahwaho B, Downing R, Balinandi S,
Lucas SB, Buonaguro L, Buonaguro FM (2006) Evaluating the role of human
papillomaviruses in conjunctival neoplasia. Br J Cancer 94(3): 446-9
Tulvatana W, Bhattarakosol P, Sansopha L, Sipiyarak W, Kowitdamrong E,
Paisuntornsug T, Karnsawai S (2003) Risk factors for conjunctival squamous cell
neoplasia: a matched case-control study. Br J Ophthalmol 87(4): 396-8
Waddell KM, Lewallen S, Lucas SB, Atenyi-Agaba C, Herrington CS, Liomba G (1996)
Carcinoma of the conjunctiva and HIV infection in Uganda and Malawi. Br J Ophthalmol
80(6): 503-8
19