Anatomic Pathology / Prevalent vs Incident CIN 3
A Descriptive Analysis of Prevalent vs Incident Cervical
Intraepithelial Neoplasia Grade 3 Following Minor
Cytologic Abnormalities
Philip E. Castle, PhD,1 Patti E. Gravitt, PhD,2 Nicolas Wentzensen, MD,3 and Mark Schiffman, MD3
Key Words: Pap; Cytology; Human papillomavirus (HPV); Cervical intraepithelial neoplasia (CIN)
DOI: 10.1309/AJCPNTK6G2PXWHOO
Abstract
Cervical intraepithelial neoplasia grade 3 (CIN 3)
is the best proxy in research and screening for invasive
cancer risk. Yet the timing of CIN 3 development is
uncertain because of measurement errors integral
to its diagnosis. We were interested in estimating the
proportions of prevalent vs incident CIN 3 within
2 years of finding a minor cytologic abnormality.
We estimate that only 17 (2.8%) of 613 CIN 3 cases
diagnosed during the 2-year duration of the atypical
squamous cells of undetermined significance (ASCUS)
and low-grade squamous intraepithelial lesion (LSIL)
triage study (ALTS) were incident CIN 3 following an
incident human papillomavirus (HPV) infection that
persisted until the CIN 3 diagnosis was made. Using
prevalent high-grade cytology as a marker of prevalent
CIN 3, we estimated that another approximately
23% of CIN 3 cases were incident CIN 3 following a
prevalently detected HPV infection that persisted until
the CIN 3 diagnosis was made. We concluded that most
CIN 3 cases diagnosed within the 2-year time frame
were prevalent cases, and most incident CIN 3 cases
followed a prevalently detected HPV infection.
© American Society for Clinical Pathology
Cervical intraepithelial neoplasia grade 3 (CIN 3), including carcinoma in situ, is the immediate precursor to invasive
cervical cancer and therefore considered the most scientifically rigorous definition of cervical precancer.1 However, very
little is known about the natural history of CIN 3 for obvious
ethical reasons. In one study in which treatment was withheld
from women diagnosed with CIN 3, approximately one third
of them developed invasive cervical cancer in the following
30 years.2 Of note, these women were approximately 10 years
older at the time of CIN 3 diagnosis than the median age of
women diagnosed with CIN 3 in current, routine screening.3
This suggests that these untreated cases of CIN 3 may have
involved larger, more mature lesions than the typical CIN
3 cases found on routine screening, and therefore are more
likely to have invasive potential.4
To understand CIN 3 and its early natural history, we
embarked on a descriptive analysis to compare prevalent vs
incident CIN 3 identified in the atypical squamous cells of
undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS), a randomized trial to compare management strategies for women
with equivocal and mildly abnormal findings on Papanicolaou
(Pap) tests. Presumably, incident CIN 3 has the least invasive potential because it is newly developed and small but
then over time develops into a larger CIN 3 with invasive
potential.4,5 In particular, because of errors in the diagnostic
process (particularly colposcopic insensitivity), it is often
challenging to differentiate between missed prevalent vs truly
incident CIN 3 among human papillomavirus (HPV)–positive
women who are subsequently diagnosed with CIN 3. Using
data from ALTS, we can begin to learn about the early natural
history of CIN 3, which is expected to include small lesions
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with low-invasive potential found in young women with mild
cytologic abnormalities.
Why is it important to differentiate between prevalent
and incident CIN 3? Most studies have focused on prevalent
CIN 3, and therefore, the timing and determinants of new
CIN 3 is poorly understood. More importantly, understanding the timing and evolution of CIN 3 will help predict the
effect of interventions.
Materials and Methods
Study Design and Population
ALTS (1997-2001) was a multisite, randomized clinical
trial comparing 3 management strategies (immediate colposcopy [IC], HPV triage, or conservative management [CM])
for women referred for ASCUS (n = 3,488) or LSIL (n =
1,572) conventional cytology.6-10 The ASCUS category under
the 1991 Bethesda System11 used in ALTS was slightly more
inclusive, particularly of probable reactive changes and atypical squamous cells, cannot rule out high-grade intraepithelial lesion (ASC-H), than ASC-US under the 2001 Bethesda
system.12 All women in the IC arm underwent colposcopy at
enrollment. Women in the HPV arm underwent colposcopy
if they tested positive to carcinogenic HPV with the Hybrid
Capture 2 (HC2, Qiagen, Gaithersburg, MD) test or had highgrade squamous intraepithelial lesion (HSIL) on cytologic
testing at enrollment. Women in the CM arm underwent colposcopy if they had HSIL on cytologic testing at enrollment.
The National Cancer Institute and local institutional review
boards approved the study and all participants provided written, informed consent.
At enrollment and follow-up visits over the 2-year duration, all women underwent a pelvic examination with collection of 2 cervical specimens; the first specimen in PreservCyt
for ThinPrep cytology (Cytyc Corporation, Marlborough,
MA; now Hologic) and the second in specimen transport
medium (Digene Corporation, Gaithersburg, MD; now Qiagen). Women in all 3 arms of the study underwent cytologic
reevaluation every 6 months during the 2 years and had a
colposcopy if the cytologic finding was HSIL. An exit examination with colposcopy was scheduled for all women. Details
on randomization, examination procedures, patient management, and laboratory and pathology methods were published
previously.6-10
HPV DNA Testing
Line blot assay (LBA) for the detection of 27 or 38
individual HPV genotypes and linear array for detection
of 37 of 38 HPV genotypes detected with LBA (excluding
HPV57) were conducted on all archived specimen transport
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medium specimens from women diagnosed with CIN 3.13-16
The results of the 2 tests were combined to maximize analytic
sensitivity and more accurately describe the natural history of
CIN 3. Of the 621 CIN 3 cases diagnosed during the 2-year
duration of ALTS by the clinical center (CC) or the quality
control (QC) pathology groups,17 613 underwent at least LBA
or linear array testing at enrollment and diagnosis. HPV16,
18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, the types
targeted by HC2, were defined as the carcinogenic HPV genotypes.18 HPV26, 53, 66, 67, 70, 73, and 82 were defined as
borderline carcinogenic HPV genotypes, HPV genotypes that
cause CIN 3 but are very unlikely to cause cervical cancer.18,19
Other HPV genotypes were classified as noncarcinogenic.
HPV results were categorized hierarchically according to
cancer risk (HPV risk groups) as carcinogenic > borderline
carcinogenic > noncarcinogenic> HPV negative.
Of the 613 CIN 3 cases that had polymerase chain
reaction (PCR) results, 584 (95.3%) also had HC2 results;
HC2-positive results were used as appropriate to reclassify
enrollment HPV status: (1) 25 women went from incident,
persistent carcinogenic HPV infection to prevalent, persistent
carcinogenic HPV (ie, we assumed that the causal type was
present at enrollment because HC2 was already positive,
but that type was missed by PCR); (2) 1 woman went from
incident, persistent borderline carcinogenic HPV infection to
prevalent, persistent borderline carcinogenic HPV (because
HC2 cross-reacts with these borderline carcinogenic HPV
genotypes); and (3) 1 woman went from HPV-negative prevalent CIN 3 to carcinogenic HPV-positive prevalent CIN 3.
Statistical Analyses
We divided CIN 3 into 4 categories: (I) “prevalent” if
found at enrollment; (II) “incident CIN 3 following prevalent,
persistent HPV” if at least 1 HPV infection was detected at
enrollment and persisted until the time of the incident CIN
3 diagnosis after enrollment; (III) “incident CIN 3 following incident, persistent HPV” if at least 1 HPV infection was
detected after enrollment and persisted until the time of the
incident CIN 3 diagnosis after enrollment; and (IV) “incident
CIN 3, no persistence” if an incident CIN 3 was not preceded
by measurable persistent HPV infection. We defined persistence for a specific HPV genotype as being positive for the
screening visit leading to colposcopic referral and diagnosis
and at least at 1 additional preceding visit.
We stratified categories of CIN 3 by HPV risk groups and
by study arm to estimate the proportions of each CIN 3 category, recognizing that differences in the treatment of women
at enrollment would affect these distributions.
Fisher exact test was used to test for differences in distributions. P values of < .05 were considered statistically significant. Stata software version 11.0 (Stata, College Station, TX)
was used for statistical analyses.
© American Society for Clinical Pathology
Anatomic Pathology / Original Article
Results
The baseline characteristics of women in ALTS with a
CIN 3 diagnosis are shown in ❚Table 1❚. Approximately half
were smokers, most (63%) were using oral contraceptives,
and most women had been pregnant at least once (72%) and
had at least 1 live birth (59%). The majority (69%) of the
women with CIN 3 were white. Their median, mean, interquartile range, and range of ages at enrollment were 23, 24.9,
21-27, and 18-70 years, respectively.
❚Table 2❚ shows the distribution of CIN 3 diagnoses by
study arm, timing of diagnosis (prevalent vs incident), timing and duration of HPV detection (prevalent vs incident;
persistent vs no persistence), and HPV risk group. There were
fewer cases of CIN 3 in the HPV arm of the trial because for
women referred to ALTS for an LSIL finding on Pap test,
an HPV testing was deemed not useful for deciding who
needed immediate colposcopy; this part of the trial was halted
before enrollment was completed.7 Of the 613 cases of CIN 3
included in this analysis, we attributed 95.1% to carcinogenic
HPV, 2.3% to borderline carcinogenic HPV, 1.5% to noncarcinogenic HPV, and 1.1% tested HPV negative.
The notable difference between study arms was that the
percentage of prevalent CIN 3 found at enrollment was less
in the CM arm compared with the IC and HPV arm (35.7%
vs 61.6% and 66.9%, respectively, P < .001, Fisher exact test)
because of the differences in the sensitivity of the management strategies by arm. As a consequence, the percentage
of incident CIN 3 following a prevalent, persistent HPV
infection was greater in the CM arm compared with the IC
and HPV arms (60.2% vs 31.9% and 28.8%, respectively,
P < .001, Fisher exact test), evidence of the insensitivity of
the CM arm, which only referred women to colposcopy with
an HSIL found on cytologic test at enrollment. The fraction
of women with incident CIN 3 following incident HPV persistence, the group more certain to have had incident CIN 3,
did not vary significantly between study arms (3.1% for IC,
1.8% for HPV, and 1.8% for CM) (P = .4, Fisher exact test).
Combining across arms, 2.8% (binomial 95% confidence
interval, 1.6%-4.4%) had incident CIN 3 following incident,
type-specific persistent HPV infection.
We then examined clinical characteristics at enrollment and at the time of diagnosis across CIN 3 categories,
restricting this and subsequent analyses to the IC and HPV
arms because of the aforementioned lack of sensitivity of the
CM arm. We also excluded cases that that were not detected
at baseline and did not follow persistent HPV because of
concern that diagnosis was due to misclassification ❚Table
3❚. We noted that the enrollment characteristics for CIN 3
following prevalent, persistent HPV were intermediate to
those for prevalent CIN 3 and CIN 3 following incident, persistent HPV but more closely resembled the characteristics
of the latter. For example, the proportions of women with a
© American Society for Clinical Pathology
❚Table 1❚
Enrollment Characteristics of the 613 Women With a
Diagnosis of CIN 3 During the 2-year Duration of ALTS
Enrollment Characteristics
Referral Pap smear
ASCUS
LSIL
Study arm
Immediate colposcopy
HPV*
Conservative management
Study center
1
2
3
4
Using oral contraceptives
No
Yes
Missing
Cigarette smoking
Never
Former
Current
Parity
Never pregnant
Pregnant, no live births
1 birth
2 births
≥3 births
Sexual partners, lifetime
1-3
4-5
6-10
≥11 Sexual partners, last year
0
1
2
≥3 Race
White
Black
Other
Missing
No. (%)
354 (58)
259 (42)
229 (37)
163 (27)
221 (36)
191 (31)
110 (18)
91 (15)
221 (36)
222 (36)
388 (63)
3 (0)
257 (42)
65 (11)
291 (47)
173 (28)
79 (13)
165 (27)
129 (21)
67 (11)
153 (25)
176 (29)
134 (22)
150 (24)
13 (2)
391 (64)
130 (21)
79 (13)
420 (69)
137 (22)
6 (1)
50 (8)
ALTS, atypical squamous cells of undetermined significance (ASCUS) and low-grade
squamous intraepithelial lesion (LSIL) triage study; CIN 3, cervical intraepithelial
neoplasia grade 3; HPV, human papillomavirus.
* The HPV arm for women with a referral cytology of LSIL was closed before
enrollment was completed.
high-grade cytology (HSIL or ASC-H) at enrollment as read
by the CC pathologists were 53.6%, 15.0%, and 0.0% for
prevalent CIN 3; CIN 3 following prevalent, persistent HPV;
and CIN 3 following incident, persistent HPV, respectively
(P < .001).
Conversely, the same characteristics at the time of diagnosis for CIN 3 following prevalent, persistent HPV and prevalent CIN 3 were similar to and different from CIN 3 following incident, persistent HPV. The proportions of women with
a high-grade cytology at the time of diagnosis as read by the
CC pathologists were 53.6%, 51.7%, and 30.8% for prevalent
CIN 3; CIN 3 following prevalent, persistent HPV; and CIN
3 following incident, persistent HPV, respectively (P = .3).
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❚Table 2❚
Distribution of CIN 3 Histopathologic Diagnoses*
IC
HPV
CMTotal
I. Prevalent CIN 3
Carcinogenic
133 (58.1)
109 (66.9)
78 (35.3)
320 (52.2)
Borderline carcinogenic
4 (1.7)
0 (0.0)
1 (0.5)
5 (0.8)
Noncarcinogenic
3 (1.3)
0 (0.0)
0 (0.0)
3 (0.5)
HPV negative
1 (0.4)
0 (0.0)
0 (0.0)
1 (0.2)
Subtotal
141 (61.6)
109 (66.9)
79 (35.7)
329 (53.7)
II. Incident CIN 3 Following Prevalent, Persistent HPV
Carcinogenic
69 (30.1)
44 (27.0)
130 (58.8)
243 (39.6)
Borderline carcinogenic
4 (1.7)
2 (1.2)
1 (0.5)
7 (1.1)
Noncarcinogenic
0 (0.0)
1 (0.6)
2 (0.9)
3 (0.5)
HPV negative
NANANA
NA
Subtotal
73 (31.9)
47 (28.8)
133 (60.2)
253 (41.3)
III. Incident CIN 3 following incident, persistent HPV
Carcinogenic
7 (3.1)
3 (1.8)
4 (1.8)
14 (2.3)
Borderline carcinogenic
1 (0.4)
0 (0.0)
0 (0.0)
1 (0.2)
Noncarcinogenic
1 (0.4)
1 (0.6)
0 (0.0)
2 (0.3)
HPV negative
NANANA
NA
Subtotal
9 (3.9)
4 (2.5)
4 (1.8)
17 (2.8)
IV. Incident CIN 3, no HPV persistent detected
Carcinogenic
3 (1.3)
1 (0.6)
2 (0.9)
6 (1.0)
Borderline carcinogenic
1 (0.4)
0 (0.0)
0 (0.0)
1 (0.2)
Noncarcinogenic
0 (0.0)
1 (0.6)
0 (0.0)
1 (0.2)
HPV negative
2 (0.9)
1 (0.6)
3 (1.4)
6 (1.0)
Subtotal
6 (2.6)
3 (1.8)
5 (2.3)
14 (2.3)
Total
229163221
613
CIN 3, cervical intraepithelial neoplasia grade 3; CM, conservative management; HPV, human papillomavirus; IC, immediate colposcopy; NA, not available.
* Cases were distributed based on study arm, timing of diagnosis (prevalent vs incident), timing and duration of HPV detection (prevalent vs incident; persistent vs no
persistence), and HPV risk group (carcinogenic > borderline carcinogenic > noncarcinogenic > HPV negative). Data are given as number (percentage). There were fewer cases
of CIN 3 in the HPV arm of the trial because HPV testing of women referred to the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous
intraepithelial lesion (LSIL) triage study (ALTS) for a Pap smear showing LSIL was deemed not useful for deciding who needed immediate colposcopy and this part of the trial
was halted before enrollment was completed.7
These data provided indirect evidence that the CIN 3 following prevalent, persistent HPV infections were primarily
incident CIN 3 (ie, there was a significant increase in highgrade cytology from the baseline to the time of diagnosis),
but a small proportion were prevalent CIN 3 undiagnosed at
enrollment.
Because enrollment high-grade cytology was most
strongly associated with the different CIN 3 groups, we used
it to estimate the proportion of CIN 3 in the “incident CIN
3 following prevalent HPV persistence” category that was
missed prevalent vs incident CIN 3. We assumed that the
proportion of missed prevalent CIN 3 (found after enrollment)
❚Table 3❚
Distribution of Selected Clinical Characteristics at Enrollment and at Diagnosis*
IC and HPV Arms
Prevalent Incident
Prevalent HPV, Inci- HPV, Inci-
Prevalent
CIN 3
dent CIN 3 dent CIN 3
CIN 3
P
(n = 141)
(n = 250)
(n = 120)
(n = 13)
IC Arm
HPV Arm
PrevalentIncident
HPV, Inci- HPV, Inci- Prevalent
dent CIN 3 dent CIN 3 CIN 3
(n = 73)
(n = 9)
(n = 109)
PrevalentIncident
HPV, Inci- HPV, Incident CIN 3 dent CIN 3
(n = 47)
(n = 4)
HSIL cytology (CC)
Enrollment
53.6
15.0
0.0
<.001
58.9
15.1
0.0
46.8
14.9
0.0
Diagnosis
53.6
51.7
30.8
.3
58.9
58.9
33.3
46.8
40.4
25.0
High-grade cervigram
Enrollment
12.8
4.2
0.0
.02
15.6
4.1
0.0
9.2
4.3
0.0
Diagnosis
12.8
10.0
0.0
.44
15.6
9.6
0.0
9.2
10.6
0.0
Consensus CIN 3
52.048.3 30.8.30
51.154.833.353.238.325.0
diagnosis
CC, clinical center pathologists; CIN 3, cervical intraepithelial neoplasia grade 3; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; IC, immediate
colposcopy.
* Cases were distributed based on study arm and CIN 3 diagnosis category. Confirmed CIN 3 means that both pathology reviews diagnosed CIN 3. High-grade cytology
includes cytologic interpretations of HSIL and atypical squamous cells, cannot rule out HSIL. Women in the conservative arm of the atypical squamous cells of undetermined
significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS) were excluded because of the insensitivity of the management strategy to
identify women with CIN 3. In this table, HPV (human papillomavirus) refers to persistent HPV; cases without evidence of previous persistent HPV were excluded from this
analysis. Data shown are percentages.
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© American Society for Clinical Pathology
Anatomic Pathology / Original Article
was directly related to the proportion of women with highgrade cytology at enrollment and we therefore estimated the
proportion of those CIN 3 cases that are probably incident
using a simple linear equation:
[(p) * % high-grade cytology among prevalent CIN 3] +
[(1 – p) * % high-grade cytology among incident CIN 3
following incident HPV persistence]
Using the CC pathology interpretation of high-grade
cytology and combining data from the IC and HPV arms, we
estimated that 28.0% of the incident CIN 3 following prevalent HPV persistence were missed prevalent cases. For reference, using high-grade colposcopic impression, we estimated
that 32.6% were missed prevalent cases. Thus, of all 383 cases
of CIN 3 diagnosed in the IC and HPV arms (excluding the
9 incident cases that were not preceded by persistent HPV),
approximately 25.8% of CIN 3 (n = 99) (estimates based on
high-grade cytology as read by CC pathology) or 26.6% of
CIN 3 (n = 102) (estimates based on high-grade cytology as
read by QC pathology) diagnosed in ALTS were probably
with incident disease, most of which followed a persistent
HPV infection detected at baseline.
Discussion
Overall, 3% of the CIN 3 cases found in ALTS were
almost certainly incident cases because the probable causal
persistent HPV infection was detected after enrollment but
we cannot completely rule out misclassification of disease or
HPV detection. A larger fraction of probably incident disease
was found among the women with persistent HPV infection
detected at baseline. However, the challenge is differentiating
the missed prevalent vs incident CIN 3 in this group because
of the known limitations of colposcopy.20,21 We illustrated
this point indirectly by showing that the number of incident CIN 3 following a prevalent, persistent HPV infection
depended on the sensitivity of the management arm.
When we used high-grade cytology as a specific marker
for prevalent CIN 3 among women with prevalent HPV and
incident CIN 3, we estimated that approximately 25% of all
CIN 3 diagnosed in the 2-year span of ALTS could be incident, with almost 90% of the incident CIN 3 found in women
who were already HPV positive at enrollment, and their HPV
infection persisted until a CIN 3 lesion was identified.
The strength of this study was the rigorous follow-up and
good disease ascertainment, including offering all women
colposcopy at the exit visit from the trial. The disadvantage
is that we only had women referred to the study for a Pap
smear finding of an ASCUS or LSIL. Yet a large proportion
of high-grade disease is found in women who have ASCUS
or LSIL cytology.22,23
In conclusion, most of the CIN 3 diagnosed over the
2-year duration of ALTS was carcinogenic HPV positive at
© American Society for Clinical Pathology
baseline and prevalent. At a single time point, carcinogenic
HPV detection identified the majority of women who had or
would develop CIN 3 in the next 2 years; small proportions of
CIN 3 either followed an incident HPV infection because of
noncarcinogenic HPV genotypes or were misclassified cases.
The results of this analysis have important implications for
estimating the effect of interventions targeting HPV infection
and/or CIN 3. First, we can infer that an earlier report from
ALTS on baseline colposcopic performance24 underestimated
its sensitivity because approximately a quarter of CIN 3 diagnosed in ALTS was probably incident. Second, future trials
of pharmacotherapeutic agents to treat HPV infections must
account for a subset of HPV infections that are associated with
missed prevalent CIN 3; these missed cases will be diagnosed
after the intervention and will be considered a treatment failure. Conversely, screening trials may underestimate the positive predictive values of tests if precautions are not taken to
diagnose all prevalent disease.
From the 1American Society for Clinical Pathology Institute,
Washington, DC; 2Departments of Epidemiology and Molecular
Microbiology and Immunology, Johns Hopkins University,
Baltimore, MD; and the 3Division of Cancer Epidemiology and
Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, MD.
This study was supported by funding from the ARUP Institute
of Clinical and Experimental Pathology, Salt Lake City, and
in part by the Intramural Research Program of the National
Institutes of Health and National Cancer Institute.
Address reprint requests to Dr Castle: American Society for
Clinical Pathology Institute, 1225 New York Ave NW, Suite 250,
Washington, DC 20005.
Dr. Castle serves on a Merck data and safety monitoring
board for HPV vaccines. Dr. Castle has received HPV testing
reagents at a reduced or no cost from Qiagen and Roche. Dr.
Schiffman has received HPV testing reagents at a reduced or no
cost from Qiagen.
Acknowledgments: National Cancer Institute, National
Institutes of Health Department of Health and Human Services
contracts CN-55153, CN-55154, CN-55155, CN-55156,
CN-55157, CN-55158, CN-55159 and CN-55105 provided
support for ALTS. Some of the equipment and supplies used
in these studies were donated or provided at reduced cost by
Digene Corporation, Gaithersburg, MD; Cytyc Corporation,
Marlborough, MA; National Testing Laboratories, Fenton, MO;
DenVu, Tucson, AZ; TriPath Imaging, Inc, Burlington, NC; and
Roche Molecular Systems Inc, Alameda, CA. We thank the ALTS
Group Investigators for their help in planning and conducting the
trial.
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