Article Type: Clinical Article

Accepted Article
Colposcopic biopsy findings among women with either HPV-16 only or HPV-18

only who have normal cervical cytology

Ibrahim Yalcin 1*, Mustafa E. Sari 1, Hanifi Sahin 1, Murat Gultekin 2, Tayfun Gungor 1,

Mehmet M. Meydanli 1

1
Department of Gynecologic Oncology, Zekai Tahir Burak Women’s Health Research and

Training Hospital, Faculty of Medicine, University of Health Sciences, Ankara, Turkey

2
Department of Gynecologic Oncology, Faculty of Medicine, Hacettepe University, Ankara,

Turkey

*
Corresponding author: Ibrahim Yalcin

Department of Gynecologic Oncology, Zekai Tahir Burak Women’s Health Research and

Training Hospital, Faculty of Medicine, University of Health Sciences, Hacettepe Mahallesi,

Talatpaşa Bulvarı No: 128 Posta kodu 06230, Samanpazarı, Altındağ, Ankara, Turkey.

E-mail: ibrahimyalcin73@gmail.com

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/ijgo.12652

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 Keywords: Cancer screening; Colposcopy; Cytology; High-grade squamous
Accepted Article intraepithelial lesions; HPV; Low-grade squamous intraepithelial lesions.

Synopsis: High-grade squamous intraepithelial lesions were increased among women with

normal cervical cytology and HPV-16 only versus women with normal cervical

cytology and HPV-18 only.

Abstract

Objective: To compare colposcopic biopsy results among women with normal cervical

cytology who had positive test results for either HPV-16 only or HPV-18 only.

Methods: A cross-sectional study was conducted at Zekai Tahir Burak Women’s

Health Research and Training Hospital, Ankara, Turkey, between July 1, 2015, and

October 31, 2017. Colposcopic biopsy results were compared among women in the

HPV-16 only (n=185) and HPV-18 only (n=43) groups.

Results: Women who had HPV-16 only were more likely to be smokers than women with

HPV-18 only (P=0.003). By contrast, women with HPV-18 only were more likely to be aged

at least 45 years than women who had HPV-16 only (P=0.038). High-grade squamous

intraepithelial lesions were detected more frequently in the HPV-16 only group (51 [27.6%])

than in the HPV-18 only group (4 [9.3%]; P=0.010. By contrast, no between-group difference

was found for the rate of invasive cervical cancer, which was detected in 1 (0.5%) woman in

the HPV-16 only group and 1 (2.3%) woman in HPV-18 only group (P=0.342).

Conclusion: Although the risk of high-grade squamous intraepithelial lesions was

increased among women with HPV-16 only, this finding did not influence the rate of

invasive cervical cancer when compared with women in the HPV-18 only group.

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 1. Introduction
Accepted Article Regardless of cervical cytology, HPV-16 is the most prevalent HPV genotype detected in

histologic specimens of precancerous lesions worldwide [1]. Indeed, HPV-16 is two-to-three

times more prevalent than HPV-18 [1], which in turn ranks as the second most frequently

detected type of HPV in cervical cancer [2]. In addition, HPV-16 and HPV-18 were the most

common HPV types among females with normal cervical cytology findings in the pre-HPV

vaccination era [3].

Persistent infection with HPV-16 and/or HPV-18 is the most important determinant

for the development of precancerous lesions and cervical cancer [2]. In the USA, the

10-year cumulative risk of cervical intraepithelial neoplasia 3 (CIN 3) or worse

associated with once-in-a lifetime detection of HPV-16 or HPV-18 was five-fold

greater when compared with other types of high-risk HPV (17% and 14% vs 3%,

respectively) [4]. According to consensus guidelines, women aged 30 years or older

who have normal cervical cytology but positive HPV-16 or HPV-18 test results

should be referred for immediate colposcopy [5]. To date, few studies have assessed

the colposcopic biopsy results of women with positive tests results for HPV-16 or

HPV-18 [6–10]. Most of the available studies demonstrated increased rates of CIN 3

among patients with HPV-16 compared with patients with HPV-18 [7–10]. However,

the women enrolled in these studies were not identified as having a single type of

HPV. Of note, only Monsonego et al. [9]—who analyzed data from the baseline

phase of the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial—

reported colposcopic biopsy results among patients with HPV-16 and HPV-18 with

normal cervical cytology. However, a direct comparison of biopsy results among

women with normal cervical cytology who have either HPV-16 only or HPV-18 only

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 has yet to be reported.
Accepted Article
A well-organized nationwide cervical cancer screening program based on HPV DNA testing

has been running in Turkey since 2014 [11]. The aim of the present study was to compare

colposcopic biopsy results of women in Turkey with normal cervical cytology who had either

HPV-16 only or HPV-18 only.

2. Materials and methods

The present cross-sectional study was conducted in the Department of Gynecologic

Oncology, Zekai Tahir Burak Women’s Health Research and Training Hospital, Ankara,

Turkey, between July 1, 2015, and October 31, 2017. The Local Ethics Committee of Zekai

Tahir Burak Women’s Health Research and Training Hospital approved the present study

on June 29, 2015 (approval number: 08). All participants provided written informed consent

for the performance of diagnostic and surgical procedures, as well as the use of their clinical

data for research purposes.

Since January 2014, women in Turkey who are aged 30–65 years have been encouraged to

participate in a nationwide HPV DNA screening program [11]. Screening is performed by

front-line healthcare personnel (i.e. general practitioners [GPs] and KETEM screening

centers—facilities for the early screening and diagnosis of cancer). The present study was

designed around this pre-existing Turkish screening program.

Kits for collecting HPV DNA samples (Hybrid Capture 2; Qiagen, Hilden, Germany) were

sent to local healthcare authorities in each province by central laboratories based in Ankara

and Istanbul. The local authorities then made these kits available to GPs and KETEM

screening centers. Every woman who attended screening provided two samples, one for

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 conventional cytology testing and the other for HPV DNA testing. A brush was used to obtain
Accepted Article the first sample, which was then placed onto a glass slide for cytology testing. As detailed

previously, the cytology tests were interpreted by four pathologists at a central laboratory

[11]. The second sample was obtained using a separate brush and placed into 5 mL of the

standard transport medium from the Hybrid Capture 2 collection kit for HPV DNA testing. As

previously described, genotyping was carried out using the CLART HPV kit (Genomica,

Madrid, Spain) for any patient who had a positive non-specific HPV test result [11]. The

specimens were evaluated at the two central laboratories in Ankara and in Istanbul. The

specimens were tracked and the results delivered online using a fully automated operational

system.

Inclusion criteria for the present study were normal cervical cytology and a positive test

result for either HPV-16 only or HPV-18 only. Women with multiple HPV positivity (i.e. HPV-

16 plus HPV-18; HPV-16 plus another type of high-risk HPV; or HPV-18 plus another type of

high-risk HPV) were excluded. Other exclusion criteria were a history of cervical histology

anomaly or cancer at any site; HIV infection; immunosuppressive treatment; and HPV

vaccination.

Colposcopy was provided free of charge at a post-screening diagnostic center for any

patient with a positive result for either HPV-16 only or HPV-18 only. At least one such center

is located in each of the 81 provinces of Turkey. The outpatient colposcopy clinic at Zekai

Tahir Burak Women’s Health Research and Training Hospital is one of the two post-

screening diagnostic centers in Ankara province. Women residing in the east of this province

who had positive HPV test results were referred to this clinic by GPs responsible for that

region.

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 Four gynecologic oncologists (IY, MES, HS, MMM) performed colposcopy and colposcopy
Accepted Article directed biopsies for the entire study cohort. A MIKRO colposcope with Leica M60LED

optics (MIKRO, Prague, Czech Republic) was used for these procedures. The cervix was

examined by colposcopy after applying a 3% solution of acetic acid to the ectocervix.

Colposcopic findings were described using the criteria of the International Federation of

Cervical Pathology and Colposcopy [12]. The colposcopy result was accepted as adequate if

the cervix could be completely evaluated and was not blocked by bleeding, inflammation, or

scarring. The squamocolumnar junction was assessed to be completely apparent when 360°

of the junction could be visualized. A colposcopically directed biopsy was obtained from the

area with the greatest degree of abnormal appearance, after which endocervical curettage

(ECC) was performed. If there were no obvious abnormal colposcopy findings, two random

cervical punch biopsies were taken from the transformation zone, and then ECC was carried

out. If unsatisfactory colposcopy findings were obtained, two random cervical punch biopsies

were taken at 12 o’clock and 6 o’clock (the midpoint of the anterior and posterior lip of the

cervix, respectively), and ECC was then carried out. Institutional policy was to perform

cervical punch biopsy and ECC for cases of high-risk HPV DNA positivity.

Cervical conization was conducted when the initial work-up revealed high-grade squamous

intraepithelial lesions. The final histologic statistical comparison was made on the most

severe histologic findings obtained from cervical punch biopsy, ECC, or cervical

conization. Findings were categorized for analysis as normal and/or inflammation;

koilocytosis; low-grade squamous intraepithelial lesion (LSIL); high-grade squamous

intraepithelial lesion (HSIL); and/or invasive cervical carcinoma. Three gynecologic

pathologists reviewed the surgical specimens in a masked manner. The final diagnosis was

made using standard criteria for the Lower Anogenital Squamous Terminology [13].

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 Patient characteristics, including age; menopausal status; age at marriage; body mass index
Accepted Article (BMI, calculated as weight in kilograms divided by the square of height in meters); level of

education; parity; smoking habit; and contraceptive use, were recorded at entry into the

present study.

The data were analyzed using SPSS version 22 (IBM, Armonk, NY, USA). Descriptive

statistics were used for the demographic data. Values were analyzed using the Mann–

Whitney U, χ2, or Fisher exact tests, as appropriate. A P value of less than 0.05 was

considered statistically significant.

3. Results

In all, 723 women aged 30–65 years were considered for eligibility for the present study;

of these, 228 women had positive test results for either HPV-16 only or HPV-18 only

and were included in the study. The median age of these patients was 44 years.

Table 1 outlines the demographic characteristics and colposcopy findings of the HPV-16

only group (n=185) versus the HPV-18 only group (n=43). Women who had HPV-16 only

were more likely to be smokers than were women with HPV-18 only (P=0.003). By contrast,

women with HPV-18 only were more likely to be aged at least 45 years than women who

had HPV-16 only (P=0.038) No other statistically significant between-group differences were

found for either the demographic characteristics or colposcopy findings.

The final pathology results for each group and for each diagnostic procedure are

shown in Table 2. In the HPV-16 only group, seven women were diagnosed as having

HSILs only by ECC. The two groups of patients were compared in terms of HSILs diagnoses

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 made using to the two diagnostic procedures. Women in the HPV-16 only group were more
Accepted Article likely to have HSILs than the women in the HPV-18 only group (51 [27.6%] vs 4 [9.3%],

respectively; P=0.010.

All 57 women diagnosed with HSILs by colposcopy underwent cold-knife conization,

and 10 women had positive surgical cone margins. Eight of these patients underwent

reconization and two underwent simple hysterectomy. No residual disease was found

after the final operations.

After the cold-knife conization, there was one invasive cervical cancer diagnosis in each

group who were initially diagnosed as HSILs. No between-group difference was found for

the rate of invasive cervical cancer (Table 2). One (0.5%) woman in the HPV-16 only group

and one (2.3%) woman in the HPV-18 only group were diagnosed with this condition

(P=0.342).

4. Discussion

To the best of our knowledge, the present study was the first to compare colposcopic biopsy

results among women with normal cervical cytology who had either HPV-16 only or HPV-18

only. The findings indicated that women in HPV-16 only group were more likely to have high-

grade lesions than were those in the HPV-18 only group. By contrast, no between-group

difference was found in the rate of invasive cervical cancer.

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 Several authors have clearly demonstrated that HPV-16 and HPV-18 status is an important
Accepted Article predictor for detection of high-grade cervical lesions [4, 9, 14–16]. In a sub-analysis of the

ATHENA data, the risk of CIN 2 or worse was increased among women in all age groups

who had HPV-16 versus women who had HPV-18 (31.5% vs 4.3%, respectively.) [10].

However, ATHENA included patients with atypical squamous cells of undetermined

significance on cytologic examination. Wright et al. [15] evaluated HPV-16 and HPV-18

genotypes for the triage of women with high-risk HPV but normal cervical cytology. The

absolute risk of CIN 3 or worse was 11.7% (95% confidence interval 7.9–15.8) among

women with HPV-16 and 5.7% (95% confidence interval 1.7–9.9) among women with HPV-

18. Unfortunately, however, these investigators did not state the absolute number of patients

in each group. Schiffman et al. [17] reported a 3-year cumulative risk of CIN 3 or worse

among a group of 18 000 women (age ≥30 years) with normal cervical cytology and a

positive high-risk HPV test result. The risk was 10.6% in the HPV-16 group versus 5.9% in

the HPV-18 group.

Table 3 summarizes data from both published studies that have reported biopsy results

among women with HPV-16 and HPV-18, irrespective of the cervical cytology findings [6–

10], and the present study. Monsonego et al. [9] reanalyzed the ATHENA data on

genotyping of the participants with normal cervical cytology (age ≥30 years). The rate of CIN

3 or worse was 8.2% (31 of 380) among women with HPV-16 versus 4.7% (8 of 169) among

women with HPV-18. By contrast, the rates in the present study were 28.1% and 11.6%,

respectively. Monsonego et al. [9] detected invasive cervical cancer in only one woman

included in the ATHENA study. This patient had HPV-18 and had normal cervical cytology.

In addition, McKenna et al. [6] did not report any invasive cervical cancer among women

who had HPV-16 or HPV-18. Similarly to the study of Monsonego et al. [9], the present study

found only two patients had invasive cervical cancer, one (0.5%) in the HPV-16 only group

and one (2.3%) in the HPV-18 group; however, this difference was not statistically

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 significant. Besides these low cervical cancer rates, two recent studies from Lagos et al. [7]
Accepted Article and Zhang et al. [8] reported invasive cervical cancer in 4 (2.1%) and 81 (8.5%) women who

had HPV-16, respectively, and invasive cervical cancer in (2.6%) and 17 (9.3%) patients

with HPV-18, respectively. Unfortunately, both Lagos et al. [7] and Zhang et al. [8] did not

report cervical cytology results from these patients.

Kurman et al. [18] first investigated individual distribution of HPV-16 and HPV-18 in various

grades of CIN and invasive squamous carcinoma. A marked difference was found regarding

the distribution of HPV-18 in intraepithelial neoplasia versus invasive squamous carcinoma

(3% vs. 22%; P<0.001). Consequently, it was suggested that HPV-18 might play a role in the

development of rapidly progressive cervical cancer. Woodman et al. [19] evaluated cytologic

anomalies that occurred subsequent to infection with HPV-16 or HPV-18. The acquisition

time of such abnormalities was not associated with the type of HPV infection (P=0.88).

Therefore, these investigators were unable to support the aggressive nature of HPV-18-

associated anomalies, a conclusion that was in line with the findings of both the present

study and that of Monsonego et al. [9].

Strengths of the current study included the fact that a specific commercial kit was used for

HPV DNA genotyping to ensure that the analysis included patients who had HPV-16 only or

HPV-18 only. This approach was important because, although HPV-16 and HPV-18 are

separate genetic species, some data suggested that prevalent HPV types can influence

each other [20]. In addition, only women with normal cervical cytology were included in the

present study, which was performed in the context of a nationwide cervical cancer screening

program based on HPV DNA. Finally, the current study was one of the largest series of

patients with normal cervical cytology and either HPV-16 only or HPV-18 only that has

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 included colposcopic punch biopsy and ECC results. Taken together, these various factors
Accepted Article reduced the possibility of confounding and enhanced the reliability of the current findings.

Nonetheless, the present study had some limitations. The inadequate tissue obtained by

ECC might have influenced the high-grade biopsy rates among both groups. Likewise, the

small number of patients in the HPV-18 only group might have influenced the histopathologic

outcomes. Causation could not be proven from the current smoking status data as the high

rate recorded in the HPV-16 only group might have resulted in selection bias. Finally, data

were lacking for patients aged younger than 30 years.

In conclusion, the present study findings are likely to contribute to the limited body of

evidence on this topic and have some important clinical implications. Although the risk of

high-grade squamous intraepithelial lesions was increased among women with HPV-16

only, this finding did not influence the rate of invasive cervical cancer when

compared with women who had HPV-18 only. This observation might help to inform

the future direction of the Turkish cervical cancer screening program. Further virology

and clinical studies are now required to determine differences in the natural history of

cervical cancer associated with infection by either HPV-16 only or HPV-18 only.

Author contributions

IY contributed to data collection, data analysis, data interpretation, and writing the

manuscript. MES contributed to the design of the study, data collection, data analysis, and

revising the manuscript. HS contributed to data collection, data analysis, and revising the

manuscript. MG contributed to data collection, data interpretation, and revising the

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 manuscript. TG contributed to data interpretation, and revising the manuscript. MMM
Accepted Article contributed to the design of the study, and revising the manuscript. All authors reviewed and

approved the final version of the manuscript for publication.

Conflicts of interest

The authors have no conflicts of interest.

References

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[3] Bruni L, Diaz M, Castellsague X, Ferrer E, Bosch FX, de Sanjose S: Cervical human

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 [6] McKenna M, McMenamin M, McDowell A: HPV16 and HPV18 genotyping triage in young
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 [14] Kjaer SK, van den Brule AJ, Paull G, et al.: Type specific persistence of high risk human
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 a
Table 1 Characteristics of patients (n=228).

Characteristic HPV-16 only group (n=185) HPV-18 only group (n=43) P value b
Accepted Article
Age, y 43 (30–66) 47 (32–66) 0.011

<45 102 (55.1) 16 (37.2) 0.038

≥45 83 (44.9) 27 (62.8)

Menopausal status 0.148

Premenopausal 123 (66.5) 23 (53.5)

Postmenopausal 62 (33.5) 20 (46.5)

Age at marriage, y 19 (11–39) 19 (15–37) 0.485

BMI 24.6 (18.0–39.5) 28.1 (21.6–36.4) 0.056

Level of education 0.195

Primary school 93 (50.3) 31 (72.0)

High school 50 (27.0) 6 (14.0)

Bachelor’s degree or 42 (22.7) 6 (14.0)

higher

Parity 0.080

<2 46 (25.0) 4 (9.3)

≥2 139 (75.0) 39 (90.7)

Smoking status 0.003

Smoker 109 (58.9) 10 (23.2)

Non-smoker 76 (41.1) 33 (76.8)

Contraceptive method 0.235

Coitus interruptus 122 (66.0) 35 (81.4)

Oral combined pills 29 (15.7) 3 (7.0)

Intrauterine device 34 (18.3) 5 (11.6)

Colposcopic findings
c
Inadequate 8 (4.3) 2 (4.6) >0.99

Normal 65 (35.1) 17 (39.5) 0.600

Low-grade d 61 (33.0) 18 (41.9) 0.289

High-grade e 51 (27.6) 6 (14.0) 0.078

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 Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by the square of height
in meters).
Accepted Article a
Values are given as median (range) or number (percentage), unless otherwise indicated.
b
Values were analyzed using the Mann–Whitney U, χ2, or Fisher exact tests, as appropriate. P<0.05
was considered statistically significant.
c
Cervix could not be visualized (e.g., obscured by inflammation, bleeding, scarring).
d
Low grade was defined as fine mosaic, fine punctation, thin acetowhite epithelium.
e
High grade was defined as harp border, inner border sign, ridge sign, dense acetowhite epithelium,
coarse mosaic, coarse punctuation, rapid appearance of acetowhitening.

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 a
Table 2 Final pathology results among patients (n=228).

Grou Diagnosis by endocervical curettage Diagnosis by cervical punch Diagno

Accepted Article
p biopsy sis by
an
excisio
nal
proced
ure

Normal Inadequ Koilocyt LSI HSI Normal Koilocyt LSI HSI Invasiv
and/or ate osis L L and/or osis L L e
inflamma tissue inflamma cervical
tion tion cancer

HPV- 132 12 (6.5) 1 (0.5) 13 27 78 (42.2) 7 (3.8) 55 45 1 (0.5)

16 (71.4) (7.0 (14. (29. (24.
only ) 6) 7) 3)
(n=18
5)

HPV- 30 (69.8) 2 (4.7) 1 (2.3) 5 5 21 (48.8) 2 (4.7) 15 5 1 (2.3)

18 (11. (11. (34. (11.
only 6) 6) 9) 6)
(n=43
)

Abbreviations: HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous

intraepithelial lesion.
a
Values are given as number (percentage).

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 a
Table 3 Comparison of the present study findings with the published literature.

Study HPV-16 HPV-18

Accepted Article
No. of Cancer CIN 3 CIN 2 No. of Cancer CIN 3 CIN 2
patients patients

Stoler et al. 47 NA 8 5 17 NA 1 NA
b
[10] (17.0) (10.6) (5.8)

McKenna 38 NA 11 6 18 NA 6 6
c
et al. [6] (28.9) (15.7) (33.3) (33.3)

Lagos et al. 186 4 (2.1) 21 13 75 2 (2.6) 5 1

d
[7] (11.2) (6.9) (6.6) (1.3)

Zhang et 943 81 (8.5) 110 106 181 17 14 11

d, e
al. [8] (11.6) (11.2) (9.3) (7.7) (6.0)

Monsonego 380 NA 31 5 169 1 (0.6) 7 2

f
et al. [9] (8.2) (1.3) (4.1) (1.2)

Present 185 1 (0.5) 51 NA 43 1 (2.3) 4 NA

f, g h
study (27.6) (9.3)
h

Abbreviation: CIN, cervical intraepithelial neoplasia; NA, not applicable.

a
Values are given as number (percentage).
b
Only patients with atypical squamous cells of undetermined significance; only patients aged >30 y
included in this table row.
c
Only patients with borderline cytology or mild dyskaryosis.
d
Cytology status was unknown.
e
Patients older than 25 years.
f
Studies that included patients with normal cytology.
g
Most severe histologic findings obtained from endocervical curettage, cervical punch biopsy, or
cervical conization.
h
Data reported according to the Lower Anogenital Squamous Terminology.

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