ORIGINAL RESEARCH ARTICLE: CERVIX AND HPV
The Natural History of Cervical Intraepithelial Neoplasia
Grades 1, 2, and 3: A Systematic Review and Meta-analysis
Diede L. Loopik, MD, PhD,1 Heidi A. Bentley, MD,2 Maria N. Eijgenraam, MsC,1 Joanna IntHout, PhD,3
Ruud L. M. Bekkers, MD, PhD,4,5 and James R. Bentley, MB, ChB, FRCSC6
Downloaded from http://journals.lww.com/jlgtd by hA/3yZfhkz1eEGl27rF4OgeLzO7FPNA8yw07waWJj/OcCipiTNApOhjRE4MmXu0dExyr/7EIJnGK8mtbsP6DnwBdI4vBEGWEoQfmBBBpkXVk4eIGJ+Rp6+rfMekVqQh6NzwdtLbvcbw= on 08/20/2021
Objective: The aim of the study was to obtain an updated overview of
regression, persistence, and progression rates of conservatively managed
cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3.
Methods: Data sources were MEDLINE, Embase, and Cochrane (January
1, 1973–April 14, 2020). Two reviewers extracted data and assessed risk of bias.
To estimate outcome rates, we pooled proportions of the individual study results
using random-effects meta-analysis, resulting in point estimates and correspond-
ing 95% CIs. Heterogeneity was quantified by the I2 and τ2 measures.
Results: Eighty-nine studies were included, 63 studies on CIN 1
(n = 6,080–8,767), 42 on CIN 2 (n = 2,909–3,830), and 7 on CIN 3
(n = 245–351). The overall regression, persistence, and progression to CIN 2
or worse and CIN 3 or worse rates for women with conservatively managed
CIN 1 were 60% (95% CI = 55–65, I2 = 92%), 25% (95% CI = 20–30,
I2 = 94%), 11% (95% CI = 8–13, I2 = 89%), and 2% (95% CI = 1–3,
I2 = 82%), respectively. The overall regression, persistence, and progression
rates for CIN 2 were 55% (95% CI = 50–60, I2 = 85%), 23% (95% CI =
19–28, I2 = 83%), and 19% (95% CI = 15–23, I2 = 88%), respectively.
Finally, for CIN 3, these were 28% (95% CI = 17–41, I2 = 68%), 67%
(95% CI = 36–91, I2 = 84%), and 2% (95% CI = 0–25, I2 = 95%), re-
spectively. Cervical intraepithelial neoplasia grade 2 regression was sig-
nificantly higher in women 30 years or younger and high-risk human
1 grades are associated with different risks of progression to inva-
Department of Obstetrics and Gynaecology, Radboud Institute for Molecular Life
Sciences, Radboud university medical center, Nijmegen, the Netherlands; 2Depart-
ment of Obstetrics and Gynaecology, Health Sciences Centre, Winnipeg, Manitoba,
Canada; 3Department of Biostatistics, Radboud Institute for Health Sciences,
Radboud university medical center, Nijmegen, the Netherlands; 4 Department of Ob-
stetrics and Gynecology, Catharina Hospital, Eindhoven, the Netherlands; 5GROW,
School for Oncology and Developmental Biology, Maastricht University Medical
Center, Maastricht, the Netherlands; and 6Division of Gynecologic Oncology, Queen
Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Correspondence to: Diede L. Loopik, MD, PhD, Department of Obstetrics and
Gynaecology, Radboud Institute for Molecular Life Sciences, Radboud
university medical center, PO Box 9101, 6500HB, Nijmegen, the
Netherlands. E-mail: diede.loopik@radboudumc.nl
The authors have declared they have no conflicts of interest.
The abstract has been submitted for oral presentation at the International
Federation of Cervical Pathology and Colposcopy Congress, Hyderabad,
India, October 1–4, 2020. However, the International Federation of Cervical
Pathology and Colposcopy Congress has been postponed to 2021 because
of COVID-19.
Our review protocol was in accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-analysis guidance and was registered in
PROSPERO: International prospective register of systematic reviews
(CRD42019123184).
All the authors have made substantial contributions to the conception; design of
the work; or the acquisition, analysis, or interpretation of data for the work.
They have participated in the drafting of the manuscript and approval of the
version to be published. All authors approved the manuscript and
submission. This publication is approved by all authors and the responsible
authorities where the work has been carried out.
D.L.L. did the conceptualization, methodology, software, validation, formal analysis,
investigation, data curation, writing of the original draft, and visualization.
H.A.B. did the conceptualization, methodology, validation, investigation, data
curation, and writing—review and editing. M.N.E. did the conceptualization,
methodology, validation, investigation, data curation, and writing of the original
draft. J.I. did the software, formal analysis, and writing—review and editing.
R.L.M.B. and J.R.B. did the conceptualization, methodology, supervision, and
writing—review and editing.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal–s Web site (www.jlgtd.com).
© 2021, ASCCP
DOI: 10.1097/LGT.0000000000000604
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
papillomavirus–negative women (66%, 95% CI = 62–70, I2 = 76%;
94%, 95% CI = 84–99, I2 = 60%). Only 2/7,180 (0.03%) and 10/3,037
(0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer.
Conclusions: Most CIN 1/CIN 2 will regress spontaneously in less than
24 months, with the highest rates in high-risk human papillomavirus–negative
and young women, whereas progression to cancer is less than 0.5%. Con-
servative management should be considered, especially in fertile women
and with expected high compliance. Given the heterogeneity in regression
rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to
guide management.
Key Words: cervical intraepithelial neoplasia, conservative treatment,
disease progression, meta-analysis, neoplasm grading, review,
systematic review, uterine cervical dysplasia, uterine cervical neoplasms
(J Low Genit Tract Dis 2021;25: 221–231)
I nfection with high-risk human papillomavirus (hrHPV) is the
necessary cause of cervical intraepithelial neoplasia (CIN),
which can progress to cervical cancer if left untreated. To achieve
a well-considered decision to treat, knowledge on the regressive
and progressive behavior of CIN is essential. Cervical intraepithe-
lial neoplasia can be divided into 3 grades of severity, and these
sive cancer, with differing management guidelines.1
High regression rates up to 70%–90% within 2–3 years of CIN
1 are observed, and conservative management with follow-up is con-
sidered to be safe. The clinical course of CIN 2 varies, with half of the
women show regression at 24 months of follow-up and even it in-
creases to 60% for women younger than 30 years.2 Recent guidelines
advise that conservative and individualized management of CIN 2 for
up to 2 years in women younger than 25 years, before treatment,
should be considered for persistent disease.1 For CIN 3 lesions, little
is known on the natural course and biological behavior. Generally,
CIN 3 is advised to be treated immediately, as one study showed an
up to 30% risk of progression to cervical cancer over a period of
30 years.3
However, excisional treatment increases the risk of obstetrical
complications, such as preterm birth, with an even more pronounced
risk after increasing cone depth and number of treatments.4 This un-
derlines the importance of avoiding overtreatment, particularly in re-
productive age women.
To avoid overtreatment and optimize the guidelines for man-
agement of CIN, it is important to understand the clinical course
of each CIN gradation. The only study that reviewed the clinical
course for all CIN grades dates from 1993.5 The aim of this sys-
tematic review and meta-analysis is to obtain an updated overview
of the regression, persistence, and progression rates of conserva-
tively managed CIN 1, CIN 2, and CIN 3.
METHODS
Literature Search
We used MEDLINE, Embase, and Cochrane databases and
searched for publications between January 1, 1973 (CIN grading
system introduced) and April 14, 2020. Details on our search
221
Loopik et al.
strategy can be found in the supplemental material. Duplicate ar-
ticles were manually filtered using the bibliographic database of
Endnote Version X9.
Eligibility Criteria
We included all English language original studies reporting
on outcomes of histologically confirmed CIN 1, CIN 2, and/or CIN
3 during conservative management for 6 months of follow-up or
more. Exclusion criteria consisted of the following: (1) women with
previous cervical dysplasia or cervical cancer, (2) immunosuppres-
sive women (e.g., HIV-positive women, women with autoimmune
diseases), (3) pregnant women or women less than 3 months postpar-
tum, (4) women who received treatment within 6 months after diag-
nosis, (5) studies with less than 10 cases, and (6) merged CIN at
baseline (e.g., CIN 1–2 or CIN 2–3).
Outcome Measures
Our outcome measures were composed of regression, persis-
tence, and progression rates for each CIN grade and for different
time points. Time points were based on exact follow-up time or
mean or median follow-up time. Time points were categorized at
6, 12, 18, 24, 36, and 54 or more months. The follow-up periods
were rounded down to these time points. Rates were calculated with
the observed number of women with the given outcome divided by
the number of women attending in that follow-up time point.
We used the definition of regression, persistence, and pro-
gression as used in each study, accepting that this would unavoid-
ably lead to heterogeneity. For regression of CIN 2 or CIN 3, the
definition was divided into strict or lenient. We defined strict re-
gression as cytological and/or histological regression to normal.
Lenient regression included low-grade cytology, CIN 1, or less.
In case of a study using both definitions, lenient regression was
used in our main analysis. Progression of CIN 1 and CIN 2 was
further specified to CIN 3 or worse, or cervical cancer if noted.
The outcomes during follow-up were preferably diagnosed via
histology, if not available cytology was accepted.
Data Extraction
The systematic review tool Covidence was used for screening
and data extraction. For each CIN grade, we extracted data on re-
gression, persistence, and progression rates per time point available.
Other data extracted from each study were the first author, year of
publication, country where the study took place, study design, total
number of participants, mean or median age of the participants, def-
inition of regression, persistence or progression used in the study,
number of participants with these outcomes at each time point avail-
able, follow-up protocol, severity of the referral cytology, hrHPV
status, and which hrHPV test was used if applicable.
Assessment of Risk of Bias
To evaluate the risk of bias, we modified the Newcastle-Ottawa
Quality Assessment Scale (Supplementary Table 4, http://links.lww.
com/LGT/A242). We used 6 criteria to assess each study: representa-
tiveness of the cohort, number of participants, ascertainment of expo-
sure, assessment of outcome, duration of the follow-up, and loss to
follow-up. Each criterion could be classified as high or low risk of
bias. If at least 1 criterion was high risk of bias, the overall risk of bias
was classified as high.
One investigator performed the literature search, and 2 inves-
tigators independently assessed the eligibility of the identified
studies, performed the data extraction, and assessed the risk of
bias assessment. In case of disagreement, a discussion took place
to reach consensus. Our review protocol was in accordance with the
Preferred Reporting Items for Systematic Reviews and Meta-analysis
222
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
guidance and was registered in PROSPERO: International prospec-
tive register of systematic reviews (CRD42019123184).
Data Synthesis and Assessment of Heterogeneity
We pooled proportions of the individual study results overall
and at 6, 12, 18, 24, 36, and 54 or more months for the 3 outcome
measures per CIN grade. For the overall outcome per CIN grade,
the mean outcome was used when a study had results at different
time points. We used the Hartung-Knapp-Sidik-Jonkman approach to
random-effects meta-analysis with inverse variance weights and the
arcsine transformation of the proportions, resulting in point estimates
and corresponding 95% CIs of the average proportions.6 Heterogene-
ity was quantified by the I2 and τ2 measures. The empirical Bayes es-
timator was used for the estimation of the between-study variance τ2.
Ninety-five percent prediction intervals (95% PIs) from the
random-effects meta-analyses were used to present the extent of
between-study variation. Visual inspection of funnel plots and the
Egger regression test for funnel plot asymmetry were used to exam-
ine possible publication bias. To explore possible sources of heteroge-
neity, we performed subgroup analyses on studies with women
30 years or younger only versus studies that included women of all
ages, studies with hrHPV-positive versus hrHPV-negative women,
studies with strict versus lenient regression criteria, and studies with
low risk versus high risk of bias. We expected higher regression rates
in younger women, in hrHPV-negative women, and in studies using
lenient criteria. We expected less heterogeneity in studies with low
risk of bias. The analyses were also stratified per continent, year of
publication, and study design. We considered a p value of less than
.001 as statistically significant to adjust for multiple testing. All statis-
tical analyses were performed in R Version 3.5.3 with the use of
“meta” package Version 4.9-9 and “metafor” package Version 2.1-0.7
RESULTS
Study Selection
We identified 6,117 studies of which 214 studies were potentially
eligible and assessed on full-text review (see Figure 1). This resulted in
125 studies being excluded. The remaining 89 studies were included
for meta-analysis, of which 63 studies with CIN 1 patients,8–70
42 studies with CIN 2 patients,11,26,27,35–37,39,41–44,50,52,53,57,69–95
and 7 studies with CIN 3 patients.3,26,41,72,81,83,88 The characteris-
tics and the follow-up protocol of the included studies are summa-
rized in Supplementary Tables 1–3, http://links.lww.com/LGT/
A239, http://links.lww.com/LGT/A240, http://links.lww.com/
LGT/A241. A summary of the natural history of CIN 1, CIN 2,
and CIN 3 is shown in Table 1.
Risk of Bias
For 36 studies, the risk of bias was determined as low (Sup-
plementary Table 4, http://links.lww.com/LGT/A242). High
risk of bias was in most studies caused by the unrepresentative-
ness of the cohort for the full population in a predefined
period11–13,24,27,28,30,32–34,36,37,40,42–44,48,50,51,53,57,59,61,71,73–77,79,83–88,91–93,95
and the low number of participants in the
study.8,9,11,12,26,27,34,36,37,39,42–44,49,53,56,58,62,63,68,69,71–73,75,76,78,81,84,95
The subgroup analysis for studies with low or high risk of bias
showed no statistically significant differences between the 3 dif-
ferent outcomes for each CIN grade.
Study Characteristics and Synthesis of Results
Cervical Intraepithelial Grade 1. For CIN 1, 8,767 women
from 63 studies had an outcome at 1 or more of the different
time points. Most studies contained 100 or more women
(n = 29, 46%); 16 studies (25%) included 50–100 women, and
© 2021, ASCCP
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021 The Natural History of CIN

FIGURE 1. Flowchart literature search.

there were 18 small studies (29%) with less than 50 women per
study. Four studies (6%) were randomized controlled trials (RCTs)
with suitable data in the nonexperimental arm, 33 (52%) were
prospective cohort studies, and 26 (41%) were retrospective cohort
studies (Supplementary Table 1, http://links.lww.com/LGT/A239).
Most follow-up protocols consisted of at least cytology and
colposcopy every 6 months. Biopsies were predominantly taken in
case of persisting lesions or when progression was suspected. Study
end points varied between 6 and 54 or more months and the
number of included women varied per time point (Figure 2 and
Supplementary Figures 1–3, http://links.lww.com/LGT/A252, http://
links.lww.com/LGT/A253, http://links.lww.com/LGT/A254).
Overall conservatively managed CIN 1 regressed 60% (95%
CI = 55–65, I2 = 92%), persisted 25% (95% CI = 20–30,
I2 = 94%), and progressed in 11% (95% CI = 8–13, I2 = 89%)
of the cases (see Figure 2). The highest number of studies
(n = 23) and patients (n = 4,749) were included at 24 months of
observation, which showed regression, persistence, and progres-
sion rates of 66% (95% CI = 59–73, I2 = 94%), 22% (95% CI =
16–29, I2 = 91%), and 12% (95% CI = 8–16, I2 = 93%),
respectively.
The overall 95% PI for regression, persistence, and pro-
gression were 25–90%, 2–63%, and 0–32%, respectively. Only
2% of the CIN 1 cases progressed to CIN 3 or worse (95% CI =
1–3, I2 = 82%) and 2 of 7,180 women (0.03%) developed cer-
vical cancer (Supplementary Table 7, http://links.lww.com/
LGT/A245, and Supplementary Figures 4, 5, http://links.lww.
com/LGT/A255, http://links.lww.com/LGT/A256).

TABLE 1. Summary of the Natural History of CIN 1, CIN 2, and CIN 3

Regression to Progression to Progression to Progression to

Regression to normal CIN 1 or less Persistence CIN 2 or worse CIN 3 or worse cervical cancer
% (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI)
CIN 1 60 (55–65) — 25 (20–30) 11 (8–13) 2 (1–3) 0.03/0.00 (0–0)a
CIN 2 47 (42–51) 55 (50–60) 23 (19–28) — 19 (15–23) 0.3/0.00 (0–0)a
CIN 3 18 (6–34) 28 (17–41) 67 (36–91) — — 2 (0–25)
a
Pooled proportions of the individual study results without using/with using random-effects meta-analysis.

© 2021, ASCCP 223

Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.

Loopik et al. Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
Cervical Intraepithelial Grade 2. A total of 3,830 women
with CIN 2 distributed over 42 studies were analyzed. There
were 17 small studies (40%) with less than 50 women per study,
18 studies (43%) with 50–100 women, and 7 studies (17%) with
100 or more included women. Four studies (10%) were RCTs
with suitable data in the nonexperimental arm, 27 (64%) were
prospective cohort studies, and the remaining 11 (26%) were
retrospective cohort studies (Supplementary Table 2, http://links.
lww.com/LGT/A240). Most follow-up protocols consisted of at
least cytology and colposcopy every 3–6 months. In most cases,
biopsies were performed when progression was suspected and/or
at exit visit. Regression was defined as “strict only” in 16 studies
(42%) and “lenient only” in 11 studies (29%). The remaining 11
studies (29%) used both strict and lenient regression as definition.
Most study end points varied between 6 and 36 months, and only
2 studies described results after 54 or more months (see Figure 3
and Supplementary Figures 6–11, http://links.lww.com/LGT/
A257, http://links.lww.com/LGT/A258, http://links.lww.com/
LGT/A259, http://links.lww.com/LGT/A260, http://links.lww.
com/LGT/A261, http://links.lww.com/LGT/A262).
The pooled regression, persistence, and progression rates of
CIN 2 per time point can be seen in Figure 3. Overall conservatively
managed CIN 2 regressed in 55% (95% CI = 50–60, I2 = 85%),
persisted in 23% (95% CI = 19–28, I2 = 83%), and progressed in
19% (95% CI = 15–23, I2 = 88%) of cases. At 12 months of obser-
vation, most studies (n = 17) had an outcome of regression, persis-
tence, or progression of 53% (95% CI = 44–63, I2 = 91%), 24%
(95% CI = 15–33, I2 = 86%), and 15% (95% CI = 9–21,
I2 = 86%), respectively. At 24 months of observation (n = 1,981),
regression, persistence, and progression rates of 57% (95% CI =
50–64, I2 = 82%), 19% (95% CI = 10–29, I2 = 91%), and 22%
(95% CI = 15–31, I2 = 93%) were demonstrated. The overall
95% PI was 27–80% for regression, 6–48% for persistence, and
3–45% for progression. Only 10 of 3,037 (0.03%) women devel-
oped cervical cancer (see Supplementary Table 10, http://links.
lww.com/LGT/A248, and Supplementary Figure 11, http://links.
lww.com/LGT/A262).
Cervical Intraepithelial Grade 3. Seven studies were
identified, containing 351 women for analysis. Most studies were
small, with 3 studies (43%) including less than 50 women26,41,81
and 3 studies (43%) including 50–100 women.72,83,88 One study
(14%) included 100 or more women.3 Two studies (29%) were
RCTs with suitable data in the nonexperimental arm,81,88 2
studies (29%) were prospective cohort studies,41,72,83 and 3 (43%)
were retrospective cohort studies3,26 (Supplementary Table 3,
http://links.lww.com/LGT/A241). Most studies had follow-up
consisted of cytology and colposcopy every 3–6 months. Biopsies
were performed in 6 of 7 studies, mainly when progression was
suspected or at predetermined time points. Regression was
defined as “strict only” in 2 studies (33%)41,88 and as “lenient
only to ≤CIN 1” in 2 studies (33%).72,81 Both strict and lenient
definitions were used in 2 studies (33%)3,83 (Supplementary
Figures 12–14, http://links.lww.com/LGT/A263, http://links.lww.
com/LGT/A264, http://links.lww.com/LGT/A265).
The pooled regression, persistence, and progression rates of
CIN 3 per time point can be seen in Figure 4. The overall regression,
persistence, and progression rates for women with conservatively
managed CIN 3 are 28% (95% CI = 17–41, I2 = 68%), 67% (95%
CI = 36–91, I2 = 84%), and 2% (95% CI = 0–25, I2 = 95%), respec-
tively. The highest numbers of patients were included at 24 months of
observation for regression and persistence outcomes (n = 156) and at
56 or more months for progression (n = 181). At these time points,
the regression, persistence, and progression rates were 28% (95%
CI = 11–49, I2 = 0%), 59% (95% CI = 0–100, I2 = 89%), and 6%
(95% CI = 0–100, I2 = 96%). The 95% PIs for CIN 3 regression,
224
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
persistence, and progression were very wide (5%–60%, 0%–100%,
and 0%–91%, respectively).
Subgroup Analyses
Most subgroup analyses showed no statistically significant
differences (Supplementary Tables 5–13, http://links.lww.
com/LGT/A243, http://links.lww.com/LGT/A244, http://
links.lww.com/LGT/A245, http://links.lww.com/LGT/A246,
http://links.lww.com/LGT/A247, http://links.lww.com/LGT/
A248, http://links.lww.com/LGT/A249, http://links.lww.com/
LGT/A250, http://links.lww.com/LGT/A251). Young women
(30 years or younger) and hrHPV-negative women with CIN 1
showed a higher, although not significant, regression rate of
66% (95% CI = 30–93, I2 = 94%) and 76% (95% CI = 56–91,
I2 = 89). Stratification by continent, year of publication, or study
design showed no effects for CIN 1 studies, except for CIN 1 pro-
gression stratified by study design, which was lower in RCTs. An
explanation could be that these studies had a short follow-up
(Supplementary Table 7, http://links.lww.com/LGT/A245).
The regression rate of CIN 2 was significantly higher for
women 30 years or younger (66% [12 studies, 1,488/2,302
women, 95% CI = 62–70, I2 = 76%] vs 50% [26 studies, 726/
1,487 women, 95% CI = 43–56, I2 = 79%]). This also applied to
hrHPV-negative women (94% [8 studies, 250/269 women, 95%
CI = 84–99, I2 = 60%] vs 50% [11 studies, 439/869 women,
95% CI = 40–61, I2 = 89%]). A significant difference was seen
for women with HPV16 and HPV18, but not for women with
hrHPV types other than 16/18 (Supplementary Table 8, http://
links.lww.com/LGT/A246). We found a regression rate of 62%
(20 studies, 1,877/3,032 women, 95% CI = 56–68, I2 = 87%) in
studies published in 2011 or later compared with 39% (7 studies,
97/248 women, 95% CI = 29–49, I2 = 49%) in studies published
in 1991–2000. There was a lower regression rate from CIN 2 to
normal than to CIN 1 or less (47% [27 studies, 793/1,733 women,
95% CI = 42–51, I2 = 68%] vs 60% [22 studies, 1,496/2,843
women, 95% CI = 54–67, I2 = 84%]).
For CIN 3, data on HPV status were missing. We found some
effects of stratification by continent, year of publication, or study
design (Supplementary Table 11, http://links.lww.com/LGT/
A249). However, all these effects need to be interpreted with cau-
tion, because of the high intrastudy heterogeneity, the small study
groups, and the small number of included studies.
Publication Bias
We found no evidence of publication bias based on the visual
inspection of the funnel plots and the Egger regression test. The
funnel plots for all analyses (i.e., all CIN grades and all outcome
measures) were symmetrical and Egger test was not significant
(p > .01) for any analysis.
DISCUSSION
Main Findings
The CIN 1 and CIN 2 regression is quite similar, with more
than half of the CIN 1 and CIN 2 lesions regressing spontaneously
(60% and 55%). Progression to a higher-grade lesion occurred in
11% of CIN 1 and 19% of CIN 2 cases. Progression of CIN 1 to
CIN 3 or worse was only 2%, and 0.03% and 0.3% of the CIN 1 and
CIN 2 cases, respectively, progressed to cervical cancer. As we only
found a few and small studies on the natural history of CIN 3, with
heterogeneous results, we could not draw firm conclusions.
Strengths and Limitations
Many guidelines still use the critical review of the natural his-
tory of all CIN grades by Ostor5 from 1993. We believe that this
© 2021, ASCCP
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021 The Natural History of CIN

FIGURE 2. Regression, persistence, and progression rates of untreated CIN 1 at different time points during follow-up.

© 2021, ASCCP 225

Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.

Loopik et al. Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021

FIGURE 3. Regression, persistence, and progression rates of untreated CIN 2 at different time points during follow-up.

226 © 2021, ASCCP

Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.

Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021 The Natural History of CIN

FIGURE 4. Regression, persistence, and progression rates of untreated CIN 3 at different time points during follow-up.

updated overview should help both clinicians and patients with in-
formed shared decision making. The strengths of our study com-
prise a systematic approach, extensive literature search, critical
and duplicate appraisal of eligibility, data extraction, and risk of
bias. We included a large number of studies and patients, executed
comprehensive subgroup analyses to explore potential confounders,
and ensured no evidence of publication bias. Only studies with
histologically proven CIN diagnosis were included to minimize
the risk of misclassification bias. As some studies provided
separate outcomes for different follow-up time points, the mean
outcome of the different time points was used to estimate the
overall outcome.
Several limitations should be noted. We found a considerable
heterogeneity between the studies for most of the executed

© 2021, ASCCP 227

Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.

Loopik et al. Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
analyses. This could be explained by the different study methods
and definitions used for the outcomes. The rates that one expects
to find in a newly conducted study are presented with the 95% PI.
The wide 95% PIs for CIN 1 outcomes are reflecting the high het-
erogeneity. The 95% PIs tended to be smaller for CIN 2. We found
the most widely spread 95% PIs for CIN 3, which confirms the
difficulty to draw conclusions from the CIN 3 analyses.
There are limited reviews in the published literature on the
natural history of CIN. The critical review from 1993 did pool
the outcomes together of the different included studies per CIN
grade but did not execute a weighted meta-analysis or subgroup
analysis.5 It also included studies with only cytologic outcomes
at baseline, which is only a moderate predictor for histologic
CIN grade. Many studies included in this review were published
before the CIN grading system was introduced, which makes it
more difficult to interpret these results.
Our CIN 3 results need to be interpreted with caution. Five of
7 studies were categorized as “high risk of bias” and the heteroge-
neity was high (I2 = 68%–95%), especially considering the small
number of included studies. Most guidelines refer to the study by
McCredie et al.,3 which estimates a risk of 31% to develop cervical
cancer after 30 years of untreated CIN 3 based on only 25 women.
A 22% progression risk was seen at 11 years and a 13% risk at 5
years of follow-up.3 We were not able to draw firm conclusions
on the natural history of CIN 3 based on the currently published lit-
erature. It will be ethically challenging to perform new longitudinal
studies with conservative managed CIN 3.
Implications
Conservative Management With Follow-up. In case of
conservative management, most guidelines suggest follow-up
until 24 months before considering treatment for persistent
disease. In our meta-analysis, we found similar progression rates
of CIN 1 between the different time points of follow-up, but an
increase in regression rates and a decline in persistent disease
over time (see Figure 2). For CIN 2, the regression, persistence,
and progression rates were similar over time, which suggest that
follow-up for 24 or more months could also be considered (see
Figure 3). The low progression rates to cervical cancer in
women with CIN 1 and CIN 2 confirm the potential for longer
follow-up if compliance can be assured. For women where loss
to follow-up for colposcopy is a real concern, treatment may be
warranted to provide safety.
Human Papillomavirus Status. As previously described in
the literature, we found that hrHPV-negative women do have a
much higher chance of spontaneous regression of CIN than
hrHPV-positive women.2,96,97 This was also seen for HPV16- and
HPV18-positive women with CIN 2, but not for women with
hrHPV types other than 16/18. Therefore, HPV genotyping is
useful in making management decisions.
Besides hrHPV status, referral cytology and colposcopic im-
pression should be taken into account as well. When discrepancies
in these results appear, closer surveillance or treatment should be
considered. In addition, morphological or molecular biomarkers
could help in understanding and predicting cervical carcinogenesis.
Two- Versus 3-Tier System. Some state that a 2-tier system of
low- and high-grade intraepithelial lesions is biologically more
meaningful and histologically more reproducible than the 3-tier
CIN terminology.98 However, our meta-analysis showed that
CIN 2 regression rates are more similar to those of CIN 1 than
those of CIN 3. A recent meta-analysis showed a regression rate of
36% for women with CIN 2–3 compared with 51% for women
with CIN 2.99 Many guidelines use the 3-tier system to distinguish
228
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
different management for CIN 2 and CIN 3 in young and fertile
women.1,100 In our meta-analysis, a statistically significantly higher
regression rate of 66% was seen in young women with CIN 2.
Taking into account these findings and the knowledge of an
increased risk of obstetrical complications after treatment,4 young
women with CIN 1 and CIN 2 should be managed conservatively.
The updated 2019 American Society for Colposcopy and Cervical
Pathology guidelines suggest cytologic follow-up in 1 year for
women with a ≥0.55–3% risk of CIN 3 or worse and colposcopic
follow-up for women with a 4–24% risk of CIN 3 or worse.101
Therefore, we may consider conservative management for CIN 2 in
women of all ages, or at least for women with the potential desire
for future pregnancy. Nonetheless, shared decision making is
important in these cases, counseling women about the risk of
progression and the risk of complications of treatment.
CONCLUSIONS
With our systemic review and meta-analysis, we give an up-
dated overview on the regression, persistence, and progression
rates of conservatively managed CIN 1, CIN 2, and CIN 3. We
show that most CIN 1 and CIN 2 will regress spontaneously in
less than 24 months, with the highest rates in hrHPV-negative
and young women, whereas progression to cancer is less than
0.5%. Based on the risk to develop CIN 3 or worse, CIN 1 should
be managed with cytological follow-up every 12 months and con-
servative management of CIN 2 should be considered for all
women, especially in women with a potential desire for future
pregnancy and expected high compliance. The few and small
studies on CIN 3 were too heterogeneous to draw firm conclu-
sions. Finally, we advise that high-grade histology should be fur-
ther classified into CIN 2 or CIN 3 to optimize management
decisions.
ACKNOWLEDGMENTS
The authors thank Dr On Ying A. Chan from the medical li-
brary team for her help with the literature search.
REFERENCES
1. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus
guidelines for the management of abnormal cervical cancer screening
tests and cancer precursors. Obstet Gynecol 2013;121:829–46.
2. Tainio K, Athanasiou A, Tikkinen KAO, et al. Clinical course of untreated
cervical intraepithelial neoplasia grade 2 under active surveillance:
systematic review and meta-analysis. BMJ 2018;360:k499.
3. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical
neoplasia and risk of invasive cancer in women with cervical
intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol
2008;9:425–34.
4. Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric
outcomes after local treatment for cervical preinvasive and early invasive
disease according to cone depth: systematic review and meta-analysis.
BMJ 2016;354:i3633.
5. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical
review. Int J Gynecol Pathol 1993;12:186–92.
6. IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman
method for random effects meta-analysis is straightforward and
considerably outperforms the standard DerSimonian-Laird method.
BMC Med Res Methodol 2014;14:25.
7. Viechtbauer W. Conducting meta-analyses in R with the metafor package.
J Stat Softw 2010;36:1–48.
© 2021, ASCCP
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
8. Alameda F, Fuste P, Boluda S, et al. The Ki-67 labeling index is not a
useful predictor for the follow-up of cervical intraepithelial neoplasia 1.
J Low Genit Tract Dis 2004;8:313–6.
9. Asemi Z, Vahedpoor Z, Jamilian M, et al. Effects of long-term folate
supplementation on metabolic status and regression of cervical
intraepithelial neoplasia: a randomized, double-blind, placebo-controlled
trial. Nutrition 2016;32:681–6.
10. Bansal N, Wright JD, Cohen CJ, et al. Natural history of established low
grade cervical intraepithelial (CIN 1) lesions. Anticancer Res 2008;28
(3B):1763–6.
11. Brummer O, Hollwitz B, Bohmer G, et al. Human papillomavirus-type
persistence patterns predict the clinical outcome of cervical intraepithelial
neoplasia. Gynecol Oncol 2006;102:517–22.
12. Cao L, Sun PL, Yao M, et al. Clinical significance of CK7, HPV-L1, and
koilocytosis for patients with cervical low-grade squamous intraepithelial
lesions: a retrospective analysis. Hum Pathol 2017;65:194–200.
13. Choi YS, Kang WD, Kim SM, et al. Human papillomavirus L1 capsid
protein and human papillomavirus type 16 as prognostic markers in
cervical intraepithelial neoplasia 1. Int J Gynecol Cancer 2010;20:
288–93.
14. Ciavattini A, Clemente N, Tsiroglou D, et al. Follow up in women
with biopsy diagnosis of cervical low-grade squamous intraepithelial
lesion (LSIL): how long should it be? Arch Gynecol Obstet 2017;295:
997–1003.
15. Ciavattini A, Serri M, Di Giuseppe J, et al. Long-term observational
approach in women with histological diagnosis of cervical low-grade
squamous intraepithelial lesion: an Italian multicentric retrospective
cohort study. BMJ Open 2019;9:e024920.
16. Cortecchia S, Galanti G, Sgadari C, et al. Follow-up study of patients
with cervical intraepithelial neoplasia grade 1 overexpressing p16Ink4a.
Int J Gynecol Cancer 2013;23:1663–9.
17. Cortes-Alaguero C, Gonzalez-Mirasol E, Morales-Rosello J, et al.
Do clinical data and human papilloma virus genotype influence
spontaneous regression in grade I cervical intraepithelial neoplasia?
J Turk Ger Gynecol Assoc 2017;18:1–8.
18. da Costa LB, Triglia Rde M, Franca Junior MC, et al. p16(INK) (4a)
expression as a potential marker of low-grade cervical intraepithelial
neoplasia progression. APMIS 2015;123:185–9.
19. De Marchi Triglia R, Metze K, Zeferino LC, et al. HPV in situ
hybridization signal patterns as a marker for cervical intraepithelial
neoplasia progression. Gynecol Oncol 2009;112:114–8.
20. del Pino M, Garcia S, Fuste V, et al. Value of p16(INK4a) as a marker
of progression/regression in cervical intraepithelial neoplasia grade 1.
Am J Obstet Gynecol 2009;201:488 e1–7.
21. Ding L, Song L, Zhao W, et al. Predictive value of p16INK4a, Ki-67 and
ProExC immuno-qualitative features in LSIL progression into HSIL.
Exp Ther Med 2020;19:2457–66.
22. Dunn TS, Charnsangavej C, Wolf D. Are there predictors for failed
expectant management of cervical intraepithelial neoplasia 1?
J Reprod Med 2008;53:213–6.
23. Elit L, Levine MN, Julian JA, et al. Expectant management versus
immediate treatment for low-grade cervical intraepithelial neoplasia: a
randomized trial in Canada and Brazil. Cancer 2011;117:1438–45.
24. Falls RK. Spontaneous resolution rate of grade 1 cervical intraepithelial
neoplasia in a private practice population. Am J Obstet Gynecol 1999;181:
278–82.
25. Furber SE, Weisberg E, Simpson JM. Progression and regression of
low-grade epithelial abnormalities of the cervix. Aust N Z J Obstet
Gynaecol 1997;37:107–12.
26. Gaarenstroom KN, Melkert P, Walboomers JM, et al. Human
papillomavirus DNA and genotypes: prognostic factors for progression of
cervical intraepithelial neoplasia. Int J Gynecol Cancer 1994;4:73–8.
© 2021, ASCCP
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
The Natural History of CIN
27. Ganguly C, Dutta K, Sanyal U, et al. Response of cervical
intra-epithelial lesions to vitamin E supplementation - a preliminary
report. Asian Pac J Cancer Prev 2001;2:305–8.
28. Giorgi Rossi P, Benevolo M, Vocaturo A, et al. Prognostic value of HPV
E6/E7 mRNA assay in women with negative colposcopy or CIN1
histology result: a follow-up study. PLoS One 2013;8:e57600.
29. Greenberg MD, Reid R, Schiffman M, et al. A prospective study of
biopsy-confirmed cervical intraepithelial neoplasia grade 1: colposcopic,
cytological, and virological risk factors for progression. J Low Genit Tract
Dis 1999;3:104–10.
30. Guerra F, Rocher AE, Villacorta Hidalgo J, et al. Argentophilic nucleolus
organizer region as a proliferation marker in cervical intraepithelial
neoplasia grade 1 of the uterine cervix. J Obstet Gynaecol Res 2014;40:
1717–24.
31. Gurumurthy M, Cotton SC, Sharp L, et al. Postcolposcopy management
of women with histologically proven CIN 1: results from TOMBOLA.
J Low Genit Tract Dis 2014;18:203–9.
32. Haidopoulos D, Voulgaris Z, Protopapas A, et al. Cervical intraepithelial
neoplasia in young women. J Obstet Gynaecol 2007;27:709–12.
33. Hariri J, Oster A. The negative predictive value of p16INK4a to assess
the outcome of cervical intraepithelial neoplasia 1 in the uterine cervix.
Int J Gynecol Pathol 2007;26:223–8.
34. Heatley MK. The prognosis in cervical epithelial changes of uncertain
significance is similar to that of cervical intraepithelial neoplasia grade 1.
J Clin Pathol 2001;54:474–5.
35. Ho GY, Einstein MH, Romney SL, et al. Risk factors for persistent
cervical intraepithelial neoplasia grades 1 and 2: managed by watchful
waiting. J Low Genit Tract Dis 2011;15:268–75.
36. Hording U, Daugaard S, Bock JE, et al. HPV 11, 16 and 18 DNA
sequences in cervical swabs from women with cervical dysplasia:
prevalence and associated risk of progression. Eur J Obstet Gynecol
Reprod Biol 1991;40:43–8.
37. Hording U, Junge J, Rygaard C, et al. Management of low-grade CIN:
follow-up or treatment? Eur J Obstet Gynecol Reprod Biol 1995;62:
49–52.
38. Hu SY, Rezhake R, Chen F, et al. Outcomes in women with
biopsy-confirmed cervical intraepithelial neoplasia grade 1 or normal
cervix and related cofactors: a 15-year population-based cohort study
from China. Gynecol Oncol 2020;156:616–23.
39. Romkina AY, Kiriukhin MY. Biochemical and molecular characterization
of the isocitrate dehydrogenase with dual coenzyme specificity from the
obligate methylotroph Methylobacillus flagellatus. PLoS One 2017;
12:e0176056.
40. Kang WD, Ju UC, Kim SM. Is human papillomavirus genotype important
in predicting disease progression in women with biopsy-proven negative
or CIN1 of atypical squamous cell of undetermined significance
(ASC-US) cytology? Gynecol Oncol 2018;148:305–10.
41. Kataja V, Syrjanen S, Mantyjarvi R, et al. Prognostic factors in cervical
human papillomavirus infections. Sex Transm Dis 1992;19:154–60.
42. Kruse AJ, Baak JP, Janssen EA, et al. Low- and high-risk CIN 1 and 2
lesions: prospective predictive value of grade, HPV, and Ki-67
immuno-quantitative variables. J Pathol 2003;199:462–70.
43. Kruse AJ, Baak JP, Helliesen T, et al. Prognostic value and reproducibility
of koilocytosis in cervical intraepithelial neoplasia. Int J Gynecol Pathol
2003;22:236–9.
44. Kruse AJ, Skaland I, Janssen EA, et al. Quantitative molecular parameters
to identify low-risk and high-risk early CIN lesions: role of markers of
proliferative activity and differentiation and Rb availability. Int J Gynecol
Pathol 2004;23:100–9.
45. Li L, Jiang W, Zeng SY, et al. Prospective study of hTERC gene detection
by fluorescence in situ hybridization (FISH) in cervical intraepithelial
neoplasia 1 natural prognosis. Eur J Gynaecol Oncol 2014;35:289–91.
229
Loopik et al. Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
46. Liao GD, Sellors JW, Sun HK, et al. p16INK4A immunohistochemical
staining and predictive value for progression of cervical intraepithelial
neoplasia grade 1: a prospective study in China. Int J Cancer 2014;134:
1715–24.
47. Liu C, Du H, Wang C, et al. HPV L1 and P16 expression in CIN1 to
predict future CIN2. Int J Gynecol Pathol 2017;36:281–8.
48. Loopik DL, Bekkers RLM, Massuger LFAG, et al. Post-colposcopy
management and progression predictors of biopsy-proven CIN1 in
women under 25 years. J Obstet Gynaecol Can 2019;41:292–9.
49. Mackerras D, Irwig L, Simpson JM, et al. Randomized double-blind trial
of beta-carotene and vitamin C in women with minor cervical
abnormalities. Br J Cancer 1999;79:1448–53.
50. Matsumoto K, Oki A, Furuta R, et al. Predicting the progression of
cervical precursor lesions by human papillomavirus genotyping: a
prospective cohort study. Int J Cancer 2011;128:2898–910.
51. Mikhail MS, Merkatz IR, Romney SL. Clinical usefulness of
computerized colposcopy: image analysis and conservative management
of mild dysplasia. Obstet Gynecol 1992;80:5–8.
52. Mizushima T, Asai-Sato M, Akimoto K, et al. Aberrant expression
of the cell polarity regulator aPKCλ/ι is associated with disease
progression in cervical intraepithelial neoplasia (CIN): a possible
marker for predicting CIN prognosis. Int J Gynecol Pathol 2016;35:
106–17.
53. Omori M, Hashi A, Nakazawa K, et al. Estimation of prognoses for
cervical intraepithelial neoplasia 2 by p16INK4a immunoexpression and
high-risk HPV in situ hybridization signal types. Am J Clin Pathol 2007;
128:208–17.
54. Ozaki S, Zen Y, Inoue M. Biomarker expression in cervical intraepithelial
neoplasia: potential progression predictive factors for low-grade lesions.
Hum Pathol 2011;42:1007–12.
55. Pacchiarotti A, Ferrari F, Bellardini P, et al. Prognostic value of
p16-INK4A protein in women with negative or CIN1 histology result: a
follow-up study. Int J Cancer 2014;134:897–904.
56. Pantano N, Hunt B, Schwarz RA, et al. Is proflavine exposure associated
with disease progression in women with cervical dysplasia? A brief report.
Photochem Photobiol 2018;94:1308–13.
57. Petry KU, Bohmer G, Iftner T, et al. Factors associated with an increased
risk of prevalent and incident grade III cervical intraepithelial neoplasia
and invasive cervical cancer among women with Papanicolaou tests
classified as grades I or II cervical intraepithelial neoplasia. Am J Obstet
Gynecol 2002;186:28–34.
58. Poomtavorn Y, Suwannarurk K, Thaweekul Y, et al. Cervical cytologic
abnormalities of cervical intraepithelial neoplasia 1 treated with
cryotherapy and expectant management during the first year follow-up
period. Asian Pac J Cancer Prev 2009;10:665–8.
59. Quinlivan JA, Petersen RW, Gani L, et al. Demographic variables routinely
collected at colposcopic examination do not predict who will default
from conservative management of cervical intraepithelial neoplasia I.
Aust N Z J Obstet Gynaecol 2005;45:48–51.
60. Quint KD, de Koning MN, Quint WG, et al. Progression of cervical
low grade squamous intraepithelial lesions: in search of prognostic
biomarkers. Eur J Obstet Gynecol Reprod Biol 2013;170:
501–6.
61. Razmpoosh M, Sansregret A, Oligny LL, et al. Assessment of correlation
between p16INK4a staining, specific subtype of human papillomavirus,
and progression of LSIL/CIN1 lesions: first comparative study. Am J Clin
Pathol 2014;142:104–10.
62. Rodolakis A, Biliatis I, Symiakaki H, et al. Role of chromosome
3q26 gain in predicting progression of cervical dysplasia.
Int J Gynecol Cancer 2012;22:742–7.
63. Glazebrook JF, Wallace R. Pathologies in functional connectivity,
feedback control and robustness: a global workspace perspective on
autism spectrum disorders. Cogn Process 2015;16:1–16.
230
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
64. Sagasta A, Castillo P, Saco A, et al. p16 staining has limited value in
predicting the outcome of histological low-grade squamous intraepithelial
lesions of the cervix. Mod Pathol 2016;29:51–9.
65. Santos AL, Derchain SF, Sarian LO, et al. Performance of Pap smear and
human papilloma virus testing in the follow-up of women with cervical
intraepithelial neoplasia grade 1 managed conservatively. Acta Obstet
Gynecol Scand 2006;85:444–50.
66. Sastre-Garau X, Cartier I, Jourdan-Da Silva N, et al. Regression of
low-grade cervical intraepithelial neoplasia in patients with HLA-DRB1
*13 genotype. Obstet Gynecol 2004;104:751–5.
67. Song SH, Lee JK, Oh MJ, et al. Risk factors for the progression
or persistence of untreated mild dysplasia of the uterine cervix.
Int J Gynecol Cancer 2006;16:1608–13.
68. Vahedpoor Z, Jamilian M, Bahmani F, et al. Effects of long-term vitamin
D supplementation on regression and metabolic status of cervical
intraepithelial neoplasia: a randomized, double-blind, placebo-controlled
trial. Horm Cancer 2017;8:58–67.
69. Wang SM, Colombara D, Shi JF, et al. Six-year regression and progression
of cervical lesions of different human papillomavirus viral loads in varied
histological diagnoses. Int J Gynecol Cancer 2013;23:716–23.
70. Yokoyama M, Iwasaka T, Nagata C, et al. Prognostic factors associated
with the clinical outcome of cervical intraepithelial neoplasia: a cohort
study in Japan. Cancer Lett 2003;192:171–9.
71. Bleecker E, Koehler E, Smith J, et al. Outcomes after management of
young women with cervical intraepithelial neoplasia 2 with a 6-month
observation protocol. J Low Genit Tract Dis 2014;18:46–9.
72. Chan JK, Monk BJ, Brewer C, et al. HPV infection and number of lifetime
sexual partners are strong predictors for ‘natural’ regression of CIN 2 and
3. Br J Cancer 2003;89:1062–6.
73. De Aloysio D, Miliffi L, Iannicelli T, et al. Intramuscular interferon-beta
treatment of cervical intraepithelial neoplasia II associated with human
papillomavirus infection. Acta Obstet Gynecol Scand 1994;73:420–4.
74. Dempster-Rivett K, Innes CR, Simcock BJ, et al. Evaluation of
guidelines for observational management of cervical intraepithelial
neoplasia 2 in young women. Am J Obstet Gynecol 2020;223:
408.e1–408.e11.
75. Discacciati MG, de Souza CA, 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.
76. Garzetti GG, Ciavattini A, Lucarini G, et al. Microinvasive cervical
carcinoma and cervical intraepithelial neoplasia: biologic significance and
clinical implications of 72-kDa metalloproteinase immunostaining.
Gynecol Oncol 1996;61:197–203.
77. Godfrey MAL, Nikolopoulos M, Garner JE, et al. Conservative
management of cervical intraepithelial neoplasia grade 2 (CIN2) in
women under 30 years of age: a cohort study. Eur J Obstet Gynecol
Reprod Biol 2018;228:267–73.
78. Guedes AC, Brenna SM, Coelho SA, et al. p16(INK4a) expression does
not predict the outcome of cervical intraepithelial neoplasia grade 2. Int J
Gynecol Cancer 2007;17:1099–103.
79. Halec G, Scott ME, Farhat S, et al. Toll-like receptors: important immune
checkpoints in the regression of cervical intra-epithelial neoplasia 2. Int J
Cancer 2018;143:2884–91.
80. Hosaka M, Fujita H, Hanley SJB, et al. Incidence risk of cervical
intraepithelial neoplasia 3 or more severe lesions is a function of
human papillomavirus genotypes and severity of cytological and
histological abnormalities in adult Japanese women. Int J Cancer 2013;
132:327–34.
81. Keefe KA, Schell MJ, Brewer C, et al. A randomized, double blind, phase
III trial using oral beta-carotene supplementation for women with
high-grade cervical intraepithelial neoplasia. Cancer Epidemiol
Biomarkers Prev 2001;10:1029–35.
© 2021, ASCCP
Journal of Lower Genital Tract Disease • Volume 25, Number 3, July 2021
82. Koeneman MM, van Lint FHM, van Kuijk SMJ, et al. A prediction model
for spontaneous regression of cervical intraepithelial neoplasia grade 2,
based on simple clinical parameters. Hum Pathol 2017;59:62–9.
83. Lee MH, Finlayson SJ, Gukova K, et al. Outcomes of conservative
management of high grade squamous intraepithelial lesions in young
women. J Low Genit Tract Dis 2018;22:212–8.
84. Loffredo D'Ottaviano MG, Discacciati MG, Andreoli MA, et al. HPV 16
is related to the progression of cervical intraepithelial neoplasia grade 2: a
case series. Obstet Gynecol Int 2013;2013:328909.
85. Loopik DL, Bekkers RLM, Massuger LFAG, et al. Justifying conservative
management of CIN2 in women younger than 25 years - a
population-based study. Gynecol Oncol 2019;152:82–6.
86. Louvanto K, Aro K, Nedjai B, et al. Methylation in predicting progression
of untreated high-grade cervical intraepithelial neoplasia. Clin Infect Dis
2020;70:2582–90.
87. McAllum B, Sykes PH, Sadler L, et al. Is the treatment of CIN 2 always
necessary in women under 25 years old? Am J Obstet Gynecol 2011;205:
478 e1–7.
88. Meyskens FL Jr., Surwit E, Moon TE, et al. Enhancement of regression of
cervical intraepithelial neoplasia II (moderate dysplasia) with topically
applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst 1994;
86:539–43.
89. Miralpeix E, Genoves J, Maria Sole-Sedeno J, et al. Usefulness of p16
(INK4a) staining for managing histological high-grade squamous
intraepithelial cervical lesions. Mod Pathol 2017;30:304–10.
100. Bentley J, Executive Council of the Society of Canadian C, Special
90. Miralpeix E, Sole-Sedeno JM, Agramunt S, et al. Role of Chlamydia
trachomatis serology in conservative management of cervical
intraepithelial neoplasia grade 2. Int J Gynaecol Obstet 2019;147:43–8.
101. Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based
91. Moore K, Cofer A, Elliot L, et al. Adolescent cervical dysplasia:
histologic evaluation, treatment, and outcomes. Am J Obstet Gynecol
2007;197:141 e1–6.
© 2021, ASCCP
Copyright © 2021 ASCCP. Unauthorized reproduction of this article is prohibited.
The Natural History of CIN
92. Moscicki AB, Ma Y, Wibbelsman C, et al. Rate of and risks for regression
of cervical intraepithelial neoplasia 2 in adolescents and young women.
Obstet Gynecol 2010;116:1373–80.
93. Munro A, Powell RG, A Cohen P, et al. Spontaneous regression of CIN2 in
women aged 18–24 years: a retrospective study of a state-wide population
in Western Australia. Acta Obstet Gynecol Scand 2016;95:291–8.
94. Nogawa T, Hiura M, Tanaka H, et al. Prospective evaluation of the
Amplicor HPV test for predicting progression of cervical intraepithelial
neoplasia 2. J Obstet Gynaecol Res 2013;39:1347–53.
95. Rahangdale L, Lippmann QK, Garcia K, et al. Topical 5-fluorouracil for
treatment of cervical intraepithelial neoplasia 2: a randomized controlled
trial. Am J Obstet Gynecol 2014;210:314 e1–8.
96. Koshiol J, Lindsay L, Pimenta JM, et al. Persistent human papillomavirus
infection and cervical neoplasia: a systematic review and meta-analysis.
Am J Epidemiol 2008;168:123–37.
97. Liu M, Yan X, Zhang M, et al. Influence of human papillomavirus
infection on the natural history of cervical intraepithelial neoplasia 1:
a meta-analysis. Biomed Res Int 2017;2017:8971059.
98. 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. Arch Pathol Lab Med 2012;136:1266–97.
99. Zhang J, Lu CX. Spontaneous regression of cervical intraepithelial
neoplasia 2: a meta-analysis. Gynecol Obstet Invest 2019;84:562–7.
Contributors. Colposcopic management of abnormal cervical cytology
and histology. J Obstet Gynaecol Can 2012;34:1188–202.
Management Consensus Guidelines for Abnormal Cervical Cancer
Screening Tests and Cancer Precursors. J Low Genit Tract Dis 2020;24:
102–31.
231