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Reviews Oncology www.AJOG.

org

2006 consensus guidelines for the management of women


with abnormal cervical cancer screening tests
Thomas C. Wright Jr, MD; L. Stewart Massad, MD; Charles J. Dunton, MD; Mark Spitzer, MD; Edward J. Wilkinson, MD;
Diane Solomon, MD, for the 2006 American Society for Colposcopy and Cervical Pathology–sponsored Consensus Conference

S ince the publication of the 2001 con-


sensus guidelines, new information
has become available, which includes the
A group of 146 experts representing 29 organizations and professional societies met
September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based,
key follow-up results from the National consensus guidelines for managing women with abnormal cervical cancer screening
Cancer Institute (NCI)–sponsored tests. Recommendations for managing atypical squamous cells of undetermined
ASCUS (atypical squamous cells of un- significance and low-grade squamous intraepithelial lesion (LSIL) are essentially
determined significance)/LSIL (low- unchanged. Changes were made for managing these conditions in adolescents for
grade squamous intraepithelial lesions) whom cytological follow-up for 2 years was approved. Recommendations for man-
Triage Study (ALTS).1,2 Moreover, mo- aging high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells
lecular testing for high-risk types of hu- (AGC) also underwent only minor modifications. More emphasis is placed on
man papillomavirus (HPV) is being used immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing
together with cervical cytology for is incorporated into the management of AGC after their initial evaluation with
screening in women 30 years of age and colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as
older. Although “interim guidance” for an adjunct to cervical cytology for screening in women 30 years of age and older was
the use of HPV DNA testing in the formally adopted with only very minor modifications.
screening setting was proposed in 2004,
Key words: atypical squamous cells of undetermined significance, cervical cancer
recommendations for how to manage
screening, cervical cytology, high-grade squamous intraepithelial lesion, human
the combination of test results have not
papillomavirus testing, low-grade squamous intraepithelial lesion
formally been evaluated by a large, mul-

From the Department of Pathology, College tidisciplinary group.3 Once the 2001 G UIDELINE D EVELOPMENT
of Physicians and Surgeons of Columbia guidelines were implemented in a variety P ROCESS
University, New York, NY (Dr Wright); of clinical settings, it became apparent The process used to develop the 2006
Department of Obstetrics and Gynecology, that there were a number of areas in Consensus Guidelines was similar to that
Washington University School of Medicine, which changes were needed. This per-
St Louis, MO (Dr Massad); Department of
for the previous guidelines and is dis-
tains particularly to special populations cussed in depth in other publications.4,5
Obstetrics and Gynecology, Lankenau
such as adolescents and postmenopausal Guidelines were developed through a
Hospital, Wynnewood, PA (Dr Dunton);
Department of Obstetrics and Gynecology, women. Therefore, in 2005, the Ameri- multistep process. Working groups re-
Brookdale University Hospital and Medical can Society for Colposcopy and Cervical viewed literature published after 2000
Center, Brooklyn, NY (Dr Spitzer); Pathology (ASCCP), together with its before developing guidelines that were
Department of Pathology, University of partner professional societies and federal
subsequently revised based on input
Florida College of Medicine, Gainesville, FL and international organizations (listed
from the professional community at
(Dr Wilkinson); and National Institutes of in Appendix A), began the process of re-
Health and National Cancer Institute, large, obtained using an Internet-based
vising the guidelines. This culminated in
Bethesda, MD (Dr Solomon). bulletin board. At the consensus confer-
the 2006 consensus conference that was
Received Apr. 6, 2007; revised Jun. 28, 2007; ence, guidelines with supporting evi-
held at the National Institutes of Health
accepted Jul. 29, 2007. in September 2006. This report provides dence were presented and underwent
Reprints: Thomas C. Wright Jr, MD, the recommendations developed with discussion, revision, and approval. The
Department of Pathology, College of
respect to managing women with cyto- terminology utilized in the new guide-
Physicians and Surgeons of Columbia lines is identical to that used previously,
University, Room 16-404, P&S Building, 630 logical abnormalities. Recommenda-
West 168th St, New York, NY 10032; tions for managing women with cervical as is the 2-part rating system (Table).4,5
tcw1@columbia.edu intraepithelial neoplasia (CIN) or ade- The terms “recommended,” “preferred,”
0002-9378/$32.00 nocarcinoma in situ (AIS) appear in the “acceptable,” and “unacceptable” are
© 2007 Mosby, Inc. All rights reserved. accompanying article. A more compre- used in the guidelines to describe various
doi: 10.1016/j.ajog.2007.07.047 interventions. The letters A through E
hensive discussion of the recommenda-
tions and their supporting evidence will are used to indicate strength of recom-
See related editorial, page 337, be made available on the ASCCP website mendation for or against the use of a par-
and related article, page 340. (www.asccp.org). ticular option. Roman numerals I-III are

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www.AJOG.org Oncology Reviews

TABLE
Rating the recommendations
Strength of Recommendation*
................................................................................................................................................................................................................................................................................................................................................................................
A Good evidence for efficacy and substantial clinical benefit support recommendation for use.
B Moderate evidence for efficacy or only limited clinical benefit supports recommendation for use.
C Evidence for efficacy is insufficient to support a recommendation for or against use, but recommendations may be made on other
grounds.
D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use.
E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use.
................................................................................................................................................................................................................................................................................................................................................................................
Quality of Evidence*
................................................................................................................................................................................................................................................................................................................................................................................
I Evidence from at least 1 randomized, controlled trial.
II Evidence from at least 1 clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than
1 center) or from multiple time-series studies or dramatic results from uncontrolled experiments.
III Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
................................................................................................................................................................................................................................................................................................................................................................................

Terminology used for recommendations
................................................................................................................................................................................................................................................................................................................................................................................
Recommended Good data to support use when only 1 option is available.
Preferred Option is the best (or 1 of the best) when there are multiple other options
Acceptable One of multiple options when there are either data indicating that another approach is superior or when there are no
data to favor any single option.
Unacceptable Good data against use.
................................................................................................................................................................................................................................................................................................................................................................................
* Modified from references.80,81

The assignment of these terms represents an opinion ratified by vote by the Consensus Conference.

used to indicate the “quality of evidence” system that applies the terms CIN 1 to Drug Administration (FDA) approval
for a given recommendation. The low-grade lesions and CIN 2,3 to high- and/or publication in peer-reviewed sci-
“strength of recommendation” and grade precursors. It is important to note entific literature. It is also important to
“quality of evidence” are provided in pa- that cytologic LSIL is not equivalent to stress that testing should be restricted to
rentheses after each recommendation. histologic CIN 1 and cytologic HSIL is high-risk (oncogenic) HPV types.7,8
not equivalent to histologic CIN 2,3. Al- Testing for low-risk (nononcogenic)
2006 C ONSENSUS G UIDELINES gorithms detailing the different manage- HPV types has no role in the evaluation
General comments ment recommendations are available at of women with abnormal cervical cyto-
Although the guidelines are based on ev- the ASCCP website (www.asccp.org). A logical results. Therefore, whenever
idence whenever possible, for certain glossary of terms used in the guidelines is “HPV testing” is referred to in the guide-
clinical situations, there is limited high- in Appendix B. lines, it applies only to testing for high-
quality evidence, and in these situations The current guidelines expand clinical risk (oncogenic) HPV types.
the guidelines have, by necessity, been indications for HPV testing based on
based on consensus expert opinion. It is studies using validated HPV assays. One Special populations
also important to recognize that these cannot assume that management deci- The exact same cytologic result has a dif-
guidelines should never substitute for sions that are based on results of HPV ferent risk of CIN 2,3 or cancer (CIN
clinical judgment. Clinical judgment tests that have not been similarly vali- 2⫹) in various groups of women. One
should always be used when applying a dated will result in the outcomes that are such special population is adolescent
guideline to an individual patient be- intended by these guidelines. Further- women (aged 20 years and younger) who
cause it is impossible to develop guide- more, the application of these guidelines have a high prevalence of HPV infec-
lines that apply to all situations. using such tests may increase the poten- tions, more minor-grade cytologic ab-
The 2001 Bethesda System terminol- tial for patient harm. The appropriate normalities (atypical squamous cells
ogy is used for cytologic classification.6 use of these guidelines requires that lab- [ASC] and LSIL) but very low risk for
This terminology utilizes the terms low- oratories utilize only HPV tests that have invasive cervical cancer, compared with
grade squamous intraepithelial lesion been analytically and clinically validated older women.9,10 This is because the vast
(LSIL) and high-grade squamous intra- with proven acceptable reproducibility, majority of HPV infections spontane-
epithelial lesion (HSIL) to refer to low- clinical sensitivity, specificity, and posi- ously clear within 2 years after infection
grade lesions and high-grade cervical tive and negative predictive values for and are of little long-term clinical signif-
cancer precursors, respectively. The his- cervical cancer and verified precancer icance.11,12 Therefore, performing col-
tologic classification used is a 2-tiered (CIN 2,3), as documented by Food and poscopy for minor cytologic abnormali-

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ties in adolescents should be discouraged nificant lesion, spares 40-60% of women antepartum colposcopic evaluation does
because it can potentially result in harm from undergoing colposcopy, and has not add to management.39
through unnecessary treatment. been shown to have a favorable cost-ef-
Pregnant women are also considered a fectiveness ratio.26,27
special population. The only indication Because a single colposcopic exami- R ECOMMENDED M ANAGEMENT
for therapy of cervical neoplasia in preg- nation can miss significant lesions, OF W OMEN WITH ASC-US
nant women is invasive cancer. There- women who are referred for colpos- General management approaches
fore, it is reasonable to defer colposcopy copy and found not to have CIN 2,3 A program of DNA testing for high-risk
in pregnant women at low risk for having require additional follow-up. ALTS (oncogenic) types of HPV, repeat cervi-
cancer. Finally, it should be cautioned evaluated different postcolposcopy cal cytologic testing, or colposcopy are
that endocervical curettage is contrain- follow-up strategies and found that all acceptable methods for managing
dicated in pregnant patients. HPV testing performed 12 months af- women over the age of 20 years with
ter the initial colposcopy and 2 repeat ASC-US. (AI) When liquid-based cytol-
cytology examinations performed at 6 ogy is used or when cocollection for HPV
Atypical squamous cells month intervals performed similarly.28 DNA testing can be done, “reflex” HPV
ASC is subcategorized into atypical Combining cytology with HPV testing DNA testing is the preferred approach.
squamous cells of undetermined signifi- did not increase sensitivity and re- (AI)
cance (ASC-US) and atypical squamous duced specificity.28 Women with ASC-US who are HPV
cells, cannot exclude HSIL (ASC-H). DNA negative can be followed up with
There are several factors that need to be repeat cytologic testing at 12 months.
taken into consideration when manag- Special populations (BII) Women who are HPV DNA posi-
ing women with ASC. One is that a cyto- The prevalence of HPV DNA positivity tive should be managed in the same fash-
logical result of ASC is the least repro- changes with age among women with ion as women with LSIL and be referred
ducible of all cytologic categories.13-15 ASC-US. Rates of HPV DNA positivity for colposcopic evaluation. (AII) Endo-
Another is that the prevalence of invasive are much higher in younger, compared cervical sampling is preferred for women
cancer is low in women with ASC (ap- with older, women with ASC-US.29,30 in whom no lesions are identified (BII)
proximately 0.1-0.2%).16 Finally, it is Thus, using HPV testing to manage ad- and those with an unsatisfactory colpos-
important to note that the prevalence of olescents with ASC-US would refer copy (AII) but is acceptable for women
CIN 2,3 is higher among women with large numbers of women at low risk for with a satisfactory colposcopy and a le-
ASC-H than women with ASC-US. Be- having cancer to colposcopy. ASC-US sion identified in the transformation
cause of this, ASC-H should be consid- is less common in postmenopausal zone. (CII) Acceptable postcolposcopy
ered to represent equivocal HSIL. than premenopausal women, and the management options of women with
Clinical data from ALTS and other risk of significant pathology in post- ASC-US who are HPV positive, but in
studies1,17-19 have demonstrated that 2 menopausal women with a history of whom CIN is not identified, are HPV
repeat cytologic examinations per- cervical cancer screening is relatively DNA testing at 12 months or repeat cy-
formed at 6-month intervals, testing for low.10,31,32 HPV testing is actually tological testing at 6 and 12 months.
HPV, and a single colposcopic examina- more efficient in older, compared with (BII) It is recommended that HPV DNA
tion are all safe and effective approaches younger, women with ASC-US because testing not be performed at intervals less
to managing women with ASC-US. it refers a lower proportion to than 12 months. (EIII)
Therefore, the 2001 Consensus Guide- colposcopy.31,33,34 When a program of repeat cytologic
lines recognized that all 3 approaches ASC-US is quite common in HIV-in- testing is used for managing women with
were acceptable for managing women fected women.35,36 Previously, based on ASC-US, it is recommended that cyto-
with ASC-US. The scientific basis for the studies that had reported a high preva- logic testing be performed at 6-month
2001 recommendation has been lence of both HPV DNA positivity and intervals until 2 consecutive “negative
strengthened over the last 5 years by ad- significant cervical pathology in this for intraepithelial lesion or malignancy”
ditional clinical studies, additional anal- population,4 it was recommended that results are obtained. (AII) Colposcopy is
yses of the ALTS data, and metaanalyses all immunosuppressed women with recommended for women with ASC-US
of published studies.18,20-25 “Reflex” ASC-US undergo colposcopy. More re- or greater cytologic abnormality on a re-
testing refers to testing either the original cent studies have found a lower preva- peat test. (AII) After 2 repeat “negative
liquid-based cytology residual specimen lence of CIN 2,3 and HPV DNA posi- for intraepithelial lesion or malignancy”
or a separate sample cocollected at the tivity; therefore, immunosuppressed results are obtained, women can return
time of the initial screening visit for HPV women should be managed in the same to routine cytologic screening. (AII)
testing. This approach eliminates the manner as women in the general popu- When colposcopy is used to manage
need for women to return to the office or lation.37,38 The risk of cancer is relatively women with ASC-US, repeat cytologic
clinic for repeat testing, rapidly assures low among pregnant women with ASC- testing at 12 months is recommended for
many women that they do not have a sig- US, and some studies have found that women in whom CIN is not identified.

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(BIII) Women found to have CIN months or cytological testing at 6 and 12 R ECOMMENDED M ANAGEMENT
should be managed according to the months is acceptable. (CIII) Referral to OF W OMEN WITH LSIL
2006 Consensus Guidelines for the Man- colposcopy is recommended for women Colposcopy is recommended for manag-
agement of Cervical Intraepithelial who subsequently test positive for HPV ing women with LSIL, except in special
Neoplasia. DNA or who are found to have ASC-US populations (see following text). (AII)
Because of the potential for overtreat- or greater on their repeat cytologic tests. Endocervical sampling is preferred for
ment, the routine use of diagnostic exci- (BII) If the HPV DNA test is negative or nonpregnant women in whom no le-
sional procedures such as the loop elec- if 2 consecutive repeat cytologic tests are sions are identified (BII) and those with
trosurgical excision procedure is negative for intraepithelial lesion or ma- an unsatisfactory colposcopy (AII), but
unacceptable for women with an initial lignancy, return to routine cytologic is acceptable for those with a satisfactory
ASC-US in the absence of histologically screening is recommended. (AI) colposcopy and a lesion identified in the
diagnosed CIN 2,3. (EII) transformation zone. (CII) Acceptable
postcolposcopy management options
ASC-US IN S PECIAL for women with LSIL cytology in whom
LSIL
P OPULATIONS CIN 2,3 is not identified are testing for
Over the last decade, the rate of LSIL has
Adolescent women high-risk (oncogenic) types of HPV at 12
increased in the United States and in
In adolescents with ASC-US, follow-up months or repeat cervical cytologic test-
2003 the mean LSIL reporting rate was
with annual cytologic testing is recom- ing at 6 and 12 months. (BII) If the HPV
2.9% for liquid-based specimens.40 A re-
mended. (BII) At the 12-month follow- DNA test is negative or if 2 consecutive
sult of LSIL is a good indicator of HPV repeat cytologic tests are negative for in-
up, only adolescents with HSIL or
infection. A recent metaanalysis re- traepithelial lesion or malignancy, re-
greater on the repeat cytology should be
ported that the pooled estimate of high- turn to routine cytologic screening is rec-
referred to colposcopy. At the 24-month
risk (oncogenic) HPV DNA positivity ommended. (AI) If either the HPV DNA
follow-up, those with an ASC-US or
among women with LSIL was 76.6%.41 test is positive or if repeat cytology is re-
greater result should be referred to col-
poscopy. (AII) HPV DNA testing and The prevalence of CIN 2 or greater iden- ported as ASC-US or greater, colposcopy
colposcopy are unacceptable for adoles- tified at initial colposcopy among is recommended. (AI) Women found to
cents with ASC-US. (EII) If HPV testing women with LSIL is 12-16%.2,42,43 have CIN should be managed according
is inadvertently performed, the results Data from ALTS indicate that the risk to the appropriate 2006 Consensus
should not influence management. of CIN 2,3 is the same in women with Guidelines on the Management of Cer-
LSIL and those with ASC-US who are vical Intraepithelial Neoplasia. In the ab-
high risk (oncogenic) HPV DNA posi- sence of CIN identified histologically,
Immunosuppressed and
postmenopausal women tive.23 This supports managing both diagnostic excisional or ablative proce-
groups of women in an identical manner dures are unacceptable for the initial
HIV-infected, other immunosuppressed
except in special populations such as management of patients with LSIL. (EII)
women, and postmenopausal women
with ASC-US should be managed in the postmenopausal women.
same manner as women in the general LSIL IN S PECIAL P OPULATIONS
population. (BII) Adolescents
S PECIAL P OPULATIONS In adolescents with LSIL, follow-up with
Pregnant women Prospective follow-up studies of ado- annual cytologic testing is recom-
Management options for pregnant lescents with LSIL have shown very mended. (AII) At the 12-month follow-
women over the age of 20 years with high rates of regression to normal, al- up, only adolescents with HSIL or
ASC-US are identical to those described though it is not unusual for regression greater on the repeat cytology should be
for nonpregnant women, with the ex- to take years to occur.44 As with ASC- referred to colposcopy. At the 24-month
ception that it is acceptable to defer col- US, the high prevalence of HPV DNA follow-up, those with an ASC-US or
poscopy until at least 6 weeks postpar- positivity in adolescents with LSIL greater result should be referred to col-
tum. (CIII) Endocervical curettage is makes HPV testing of little value in this poscopy. (AII) HPV DNA testing is un-
unacceptable in pregnant women. (EIII) population. Some, but not all, studies acceptable for adolescents with LSIL.
have found that the prevalence of both (EII) If HPV DNA testing is inadver-
HPV DNA positivity and CIN 2,3 de- tently performed, the results should not
R ECOMMENDED M ANAGEMENT
cline with age in women with LSIL.33,45 influence management.
OF W OMEN WITH ASC-H
The recommended management of This suggests that postmenopausal
women with ASC-H is referral for colpo- women with LSIL can be managed less Postmenopausal women
scopic evaluation. (AII) In women in aggressively than premenopausal Acceptable options for the management
whom CIN 2,3 is not identified, fol- women and that triage using HPV test- of postmenopausal women with LSIL in-
low-up with HPV DNA testing at 12 ing may be attractive. clude “reflex” HPV DNA testing, repeat

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cytological testing at 6 and 12 months, poscopy in a woman with HSIL does when colposcopy has not been per-
and colposcopy. (CIII) If the HPV DNA not necessarily mean a CIN 2,3 lesion is formed, CIN 2,3 is not identified histo-
test is negative or CIN is not identified at not present. As a result, most women logically, or the endocervical assessment
colposcopy, repeat cytology in 12 with HSIL eventually undergo a diag- identifies CIN of any grade. (EII) Triage
months is recommended. If either the nostic excisional procedure. Because of utilizing either a program of only repeat
HPV DNA test is positive or the repeat this, many have advocated see-and- cytology or HPV DNA testing is unac-
cytology is ASC-US or greater, colpos- treat approaches for managing women ceptable. (EII)
copy is recommended. (AII) If 2 consec- with HSIL in which a loop electrosur-
utive repeat cytologic tests are negative gical excision is used for initial evalua-
for intraepithelial lesion or malignancy, tion.47,50,51 It should be recognized,
HSIL IN S PECIAL P OPULATIONS
Adolescent women
return to routine cytologic screening is however, that many CIN 2,3 lesions,
In adolescents with HSIL, colposcopy is
recommended. especially in adolescents and young
recommended. Immediate loop electro-
adults, spontaneously regress.52,53
surgical excision (ie, “see-and-treat”) is
Pregnant women unacceptable in adolescent women.
Colposcopy is preferred for pregnant, (AII) When CIN 2,3 is not identified his-
nonadolescent women with LSIL cytol-
R ECOMMENDED M ANAGEMENT
tologically, observation for up to 24
OF W OMEN WITH HSIL
ogy. (BII) Endocervical curettage is un- months using both colposcopy and cy-
An immediate loop electrosurgical exci-
acceptable in pregnant women. (EIII) tology at 6-month intervals is preferred,
sion or colposcopy with endocervical as-
Deferring the initial colposcopy until at provided the colposcopic examination is
sessment is an acceptable method for
least 6 weeks postpartum is acceptable. satisfactory and endocervical sampling is
managing women with HSIL, except in
(BIII) In pregnant women who have no negative. (BIII) In exceptional circum-
special populations (see following text).
cytologic, histologic, or colposcopically stances, a diagnostic excisional proce-
(BII) When CIN 2,3 is not identified his-
suspected CIN 2,3 or cancer at the initial dure is acceptable. (BIII) If during fol-
tologically, either a diagnostic excisional
colposcopy, postpartum follow-up is low-up a high-grade colposcopic lesion
procedure or observation with colpos-
recommended. (BIII) Additional colpo- is identified or HSIL cytology persists for
copy and cytology at 6 month intervals
scopic and cytologic examinations dur- 1 year, biopsy is recommended. (BIII) If
for 1 year is acceptable, provided in the
ing pregnancy are unacceptable for these CIN 2,3 is identified histologically, man-
latter case that the colposcopic examina-
women. (DIII) agement should follow the 2006 Consen-
tion is satisfactory and endocervical
sus Guideline for the Management of
sampling is negative. (BIII) In this cir-
Women with Cervical Intraepithelial
HSIL cumstance it is also acceptable to review
Neoplasia. (BIII) If HSIL persists for 24
The mean reporting rate of HSIL in US the cytological, histological, and colpo-
months without identification of CIN
laboratories is 0.7%.40 The rate of HSIL scopic findings; if the review yields a re-
2,3, a diagnostic excisional procedure is
varies with age. In 1 US center, the rate of vised interpretation, management
recommended. (BIII) After 2 consecu-
HSIL in women 20-29 years of age is should follow guidelines for the revised
tive “negative for intraepithelial lesion or
0.6%, compared with 0.2% and 0.1% in interpretation. (BII) If observation with
malignancy” results, adolescents and
women 40-49 years and 50-59 years of cytology and colposcopy is elected, a di-
young women without a high-grade col-
age, respectively.10 The finding of a HSIL agnostic excisional procedure is recom-
poscopic abnormality can return to
result on cytology carries a high risk for mended for women with repeat HSIL cy-
routine cytological screening. (BIII) A
significant cervical disease. A single col- tological results at either the 6 or 12
diagnostic excisional procedure is rec-
poscopic examination identifies CIN 2 month visit. (CIII) After 1 year of obser-
ommended for adolescents and young
or greater in 53-66% of women with vation, women with 2 consecutive “neg-
women with HSIL when colposcopy is
HSIL and CIN 2 or greater is diagnosed ative for intraepithelial lesion or malig-
unsatisfactory or CIN of any grade is
in 84-97% of women evaluated using a nancy” results can return to routine
identified on endocervical assessment
loop electrosurgical excision proce- cytological screening.
(BII).
dure.42,46,47 Approximately 2% of A diagnostic excisional procedure is
women with HSIL have invasive recommended for women with HSIL in
cancer.48 whom the colposcopic examination is Pregnant women
There is a considerable risk of a CIN unsatisfactory, except in special popula- Colposcopy is recommended for preg-
2 or greater and a high prevalence of tions (eg, pregnant women). (BII) nant women with HSIL. (AII) It is pre-
HPV DNA positivity in women with Women with CIN 2,3 should be man- ferred that the colposcopic evaluation of
HSIL, and intermediate triage using aged according to the appropriate 2006 pregnant women with HSIL be con-
HPV testing or cytology is inappropri- Consensus Guideline for the Manage- ducted by clinicians who are experienced
ate.42,45,46,48,49 Because colposcopy can ment of Women with Cervical Intraepi- in the evaluation of colposcopic changes
miss a significant number of CIN 2,3 thelial Neoplasia. Ablation is unaccept- induced by pregnancy. (BIII) Biopsy of
lesions, failure to detect CIN 2,3 at col- able in the following circumstances: lesions suspicious for CIN 2,3 or cancer

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is preferred; biopsy of other lesions is ac- women with AGC-favor neoplasia,” AIS, formed at the initial evaluation or de-
ceptable (BIII). Endocervical curettage is or repeat AGC cytology.4 ferred until the results are known. If no
unacceptable in pregnant women. (EIII) endometrial pathology is identified, col-
Diagnostic excision is unacceptable un- poscopy is recommended. (AII) If not al-
O THER G LANDULAR
less invasive cancer is suspected based on ready obtained, HPV DNA testing at the
A BNORMALITIES
the referral cytology, colposcopic ap- time of colposcopy is preferred in
Benign-appearing endometrial cells in a
pearance, or cervical biopsy. (EII) Re- women with atypical endocervical, en-
woman 40 years of age and older and en-
evaluation with cytology and colposcopy dometrial, or glandular cells not other-
dometrial stromal cells or histiocytes are
is recommended no sooner than 6 weeks wise specified (NOS). (CIII) The use of
occasionally encountered cytologically.
postpartum for pregnant women with HPV DNA testing alone or a program of
Approximately 0.5-1.8% of cervical cy-
HSIL in whom CIN 2,3 is not diagnosed. repeat cervical cytology is unacceptable
tology specimens from women 40 years
(CIII) for the initial triage of all subcategories of
of age and older will have endometrial
AGC and AIS. (EII)
cells.61 Benign-appearing exfoliated en-
dometrial cells in premenopausal
Atypical glandular cells (AGC)
women are rarely associated with signif-
AGC results are relatively uncommon, Subsequent evaluation or
icant pathology.61 Similarly, the pres-
with a mean reporting rate of only 0.4% follow-up
ence of endometrial stromal cells/histio-
in the United States in 2003.40 Although The recommended postcolposcopy
cytes rarely has clinical significance. In
AGC is frequently caused by benign con- management of women of known HPV
contrast, benign-appearing endometrial
ditions, such as reactive changes and pol- status with atypical endocervical, endo-
cells in postmeonopausal women are not
yps, clinicians should be aware that it is metrial, or glandular cells NOS who do
infrequently associated with significant
not uncommon for AGC to be associated not have CIN or glandular neoplasia
endometrial pathology.62 Although hor-
with a significant underlying neoplastic identified histologically is to repeat cyto-
mone replacement therapy can increase
condition including adenocarcinomas of logic testing combined with HPV DNA
the rate of shedding of benign-appearing
the cervix, endometrium, ovary, and fal- testing at 6 months if they are HPV DNA
endometrial cells, the prevalence of sig-
lopian tube. Recent series have reported positive and at 12 months if they are
nificant pathology remains elevated in
that 9-38% of women with AGC have HPV DNA negative. (CII) Referral to
this setting.61,62 Benign-appearing glan-
significant neoplasia (CIN 2,3, AIS, or colposcopy is recommended for women
dular cells derived from small accessory
cancer), and 3-17% have invasive who subsequently test positive for high-
ducts, foci of benign adenosis, or pro-
cancer.54,55,56,57 risk (oncogenic) HPV DNA or who are
lapse of the fallopian tube into the vagina
The rate and type of significant find- found to have ASC-US or greater on
are sometimes seen in cytology speci-
ings in women with AGC varies with their repeat cytologic tests. If both tests
mens after total hysterectomy and have
age.55 Although a variety of glandular le- are negative, women can return to rou-
no clinical significance.
sions, including malignancies, are asso- tine cytologic testing. (BII) The recom-
ciated with AGC, CIN is the most com- mended postcolposcopy management of
mon significant finding identified in R ECOMMENDED M ANAGEMENT women of unknown HPV status with
women with AGC.58 Gynecologic malig- OF W OMEN WITH AGC atypical endocervical, endometrial, or
nancy is less common in women under Initial workup glandular cells NOS who do not have
the age of 35 years than in older Colposcopy with endocervical sampling CIN or glandular neoplasia identified
women.54 Pregnancy does not appear to is recommended for women with all sub- histologically is to repeat cytologic test-
change the underlying associations be- categories of AGC and AIS. (AII) Endo- ing at 6-month intervals. After 4 consec-
tween AGC and gynecologic neoplasia. metrial sampling is recommended in utive “negative for intraepithelial lesion
Neither HPV testing nor repeat cervi- conjunction with colposcopy and endo- or malignancy” results are obtained,
cal cytology has the requisite sensitivity cervical sampling in women 35 years and women can return to routine cytologic
to be utilized alone as an initial triage test older with all subcategories of AGCs and testing. (CIII)
for women with AGC.57,59,60 Because of AIS. (BII) Endometrial sampling is also If CIN, but no glandular neoplasia, is
the spectrum of neoplasia linked to recommended for women under the age identified histologically during the initial
AGC, initial evaluation must include of 35 years with clinical indications sug- workup of a woman with atypical endo-
multiple testing modalities.57,59 These gesting they may be at risk for neoplastic cervical, endometrial, or glandular cells
include colposcopy, endocervical evalu- endometrial lesions. These include un- NOS, management should be according
ation and sampling, HPV testing, and explained vaginal bleeding or conditions to the 2006 Consensus Guidelines for the
endometrial evaluation. Because of the suggesting chronic anovulation. It is rec- Management of Women with Cervical
high incidence of neoplasia and the poor ommended that women with atypical Intraepithelial Neoplasia. If invasive dis-
sensitivity of all test modalities, diagnos- endometrial cells be initially evaluated ease is not identified during the initial
tic excisional procedures may be neces- with endometrial and endocervical sam- colposcopic workup, it is recommended
sary, despite initial negative testing, for pling. Colposcopy can be either per- that women with atypical endocervical

OCTOBER 2007 American Journal of Obstetrics & Gynecology 351


Reviews Oncology www.AJOG.org

or glandular cells “favor neoplasia” or ther liquid-based or conventional cytol- fornia, the overall prevalence of HPV
endocervical AIS undergo a diagnostic ogy).67,68 In screening studies from positivity was 6.5%, and 58% of the
excisional procedure. (AII) It is recom- North America and Europe, the pooled HPV-positive women had a concurrent
mended that the type of diagnostic exci- sensitivity and specificity of HPV testing negative cytology.60 HPV-positive
sional procedure used in this setting for the detection of CIN 2 or greater in women require counseling with respect
provide an intact specimen with inter- women 35 years and older is 95% and to their risk for CIN 2 or greater, source
pretable margins. (BII) Concomitant en- 93%, respectively.69 For comparison, of their infection, and their infectivity.
docervical sampling is preferred. (BII) pooled sensitivity and specificity of cy- The risk of having an undetected CIN 2
tology at a threshold of ASC-US are 60% or greater is quite low in cytology-nega-
AGC IN S PECIAL P OPULATIONS and 97%, respectively. Sensitivity using a tive, HPV-positive women in screened
Pregnant women combination of HPV testing and cytol- populations, ranging from 2.4-
In pregnant women, the initial evalua- ogy is significantly higher than that of ei- 5.1%.75-78 For comparison, CIN 2 or
tion of AGC should be identical to that of ther test alone with negative predictive greater was detected at enrollment col-
nonpregnant women, except that endo- values of 99-100%.69,70 poscopy in 10.2% of women of unknown
cervical curettage and endometrial bi- Molecular testing for high-risk (onco- HPV status with ASC-US in ALTS.1 It is
opsy are unacceptable. (BII) genic) types of HPV is now approved by also important to note that even in
the FDA for use as an adjunct to cervical women 30 years and older, the majority
cytology for screening in women 30 years of HPV-positive women become HPV
O THER F ORMS OF G LANDULAR of age and older.71 Interim guidance on negative during follow-up. After a me-
A BNORMALITIES how to manage women with different dian follow-up of 6 months, 60% of
Benign-appearing endometrial combinations of screening results was HPV-positive women in a prospective
cells developed by a NCI, ASCCP, and Amer- study from France became HPV-nega-
For asymptomatic premenopausal
ican Cancer Society joint workshop in tive.78 Based on these considerations,
women with benign endometrial cells,
2003.3 The 2006 Consensus Conference conservative follow-up with repeat
endometrial stromal cells, or histiocytes,
formally reviewed and modified the pre- cytology and HPV testing at 12 months
no further evaluation is recommended.
vious interim guidance. The two contro- appears to be the best management ap-
(BII) For postmenopausal women with
versial areas are when women negative proach for cytology-negative, HPV-pos-
benign endometrial cells, endometrial
by both cytology and HPV testing should itive women. Women who on repeat
assessment is recommended regardless
be rescreened and how to manage cytol- testing are persistently HPV positive
of symptoms. (BII)
ogy-negative, HPV-positive women. should undergo colposcopy, whereas
Women who are negative by both cytol- women who are negative on both tests
Benign-appearing glandular cells ogy and HPV testing have a less than 1 in can be rescreened in 3 years.
after hysterectomy 1000 risk of having CIN 2 or greater, and
For posthysterectomy patients with a cy- prospective follow-up studies have
tologic report of benign glandular cells, shown that the risk of developing CIN 3 HPV G ENOTYPING
no further evaluation is recommended. over a 10-year period is quite low.3,72,73 Emerging data suggest that the specific
(BII) Less than 2% of cytology- and HPV-neg- type of high-risk (oncogenic) HPV that a
ative Danish women 40-50 years of age woman has may be an important indica-
HPV DNA T ESTING W HEN developed CIN 3 or greater during 10 tor of her risk for CIN 2 or greater.
U SED FOR S CREENING years of follow-up.72 Identical results Among cytology-negative women 30
Despite the successes of cytology as a cer- have been reported for women 30 years years of age and older in the Portland
vical cancer screening method, cytology of age and older in Portland, OR.73 study, CIN 3 was identified during 10
has a number of significant limitations.63 Health policy modeling studies demon- years of follow-up in 21% and 18% of
These limitations have led to consider- strate that 3 year screening using a com- those with HPV 16 or 18, respectively, at
able interest in using a combination of bination of cytology and HPV testing in enrollment.73 In contrast, the risk of CIN
HPV testing and cytology for screen- women 30 years and older provides 3 among women with other high-risk
ing.64 Most newly acquired HPV infec- equivalent or greater benefits than those HPV types was only 1.5%. Schlecht et
tions clear spontaneously and the preva- provided by annual conventional cytol- al79 also found a higher incidence of cy-
lence of HPV DNA positivity drops with ogy.74 Therefore, women who are nega- tological HSIL during follow-up in Bra-
age from a peak in adolescents and tive by both cytology and HPV testing zilian women who were positive for HPV
women in their 20s.11,65 Therefore, HPV should not be rescreened before 3 years. 16 or 18, compared with women with
testing should be used only for routine Many women in screened populations other high-risk HPV types, although the
screening in women 30 years of age and who test positive for HPV will have a difference in incidence was not as
older.3,66 A number of large studies have negative cervical cytology. In a series of marked as observed in Portland.
evaluated screening using a combination more than 213,000 women 30 years and Genotyping assays to determine spe-
of HPV testing and cervical cytology (ei- older enrolled in Kaiser Northern Cali- cific high-risk HPV type(s) have not

352 American Journal of Obstetrics & Gynecology OCTOBER 2007


www.AJOG.org Oncology Reviews

yet been approved by the FDA. How- type-specific HPV genotyping cannot be 8. Wright TC, Schiffman M. Adding a test for
ever, should the FDA approve HPV made. Once such assays are FDA ap- human papillomavirus DNA to cervical-cancer
screening. N Engl J Med 2003;348:489-90.
genotyping assays, it would be reason- proved, emerging data support the triage 9. SEER Cancer Statistics Review 1975-2003.
able to utilize genotyping in cytology- of women 30 years of age and older with Vol 2006. Bethesda, MD: National Institutes of
negative, HPV-positive women in the a cytology result of “negative for an in- Health, 2006.
same manner as high-risk HPV testing traepithelial lesion or malignancy” but 10. Insinga RP, Glass AG, Rush BB. Diagnoses
is utilized in women with ASC-US. who are HPV positive with HPV geno- and outcomes in cervical cancer screening: a
population-based study. Am J Obstet Gynecol
Samples from cytology-negative, HPV- typing assays to identify those with HPV 2004;191:105-13.
positive women would be genotyped for 16 and 18. (AII) f 11. Moscicki AB, Schiffman M, Kjaer S, Villa LL.
specific high-risk types of HPV, and Updating the natural history of HPV and ano-
women with specific high-risk types, genital cancer. Chapter 5. Vaccine 2006;
ACKNOWLEDGMENTS 24(Suppl 3):S42-51.
such as HPV 16 or 18, would be referred
We would like to thank all of the participants and 12. Burchell AN, Winer RL, de Sanjose S,
for colposcopy.73 Women with other formal observers to the 2006 Consensus Con- Franco EL. Epidemiology and transmission dy-
high-risk types would be told to return in ference who worked so hard to develop the namics of genital HPV infection. Chapter 6.
12 months for retesting for both cytology guidelines. Their names and organizations are Vaccine 2006;24(Suppl 3):S52-61.
and HPV. This would allow women at available at www.asccp.org. We would like to 13. Stoler MH, Schiffman M. Interobserver re-
increased risk for having a false-nega- also thank Ms Kathy Poole for administrative producibility of cervical cytologic and histologic
support during the development of the guide- interpretations: realistic estimates from the
tive cytology result to be referred to lines and Dr Anna Barbara Moscicki, who ASCUS-LSIL Triage Study. JAMA 2001;285:
colposcopy. chaired the adolescent working group. These 1500-5.
guidelines were developed with funding from 14. Confortini M, Carozzi F, Dalla Palma P, et al.
the American Society for Colposcopy and Cer- Interlaboratory reproducibility of atypical squa-
R ECOMMENDED M ANAGEMENT vical Pathology and the National Cancer Insti- mous cells of undetermined significance report:
D IFFERENT C OMBINATIONS OF tute. Its contents are solely the responsibility of a national survey. Cytopathology 2003;14:
R ESULTS the authors and the American Society for Col- 263-8.
General recommendations poscopy and Cervical Pathology and do not 15. Gatscha RM, Abadi M, Babore S, Chhieng
necessarily represent the official views of the D, Miller MJ, Saigo PE. Smears diagnosed as
It is recommended that HPV DNA test-
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OCTOBER 2007 American Journal of Obstetrics & Gynecology 355