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OBJECTIVE: To estimate the risks of cervical intraepithe- RESULTS: Cervical intraepithelial neoplasia-3 was found
lial neoplasia (CIN) 3 among girls and women aged 13 to in 6.6% (95% confidence interval [CI] 4.6 – 8.6%) of the
24 years who were referred for abnormal cytology while 622 girls and women referred and no cancers were
receiving care in a large health maintenance organization. detected. Risk for CIN 3 compared to CIN 1 or less
METHODS: At the time of referral, patients had a colpo- included human papillomavirus 16 or 18 (odds ratio [OR]
scopic examination and biopsy if needed. Histology was 30.93, 95% CI 6.95–137.65), high-risk, non-16/18 human
sent to a centralized laboratory. Patients were inter- papillomavirus (OR 6.3, 95% CI 1.3–29.4), and time on
oral contraceptives (OR 1.36 per year of use, 95% CI
viewed for risk behaviors. Data analysis included multi-
1.08 –1.71).
nomial logistic regression analysis to compare three
groups: CIN 3 to CIN 1 or less, CIN 3 to CIN 2, and CIN CONCLUSION: Our data support conservative care for
2 to CIN 1 or benign. adolescents and young women with abnormal cytology
since CIN 3 was rare and cervical cancer was never
found. Human papillomavirus 16 or 18 was strongly
associated with for CIN 3, and testing for these types may
From the Department of Pediatrics, School of Medicine, University of California,
San Francisco; Teenage Clinic, Kaiser Permanente San Francisco; Department
be warranted for triage of abnormal cytology in this age
of Pathology, University of California, San Francisco; Women’s Health Research group.
Institute, Kaiser Permanente Daly City; and Department of Epidemiology and (Obstet Gynecol 2008;112:1335–42)
Biostatistics, University of California, San Francisco, San Francisco, California.
LEVEL OF EVIDENCE: II
Supported by grant 3 R01 CA87905 from the National Institutes of Health.
Roche Molecular Diagnostics (Pleasanton, CA) provided supplies for HPV DNA
detection.
Presented in part at the 23rd International Papillomavirus Conference, Prague,
September 1–7, 2006.
A lthough human papillomavirus (HPV) infections
are quite common in adolescents, HPV-associ-
ated cancers are extremely rare.1,2 This discrepancy is
The authors thank the following staff of the Kaiser Permanente/University of
California, San Francisco CIN 2 Study for undergoing study training, complet- thought to be due to the benign nature of HPV early
ing study-specific forms, and processing samples: Amber Dimick-Flores, MA, after infection and the requirement of long-time per-
Cheryl Godwin de Medina, Wanda Griffin, RN, Debra Guisto, RN, Janet Jonte, sistence for the development of cancer. Human pap-
NP, Katy Kurtzman, MD, Lesley Levine, MD, Anita Levine-Goldberg, NP,
Carol Lopez, LVN, Ellen McKnight, NP, Karen Milligan-Green, RN, Laura illomavirus is commonly acquired shortly after the
Minikel, MD, Heidi Olander, MD, Mary Phelps, MA, Diane Ragni, RN, Katy onset of sexual activity, and new infections are
Ryan, MD, Debbie Russell, RN, Greg Sacher, MD, Mark Seaver, MD, Carolyn
Taylor, RN, and Nicole Zidenberg, MD.
strongly associated with new sexual partners.3 There-
fore, the high rate of sexual activity and reported
The authors thank Dr. Ted Miller for his assistance in reviewing histology for the
methods, Lisa Clayton for data entry and management, and Anthony Kung for number of partners in adolescents explains the high
data and site overview. rate of HPV detection in this population.3,4 Most of
Corresponding author: Anna-Barbara Moscicki, MD, University of California, these infections in young women, however, are tran-
San Francisco, 3333 California Street, Suite 245, San Francisco, CA 94143; sient with only 5–10% persisting.5,6 Since HPV can be
e-mail: moscickia@peds.ucsf.edu.
cleared even after 1–3 years of persistence, most
Financial Disclosure
The authors have no potential conflicts of interest to disclose.
believe that the risk of developing cancer and its
precursor, cervical intraepithelial neoplasia (CIN) 3,
© 2008 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins. requires at least several years of viral persistence. This
ISSN: 0029-7844/08 lag from initial infection to cancer is supported by the
(Dr. Ted Miller). Other diagnoses were not reviewed. 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73,
For purposes of this analysis, if a patient had more 81, 82, 83, 84, IS39, and CP6108 was performed as
than one biopsy, the most severe diagnosis was used. previously described (Roche Molecular Diagnostics,
For patients who had a normal colposcopy with no Inc., ALmeda, CA).13,14 Polymerase chain reaction
indication for biopsy or ECC and had normal cytol- data were classified as negative or positive for the
ogy, the colposcopy visit was considered normal and types identified. Samples without -globin signal or
they were included in the benign group. We excluded positive for three or more HPV types were re-
these patients who had normal colposcopy (no bi- prepped and retested. Samples with two negative
opsy) but had a repeat abnormal cytology at the time -globin signals were considered inadequate and ex-
of the colposcopic examination since we lacked any cluded from analysis. In addition, 5% of samples
histologic verification and misclassification was likely chosen at random were tested in duplicate.
if we based their diagnosis on cytology alone (Table 1 Sample size estimates were based on HPV status.
and Fig. 1). Comparison of CIN 3 or CIN 2 and CIN 1 or less by
The samples in PreservCyt media were sent to HPV status gave us an estimated power over 0.99
the University of California San Francisco laboratory, with ␣⫽0.05 and two-sided test. Comparison of CIN
where 7 mL was removed for polymerase chain 3 and CIN 2 gave us a lower estimated power over
reaction under polymerase chain reaction sterile con-
0.64. For purposes of the risk analysis, the following
ditions and the remaining sent to the University of
outcome categories were used: CIN 1 or less, CIN 2,
California San Francisco Anatomic Pathology labora-
and CIN 3. Since CIN 1 is considered benign, CIN 1
tory for cytology processing. Testing for HPV types 6,
and benign (referred to CIN 1 or less in the text)
11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54,
diagnoses were combined for analysis. Statistical anal-
yses were performed on each of the pairs of outcomes
Consented to participate and (ie, CIN 3 compared with CIN 1 or less, CIN 3
completed initial questionnaire compared with CIN 2, CIN 2 compared with CIN 1
N=678
or less). Although CIN 3 was our primary outcome,
Missing histologic diagnosis
from centralized lab
we compared CIN 2 and CIN 1 or less and CIN 2 and
n=32 CIN 3 to see if risk factors might differentiate CIN 3
Histologic diagnosis from compared with CIN 2. Predictor variables examined
centralized lab present included those listed in Table 2. Reported history of
n=646
sexually transmitted diseases and vaginal infections
Normal colposcopy and no
biopsy obtained, but repeat was used instead of chart review since the chart
cytology abnormal or missing review likely underestimated the number of infec-
n=24
tions. We report both in Table 2. We collapsed HPV
Final sample size
n=622* status into three categories: 1) high-risk HPV with
type other than HPV 16 and/or 18; 2) HPV 16/18
Fig. 1. Algorithm for inclusion in the study. * Includes 19
patients with normal colposcopy, no biopsy, and repeat only; and 3) low-risk only and HPV negative. Low-
cytology benign. risk HPV-positive and HPV-negative results were
Moscicki. CIN 3 in Adolescents. Obstet Gynecol 2008. pooled because they did not show any statistical
CIN 3 vs CIN 2 vs
CIN 1 or CIN 1 or CIN 3 vs CIN 1 or
Less† CIN 2 CIN 3 Less* CIN 2 Less†
Variable (continuous)
Age 20.2 (⫾2.1) 19.8 (⫾2.2) 19.9 (⫾1.6) .37 .72 .07
Age at first intercourse 15.8 (⫾1.8) 15.7 (⫾1.8) 15.5 (⫾1.7) .22 .61 .40
Years sexually active 4.4 (⫾2.1) 4.1 (⫾2.4) 4.4 (⫾2.2) .95 .48 .30
Months currently on OCs 5.9 (⫾11.9) 7.8 (⫾12.9) 8.4 (⫾16.6) .22 .84 .22
Months currently on 3.6 (⫾9.1) 7.7 (⫾14.6) 6.4 (⫾13.2) .07 .65 .002
medroxyprogesterone use
Months of OC use (ever) 13.2 (⫾17.4) 14.2 (⫾18.7) 18.2 (⫾20.7) .09 .29 .62
Number of pregnancies 0.6 (⫾1.0) 0.5 (⫾0.7) 0.6 (⫾0.8) .91 .81 .82
Days since last intercourse 24.9 (⫾73.6) 22.3 (⫾53.3) 8.5 (⫾12.9) .14 .16 .76
Lifetime sex partners 8.0 (⫾8.9) 7.8 (⫾7.1) 8.0 (⫾8.2) .90 .91 .99
Years smoked 1.8 (⫾3.0) 2.2 (⫾3.8) 1.8 (⫾2.5) .94 .48 .28
No. of cigarettes smoked last 24 h 1.4 (⫾3.3) 1.5 (⫾3.5) 2.5 (⫾4.4) .05 .18 .75
Variable (dichotomous)
Current OC use 186 (37.2) 35 (43.2) 15 (36.6) .94 .48 .30
Current condom use 166 (33.2) 22 (27.2) 12 (29.3) .61 .81 .28
Current smoker 137 (27.4) 25 (30.9) 15 (36.6) .21 .53 .52
History of anal intercourse (ever) 196 (39.2) 27 (33.3) 19 (46.3) .37 .16 .31
History of chlamydia‡ 122 (24.4) 29 (35.8) 9 (22.0) .73 .12 .03
History of gonorrhea‡ 23 (4.6) 5 (6.2) 1 (2.4) .53 .38 .54
History of trichomonas‡ 16 (3.2) 3 (3.7) 1 (2.4) .79 .71 .81
History of bacterial vaginosis‡ 97 (19.4) 14 (17.3) 6 (14.6) .46 .71 .65
History of yeast vaginitis‡ 260 (52.0) 44 (54.3) 21 (51.2) .92 .75 .79
History of herpes‡ 16 (3.2) 5 (6.2) 2 (4.9) .57 .77 .19
One new sex partner in last 2 months§ 369 (73.0) 60 (74.1) 31 (75.6) .10 .12 .95
Two new sex partners in last 2 months§ 77 (15.4) 12 (14.8) 9 (22.0) .05 .07 .89
Ever pregnant 185 (37.0) 34 (42.0) 17 (41.5) .57 .96 .39
Smokes marijuana at least once per week 70 (14.0) 13 (16.0) 6 (14.6) .91 .84 .63
Drinks alcohol at least once per week 105 (21.0) 14 (17.3) 7 (17.1) .55 .98 .44
Uses drugs (other than marijuana) at least 2 (0.4) 1 (1.2) 0 (0.0) .40 .27 .36
once per week
CIN, cervical intraepithelial neoplasia; OC, oral contraceptives.
Data are presented as mean (⫾standard deviation) or n (%).
* P values reflect the association between a single predictor and CIN outcome categories from a multinomial logistic regression model.
†
CIN 1 or less includes benign.
‡
Obtained by history: overall,108 (68%) cases of C trachomatis, 19 (73%) of N gonorrhoeae, 12 (60%) of T vaginalis, 110 (94%) of bacterial
vaginosis, 128 (39%) of yeast vaginitis, and 8 (35%) of herpes simplex virus verified by chart review.
§
P values are for comparisons with the group with no new sex partner in the last 2 months.
significant differences between the CIN comparison tors singly, and all those with associations significant
groups (data not shown). High-risk HPV types in- at the 10% level were considered further in models
cluded 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, with multiple predictors. To adjust for possible years
59, 66, 68, 73, and 82.15 of exposure to HPV and site differences, years of
In this analysis, we used t tests to evaluate the sexual activity and clinical site were also included in
differences in average number of biopsies among the final model. The model estimated the odds ratios
CIN comparison groups. To compare the differences of having the more serious diagnoses in all three
among included and excluded samples, we used t comparisons simultaneously. All the analyses were
tests for continuous variables, and 2 and Fisher exact performed with SAS 9.1.
tests for categorical variables. Because our outcome
variable was polytomous, multinomial logistic regres- RESULTS
sion method was used to investigate the associations Six hundred seventy-eight women were consented
between selected predictor variables and three CIN and completed a baseline questionnaire. Fifty-six
outcomes.16 Initial models included candidate predic- women were excluded from the analysis based on
ciation for each of the following outcome compari- negative for HPV or low-risk HPV. No statistically
sons: CIN 3 compared with CIN 1 or less, CIN 3 significant differences were found for the comparison
compared with CIN 2, and CIN 2 compared with between CIN 3 and 2. The results are presented in
CIN 1 or less. These results are summarized in Table Table 3.
2. The first comparison (CIN 3 compared with CIN 1
and less) showed that the following variables associ- DISCUSSION
ated with risk for CIN 3 at P⬍.1 level: total months of Little is known about adolescents and young women
oral contraceptive pill (OCP) use, total months on who develop CIN 3 because most studies focus on
medroxyprogesterone, number of sex partners in last older women. In this study of adolescents and young
2 months, and number of cigarettes smoked in the last women attending a large health maintenance organi-
24 hours. The second comparison (CIN 3 compared zation, less than 7% of the population referred for
with CIN 2) found only number of sex partners in last abnormal cytology was found to have CIN 3. Similar
2 months significant at P⬍.1 level. The third compar- to older adults, most of the study participants were
ison (CIN 2 compared with CIN 1 or less) showed referred because of ASC-US and LSIL.18 In contrast,
that the risk of CIN 2 is associated with younger age, the rate of CIN 3 among study participants referred
history of chlamydia, and total months on medroxy- for ASC-US or LSIL was less than half of that
progesterone at the P⬍.1 level. reported for older adults. It is estimated that 10 –16%
Predictor variables with associations significant at of adult women with HPV-positive ASC-US/LSIL
P⬍.1 level in Table 2 were included together in a final will have underlying CIN 3.19 –21 We found CIN 3 in
multinomial logistic model, with results summarized 6.3% (95% CI 4.3– 8.3%) of adolescents and young
as odds ratios (and 95% CIs) for the outcome com- women with ASC-US or LSIL on referral Pap. This
parisons introduced above. The model also adjusted lower rate of CIN 3, along with data showing high
for years of sexual activity and clinic site. The first rates of LSIL regression,13 support the new 2006
comparison for CIN 3 compared with CIN 1 or less American Society for Colposcopy and Cervical Pa-
found total years of OCP use increased risk of CIN 3. thology Consensus Guidelines, which recommend
For each one additional year on OCPs, the odds of following adolescents with ASC-US/LSIL by cytology
having CIN 3 increases by 36% on average. Although rather than immediate referral to colposcopy.18 Our
not statistically significant, having two or more data suggest that extending this conservative manage-
recent sex partners had an increased odds of CIN 3 ment to young women under the age of 25 years may
(P⫽.08). be reasonable and that further analysis by guideline
The second comparison for CIN 2 and CIN 1 or groups is warranted. The consensus guidelines also
less found that for each additional year on medroxy- recommend continued follow-up of these young
progesterone increases the odds of CIN 2 by 46%. women with ASC-US/LSIL because the possibility of
Both analyses found HPV 16 and/or 18 and other CIN 3 is not nil, as demonstrated in our study.
high-risk HPV detection significant: the former in- However, the likelihood of progression to cancer is
creases the odds of CIN 3 by almost 3,000%, and CIN extremely low during this young age period.2 This
2 by 600%; the latter increases the odds of CIN 3 by assumption was supported by the lack of finding a
500%, and CIN 2 by 260%, comparing with those single cancer case in our study.