Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006 ARTICLES 765
Human Papillomavirus Testing and Liquid-Based Cytology:
Results at Recruitment From the New Technologies for
Cervical Cancer Randomized Controlled Trial
Guglielmo Ronco , Nereo Segnan , Paolo Giorgi-Rossi , Marco Zappa , Gian
Piero Casadei , Francesca Carozzi , Paolo Dalla Palma , Annarosa Del Mistro ,
Stefania Folicaldi , Anna Gillio-Tos , Gaetano Nardo , Carlo Naldoni , Patrizia
Schincaglia , Manuel Zorzi , Massimo Confortini , Jack Cuzick
For the New Technologies for Cervical Cancer Working Group
Background: Although testing for human papillomavirus
(HPV) has higher sensitivity and lower specifi city than
cytology alone for detecting cervical intraepithelial neopla-
sia (CIN), studies comparing conventional and liquid-based
cytology have had confl icting results. Methods: In the fi rst
phase of a two-phase multicenter randomized controlled
trial, women aged 35 – 60 years in the conventional arm ( n =
16 658) were screened using conventional cytology, and
women in the experimental arm ( n = 16 706) had liquid-
based cytology and were tested for high-risk HPV types
using the Hybrid Capture 2 assay. Women in the conven-
tional arm were referred to colposcopy with atypical cells of
undetermined signifi cance (ASCUS) or higher and those in
the experimental arm were referred with ASCUS or higher
cytology or with a positive ( ≥ 1 pg/mL) HPV test. Sensitivity
and positive predictive value (PPV) for detection of cervical
intraepithelial neoplasia grade 2 or higher (CIN2+) were
calculated. Results: The screening methods and referral cri-
terion applied in the experimental arm had higher sensitiv-
ity than that in the conventional arm (relative sensitivity =
1.47; 95% confi dence interval [CI] = 1.03 to 2.09) but a lower
PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV
testing alone at ≥1 pg/mL and at ≥2 pg/mL, the gain in sensi-
tivity compared with the conventional arm remained similar
(relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative
sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but
PPV progressively improved (relative PPV = 0.58, 95% CI =
0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27,
respectively). Referral based on liquid-based cytology alone
did not increase sensitivity compared with conventional
cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55)
but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82).
Conclusions: HPV testing alone was more sensitive than con-
ventional cytology among women 35 – 60 years old. Adding
liquid-based cytology improved sensitivity only marginally
but increased false-positives. HPV testing using Hybrid Cap-
ture 2 with a 2 pg/mL cutoff may be more appropriate than
a 1 pg/mL cutoff for primary cervical cancer screening.
[J Natl Cancer Inst 2006;98:765 – 74]
Several studies have demonstrated that human papillomavirus
(HPV) testing has a greater sensitivity but lower specifi city than
cytology for detecting high-grade cervical intraepithelial neoplasia
(CIN) ( 1 – 13 ). All of these studies have employed a split- sample,
or two-sample, design, in which each woman is her own control.
Although this is a suitable design for examining the cross-sectional
sensitivity and false-positive rate for different tests, it does not
permit long-term evaluation of different management strategies
because usually all women with abnormal results from either test
are subjected to further assessment and, possibly, treatment.
Liquid-based cytology has been widely introduced, especially
in the last 5 years. However, evaluations of its sensitivity and spec-
ifi city have severe limitations ( 14 ), because only a few studies
computed relative sensitivity and false-positives in a primary
screening setting using high-grade histology as the endpoint
( 15 – 19 ) . In addition, either comparisons were made between non-
randomized populations ( 16 , 17 ) or a split-sample design was used
( 15 , 18 ) . The latter approach may compromise the accuracy of liquid-
based cytology that is performed on the second sample because the
diagnostic cells can be removed when taking the fi rst sample.
We designed a population randomized controlled trial, the
New Technologies for Cervical Cancer (NTCC) study, to com-
pare the effectiveness, acceptability, and cost of HPV testing and
conventional cytology for primary screening for cervical cancer.
In this study, we randomly assigned women to either conventional
cytology or to the experimental arm. In the fi rst phase of the trial,
women in the experimental arm were screened using thin-layer
cytology and HPV testing of samples that were collected in liquid
medium, and in the second phase women were screened using
HPV testing alone. Thus, different groups of women were tested
Affi liations of authors: Unit of Cancer Epidemiology, Centro per la Prevenzi-
one Oncologica, Turin, Italy (GR, NS); Agency for Public Health, Lazio Region,
Rome, Italy (PGR); Centro per lo Studio e la Prevenzione Oncologica, Florence,
Italy (MZ, FC, MC); Unit of Pathology, Ospedale Maggiore, AUSL Bologna,
Italy (GPC); Unit of Pathology, Ospedale di Trento, Trento, Italy (PDP); Service
of Immunology and Cancer Molecular Diagnostics, Azienda Ospedaliera di Pa-
dova, Padua, Italy (ADM); Unit of Pathology, Presidio Ospedaliero, AUSL Imola,
Imola, Italy (SF); Unit of Cancer Epidemiology and CPO, CERMS, University
of Turin, Turin, Italy (AGT); Preventive Gyneacological Oncology, Ospedale
Civile Maggiore di Verona, Verona, Italy (GN); Centro di riferimento screening —
Assessorato alla Sanità — Regione Emilia-Romagna, Bologna, Italy (CN); Centro
Pre venzione Oncologica, AUSL Ravenna, Ravenna, Italy (PS); Venetian Tumour
Registry, Azienda Ospedaliera di Padova, Padua, Italy (MZ); Queen Mary’s
School of Medicine and Dentistry and Cancer Research UK, London, U.K. (JC).
Correspondence to: Guglielmo Ronco, MD, PhD, Unit of Cancer Epidemiol-
ogy, Centro per la Prevenzione Oncologica Piemonte, via San Francesco da Paola
31, 10123 Torino, Italy (e-mail: firstname.lastname@example.org ).
See “ Notes ” following “ References. ”
© The Author 2006. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: email@example.com.
766 ARTICLES Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006
and underwent assessment and treatment according to different
screening strategies. This design was chosen to permit the evalu-
ation of sub sequent long-term rates of disease (CIN and cancer)
associated with each strategy. In addition, the study was con-
ducted on a very large population within the routine activity of
organized screening programs. Therefore, it evaluates the impact
of introducing HPV testing in routine screening practice.
We present here data from the fi rst phase of the trial on cross-
sectional sensitivity and specifi city at the fi rst screening exami-
nation, which was conducted at recruitment. We focus on the
effect of using different criteria for referral to colposcopy (con-
cerning the combined use of HPV and liquid-based cytology and
the cutoff used for HPV testing). These criteria are essential for
defi ning the best modalities of screening by HPV testing before it
can be adopted routinely.
Because more women who are younger than 35 years of age
are HPV-positive than women 35 years and older ( 20 ) , we ap-
plied a different protocol in the two age groups. Women younger
than 35 years who were HPV-positive in the absence of cytologic
abnormalities were advised to have repeat cytology and HPV
testing, and women aged 35 years and older were referred di-
rectly to colposcopy if they were HPV-positive, independent of
cytology. Because a different presentation of data is needed with
the two phases, this report focuses only on the fi rst phase, among
women aged 35 years and older.
S UBJECTS AND M ETHODS
A randomized controlled trial was conducted in nine organized
cervical screening programs in Italy that routinely actively invite
women aged 25 – 64 years for screening ( Table 1 ). Women aged
25 – 60 years who were attending a new routine cervical screening
episode were asked to participate in the trial. Women who were
pregnant, had undergone hysterectomy, or had been treated for
CIN within the last 5 years were excluded. The persons acquiring
the cervical samples, who had attended specifi c training, were
required to obtain written informed consent from participants
they recruited. Women were then randomly assigned to the con-
ventional or to the experimental arm at a 1 : 1 ratio. In the Turin
and Viterbo centers, computers were used. In the other centers,
sealed numbered envelopes containing the random allocation were
prepared by the local coordinating center, provided to each unit,
and opened in sequence. The results of the assignment were then
communicated to consenting women. The study was approved by
the local ethics committees of the participating centers. The ran-
domized clinical trial registration number is ISRCTN81678807.
Here we report on the fi rst phase of the randomized trial among
women aged 35 years and older.
The cervical cell samples were obtained by using a plastic
Ayre’s spatula and a cytobrush. A conventional smear was pre-
pared for women who were randomly assigned to the conven-
tional arm. During the fi rst phase of the trial, cervical cells of
women who were randomly assigned to the experimental arm
were put in PreservCyt solution (ThinPrep; Cytyc Corporation,
Boxborough, MA) and were used for both liquid-based cytology
preparation and HPV testing.
Women assigned to the experimental arm were referred to
colposcopy if cytology indicated atypical cells of undetermined
signifi cance (ASCUS) or higher. Women in this arm who were
HPV-positive, independent of cytology results, were also referred
Women assigned to the conventional arm underwent conven-
tional cytology screening and were managed according to the
protocol already in use for routine screening activity in each
center. They were always referred to colposcopy if cytology was
low-grade squamous intraepithelial lesion (LSIL) or higher. De-
pending on the protocol already in use in each center, women
with ASCUS cytology were either directly referred to colposcopy
(72%) or were recommended for repeat screening (28%) and
were referred for colposcopy if repeat cytology results were LSIL
or higher ( Table 1 ).
The endpoint of the present analysis was histology-confi rmed
cervical intraepithelial neoplasia grade 2 (CIN2) or higher or cer-
vical cancer detected as a result of the screening test performed
at recruitment and of its assessment. Results of tests performed
after a recommendation to repeat at the standard Italian screening
interval (3 years) were not considered. We included lesions that
were detected up to 1 year after the fi rst referral to colposcopy.
Liquid-based cytology was performed by using the ThinPrep
system (Cytyc Corporation). One slide per woman was prepared
according to the manufacturer’s instructions. Both conventional
cytology and liquid-based cytology were performed, without
knowledge of HPV results, in the 14 laboratories (six in the Turin
center) that routinely interpret cytology in regular screening pro-
grams. The same cytologists were assigned to liquid-based and
conventional cytology. Abnormal slides were reviewed by a local
supervisor (or, in Florence, by a panel of cytologists) before they
reported the results to the women. This diagnosis was used both
for the woman’s management and for the study analysis. Two
laboratories had no previous experience in interpreting liquid-
based cytology, seven had previous experience with the ThinPrep
system (500 – 10 000 slides read per laboratory), and fi ve labora-
tories had previous experience with another liquid-based system
(approximately 1000 slides read per laboratory). Cytologists
from all laboratories attended a training course that was provided
by the manufacturer before the start of the study.
Cytology was classifi ed according to the Bethesda 1991
guidelines (TBS 1991). The ASCUS subcategories recommended
in the TBS 1991 were not applied. We used the TBS 1991 guide-
lines to avoid problems due to a switch to the 2001 classifi cation,
which was introduced just before the start of the study.
Table 1. Features of participating centers
Period of random
Management of ASCUS in
conventional arm *
Mar 2002 – Feb 2003
Feb 2002 – May 2003
Apr 2002 – Jan 2003
Aug 2002 – Jun 2003
Mar 2002 – May 2003
Mar 2002 – Apr 2003
Mar 2002 – Nov 2002
Feb 2002 – Jun 2003
Mar 2002 – Mar 2003
* Women at Trento and Imola were referred to colposcopy if repeat cytology
showed low-grade squamous intraepithelial lesion or higher. ASCUS = atypical
cells of undetermined signifi cance.
Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006 ARTICLES 767
All centers routinely conducted activities to improve the sensi-
tivity and specifi city of cytologists. These included monitoring the
distribution of diagnoses and positive predictive values (PPVs)
and the circulation of Pap smears and discussion within and among
laboratories. These activities were continued during the study pe-
riod. In addition, as an exercise to improve consistency between
centers, a set of 30 liquid-based cytology slides that were diffi cult
to classify was circulated to each center during the study. The slides
were read blindly at each center, and slides with discrepant diagno-
ses were discussed among the representatives of each center.
HPV testing was done, blind to cytology results, in seven lab-
oratories by using the Hybrid Capture 2 assay (HC2; Digene Cor-
poration, Gaithersburg, MD). Only the group of probes designed
to detect high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 59, and 68 was used. After preparation of one cytology slide,
4 mL of the remaining PreservCyt sample was processed with the
Sample Conversion Kit (Digene) followed by HC2 assay, ac-
cording to the manufacturer’s instructions. When less than 4 mL
of sample was available (for 310 women), women were recalled
for another sample. HC2 results were expressed as the ratio of the
specimen’s light emission to that of three concurrently tested
1 pg/mL HPV DNA controls (Relative Light Units [RLU]).
Therefore, RLU is an (indirect) measure of the specimen’s viral
concentration relative to 1 pg/mL. Before the start of the study,
technicians in all centers attended a training course that was pro-
vided by Digene. A set of quality assurance procedures was im-
plemented, including the use of controls from the manufacturer
with known HPV DNA content and the circulation of clinical
samples prepared by one of the participating laboratories. These
procedures showed high accuracy and reproducibility of HPV
detection — only three of 1024 target samples containing purifi ed
concentration-defi ned HPV DNA were incorrectly scored in a
positive versus negative classifi cation, and the multiple-rater
k scores were 0.91, 0.60, and 0.69 for HPV negative, HPV low-
positive, and HPV high-positive, respectively ( 21 ) .
Colposcopy and Histology
The same colposcopists who had access to the participants’
cytology and HPV status were used in the experimental and con-
ventional arms of the study. Suspicious areas identifi ed by colpos-
copy were biopsied. Women were referred for repeat colposcopy
using routine protocols according to the colposcopist’s judgment.
The main reason for repeating the colposcopy was a lack of
histology-confi rmed CIN in the presence of clearly abnormal cy-
tology. Histology was read locally by pathologists who were not
blinded to cytology and HPV results but was reviewed centrally
by investigators who were blinded to study arm, to the original
diagnosis, and to the cytology and HPV results.
All specimens of women who had histologically determined
CIN1+ within 1 year after referral to colposcopy were reviewed
blindly and independently. For each woman, all histologic slides
were provided together, and the most severe diagnosis was used.
If the relevant material could not be retrieved (22 of 650 women),
the most severe initial diagnosis was considered.
Each patient’s specimens were reviewed blindly and indepen-
dently by one or two pathologists. If a pathologist did not agree
with the original diagnosis regarding the presence of CIN2+, the
information was discussed by a group of pathologists and a con-
sensus diagnosis was reached. This consensus diagnosis was then
used in the analysis.
For most women who were diagnosed with CIN2/3 and for
12% of those with CIN1, each patient’s specimens were indepen-
dently reviewed by two pathologists who were randomly selected
from a pool of nine, i.e., one per center. Consensus discussions
included all nine pathologists when necessary. The remaining cases
(88% of CIN1, with fi ve of CIN2/3 also included to ensure that
reviewers were blinded to the original diagnosis) were reviewed
by one pathologist who was selected among the three most expert,
and, if needed, consensus discussions included all three patholo-
gists. Overall, considering all age groups, 4.2% of women with
CIN1 were upgraded to CIN2 (and none was upgraded to CIN3),
with no difference by method of review ( P = .98); 11.3% of women
with CIN2/3 were downgraded to CIN1 or to no CIN.
Sensitivity and specifi city of different combinations of HPV
and liquid-based cytology were computed within the experimen-
tal arm. Exact confi dence intervals were calculated. Only women
who had a valid relevant test were included in the analyses. The
sensitivity and specifi city of different approaches among subjects
with valid results for both tests were compared by the McNemar
test ( 22 ).
The relative sensitivity of different combinations of liquid-
based cytology and HPV versus conventional cytology was esti-
mated using CIN2+ and CIN3+ detection rates relative to the
conventional arm. All randomly assigned eligible women were
included in the analyses. The relative PPV versus that of conven-
tional cytology was computed by including only women who
actually underwent colposcopy. If a center effect on relative sen-
sitivity or relative PPV was present, the confi dence interval was
calculated by using a multilevel random effects model with ran-
dom intercept and random slope ( 23 ) . All P values are two-sided,
and P <.05 was considered statistically signifi cant.
Performing random colposcopies on a sample of women who
were negative for both tests was judged as unfeasible for the ex-
pected strong negative impact on recruitment. Therefore, abso-
lute sensitivity and specifi city estimates are not corrected for
verifi cation bias.
The study size of the entire trial (that includes two phases, one
with HPV plus liquid-based cytology and one with HPV only in
the experimental arm) was determined to have suffi cient statisti-
cal power to show a reduction in the detection rate of CIN2+ in
the experimental versus conventional arms at the next screening
examination. Assuming a loss to follow-up of approximately 30%
and a detection rate of 3.0 CIN per 1000 women in the conven-
tional arm, the target study size of approximately 100 000 women
provides greater than 80% power to detect a 32% reduction of
detection rate in the experimental versus conventional arms as
statistically signifi cant at the 5% level using a two-sided test.
We randomly assigned 45 307 women in the fi rst phase of
recruitment ( Fig. 1 ). Of them, 133 (81 from the conventional and
768 ARTICLES Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006
Fig. 1. Trial profi le. ASCUS = atypical squamous cells of undetermined signifi cance; HPV = human papillomavirus; SIL = squamous intraepithelial lesion.
Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006 ARTICLES 769
52 from the experimental arm) were excluded because they had
been randomly assigned but were not eligible. Therefore, a total
of 22 466 eligible women were randomly assigned to the conven-
tional arm and 22 708 to the experimental arm.
Further analyses are based on the 16 658 and 16 706 women
aged 35 years and older who were randomly assigned to the con-
ventional and experimental arm, respectively. Median age was
45 years in both arms ( P = .97). More than half of the women in
the conventional (53.0%) and the experimental arm (53.8%), re-
spectively, had been screened for cervical cancer in an organized
program within 4 years of enrollment ( P = .14).
Women were managed according to the intended protocol,
with a few exceptions due to local clinical decisions ( Fig. 1 ). At
least one colposcopy was received by 93.0% of referred women
(90.8% in the conventional arm and 93.7% in the experimental
arm). Among women who received colposcopy, the mean num-
ber of colposcopies per woman was 1.32 in the conventional and
1.21 in the experimental arm. Two of 51 women were diagnosed
with CIN2+ as a result of repeat colposcopies in the conventional
arm versus fi ve of 75 in the experimental arm.
Liquid-Based Cytology and Conventional Cytology Results
A statistically signifi cantly lower proportion of women in
the experimental arm (liquid-based cytology) than in the conven-
tional arm had at least one unsatisfactory Pap smear ( n = 418
[2.5%] versus n = 620 [3.7%], P <.001). In particular, the fre-
quency of women with unsatisfactory cytology because of ob-
scuring infl ammation was much lower in the experimental arm
than in the conventional arm ( n = 71 [0.42%] versus n = 325
[2.0%], P <.001), but the frequency of women with unsatisfactory
cytology for other reasons was slightly higher in the experimen-
tal arm than in the conventional arm ( n = 347 [2.1%] versus
n = 295 [1.8%]).
Cytology results and reviewed histologic results by study arm
are summarized in Table 2 . More women in the experimental arm
than in the conventional arm were classifi ed as having ASCUS
and LSIL cytology (for ASCUS, n = 553 [3.3%] versus n = 382
[2.3%], P <.001; for LSIL, n = 297 [1.8%] versus n = 170 [1.0%],
P <.001). High-grade squamous intraepithelial lesion (HSIL) or
more severe cytology was detected in 54 (0.32%) of women in
the experimental arm and in 42 (0.25%) in the conventional arm
( P = .23). Overall, 594 women in the conventional arm (3.6%)
had ASCUS or more severe cytology versus 904 in the experi-
mental arm (5.4%). The proportion of women with ASCUS+
cytology decreased with age in both arms but more steeply in the
experimental arm ( Fig. 2 ).
HPV Positivity Rate
Overall, 7.1% of women in the experimental arm were HPV-
positive ( Table 2 ); the rate of HPV-positive women decreased
with age ( Fig. 2 ). Among women with normal cytology, 5.4%
were HPV-positive at 1 pg/mL cut-off versus 24.1%, 42.1%, and
Table 2. Cytology, human papillomavirus (HPV) status, and reviewed histologic outcome by study arm*
No CIN §
No CIN §
No CIN §
No valid HPV test ||
No CIN §
15 785130 ( 27 ) ‡
213 (211) ‡
30 ( 30 ) ‡
4 ( 3 ) ‡
5 ( 4 ) ‡
382 (275) ‡
2 16 203
15 789170 16 658
114 14 5132882
11514 516 4161661215 225
3 555 17
* ASCUS = atypical squamous cells of undetermined signifi cance; AGUS = atypical glandular cells of undetermined signifi cance; LSIL = low-grade squamous
intraepithelial lesion; HSIL = high-grade squamous intraepithelial lesion; CIN = cervical intraepithelial neoplasia; HPV = human papilloma virus.
† In 30 women, no test was performed.
‡ Women directly referred to colposcopy are shown in parentheses.
§ Includes women who had colposcopy but not histology.
|| In 35 women, no test was performed; in 247, conventional samples were taken; and in 14, there was insuffi cient material.
770 ARTICLES Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006
77.8% of women with ASCUS, LSIL, and HSIL+ cytology, re-
spectively ( Table 2 ). Overall, therefore, 10.6% of all women in
the experimental arm were either HPV-positive or had ASCUS+
cytology, whereas 1.80% were both HPV-positive and had
ASCUS+ cytology. The proportion of women who were HPV-
positive was reduced to 5.4% using a cutoff of 2 pg/mL and to
3.4% using a cutoff of 10 pg/mL ( Table 3 ).
Sensitivity and Specifi city of HPV Versus Liquid-Based
Cytology and Effect of Different Cutoffs for HPV Testing
on Referral to Colposcopy
Overall, 75 women with CIN2 or more severe histology were
identifi ed in the experimental arm. Among them, 54 had ASCUS
or more severe cytology and 73 were HPV-positive ( Table 2 ).
Among those who were HPV-positive, 68 had a RLU ≥ 10.0 and
72 had a RLU ≥ 2.0, whereas only one woman with CIN3 (none
with CIN2) had a RLU between 1.0 and 2.0, thus a viral concen-
tration between 1 and 2 pg/mL ( Table 3 ).
HPV testing with a 1 pg/mL cutoff was more sensitive but less
specifi c than liquid-based cytology with an ASCUS cutoff, con-
sidering both CIN2+ and CIN3+ histology endpoints. HPV test-
ing with a cutoff of 2 pg/mL was also more sensitive for CIN2+
than ASCUS+ liquid-based cytology, with a similar specifi city
for both CIN2+ and CIN3+ ( Table 4 ).
Comparison of Different Strategies Versus Regular
Practice With Conventional Cytology
In the conventional arm, 51 women with CIN2+ histology
were identifi ed ( Table 2 ). When compared with conventional
cytology (in which ASCUS was the cutoff for colposcopy), the
relative sensitivity for CIN2+ histology in the experimental arm
(either ASCUS+ from liquid-based cytology or HPV ≥ 1 pg/mL)
was 1.47 (95% CI = 1.03 to 2.09) ( Table 5 ). However, this re-
sulted in a decrease of PPV from 11.4% to 4.5% (relative PPV =
0.40, 95% CI = 0.23 to 0.66). With HPV ≥ 1 pg/mL alone as a
criterion for colposcopy, the sensitivity relative to conventional
cytology was still increased (relative sensitivity = 1.43, 95%
CI = 1.00 to 2.04), whereas PPV was 6.6% (relative PPV = 0.58,
95% CI = 0.33 to 0.98). With HPV ≥ 2 pg/mL alone as a criterion
for colposcopy, an increase in sensitivity was suggested com-
pared with conventional cytology (relative sensitivity = 1.41,
95% CI = 0.98 to 2.01), and PPV was 8.5% (relative PPV = 0.75,
95% CI = 0.45 to 1.27).
By using liquid-based cytology with ASCUS+ as the only cut-
off for referral to colposcopy, the sensitivity was similar to that
obtained in the conventional arm with conventional cytology
(relative sensitivity = 1.06), but PPV was decreased to 6.5% (rel-
ative PPV = 0.57, 95% CI = 0.39 to 0.82). The relative sensitivity
and relative PPV for CIN2+ of liquid-based ASCUS+ cytology
versus conventional ASCUS+ cytology were 1.03 and 0.67,
respectively, when the analysis was restricted to the seven cen-
ters that referred to colposcopy all women with ASCUS cytology
in both arms. Relative sensitivity and PPV for HPV testing alone
and for HPV testing with liquid-based cytology also changed
only slightly when only these seven centers were considered
(data not shown), and there was no evidence of heterogeneity in
relative sensitivity and relative PPV between these centers and
the centers that referred women in the conventional arm with
ASCUS cytology for repeat testing.
No statistically signifi cant variation of relative sensitivity and
relative PPV by age group was observed. There was also no ef-
fect of center on relative sensitivity. However, there was hetero-
geneity between centers regarding the relative PPV versus
conventional cytology of HPV at 1 pg/mL ( P = .02); the same
was true for HPV at 2 pg/mL ( P = .028) and for liquid-based cy-
tology with HPV ( P = .042) but not for ASCUS+ liquid-based
cytology alone ( P = .13).
With CIN3+ histology as the endpoint, relative sensitivity and
PPV results were in the same direction as with CIN2+. In particular,
the relative sensitivity versus that in the conventional arm was 1.25
with either ASCUS+ liquid-based cytology or HPV >1 pg/mL as a
% of women
Fig. 2. The percentage of women who were human papillomavirus (HPV)-
positive and with atypical squamous cells of undetermined signifi cance or higher
(ASCUS+) cytology by age group; point estimates and 95% confi dence intervals
are shown. HPV-positive ( diamonds ) and ASCUS+ cytology in the experimental
arm ( squares ); ASCUS+ cytology in the conventional arm ( triangles ). Percent
HPV-positive was determined for women with valid HPV tests ( n = 16410).
Percent ASCUS+ was determined for women with valid cytology who were
randomly assigned to the conventional ( n = 16 255) and experimental arms ( n =
16 383), respectively.
Table 3. Number of women in the experimental arm by human papillomavirus (HPV) value and histologic outcome *
Histology<0.30 0.30 – 0.99 1.00 – 1.992.00 – 3.994.00 – 9.99 ≥ 10.00Total
Total (%) ‡
29610 6624509256 15414543916 461
37 1520 13
296 (1.8%)10 701 (64.1%)4524 (27.1%) 277 (1.7%) 170 (1.0%) 166 (1.0%) 572 (3.4%)16 706 (100%)
* CIN = cervical intraepithelial neoplasia.
† RLU is the ratio of the specimen’s light emission (RLU relative light units) to the average light emission of three concurrently tested 1 pg/mL HPV DNA controls.
‡ Percents are on row total.
Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006 ARTICLES 771
criterion for colposcopy and was 1.22 with HPV ≥ 1 pg/mL alone,
although none of these differences reached statistical signifi cance.
This study presents the fi rst results from a randomized trial
that compares conventional cytology and the combined use of
HPV testing and liquid-based cytology. It also allowed HPV test-
ing and liquid-based cytology to be compared in the same women.
With respect to conventional cytology, HPV testing with a 1 pg/mL
cutoff supplemented by liquid-based cytology led to a substantial
(47%) increase in sensitivity for CIN2+ but also to a 60% loss in
PPV. Increases in sensitivity were still obtained with HPV alone
at 1 and 2 pg/mL cutoffs (43% and 41%, respectively, compared
with conventional cytology), and these approaches reduced the
losses in PPV (42% and 25%, respectively, compared with
conventional cytology). Liquid-based cytology did not cause an
increase in sensitivity compared with conventional cytology but
led to a substantial (43%) reduction in PPV.
The study was conducted within organized screening pro-
grams on a large population, a situation very similar to routine
application. Nearly 80% of eligible women were enrolled. There-
fore, our results are representative of those that would be ex-
pected in routine application. The referral rate, detection rate of
CIN2+, and PPV observed in the conventional arm were similar
to those observed in the Italian organized cervical screening pro-
grams among women aged 25 – 64 years in 2000 – 2002 [2.7 – 3.0%,
2.8 – 3.0 per 1000, and 11.4 – 15.4%, respectively ( 24 ) ]. The detec-
tion rate (and consequently PPV) was low compared with that in
other countries, even considering the age distribution, refl ecting
the low risk of cervical neoplasms in Italy ( 25 ) . A very low inci-
dence of interval cancers was previously observed during the
regular screening activity of the largest center ( 26 ) , strongly
Table 4. Sensitivity and specifi city of liquid-based cytology and human papillomavirus (HPV) testing in the experimental arm *
Sensitivity (95% CI) Specifi city (95% CI)
CriterionCIN2+ CIN3+ CIN2+ CIN3+
Liquid-based cytology ≥
HPV ≥ 1 pg/mL
54/73 = 74.0%
(62.4 to 83.6)
73/75 = 97.3%
(90.7 to 99.7) †
72/75 = 96.0%
(88.8 to 99.2) †
31/38 = 81.6%
(65.7 to 92.3)
38/39 = 97.4%
(86.5 to 99.9) ‡
37/39 = 94.9%
(82.7 to 99.4)
15 593/16 443 = 94.8%
( 94.5 to 95.2)
15 223/16 335 = 93.2%
(92.8 to 93.6) †
15 499/16 335 = 94.9%
(94.5 to 95.2)
15 605/16 478 = 94.7%
(94.4 to 95.0)
15 224/16 371 = 93.0%
(92.6 to 93.4) †
15 500/16 371 = 94.7%
(94.3 to 95.0)
HPV ≥ 2 pg/mL
* Women (including one CIN2 and one CIN3+) without valid cytology ( n = 190) were excluded from computations for liquid-based cytology ≥ ASCUS. Women
without a valid HPV test (no CIN2+) were excluded from computations for HPV ( n = 296). Women (including one CIN2 and one CIN3+) without either valid test were
excluded from computations of P values comparing tests ( n = 451). CI = confi dence interval; CIN2+ = histology-confi rmed cervical intraepithelial neoplasia grade 2 or
more severe; CIN3+ = histology-confi rmed cervical intraepithelial neoplasia grade 3 or more severe; ASCUS = atypical squamous cells of undetermined signifi cance.
† P <.001 versus liquid-based cytology ≥ ASCUS (two-sided McNemar test).
‡ P = .034 versus liquid-based cytology ≥ ASCUS (two-sided McNemar test).
Table 5. Detection rate, positive predictive value (PPV), relative sensitivity, and relative PPV for histology-confi rmed CIN2+ and CIN3+ of
different screening strategies in the experimental arm versus conventional cytology ≥ ASCUS *
Endpoint CIN2+ Endpoint CIN3+
(95% CI) PPV %
(95% CI) PPV%
cytology ≥ ASCUS
or HPV ≥ 1 pg/mL
cytology ≥ LSIL
HPV ≥ 1 pg/mL
HPV ≥ 2 pg/mL
cytology ≥ ASCUS
and HPV ≥ 1 pg/mL
cytology ≥ ASCUS
cytology ≥ LSIL
4.49 1.47 (1.03 to 2.09)4.5 0.40 (0.23 to 0.66)2.33 1.25 (0.78 to 2.01)2.30.34 (0.21 to 0.54)
3.23 1.06 (0.72 to 1.55)6.50.57 (0.39 to 0.82)1.86 1.00 (0.61 to 1.64) 3.70.54 (0.33 to 0.87)
2.39 0.78 (0.52 to 1.18)12.71.11 (0.75 to 1.64)1.500.80 (0.48 to 1.36)7.91.14 (0.69 to 1.90)
1.43 (1.00 to 2.04) †
1.41 (0.98 to 2.01)
1.02 (0.69 to 1.50)
0.58 (0.33 to 0.98)
0.75 (0.45 to 1.27)
1.66 (1.16 to 2.36)
1.22 (0.76 to 1.96)
1.19 (0.74 to 1.92)
0.96 (0.58 to 1.59)
0.50 (0.32 to 0.79)
0.63 (0.40 to 1.00) ‡
1.57 (0.97 to 2.54)
3.06 1.00 (referent)11.4 1.00 (referent)1.86 1.00 (referent)6.91.00 (referent)
2.52 0.82 (0.69 to 0.95)21.4 1.88 (1.60 to 2.06)1.56 0.84 (0.66 to 0.95)13.3 1.92 (1.53 to 2.13)
* All eligible randomly assigned women were considered for the detection rate and relative sensitivity. Only women who actually had colposcopy were included
in PPV and relative PPV calculations. CIN2+ = histology-confi rmed cervical intraepithelial neoplasia grade 2 or more severe; CIN3+ = histology-confi rmed cervi-
cal intraepithelial neoplasia grade 3 or more severe; ASCUS = atypical squamous cells of undetermined signifi cance; HPV, human papilloma virus; CI = confi dence
interval; LSIL = low-grade squamous intraepithelial lesion.
† P = .0496 by Mantel – Haenszel chi square.
‡ P = .0503 by Mantel – Haenszel chi square.
772 ARTICLES Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006
suggesting that a low detection rate does not result from failure to
identify progressive lesions. Individual randomization of this
large population guarantees that a difference in the detection rate
of histologically confi rmed lesions between arms can be attrib-
uted to test sensitivity and not to a difference in baseline risk of
Liquid-based and conventional cytology showed similar sen-
sitivity, but the PPV was greatly reduced with liquid-based cytol-
ogy, even when restricting the analysis to the centers that used
the same criteria of referral to colposcopy with both methods.
This reduction was the result of a larger proportion of women
being classifi ed as having ASCUS+ cytology with liquid-based
cytology but of no increase in the detection of histology- confi rmed
lesions. In previous studies without split sampling (direct-
to-vial), a higher proportion of LSIL was generally reported with
liquid-based cytology than with conventional cytology ( 16 , 17 ,
27 – 33 ), whereas an increase in HSIL cytology was frequently
( 16 , 27 – 31 ) but not always ( 19 , 32 ) reported. Regarding ASCUS,
some studies found lower detection rates ( 16 , 27 – 29 ,34) whereas
others found higher rates ( 31 – 33 , 35 ) . The few studies, each with
less than 10 000 women, which computed relative sensitivity for
biopsy-proven high-grade CIN in a primary screening setting
provided confl icting results ( 15 – 18 ) . In most of these studies
( 15 , 16 , 18 ), the false-positive rate was higher with liquid-based
cytology than with conventional cytology. The main advantage
of liquid-based cytology was an overall reduction of unsatisfac-
tory slides, which has been consistently observed in previous
direct-to-vial studies ( 16 , 28 – 33 , 35 ) .
HPV testing for high-risk types was more sensitive than both
conventional (by approximately 40%) and liquid-based (by ap-
proximately 30%) cytology. This was true both with CIN2+ and
with CIN3+, the more proximal precursor of cancer, as the end-
point. Previous studies comparing HPV testing with conventional
( 1 – 9 , 11 – 13 ) and liquid-based ( 4 , 10 ) cytology consistently found
higher sensitivity with HPV testing. Many of them, however,
were based on self-referred women ( 2 , 4 , 5 , 8 , 10 , 12 , 13 ) . In addi-
tion, some were conducted in populations at high risk ( 6 , 7 , 9 ) or
women who were younger than the overall spectrum of the
screened population ( 1 , 5 , 10 ) . Results of these previous studies
are consistent with our fi ndings in a large, population-based ran-
domized study addressing a low-risk population.
Only two of the 75 women in the experimental arm with
CIN2+ were HPV-negative, and little was gained by performing
liquid-based cytology on every woman. However, doing this
reduced specifi city and led to many unnecessary referrals. Thus,
our data strongly suggest that supplementing HPV testing with
cytology provides little advantage and mainly increases costs and
anxiety. Based on these results, a second phase of the trial, in
which HPV testing alone is compared with conventional cytol-
ogy is now being undertaken.
Moreover, no high-grade lesion was found among 845 HPV-
negative women with ASCUS cytology. Therefore, this result
strongly supports the use of HPV in triaging ASCUS when cytol-
ogy is performed fi rst, as previously reported ( 11 , 36 – 38 ) .
HPV testing alone using a 1 pg/mL cutoff reduced PPV by ap-
proximately 40% compared with conventional cytology ( Table 5 ).
Using a 2 pg/mL cutoff provided almost the same sensitivity
but strongly reduced the number of women to be referred for
colposcopy. The 2 pg/mL cutoff led to a PPV only 25% lower
than that obtained with conventional cytology, suggesting this is
more appropriate for population screening at least when liquid-
based cytology samples are used. A similar result was obtained in
the HPV in Addition to Routine Testing (HART) study ( 11 ) .
However, in a high-risk population in Costa Rica the optimal cut-
off was 1 pg/mL ( 7 ) . It should, however, be noted that relative
PPV for HPV versus conventional cytology varied statistically
signifi cantly between centers. An explanation could be different
progression from infection to high-grade CIN, possibly depend-
ing on a different HPV type and variant mix in different centers.
The study has a few potential limitations. Because colposco-
pies were performed only on women who were positive for either
test, estimates of absolute values of sensitivity and specifi city
could not be corrected for verifi cation bias. In addition, although
cytologists were blinded to HPV results, they knew that women
having liquid-based cytology were also tested for HPV. This situ-
ation could have unconsciously caused the application of broader
criteria of interpretation.
The HART study ( 11 ) showed that surveillance of HPV-
positive but cytologically normal women by repeat HPV testing
and cytology at 12 months led to the same detection rates of
CIN2+ as direct referral for colposcopy. A possible strategy is,
therefore, to test women for HPV, triage by cytology those who
are positive, and directly refer women who are positive for both
tests for colposcopy. Women who are HPV-positive but cytologi-
cally normal could repeat tests at 1 year. In our study, 1.80% of
women in the experimental arm were positive both for high-risk
HPV and had ASCUS+ cytology. Another 5.29% were HPV-
positive but cytologically normal. Assuming a clearance of HPV
after 1 year to be approximately 50%, as observed in most pub-
lished studies ( 11 , 39 ), the overall referral rate would be approxi-
mately 4.5%, compared with 3% in the conventional arm. When
a cutoff of 2 pg/mL is used, the same strategy would lead to a
referral rate of approximately 3.5%. However, a high rate of
compliance to repeat testing is essential for this approach to
work, and immediate referral should be considered for HPV-
positive women unlikely to comply with repeat testing.
The follow-up phase of this study will compare the detec-
tion rate of CIN2+ after recruitment and up to and including
the next regular screening invitation at 3 years in the two arms.
Women with normal cytology in the conventional arm will be
compared with those negative for both tests in the experimen-
tal arm. A very low detection rate in the experimental arm
would prove that longer intervals could be used with HPV
testing. The study has adequate power to investigate a reduc-
tion of CIN2+ at follow-up, but it is also the pilot study for a
larger proposed study to examine reduction in cancer incidence
as an endpoint.
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This work was supported by the European Union (Europe against Cancer
contracts SI.2.327046 and SPC.2002475), by the Italian Ministry of Health
(Progetto Speciale “ Valutazione di nuove tecnologie per lo screening del cervico-
carcinoma ” ), by the Special Project “ Oncology, ” Compagnia di S. Paolo FIRMS,
and by the participating Italian regions. The sponsors had no role in the study
design, the collection of the data, analysis, interpretation of the results, or the
writing of the manuscript.
We thank all the staff who assisted in running the study. We also thank the
thousands of women who have participated into this study.
The following are contributing members of the NTCC Working Group:
Turin: R. Rizzolo and D. Mari (CPO Piemonte), L. De Marco (Unit of Cancer
Epidemiology and CPO, CERMS, University of Turin), B. Ghiringhello and
F. Parisio (Unit of Pathology, OIRM S. Anna), R. Volante (Centre for Early Cancer
Diagnosis and Treatment, OIRM S. Anna), E. Berardengo (Unit of Pathology,
Ospedale S. Giovanni AS), A. Andrion (Unit of Pathology, Ospedale Martini),
S. Coverlizza (Unit of Pathology, Ospedale Giovanni Bosco), S. Taraglio (Unit of
Pathology, Ospedale Maria Vittoria), M. G. Accinellli (Unit of Pathology,Universityof
Turin); Trento: E. Polla, A. Pojer, S. Girlando, and D. Aldovini (Unit of Pathol-
ogy, Ospedale di Trento); Veneto: M. Vettorazzi (Venetian Tumour Registry,
Azienda Ospedaliera di Padova), D. Minucci, and M. Matteucci (Unity of Ginae-
cology, Azienda Ospedaliera di Padova), L. Onnis and E. Insacco (Department of
Pathology, University of Padua), M. Lestani (Department of Pathology, University
774 ARTICLES Journal of the National Cancer Institute, Vol. 98, No. 11, June 7, 2006 Download full-text
of Verona) and A. Vignato (Servizio di Citologia, Ostetricia e Ginecologia, Osped-
ale di Soave); Emilia-Romagna: M. Manfredi (Centro screening, AUSL Bologna),
P. Pierotti (Unit of Pathology, Ospedale Maggiore, AUSL Bologna), G. Collina
(Unit of Pathology Ospedale Bellaria, AUSL Bologna) M. Serafi ni (Centro Pre-
venzione Oncologica, AUSL Ravenna), C. Sintoni (Unit of Pathology, Presidio
Ospedaliero di Ravenna, AUSL Ravenna), M. Aldi (Unit of Pathology, Presi-
dio Ospedaliero di Faenza, AUSL Ravenna), A. Bondi and G. Galanti (Unit of
Pathology, Presidio Ospedaliero, AUSL di Imola); Florence: A. Iossa, S. Ciatto,
M. P. Cariaggi, S. Cecchini, C. Sani (CSPO Firenze), and G. L. Taddei (Unit of
Pathology Uni versity of Florence); Lazio: S. Brezzi, P. Raggi, and E. Gomes
(Local Health Unit, Viterbo, Italy), A. Pellegrini and M. L. Schiboni (Ospedale
S. Giovanni, Rome).
Manuscript received June 17, 2005 ; revised March 15, 2006 ; accepted
April 14, 2006.