Research ajog.

org

GYNECOLOGY
Recurrence of high-grade cervical abnormalities
following conservative management of cervical
intraepithelial neoplasia grade 2
Tom M. Wilkinson, MBChB; Peter H. H. Sykes, MBChB, FRANZCOG;
Bryony Simcock, MD; Simone Petrich, MD

OBJECTIVE: Conservative management of cervical intraepithelial
neoplasia (CIN) grade 2 in women younger than 25 years may reduce
overtreatment. However, long-term efficacy remains uncertain. This
retrospective cohort study aimed to determine the rate of recurrence of
high-grade abnormalities among young women with a history of CIN 2
that spontaneously regressed within 2 years and compare this with the
rate of high-grade abnormality in similar women with an initial diag-
nosis of CIN 1.
STUDY DESIGN: We identified all women aged younger than 25 years
who were diagnosed with CIN 1 or CIN 2 between January 2005 and
August 2009 within 2 colposcopy units. Follow-up data from the
National Cervical Screening Programme were obtained to identify
those women who developed recurrent high-grade lesions before
October 2012. Comparisons were made using Cox proportional haz-
ards regression.
RESULTS: A total of 683 women were included: 106 with CIN 2 that
spontaneously regressed, 299 with treated CIN 2, and 278 with
conservatively managed CIN 1. Median follow-up was 4 years. There was
no significant difference in the risk of development of high-grade ab-
normalities after 2 years between the spontaneously regressing CIN 2
and CIN 1 groups (P ¼ .83). Women with treated CIN 2 had a significantly
lower risk of recurrence than women with untreated CIN 2 (P ¼ .01).
CONCLUSION: CIN 2 that has spontaneously regressed appears to
behave as a low-grade lesion. This study contributes to the growing
body of evidence that careful observation of CIN 2 is an efficacious and
appropriate initial management option for women aged younger than
25 years at diagnosis.
Key words: cervical intraepithelial neoplasia, conservative manage-
ment, grade 2, young women

Cite this article as: Wilkinson TM, Sykes PHH, Simcock B, et al. Recurrence of high-grade cervical abnormalities following conservative management of cervical
intraepithelial neoplasia grade 2. Am J Obstet Gynecol 2015;212:769.e1-7.

R outine cervical screening of women

under the age of 25 years is
controversial and varies internation-
ally. In New Zealand, all women are
From the Department of Obstetrics and
Gynecology, University of Otago Christchurch,
Christchurch (Drs Wilkinson, Sykes, and
Simcock), and Department of Women’s and
Children’s Health, Dunedin School of Medicine,
University of Otago, Dunedin (Dr Petrich),
New Zealand.
Received July 29, 2014; revised Nov. 3, 2014;
accepted Jan. 7, 2015.
T.M.W. received financial support to conduct
this study from the Cancer Society of New
Zealand, Canterbury/West Coast Division,
and Diamond Harbour Group.
The authors report no conflict of interest.
Corresponding author: Tom Wilkinson, MBChB.
wilth689@student.otago.ac.nz
0002-9378/$36.00
ª 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.01.010
offered screening from the age of 20
years onward,1 whereas screening starts
at age 18 years in Australia2 and age 25
years in the United Kingdom.3 The
decision in the United Kingdom to start
screening at age 25 years was made on
the basis of an analysis that demon-
strated no reduction in the incidence of
cervical cancer among women screened
under the age of 25 years.4 The US
Preventive Services Task Force recom-
mends commencing screening at age 21
years.5
Given that the benefits of screening
in this age group may be limited, if
screening is to take place, there is a
strong obligation to minimize the harms
of unnecessary treatment.
Cervical intraepithelial neoplasia
(CIN) grades 2 and 3 are collectively
classified as high-grade squamous
intraepithelial lesions (HSIL). Indeed,
according to the Lower Anogenital
Squamous Terminology, they are not
distinguished.6 These lesions are
generally managed similarly, using
curative treatment. This generalized
approach has historically been followed
to ensure the safety of women; however,
in the case of CIN 2, it is largely un-
supported by firm evidence.7 Although
CIN 3 has been convincingly shown to
carry a high risk of subsequent cancer,8
CIN 2 is not so obviously
precancerous.9
The risk of overtreatment is highest in
women under the age of 25 years because
the incidence of CIN 2 peaks in this
group, yet there is a low incidence of
cervical cancer.7,10,11 Sasieni et al12 in
2009 estimated a less than a 1.5% risk of
developing cervical cancer by age 25
years in women with untreated CIN 2 or
3 diagnosed at younger than 25 years.
Given that CIN 3 has been shown to
carry a higher risk of subsequent cancer

JUNE 2015 American Journal of Obstetrics & Gynecology 769.e1

Research Gynecology
than CIN 2,9 this risk is likely to be an
overestimate when considering CIN 2
alone. Furthermore, it has been shown
that 40-74% of CIN 2 in women younger
than 25 years spontaneously regresses
within 24 months.13-18
In light of this fact and the harms of
intervention (which may include ob-
stetric complications19-22), international
guidelines have shifted to recommend
considering conservative management
in young women with histologically
proven CIN 2.1,23,24 The 2006 American
Society of Colposcopy and Cervical Pa-
thology consensus guidelines suggest a 6
month observation with colposcopy and
cytology for 24 months for HSIL, fol-
lowed by excision if the lesion is still
present.24 Perkins et al25 in 2012 found
that the introduction of this guideline
reduced the use of loop electrosurgical
excision procedures to treat moderate
dysplasia in women aged 18-23 years
from 55% to 18%. The 2012 American
Society of Colposcopy and Cervical Pa-
thology guidelines also agree with 24
months of follow-up.26
Prior research has shown no progres-
sion to cancer among conservatively
managed women with CIN 2 and a high
rate of regression in both the adolescent
and 20-25 year old age groups.14-17 How-
ever, these studies have encapsulated only
short-term outcomes (up to 24 months of
follow-up). There is therefore an unex-
plored possibility that, following apparent
spontaneous regression, women with
conservatively managed CIN2 may be at
increased risk of recurrent high-grade ab-
normalities. This would suggest dimin-
ished efficacy of conservative management
(with treatment being delayed rather than
prevented), create a need for close obser-
vation beyond 2 years, and raise questions
of safety. Investigation is therefore
necessitated.
CIN 1 is generally accepted to be a
manifestation of human papillomavirus
(HPV) infection only, carrying a very
low risk for subsequent malig-
nancy.9,27,28 This group therefore pro-
vides a good measure of what an
acceptable degree of recurrence is.
This retrospective cohort study aimed
to determine the long-term rate of
recurrence of high-grade abnormalities
769.e2 American Journal of Obstetrics & Gynecology JUNE 2015
of the cervix among women with a his-
tory of spontaneously regressing CIN 2
and compared this with the rate of high-
grade abnormality in similar women
with an initial diagnosis of CIN 1.
As a secondary aim, we also intended
to compare with recurrence in women
who have received treatment for CIN 2.
M ATERIALS AND M ETHODS
Our study cohort was derived from 2
colposcopy units in New Zealand
(Christchurch and Dunedin).
Data were extracted retrospectively;
therefore, the study investigators had no
influence on management decisions
made regarding cohort members. All
cohort members received a new histo-
logical diagnosis of CIN 1 or CIN 2 be-
tween January 2005 and August 2009. At
this time, local management guidelines
were in favor of a conservative approach
to managing CIN 1, consisting of
12 month cytological surveillance for 24
months and in favor of immediate treat-
ment for CIN 2.1
A selection of cohort members with
a diagnosis of CIN 2 were managed
conservatively with 6 month cytological
and colposcopic surveillance for 24
months; however, this decision was
dependent on individual patient and
clinician preferences.
Local colposcopy records at each unit
were searched to identify all women who
received a new histological diagnosis of
CIN 1 or CIN 2 between January 2005
and August 2009 and who were aged
younger than 25 years at the time of
diagnosis. These records were also used
to determine age at diagnosis, ethnicity,
smoking status at diagnosis, parity at
diagnosis, and to determine whether any
woman had undergone hysterectomy.
Full cervical screening records for
these women were obtained from the
National Cervical Screening Programme
register. This provided records of all
smear tests and colposcopies received by
the women, across all centers in New
Zealand, in both the public and private
health care sector, along with cytological
and histological results, and a record
of any treatments received, prior to
October 2012.
ajog.org
All screening records were compared
against inclusion and exclusion criteria
for the cohort. Women were excluded if
they had fewer than 2 years of available
follow-up data, if they opted out of the
screening register, or if they received
treatment for an initial diagnosis of CIN
1. Women were also excluded if both their
last result prior to 24 months and their
first result after 24 months indicated a
high-grade abnormality, with no docu-
mented treatment between these 2 results
(ie, if there was no documented treatment
or regression) because this would violate
both conventional treatment and con-
servative management protocols. In
practice this means that all women in the
study cohort were free of known high-
grade disease at 2 years of follow-up.
Women with an initial diagnosis of
CIN 2 were divided into 2 groups:
spontaneous regression and treatment.
The spontaneous regression group
included all women in whom there was
evidence of regression within 2 years
of initial diagnosis and no evidence of
treatment. The treatment group included
all women who received some form of
treatment for cervical dysplasia within
2 years.
Evidence of regression was defined as
at least 1 histology or cytology result
showing normal cervix or low-grade
changes only (CIN 1, HPV infection
only, low-grade squamous intraepithelial
lesion, atypical squamous cells of unde-
termined significance), in the absence of
a second sample taken concomitantly
showing high-grade changes (CIN2, CIN
3, HSIL, atypical squamous cells: high
grade squamous intraepithelial lesion
cannot be excluded [ASC-H], adenocar-
cinoma in situ, and atypical glandular
cells).
Treatments included local loop exci-
sion of the transition zone, cold knife
cone biopsy, and laser ablation.
In accordance with our cohort selec-
tion criteria, all included women with
CIN 1 did not receive any treatment
within 2 years of initial diagnosis so were
comparable in management with the
CIN 2 spontaneous regression group.
We anticipated the total number of
women with CIN 1 being too large to be
logistically manageable. Accordingly, we
ajog.org Gynecology Research
obtained full screening records for only a
proportion of the women with CIN 1 FIGURE 1
and excluded the remainder. Cohort numbers, inclusions and exclusions
The selection of women with CIN 1 to
be excluded was random but with a
modification to create comparability
between the CIN 2 spontaneous regres-
sion and CIN 1 cohorts in the duration
of follow-up.
All women were stratified by year of
initial diagnosis. For a given year, if the
number of women in the CIN 1 group was
less than 3 times the number of women in
the CIN 2 spontaneous regression group,
all of the women with an initial diagnosis
of CIN 1 were included. If not, then
women with an initial diagnosis of CIN 1
were randomly excluded by a researcher
blinded to their long-term outcome, such
that the total number of women in the
CIN 1 group was 3 times the number in
the CIN 2 spontaneous regression group.
This process was carried out after
biostatistical consultation.
Baseline characteristics of the cohort
across the 3 groups were compared using
c2 tests for categorical variables, and
1-way analysis of variance for continuous
variables. Independent-sample Student t
tests were used when comparing 2 CIN, cervical intraepithelial neoplasia
groups only. When more than 1 follow- Wilkinson. Recurrence of CIN2 in women managed conservatively. Am J Obstet Gynecol 2015.
up event (defined as a colposcopy or
community smear test) had occurred
beyond 2 years, the average time between
each event was calculated and compared Ethics approval was obtained from the for percentages presented is women with
between groups. University of Otago Human Ethics available data.
Outcomes were determined from Committee and regional authorization Women in the CIN 2 spontaneous
cytological and histological results. to use clinical data gained in both regression group were significantly more
Where both cytology and histology were Christchurch and Dunedin. likely than women in the other 2 groups
available from 1 colposcopy visit, the Analyses were performed using to be aged less than 20 years at the time of
histology result was used unless the SPSS 19.0 for windows (SPSS Inc, diagnosis, but there was no significant
histology result was normal and the Chicago, IL). difference between groups in ethnicity or
cytology result abnormal, in which case rates of smoking and nulliparity. No
the cytology result was used. R ESULTS women were documented as having
The primary outcome was develop- The final study cohort included 683 undergone a hysterectomy at any point
ment of high-grade changes (defined as women: 106 (16%) with spontaneously in time.
cytological or histological evidence of regressing CIN 2, 299 (44%) with treated The median length of follow-up for
CIN2/3, HSIL, ASC-H, adenocarcinoma CIN 2, and 278 (41%) with conserva- the overall cohort was 4.1 years from
in situ, atypical glandular cells, or worse) tively managed CIN 1. Exclusions are time of initial diagnosis, with 26% of the
at least 2 years after the initial diagnosis. outlined in Figure 1. women having at least 5 years of follow-
Accordingly, Kaplan-Meier curves were Baseline data of the cohort are pre- up data available.
constructed starting at 2 years. A Cox sented in Table 1. Some of these data Significant differences in follow-up were
proportional hazards model was used to were missing because of individual cli- found between the 3 study groups. How-
calculate hazard ratios and confidence nicians not recording full demographic ever, as expected under the study design,
intervals and to adjust for potential or background clinical features in the there was no difference between the CIN 1
confounders. colposcopy database. The denominator and CIN 2 spontaneous regression group

JUNE 2015 American Journal of Obstetrics & Gynecology 769.e3

Research Gynecology ajog.org

TABLE 1
Descriptive data for the cohort
CIN 1 (conservative CIN 2 spontaneous CIN 2
Variable management) regression treatment Sig (P value)a
Age at diagnosis, y
<20 46 (18%) 32 (31%) 45 (15%) .002
20 214 (82%) 72 (69%) 253 (85%)
Age range, y (mean) 16e24 (21.4) 16e24 (20.7) 17e24 (21.7) < .001
Nulliparous at diagnosis
Yes 194 (83%) 67 (80%) 189 (76%) .16
No 40 (17%) 17 (20%) 60 (24%)
Hysterectomy during follow-up
Yes 0 (0%) 0 (0%) 0 (0%) N/A
No 178 (100%) 75 (100%) 165 (100%)
Smoker at diagnosis
Yes 79 (42%) 31 (36%) 82 (46%) .37
No 110 (58%) 54 (64%) 98 (54%)
Ethnicity
NZ European 200 (81%) 84 (88%) 235 (82%) .07
NZ Maori 19 (8%) 8 (8%) 27 (9%)
Pacific Islander 1 (0.4%) 0 (0%) 6 (2%)
Other 28 (11%) 4 (4%) 18 (6%)
Average gap between 1.07 1.02 1.20 .020
follow-up visits, y
Mean duration of 4.08 (2.00e7.36) 3.96 (2.02e6.92) 4.55 (2.03e7.73) < .001
follow-up, y (range)
Median duration of 3.86 3.69 4.45
follow-up, y
Five year follow-up 58 (21%) 20 (19%) 97 (32%) .001
data available
Year of initial diagnosis
2005 40 (14%) 12 (11%) 63 (21%) < .001
2006 30 (11%) 16 (15%) 69 (23%)
2007 78 (28%) 23 (22%) 76 (25%)
2008 83 (30%) 29 (27%) 61 (20%)
2009 47 (17%) 26 (25%) 30 (10%)
CIN, cervical intraepithelial neoplasia; N/A, not available; NZ, New Zealand; Sig, significance.
a
Determined from the X2 distribution for categorical variables, and using one-way analysis of variance for continuous variables.
Wilkinson. Recurrence of CIN2 in women managed conservatively. Am J Obstet Gynecol 2015.

with regard to percentage of women
with 5 year follow-up data (P ¼ .76),
in average length of follow-up (P ¼
.43), or year of initial diagnosis (P ¼
.25). There was also no difference
between these 2 groups in frequency of
follow-up (P ¼ .54).
Kaplan-Meier curves for the 3 groups
are presented in Figure 2. Hazard ratios
for development of high-grade
abnormalities (calculated from Cox
proportional hazards regression) are
presented in Table 2. Adjustments were
made for age at diagnosis, smoking
status at diagnosis, ethnicity, and initial

769.e4 American Journal of Obstetrics & Gynecology JUNE 2015

ajog.org Gynecology Research
treatment center. After adjustment, no
significant difference was found FIGURE 2
between the CIN 2 spontaneous Development of high-grade changes across the 3 study groups
regression and CIN 1 groups (P ¼ .83).
However, the CIN 2 treatment group
was found to have a significantly lower
risk of high-grade abnormality than
both the CIN 2 spontaneous regression
and CIN 1 groups (P ¼ .01 and P ¼ .001,
respectively). The treatment center was
found to have a significant effect on the
risk of high-grade abnormality (P ¼
.007); no other covariate in the model
was significantly associated with this
outcome.
The risk of development of high-grade
abnormality over the follow-up period
for each of the study groups was 17% for
CIN 2 spontaneous regression (18 of
106), 12% for CIN 1 (32 of 278), and 4%
for CIN 2 treatment (13 of 299). High-
grade abnormalities detected included
CIN 2, CIN 3, HSIL, and ASC-H. The
low number of cohort members devel-
Graph is truncated at 5 years for clarity. However, note that the hazard ratios presented in Table 2
oping such abnormalities precludes
consider the full length of follow-up data available for each patient. Follow-up time is in relation to the
further analysis regarding the risk of
initial diagnosis of CIN 1 or CIN 2. Because of the study design, no cohort members had a known
developing a specific abnormality.
high-grade abnormality at 2 years. The period of interest is the time after 2 years; hence, the first 2
In light of the finding of significantly
years are being presented as a flat line.
different outcomes between treatment
CIN, cervical intraepithelial neoplasia.
centers (with a higher rate of recurrence
Wilkinson. Recurrence of CIN2 in women managed conservatively. Am J Obstet Gynecol 2015.
in Christchurch than in Dunedin),
2 post-hoc analyses were performed.
First, the average length and frequency (Follow-up frequency refers to the mean when histologically detected abnormality
of follow-up were compared between the time between any 2 consecutive follow- was used as the outcome (hazard ratio,
2 centers. No significant differences were up events, from 2 years after the diag- 3.19; 95% confidence interval [CI],
found, with average follow-up lengths nosis onward). 1.24e8.22; P ¼ .02); however, no differ-
from initial diagnosis of 4.26 years in Second, Cox proportional hazards ence was found in the risk of cytologically
Christchurch and 4.31 years in Dunedin regression analyses were conducted ac- detected abnormality (hazard ratio, 1.00;
(P ¼ .64), and average follow-up fre- counting for the method of diagnosis 95% CI, 0.40e2.47; P ¼ .99).
quencies of 1.10 years in Christchurch (cytology or histology). A significant raw Finally, the average number of avail-
and 1.17 years in Dunedin (P ¼ .19). difference was found between the 2 centers able histology results from 2 years after

TABLE 2
Hazard ratios for development of high-grade abnormalities after 2 years
Hazard ratio (raw) Hazard ratio (adjusted)
Comparison (95% CI) Sig (P value) (95% CI)a Sig (P value)
CIN 2 conservative compared with CIN 1 0.87 (0.43e1.77) .70 0.92 (0.44e1.94) .83
CIN 2 conservative compared with 2.98 (1.30e6.86) .01 2.97 (1.24e7.09) .01
CIN 2 treatment
CIN 1 compared with CIN 2 treatment 3.44 (1.80e6.58) < .001 3.23 (1.66e6.29) .001
CI, confidence interval; CIN, cervical intraepithelial neoplasia; Sig, significance.
a
Adjusted for smoking status, age, ethnicity, and treatment center.
Wilkinson. Recurrence of CIN2 in women managed conservatively. Am J Obstet Gynecol 2015.

JUNE 2015 American Journal of Obstetrics & Gynecology 769.e5

Research Gynecology
the initial diagnosis onward for women
from each center was calculated. This
was higher for Christchurch (0.41) than
Dunedin (0.33), although the difference
was not significant (P ¼ .14).
C OMMENT
To the best of our knowledge, this is the
first time long-term outcomes (beyond 2
years) of CIN 2 conservative manage-
ment have been reported in the litera-
ture. The main finding of this study is
that, where CIN 2 is present in a young
woman (age younger than 25 years) and
spontaneously regresses within 2 years,
the risk of recurrent high-grade abnor-
malities is not significantly higher than
the risk among women initially diag-
nosed with CIN 1. This affirms the value
of conservative management of CIN 2 in
this group by demonstrating that a large
subset of CIN 2 behaves as a low-grade
lesion (and hence a case can be made
for managing it as one).
Specific inclusion and exclusion
criteria mean that these 2 groups of
interest (CIN 1 and CIN 2 conservative)
were comparable within the study
cohort. No differences were found in the
distribution of year of initial diagnosis,
frequency of follow-up, or length of
follow-up, so the results are unlikely to
be biased by changing management
protocols or differential follow-up.
Although the 2 groups did signifi-
cantly differ in age at diagnosis (with
CIN 2 women more likely to be younger
than 20 years), adjusting for this in the
analysis did not alter the result.
Furthermore, all women in both groups
underwent a biopsy for the purposes of
providing a histological diagnosis. Any
possibility of such a biopsy having an
impact on the natural history of CIN 1 or
2 has therefore been negated for the
purposes of comparison.
In comparison with women who have
undergone treatment, conservatively
managed women appear to remain at an
increased risk of high-grade abnormality
for at least 5 years. This finding has im-
plications for conservative management
protocols, and full exploration of this
effect requires follow-up on a longer
time scale than that present here.
769.e6 American Journal of Obstetrics & Gynecology JUNE 2015
The percentage of women in each group
who developed high-grade abnorma-
lities is apparently high: 17% for the CIN
2 spontaneous regression group, 12%
for the CIN 1 group, and 4% for the CIN
2 treatment group. However, this is
unsurprising, given the study design,
which purposely took a very generous
approach, requiring only 1 result (cytology
or histology), suggesting a high-grade
change to declare that such an abnormal-
ity was present. This ensured sufficient
power and was applied consistently be-
tween groups. However, it does mean
that the apparent rate of such abnor-
malities reported is likely to be an
overestimate.
The effect of this approach can be best
seen in the difference noted between the
2 study centers, with women in Christ-
church having a higher risk of high-
grade abnormality than women in
Dunedin. Post-hoc analysis suggested
that if only cytological results were
considered, there would be no difference
in the observed rate of high-grade ab-
normality between the 2 centers.
This is likely to be in part because of
more biopsies being carried out per
woman in Christchurch (reflected in the
greater number of histology results per
woman and in follow-up being slightly
more frequent on average), rather than a
higher rate of cytological abnormalities.
Clearly, differences in clinical approaches
to colposcopy can influence the observed
rate of cervical dysplasia. Reassuringly,
controlling for the difference between
the 2 study centers did not substantially
alter the study findings (the raw and
adjusted hazard ratios were similar).
This illustrates an important weakness
in the study design: its retrospective na-
ture means that patient management
and follow-up was not standardized. A
liberal definition of regression of CIN 2
was applied, including all women with at
least 1 cytology or histology specimen
confirming CIN 1 or less and no evi-
dence of subsequent high-grade change
within 24 months. Although we would
normally expect 2 such specimens
because of the heterogeneous nature of
this group and allowing for delays in
follow-up, a stricter definition could not
be applied. If this would introduce a bias,
ajog.org
one would expect that it may result in a
higher rate of high grades in this group,
so exclusion of a subgroup is unlikely to
alter the conclusion of the study.
Any bias introduced by varied follow-
up regimens is minimized by the use of
data from a national screening program
(allowing for systematic identification of
patients and ensuring a degree of regular
follow-up), and the impact of differing
management philosophies at different
centers is apparent. Regardless, the main
findings of the study remained the same
after adjusting for treatment center,
indicating a good degree of generaliz-
ability. Furthermore, the observed dif-
ferences between centers provide insight
into the difficulties of interpretation of
the studies and management protocols
reliant on a histological and cytological
diagnosis of CIN grade.
It should also be acknowledged that
there is clear evidence of inter- and
intraobserver variation in histological
and cytological diagnosis of cervical ab-
normalities.29-31 In this study, results
were not adjudicated, and therefore,
there may be inaccuracies. In particular,
results initially thought to be CIN 2 may
actually represent CIN 1. Although this
is an important caveat, it is not a signif-
icant limitation, given the clinical
context of the question at hand. When
deciding on an appropriate management
plan, the clinician must act on the basis
of the data available, and therefore, our
study groups were also classified on this
same basis.
A further implication of the variability
of testing is that CIN 2 may in fact cover
a range of biological entities. Our main
group of interest was women who had
CIN 2 spontaneously regress within 2
years, and this is likely to represent a
specific subset of all CIN 2. In particular,
it may represent a subset with an un-
derlying biology similar to CIN 1.
Further research is needed into the
stratification of CIN 2, in particular
looking for predictors of regression.
Because of the small size and retro-
spective nature of this study, larger pro-
spective studies need to be performed
before definitive conclusions can be
made. The cohort size was determined
by the number of women who happened
ajog.org
to diagnosed with CIN 2 in a particular
time period. Formal power calculations
were therefore not performed. In terms
of the primary outcome (the hazard ratio
for development of high grade abnor-
mality, comparing the CIN 2 sponta-
neous regression and CIN 1 groups), the
95% CI is uncomfortably wide to use as
the sole basis for clinical decision making
(0.44e1.94).
Clearly a more precise result would be
expected with a larger cohort. Addi-
tionally, the very low risk of cancer in
this age group means that study was not
powered to effectively investigate the
safety of conservative management.
Finally, the ad hoc nature of the cohort
division leaves the results susceptible to
an uncertain degree of selection bias.
Within these limitations we conclude
that it is likely that in selected women
with CIN 2, if spontaneous regression
occurs, recurrent high-grade abnormal-
ities occur with similar frequency to
women with conservatively managed
CIN 1. This study contributes to the
growing body of evidence that careful
observation of CIN 2 is an efficacious
and appropriate initial management
option for women under the age of 25
years. - Gynecol 2009;113:18-25.
REFERENCES
1. National Cervical Screening Programme.
Guidelines for cervical screening in New Zea-
land. Wellington (New Zealand): National
Screening Unit, Ministry of Health; 2008.
2. Australian Government, Department of
Health and Ageing. National Cervical Screening
Programme, 2009. Available at: www.
cancerscreening.gov.au/internet/screening/
publishing.nsf/Content/cervical-about. Accessed
Nov. 2, 2012.
3. National Health Service Cervical Screening
Programme. About cervical screening, 2012.
Available at: www.cancerscreening.nhs.uk/
cervical/about-cervical-screening.html. Accessed
Nov. 2, 2012.
4. Sasieni P, Castanon A, Cuzick J. Effective-
ness of cervical screening with age: population
based case-control study of prospectively
recorded data. BMJ 2009;339:b2968.
5. US Preventive Services Task Force.
Screening for cervical cancer, 2012. Available at:
http://www.uspreventiveservicestaskforce.org/
uspstf/uspscerv.htm. Accessed Sept. 21, 2014.
6. Darragh TM, Colgan TJ, Cox JT, et al. The lower
anogenital squamous terminology standardization
project for HPV-associated lesions: background
and consensus recommendations from the
College of American Pathologists and the American
Society for Colposcopy and Cervical Pathology.
Ann Pathol Lab Med 2012;136:1266-97.
7. Petry KU. Management options for cervical
intraepithelial neoplasia. Best Pract Res Clin
Obstet Gynaecol 2011;25:641-51.
8. McCredie MRE, Sharples KJ, Paul C, et al.
Natural history of cervical neoplasia and risk of
invasive cancer in women with cervical intra-
epithelial neoplasia 3: a retrospective cohort
study. Lancet Oncol 2008;9:425-34.
9. Östör AG. Natural history of cervical intra-
epithelial neoplasia: a critical review. Int J
Gynecol Pathol 1993;12:186-92.
10. New Zealand Ministry of Health. Cancer:
selected sites 2009, 2010, 2011. Available at:
http://www.health.govt.nz/publication/cancer-
selected-sites-2009-2010-2011. Accessed
Nov. 2, 2012.
11. Peto J, Gilham G, Deacon J, et al. Cervical
HPV infection and neoplasia in a large
population-based prospective study: the Man-
chester cohort. Br J Cancer 2004;91:942-53.
12. Sasieni P, Castanon J, Parkin DM. How
many cancers are prevented by treatment of
screen-detected disease in young women? Int J
Cancer 2009;124:461-4.
13. Castle PE, Schiffman M, Wheeler CM,
Solomon D. Evidence for frequent regression of
cervical intraepithelial neoplasia-grade 2. Obstet
14. Discacciati MG, de Souza CAS,
d’Otavianno MG, et al. Outcome of expectant
management of cervical intraepithelial neoplasia
grade 2 in women followed for 12 months.
Eur J Obstet Gynecol Reprod Biol 2011;155:
204-8.
15. Fuchs K, Weitzen S, Wu L, Phipps MG,
Boardman LA. Management of cervical intra-
epithelial neoplasia 2 in adolescent and young
women. J Paediatr Adolesc Gynaecol 2007;20:
269-74.
16. McAllum B, Sykes PHH, Sadler L,
Macnab H, Simcock BJ, Mekhail AK. Is the
treatment of CIN 2 always necessary in women
under 25 years old? Am J Obstet Gynecol
2011;205:478.e1-7.
17. Moore K, Cofer A, Elliot L, Lanneau G,
Walker J, Gold MA. Adolescent cervical
dysplasia: histologic evaluation, treatment, and
outcomes. Am J Obstet Gynecol 2007;197:141.
e1-6.
18. Guedes AC, Zeferino LC, Syrjänen KJ,
Brenna SMF. Short-term outcome of cervical
intraepithelial neoplasia grade 2: considerations
for management strategies and reproducibility
JUNE 2015 American Journal of Obstetrics & Gynecology
Gynecology Research
of diagnosis. Anticancer Res 2010;30:
2319-23.
19. Kyrgiou M, Koliopoulos G, Martin-Hirsch P,
Aybyn M, Prendiville W, Paraskevaidis E. Ob-
stetric outcomes after conservative treatment for
intraepithelial or early invasive cervical lesions:
systematic review and meta-analysis. Lancet
2006;367:489-98.
20. Sadler L, Saftlas A, Wang W, Exeter M,
Whittaker J, McCowan L. Treatment for cervical
intraepithelial neoplasia and risk of preterm
delivery. JAMA 2004;291:2100-6.
21. Samson S-LA, Bentley JR, Fahey TJ,
McKay DJ, Gill GH. The effect of loop electro-
surgical excision procedure on future pregnancy
outcome. Obstet Gynecol 2005;105:325-32.
22. Castanon A, Brocklehurst P, Evans H, et al.
Risk of preterm birth after treatment for cervical
intraepithelial neoplasia among women
attending colposcopy in England: retrospective-
prospective cohort study. BMJ 2012;345:
e5174.
23. Moscicki A-B. Conservative management of
adolescents with abnormal cytology and histol-
ogy. J Natl Compr Canc Netw 2008;6:101-6.
24. Wright TC, Massad LS, Dunton CJ,
Spitzer M, Wilkinson EJ, Solomon D.
2006 consensus guidelines for the manage-
ment of women with abnormal cervical
screening tests. J Lower Genit Tract Dis
2007;11:201-22.
25. Perkins RB, Jorgensen JR, McCoy ME,
Bak SM, Battaglia TA, Freund KM. Adherence to
conservative management recommendations
for abnormal pap test results in adolescents.
Obstet Gynecol 2012;119:1157-63.
26. Massad LS, Einstein MH, Huh WK, et al.
2012 updated consensus guidelines for the
management of abnormal cervical cancer
screening tests and cancer precursors. J Lower
Genit Tract Dis 2013;17:S1-27.
27. Woodman C, Collins S, Young L. The nat-
ural history of cervical HPV infection: unresolved
issues. Nat Rev Cancer 2007;7:11-22.
28. Mitchell H. Outcome after a cervical cytology
report of low-grade squamous abnormality
in Australia. Cancer Cytopathol 2005;105:
185-93.
29. Robertson AJ, Anderson JM, Swanson
Beck J, et al. Observer variability in histopatho-
logic reporting of cervical biopsy specimens.
J Clin Pathol 1989;42:231-8.
30. Stoler MH, Schiffman M. Interobserver
reproducibility of cervical cytologic and histo-
logic interpretations: realistic estimates from the
ASCUS-LSIL triage study. JAMA 2001;285:
1500-5.
31. Gage JC, Schiffman M, Hunt WC, et al.
Cervical histopathology variability among
laboratories: a population-based statewide
investigation. Am J Clin Pathol 2013;139:
330-5.
769.e7