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ONCOLOGY
assessment was also associated with a higher risk (odds ratio, 5.65;
95% confidence interval, 1.39-23.05). After high-grade squamous
atypia, absence of any cytologic or histologic specimen was a major
determinant of cancer risk (odds ratio, 12.52; 95% confidence interval,
1.42-infinitive).
CONCLUSION: For adequate protection against invasive cervical can-
Cite this article as: Silfverdal L, Kemetli L, Andrae B, et al. Risk of invasive cervical cancer in relation to management of abnormal Pap smear results. Am J Obstet
Gynecol 2009;201:188.e1-7.
188.e1
Oncology
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FIGURE
Age > 66
y
n = 370
Cases
n = 1,230
Age > 66
y
n = 1,845
Controls
n = 6,124
No Pap
smear
n = 288
Age < 67
y
n = 860
No Pap
smear
n = 710
Age < 67
y
n = 4,279
Benign
smear
n = 413
Pap smear
n = 572
Benign
smear
n = 3,311
Unsatisfactory
for evaluation, n = 22
Atypical
smear
n = 137
Low
grade
n = 64
Nonsquamous
n = 49
High
grade
n = 24
Unsatisfactory
for evaluation, n = 84
Low
grade
n = 110
High
grade
n = 34
Pap smear
n = 3,569
Atypical
smear
n = 174
Nonsquamous
n = 30
Flowchart illustrating data generation process for case subjects having primary epithelial invasive
cervical cancer and their respective control subjects. Study groups are below broken line and
included case and control subjects with first abnormal smear finding being atypical or unsatisfactory
for evaluation 0.5-6.5 years before case subjects cancer diagnosis.
Silfverdal. Risk of invasive cervical cancer in relation to management of abnormal Pap smear results. Am J Obstet Gynecol
2009.
had an abnormal Pap smear finding registered 0.5-6.5 years before the date of the
patients cancer diagnosis and who were
aged 67 years. Age 67 years was chosen to only include the recommended
screening ages plus recently tested women
aged 60 years. The longest time for
which nationwide data were available was
6.5 years. A test that had been taken within
6 months before the date of the cancer diagnosis was not considered as part of the
screening history but rather as a test leading to the detection of invasive cancer. The
Figure illustrates how the study groups
were derived and subdivided into those
with a primary abnormal smear result being low-grade atypia, high-grade atypia,
nonsquamous atypia, or unsatisfactory for
Research
188.e2
Research
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TABLE 1
Odds ratio for invasive cervical cancer in women assessed with cytology only,
or with histology, or having no morphology registered
Diagnosisa
Category
Assessmentb
Case
Koilocytosis
Cytology only
1.00
Reference
Histology
1.88
(0.04-82.80)
No morphology
1.58
(0.03-99.09)
Control
OR
(95% CI)
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
ASCUS
Cytology only
15
20
1.00
Reference
Histology
18
0.68
(0.24-1.96)
No morphology
1.78
(0.34-9.18)
Cytology only
19
23
1.00
Reference
Histology
11
40
0.33
(0.13-0.81)
4.36
(0.45-Infinitive)
Cytology only
35
45
1.00
Reference
Histology
21
59
0.46
(0.24-0.89)
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
CIN1
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
c
No morphology
................................................................................................................................................................................................................................................................................................................................................................................
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
No morphology
1.71
(0.54-5.38)
Cytology only
1.00
Reference
Histology
25
0.29
(0.06-1.44)
No morphology
8.75
(0.94-Infinitive)
Cytology only
1.00
Reference
Histology
No morphology
Cytology only
................................................................................................................................................................................................................................................................................................................................................................................
CIN2
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
c
................................................................................................................................................................................................................................................................................................................................................................................
CIN3/cancer in situ
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
1.00
Reference
...........................................................................................................................................................................................................
Histology
29
0.39
No morphology
11
12.52
(0.09-1.77)
Cytology only
14
1.00
Reference
1.42
(0.27-7.52)
...........................................................................................................................................................................................................
c
(1.42-Infinitive)
................................................................................................................................................................................................................................................................................................................................................................................
...........................................................................................................................................................................................................
Histology
...........................................................................................................................................................................................................
No morphology
0.35
(0.08-1.60)
Cytology only
1.00
Reference
Histology
10
0.23
(0.04-1.38)
No morphology
0.76
(0.05-11.97)
1.00
Reference
................................................................................................................................................................................................................................................................................................................................................................................
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Adenocarcinoma/adenocarcinoma in situ
Cytology only
Histology
No morphology
Cytology only
22
Histology
19
8
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Total nonsquamous
1.00
Reference
14
0.50
(0.17-1.46)
0.39
(0.11-1.42)
...........................................................................................................................................................................................................
...........................................................................................................................................................................................................
No morphology
................................................................................................................................................................................................................................................................................................................................................................................
ASCUS, atypical squamous cells of undetermined significance; CI, confidence interval; CIN, cervical intraepithelial neoplasia; H, high-grade squamous abnormality; L, low-grade squamous
abnormality; N, nonsquamous abnormality; OR, odds ratio.
a
Diagnosis of first abnormal smear finding 0.5-6.5 years prior to patient cancer diagnosis; b assessment within 25 months after first abnormal smear finding; c OR and CI estimated using exact
method.
Silfverdal. Risk of invasive cervical cancer in relation to management of abnormal Pap smear results. Am J Obstet Gynecol 2009.
within 60 days prior to the cancer diagnosis was excluded, so as not to include assessments having led to the detection of an
invasive cancer. The initial assessment of
188.e3
first repeated cytology, and/or histopathology, was considered as being the first
further assessment visit. If the laboratory
registration dates of cytology and histopa-
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Research
TABLE 2
Age at first atypical smear and time from first atypical smear to date of cancer diagnosis among cases
Category low-grade
Category high-grade
Category nonsquamous
Cases
Controls P
Cases
Controls P
Cases
Controls P
(n 64) (n 110) value (n 24) (n 34) value (n 49) (n 30) value
Mean age at first abnormal smear finding (y)
38.1
37.5
.680
38.3
36.6
.469
42.4
45.1
.243
47.0
.124
36.1
45.8
.132
30.0
42.0
.015
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Silfverdal. Risk of invasive cervical cancer in relation to management of abnormal Pap smear results. Am J Obstet Gynecol 2009.
R ESULTS
The mean age at the date of the first abnormal smear finding, and the mean
time from first abnormal smear finding
to the date of the cases cancer diagnosis,
are shown in Table 2.
Category low-grade
The ORs for invasive cervical cancer in
women assessed with histology, or with no
morphology registered, compared to re-
(Table 1). Among women under cytologic surveillance only (data not shown),
the mean number of repeated smears
was similar between cases and controls
(1.69 vs 1.78; P .635), and we found no
clear difference regarding the proportions having presented with 2 normal,
and no atypical, smear results: 28.6%
(10/35) vs 37.8% (17/45); (OR, 0.66;
95% confidence interval, 0.25-1.7).
Categories high-grade
and nonsquamous
After a high-grade squamous atypia, the
absence of morphology strongly increased the risk for invasive cancer (Table 1). The decreased risk with histologic
assessment, compared to cytology, was
not statistically significant.
Among nonsquamous abnormalities,
we found a tendency toward decreased risk
with histology, compared to repeated cytology, although not statistically significant
(Table 1). Repeated smear was not associated with a lower risk compared to absence
of morphology.
The majority of the histologically assessed cases and controls with a highgrade or a nonsquamous atypia had the
biopsy specimen taken at the first visit
(21/28 cases and 33/43 controls). The
TABLE 3
Odds ratios for invasive cervical cancer in women assessed with histology at different time periods
Category low-grade
a
Case
Control
Histology within 6 mo
(95% CI)
Case
Control
OR
(95% CI)
13
49
1.00
Reference
23
40
1.00
Reference
Histology 7-12 mo
5.65
(1.39-23.05)
2.61
(0.41-16.78)
Histology 13-25 mo
1.26
(0.23-6.97)
3.48
(0.30-40.49)
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Assessment after first atypical smear 0.5-6.5 years before patient cancer diagnosis.
Silfverdal. Risk of invasive cervical cancer in relation to management of abnormal Pap smear results. Am J Obstet Gynecol 2009.
188.e4
Research
Oncology
C OMMENT
The main finding in our study was that
histologic assessment was strongly associated with a decreased risk of invasive
cervical cancer compared to repeated cytology in women with a low-grade squamous abnormal smear result. As expected, absence of morphological
assessment strongly increased the risk in
women with a high-grade squamous
atypia.
The study has several strengths. The
cases were identified from a study base
comprising all new cases of invasive cervical cancer that occurred in Sweden
during a 3-year period, and their histopathological specimens had been rereviewed. Both cases and controls come
from the same study base, as defined by
very accurate national population registers.11 The access rate to data from all
eligible cases and controls was estimated
to be least 93%, as the data on cytology
and histopathology were collected from
a national database of high quality, with
data lacking only from some laboratories
and for only half a year or at most a few
years.
Limitations to the study are the fact
that the statistical power was limited,
particularly for some rare diagnoses; our
matching on age at diagnosis rather than
on screening histories; and the lack of
data on colposcopical examination.
However, despite the limited power,
some strong associations were observed.
The age differences between cases and
188.e5
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controls at first abnormal smear finding
were negligible and adjusted for in the
analysis (Table 2). A difference in time
from first abnormal smear result to diagnosis of cancer among the cases would
make the results less reliable if the controls had shorter intervals than the cases,
because they would then have had less
time to develop invasive cancer. In this
study the time intervals were longer for
the controls (Table 2), which supports
the results indicating a protective effect
by the management of controls. In the
categories low-grade and nonsquamous
abnormality the proportions of the different cytologic diagnoses were equal at
the primary abnormal smear finding
(Table 1). In category high-grade there
was a larger proportion of CIN3 among
the cases, which means that the results in
this category should be interpreted with
caution. No information on whether or
not colposcopies had been done was
available. The occurrence of colposcopical examinations where no biopsy or cytology is taken among the no-morphology subjects might explain the finding
that no morphology and cytology
only were equivalent in terms of risks in
the categories low-grade and nonsquamous. However, colposcopy not accompanied by a repeated smear or a biopsy is
not likely to have occurred to any appreciable extent, as it is not recommended
practice and not in accordance to traditional practice in Sweden. Therefore, it is
likely that there had been no further assessment when no morphology had been
registered.
Differences between cases and controls in the management were expected.
Sasieni et al3 reported that 13% of the
cases and 1% of the controls had encountered inadequate assessment in a
case-control study on smear histories of
women aged 70 years with cervical
cancer. In the same study, no significant
difference was found between the proportions of cases and controls with an
abnormal smear result followed by 2
negative results. This lack of protective
effect even by 2 normal smear results after a low-grade abnormal smear result is
in concordance with our findings. In the
present study we chose a different approach from previous publications, by
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Another important aspect of delayed assessment is the negative psychological side
effect of not knowing whether one is
healthy or ill. It has been shown that the
intermediary period between the notification of an abnormal smear result and the
clarification of the nature and the degree of
the pathological findings is particularly
stressful for many women.24
In the categories high-grade and
nonsquamous abnormalities, the expected management according to guidelines would be histologic assessment,10
and therefore the low rate of biopsy in
controls with a nonsquamous atypia
(47%) was unexpected and indicates a
poor adherence to guideline recommendations. Women presenting with glandular cell atypia have been found to have
underlying invasive disease in 4-16% and
preinvasive disease in 17-40%,25,26 and
therefore colposcopy and histologic investigation has been recommended.7,8,25,26
It is well known that women with highgrade squamous abnormalities in cytology
have a high rate of underlying CIN2-3 (7790%)27 and a substantial risk of developing
an invasive cancer within 24 months
(1.44%).23 The results of the current study
suggest that there is a substantial risk of developing invasive disease when women in
this category are not further assessed. Assessment with cytology only occurred
rarely and only in women with CIN2.
In women having a first nonnormal
smear finding unsatisfactory for evaluation, our finding of no correlation between
further assessment and prevention of invasive disease is in disagreement with the results presented by Nygrd et al,28 something that could be explained by the
smaller numbers in our study. Nygrd et
al28 reported an increased hazard ratio of
invasive cervical cancer for women with an
unsatisfactory smear, which was mostly attributable to women who did not have a
repeated smear within 2 years.
Our finding, showing that cytologic
surveillance of women with low-grade
squamous cytologic abnormalities is less
protective than biopsy, should have implications for guidelines. This means a
need of increased colposcopy resources.
As human papillomavirus-DNA testing
has shown to be efficient in triaging
women with ASCUS, this could be used
Research
188.e6
Research
Oncology
188.e7
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changes: an unintentional transition from health
to liminality? Soc Health Illn 2004;26:306-25.
25. Kennedy AW, Salmieri SS, Wirth SL,
Biscotti CV, Tuason LJ, Travarca MJ. Results of
the clinical evaluation of atypical glandular cells
of undetermined significance (AGCUS) detected on cervical cytology screening. Gynecol
Oncol 1996;63:14-8.
26. Mohammed DK, Lavie O, de B Lopez A,
Cross P, Monaghan JM. A clinical review of borderline glandular cells on cervical cytology.
BJOG 2000;107:605-9.
27. Bigrigg MA, Codling BW, Pearson P, Read
MD, Swingler GR. Colposcopic diagnosis and
treatment of cervical dysplasia at a single clinic