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The long-awaited new recommendations from the American
Society for Colposcopy and Cervical Pathology have arrived.
The second ASCCP consensus conference for the management
of women with cervical cytological abnormalities and cervical intraepithelial
neoplasia was held in Bethesda, Md., in September 2006. The conference
addressed management of women with abnormal cervical cancer screening
tests and with cervical intraepithelial neoplasia or adenocarcinoma in
situ on colposcopic biopsy. With the recent publication of the recommendations
from this meeting in the American Journal of Obstetrics and Gynecology
and the Journal of Lower Genital Tract Disease, the press embargo
has been lifted.
Here, we will highlight key points and summarize changes
to the management recommendations. Key points of interest to pathologists
are summarized in Table 1.
The second consensus conference was convened for two
reasons. First, the management recommendations needed to be simplified.
The maze of recommendations from the 2001 conference proved difficult
for many to recall and use, except for experts in the field; they were
hardly at the fingertips of many clinicians who care for women. Second,
since 2001, a wealth of clinical evidence from randomized, controlled
studies, particularly from ALTS and the National Cancer Institute's Guanacaste
and Portland cohorts, has become available. Thus, simplifying the management
recommendations and incorporating our new understanding of HPV-related
cervical disease were the prime goals of the 2006 ASCCP consensus conference.
Two fundamental principles guided the revision of the
guidelines: assessment of risk and detection of proven cancer precursor
lesions. All management recommendations are based on an assessment of
the risk for significant cervical disease in a given clinical situation.
Women with a similar risk should be managed using a similar or identical
method. It was acknowledged that no management strategy can eliminate
all risk through absolute assurance that every significant cervical lesion
has been detected. Second, cervical cancer screening programs aim to identify
and treat true cervical cancer precursors—that is, CIN2, CIN3, and
adenocarcinoma in situ. (Though CIN2 is a heterogeneous diagnosis, its
inclusion with the management recommendations for CIN3 provides a margin
of safety.) Thus, triage to colposcopy or conservative followup via Pap
or HPV testing or both is also based on the likelihood of detecting these
lesions. CIN1 is essentially evidence of an active HPV infection, the
majority of which will spontaneously regress; it is not considered a true
precancer, though it may be useful in establishing current and future
risk.
The updated guidelines also use high-risk-HPV testing
in cervical cancer screening and triage to an increasing degree. The guidelines
recommend use of an analytically sensitive and clinically validated HPV
test. Only testing for high-risk HPV types is recommended; testing for
low-risk HPV types is not applicable to a cancer screening program. The
major changes from 2001 to 2006 in the management of women with Pap test
abnormalities (that is, triage) and of women with histologically proven
abnormalities (on colposcopic biopsy) are summarized here by category
of cytologic interpretation, histologic diagnosis, or both. Bethesda terminology
is used when referring to cytologic results (for example, LSIL, HSIL)
whereas a modified two-tiered CIN classification (CIN1 and CIN2,3) is
used for histologic results. Some basic principles apply:
- Triage to colposcopy or conservative management
is based on the risk associated with underlying CIN2+.
- Post-colposcopy followup evaluation for squamous
disease (with or without treatment) is usually at six- and 12-month
intervals when using Paps (until two negatives) and in 12 months when
using HPV testing (until one negative).
- During the followup period, the threshold to send
a patient to colposcopy is greater than or equal to ASC-US on Pap or
a positive HPV test, except in special populations.
- Adolescents are considered a "special population"
for which the management strategies differ from those for women 21 years
of age and older.
Atypical squamous cells: ASC-US and ASC-H
No major changes were made in the recommendations
for managing women with ASC-US. Reflex high-risk-HPV testing remains the
preferred approach when liquid-based cytology is used or an HPV specimen
has been co-collected. Women with ASC-US on a screening cytology, who
are high-risk-HPV positive, should proceed to colposcopy. It is now recommended
that postmenopausal and immunosuppressed (including HIV+) women with ASC-US
be managed in the same manner as the general population of women undergoing
regular cervical cancer screening. If colposcopic-directed biopsy does
not show CIN 2+, then post-colposcopic followup with either Pap at six
and 12 months or high-risk-HPV testing at 12 months is acceptable.
Colposcopy remains the recommended management for women
with ASC-H on Pap. Data from ALTS demonstrated that over 85 percent of
women with ASC-H on Pap were high-risk-HPV positive and about 40 percent
of women were found to have CIN2+ on biopsy. Future studies may clarify
the utility of high-risk-HPV testing in the management of women with ASC-H
in various subgroups—for example, the postmenopausal age group,
but there is insufficient evidence at this time to alter the recommendation
for colposcopy for all women with ASC-H. If no CIN2,3 is identified at
colposcopy, it is acceptable to follow up with Paps at six and 12 months
or HPV testing at 12 months. The prior 2001 recommendation for a review
of the original, index ASC-H Pap in the absence of biopsy-proven CIN2,3
has been eliminated, since few pathologists are willing to actually "downgrade"
an initial ASC-H interpretation.
LSIL and CIN1
Women with LSIL on Pap have approximately the same
risk of having biopsy-proven CIN2,3 as those who are ASC-US and high-risk-HPV
positive. Consequently, similar management strategies are recommended
for both groups—colposcopy. Adolescents and possibly postmenopausal
women are exceptions to this rule. Since the prevalence of high-risk-HPV
is lower in postmenopausal women, reflex high-risk-HPV testing for LSIL
in these women, with triage to colposcopy if HPV positive, is acceptable.
The main purpose of colposcopy is the detection of CIN2,3 and cancer.
Our increasing understanding of the natural history
of HPV infection and high spontaneous regression rates yields one of the
major take-home messages from the new guidelines: It is recommended that
all women with CIN1 be observed for up to two years before being treated.
This applies to women whose diagnosis of CIN1 was preceded by a Pap showing
ASC-US, ASC-H, or LSIL (whether or not they have a satisfactory colposcopy).
Followup may consist of high-risk-HPV testing every 12 months or repeat
Paps at six- to 12-month intervals. Repeat colposcopy is recommended if
followup shows high-risk-HPV+ or ASC-US or worse. If after two years of
observation, no CIN2+ is detected and CIN1 persists, either continued
followup or treatment is acceptable. For CIN1 preceded by a Pap showing
HSIL or atypical glandular cells, more surveillance is recommended, given
the higher risk associated with these Pap interpretations. These women
may be followed by colposcopy and cytology at six-month intervals for
one year, have a diagnostic excisional procedure, or have their findings
reviewed with subsequent management based on any revisions. For pregnant
women with LSIL, colposcopy may be performed once (rather than every trimester)
to exclude high-grade disease or deferred to the postpartum period.
HSIL and CIN 2,3
The principal 2001 recommendations for colposcopy
of all women with HSIL and management of CIN 2,3 are unchanged by the
2006 consensus conference. All biopsy-proven CIN 2,3 should be treated
(adolescents remain a possible exception). More emphasis was placed on
immediate LEEP ("see and treat") as an acceptable initial management option
for women with HSIL on Pap, except in special populations. Treatment of
CIN 2,3 is deferred during pregnancy, unless cancer is suspected. An option
for conservative management of adolescents with CIN2,3 will be discussed
later. Many pathologists now use a two-tiered classification for histologic
diagnosis of intraepithelial lesions, lumping together CIN2 and CIN3,
often by simply using the cytologic term "HSIL" for CIN2,3. This two-tiered
diagnostic category of CIN1 and CIN2,3 better reflects our understanding
of the natural history of HPV-related lesions—as low-grade mucosal
infections and as potential cervical cancer precursors. It also bows to
the interobserver variability inherent in these diagnoses. With the exception
of managing adolescents with high-grade disease, which will be discussed
in the "special populations" section, the lumped diagnostic category of
CIN2,3 triggers the appropriate clinical response.
Atypical glandular cells
The basic guidelines for the management of women with
the atypical glandular cells, or AGC, of all subcategories and AIS on
Pap have not changed. Colposcopy with endocervical sampling is recommended
for all (with the exception of women with atypical endometrial cells).
If the patient is 35 years of age or older, or less than 35 years with
any clinical suggestion of increased risk for endometrial neoplasia, endometrial
sampling should also be performed at the time of colposcopy. If atypical
endometrial cells were present on the index Pap, endometrial and endocervical
sampling are recommended as the initial evaluation; colposcopy can be
deferred if no pathology is found. If CIN is identified histologically
in this assessment, management follows that specific guideline. If AIS
is found, a diagnostic excisional procedure is recommended; ablative therapy
is unacceptable. The 2006 management guidelines accept the possibility
of using LEEP as an alternative to cold knife cone biopsy and stress that
either excisional biopsy technique should be designed to obtain an intact
specimen with interpretable margins.
If no CIN2,3, AIS, or cancer is identified, the post-colposcopy
management varies by original Pap interpretation. A diagnostic excisional
procedure is still recommended for women with Pap showing AGC-favor neoplasia,
atypical endocervical cells-favor neoplasia, or adenocarcinoma in situ.
Women with AGC, NOS may be managed more conservatively.
While high-risk-HPV testing is still not acceptable
for the initial triage of women with AGC of any variety, it is useful
in the post-colposcopy followup of women with AGC, NOS in which no CIN2,3
or AIS have been found. Women who are negative for high-risk HPV can be
followed less aggressively than those who are high-risk-HPV positive.
The high-risk-HPV negative woman may have followup with repeat Pap and
HPV testing delayed to 12 months. In contrast, this time interval is shortened
to six months if the patient is high-risk-HPV positive. A shortened time
interval for followup using cytology only at six-month intervals until
four negative Paps is recommended for women with unknown HPV status.
The new guidelines also include comprehensive management
recommendations for women with biopsy-confirmed AIS of the cervix. For
those in whom future fertility is desired, conservative management by
cone or LEEP excision, followed by long-term surveillance, is acceptable.
If margins or endocervical sampling at the time of excision are positive,
re-excision to ensure negative margins is preferred. However, repeat Pap,
HPV testing, colposcopy, and endocervical evaluation at six months is
acceptable in this circumstance, too. Whenever the conservative management
option is chosen, long-term followup is recommended. For women who have
completed childbearing, hysterectomy is the preferred management for AIS
found on an excisional procedure.
Special populations: pregnant women, adolescents
Only cervical cancers are treated during pregnancy.
For women with low-grade cytologic abnormalities, colposcopy can be deferred
until the postpartum period. The goal of colposcopic evaluation of women
with HSIL during pregnancy is to rule out invasive cancer; if no cancer
is identified, treatment is deferred until the postpartum evaluation.
Endocervical curettage is unacceptable during pregnancy.
Adolescents, defined as girls and women less than 21
years of age, have a very high prevalence of HPV infection, low-grade
cytologic abnormalities, and CIN1, yet have a very low risk of cervical
cancer. The majority of these infections will regress spontaneously and
are of little long-term clinical significance. Colposcopy and overtreatment
of these transient HPV infections may lead to potential harm. High-risk-HPV
testing in this age group is unacceptable because of the high
prevalence of transient HPV infection in adolescents.
Adolescents with HSIL on Pap should be sent for immediate
colposcopy. Adolescents with either ASC-US or LSIL on Pap should be followed
by repeat Pap at 12 and 24 months, and referred to colposcopy only if
HSIL or worse is detected at 12 months, or if ASC-US or greater results
persist for 24 months. Since the risk of CIN2+ is low, colposcopy is not
recommended for the initial management of these low-grade Pap abnormalities
in adolescents. HPV testing is not recommended in this group due to high
prevalence of infection. Treatment of CIN1 in adolescents is unacceptable.
Immediate LEEP (that is, "see and treat") is unacceptable in
adolescents. The take-home message regarding cervical cancer screening
in adolescents is, Leave adolescents alone.
The pathologic grading of cervical biopsies will play
a significant role in managing adolescents with high-grade disease. More
and more pathologists are using Bethesda terminology for histologic diagnosis;
a two-tiered system more accurately reflects our understanding of HPV-related
infection and precancer. However, clinical management in adolescents now
depends on a more subtle and nuanced histologic reporting. If CIN2,3 is
diagnosed in an adolescent, either observation for up to 24 months or
treatment is acceptable, provided the colposcopy is satisfactory. If CIN2
is specified, observation is the preferred approach, though treatment
is acceptable. If CIN3 is specified on biopsy or the colposcopy is unsatisfactory,
treatment is preferred. This acknowledges, once again, that the histologic
diagnosis of CIN2 is a heterogeneous group with high spontaneous regression
rates, particularly in adolescents, and that there is poor interobserver
reproducibility of this diagnostic category.
The 2006 guidelines acknowledge that although LEEP
(loop electrosurgical excisional procedure) has become an important tool
in the clinical repertoire, it is not without potential reproductive consequences
for our patients. As such, LEEP should be used judiciously to treat high-grade
disease, particularly in adolescents and young women of reproductive age.
Similarly, see-and-treat is not a recommended management option in adolescents.
High-risk-HPV DNA testing
HPV testing is being used with increasing frequency
in cervical cancer screening and in managing HPV-related disease. However,
it must be used judiciously to prevent increasing the costs of cervical
cancer prevention without reaping its benefits. HPV testing may be used
in several clinical scenarios: in screening in conjunction with the Pap
in women 30 years and older, in the triage of ASC-US on Pap, in the triage
of postmenopausal women with LSIL on Pap, and in the post-colposcopy followup
of abnormalities (Table 2).
In 2004, the interim guidance recommendations were
proposed for the management of women undergoing cervical screening using
high-risk-HPV and Pap testing. These recommendations were adopted at the
2006 consensus conference. Women over 30 years of age, who are Pap negative
and HPV negative, may be re-screened at three-year intervals. Women who
are Pap negative but HPV positive are re-screened by repeating both tests
in 12 months.
High-risk-HPV testing also plays an increasing role
in the post-colposcopy management of women with either high-grade squamous
or glandular disease. In the standard followup of low-grade abnormalities
after colposcopy, it may be used at 12-month intervals, allowing time
for spontaneous regression. After diagnostic excisional procedure for
either CIN2,3 or AIS, it is used at six- to 12-month intervals, as a test
of cure.
In the future, HPV genotyping may play an important
role in the triage and management of women with HPV-related disease. HPV
16 and 18 are known as "bad actors" in the disease process, with a higher
representation among cervical cancer than other high-risk HPV types. Once
these tests become available and gain FDA approval, data may support the
triage of HPV-positive women using assays that specifically identify HPV
16 and 18.
Many new and exciting changes are happening in the
world of cervical cancer screening. Our understanding of the disease process
and risk for cervical cancer indicated by specific abnormalities is expanding.
Risk assessment is becoming a guiding force behind our management strategies.
In addition, the full impact of the newly approved cervical cancer vaccine,
Gardasil, on cervical cancer screening and prevention is still unfolding.
Stay tuned.
References
The 2006 Consensus Guidelines for the Management of
Women with Abnormal Cervical Cancer Screening Tests were published in
the American
Journal of Obstetrics and Gynecology (2007;197[4];346-355) and
the Journal of Lower Genital Tract Disease (2007;11[4];201-222).
The 2006 Consensus Guidelines for the Management of
Women with Cervical Intraepithelial Neoplasia or Adenocarcinoma In Situ
were published in the American Journal of Obstetrics and Gynecology
(2007;197[4]:340-345) and the Journal
of Lower Genital Tract Disease (2007;11[4];223-239).
Link to ASCCP Web site for management algorithms and
additional information: www.asccp.org.
Dr. Darragh, a member
of the CAP Cytopathology Committee, is professor of clinical pathology,
Departments of Pathology and Ob/Gyn, University of California San Francisco/Mt.
Zion Medical Center, San Francisco. Dr. Colgan, a former member of the Cytopathology
Committee, is chief, gynecologic pathology, Department of Pathology and
Laboratory Medicine, Mount Sinai Hospital, Toronto, and professor, University
of Toronto.
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