ACOG Practice Bulletin No 99 Management of 39 PDF

ACOG
PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN–GYNECOLOGISTS
NUMBER 99, DECEMBER 2008
Replaces Practice Bulletin Number 66, September 2005
Management of
Abnormal Cervical
Cytology and Histology
This Practice Bulletin was devel- Recent evidence has shown that the risk of malignant and premalignant cervi-
oped by the ACOG Committee on cal disease and human papillomavirus (HPV) infections varies significantly
Practice Bulletins—Gynecology with age (1, 2). Furthermore, evidence now shows that treatment for cervical
with the assistance of Mark Spitzer, disease carries significant risk for future pregnancies (3–7). These factors have
MD. The information is designed to led to a re-evaluation of the guidelines for the management of premalignant
aid practitioners in making deci-
cervical disease. The purpose of this document is to define strategies for diag-
sions about appropriate obstetric
nosis and management of abnormal cervical cytology and histology results. In
and gynecologic care. These guide-
lines should not be construed as this document, HPV refers to high-risk oncogenic forms of the virus.
dictating an exclusive course of
treatment or procedure. Variations
in practice may be warranted based Background
on the needs of the individual
patient, resources, and limitations
Cytology and Histology Findings and Interpretation
unique to the institution or type of The 2001 Bethesda System terminology (see box) is used throughout this doc-
practice. ument to describe the categories of epithelial cell abnormalities, including atyp-
ical squamous cells (ASC), low-grade or high-grade squamous intraepithelial
lesions (LSIL or HSIL), and glandular cell abnormalities, including atypical
glandular cells (AGC) and adenocarcinoma in situ (AIS). Histology diagnoses
of abnormalities are reported as cervical intraepithelial neoplasia (CIN) grades
1–3 (8).
The key to developing effective guidelines for the management of cervical
abnormalities is to distinguish true cervical cancer precursors from benign cer-
vical abnormalities with little premalignant potential. Both LSIL and CIN 1
THE AMERICAN COLLEGE OF reflect the cytologic and pathologic effects of infection with HPV. Most of these
OBSTETRICIANS AND lesions will never progress to cancer. However, as many as 28% of women with
GYNECOLOGISTS cytologic LSIL harbor CIN 2 or CIN 3, approximately two thirds of which is
WOMEN’S HEALTH CARE PHYSICIANS identified by colposcopy (9). Cervical intraepithelial neoplasia grade 3 and AIS
VOL. 112, NO. 6, DECEMBER 2008 OBSTETRICS & GYNECOLOGY 1419

for most cases but are not a substitute for clinical judg-
The 2001 Bethesda System Terminology ment because it is impossible to develop guidelines that
would apply to all situations (12, 13). Newer data show
Squamous Cell that cervical treatments, such as ablation or excisional
• Atypical squamous cells procedures, may have adverse effects on pregnancy,
— Of undetermined significance including preterm delivery and low birth weight (7, 14);
thus, risk–benefit assessment sometimes favors observa-
— Cannot exclude high-grade squamous intraepithelial
tion of CIN 2, especially among younger women (12).
lesions
Finally, there is increasing recognition that col-
• Low-grade squamous intraepithelial lesions—encom- poscopy is less sensitive than previously thought. A sin-
passing human papillomavirus, mild dysplasia, and
gle colposcopy examination in women with positive
CIN 1
low-grade cytology results identified only 60% of
• High-grade squamous intraepithelial lesions— women with CIN 2,3 lesions and 54% of women with
encompassing moderate and severe dysplasia, CIN 3 lesions who received their diagnoses within 2
carcinoma in situ, CIN 2, and CIN 3
years of study enrollment (9). Some lesions with meta-
• Squamous cell carcinoma plastic or low-grade features contain CIN 2,3, whereas
some lesions with high-grade features contain CIN 1,
Glandular Cell
condylomatous changes, or atypical metaplasia. Recent
• Atypical glandular cells (specify endocervical, studies suggest that the correlation between colposcopy
endometrial, or not otherwise specified)
impression and biopsy grade is poor (15–17). The sensi-
• Atypical glandular cells, favors neoplasia (specify tivity of colposcopy is significantly greater when two or
endocervical or not otherwise specified) more biopsy specimens are obtained (18).
• Endocervical adenocarcinoma in situ
• Adenocarcinoma Natural History of Cervical
Intraepithelial Neoplasia
Abbreviation: CIN indicates cervical intraepithelial neoplasia.
Carriage of HPV DNA is quite common in the general
Modified from Solomon D, Davey D, Kurman R, Moriarty A,
O’Connor D, Prey M, et al. The 2001 Bethesda System: terminology
population, reported in one study to occur at least once
for reporting results of cervical cytology. Forum Group Members; over a 3-year period in 60% of young women (19). The
Bethesda 2001 Workshop. JAMA 2002;287:2114–9. Copyright © lifetime cumulative risk is at least 80% (20). Most
2002, American Medical Association. All rights reserved.
women clear the virus or suppress it to levels not associ-
ated with CIN 2,3+, and for most women this occurs
promptly (21, 22). The duration of HPV positivity is
are cervical cancer precursors (10). Cervical intraepithe- shorter and the likelihood of clearance is higher in
lial neoplasia grade 2 lesions are more heterogeneous, younger women (23–25).
and their significance is less clear than that of CIN 3. The The presence of high-risk HPV is a marker for the risk
reproducibility of a diagnosis of CIN 2 is poor, and many of diagnosis of CIN 2,3+; only 1 in 10 to 1 in 30 HPV
women will have either CIN 1 or CIN 3 (11). Cervical infections are associated with abnormal cervical cytology
intraepithelial neoplasia grade 2 is more likely to results (26–28), with an even smaller proportion associat-
progress to CIN 3 and cancer than CIN 1. However, ed with CIN 2,3+ (29). Among women with negative cytol-
many CIN 2 lesions will regress without therapy. Many ogy test results and a positive HPV test result, only 15%
pathologists do not attempt to distinguish between CIN will have abnormal cytology results within 5 years (30).
2 and CIN 3, instead reporting a composite diagnosis of However, high-risk HPV is necessary for the development
CIN 2,3 or high-grade CIN (CIN 2,3+). and maintenance of CIN 3 (31). Persistent high-risk HPV
The guidelines discussed in this document follow is a necessary but not sufficient condition for the develop-
the 2006 consensus guidelines published by the American ment of almost all types of invasive cervical cancer (32,
Society for Colposcopy and Cervical Pathology (12, 13). 33). Conversely, the risk of cervical cancer in women who
These guidelines recognized that a small risk of failing do not harbor oncogenic HPV is extremely low (34). The
to detect high-grade CIN and even cancer must be longer high-risk HPV is present and the older the patient,
accepted. It is unreasonable for patients or clinicians to the greater the risk of CIN (35). When HPV is present,
expect that the risk can be reduced to zero, and attempts smoking doubles the risk of progression to CIN 3 (36).
to achieve zero risk will result in greater harm than good From a clinical perspective, it is important to distin-
in the form of overtreatment. When providing care for an guish which intraepithelial neoplastic lesions will
individual patient, guidelines define the evidence base progress to invasive cancer if left untreated. However,
1420 ACOG Practice Bulletin Abnormal Cervical Cytology and Histology OBSTETRICS & GYNECOLOGY
the diagnostic categories currently available have only (10, 21, 50–52). As new tests are introduced, decisions
modest predictive value, and that value decreases as the about clinical practice implementation must be based on
lesions become less severe. The likelihood of progres- clinical sensitivity (relationship of the test result to CIN
sion to cancer is higher and the time to progression is 2,3+), not analytic sensitivity (ability of the test to detect
shorter as the grade of dysplasia increases (37). low levels of HPV).
Although expression of the presence of HPV as CIN can Human papillomavirus DNA positivity is much more
occur within months of viral acquisition (10), the time prevalent in women aged 18–22 years (71%) versus those
course from CIN 3 to invasive cancer averages between older than 29 years (31%) (88). In the algorithms used in
8.1 years and 12.6 years (9, 38, 39). The slow pace of the management of abnormal cervical cytology results or
these changes in immunocompetent women means that CIN, persistent HPV positivity is used as evidence of per-
accurate estimates of progression risk require long fol- sistent HPV infection and, therefore, a marker of disease.
low-up periods. Perhaps more relevant for clinical prac- However, many adolescents experience multiple sequen-
tice are estimates of regression to normal status. A tial HPV infections, so a repetitively positive HPV DNA
review of the literature from 1950 to 1992 noted the like- test in this age group may represent consecutive incident
lihood of regression to be 60% for CIN 1 and 40% for infections rather than a single persistent infection.
CIN 2 (40, 41). Consequently, HPV testing should not be used in this age
group and if inadvertently performed, a positive result
Cervical Cytology should not influence management.
Cervical cytology screening programs are associated
with a reduction in the incidence of and mortality from Colposcopy With and Without
invasive squamous cancer. Conventional cytology is Directed Biopsy
reported to be 30–87% sensitive for dysplasia (42). A Colposcopy with directed biopsy has been the criterion of
meta-analysis of conventional cervical cytology studies disease detection and remains the technique of choice for
suggested a sensitivity of 58% when used for population treatment decisions. Evaluation of colposcopy sensitivity
screening (43). Another meta-analysis comparing the has, until recently, focused on populations with identified
performance of ThinPrep® liquid-based cervical cytol- lesions sufficient to produce abnormal cytology.
ogy screening with conventional cytology screening Some recent studies have used colposcopy with
methods found sensitivity rates, relative to histology, endocervical curettage and blind four-quadrant ectocer-
were 68% (conventional) and 76% (ThinPrep®), and vical biopsies or loop electrosurgical excision procedure
specificity rates were 79% (conventional) and 86% (LEEP) as the diagnostic criteria (38, 53). This approach
(ThinPrep®) (44). permits a more realistic evaluation of the sensitivity of
Because the range of sensitivity (30–87%) is so colposcopy with directed biopsy. The presence of CIN
broad, all abnormal cytology results must be evaluated, 2,3+ was missed on directed biopsy but detected on the
although the vast majority of results do not represent random four-quadrant biopsies in 18.6–31.6% of CIN
underlying CIN 2,3+ (25). Reproducibility among 2,3+ cases (53, 54). These figures may underestimate the
observers and among multiple readings by the same prevalence of CIN 2,3+ not diagnosed on colposcopy-
observer is quite modest, even under optimal research directed biopsy because excisions were not performed in
conditions (45–48). In the ASC-US LSIL Triage Study the entire population—many women had normal screen-
(ALTS), the quality control reviewer at the National ing test results. Comparing directed biopsy to conization
Cancer Institute and the university-based cytopatholo- also demonstrates a significant rate of underdiagnosis of
gist at the study site agreed on an ASC result in 43% of CIN 2 and CIN 3 (55, 56).
1,473 cases, on an LSIL result in 68% of 1,335 cases, Similar conclusions are reported in ALTS. Women
and on an HSIL result in 47% of 433 cases (45). with a previous LSIL or ASC-US HPV-positive test
result and a CIN 1 biopsy were offered LEEP after
Human Papillomavirus Testing 2 years of follow-up (38). Of the 189 women with CIN
Testing for low-risk HPV types has no role in cervical 2,3+ diagnosed during the 2-year study in the ”immedi-
cancer prevention. Low-risk HPV types are associated ate colposcopy” arm of the trial, only 106 (56%) women
with genital warts and with some low-grade intraepithe- received the diagnoses on the initial colposcopy. The
lial lesions of the cervix, vagina, and vulva (49). other cases were identified after HSIL cytology, an exit
For women 30 years and older, high-risk HPV test- colposcopy, or LEEP.
ing can help predict whether CIN 2,3+ will be diagnosed Results of these studies indicate that biopsies of all
in the next few years despite a normal cytology result visible lesions are warranted, regardless of colposcopy
VOL. 112, NO. 6, DECEMBER 2008 ACOG Practice Bulletin Abnormal Cervical Cytology and Histology 1421
impression, and that follow-up should include multiple colposcopy suggest that its addition to directed biopsy
colposcopy examinations over time for those women may be expected to add 5–9% to the total number of CIN
with abnormal cytology or histology results who have 2,3+ diagnoses (65, 67–69). This percentage becomes
persistent low-grade abnormalities or persistently test more important as the risk of CIN 2,3+ increases with
positive for HPV. higher-grade abnormal cytology results. As a consequence,
in women with ASC-H, HSIL, AGC, or AIS cytology
Endocervical Sampling results, endocervical sampling should be considered as
Endocervical sampling may be conducted either with part of the initial colposcopy evaluation (70), unless
vigorous endocervical brushing or by traditional endo- excision is planned. If an excision is planned, endocervi-
cervical curettage with a sharp curette. Compared with cal sampling may be omitted (64), although it may be
curettage, the brush technique is at least as sensitive for performed at the time of the procedure after the excision
endocervical dysplasia (57–61) and returns fewer reports to assess the completeness of the procedure.
of insufficient specimens (60, 61). The disadvantage is
that the result can be equivocal, such as ASC, in which
case the patient must be recalled for sharp curettage. Clinical Considerations and
Endocervical sampling is not indicated in the preg-
nant patient. The following discussion of indications
Recommendations
applies to the nonpregnant patient. In the evaluation of When the results of cervical cytology screen-
an ASC or LSIL cytology result with a satisfactory col- ing are normal but a concurrent HPV test
poscopy result, endocervical sampling may be consid- result is positive, what is the appropriate
ered, although the identification of cancer cases is low follow-up?
(62, 63). Sampling should be performed if colposcopy
results are unsatisfactory (64, 65) or if ablative treat- The best management approach for HPV-positive, cytol-
ment, such as cryotherapy or laser ablation, is contem- ogy-negative women 30 years and older is to repeat
plated. Higher rates of postablation CIN 2 or CIN 3 and cytology and HPV testing at 12 months (Figure 1).
cancer have been reported if pretreatment endocervical Women whose HPV result is still positive on repeat test-
assessment is not done (66). Studies of the contribution ing 12 months later or whose cytology result is ASC or
of endocervical curettage to diagnosis of CIN 2,3+ at greater should undergo colposcopy, whereas women
Figure 1. Use of HPV DNA testing as an adjunct to cytology for cervical cancer screening in women 30 years and older. Abbreviations:
ASCCP indicates American Society for Colposcopy and Cervical Cytology; ASCUS, atypical squamous cells of undetermined signifi-
cance; HPV, human papillomavirus. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;
11:201–22. Reprinted from the Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American
Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of
ASCCP.
whose results are negative on both tests can defer screen- In the Bethesda 2001guidelines, ASC is subcategorized
ing for 3 years. Incorporating HPV testing into routine into atypical squamous cells of undetermined signifi-
screening should be reserved for women aged 30 years cance (ASC-US) and atypical squamous cells, cannot
and older (71, 72). In screening studies from North exclude HSIL (ASC-H). The difference in the manage-
America and Europe, the sensitivity using a combination ment guidelines for these two cytology findings relates
of HPV testing and cytology is significantly higher than to their inherent risk of CIN 2,3. Atypical squamous cells
that of either test alone with negative predictive values of of undetermined significance is the most common cervi-
99–100% (73). Women who receive negative results cal cytology abnormality, accounting for 4.4% of all Pap
from both initial cytology and HPV testing have a less test results. Although the risk of cancer for any individ-
than 1 in 1,000 risk of having CIN 2 or greater (CIN 2+), ual patient is very low (0.1–0.2%) (79, 80), and the risk
and prospective follow-up studies in both Europe and the of CIN 2,3+ also is low (6.4–11.9%) (38, 81, 82),
United States have shown that the risk of developing because there are so many people with this cytology
CIN 3 over a 10-year period is less than 2% (71, 74, 75). abnormality, it is the presenting cytology result for
Modeling studies demonstrate that in women 30 years approximately one half of the women with CIN 2,3+.
and older, screening at 3-year intervals using a combina- The first step in the evaluation of women with ASC-US
tion of cytology and HPV testing provides benefits is to triage those who are at higher risk to more intensive
equivalent or greater than those provided by annual evaluation (colposcopy) and directing the rest to more
screening with conventional cytology (76). Even in routine follow-up. Premenopausal women 21 years and
women 30 years and older, most HPV-positive women older with ASC-US cytology results may undergo imme-
become HPV negative during follow-up (60% in a diate colposcopy or may undergo triage testing to deter-
prospective study from France after a median follow-up mine whether they should be referred to colposcopy.
of 6 months) (48). In a well-screened population, the risk Triage testing may be performed by a single test for
of CIN 2+ in HPV-positive, cytology-negative women high-risk (oncogenic) types of HPV or by repeat cytol-
ranges from 2.4% to 5.1% (53, 77, 78). ogy screening at 6 months and 12 months. When the
index cytology test specimen is obtained by liquid-based
When the results of cervical cytology are cytology or when an HPV specimen is co-collected,
reported as atypical squamous cell of “reflex” HPV testing is the preferred approach (Figure
undetermined significance, how should 2). Data from ALTS demonstrated that two repeat cytol-
they be managed? ogy examinations at 6 months and 12 months at an
Figure 2. Management of women with atypical squamous cells of undetermined significance (ASC-US). Abbreviations: ASC indicates
atypical squamous cells; ASCCP, American Society for Colposcopy and Cervical Cytology; CIN, cervical intraepithelial neoplasia; HPV,
human papillomavirus; LSIL, low-grade squamous intraepithelial lesion. Wright TC. Management of cervical cytologic abnormalities.
J Low Genit Tract Dis 2007;11:201–22. Reprinted from the Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission
of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the
prior consent of ASCCP.
ASC-US threshold detected 88% of the CIN 2,3+ while (71%) than those older than 29 years (31%) (85). Thus,
referring 63.6% of the women to colposcopy. Human using HPV DNA testing to triage adolescents and young
papillomavirus testing alone detected 92.2% of the CIN women with ASC-US would refer large numbers of
2,3+ while referring 55% of the women to colposcopy. women to colposcopy who are at low risk for having cer-
The presence of ASC-US is less common in post- vical cancer. Also, many adolescents experience multiple
menopausal women, as is the risk of significant patho- sequential HPV infections, so a repetitively positive
logic results (2, 83, 84). Human papillomavirus DNA HPV DNA test in this age group may represent consec-
positivity rates also decrease dramatically as women age utive incident infections rather than a single persistent
(85, 86). This means that HPV testing actually is more infection. In adolescents with ASC-US, follow-up with
efficient in older women because it refers a lower pro- annual cytology testing is recommended. Human papil-
portion of these women to colposcopy (87–89). The lomavirus DNA testing and colposcopy are unacceptable
prevalence of CIN 2,3 is much higher among women for adolescents with ASC-US, and if HPV testing is
with ASC-H than women with ASC-US, so ASC-H inadvertently performed, a positive test result should not
should be considered to represent equivocal HSIL. influence management. Also, in adolescents, the thresh-
old for referral to colposcopy is different than in adult
What is the management of ASC-US for women (Figure 3). At the 12-month follow-up visit, only
women 20 years or younger? the patients with the diagnosis of HSIL or greater on the
repeat cytology should be referred to colposcopy. At the
Invasive cervical cancer is very rare in adolescent 24-month follow-up, the patients with a diagnosis of
women before age 21 years. The National Cancer ASC-US or greater should be referred to colposcopy
Institute’s SEER program reported that from 1995 to (Figure 3).
1999 the incidence rate of invasive cervical cancer was 0
per 100,000 per year for women aged 10–19 years and When the results of cervical cytology are
1.7 per 100,000 per year for women aged 20–24 years reported as atypical squamous cells, cannot
(1). In contrast, minor grade cytology abnormalities exclude HSIL (ASC-H), how should they be
(ASC and LSIL) are more common in women aged managed?
15–19 years than in older women (2), and these HPV-
associated abnormalities are of little long-term clinical Women with ASC-H have a 20–50% risk of having a
significance (90). Human papillomavirus DNA positiv- CIN 2,3 lesion and should be evaluated with immediate
ity is much more prevalent in women aged 18–22 years colposcopy (Figure 4). Most women with ASC-H are
Figure 3. Management of adolescent women with either atypical squamous cells of undetermined significance (ASC-US) or low-grade
squamous intraepithelial lesion (LSIL). Abbreviations: ASC indicates atypical squamous cells; ASC-US; atypical squamous cells of unde-
termined significance; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. Wright TC.
Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the Journal of Lower Genital
Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No
copies of the algorithms may be made without the prior consent of ASCCP.
HPV DNA positive (ranging from 67–84%) (91–93), so age in women with LSIL (94, 95). Well-screened, post-
intermediate triage is inappropriate and HPV testing is menopausal women with previously negative results are
not recommended. If CIN 2,3 is not identified by col- likewise at low risk for invasive cervical cancer (96).
poscopy, women aged 21 years and older should be mon- This suggests that postmenopausal women with LSIL
itored in a manner similar to HPV-positive women with may be managed using HPV testing for triage in the
ASC-US. same protocol as is used in reproductive-aged women
with ASC-US.
When the results of cervical cytology are
reported as LSIL or ASC-US with HPV posi- When the results of colposcopy performed for
tive results, how should they be managed in the evaluation of ASC-US, ASC-H, or LSIL
patient 21 years and older? reveal no CIN 2,3, how should the patient’s
condition be managed?
Although a cytology result of LSIL is thought to reflect
the cytopathic effects of HPV infection rather than a true Because a single colposcopy examination can miss sig-
premalignant lesion, women with LSIL remain at mod- nificant lesions, women who are referred for colposcopy
erate risk for having CIN 2+. In ALTS, 27.6% of women and found not to have CIN 2,3 require some form of
with LSIL were found to have CIN 2+ either on colpo- additional follow-up. In ALTS, the initial colposcopy
scopically directed biopsies or on close follow-up over identified only 58% of the CIN 2+ lesions. For the
the next 2 years (9). This rate is virtually identical to the women not found to have CIN 2+ at the initial col-
rate of CIN 2+ in women who presented with HPV-pos- poscopy, the rate of CIN 2+ during follow-up (approxi-
itive ASC-US results in the same population (26.7%). mately 10–13%) was unaffected by the findings at
Two thirds of the cases (17.9%) were identified on the ini- colposcopy (negative findings not worthy of biopsy, neg-
tial colposcopy and the remainder at follow-up. Therefore, ative biopsy, or CIN 1 biopsy). The ASC-US–LSIL
colposcopy is recommended in premenopausal women Triage Study evaluated different postcolposcopy follow-
aged 21 years and older with ASC-US who are HPV pos- up strategies and found that HPV testing performed
itive, or have two consecutive ASC-US cytology results 12 months after the initial colposcopy and two repeat
(Figure 2), or have LSIL (Figure 5). cytology examinations performed at 6-month intervals
Many studies have shown that the prevalence of were equally effective (97). Because of the additional
both HPV DNA positivity and CIN 2,3 decreases with cost and lack of increased sensitivity, the strategy of
Figure 4. Management of women with atypical squamous cells: cannot exclude high-grade SIL (ASC-H). Abbreviations: ASC indicates
atypical squamous cells; ASCCP, American Society for Colposcopy and Cervical Pathology; ASC-H, atypical squamous cells—cannot
exclude high-grade squamous intraepithelial lesion; CIN, cervical intraepithelial neoplasia; DNA deoxyribonucleic acid; HPV, human
papillomavirus; SIL, squamous intraepithelial lesion. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract
Dis 2007;11:201–22. Reprinted from the Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP ©
American Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent
of ASCCP.
Figure 5. Management of women with low-grade squamous intraepithelial lesion (LSIL). Abbreviations: ASC indicates atypical squa-
mous cells; ASCCP, American Society for Colposcopy and Cervical Pathology; CIN, cervical intraepithelial neoplasia; HPV, human papil-
lomavirus. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the
Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical
Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP.
combined cytology plus HPV testing was discouraged. sional procedure, a single-visit strategy (see and treat) is
In the absence of CIN identified histologically, diagnos- attractive in women in whom future fertility is not an
tic excisional or ablative procedures are unacceptable for issue (Figure 6). This strategy has been shown to be fea-
the initial management of patients with LSIL. Follow-up sible and cost-effective (102–105). A diagnostic exci-
with either HPV testing at 12 months or cervical cytol- sional procedure also is recommended for women with
ogy at 6 months and 12 months (ASC-US threshold) is HSIL in whom the colposcopy examination is unsatis-
acceptable. If the HPV DNA test result is negative or if factory, except in pregnant women. Because of the limit-
two consecutive repeat cytology test results are negative, ed accuracy of colposcopy generally and of colposcopy
return to routine screening is recommended. If either the grading particularly, colposcopy assessment is no longer
HPV DNA test result is positive or if the result of repeat required before immediate LEEP. Nevertheless, pru-
cytology is reported as ASC-US or greater, colposcopy is dence would suggest that colposcopy is helpful to tailor
recommended (Figures 2, 4, and 5). the excision to the size of the lesion and the limits of the
transformation zone.
When the results of cervical cytology tests Some CIN 2,3 lesions will regress spontaneously,
are reported as HSIL, how should these be especially in adolescents and young adults (11, 106).
managed in the adult patient? Therefore, in younger women in whom future fertility is
an issue, colposcopy evaluation with endocervical
The mean reporting rate of HSIL in U.S. laboratories is assessment is more appropriate for initial evaluation (90,
0.7% (98). The rate of HSIL varies with age. A cytology 107, 108).
result of HSIL carries a high risk of significant cervical
disease. A single colposcopy examination identifies When the initial evaluation of an HSIL
CIN 2+ in 53–66% of women with HSIL, and CIN 2+ is cytology result is a diagnosis of CIN 1 or
diagnosed in 84–97% of women evaluated with LEEP less, how should this condition be managed
(96, 99, 100). Traditionally, the management of HSIL in the adult patient?
cytology results has relied on the colposcopy identifica-
tion of high-grade CIN, followed by treatment when An important consideration before treatment should be
lesions are found (101). This strategy has proved to be whether the high-grade cytology result is due to a vagi-
highly successful in reducing cervical cancer rates in nal lesion. Careful examination of the vagina using both
developed countries. Because colposcopy can miss a sig- 3–5% acetic acid and Lugol’s solution may reveal a
nificant number of CIN 2,3 lesions and most women high-grade vaginal lesion. In such a case, although the
with HSIL will eventually undergo a diagnostic exci- cervix has no lesion, the cytology result is correctly pos-
Figure 6. Management of women with high-grade squamous intraepithelial lesion (HSIL). Abbreviations: ASCCP indicates American
Society for Colposcopy and Cervical Pathology; CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial
lesion. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the Journal
of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical
Figure 7. Management of adolescent women (20 years and younger) with high-grade squamous intraepithelial lesion (HSIL).
Abbreviations: ASCCP indicates American Society for Colposcopy and Cerviccal Pathology; CIN, cervical intraepithelial neoplasia; HSIL,
high-grade squamous intraepithelial lesion. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis
2007;11:201–22. Reprinted from the Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American
Society for Colposcopy and Cervical Pathology 2007. No copies of the algorithms may be made without the prior consent of ASCCP.
itive, and the patient’s disease can be cleared with appro- moderate or severe dyskaryosis (HSIL) had CIN found
priate therapy. Application of Lugol’s solution to the during follow-up (109), whereas a Swedish study found
cervix also may identify high-grade lesions not previ- that 22% of women with an HSIL cytology result had
ously appreciated. However, the sensitivity of col- CIN during follow-up after negative colposcopy result
poscopy is limited, and these women may harbor an (110). Women with an HSIL cytology result remain at
unsuspected high-grade cervical lesion. A British study significant risk for high-grade CIN not evident on their
found that 44% of women with negative evaluations after colposcopy or biopsy. However, the predictive value of
an HSIL cytology result is limited, and some women that should be taken into consideration in applying this
with HSIL have CIN 1, subclinical HPV infections with- definition are the number of years since first intercourse
out colposcopically visible lesions, or even no disease. and the woman’s parity and desire for future fertility.
Finally, cytology interpretation is subjective, and women When the colposcopy results are satisfactory, the endo-
with HSIL diagnoses may not have HSIL. In a study of cervical sampling is negative and no lesion is identified,
the reproducibility of cervical cytology, 27% of women or when biopsies show either CIN 1 or no neoplasia,
with HSIL were found to have LSIL on review of their serial Pap testing and colposcopy at 6-month intervals
slides, whereas 23% had ASC-US, and 3% had negative for as long as 2 years are advised. If both Pap test results
results (45). Therefore, both the possibility of missed and colposcopy results are negative at two consecutive
disease and the potential for overtreatment must be con- visits, then routine annual assessment can resume.
sidered, and the management must be individualized Diagnostic excision is recommended when colposcopy
based on the patient’s needs. When CIN 2,3 is not iden- results are unsatisfactory or when endocervical sampling
tified histologically, either a diagnostic excisional proce- yields CIN, but this should be unusual in young women.
dure or observation with colposcopy and cytology at If during follow-up a high-grade colposcopy lesion is
6 months and 12 months is acceptable, provided in the identified or a HSIL cytology result persists for 1 year,
latter case that the colposcopy examination is satisfacto- biopsy is recommended. However, if HSIL cytology
ry and endocervical sampling is negative. A diagnostic result persists for 2 years, then a diagnostic excisional
excisional procedure is more appropriate in women not procedure is recommended. After two consecutive nega-
concerned about future fertility. However, because of the tive Pap test results, adolescents and young women with-
potential effect that treatment for cervical disease may out a high-grade colposcopy abnormality can return to
have on future fertility and the possibility that these routine screening.
women may not have CIN 2,3, and that some CIN 2,3
lesions spontaneously regress, especially in adolescents When the results of cervical cytology tests
and young adults (11, 106), the option of watchful wait- are reported as AGC or AIS, how should they
ing was added in the 2006 consensus guidelines. In this be managed?
circumstance it also is acceptable to review the cytology,
histology, and colposcopy findings; if the review yields a The results of AGC are relatively uncommon, with a
revised interpretation, management should follow con- mean reporting rate of only 0.4% in the United States in
sensus guidelines for the revised interpretation. If obser- 2003 (98). Although AGC is frequently caused by benign
vation with cytology and colposcopy is elected, a conditions, such as reactive changes and polyps, it is
diagnostic excisional procedure is recommended for sometimes associated with a significant underlying neo-
women with the results of HSIL on repeat cytology at plasia, such as adenocarcinoma of the cervix, endometri-
either the 6-month or 12-month visit. After 1 year of um, ovary, or a fallopian tube. The risk associated with
observation, women with two consecutive negative AGC is dramatically higher than that seen with ASC.
cytology results can return to routine screening. Ablation The risk associated with glandular abnormalities increas-
is unacceptable when CIN 2,3 is not identified histolog- es as the description in the Bethesda classification sys-
ically or the endocervical assessment identifies CIN of tem advances from AGC, not otherwise specified (NOS)
any grade (Figure 6). to AGC, favors neoplasia and, finally, AIS. Recent series
have reported that 9–38% of women with AGC have sig-
When the results of cervical cytology tests nificant neoplasia (CIN 2,3, AIS, or cancer) and 3–17%
are reported as HSIL in an adolescent have invasive cancer (111–113). The rate and type of sig-
nificant findings in women with AGC varies with age
(before age 21 years), how should they be
(112). Women younger than 35 years with AGC are more
managed?
likely to have CIN and less likely to have cancer, where-
Because the likelihood of cancer in adolescents is quite as in older women the risk of glandular lesions, including
small and the window of opportunity for identifying per- malignancies, is higher (111). Human papillomavirus
sistent high-grade cancer precursors is consequently testing, cervical cytology, and colposcopy are all subop-
longer, immediate excision is inappropriate, and col- timal at detecting glandular disease (114, 115). Colpos-
poscopy with biopsy of visible lesions is the recom- copy with endocervical sampling is recommended for all
mended initial management for all adolescents and women with all subcategories of AGC or AIS cytology
young women with HSIL cytology (Figure 7). In the results. In addition, endometrial sampling is recom-
2006 consensus guidelines, the definition of young mended in women 35 years and older or in women
women was left deliberately vague but among the factors younger than 35 years with clinical indications suggest-
ing a risk of neoplastic endometrial lesions (eg, unex- vides an intact specimen with interpretable margins (12).
plained vaginal bleeding, chronic anovulation, or atypi- In pregnant women, the initial evaluation of AGC should
cal endometrial cells). In the latter case, colposcopy can be identical to that of nonpregnant women, except that
be deferred until the results of the initial biopsies are endocervical curettage and endometrial biopsy are unac-
known. ceptable.
The 2006 consensus guidelines recommend HPV
DNA testing at the time of colposcopy in women with What is the significance of endometrial cells
atypical endocervical, endometrial, or glandular cells, found in cervical cytology?
NOS (Figure 8). Knowledge of the HPV status in these
women who do not have CIN 2,3 or glandular neoplasia In premenopausal women, benign-appearing endometrial
identified histologically will allow expedited triage. cells or the presence of endometrial stromal cells or histi-
Women with a positive HPV result would have their ocytes is rarely associated with significant pathology
cytology and HPV test repeated at 6 months, and those (116). However, approximately 0.5–1.8% of cervical
with a negative HPV result would receive repeat cytol- cytology specimens from women 40 years and older will
ogy at 12 months. Those with a positive HPV result or an have endometrial cells (116), and in postmenopausal
abnormal cytology result would be referred to col- women they may be associated with significant endome-
poscopy, and those in whom both tests are negative can trial pathology (117). Benign-appearing glandular cells
return to routine screening. In contrast, if the HPV status derived from small accessory ducts, foci of benign adeno-
is unknown, cervical cytology testing should be repeated sis, or prolapse of the fallopian tube into the vagina are
every 6 months until there are four consecutive negative sometimes seen in cytology specimens after total hys-
test results before the woman can return to routine terectomy and have no clinical significance.
screening (12). Because the risk of neoplasia (including For asymptomatic premenopausal women with
invasive cancer) is high in women with AGC, favors neo- benign endometrial cells, endometrial stromal cells, or
plasia, AIS, or repeat AGC and the sensitivity of avail- histiocytes, no further evaluation is recommended. For
able diagnostic tests is poor, diagnostic excisional postmenopausal women with benign endometrial cells,
procedures are recommended for these women. Human endometrial assessment is recommended regardless of
papillomavirus testing is not useful in managing these symptoms. For posthysterectomy patients with a cytol-
patients (Figure 9). It is recommended that the type of ogy report of benign glandular cells, no further evalua-
diagnostic excisional procedure used in this setting pro- tion is recommended.
Figure 8. Initial workup of women with atypical glandular cells (AGC). Abbreviation: HPV indicates human papillomavirus. Wright TC.
Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the Journal of Lower Genital
Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007. No
copies of the algorithms may be made without the prior consent of ASCCP.
Figure 9. Subsequent management of women with atypical glandular cells (AGC). Abbreviations: AGC indicates atypical glandular
cells; AGC-NOS, atypical glandular cells—not otherwise specified; AIS, adenocarcinoma in situ; ASC, atypical squamous cells; ASCCP,
American Society for Colposcopy and Cervical Pathology; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. Wright
TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the Journal of Lower
Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical Pathology 2007.
No copies of the algorithms may be made without the prior consent of ASCCP.
When should endocervical curettage be used If colposcopy is satisfactory and consistent

in the colposcopy examination? with the results of cervical cytology, is biopsy
necessary?
The value of routine endocervical curettage (ECC) is
controversial. Endocervical sampling is preferred for Colposcopy assessment may assist the examiner in iden-
nonpregnant women in whom no lesions are identified, tifying appropriate biopsy sites, but colposcopy assess-
women with an unsatisfactory colposcopy, and women ment is not sufficiently accurate to eliminate the need for
who have follow-up colposcopy after a conization for one or more biopsy procedures. A meta-analysis com-
CIN 2,3 with a positive endocervical margin. Endo- paring colposcopy impression to colposcopy biopsy
cervical curettage is preferred in cases where the results reported an average 48% sensitivity of colposcopy
are expected to change the patient’s management. impression for separation of CIN 2,3+ from other diag-
Endocervical curettage is especially valuable for women noses (120). Use of colposcopy impression alone could
40 years and older. An analysis of ALTS data showed have caused 18–60% of patients to be treated incorrect-
that ECC identified an additional 2.2% of CIN 2+ in ly. Recent data suggest that taking additional biopsy
women younger than 40 years, whereas it increased the specimens in other abnormal areas also may improve
detection by 13% in women 40 years and older (128). detection regardless of the colposcopist’s level of experi-
Endocervical curettage is recommended in women with ence (16). Biopsy of any visible lesion is an important
a glandular abnormality on cytology and those who component of a colposcopy examination, regardless of
have any abnormal cytology result or HPV test result colposcopy impression. The only exceptions are women
after cervical treatment. This procedure is unacceptable for whom a diagnostic excision is planned, and pregnant
in pregnant women. However, in nonpregnant women women without a colposcopically-diagnosed high-grade
with a satisfactory colposcopy result, a positive ECC lesion.
result is most likely due to contamination that incorrect-
Is excision or ablation the better treatment
ly indicates the need for a deeper excisional procedure
rather than an ablative procedure or a shallower exci-
for CIN?
sion. Endocervical curettage may be especially helpful Treatment modalities for CIN should be evaluated based
in such patients if ablative therapy is planned but may on their effectiveness and appropriateness in treating
not change the management if excisional therapy is CIN 2,3. The recommended management of CIN 1 is
planned (119). follow-up without treatment for at least 2 years during
which regression of many of the lesions is expected. avoiding treatment in favor of more conservative follow-
After 2 years, the patient may be treated, but continued up is related to the cost, discomfort, and potential mor-
follow-up is acceptable. Treatment options include bidity of commonly used treatment modalities. Recent
cryotherapy, laser ablation, laser conization, knife studies have shown a significant risk of premature deliv-
conization, and loop electrosurgical excision. Although ery and preterm premature rupture of membranes in
studies in general have been small and may have diffi- pregnant women previously treated with LEEP (3, 4,
culty in distinguishing subtle differences among treat- 115). This is especially significant in young women with
ments, various treatments appear to be similarly CIN 1, a group for whom future pregnancy complica-
efficacious in eradicating preinvasive disease (121–123). tions are a concern and a group very likely to have spon-
Selection of the appropriate treatment modality depends taneous regression (127). Conservative management
on the operator’s experience, equipment availability, allows adequate time to identify cases that might have
lesion size, and other factors. Alternatively, if the lesion been initially misclassified or to allow identification of
extends onto the vagina, laser ablation may be more those that would progress to higher-grade lesions where-
appropriate than other treatment because it can be tai- as the risk of developing cancer remains minimal.
lored to encompass the entire lesion with excellent depth Because the finding of CIN 1 on histology does not
control. When microinvasive cancer or AIS is suspected, affect the risk of CIN 2,3 among women with HPV-
then conization provides a histology specimen for positive ASC-US, ASC-H, or LSIL cytology results
assessment. (compared with those in whom no disease was found),
Ablative treatments (eg, cryotherapy or laser vapor- women 21 years and older with CIN 1 preceded by these
ization) should be used only after rigorously excluding cytology findings should be managed similarly with
invasive cancer. When endocervical assessment shows either HPV DNA testing every 12 months or repeat cer-
CIN, the colposcopy result is not satisfactory, cytology vical cytology at 6 months and 12 months. The decision
or colposcopy examination suggests cancer, or after to treat is unaffected by whether the colposcopy result is
prior therapy, cancer may be present but unseen and satisfactory, and treatment during the first 2 years of fol-
ablative therapy is not appropriate (119, 124). Laser and low-up is not recommended. Although persistence of
loop electrosurgical excision minimize blood loss by CIN 1 beyond 2 years is associated with a higher risk of
thermal cautery during excision but may cause thermal high-grade dysplasia and the likelihood of regression
artifact that impairs the interpretability of a specimen decreases the longer dysplasia persists, cancer can be
(125, 126). This may be clinically significant at a focus effectively prevented with continued follow-up, and
of possible microinvasion or AIS. In these cases, knife there are no data to preclude continued follow-up
conization may be preferable. beyond 2 years. Thus, it is safe to monitor these patients
with semi-annual cytology examinations or annual HPV
How should CIN 1 be managed in women DNA testing with colposcopy for women with positive
who present with HPV-positive ASC-US, high-risk HPV DNA testing or cytology of ASC-US or
ASC-H, or LSIL results? greater. If CIN 1 has not resolved after 2 years, treat-
ment is acceptable with excision or ablation if the col-
Most CIN 1 in ALTS regressed spontaneously and poscopy result remains satisfactory (13).
CIN 1 uncommonly progressed to CIN 2,3 (9). In ALTS, If the decision has been made to treat the patient
many of the CIN 2,3 lesions subsequently identified in and the colposcopy result is unsatisfactory, the endocer-
women diagnosed with CIN 1 appeared to represent
vical sampling contains CIN, or the patient has been
lesions that were missed during the initial colposcopy
previously treated, ablative procedures are unacceptable
evaluation (9). The management of women with LSIL is
and a diagnostic excisional procedure is recommended.
dependent on their risk of CIN 2,3 and cancer that is in
The management of adolescents with CIN 1 is the
turn related to their presenting cytology. Among women
same as that of adolescents with LSIL. The recommend-
enrolled in ALTS who presented with LSIL or HPV-
ed management of histologically diagnosed CIN 1 in
positive ASC-US on cytology and were found to have
pregnant women is follow-up without treatment.
CIN 1 on initial colposcopy, 13% were subsequently
Treatment of pregnant women for CIN 1 is unacceptable.
found to have CIN 2,3 (8.9% CIN 3) and none had can-
cer during the 24-month follow-up period. This rate of How should CIN 1 be managed in women
CIN 2,3 on follow-up was similar to women whose col-
who presented with HSIL or AGC-NOS?
poscopy results were completely negative and who had
no biopsy (11.3%), and those whose biopsy specimens Either a diagnostic excisional procedure or observation
were negative for CIN (11.7%) (9). The rationale for with colposcopy and cytology at 6-month intervals for 1
year is acceptable for women 21 years or older with a his- States has been to consider CIN 2 the threshold for treat-
tology diagnosis of CIN 1 preceded by an HSIL or AGC- ment for most U.S. women.
NOS cytology result, provided in the latter case that the However, there are exceptions. The risk of progres-
colposcopy examination is satisfactory and endocervical sion to invasive cancer is low before age 21 years, and
sampling is negative. A diagnostic excisional procedure is some CIN 2,3 lesions regress, especially in younger
recommended for women with CIN 1 preceded by an women. For this reason, observation of adolescents and
HSIL or AGC-NOS cytology result in whom the colpos- young women appears to be a safe and reasonable
copy examination is unsatisfactory, except in pregnancy. approach, provided cancer has been ruled out. When a his-
The risk of an undetected CIN 2,3 or an adenocarci- tology diagnosis of CIN 2 is specified, observation is pre-
noma in situ lesion is expected to be greater in women ferred. One study found unsuspected cancerous lesions in
with CIN 1 preceded by an HSIL or AGC cytology result 8% of women undergoing hysterectomy for CIN 2,3,
than in women with CIN 1 preceded by an ASC or LSIL which suggests that prior conization is mandatory to
cytology result. Cervical intraepithelial neoplasia grade exclude malignancy (129). For these reasons, hysterec-
2,3 is identified in 84–97% of women with HSIL cytology tomy is unacceptable as the primary therapy for CIN 2,3.
results evaluated with a LEEP (96, 99, 100). Therefore,
separate recommendations are made for women with CIN 1 Does management of CIN 2 or CIN 3 differ
preceded by an HSIL or AGC cytology result. for women who are HIV positive?
How should CIN 2 and CIN 3 be managed? Standard ablative or excisional treatment is recommend-
ed for women who are HIV positive with documented
Cervical intraepithelial neoplasia grade 3 generally is CIN 2 or CIN 3, regardless of HIV viral load. Effective
considered to be a cancer precursor, although not all treatment of CIN requires immunologic clearance or
CIN 3 lesions will progress to cancer. The prevalence of suppression of HPV to avoid recurrence (130). Women
CIN 3 peaks between ages 25 years and 30 years, and who are HIV positive have difficulty clearing HPV and,
progression to cancer usually takes at least a decade therefore, are at increased risk of recurrent disease in
longer (90). The risk of progression of CIN 3 is unclear direct relation to their level of immunosuppression
because most experts consider the risk too high to justi- (131–134). Treatment of CIN should be pursued despite
fy observation. A biopsy diagnosis of CIN 3 may miss high recurrence rates (greater than 50% recurrence rate
occult invasive cancer and apparent progression after a after standard treatment) because it can effectively inter-
colposcopy biopsy diagnosis may reflect missed preva- rupt progression to invasive cancer (131, 135–138).
lent cancer. One review found that the likelihood of CIN Women who are HIV positive also appear more likely to
3 progressing to invasion was 12%, with 33% of patients have positive surgical margins, which may contribute to
regressing and the remainder having stable disease (10). increased recurrence rates (139). Because recent studies
Smaller lesions with fewer colposcopy features are more reported a lower prevalence of high-grade disease and
likely to regress, whereas larger lesions with coarse vas- HPV DNA positivity among immunosuppressed women,
cular changes are less likely to regress (128). Cervical the 2006 consensus guidelines recommend that the man-
intraepithelial neoplasia grade 2,3 lesions associated agement of these conditions be similar to that in the gen-
with HPV 16 genotype are less likely to regress, as are eral population (140–142).
those in women with the HLA 201 phenotype (107). The The role of highly active antiretroviral therapy in the
significance of CIN 2 is unclear. The risk of progression management of precancerous cervical lesions remains
to CIN 3 and cancer appears greater for women with unclear (143). Therefore, CIN 2 and CIN 3 should be
CIN 2 than for women with CIN 1. However, many treated similarly in women who are HIV positive regard-
women with CIN 2 will have regression of their lesions less of their use of antiretroviral therapy.
without therapy. In one review, CIN 2 progressed to can-
cer in 5% of patients and to CIN 3 in 20% of patients, How should AIS be managed? How should
persisted in 40% of patients, and regressed in 40% of patients with AIS be monitored after
patients (10). No accepted tests are available to distin- treatment?
guish CIN 2 that reflects an exuberant HPV infection
from that with true malignant potential. The cutoff Although the overall incidence of AIS is increasing, it
between CIN 1 and CIN 2 and between CIN 2 and CIN remains relatively rare compared with CIN 2,3 (144). In
3 is arbitrary. Because of the moderate cancer risk asso- 1991–1995, the overall incidence of squamous carcino-
ciated with CIN 2, the decision among leaders in col- ma in situ of the cervix among white women in the
poscopy and cervical cancer prevention in the United United States was 41.4 per 100,000, whereas the inci-
dence of AIS was only 1.25 per 100,000 (144). Because How should a patient’s condition be moni-
cytology screening and colposcopy detection of AIS are tored after treatment for CIN?
so challenging and the clinical behavior of AIS is so dif-
ferent from CIN 2,3, the principles involved in the man- Observation after treatment requires long-term surveil-
agement of AIS differ from what is the norm for lance. Although most recurrent or persistent CIN is
squamous disease. The colposcopy changes associated found within the first 1–5 years, cases of cancer have
with AIS can be minimal or unfamiliar to most colpo- been found as late as 20 years after initial therapy (151,
scopists. Adenocarcinoma in situ frequently is multifo- 152). In one large study of women monitored after treat-
cal, may have “skip lesions,” and frequently extends for ment for CIN 3, the sensitivity of cytology in identify-
a considerable distance into the endocervical canal, making recurrent or persistent CIN was only 64%, whereas
ing complete excision difficult. Thus, negative margins adding colposcopy improved the sensitivity to 91% but
on a diagnostic excisional specimen do not necessarily reduced specificity from 95% to 88% (153). The sensi-
tivity of cytology improves with repeated testing, and
mean that the lesion has been completely excised.
whereas few women with CIN 2,3 present soon after
Hysterectomy continues to be the treatment of
treatment with invasive cancer, usually there is time for
choice for AIS in women who have completed child-
serial cytology assessment 6 months and 12 months
bearing. However, an excisional procedure is still cura-
after the treatment because the risk for persistence and
tive in most of these patients. A comprehensive review of
recurrence is highest during the first year. The outcomes
the published literature conducted in 2001 identified 16
of treatment of recurrent or persistent disease are unaf-
studies that included a total of 296 women with AIS who
fected by a short delay in diagnosis as long as persistent
were treated with a diagnostic excisional procedure
disease is identified and eradicated before invasion
(145). The overall failure rate was 8% (145). Margin
occurs. Human papillomavirus testing alone is highly
status and endocervical sampling at the time of an exci- sensitive, and a single test at 1 year will detect most
sional biopsy are clinically useful predictors of residual recurrences. A combination of HPV testing and cytol-
disease (146–149). Excisional biopsy is required in all ogy was only marginally more sensitive but was the
women with AIS before making any subsequent man- least specific and most costly program for identifying
agement decisions. Conservative management is accept- persistent or recurrent CIN (154). Colposcopy with
able if future fertility is desired. If conservative endocervical sampling is indicated with cytology results
management is planned and the margins of the specimen of ASC-US or greater or a positive HPV test result. If
are involved or endocervical sampling obtained at the the HPV DNA test result is negative or if two consecu-
time of excision contains CIN or AIS, re-excision to tive repeat cytology tests yield negative results, routine
increase the likelihood of complete excision is preferred. screening commencing at 12 months is recommended
These women should be reevaluated at 6 months using a for at least 20 years.
combination of cervical cytology, HPV DNA testing,
and colposcopy with endocervical sampling. Long-term If LEEP or cone biopsy reveals a positive
follow-up after treatment is recommended for all women margin, how should management proceed?
with AIS.
Most women with positive margins do not have residual
How should inconclusive colposcopic biopsy disease, so although repeat conization to prevent recur-
results for early invasive cancer be managed? rence is acceptable, it usually is not necessary.
Observation without retreatment using cytology with
Colposcopic biopsy results that are inconclusive for can- endocervical sampling at 4–6 months after treatment is
cer should be followed by excision to define whether preferred in these women. Women with CIN 2,3 involv-
cancer is present and to permit treatment planning. The ing the excision margins of a conization specimen and
management of early invasive cervical cancer depends those with CIN 2,3 at a postprocedure endocervical
on the depth of invasion and the presence or absence of sampling are at increased risk for persistence of disease
lymph and vascular space invasion. Biopsy alone does compared with those with clear margins (155–160). One
not adequately provide this information. Cold-knife center reporting on 5,386 women after conization for
conization is preferred for this purpose because it main- CIN 3 (two studies combined) found recurrence in 0.4%
tains tissue orientation in a single specimen, which is of women with clear margins and in 22% of women
essential to permit pathologic evaluation of depth of with involved margins, with cancerous lesions in 7% of
invasion and other variables that define stage and treat- recurrences (161, 162). In a meta-analysis of studies
ment (150). Loop and laser excisions are acceptable in describing more than 35,000 women after an excision,
experienced hands. the relative risk of CIN 2,3 after incomplete excision
compared with complete excision was 6.09 (163). A pos- How do care and follow-up differ for women
itive excision margin is a convenient marker for recur- during pregnancy?
rence, especially when the endocervical margin is
involved. However, multiple studies have shown that In pregnancy, the only diagnosis that may alter manage-
margin involvement by CIN is not an independent mark- ment is invasive cancer. The presence of cancer may
er for recurrence or persistence (155–157). Risk factors change treatment goals or change the route and timing of
for recurrence or persistence of CIN include older age, delivery. Therefore, colposcopy examination during
larger lesions, and higher-grade disease, with risks as pregnancy should have as its primary goal the exclusion
high as 50% for older women with large CIN 3 lesions. of invasive cancer.
Repeat diagnostic excisional procedures should be Management of LSIL and HPV-positive ASC-US
discouraged in adolescents because of the potential results during pregnancy should be the same as in the
effect on future fertility. A hysterectomy for this indica- nonpregnant state, although the evaluation of these con-
tion is unacceptable in this population. ditions may be deferred until after delivery (Figure 10).
If colposcopy is performed for LSIL during pregnancy,
When is hysterectomy appropriate in women additional colposcopy examinations are not indicated.
with CIN 2,3+? The practice of repeating the colposcopy once per
Hysterectomy in the absence of other indications, such trimester in pregnant women with LSIL is unacceptable
as abnormal bleeding or uterine leiomyomas, usually is unless CIN 2,3 is diagnosed. During pregnancy, limiting
not required. However, one indication is in a patient with biopsy to lesions suspicious for CIN 2,3 or cancer is pre-
recurrent disease when the residual cervix is too small to ferred, but biopsy of any lesion is acceptable. Biopsy
allow safe repeat conization without risk of bladder and during pregnancy has not been linked to fetal loss or
vaginal injury. A repeat diagnostic excision or hysterec- preterm delivery, whereas failure to perform biopsy dur-
tomy is acceptable for women with a histology diagno- ing pregnancy has been linked to missed invasive cancer
sis of recurrent or persistent CIN 2,3. If excision is (164–166). Pregnant adolescents should be treated in the
indicated, it should be performed (where possible) same manner as nonpregnant adolescents.
before hysterectomy to rule out invasive cancer. If hys- All women with HSIL should undergo colposcopy,
terectomy is performed, the choice of either vaginal or including those who are pregnant. The goal of cytology
abdominal approach should be dictated by other indica- and colposcopy during pregnancy is to identify invasive
tions, such as the surgeon’s experience and patient char- cancer that requires treatment before or at the time of
acteristics and preferences. delivery. However, unless cancer is identified or suspected,
Figure 10. Management of pregnant women with low-grade squamous intraepithelial lesion (LSIL). Abbreviations: ASCCP indicates
American Society for Colposcopy and Cervical Pathology; CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraep-
ithelial lesion. Wright TC. Management of cervical cytologic abnormalities. J Low Genit Tract Dis 2007;11:201–22. Reprinted from the
Journal of Lower Genital Tract Disease Vol. 11 Issue 4, with the permission of ASCCP © American Society for Colposcopy and Cervical
treatment of CIN is contraindicated during pregnancy. Colposcopy is recommended in premenopausal
Cervical intraepithelial neoplasia has no effect on the women 21 years and older with ASC-US who are
woman or fetus, whereas cervical treatments designed to HPV positive, those with two consecutive ASC-US
eradicate CIN can result in fetal loss, preterm delivery, cytology results or with LSIL, or women of any age
and maternal hemorrhage. Endocervical curettage may with ASC-H.
result in laceration of the soft cervix with consequent
hemorrhage and it also may rupture the amniotic mem- For premenopausal women 21 years and older with
branes. Endocervical curettage is contraindicated during an HPV-positive ASC-US, or ASC-H or LSIL cytol-
pregnancy. Colposcopy during pregnancy is challenging ogy result in whom CIN 2,3 is not identified, fol-
because of cervical hyperemia, the development of low-up without treatment is recommended using
prominent normal epithelial changes that mimic preinva- either repeat cervical cytology tests at 6 months and
sive disease colposcopically, obscuring mucus, contact 12 months or an HPV test at 12 month-intervals; a
bleeding, prolapsing vaginal walls, and bleeding after repeat colposcopy is indicated for a cytology result
biopsy (167). Biopsy is important if the colposcopy of ASC-US or higher-grade abnormality or a posi-
impression is high grade, especially in older pregnant tive high-risk HPV test result. After two consecu-
women at higher risk of invasive cancer. Once cancer has tive negative cytology results or one negative HPV
been excluded, cervical therapy can be deferred until result women can return to routine screening.
postpartum. Cervical intraepithelial neoplasia may In women 21 years and older with HSIL cytology
regress during the interval between antenatal cytology results, immediate loop electrosurgical excision or
and a postpartum examination. In women with biopsy- colposcopy with endocervical assessment are both
proven CIN 2 during pregnancy, the risk of microinva- acceptable management options. In adolescents and
sive cancer at the postpartum visit is negligible, whereas pregnant women with HSIL cytology results, col-
the risk after CIN 3 is substantially less than 10%, and poscopy is recommended. Immediate excision is not
deeply invasive cancers are rare (168, 169). For this rea- acceptable in adolescents and pregnant women. A
son, re-evaluation during pregnancy may prompt need- diagnostic excisional procedure is recommended for
less intervention that may jeopardize current and future all nonpregnant women with HSIL when col-
pregnancies. Reassessment with cytology and colposcopy is unsatisfactory or when CIN of any grade
poscopy no sooner than 6 weeks after delivery is impor- is identified on endocervical assessment.
tant in tailoring therapy.
Cervical intraepithelial neoplasia 2,3 rarely pro- Posttreatment management options for women
gresses to invasive cancer during the few months of preg- 21 years and older who have CIN 2,3 include a sin-
nancy. For these reasons, observation of pregnant women gle HPV DNA test at 6–12 months, cytology alone
appears a safe and reasonable approach, provided cancer at 6-month intervals or a combination of cytology
has been ruled out. and colposcopy at 6-month intervals. For adoles-
cents who have undergone treatment, cytology fol-
low-up is preferred. Colposcopy with endocervical
Summary of sampling is recommended for women who are
HPV DNA positive or have a result of ASC-US or
Recommendations greater on repeat cytology. If the HPV DNA test is
The following recommendations are based on negative or if two consecutive repeat cytology test
good and consistent scientific evidence (Level A): results are negative, routine screening commencing
at 12 months is recommended for at least 20 years.
Premenopausal women 21 years and older with
ASC-US cytology results may undergo immediate The following recommendations are based on lim-
colposcopy or may undergo triage testing to deter- ited and inconsistent scientific evidence (Level B):
mine which of them should be referred to col-
poscopy. Triage testing may be performed by a Women 21 years or older with ASC-US who test
single test for high-risk (oncogenic) types of HPV negative for HPV, or whose HPV status is unknown
or by repeat cytology screening at 6 months and 12 and who test negative for abnormalities using col-
months. When the index cytology test specimen was poscopy, should have a repeat cytology test in 1
obtained by liquid-based cytology or when an HPV year. Women with ASC-US who have two negative
specimen was co-collected, “reflex” HPV testing is results on repeat cytology at 6-month intervals can
the preferred approach. return to routine screening.
In adolescents (before age 21 years) with ASC-US ing a repeat diagnostic excisional procedure is
or LSIL cytology results, or CIN 1 histology results acceptable, as is a hysterectomy if a repeat diagnos-
preceded by ASC-US or LSIL or AGC-NOS cytol- tic procedure is not feasible and for women with a
ogy results, follow-up is recommended at 12-month histology diagnosis of recurrent or persistent CIN
intervals. At the first follow-up visit (at 12 months), 2,3.
only adolescents with HSIL or greater on the repeat In nonpregnant women 21 years and older, both
cytology should be referred to colposcopy. At the excision and ablation are acceptable treatment
24-month follow-up, those with an ASC-US or modalities in the presence of histology diagnoses of
greater result should be referred to colposcopy. CIN 2,3 and satisfactory colposcopy results.
Human papillomavirus DNA testing is unacceptable Ablation is unacceptable when colposcopy has not
for adolescents. If HPV testing is inadvertently per- been performed, the endocervical sampling is posi-
formed, a positive result should not influence man- tive for any grade of CIN, the colposcopy result is
agement. unsatisfactory, or a woman has recurrent CIN 2,3.
In nonpregnant women with ASC and LSIL cytol- Colposcopy with endocervical sampling is recom-
ogy results who are undergoing colposcopy, endo- mended and HPV DNA testing is preferred for
cervical sampling using a brush or curette is women with all subcategories of AGC and AIS. In
preferred for women in whom no lesions are identi- addition, endometrial sampling is recommended in
fied and those with an unsatisfactory colposcopy women 35 years and older and in women younger
results. Endocervical sampling is acceptable for than 35 years with clinical indications suggesting
women with satisfactory colposcopy results and a they may be at risk of neoplastic endometrial lesions
lesion identified in the transformation zone. Endo- (eg, unexplained vaginal bleeding, chronic anovula-
cervical assessment either with colposcopy or by tion, or atypical endometrial cells). Colposcopy can
sampling is recommended for all nonpregnant be performed either at the initial evaluation or after
women with HSIL cytology results. Endocervical the results are known. If no endometrial pathology
curettage is unacceptable in pregnant women. is identified, colposcopy is recommended.
The recommended management of pregnant women Endometrial and endocervical sampling are unac-
with a histology diagnosis of CIN 1 is follow-up ceptable in pregnant women.
without treatment. Treatment of pregnant women Women 21 years and older with either atypical
for CIN 1 is unacceptable. endocervical, endometrial, or glandular cells NOS
In a woman 21 years and older with CIN 1 that has who do not have CIN or glandular neoplasia identi-
persisted for at least 2 years, either continued fol- fied histologically should receive repeat cytology
low-up or treatment is acceptable. If treatment is testing combined with HPV DNA testing at 6
selected and the colposcopy result is satisfactory, months if they are HPV DNA positive and at 12
either excision or ablation is acceptable. If treatment months if they are HPV DNA negative. Referral to
is selected and the colposcopy examination is unsat- colposcopy is recommended for women who subse-
isfactory, the ECC is positive, or the woman has quently test positive for high-risk HPV DNA or who
been previously treated, excision is recommended are found to have ASC-US or greater on their repeat
and ablative procedures are unacceptable. cytology tests. If both tests are negative, women can
return to routine cytology testing.
Pregnant women with biopsy-proven CIN 2 or CIN
3 in whom there is no suspicion of invasive cancer Women with AGC, favors neoplasia or AIS cytology
may postpone re-evaluation with cytology and col- results should undergo a diagnostic excisional pro-
poscopy to no sooner than 6 weeks postpartum. cedure unless invasive disease is identified during
Treatment during pregnancy is unacceptable unless the initial colposcopy workup. The diagnostic exci-
invasion is suspected. When invasion is suspected, a sional procedure used in this setting should provide
diagnostic excisional procedure is recommended. an intact specimen with interpretable margins.
Concomitant endocervical sampling is preferred,
For women 21 years and older, the preferred man- except in pregnant women.
agement of CIN 2,3 identified at the margins of a
diagnostic excisional procedure or in an endocervi- Hysterectomy is unacceptable as the primary therapy
cal sample obtained at the end of the procedure is for CIN.
reassessment using cytology with endocervical sam- Diagnostic ablation or excision is unacceptable as
pling at 4–6 months following treatment. Perform- the initial management for ASC or LSIL.
The following recommendations are based prima- colposcopy findings and management of the patient
rily on consensus and expert opinion (Level C): according to the revised interpretation; or if the col-
poscopy is satisfactory and endocervical sampling
In nonpregnant women 21 years and older with HSIL is negative, observation with colposcopy and cytol-
in whom CIN 2,3 has not been identified, three man- ogy at 6-month intervals for 1 year. A diagnostic
agement options are acceptable: diagnostic excisional excisional procedure is recommended for women
procedure; review of the cytology, histology, and col- with repeat HSIL cytology results at either the 6-
poscopy findings and management of the patient month or 12-month visit. Women with two consec-
according to the revised interpretation; or if the col- utive negative cytology results can return to routine
poscopy is satisfactory and endocervical sampling is cytology screening.
negative, observation with colposcopy and cytology at
In women 21 years and older with atypical endo-
6 month-intervals for 1 year. A diagnostic excisional
cervical, endometrial, or glandular cells NOS, HPV
procedure is recommended for women with repeat
DNA testing is preferred at the time of colposcopy
HSIL cytology results at either the 6-month or 12-
(if not already performed). For women of unknown
month visit. Women with two consecutive negative
HPV status who do not have CIN or glandular neo-
cytology results can return to routine screening.
plasia identified histologically, the recommended
In adolescents (before age 21 years) with HSIL postcolposcopy management is to repeat cytology
cytology results, a satisfactory colposcopy result, testing at 6-month intervals. After four consecutive
negative endocervical sampling, and no CIN 2,3 negative cytology results, women can return to rou-
identified on colposcopy biopsy, follow-up is rec- tine cytology testing.
ommended at 6-month intervals with Pap testing
Women with a cervical biopsy diagnosis of AIS
and colposcopy for up to 24 months. If during fol-
should undergo excision to exclude invasive cancer.
low-up a high grade colposcopy lesion is identified
A conization technique that preserves specimen ori-
or HSIL cytology results persist for 1 year, biopsy is
entation and permits optimal interpretation of his-
recommended. If HSIL persists for 24 months with-
tology and margin status is recommended. After
out identification of CIN 2,3, or if the colposcopy
conization, hysterectomy is preferred for women
result is unsatisfactory, a diagnostic excisional pro-
who have completed childbearing. Conservative
cedure is recommended. After two consecutive neg-
management is acceptable if the margins of the spec-
ative cytology results, women can return to routine
imen and the postprocedure endocervical curettage
cytology testing.
results are negative and future fertility is desired. If
For adolescents and young women with a histology conservative management is planned and the margins
diagnosis of CIN 2,3 NOS and a satisfactory col- of the specimen are involved or the postprocedure
poscopy result either treatment or observation for up endocervical curettage specimen contains CIN or
to 24 months using both colposcopy and cytology at AIS, re-excision is preferred. Reevaluation at 6
6-month intervals is acceptable. When a histology months using a combination of cervical cytology,
diagnosis of CIN 2 is specified, observation is pre- HPV DNA testing, and colposcopy with endocervi-
ferred. When a histology diagnosis of CIN 3 is spec- cal sampling is acceptable in this circumstance.
ified or when the colposcopy result is unsatisfactory, Long-term follow-up after treatment is recommend-
treatment is recommended. If the colposcopy ed for all women with AIS.
appearance of the lesion worsens or if an HSIL
cytology result or a high-grade colposcopy lesion
persists for 1 year, repeat biopsy is recommended. References
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lished between January 1995 and November 2007. The
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cians and Gynecologists were reviewed, and additional
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L, Navrozoglou I, Zikopoulos K, et al. Management and fied articles. When reliable research was not available,
evolution of cervical intraepithelial neoplasia during expert opinions from obstetrician–gynecologists were used.
pregnancy and postpartum. Eur J Obstet Gynecol Reprod
Biol 2002;104:67–9. (Level III) Studies were reviewed and evaluated for quality according
to the method outlined by the U.S. Preventive Services
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cervix during pregnancy and the puerperium. J Obstet
Gynaecol Br Commonw 1966;73:575–85. (Level III) I Evidence obtained from at least one properly
designed randomized controlled trial.
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Schnadig VJ. Management of cervical intraepithelial trials without randomization.
neoplasia during pregnancy: a simplified and cost-effec- II-2 Evidence obtained from well-designed cohort or
tive approach. J Low Genit Tract Dis 1998;2:67–70. case–control analytic studies, preferably from more
(Level III) than one center or research group.
169. Boardman LA, Goldman DL, Cooper AS, Heber WW, II-3 Evidence obtained from multiple time series with or
Weitzen S. CIN in pregnancy: antepartum and postpar- without the intervention. Dramatic results in uncon-
tum cytology and histology. J Reprod Med 2005;50: trolled experiments also could be regarded as this
13–8. (Level II-3) type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to the
following categories:
Level A—Recommendations are based on good and con-
sistent scientific evidence.
Level B—Recommendations are based on limited or incon-
sistent scientific evidence.
Level C—Recommendations are based primarily on con-
sensus and expert opinion.
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Management of abnormal cervical cytology and histology. ACOG
Practice Bulletin No. 99. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2008;112:1419–44.

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When should endocervical curettage be used If colposcopy is satisfactory and consistent

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