I x ~Pap3bor2xPap3a Total
hi h risk - 1 x Pap3a' Pap 1.2 % (4
H P 6 &,US CIN 111 CIN I1 CINl ~
96 (n)
(5 (n\ Vo (nl 5% In\ 4 (n)
Positive
Negative
Total
7.0% 6
0.1% 111
0.4% 7
2.3% 2
0.1% 11)
0.2% 3
2.3% 2
0.3%
0.4% 7
13 8.1% 7)
2.0% (311
2.3% 38
80% 69)
98% 11498
97% (15671
5.3% 86)
94.7% 11536
100% (16221
'(a) Screening population (34-54 years of age); (b) no past history of cervical dys lasia; (c)
initially normal cervical smear; (d) known follow-up data on cervical cytology; (e) initiay high-risk
HPV status assessed by PCR. Crude OR associated with development of CIN 1-111, CIN 11-111 and
CIN 111 are 29 (95% CI, 10-78), 79 (95% CI, 16-380) and 115 (95% C1, 14-970) respectively.-
2According to the criteria used in the Dutch cervical-cancer screening programme, women were
referred for colposcopically directed biopsies if they had had 2 successive cervical smears read as
Pap 3a (mild to moderate dyskaryosis) or one read as 2 Pap 3b (severe dyskaryosis).-'Women with
a single, transient Pap smear read as Pap 3a have no biopsy.
768 ROZENIMALETAL
reading, 0.4% (n = 5) developed CIN 111, 0.2% (n = 2) CIN was shown that women with cytomorphologieally normal
11, 0.3% (n = 3) CIN I and 1.9% (n = 24) had a single, cervical smears, who were positive in a HPV-PCR tcst that can
transient Pap smear read as Pap 3a. identify 14 high-risk HPV types, were 116 (95% CI 13-990)
The crude O R for dcvclopment of CIN I11 among women times more at risk of developing CIN I11 than womcn with
with Pap 2 vs. those with Pap 1 was calculated for the women high-risk HPV-negative scrapes. The womcn with an initial
with a known baseline HPV status (n = 1622; OR, 1.5; 95% Pap smear read as Pap 2 (very mild dyskaryosis. including
CI, 0.3-7.6;~ = 0.6) and for all women with follow-up data on atypical squamous cells of unknown signifieancc; ASCUS)
ccrvical cytology (n = 2454; OR, 1.8; 95% CI, 0.5-7;p = 0.4). showed an increased risk of 1.5 (95% CI, 0.3-7.7) for develop-
The high-risk HPV-adjusted O R for dcvcloping CIN III was mcnt of CIN I11 when compared with women with initially Pap
1.0 (95% CI, 0.2-5.9; Table HI). This mcans that the O R of 1.5 1. The O R of 1.5 is cntirely explained by the higher rate of
of developing CIN 111 among women with Pap 2 vs. those with high-risk HPV typcs in women with a smear read as Pap 2.
Pap 1 is entirely explaincd by thc higher rate of high-risk HPV These findings underline the potential value of HPV testing in
typcs in women with a smcar read as Pap 2 (7.5% high-risk cervical-cancer screening programmes.
HPV) vs. Pap 1 (4.7% high-risk HPV). We found that 5.3% of the women had high-risk HPV-
Characterization of women developing high-grade CIN lesions, positive cervical smears. From earlicr data (Walboomers et al.,
and review of cytology 1994) and currcnt findings (data not shown) of cross-sectional
studies we estimatc that about 4% of women with normal
Data on the 10 women who dcvcloped high-grade CIN cytology at 34 to 54 ycars of age have high-risk HPV-positive
lesions, i.e., 7 cases of CIN 111 and 3 cases of CIN 11, are given cervical smcars. The higher prcvalcnce of high-risk HPV in our
in Table IV. In 1 case, the high-grade CIN lesion was detected cohort may be explained by the requirement that follow-up
as a result of the first follow-up smear aftcr 5 ycars, in 5 cases data on cervical cytology is available for the women included in
after 3 years and in 4 cases within 2 ycars aftcr the initial Pap the analysis, which is also related to the slight over-
smear. In 3 of the latter 4 cases, it had been advised to rcpeat rcprcsentation of women with a Pap-2 smear (21%), who have
the Pap smear within one year, bccause the initial Pap smcar a stricter follow-up scheme, with an additional smear after 12
had been classified as Pap 2 (n = 2) or endoccrvical cells had months. However, thc rclatively high initial high-risk HPV
bccn missing (n = 1). Blind review of the initial Pap smcars prevalcncc does not influence the estimated OR or the
revealed that 2 of them could have been classified as Pap 3a, cstimatcd proportion of high-risk HPV-positive womcn dcvcl-
moderate dyskaryosis. Review of the (follow-up) histology oping CIN Ill.
yiclded identical rcsults for all cases.
The results of our study are in line with those of Koutsky et
al. (1992): in a prospectivc cohort of womcn selected in a clinic
DISCUSSION for scxually transmitted diseases they found a relative risk of 11
This study of women with cytomorphologically normal (95% CI 4 . 6 2 6 ) of developing CIN I1 and CIN Ill lcsions
cervical smcars participating in a triannual population-based among HPV-positive women whcn compared with HPV-
cervical-cancer screening programme and a follow-up time of negative womcn. Our strongcr correlation bctwccn initial
up to 73 months cvaluatcs the significancc of high-risk HPV HPV status and development of CIN I1 and CIN Ill (crude
types as a risk factor for development of CIN lesions. Women O R , 79; 95% CI, 1 6 3 8 0 ) might be attributed to the population
with histologically confirmed CIN Ill were considcrcd positive studicd and the detection method used. The dot-filtcr-
cases, since CIN I11 lesions are most closely related to cervical hybridization proccdure used by Koutsky et al. (1992) is
cancer and should be treatcd (Cannistra and Niloff, 1996). It considered to bc lcss sensitive than the PCR-based mcthod we
applied (Walboomers et al., 1994), leaving possiblc HPV-
positive cases with progression unidentified. In addition, Kout-
TABLE 111 - LOGISTIC-REGKESSIOS AVALYSIS FOR DEVELOPMENT OF sky el al. (1992) tested for only 5 high-risk HPV genotypes. The
CIS 111 WITH TlIE INITIAL HPV STATUS A N D INITIAL PAP READING AS
INDEPEKDEST RISK FACIOKS PCR method used in our study results in almost equal
amplification of the different HPV gcnotypes, including all 14
risk ;F
: py,r;,l; Unagwd Mutually ddiuslcd
OR 1 9 5 9 C1)
high-risk HPV types detected in a worldwide study on ccrvical
~ __ -
cancer (Bosch eta/., 1995).
High-risk HPV 6 80 119 116?(13-990) Our observations are consistent with the current epidemio-
positive logical model of cervical carcinogencsis (for review, sec Schiff-
Pap 2 2 344 1.5 1.0 (0.2-5.9)
man and Brinton, 1995). According to this model, H P V is the
OR were mutually adjusted for the baseline hi h-risk HPV primary risk factor for cervical cancer. Most HPV infections
status and Pap classification.-2Statisticallysignificant < 0.WOl). &, are transient (Meijer et al., 1992; Walboomers et al., 1994) and
do not lead to CIN. Mild to moderate dysplastic cervical
TABLE W - CHARACTERIZATION OF WOMEN W t 1 0 DEVELOPED lesions are associated with productive, and still transient, HPV
CIS 11-111 LESIONS
. ~.
infections. A minority of HPV-infected women will progress to
Status at intake (t,,) Status after follow-up ( t i )
CIN Ill and an even smallcr numbcr to ccrvical cancer. On the
- __ ~
basis of data from thc British Columbia cytological screening
programme (Boyes et al., 1982). Van Oortmarssen and
Habbcma (1991) estimated a mean time of 12 ycars for the
detectable phase of pre-malignant ccrvical lesions. Gustafsson
53 2 3a1 16 9 4 111
and Adami (1989) estimated a similar time (13 ycars) on the
42 1 1 18 61 4 I11
38 I 2 35 18 4 111 basis of Swedish ccrvical-cancer screening data. A detectable
38 1 3a 35 37 3b 111 HPV infection that precedes development of prc-malignant
35 1 1 18 38 3b 1I1 lesions dctcctablc by cytology would lengthen the total detcct-
35 2 2 16 31 3b Ill able phase. More cxtcnsive studies should be performed to
34 1 I? negative 25 3b 111 estimate the mean time between acquisition of high-risk HPV
47 2 2 negative 13 3al I1 and development of pre-malignant ccrvical lesions detectable
44 1 1 16, 18 31 3a2 II by cytology.
36 1 1 ~-
16 31 3b II
~
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