Table of Contents
A. EXECUTIVE SUMMARY
Updated US consensus guidelines for management of cervical screening abnormalities
are needed to accommodate the 3 available cervical screening strategies: primary human
papillomavirus (HPV) screening, cotesting with HPV testing and cervical cytology,
and cervical cytology alone. New data indicate that a patient's risk of developing
cervical precancer or cancer can be estimated using current screening test results
and previous screening test and biopsy results, while considering personal factors
such as age and immunosuppression. Routine screening applies only to asymptomatic
individuals who do not require surveillance for prior abnormal screening results.
The 2012 consensus guidelines were the first to be based on the principle of equal
management for equal risk, specifically, the risk of a patient developing cervical
cancer, estimated by the surrogate end point of the 5-year risk of cervical intraepithelial
neoplasia (CIN) grade 3 (CIN 3) or more severe diagnoses (CIN 3+), regardless of which
test combinations yielded this risk level. Introduction of risk-based guidelines in
2012 was a conceptual breakthrough, but the recommendations retained a continued reliance
on complicated algorithms and insufficiently incorporated screening history. With
a more nuanced understanding of how previous results affect risk, and more variables
to consider, the 2019 guidelines further align management recommendations with current
understanding of HPV natural history and cervical carcinogenesis. More frequent surveillance,
colposcopy, and treatment are recommended for patients at progressively higher risk,
whereas those at lower risk can defer colposcopy, undergo follow-up at longer surveillance
intervals, and, when at sufficiently low risk, return to routine screening. Clearly
defined risk thresholds to guide management are designed to continue functioning appropriately
when population-level prevalence of CIN 3+ decreases because of HPV vaccination and
also as new screening and triage tests are introduced. The revised guidelines provide
a framework for incorporating new data and technologies as ongoing incremental recommendation
revisions, minimizing the time needed to implement changes that are beneficial to
patient care.
B. INTRODUCTION
This is the fourth American Society of Colposcopy and Cervical Pathology (ASCCP)-sponsored
consensus guidelines for management of cervical cancer screening abnormalities, after
the original consensus conferences in 2001
1
and subsequent updates in 2006
2
and 2012.
3
An interim guidance publication providing management recommendations for primary HPV
screening was released in 2015.
4
This document updates and replaces all previous guidance. The key difference between
2019 guidelines and previous versions is the change from primarily test results–based
algorithms (e.g., “Colposcopy is recommended for patients with HPV-positive atypical
squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial
lesion [LSIL],” etc.) to primarily “risk-based” guidelines (e.g., “Colposcopy is recommended
for any combination of history and current test results yielding a 4.0% or greater
probability of finding CIN 3+,” etc.). See Box 1 for essential changes. Tables of
risk estimates for possible combinations of current screening test results and screening
history (including unknown history) have been generated from a prospective longitudinal
cohort of more than 1.5 million patients followed for more than a decade at Kaiser
Permanente Northern California (KPNC). All KPNC estimates of risk underlying guideline
decisions are detailed in the accompanying article by Egemen et al.
5
The applicability of these risk estimates to other United States regions and populations
has been confirmed in other data sets from screening programs and clinical trials.
6
Many patients, especially those with minor abnormalities, can be managed by identifying
their risk level using Tables 1A to 5B in Egemen et al
5
and linking it to a recommended clinical action (return to routine screening, surveillance
with repeat testing at 1- or 3-year intervals, colposcopy, or treatment). To facilitate
use of these tables, the same information will be accessible via smartphone app (for
purchase) and web (no cost) through http://www.asccp.org. Decision aids may facilitate
use of the tables.
7
Common abnormalities are managed using risk estimates outlined in Section E, and rare
abnormalities are managed via the result-specific consensus recommendations outlined
in Sections G-K.
TABLE 1
Participating Organizations
Box 1. Essential Changes From Prior Management Guidelines
1) Recommendations are based on risk, not results.
Recommendations of colposcopy, treatment, or surveillance will be based on a patient's
risk of CIN 3+ determined by a combination of current results and history (including
unknown history). The same current test results may yield different management recommendations
depending on the history of recent past test results.
2) Colposcopy can be deferred for certain patients.
Repeat HPV testing or cotesting at 1 year is recommended for patients with minor screening
abnormalities indicating HPV infection with low risk of underlying CIN 3+ (e.g., low-grade
cytologic abnormalities after a documented negative screening HPV test or cotest).
At the 1-year follow-up test, referral to colposcopy is recommended if results remain
abnormal.
3) Guidance for expedited treatment is expanded (i.e., treatment without colposcopic
biopsy).
Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines;
this guidance is now better defined.
For nonpregnant patients 25 years or older, expedited treatment, defined as treatment
without preceding colposcopic biopsy demonstrating CIN 2+, is preferred when the immediate
risk of CIN 3+ is ≥60%, and is acceptable for those with risks between 25% and 60%.
Expedited treatment is preferred for nonpregnant patients 25 years or older with high-grade
squamous intraepithelial lesion (HSIL) cytology and concurrent positive testing for
HPV genotype 16 (HPV 16) (i.e., HPV 16–positive HSIL cytology) and never or rarely
screened patients with HPV-positive HSIL regardless of HPV genotype.
Shared decision-making should be used when considering expedited treatment, especially
for patients with concerns about the potential impact of treatment on pregnancy outcomes.
4) Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN
2 or CIN 3) in the United States. Excision is recommended for adenocarcinoma in situ
(AIS).
5) Observation is preferred to treatment for CIN 1.
Treatment remains acceptable for patients with repeat diagnoses of CIN 1 persisting
2 years or more.
6) Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World
Health Organization (WHO) recommendations for reporting histologic HSIL should include
CIN 2 or CIN 3 qualifiers, i.e., HSIL(CIN 2) and HSIL (CIN 3).
7) All positive HPV tests, regardless of genotype, should have additional reflex triage
testing performed from the same laboratory specimen (e.g., reflex cytology).
Additional testing from the same laboratory specimen is recommended because the findings
may inform colposcopy practice. For example, those with HSIL cytology and concurrent
positive testing for HPV genotype 16 qualify for expedited treatment.
HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional
evaluation (e.g., colposcopy with biopsy) is necessary even when cytology results
are negative.
If HPV 16 and 18 testing is positive, and additional laboratory testing of the same
sample is not feasible, the patient should proceed directly to colposcopy.
8) Continued surveillance with HPV testing or cotesting at 3-year intervals for at
least 25 years is recommended after treatment of histologic HSIL, CIN 2, CIN 3, or
AIS. Continued surveillance at 3-year intervals beyond 25 years is acceptable for
as long as the patient's life expectancy and ability to be screened are not significantly
compromised by serious health issues.
The 2012 guidelines recommended return to 5-year screening intervals and did not specify
when screening should cease. New evidence indicates that risk remains elevated for
at least 25 years, with no evidence that treated patients ever return to risk levels
compatible with 5-year intervals.
Surveillance with cytology alone is acceptable only if testing with HPV or cotesting
is not feasible. Cytology is less sensitive than HPV testing for detection of precancer
and is therefore recommended more often. Cytology is recommended at 6-month intervals
when HPV testing or cotesting is recommended annually. Cytology is recommended annually
when 3-year intervals are recommended for HPV or cotesting.
9) Human papilloma virus assays that are Food and Drug Administration (FDA)-approved
for screening should be used for management according to their regulatory approval
in the United States. (Note: all HPV testing in this document refers to testing for
high-risk HPV types only).
For all management indications, HPV mRNA and HPV DNA tests without FDA approval for
primary screening alone should only be used as a cotest with cytology, unless sufficient,
exceptionally rigorous data are available to support primary HPV testing in management.
The minimum amount of data required to generate a recommendation will include the
patient's age and current test results, as we recognize that previous screening history
is often not known. Increased precision of management guidance will be possible if
information is available on test results within the past 5 years and previous precancer
treatment within the past 25 years.
3
Current results and past history are designed to generate the patient's risk estimate
from data tables.
5
Risk estimates are available for the following clinical situations: abnormal screening
test results with unknown history, abnormal screening test results with medical record
documentation of a preceding negative HPV test or cotest, surveillance of previous
abnormal screening test results that did not require immediate colposcopic referral
(e.g., follow-up after an HPV-positive cytology negative result), colposcopy/biopsy
results, and follow-up surveillance tests after colposcopy or after treatment for,
or resolution of, high-grade abnormalities (e.g., CIN 2+).
The recognition that persistent HPV infection is necessary for developing precancer
and cancer (defined as CIN 3+, which includes diagnoses of CIN 3, AIS, and cancer)
underlies the 2019 guideline update. Prospective longitudinal data indicate that when
a new abnormal screening test result follows a negative HPV test or cotest within
the past 5 years, the estimated risk of CIN 3+ is reduced by approximately 50%.
8
A negative cytology result within 3 years of a new abnormal screening test, however,
does not confer a similar reduction in risk.
9
The 2019 guidelines also recognize that a colposcopic examination performed according
to accepted standards (e.g., using the KPNC colposcopy protocol or the ASCCP Colposcopy
Standards
10
) confirming low-grade or normal histology reduces a patient's estimated risk of having
precancer/cancer in the next 2 years.
11
This allows patients with an HPV-positive ASC-US or LSIL result at their 1-year follow-up
visit after a colposcopy confirming normal- or low-grade histology to return for repeat
HPV or cotesting in 1 more year, rather than immediately return to colposcopy. Thus,
incorporating a patient's history of previous HPV tests and colposcopy/biopsy results
will permit detection and treatment of CIN 3+ while avoiding unnecessary interventions
for patients with new HPV infections who are at lower risk.
12
C. GUIDING PRINCIPLES
Guidelines are based on several guiding principles. The first 4 guiding principles
are new for 2019, whereas the others are from the 2012 guidelines. As the 2012 guidelines
are familiar to providers, we changed management recommendations only when new evidence
favored an altered management strategy. Note that management guidelines apply only
to patients with current or previous abnormal screening test results; screening guidelines
for individuals in the general population, that are not being followed for a screening
abnormality, are addressed elsewhere.
13,14
New 2019 Principles
1. HPV–based testing is the basis for risk estimation. The term HPV-based testing
is used throughout this document and refers to use of either primary HPV testing alone
or HPV testing in conjunction with cervical cytology (cotesting).
Characteristics of HPV infections, including HPV type and the duration of infection,
determine a patient's risk of CIN 3+.
15–18
Although cytology has high specificity (apart from ASC-US) and can be helpful when
estimating immediate risk, its lower sensitivity and lower negative predictive value
compared with HPV testing reduces its utility for long-term risk prediction.
9
The results of HPV tests alone or in conjunction with cytology are used to guide recommendations
that allow lengthening of follow-up intervals and deferral of colposcopy for low-risk
results. Of note, risk estimates underlying the 2019 management guidelines are based
on HPV DNA testing.
2.
Personalized risk-based management is possible with knowledge of current results and
past history. A patient's risk of having or developing CIN 3+ is estimated based on
current and previous results, as well as history of previous precancer treatment.
Management recommendations use thresholds of risk.
19
Recommendations of routine screening, 1-year or 3-year surveillance, colposcopy, or
treatment correspond to a risk stratum, a range of risk for CIN 3+. The lower threshold
of each risk stratum, called Clinical Action Threshold, defines the level at which
the management recommendation changes. The Clinical Action Thresholds for each risk
stratum were determined through the consensus process. Risks were estimated for all
combination of current results and past history (including unknown history) for which
adequate data were available at KPNC. Management can be determined via look-up tables,
5
and use of the tables can be facilitated using decision aids.
3.
Guidelines must allow updates to incorporate new test methods as they are validated,
and to adjust for decreasing CIN3+ risks as more patients who received HPV vaccination
reach screening age. The field of cervical cancer prevention is rapidly evolving,
with new technologies being continually validated. Data on the validation of new technologies
are being published frequently, and risk reduction from HPV vaccination is increasing
as vaccine coverage increases and vaccinated individuals age into screening cohorts.
Up to now, guideline revisions have required full consensus conferences, which are
time-consuming, expensive, and not compatible with the rapid evolution of the field.
The 2019 guidelines build a framework that allows incorporation of new technologies
and modified strategies without requiring full consensus conferences, so that revisions
may rapidly incorporate new findings and be quickly disseminated to optimize patient
care.
Clinical Action Thresholds for management created through the 2019 consensus process
will remain in place, but as new tests become available and more long-term data accrue,
the test combinations used to reach these thresholds will change. For example, at
the 2019 consensus conference, HPV vaccination levels in the United States population
currently 25 years or older were deemed too low to warrant incorporating HPV vaccination
into the 2019 management recommendations. However, this is expected to change in the
near future as more vaccinated patients, who have lower CIN 3+ risk, reach the age
of 25 years and additional data accrue demonstrating the impact of vaccination on
the CIN 3+ risk associated with abnormal test result combinations. The framework outlined
here will allow guideline modification as robust data become available and are publicized.
Because Clinical Action Thresholds remain constant, new data can be added while the
Clinical Action Thresholds remain unchanged. This design is intentional to reduce
clinician confusion associated with frequently changing guidelines.
4.
Colposcopy practice must follow guidance detailed in the ASCCP Colposcopy Standards.
10
Colposcopy with targeted biopsy remains the primary method of detecting precancers
requiring treatment. Because patients are managed less aggressively after a colposcopic
examination where CIN grade 2 or higher (CIN 2+) is not found, maximizing detection
of CIN 2+ at each colposcopy visit is paramount. Evidence-based practice recommends
that biopsies be taken of all discrete acetowhite areas, usually 2 to 4 biopsies at
each colposcopic examination. For those at lowest risk, defined as less than HSIL
cytology, no evidence of HPV 16/18 infection, and a completely normal colposcopic
impression (i.e., no acetowhitening, metaplasia, or other visible abnormality, and
a fully visualized squamocolumnar junction), untargeted (random) biopsies are not
recommended and patients with a completely normal colposcopic impression can be observed
without biopsy. To ensure that CIN 2+ is not missed, the ASCCP Colposcopy Standards
emphasize the need for biopsies even when the colposcopic impression is normal but
any degree of acetowhitening, metaplasia, or other abnormality is present.
2012 Principles Carried Forward
5.
The primary goal of screening and management is cancer prevention through detection
and treatment of cervical precancer. Numerous population-level studies indicate that
incidence and mortality from cervical cancer decrease as detection and treatment of
high-grade histologic cervical abnormalities (generally defined as CIN 2+) increases.
20,21
Timely detection and treatment of the highest grade of precancers (CIN 3/AIS) have
been the benchmark used for previous guidelines
3
and remain the primary goal of the 2019 management guideline; a secondary goal (because
of the relative rarity of this finding in the United States) is early diagnosis of
cervical cancer to reduce related morbidity and mortality. A patient's risk of having
or developing CIN 3+ is estimated based on current and previous results, as well as
history of previous precancer treatment. Management recommendations are guided by
risk thresholds.
19
Recommendations of routine screening, 1- or 3-year surveillance, colposcopy, or treatment
each correspond to a risk stratum. These risk strata (ranges of risk for CIN 3+) are
defined by Clinical Action Thresholds that were determined through the consensus process
(Section E).
6.
Guidelines apply to all individuals with a cervix. Guidelines apply to women and transgender
men with a cervix, including individuals who have undergone supracervical hysterectomy.
Risk estimates were validated in individuals of diverse racial, ethnic, and socioeconomic
backgrounds and shown to be comparable.
6
Though not the primary focus of the 2019 guidelines, management recommendations are
also provided for patients who have undergone hysterectomy with removal of the cervix
and who have a previous diagnosis of histologic HSIL, CIN 2, CIN 2/3, CIN 3, and/or
AIS, irrespective of whether the hysterectomy was performed for precancer treatment
or another indication.
7.
Equal management for equal risk. History and current test results are used to calculate
a patient's current and future risk of CIN 3+. Similar risks are managed similarly,
regardless of the combination of results/history used to estimate the risk.
8.
Balancing benefits and harms. Providing the best care means balancing cancer prevention
with overtesting and overtreatment. Preventing all cervical cancers is unfortunately
not an achievable goal. Interventions to prevent cervical cancer can cause harm. The
2019 guidelines are designed to maximize cervical cancer prevention and minimize harms
from overtesting and overtreating by managing patients according to their current
and future risks of CIN 3+. High-risk patients require closer follow-up to maximize
detection of CIN 3+, whereas low-risk patients require fewer tests and procedures.
9.
Guidelines apply to asymptomatic patients that require management of abnormal cervical
screening test results. Patients with symptoms such as abnormal uterine or vaginal
bleeding or a visibly abnormal-appearing cervix require appropriate diagnostic testing
as this may be a sign of cancer.
22
This evaluation may include cervical cytology, colposcopy, diagnostic imaging, and
cervical, endocervical, or endometrial biopsy. Guidelines cannot cover all clinical
situations and clinical judgment is advised, especially in those circumstances which
are not covered by the 2019 guidelines.
10.
Guidelines are intended for use in the United States. Appropriate management may differ
in countries with limited follow-up capabilities, less availability of colposcopy,
limited pathology infrastructure, or different views of the trade-offs between cancer
risk, cost, and overtesting/overtreatment.
D. METHODS
D.1 Process and Timeline
The ASCCP and National Cancer Institute (NCI) established a Memorandum of Understanding
in January 2017 to undertake the work of this guideline update. As with the previous
2001, 2006, and 2012 guidelines,
1–3
NCI produced risk data and other scientific support for the consensus guideline process.
The ASCCP sponsored the consensus effort to develop and ratify the guidelines. Stakeholder
organizations representing best practice in the United States were identified and
invited to participate. These included medical professional societies, patient advocacy
groups, and federal agencies integral to cervical cancer screening and management
of abnormal results (see Table 1). Participation of the stakeholder organizations
included identifying organization representatives and, for nongovernment participants,
sponsoring their travel to consensus conferences. Representatives from 19 organizations
attended the initial meeting in February 2018. At that time, 7 working groups were
convened. In previous consensus conferences, working groups considered specific test
outcomes (e.g., ASC-US/HPV-positive) and special populations. In contrast, the 7 working
groups for the 2019 guidelines were organized with the goal of establishing consensus
Clinical Action Thresholds.
The treatment group evaluated which risk levels of CIN 3+ warrant expedited treatment
without confirmatory biopsy, as well as addressing treatment-related issues.
The colposcopy group considered the threshold for colposcopy referral.
The surveillance group created a hierarchy of retesting at shorter intervals than
currently recommended for routine screening with either HPV primary testing or cotesting
(5 years) and also examined when patients could return to routine screening. Patients
undergoing surveillance include those with minimally abnormal screening results not
requiring colposcopy (e.g., HPV-positive Negative for Intraepithelial Lesion or Malignancy
[NILM]), after colposcopy with low-grade results, or after treatment for high-grade
abnormality.
The risk modification group evaluated factors that might change a patient's estimated
risk or management, focusing on pregnancy and immunosuppression.
The high value care group performed decision analyses related to proposed management
strategies and will continue to assess value as the 2019 guidelines are implemented.
The new technologies group evaluated laboratory terminology and emerging technologies
specifically related to management.
The communications group created and reviewed relevant content for public communication
to both clinicians and the lay public about the guidelines and the development process.
Working groups were composed of 2 to 8 members, including representatives of participating
stakeholder organizations, content experts, and nonclinician representatives of patient
advocacy organizations. Working groups met regularly from summer 2018 through fall
2019 to review data and develop guidelines for management. The consensus process was
overseen by a 23-person steering committee convened by the ASCCP and was directed
by a leadership team consisting of 1 NCI representative (M.S.) and 2 ASCCP representatives
(R.G., R.P.). Because the guidelines represent a paradigm shift, the guidelines process
included a deliberate and extensive process of stakeholder engagement. These included
patient and provider surveys, a consensus meeting to review preliminary guidelines,
and a 6-week open public comment period before the final consensus voting meeting
in October 2019.
23
D.2 Choice of CIN 3+ as Main Clinical End Point for Risk Estimates
For the management guidelines, we chose CIN 3+ as the best surrogate for cancer risk.
The definition of CIN 3+ as used in these guidelines includes CIN 3, AIS, and the
rare cases of invasive cervical cancer that are found in screening programs. These
management guidelines consider CIN 3+ risk at the time point relevant for the clinical
action being considered—Clinical Action Thresholds for colposcopy and treatment consider
immediate risks of CIN 3+, whereas longer-term surveillance recommendations use 5-year
risks.
CIN3+ was chosen as an endpoint instead of cancer because cancer is uncommon in the
United States, and risk is profoundly decreased by precursor treatment. Cancers that
are found in robust screening programs may represent cancers already prevalent at
first screening, rare instances of aggressive or HPV-negative tumors not detectable
by screening, or false negative results.
24
CIN 3+ was chosen instead of CIN 2+ because it is a more pathologically reproducible
diagnosis,
25
the HPV type distribution in CIN 3+ lesions more closely approximates that of invasive
cervical cancers than the larger range of types found in CIN 2,
15–18,26
and CIN 2 has appreciable regression rates in the absence of treatment.
27–29
The choice of CIN 3+ does have some limitations, as even among CIN 3/AIS lesions,
risks of progression to cancer differ. Glandular lesions including AIS, lesions with
HPV 16 and 18 infections, and those occurring in older patients have higher cancer
risks than HPV-negative lesions and those occurring in younger patients.
30
Different nomenclatures for cervical histopathology are in use in the United States.
The LAST Project and the WHO recommend a 2-tiered terminology (histologic LSIL/HSIL)
for reporting histopathology of HPV-associated squamous lesions, similar to the Bethesda
system used for reporting cervical cytology.
31,32
However, the CIN nomenclature is still commonly used, and data used to generate this
set of guidelines relied on CIN nomenclature. Although no direct correlation is possible
without use of the p16 biomarker, histologic HSIL is similar but not identical to
CIN 2/3.
33
D.3 Multiple Data Sets Used to Validate Risks
Prior guidelines relied heavily on a large prospective data set including results
of cytology, HPV testing, colposcopy, histology, and follow-up outcomes from KPNC,
which adopted triennial cotesting as standard practice in 2003. The KPNC data continue
to be the largest, most comprehensive data source in the United States for risk estimation
of combinations of HPV DNA testing and cytology. For the 2019 guidelines, several
additional databases were analyzed to ensure that results are applicable to patients
of diverse racial, ethnic, and socioeconomic strata. Risk estimates were compared
using screening and follow-up data from clinical trials (BD Onclarity registrational
trials),
34,35
a state registry (New Mexico HPV Pap Registry
36,37
), and the Centers for Disease Control and Prevention's (CDC's) National Breast and
Cervical Cancer Early Detection Program, a national program that includes many low-income
and minority patients.
38
The populations vary in rates of abnormal screening results and the prevalence of
CIN 3+. Nonetheless, the comparison showed that the risks of CIN 3+ for the specific
combination of current results and screening history were similar in that they fell
within the same risk bands for management. Cheung et al
6
demonstrates the similarity of CIN 3+ risks associated with screening test result
combinations among the different populations of screened patients from these data
sets. In summary, different populations within the United States have higher or lower
rates of CIN 3+ due to factors including access to screening and HPV infection prevalence.
Nonetheless, patients with similar test results and screening history combinations
have largely similar CIN 3+ risk, regardless of their geographic location, race, ethnicity,
or socioeconomic status.
D.4 Estimation of Risks
Details of how risks of CIN 3+ were calculated for the many combinations of test results,
including longitudinal series of tests over time, are described in the accompanying
Methods article.
6
In brief, for each combination of past and current test results, the risk of CIN 3+
was estimated using prevalence-incidence mixture models,
39
which consist of joint estimation of prevalent CIN 3+ at the time of the current testing
using a logistic regression model, and incident CIN 3+ at subsequent testing using
a proportional hazards model. These joint models are designed to handle verification
bias and interval censoring. Verification bias in this context means that histopathologic
outcomes are only available for patients referred to colposcopy; thus, CIN3+ cases
that occur in the setting of false negative screening or abnormal screening tests
that were not referred for colposcopy will not be detected. Interval censoring in
this context means that the CIN 3+ is diagnosed at colposcopy visits, but the actual
time of onset of incident CIN 3+ cannot be determined as it is typically asymptomatic
and occurs between testing visits. These flexible models are designed to provide risk
estimates without forcing the data into a rigid distribution assumption (e.g., Weibull).
D.5 Assigning Combinations of Test Results to Clinical Actions
For each combination of current test results and screening history (including unknown
history), recommended management was determined by first estimating immediate and
5-year risk of CIN 3+. The estimated risk was compared with the proposed Clinical
Action Thresholds to determine management recommendation, under the principle of “equal
management for equal risk.” For example, HPV-positive ASC-US and LSIL cytology have
very similar risks of CIN 3+ and are therefore managed similarly. For some rare combinations
of test results, too few patients developed CIN 3+ to estimate risk with statistical
certainty. In these situations, a combination of published literature, previous guidelines,
and expert consensus opinion were used to develop recommendations.
D.6 Rating the Recommendations
Recommendation strength (A–E) and quality of evidence (I–III) were graded using the
system that has been used for previous consensus guidelines (Table 2). Two types of
evidence were considered to be strong enough to permit a level A recommendation: (a)
systematic literature reviews of trials and observational studies, evaluated by the
new technologies group using the QUADAS-2 adapted criteria to inform risk estimates
for the guidelines
40
and (b) reliable risk estimates from the KPNC prospective longitudinal cohort study.
Reliable point estimates are defined as having an 80% certainty of falling within
the risk bounds for the recommended management (based on the standard errors of the
immediate and 5-year risk estimates) (e.g., colposcopy and surveillance respectively)
6
High-quality evidence from systematic reviews and reliable risk estimates from KPNC
are considered level 2 evidence. Strong recommendations against a management option
(level E) rarely had substantial evidence because the obvious risk of harm precluded
a clinical trial (e.g., endometrial biopsy in pregnancy). When neither primary data
nor literature provided high-level evidence, previous guidelines or newly developed
expert consensus opinions were used (level 3 evidence), usually leading to a C recommendation.
Some recommendations are endorsements of guidelines from other organizations, which
were not rated. When considering specific guideline recommendations, each group reviewed
evidence derived from systematic reviews of published evidence and primary data from
the KPNC cohort, assessed the strength and consistency of this evidence, and made
recommendations based on quality of data and a balance of benefits and harms.
TABLE 2
Rating the Recommendations
E. PARADIGM SHIFT: CLINICAL ACTION THRESHOLDS
This section explains the paradigm shift from results-based to risk-based guidelines.
We describe the primary Clinical Action Thresholds on which management recommendations
are based and the clinical situations in which these Clinical Action Thresholds are
applied. For most abnormal screening results and subsequent management visits, the
recommendations are based on risks estimated and validated by prospective data from
large cohorts. Clinicians can use the 2019 guidelines to manage their patients via
the tables in Egemen et al
5
or by using an app or website designed to facilitate navigation of the tables available
at http://www.asccp.org, including a no cost version. Sections G to K describe recommendations
for rare clinical situations where management is based on factors other than risk
estimates.
Management recommendations are based on Clinical Action Thresholds and correspond
to risk strata (see Figure 1):
FIGUR'E 1
This figure demonstrates how patient risk is evaluated. For a given current results
and history combination, the immediate CIN 3+ risk is examined. If this risk is 4%
or greater, immediate management via colposcopy or treatment is indicated. If the
immediate risk is less than 4%, the 5-year CIN 3+ risk is examined to determine whether
patients should return in 1, 3, or 5 years.
The 5-year return Clinical Action Threshold approximates the risk for a patient after
a negative screening test using HPV testing or cotesting in the general population,
for whom retesting in 5 years is recommended by national screening guidelines.
13,14
Patients with risks at or below this threshold are recommended to receive routine
screening at 5-year intervals with HPV-based testing (Section E.1).
The 3-year return Clinical Action Threshold approximates the risk for a patient after
a negative cervical cytology screen in the general population, for whom retesting
in 3 years is recommended by national screening guidelines.
13,14
Patients with risks at or below this threshold but above the 5-year threshold are
recommended to receive HPV-based testing in 3 years (Section E.1).
One-year return is recommended for patients with risks above the 3-year threshold
but below the Clinical Action Threshold for colposcopy (Section E.1).
The colposcopy Clinical Action Threshold approximates the risk for a patient after
an HPV-positive ASC-US or LSIL screening result in the general population, for whom
colposcopy is recommended in the 2012 guidelines.
3
Patients with risks at or above this threshold but below the expedited treatment threshold
are recommended to receive colposcopy (Section E.2).
The expedited treatment or colposcopy acceptable Clinical Action Threshold approximates
the risk for a patient after an HPV-positive atypical squamous cells cannot exclude
HSIL (ASC-H) cytology screening result in the general population. Patients with risks
at or above this threshold but below the expedited treatment preferred threshold are
recommended to receive counseling from their providers to choose between evaluation
with colposcopy and biopsy or expedited treatment (Section E.3). Expedited treatment
is defined as treatment without confirmatory colposcopic biopsy.
The expedited treatment preferred Clinical Action Threshold approximates the risk
for a patient after an HPV 16–positive HSIL cytology screening result in the general
population. It is preferred that patients with risks at or above this threshold receive
expedited treatment unless they are pregnant, younger than 25 years, or have concerns
about the potential effects of treatment on future pregnancy outcomes that outweigh
concerns about cancer (Section E.3).
Of note, patients with histologic HSIL (CIN 2) who have chosen observation are recommended
to receive colposcopy and HPV-based testing at 6-month intervals (Section I.3).
E.1 Clinical Action Thresholds Leading to Recommendation of Surveillance
Introduction
Surveillance is defined as follow-up testing at a shorter interval than that currently
recommended for routine screening with either HPV primary testing or cotesting (5
years). Surveillance is recommended for patients whose risk of CIN 3+ based on current
test results and screening history is higher than the risk for the general screening
population, but lower than the risk at which colposcopy is recommended. Unlike colposcopy
and treatment, which are performed as soon as possible after a qualifying abnormal
result, surveillance entails retesting at intervals of 1 to less than 5 years. Therefore,
we used the 5-year risk of CIN 3+ as the estimated risk level when assigning surveillance
Clinical Action Thresholds. Surveillance intervals are defined in Figure 1 and explained
in detail hereinafter. Surveillance thresholds are based on the principle of equal
management for equal risks and were designed to support current screening and surveillance
recommendations, which are generally accepted as a reasonable balance of benefits
and harms.
3
In the 2012 guidelines, intervals of 1 and 3 years were used for surveillance, with
return to routine HPV-based screening at 5 years.
3
Because clinicians and patients are familiar with these intervals, and review of evidence
did not reveal a compelling reason to change these intervals, these intervals are
retained. Note that for observation in very high-risk patients (e.g., untreated CIN2,
AIS treated with conization) colposcopy and repeat testing at 6-month intervals is
recommended.
Guideline: When patients have an estimated 5-year CIN 3+ risk of less than 0.15% based
on past history and current test results, return to routine screening at 5-year intervals
using HPV-based testing is recommended (AII).
Rationale: Using the principle of equal management for equal risk, this Clinical Action
Threshold corresponds to the 5-year CIN 3+ risk after negative HPV-based screening
(HPV testing or cotesting) in the general population (see Table 1A in Egemen et al
5
) for whom national guidelines recommend a 5-year return.
13,14
Estimated 5-year CIN 3+ risks in the KPNC database after a negative HPV test and cotest
are 0.14% (95% CI = 0.13%–0.15%) and 0.12% (95% CI = 0.12%–0.13%), respectively. Note
that cytology alone is never recommended at 5-year intervals.
Guideline: When patients have an estimated 5-year CIN 3+ risk of 0.15% or greater
but less than 0.55% based on history and current test results, repeat testing in 3
years with HPV-based testing is recommended (AII).
Rationale: Using the principle of equal management for equal risk, the 3-year return
Clinical Action Threshold corresponds to the 5-year CIN 3+ risk after negative cervical
cytology in the general population, for whom national guidelines recommend a 3-year
return.
13,14
Estimated 5-year CIN 3+ risks after a negative cytology result without HPV testing
ranged from 0.33% in the KPNC population to 0.52% in the New Mexico HPV Pap Registry,
to an estimated 0.45% in the screened population of the CDC's National Breast and
Cervical Cancer Early Detection Program. Thus, 0.55% was considered an appropriate
value for the Clinical Action Threshold. Three-year surveillance is recommended for
patients whose risk falls between the 3- and 5-year follow-up thresholds. Consistent
with the 2012 guidelines, patients with a low-grade cotest result (e.g., HPV-positive
ASC-US or LSIL) followed by a colposcopy with results of less than CIN 2, followed
in turn by a negative follow-up HPV test or cotest reach the 3-year return threshold
(see Figure 2). Also consistent with previous guidelines, patients with an HPV-negative
ASC-US screening result in the setting of an unknown history can return at 3 years
(estimated 5 year CIN 3+ risk 0.40%).
5
FIGURE 2
This figure demonstrates how a patient with a common low-grade screening abnormality
(HPV-positive ASC-US) would be managed based on risk estimates. The initial screening
result would lead to colposcopy (immediate risk 4.2%). Colposcopy of less than CIN
2 has a 5-year risk of 3.2% (1-year return). At the 1-year return visit, a second
HPV-positive ASC-US result has an immediate risk of 3.1% (1-year return). If the patient
has a repeat abnormal screen at the next follow-up, colposcopy is recommended. If
the HPV-based test is negative, return in 3 years is recommended. NA, not applicable
because stable risk estimates are not available.
Guideline: When patients have an estimated risk of CIN 3+ based on history and current
results that is below the threshold for immediate colposcopy (4.0% immediate risk)
and above the 3-year follow-up threshold (≥0.55% at 5 years), repeat testing in 1
year with HPV-based testing is recommended (AII).
Rationale: One-year surveillance implies close follow-up for those whose risks fall
between the Clinical Action Thresholds for colposcopy and 3-year follow-up. Consistent
with the 2012 consensus recommendations,
3
follow-up at 1 year is recommended after screening tests showing minimal abnormalities:
HPV-positive/NILM or HPV-negative/LSIL with unknown previous screening history (immediate
risks 2.1% and 1.1% respectively
5
); 1-year surveillance is also recommended after colposcopy with biopsies of histologic
LSIL (CIN 1) or less preceded by a low-grade cotest result (defined as HPV-positive
LSIL, HPV-positive ASC-US, or repeated HPV-positive NILM). New data for these guidelines
find that the risk of CIN 3+ is substantially reduced after a documented negative
HPV primary screening test or cotest or normal colposcopic examination with biopsy
confirmation of less than CIN 2.
5
Based on lower CIN 3+ risks, 1-year surveillance, not colposcopy, is recommended for
most patients with new HPV-positive ASC-US or LSIL results after a documented negative
HPV test or cotest within an appropriate screening interval (approximately 5 years)
or colposcopic examination less than CIN 2 within the past year (see Figure 2). Of
note, a previous negative cytology result alone does not reduce subsequent risk like
a negative HPV-based screen; therefore, cytology alone is not used to modify subsequent
management recommendations.
E.2 Clinical Action Threshold Leading to Recommendation of Colposcopy
Guideline: When patients have an estimated immediate risk of diagnosis of CIN 3+ of
4.0% or greater based on history and current results, referral to colposcopy is recommended
(AII).
Rationale: The following principles were used to develop the Clinical Action Threshold
for referral to colposcopy: (a) colposcopy visits recommended by the threshold should
yield information useful for clinical decision-making. Thus, the threshold was based
on the risk of diagnosing CIN 3+ upon immediate referral to colposcopy. (b) In the
absence of a compelling rationale, the colposcopy threshold should be similar to 2012
referral recommendations that are generally accepted as an appropriate balance of
benefits and harms.
The 2001 consensus guidelines
1
were the first to standardize the colposcopy referral threshold, referring patients
with LSIL and HPV-positive ASC-US to colposcopy. This recommendation has been carried
forward through revisions in 2006 and 2012.
2,3
The workgroup reviewed frequently cited studies and noted that immediate risk (CIN
3+ found among patients referred directly to colposcopy) ranged from 3% to 7%.
41–44
Current KPNC data were reviewed,
5
and it was noted that immediate CIN 3+ risk clustered in 3 groups: (a) high-grade
test results (defined as cytology ASC-H, atypical glandular cell [AGC], HSIL, or higher)
having high (>25%) risk; (b) low-grade results (HPV-positive ASC-US or HPV-positive
LSIL cytology with unknown previous screening history and HPV-positive NILM cytology
occurring at 2 consecutive annual visits) having just over 4.0% risk; and (c) result
combinations for which colposcopy has historically not been performed having risks
below 4% (HPV-positive NILM cytology, HPV-negative LSIL cytology, and HPV-negative
ASC-US cytology with unknown previous screening histories). The Clinical Action Threshold
of a 4% immediate CIN 3+ risk was considered a reasonable balance of benefits and
harms as, in a population with unknown screening history, it led to referral of HPV-positive
patients with ASC-US or LSIL cytology, but not the large group of patients with HPV-positive
NILM cytology.
To validate the 4.0% Clinical Action Threshold for colposcopy, the KPNC CIN 3+ prevalent
risk estimates were compared with those from other study populations with more diversity
in sociodemographic characteristics including the New Mexico HPV Pap Registry,
45
CDC's National Breast and Cervical Cancer Early Detection Program, and the BD Onclarity
registrational trials. The 4% threshold functioned similarly.
3,6
The 4.0% immediate risk Clinical Action Threshold has important implications for patients
with at least 1 previous negative HPV-based test because surveillance is recommended
rather than immediate colposcopy for low-grade abnormalities (HPV-positive ASC-US
or LSIL) in patients whose preceding screening result was a negative HPV test or cotest
within a routine screening interval (approximately 5 years).
5
This additional information reduces the immediate CIN 3+ risk to approximately 2%,
leading to a recommendation of 1-year surveillance instead of immediate colposcopy.
Adoption of the 4.0% Clinical Action Threshold reduces the number of patients referred
for colposcopy over 2 rounds of screening from an estimated 9.8%, using the 2012 ASCCP
recommendations, to 8.3% using the 2019 recommendations. Exceptions to the 4.0% threshold,
encompassing results with cancer risk disproportionately higher than CIN 3+ risk,
are discussed in Section H.2.
E.3 Clinical Action Thresholds Leading to Recommendations of Treatment
The primary goal of treatment is cancer prevention through destruction or excision
of precancerous lesions (CIN 3, AIS) to prevent the development of invasive cancer.
In the only known observational study of untreated CIN 3, the long-term risk of developing
invasive cancer was as high as 30% for 30 years
46
; progression rates could not be estimated at KPNC because of high rates of timely
treatment. Because treatment is generally recommended as soon as possible after the
identification of a precancerous lesion, the immediate CIN 3+ risk was used when evaluating
potential thresholds. Historically, the treatment threshold has been histologic CIN
2. The LAST guidelines reports both p16-positive CIN 2 and CIN 3 as histologic HSIL.
Consistent with previous guidelines, the threshold for treatment remains histologic
HSIL/AIS (by LAST terminology) or CIN 2+ (by 3-tiered terminology) except in special
circumstances (Sections I.3, K.1, and K.2). When considering expedited treatment versus
colposcopy with biopsy, clinicians should have a thorough discussion with patients
regarding the risks and benefits. Treatment without preceding histologic confirmation
can be conducted in one visit among those at high immediate risk of CIN 3+. Reasons
for choosing expedited treatment vary and may include personal preference, limited
healthcare access, financial concerns, and cancer-related anxiety. The age cutoff
of 25 years or older for recommending expedited treatment was chosen as an appropriate
balance of benefits and harms due to very low cancer rates and high rates of regression
of precancers among women in this age group.
27,47
Guideline: For nonpregnant patients 25 years or older with an estimated immediate
risk of CIN 3+ of 60% or greater based on history and current results, treatment using
an excisional procedure without previous biopsy confirmation is preferred but colposcopy
with biopsy is acceptable (BII).
Rationale: In the 2012 guidelines, expedited treatment (i.e., without biopsy confirmation)
was an acceptable management option for HSIL cytology.
3
Patients with HSIL cytology undergoing expedited treatment are diagnosed with CIN
3+ in 49% to 75% of cases.
48–52
The KPNC data show similar risks: HPV-positive HSIL cytology has immediate risks of
CIN 3+ and CIN 2+ of 49% and 77%, respectively.
5
Two clinical situations currently exceed the 60% threshold where expedited treatment
is preferred. HSIL cytology that is HPV 16–positive has an immediate CIN 3+ of 60%,
CIN 2+ risks of 77%, and immediate cancer risks of 8.1%.
53
In the CDC's National Breast and Cervical Cancer Early Detection Program, women with
HPV-positive HSIL cytology (regardless of genotype) who were underscreened (generally
defined as no screening in >5 years) had an immediate CIN 3+ risk of 64% and CIN 2+
risks of 82% (cancer risk not available). Based on the KPNC data, for clinical situations
that exceed the 60% threshold, 1.7 patients will receive diagnostic excisional procedures
for every CIN 3+ treated, a low rate of overtreatment.
Guideline: For nonpregnant patients 25 years or older with an estimated immediate
risk of CIN 3+ 25% or greater and less than 60% based on history and current results,
treatment using an excisional procedure without previous biopsy confirmation or histologic
evaluation with colposcopy and biopsy are both acceptable (AII).
Rationale: The 2012 guidelines allow treatment without biopsy-proven histologic confirmation
include patients who have HSIL cytology independent of HPV status. In the KPNC data
set, the 25% to 59% risks strata includes patients with the following results and
immediate CIN 2+/CIN 3+ risks, respectively: (a) HPV-negative HSIL cytology: 47%/25%;
(b) HPV-positive ASC-H cytology: 50%/26%; (c) HPV-positive AGC (all categories): 40%/26%;
and (d) HPV-positive HSIL cytology: 77%/49%. Using this threshold, 2.8 patients will
undergo excisional procedures for every CIN 3+ treated.
E.4 Clinical Situations Leading to Management Recommendations
Patients with abnormal cervical cancer screening results enter management via 5 common
clinical situations: (a) initial management of an abnormal screening test result (see
Tables 1A, B; Egemen et al
5
); (b) return visit for surveillance of a previous abnormal result that did not lead
to colposcopy referral (e.g., HPV-negative ASC-US), with consideration of whether
to continue surveillance or refer to colposcopy (see Tables 2A–C; Egemen et al
5
); (c) evaluation of the colposcopic biopsy results with consideration of whether
to treat or begin postcolposcopy surveillance (see Table 3; Egemen et al
5
); (d) managing test results at the return visit for surveillance after a colposcopic
biopsy showing less than CIN 2 (Tables 4a, b; Egemen et al
5
); and (e) follow-up after treatment of CIN2 or CIN3 (see Tables 5a, 5b; Egemen et
al
5
).
Recommendations are based on risks of immediate and future CIN 3+ diagnoses in light
of current and past results. Regardless of the pathway by which patients enter management,
equivalent risks are managed similarly. For each of the 5 clinical situations, risk
tables and recommendations based on the Clinical Action Thresholds are detailed in
the accompanying article by Egemen et al.
5
The reader is directed to the definitive updated source of risk tables, which are
freely available online (https://CervixCa.nlm.nih.gov/RiskTables). A small percentage
of patients will present with a combination of results and personal characteristics
requiring consideration outside of the available risk data. Management of these special
situations is described in Sections G to K.
F. UPDATES RELATED TO PATHOLOGY REPORTING AND LABORATORY TESTS
Although most of the 2019 guidelines describe clinical management of patients by providers,
the consensus process also addressed laboratory considerations that directly relate
to results reporting and use of ancillary tests.
F.1 Statement on the Use of a 2-Tier Terminology (Histologic LSIL/HSIL) for Reporting
Histopathology of Squamous Lesions of the Lower Anogenital Tract
Guideline: It is important to use p16 immunohistochemical staining according to the
guidance provided by the CAP-ASCCP LAST Project.
31
p16 immunohistochemistry should be used for specific indications as recommended by
the LAST guidelines when interpreting the hematoxylin and eosin (H&E) slide. A positive
p16 immunostain supports the diagnosis of histologic HSIL if the morphological assessment
of H&E slides is consistent with CIN 2 or CIN 3. There is a risk of overcalling cervical
histology results when p16 is used incorrectly. Most importantly, a morphologic CIN
1 on H&E should not be upgraded to histologic HSIL (CIN 2) even if p16 positive.
For epidemiologic and clinical management purposes, it is strongly recommended to
qualify a histologic HSIL result by CIN 2 or CIN 3, according to the options given
by the LAST guidelines (example histologic HSIL [CIN 2]).
Rationale: This CIN qualification can have clinical importance (e.g., to identify
cases of CIN 2 in patients for whom conservative management is an acceptable option).
It is also important for postvaccine surveillance studies and quality control assessments
of cervical precancer that have historically relied on CIN 2 and CIN 3 end points.
Furthermore, it is important for future research efforts to distinguish diagnoses
of histologic HSIL (CIN 2) from HSIL (CIN 3) so that diagnostic categories are compatible
with the histologic end points used for current guidelines.
In 2012, consensus recommendations were published on the use of a 2-tiered terminology
for reporting histopathology of squamous lesions of the anogenital tract by the College
of American Pathologists and the ASCCP.
31
The central components of the LAST guidelines include a 2-tiered nomenclature that
distinguishes histologic LSIL and histologic HSIL and recommendations for the use
of adjunctive p16 immunohistochemistry to assist interpretation of anogenital histology.
p16 is a tissue marker of HPV oncogene overexpression and transformation and can support
histologic assessment.
Current guidelines are based on CIN 3 end points, the most reliable correlate of a
cervical precancer. Currently, there are insufficient data to evaluate risk estimates
with histologic HSIL end points. Recent studies have shown that distinguishing CIN
2 and CIN 3 within the LAST histologic HSIL group is biologically and clinically meaningful.
33
Although some studies have shown that p16 immunohistochemistry improves interpretation
of cervical biopsies, others have raised concerns about overuse and overdiagnosis.
54–59
F.2 Updated Management of Primary HPV Screening (Replaces Interim Guidance)
Guideline: When primary HPV screening is used, performance of an additional reflex
triage test (e.g., reflex cytology) for all positive HPV tests regardless of genotype
is preferred (this includes tests positive for genotypes HPV 16/18) (CIII). However,
if primary HPV screening test genotyping results are HPV 16 or HPV 18 positive and
reflex triage testing from the same laboratory specimen is not feasible, referral
for colposcopy before obtaining additional testing is acceptable (CIII). If genotyping
for HPV 16 or HPV 18 is positive, and triage testing is not performed before the colposcopy,
collection of an additional triage test (e.g., cytology) at the colposcopy visit is
recommended (CIII).
Rationale: The US FDA approved the cobas HPV test (Roche, Indianapolis, IN), in March
2014, and the Onclarity HPV Test (Becton Dickinson, Franklin Lakes, NJ), in April
2018, for primary HPV testing for screening for patients 25 years or older.
60
Both these tests offer and are approved for partial HPV genotyping. Use of primary
HPV screening will likely increase in the future, as it is more effective than screening
with cytology alone and performs similarly to and with lower costs than screening
with cotesting.
4,42
Because HPV–16 positive and HPV 18–positive test results have the highest risk of
CIN 3 and occult cancers, additional diagnostic procedures are recommended for all
positive test results (e.g., colposcopy with biopsy for NILM and low-grade cytology
and expedited treatment for HSIL cytology that is positive for HPV type 16). This
guideline replaces interim guidance (2015) for the management of a positive result
for HPV primary screening, which recommended direct referral to colposcopy for HPV
test results positive for HPV 16 and/or HPV 18, and performance of cytology for positive
results due to other (non-16/18) high-risk HPV types.
4
The immediate risk of CIN3+ in patients with HPV 16–positive and HSIL cytology exceeds
the treatment threshold of 60%; therefore, these patients should be given the option
for expedited treatment without preceding confirmatory biopsy (see Section E.3). Expedited
treatment is only possible if cytology is performed. Therefore, reflex cytology is
recommended for all HPV-positive primary screening results, regardless of HPV genotype.
If reflex testing from the same laboratory specimen as the HPV test is not feasible,
patients should proceed directly to colposcopy.
4
In this situation, collection of an additional triage test (e.g., cytology) is recommended
at the time of colposcopy to provide further information for risk-based management
(e.g., if HPV 16–positive HSIL cytology is identified, treatment may be considered
even if CIN 2+ is not identified on biopsy). Combining a test with high specificity
(e.g., cytology when it is interpreted as HSIL) with a test with high sensitivity
(i.e., HPV test) allows more precise, risk-based management of these patients.
F.3 Statement on HPV Tests Used in Management
Guideline: HPV assays should be used for management according to their regulatory
approval for screening, unless there are sufficient data to support use of the assay
differently (AI).
Rationale: Several HPV assays have been approved in the United States for clinical
use in screening and triage.
61
None of these assays have specific indications for management, but they are widely
used for postcolposcopy and posttreatment surveillance. For these indications, HPV
assays approved for screening should be used according to their regulatory approval.
For example, when an HPV test has been approved for cotesting, it should be used in
management in the context of cotesting, unless there are sufficient, exceptionally
rigorous data to support use of the assay differently (e.g., as outlined in Clarke
et al.
40
). Approved assays include target- and signal-amplification assays of HPV DNA, as
well as HPV mRNA. Most FDA-approved HPV DNA assays have similar performance characteristics.
62
Most assays are approved for adjunct testing with cytology (also referred to as cotesting),
whereas a subset of HPV DNA assays have also been approved for primary HPV testing
alone, without concomitant cytology.
G. RARE CYTOLOGY RESULTS
G.1 Evaluation of Cytology Interpreted as AGC or AIS
Guideline: For nonpregnant patients of all ages with all subcategories of AGC and
AIS, except when atypical endometrial cells are specified, colposcopy is recommended
regardless of HPV test result; endocervical sampling is recommended at initial colposcopy
except in pregnancy (for management in pregnancy, see Section K.2) (AII). Accordingly,
triage by reflex HPV testing is not recommended, and triage by repeat cytology is
unacceptable (DII). Endometrial sampling is recommended in conjunction with colposcopy
and endocervical sampling in nonpregnant patients 35 years or older with all categories
of AGC and AIS (AII). Endometrial sampling is also recommended for nonpregnant patients
younger than 35 years at increased risk of endometrial neoplasia based on clinical
indications (e.g., abnormal uterine bleeding, conditions suggesting chronic anovulation,
or obesity) (AII). For patients with atypical endometrial cells specified, initial
evaluation limited to endometrial and endocervical sampling is preferred, with colposcopy
acceptable at the time of initial evaluation. If colposcopy was deferred and no endometrial
pathology is identified, additional evaluation with colposcopy is then recommended
(see Figure 3).
FIGURE 3
This figure describes the initial workup of AGC found on cervical cytology.
Subsequent Management
Guideline: For patients with cytology showing AGC not otherwise specified or atypical
endocervical cells not otherwise specified in whom histologic HSIL (CIN 2+) or AIS/cancer
is not identified, cotesting at 1 and 2 years is recommended. If both cotests are
negative, repeat cotesting at 3 years is recommended. If any test is abnormal, then
colposcopy is recommended (BII). If CIN 2 or CIN 3 but no glandular lesion is identified
histologically for patients with cytology atypical glandular, endocervical, or endometrial
cells not otherwise specified, management should be according to the 2019 guidelines
for the lesion diagnosed (Section I) (CII). For patients with atypical glandular or
endocervical cells “favor neoplasia” or endocervical AIS cytology, if invasive disease
is not identified during initial colposcopic workup, a diagnostic excisional procedure
is recommended. The diagnostic excisional procedure used in this setting should provide
an intact specimen with interpretable margins (BII). Endocervical sampling above the
excisional bed is preferred (BII) (see Figure 4).
FIGURE 4
This figure describes follow-up management that should occur after the diagnostic
examinations described in Figure 3.
Rationale: Atypical glandular cells on cytology is a poorly reproducible diagnostic
category.
63
Positive HPV test results, especially when positive for HPV type 18, can be indicative
of higher risk of CIN 2+ lesions. However, colposcopy is recommended for all patients
regardless of HPV result. Literature is limited, and comparisons between studies are
difficult because of inconsistent use of the Bethesda system for classification of
AGC.
64
Atypical glandular cells can be associated with polyps and metaplasia as well as adenocarcinomas
of the cervix; cancers of the endometrium, fallopian tube, ovary, and other sites
are also found, especially in older women who test HPV negative.
65,66
Using the Bethesda terminology, AGC, favor neoplasia, or adenocarcinoma cytology is
frequently indicative of invasive or preinvasive disease.
64
For this reason, diagnostic excisional procedures are recommended even when histologic
HSIL or AIS has not been identified. Cytologic AGC results are associated with a histologic
diagnosis of AIS in 3% to 4%, CIN 2+ in 9%, and invasive cancer in 2% to 3%.
67–69
In the KPNC data, HPV-positive AGC (all categories) had an immediate CIN 3+ risk of
26% and HPV-negative AGC had an immediate CIN 3+ risk of 1.1%. Consistent with other
literature, cotest results of HPV-positive AGC favor neoplasia or adenocarcinoma had
an immediate CIN 3+ risk of 55%, whereas other HPV-positive AGC categories had immediate
CIN 3+ risks of approximately 20%. Although endometrial cancer is rare in premenopausal
patients without risk factors, the prevalence of premenopausal endometrial cancer
is increasing, underscoring the importance of endometrial sampling when indicated.
70,71
G.2 Unsatisfactory Cytology
Guideline: For patients with an unsatisfactory cytology result and no, unknown, or
a negative HPV test result, repeat age-based screening (cytology, cotest, or primary
HPV test) in 2 to 4 months is recommended (BIII). Triage using HPV testing is not
recommended (DIII). Before repeat cytology, treatment to resolve atrophy or obscuring
inflammation when a specific infection is present is acceptable (CIII). For patients
25 years and older who are cotested and have unsatisfactory cytology and a positive
HPV test without genotyping, repeat cytology in 2 to 4 months or colposcopy is acceptable
(BII). If a positive HPV test with partial genotyping is positive for HPV 16 or HPV
18, direct referral for colposcopy is recommended (BII) (see Figure 5).
FIGURE 5
This figure describes the steps involved in clinical management of unsatisfactory
cytology. Note that “unknown genotype” refers to both HPV testing without genotyping,
and HPV testing where genotyping is negative for HPV 16 and 18 but positive for other
high-risk HPV types.
Rationale: Literature was reviewed from 2012 to 2019, and no evidence was found to
change recommendations.
72–82
When cotesting is performed, a negative HPV test in the setting of an unsatisfactory
cytology may reflect an inadequate sample. Although a negative HPV test (performed
from the same vial as the cytology) may be adequate for testing even when the cytology
cellularity is inadequate for diagnosis, interpreting the HPV result in the setting
of insufficient cellularity has not been validated, which is of concern given that
repeat testing is not recommended for up to 5 years after a negative HPV screen. Negative
results on HPV tests that are not FDA approved for primary cervical cancer screening
should not be considered valid in the absence of adequate cytology (Section F.3).
In summary, a negative HPV result from a cotest with inadequate cellularity on cytology
should not be interpreted as negative primary HPV test and should be repeated.
G.3 Absent Transformation Zone on Screening Cytology
Guideline: For patients aged 21 to 29 years with negative screening cytology and absent
endocervical cells/transformation zone component (i.e., endocervical cells or squamous
metaplastic cells), routine screening is recommended (BIII). When cervical cytology
alone is performed for screening, HPV testing as a triage test after negative cytology
and absent endocervical cells/transformation zone component in this age group is unacceptable
(DIII). For patients 30 years or older with NILM cytology and absent endocervical
cells/transformation zone component and no or unknown HPV test result, HPV testing
is preferred (BIII). Repeat cytology in 3 years is acceptable if HPV testing is not
performed (BIII). If HPV testing is performed, manage using Clinical Action Thresholds
according to 2019 consensus guidelines (see Figure 6).
FIGURE 6
This figure describes the steps involved in clinical management of cytology that is
negative for intraepithelial lesion or malignancy, but with absent transformation
zone or endocervical cells.
Rationale: Literature reviewed for the 2012 guidelines indicated a lower risk of CIN
3+ for patients with absent transformation zone/endocervical cells than those with
cells present, leading to a recommendation to manage these results similarly.
3
The HPV testing is preferred in women 30 years or older to facilitate subsequent risk-based
management. A review of the literature from 2012 to 2019 on whether the absence of
a transformation zone component (TZ/EC, i.e., endocervical cells or squamous metaplastic
cells) on NILM cytology slides affected patients' subsequent risks of histologic HSIL
(CIN 2, CIN 3) diagnoses showed no evidence to change the 2012 recommendations.
83,84
G.4 Benign Endometrial Cells in Premenopausal Patients or Benign Glandular Cells in
Posthysterectomy Patients
Guideline: For asymptomatic premenopausal patients with benign endometrial cells,
endometrial stromal cells, or histiocytes, no further evaluation is recommended (BII).
For postmenopausal patients with benign endometrial cells, endometrial assessment
is recommended (BII). For posthysterectomy patients with a cytology report of benign
glandular cells, no further evaluation is recommended (BII).
Rationale: In the Bethesda system for reporting cervical cytology, cytologically benign-appearing
endometrial cells are reported in women 45 years or older under the “other” general
category, and follow-up left to the clinical provider. Benign glandular cells in women
after hysterectomy are reported in the negative (NILM) Bethesda category. Literature
review for the 2012 guidelines indicated increased risk of endometrial pathology in
postmenopausal patients with endometrial cells on cytology but did not indicate increased
endometrial cancer risk for premenopausal patients with benign endometrial cells in
the absence abnormal uterine bleeding.
3
The literature review was updated using a PubMed search for recent publications since
2012 that address benign-appearing endometrial cells in postmenopausal and glandular
cells in posthysterectomy individuals. References were reviewed and no evidence was
found to change the 2012 recommendations.
85–93
H. COLPOSCOPY PRACTICE STANDARDS AND EXCEPTIONS TO COLPOSCOPY CLINICAL ACTION THRESHOLD
H.1 ASCCP Colposcopy Standards
The ASCCP Risk-Based Management Consensus Guidelines reaffirm that colposcopy should
be practiced according to the ASCCP Colposcopy Standards.
10,94
For those at lowest risk, defined as less than HSIL cytology, no evidence of HPV 16/18
infection, and a completely normal colposcopic impression (i.e., no acetowhitening,
metaplasia, or other visible abnormality, and a fully visualized squamocolumnar junction),
untargeted (random), biopsies are not recommended and patients with a completely normal
colposcopic impression can be observed without biopsy. For those not meeting the lowest
risk criteria, multiple targeted biopsies, at least 2 and up to 4, are recommended
targeting all acetowhite areas to improve detection of prevalent precancers. The ASCCP
Colposcopy Standards emphasize the need for biopsies even when the colposcopic impression
is normal but any degree of acetowhitening, metaplasia, or other abnormality is present
to ensure that CIN 2+ is not missed.
94
As more patients are allowed to defer colposcopy under the ASCCP Risk-Based Management
Consensus guidelines, obtaining adequate biopsies to effectively rule out CIN 2+ at
each colposcopy examination is paramount.
Note that the KPNC colposcopy protocols precede the Colposcopy Standards and are based
on 4-quadrant biopsies and an ECC that were widely conducted in KPNC. The recommendations
against untargeted biopsies are based on the risk of occult CIN 2+ of 1% to 7% and
CIN 3+ of less than 1% among patients with less than HSIL cytology, HPV 16/18 negative,
and normal colposcopic impression. This indicates that management recommendations
using the ASCCP Colposcopy Standards would be equivalent to those using KPNC protocols
in nearly all cases. The most recent recommendations pertaining to the use of ECC
are from the 2012 guidelines, restated here for clarity: ECC is preferred for non-pregnant
patients when colposcopy is inadequate, in those not at lowest risk in whom no lesion
is identified, and is acceptable when a lesion is seen.
H.2 Exceptions to Colposcopy Threshold
Guideline: For patients with ASC-H cytology, colposcopy is recommended regardless
of HPV result (AII).
Rationale: In the KPNC data, HPV-negative ASC-H and HPV-positive ASC-H had very different
CIN 3+ rates, but similar cancer rates. The HPV–positive ASC-H had an immediate CIN
3+ risk of 26% and a cancer risk of 0.92%, whereas HPV-negative ASC-H had an immediate
CIN 3+ risk of 3.4%, but an immediate cancer risk of 0.69%. Because the immediate
cancer risk for ASC-H is disproportionately high compared with the CIN 3+ risk, the
working group carried forward the 2012 recommendations and recommended colposcopy
for all patients with ASC-H, regardless of HPV test results.
3
Guideline: For patients with HPV 18–positive NILM, colposcopy is recommended (AII).
(Note colposcopy is also recommended for HPV 16–positive NILM, repeated here for clarity.)
Rationale: HPV 18–positive NILM had a 3.0% prevalent CIN 3+ risk, less than the Clinical
Action Threshold for colposcopy. However, HPV 18–positive NILM had a disproportionately
high cancer risk compared with other results: 0.2% immediately and 0.56% at 5 years.
This suggests that HPV 18-related CIN 3 or AIS may be difficult to diagnose and/or
more apt to rapidly progress from precancer to cancer. The elevated cancer prevalence
with HPV 18 positivity has been previously noted,
95
and HPV 18 is one of the most common HPV types found in invasive cervical cancers.
96
Given the elevated cancer risk, referral to colposcopy is recommended.
Guideline: Colposcopy should be performed after 2 consecutive unsatisfactory screening
tests (CIII).
Rationale: No new evidence was found, so the 2012 guideline was carried forward.
3
I. MANAGING HISTOLOGY RESULTS
Treatment Considerations for Patients 25 Years or Older
Individuals who exceed treatment thresholds may undergo expedited treatment, defined
as excisional treatment without preceding histologic confirmation. However, most patients
will require both screening test and colposcopic biopsy results to determine the next
step in management. The following section outlines guiding principles to consider
when managing these results. Treatment guidelines are dichotomized by younger than
25 years or 25 years or older because of high spontaneous regression rates of HPV
infection and CIN 2 and low incidence of cancer in those younger than 25 years. Individuals
younger than 25 years are discussed under Special Populations (Section K). The term
“young women” is no longer used. The consensus guidelines recognize that patients
of various ages are concerned with the potential impact of treatment on future pregnancy
outcomes. Shared decision-making is especially critical when individuals consider
treatment of histologic HSIL (CIN 2) and abnormalities with a relatively low likelihood
of underlying CIN 3+, such as histologic LSIL (CIN 1) preceded by HSIL or ASC-H cytology,
or persistent histologic LSIL (CIN 1).
I.1 Management of Histologic HSIL, not Further Specified or Qualified
Histologic reporting of cervical biopsies has moved to the LAST/WHO criteria, but
its uptake by pathologists has not been universal. The consensus recommendation of
the LAST guidelines (Section F.1) is to qualify histologic HSIL using the CIN nomenclature
(CIN 2 or CIN 3). Because of measurable regression rates for CIN 2,
26
the present guidelines subdivide treatment options based on the CIN qualifiers of
CIN 2 and CIN 3. However, pathology reports incorporating the LAST criteria may not
specify a CIN diagnosis.
Guideline: Treatment is preferred if histologic HSIL cannot be specified (e.g., reported
as histologic HSIL or histologic HSIL [CIN 2,3]) (CIII) (see Figure 7).
FIGURE 7
This figure describes the steps involved in clinical management of histologic HSIL.
Rationale: CIN 3 is considered a direct cervical cancer precursor. If CIN 3 cannot
be excluded, managing the patient as if CIN 3 is present is preferred. This conservative
approach was considered safest for patients. Alternatively, the clinician could call
the pathologist to further qualify the CIN equivalent and issue an additional report,
then manage using the revised diagnosis.
I.2 Management of Histologic HSIL (CIN 2 or CIN 3)
Guideline: In all nonpregnant patients with a diagnosis of histologic HSIL (CIN 3),
treatment is recommended and observation is unacceptable (AII). In nonpregnant patients
with histologic HSIL (CIN 2), treatment is recommended, unless the patient's concerns
about the effect of treatment on future pregnancy outweigh concerns about cancer (BII).
Observation is unacceptable when the squamocolumnar junction or the upper limit of
the lesion is not fully visualized or when the results of an endocervical sampling,
if performed, is CIN 2+ or ungraded (EIII) (see Figure 7).
3
Rationale: As CIN 3 is considered an immediate cancer precursor, treatment is always
recommended and observation is never acceptable, except during pregnancy (Section
K.2). Observation is acceptable for CIN 2 in patients concerned about the potential
effects of treatment on future pregnancy outcomes.
Guideline: When treatment of histologic HSIL is planned, excisional treatment is preferred,
and treatment with ablation is acceptable (BI). Outside of the setting of a clinical
research trial, nonsurgical therapies, including topical agents, therapeutic vaccines,
and other biologics, are unacceptable for the treatment of histologic HSIL (CIN 2
or CIN 3) (DIII). Hysterectomy is unacceptable as primary therapy solely for the treatment
of histologic HSIL (CIN 2, CIN 3, or unqualified) (EII). When considering ablative
therapy, in particular cryotherapy, ablation is unacceptable in the following circumstances.
as defined by the WHO: (a) the lesion extends into the canal and (b) when the lesion
covers more than 75% of the surface area of the ectocervix or extends beyond the cryotip
being used.
97
Additional situations for which cryotherapy is not recommended include the following:
(a) the squamocolumnar junction or the upper limit of any lesion is not fully visualized;
(b) endocervical canal sample is diagnosed as CIN 2+ or CIN that cannot be graded;
(c) after previous treatment for CIN 2+; (d) in the setting of inadequate biopsies
of the cervix to confirm histologic diagnosis; and (e) if cancer is suspected (EIII).
Rationale: The WHO recommends LEEP over cryotherapy in settings where LEEP is “available
and accessible.”
97
In the United States, excisional treatment is used more commonly than ablation treatment
for the treatment of histologic HSIL. Excisional therapy consists of loop electrosurgical
excision procedure (LEEP or LLETZ), cold knife conization, and laser cone biopsy.
Ablation treatment includes cryotherapy, laser ablation, and thermoablation.
98
Few recent data have compared the effectiveness of excisional and ablative therapy.
Most recent studies evaluating ablative therapies have been performed outside of the
United States, primarily in low-resource settings. A meta-analysis of randomized trials
demonstrated a CIN recurrence rate of 26.6% at 12 months after LEEP compared 31.0%
for cryotherapy.
99
However, another meta-analysis calculated that the recurrence rate of CIN 2–3 was
5.3% after both cryotherapy and LEEP and 1.4% after cold knife conization. More adverse
events were noted with cold knife conization than with LEEP, and more with LEEP than
with cryotherapy.
100
A Cochrane review comparing surgical techniques for treatment of CIN concluded that
no technique was clearly superior in terms of treatment failure or associated morbidity.
101
However, for high-grade abnormalities, LEEP has the benefit of providing a histologic
specimen, which may reveal a higher grade of squamous abnormality or a glandular abnormality,
and also provides information on margin status, a predictor of CIN 2+ persistence
or recurrence.
102,103
Laser ablation differs from other ablative techniques and, when performed by highly
experienced providers, may be appropriate in special circumstances including treatment
of large cervical lesions or when lesion extends to the vagina, provided all other
criteria for ablation are met.
I.3 Management of CIN 2 in Those Who Are Concerned About the Potential Effect of Treatment
on Future Pregnancy Outcomes
Guideline: For patients with a diagnosis of histologic HSIL (CIN 2) whose concerns
about the effects of treatment on a future pregnancy outweigh their concerns about
cancer, either observation or treatment is acceptable provided the squamocolumnar
junction is visible and CIN 2+ or ungraded CIN is not identified on endocervical sampling
(CII) (see Figure 8). If the histologic HSIL cannot be specified as CIN 2, treatment
is preferred, but observation is acceptable (CIII). For patients 25 years or older,
observation includes colposcopy and HPV-based testing at 6-month intervals for up
to 2 years (See Section K.1 for management age of younger than 25 years). If during
surveillance, all evaluations demonstrate less than CIN 2 and less than ASC-H on 2
successive occasions, 6 months apart, subsequent surveillance should occur at 1 year
after the second evaluation and use HPV-based testing. If negative on 3 consecutive
annual surveillance tests, proceed to long-term surveillance (Section J.3). If CIN
2 remains present for a 2-year period, treatment is recommended (CII) (see Figure
8).
FIGURE 8
This figure describes management of CIN 2 in patients whose concerns about the effects
of treatment on a future pregnancy outweigh their concerns about cancer. Also addressed
is the management of histologic HSIL not further specified in women younger than 25
years, for whom observation is acceptable, and for women 25 years or older for whom
treatment is preferred.
Rationale: Unlike CIN 3, which is considered a direct cancer precursor, CIN 2 has
an appreciable regression rate. A systematic review and meta-analysis of studies from
1973 to 2016 indicated that among CIN 2 managed conservatively, 50% regressed, 32%
persisted, and 18% progressed to CIN 3+. Notably, most regression occurred within
the first 12 months, whereas rates of progression continued to increase over time.
Regression rates were higher (60%) in women younger than 30 years.
29
A recent study at the KPNC of 2,417 patients followed for a median of 48 months with
colposcopy and cotesting at 6-month intervals found similar results: 50% regressed
to CIN 1 or less, though remained in intensive surveillance for persistent HPV positivity,
30% were treated for persistence or progression, and 20% returned to routine screening.
Six patients in the KPNC cohort developed cervical cancer, half of whom had significant
follow-up delays.
27
The primary rationale for deferring treatment of CIN 2 is the potential risk of adverse
obstetric outcomes after excisional or ablative therapy; however, the magnitude of
this risk is debated.
104
Studies are complicated by the finding that patients with untreated CIN have a higher
risk of premature delivery than the general population.
105,106
Although several studies have concluded that excision is associated with increased
risk of preterm birth, especially as excision depth increases,
104,105,107–109
others have found no such association after adjustment for potential confounding factors.
110–113
Ablation treatment seems to have little or no effect on adverse pregnancy outcomes.
105,107,108,114
A Cochrane Review concluded that results should be interpreted with caution because
of data being of low or very low quality.
105
I.4 Management of LSIL (CIN 1) or Less Preceded by ASC-H or HSIL Cytology
Guideline: When CIN 2+ is not identified histologically after an ASC-H or HSIL cytology
result, it is acceptable to review the cytologic, histologic, and colposcopic findings.
If the review yields a revised interpretation, management should follow guidelines
for the revised diagnosis (CIII). When CIN 2+ is not identified, HSIL cytology is
managed more aggressively than ASC-H cytology. For cytology showing HSIL, but biopsy
showing histologic LSIL (CIN 1) or less, either an immediate diagnostic excisional
procedure or observation with HPV-based testing and colposcopy at 1 year is acceptable,
provided in the latter case that the initial colposcopic examination fully visualized
the squamocolumnar junction and the upper limit of any lesion, and that the endocervical
sampling, if collected, was less than CIN 2 (BII). For ASC-H, if the colposcopic examination
can fully visualize the squamocolumnar junction and the upper limit of any lesion
and that the endocervical sampling, if collected, is negative, observation at 1 year
with HPV-based testing is recommended; a diagnostic excisional procedure is not recommended
(BII). For both HSIL and ASC-H cytology, if observation is elected, and all tests
are negative at the 1-year visit, repeat HPV-based testing is recommended in 1 year
(at 2 years from the original cytology). If all tests are negative at both the 1-
and 2-year follow-up visits, return for retesting with HPV-based testing in 3 years
is recommended, then proceed with long-term surveillance (Section J.3). If any test
is abnormal during the observation period, repeat colposcopy is recommended, and management
based on resulting biopsies is recommended. A diagnostic excisional procedure is recommended
for patients with HSIL cytology results at either the 1- or 2-year visit, or ASC-H
results that persist at the 2-year visit (CIII) (see Figures 9, 10).
FIGURE 9
This figure describes management of histologic LSIL (CIN 1) preceded by HSIL cytology.
FIGURE 10
This figure describes management of histologic LSIL (CIN 1) preceded by ASC-H cytology.
Rationale: Patients with a diagnosis of histologic LSIL (CIN 1) after HSIL and ASC-H
cytology have 1-year CIN 3+ risks of 3.9% and 1.4%, respectively.
5
Because HSIL cytology is associated with a higher risk than ASC-H cytology, colposcopy
is recommended in addition to HPV-based testing at the 1-year follow-up if excision
is not elected. Failure to detect CIN 2+ at colposcopy in patients with HSIL cytology
does not mean that a CIN 2+ lesion has been excluded, although occult carcinoma is
unlikely. As a result, patients with HSIL cytology who do not have immediate diagnostic
excision require close follow-up. Few studies of HSIL cytology managed without treatment
have been reported, and follow-up in those is limited; management relies on expert
opinion.
3
Of note, at all colposcopic examination when no lesion is identified on the cervix,
the vagina and vulva must be examined for vaginal or vulvar intraepithelial neoplasia.
I.5 Histologic LSIL (CIN 1) Diagnosed Repeatedly for at Least 2 Years
Guideline: For patients 25 years or older with histologic LSIL (CIN 1) who is diagnosed
at consecutive visits for at least 2 years, observation is preferred (BII) but treatment
is acceptable (CIII). If treatment is selected and the entire squamocolumnar junction
and all lesions were fully visualized during colposcopic examination, either excision
or ablation treatments are acceptable (CII).
Rationale: Histologic LSIL (CIN 1) is the histologic manifestation of HPV infection.
CIN 1 may be associated with oncogenic (high-risk) or low-risk HPV infections and
may be due to persistent infection with 1 type or sequential infections with different
types. HPV 16 is less common in CIN 1 than in CIN 3.
3
Histologic LSIL (CIN 1) and cytologic ASC-US/HPV+ and LSIL are the same biologically
and thus should be managed similarly. Regression rates are high, especially in younger
patients, and subsequent diagnosis of CIN 2+ is uncommon regardless of whether CIN
1 is found on endocervical sampling or a biopsy of the transformation zone.
3,115
The KPNC data showed a similar, relatively low 5-year risk of CIN 3+ of approximately
2% when CIN 1 or no lesion was found on colposcopy/biopsy after HPV-positive cytologic
ASC-US or LSIL. In the KPNC data set of individuals with CIN 1 on biopsy on 2 consecutive
visits, the subsequent follow-up demonstrated that 52% were HPV negative, 48% were
HPV positive, and of the HPV-positive group, 92% had NILM, ASC-US, or LSIL cytology.
A study of 126 women undergoing LEEP for CIN 1 diagnosed at consecutive visits for
2 years found that 87% had CIN 1 or negative pathology, whereas 13% had histologic
HSIL (CIN 2+).
116
Based on these data, and considering the potential harms of treatment, the present
recommendations prefer continued observation of those with histologic LSIL (CIN1)
diagnosed on consecutive visits for at least 2 years. Treatment is an acceptable option
based on patient preference, after shared decision-making. Because the immediate estimated
CIN3+ risk is less than the 25% treatment threshold, this is considered a special
situation.
I.6 Management of AIS: Adoption of Society of Gynecologic Oncology Recommendations
The Society of Gynecologic Oncology recently completed guidelines on the management
of AIS; recommendations were adopted by the 2019 ASCCP Risk-Based Management Guidelines
consensus committee and are summarized below. Evidence is not graded as the consensus
committee did not perform primary data review.
Guideline: A diagnostic excisional procedure is recommended for all patients with
a diagnosis of AIS on cervical biopsy to rule out invasive adenocarcinoma, even when
definitive hysterectomy is planned. Excisional procedures should optimally remove
an intact specimen to facilitate accurate interpretation of margin status. Although
there is no preference for cold knife conization versus LEEP, intentional disruption
of the specimen by performance of a LEEP followed by a “top hat” endocervical excision
to achieve the desired specimen length is unacceptable. An excisional specimen length
of at least 10 mm is preferred, and this can be increased to 18 to 20 mm for patients
who are not concerned about the effect of treatment on future pregnancy. These dimensions
are preferred regardless of whether hysterectomy is planned.
After the initial diagnostic procedure, hysterectomy is the preferred management for
all patients who have a histologic diagnosis of AIS, although fertility-sparing management
for appropriately selected patients is acceptable. For patients with confirmed AIS
with negative margins on the excisional specimen, simple hysterectomy is preferred.
For patients with confirmed AIS with positive margins on the excisional specimen,
re-excision to achieve negative margins is preferred, even if hysterectomy is planned.
For patients with AIS and persistent positive margins for whom additional excisional
procedures are not feasible, either a simple or modified radical hysterectomy is acceptable.
After hysterectomy, surveillance per the ASCCP surveillance guidelines for treated
CIN 2+ is recommended (Section J.3).
For patients of reproductive age who desire future pregnancy, fertility-sparing management
with an excisional procedure is acceptable provided that negative margins have been
achieved on the excisional specimen, and the patient is willing and able to adhere
to surveillance recommendations. If negative margins cannot be achieved after maximal
excisional attempts, fertility-sparing management is not recommended. For patients
who undergo fertility-sparing management, surveillance with cotesting and endocervical
sampling is recommended every 6 months for at least 3 years, then annually for at
least 2 years, or until hysterectomy is performed. For patients who have consistently
negative cotesting and endocervical sampling results for 5 years, extending the surveillance
interval to every 3 years starting in the sixth year of surveillance is acceptable.
Small retrospective studies have shown HPV test results to be the best predictor for
recurrent disease. Therefore, for patients who have consistently negative cotesting
and endocervical sampling results, continued surveillance is acceptable after completion
of childbearing. For patients who have had positive HPV test results or abnormal cytology/histologic
results during surveillance, hysterectomy at the completion of childbearing is preferred
(see Figure 11).
FIGURE 11
This figure describes management of AIS. This management algorithm was developed by
the Society of Gynecologic Oncology and endorsed by the ASCCP Risk-Based Management
Consensus process.
Rationale: The Society of Gynecologic Oncology recently conducted a literature review
and is publishing recommendations for management of AIS. The ASCCP recommendations
adopted the Society of Gynecologic Oncology recommendations, and additional details
are provided in the Society of Gynecologic Oncology reference.
117
A brief summary of the rationale is provided below. Hysterectomy is recommended for
AIS for several reasons. Adenocarcinoma in situ is frequently located within the endocervical
canal and colposcopic changes may be minimal; therefore, determination of the necessary
length of a cervical excisional specimen may be difficult. Adenocarcinoma in situ
also has a higher risk of being multifocal, so negative margins on an excisional procedure
specimen do not ensure complete excision of disease. Importantly, in the setting of
histologic AIS on biopsy, invasive cancer cannot be excluded without a diagnostic
excisional procedure. Finally, although increased detection and treatment of squamous
cell cancer precursors (e.g., CIN 3) is associated with a decrease in the incidence
of invasive squamous cell carcinoma, the same has not been demonstrated for AIS.
118
Because of the challenges in diagnosing and monitoring AIS, hysterectomy remains the
standard treatment for AIS for patients who do not desire future pregnancy. For patients
desiring future pregnancy, observation after an excisional procedure remains an option,
but this carries a less than 10% risk of recurrent AIS and a small risk of invasive
cancer even with negative margins. Both margin status and endocervical sampling performed
at the time of excisional procedure predict residual disease and risk of invasive
cancer on hysterectomy specimen. After treatment, HPV tests results are the strongest
predictor for recurrent AIS.
119–122
J. SURVEILLANCE AFTER ABNORMALITIES
J.1 Guidance for Specific Tests and Testing Intervals When Managing Abnormal Results
Guideline: After abnormal cervical cancer screening test results for patients 25 years
or older, colposcopic biopsy results, or treatment of histologic HSIL, surveillance
with either HPV testing alone or cotesting is preferred (AI). Surveillance with cervical
cytology alone is acceptable only if testing with HPV or cotesting is not feasible
(CIII). Cytology is recommended at 6-month intervals when 1-year intervals are recommended
for HPV or cotesting, and annually when 3-year intervals are recommended for HPV or
cotesting (AII). Cytology should be used for patients younger than 25 years, with
transition to HPV-based testing at 25 years or older (AII).
Rationale: Individuals treated for histologic HSIL or with a recent abnormal screening
test result have an elevated risk of cervical precancer warranting close follow-up.
5,123
HPV testing and cotesting are more sensitive than cytology alone in detecting CIN
2+ in both the postcolposcopy and posttreatment settings.
124–126
As there is marginal difference between cotesting and HPV testing alone in detection
of recurrent or persistent CIN 2+, either test may be used for surveillance.
126,127
Because cytology is less sensitive than HPV or cotesting, cytology must be performed
more frequently to achieve similar sensitivity for the detection of CIN 3+. For example,
in cases of low-grade cytology followed by colposcopy/biopsy less than CIN 2, follow-up
testing at 1 year is recommended. If the follow-up test is an HPV test with negative
results, the 5-year CIN 3+ risk is 0.51%, consistent with a 3-year return. However,
if the follow-up test is cytology only with negative results, the 5-year CIN 3+ risk
is 1.5%, consistent with a 1-year return.
J.2 Short-Term Follow-up After Treatment for Histologic HSIL
Guideline: After treatment, HPV-based testing at 6 months is preferred regardless
of the margin status of the excisional specimen (BII) (see Figure 7). If HPV-based
tests are positive, colposcopy and appropriate biopsies should be performed (AII).
Follow-up at 6 months with colposcopy and ECC is acceptable (BIII).
When margins are positive for CIN 2+ or ECC performed at the time of the excisional
procedure shows CIN 2+ in patients 25 years or older who are not concerned about the
potential effect of treatment on future pregnancy outcomes, repeat excision or observation
is acceptable. For observation, HPV-based testing in 6 months is preferred; it is
also acceptable to perform a colposcopy and ECC at 6 months. For patients younger
than 25 years or those who are concerned about the potential effect of treatment on
future pregnancy outcomes, observation is recommended. (See Section J.3 for subsequent
management). If recurrent histologic HSIL (CIN 2+) develops after excisional treatment,
and repeat excision is not feasible or not desired, hysterectomy is recommended (see
Figure 7).
Rationale: The preferential use of HPV-based testing (cotesting or HPV primary testing)
is supported by evidence that posttreatment HPV testing is the most accurate predictor
of treatment outcome.
125
Although the relative risk of persistent or recurrent histologic HSIL (CIN 2+) is
almost 5 times higher after excisional treatment with positive margins compared with
negative margins (RR = 4.8; 95% CI = 3.2–7.2),
103
only 56% (95% CI, 49–66%) of persistent/recurrent precancer was predicted by positive
margin status. The poor ability for margin status to predict persistent/recurrent
precancer argues against differentiating follow-up testing by margin status alone.
In contrast, the ability of HPV-based testing to predict persistent/recurrent histologic
HSIL (CIN 2+) is 91% (95% CI = 82%–96%) and does not differ significantly between
patients with positive versus negative margins. The absolute risk of persistent/recurrent
histologic HSIL (CIN 2+) after excision with positive margins is 17% (95% CI = 13–22%).
However, repeat excisional treatment without repeat testing is considered acceptable
for certain patients after appropriate counseling and consideration of age, likelihood
of subsequent resolution of histologic HSIL/HPV infection, concern for the effect
of treatment on future pregnancy, and ability to adhere to surveillance recommendations.
J.3 Guidance for Long-Term Follow-up After Treatment for High-Grade Histology or Cytology
Guideline: In patients treated for histologic or cytologic HSIL, after the initial
HPV-based test at 6 months, annual HPV or cotesting is preferred until 3 consecutive
negative tests have been obtained (AII). After the initial intensive surveillance
period, continued surveillance at 3-year intervals is recommended for at least 25
years after treatment of high-grade histology (histologic HSIL, CIN 2, CIN 3, or AIS)
or high-grade cytology (HSIL or persistent ASC-H) even if this is beyond the age of
65 years (BII). When patients with a history of treated high-grade histology or cytology
reach the age of 65 years, if they have completed the initial 25-year surveillance
period, continued surveillance at 3-year intervals is acceptable and may continue
as long as the patient is in reasonably good health (BIII). Discontinuation of screening
is recommended if a patient has a limited life expectancy. Management according to
the highest-grade abnormality found on histology or cytology is recommended.
Rationale: According to KPNC data, the 5-year CIN 3+ risks after treatment of CIN
3 for 1, 2, and 3 negative cotests/primary HPV tests were 1.7%/2.0%, 0.68%/0.91%,
and 0.35%/0.44%, respectively.
5
Therefore, annual surveillance by cotesting or HPV testing is recommended until 3
negative annual HPV-based tests have been obtained. After a third negative HPV-based
test, KPNC data suggest that the 5-year CIN 3+ risk remains above the 0.15% threshold
for return to routine, 5-year HPV-based cervical screening. Long-term population studies
support this finding, as they demonstrate a persistent twofold increase in cervical
cancer risk after treatment of histologic HSIL. Risk persists for at least 25 years
and seems to be increased for patients older than 50 years.
123,128,129
Therefore, continued 3-year surveillance is recommended for a minimum of 25 years.
As cervical cancer risk seems to remain above general population levels,
123
continued screening for as long the patient remains in good health is acceptable.
J.4 Guidance for Long-Term Follow-up After Low-Grade Cytology (HPV-Positive NILM,
ASC-US, or LSIL) or Histologic LSIL (CIN 1) Abnormalities Without Evidence of Histologic
or Cytologic High-Grade Abnormalities
Guideline: Among patients initially diagnosed with low-grade cytology or histologic
abnormalities or HPV infections, continued surveillance according to risk estimation
using available data is recommended (CIII).
Rationale: The 5-year CIN 3+ risks for abnormal screening test results without evidence
of cytologic or histologic HSIL followed by negative HPV-based testing were 0.51%
after the first negative test and 0.23% after the second negative test. Thus, patients
reach criteria for a 3-year return after the second negative HPV-based test.
5
The ability to perform accurate risk estimation for 3 or more rounds of negative testing
after abnormalities is limited by very small numbers of CIN 3+ diagnoses in patients
with persistently negative follow-up testing after low-grade cytologic or histologic
abnormalities. We estimated risk for two common scenarios related to long-term negative
follow-up. The first was HPV+/NILM followed by 3 rounds of negative cotesting. At
KPNC, the estimated 5-year CIN 3+ risk was 0.17% (95% CI = 0.14%–0.44%), therefore
continued testing at 3-year intervals is recommended at this time. The second group
included patients with low-grade abnormalities, who underwent colposcopy at which
CIN2+ was not found, and then had 3 rounds of negative cotesting. This group had an
estimated 5-year CIN3+ risk of 0.03% (95% CI= 0.0–0.19%), and thus does qualify for
return to a 5-year interval. The 5-year CIN3+ risks for various clinical scenarios
will be re-estimated as either longer-term follow-up accrue or risk modification based
on genotyping are available, and publicly available tables will be modified accordingly
(https://CervixCa.nlm.nih.gov/RiskTables).
K. SPECIAL POPULATIONS
Introduction: Guidelines described previously apply to the average risk individual
with an intact cervix and are based primarily on screening and management data from
patients aged 25 to 65 years in the KPNC population. However, several populations
require special management considerations. Management of patients who are younger
than 25 years, pregnant, immunosuppressed, posthysterectomy, and older than 65 years
are detailed hereinafter.
K.1 Management of Patients Younger Than 25 Years
In the 2012 guidelines, patients aged 21 to 24 years were considered to be a special
population. In the current guidelines, the consensus was to reference this group as
“patients younger than 25 years.”
Initial Management After an Abnormal Screening Test Result
Guideline: In patients younger than 25 years with low-grade cytology screening results
of LSIL, ASC-US HPV-positive, or ASC-US without HPV testing, repeat cytology alone
at 1 and 2 years after the initial abnormal result is recommended (BII). Colposcopy
is recommended if high-grade cytology is found at any point (HSIL, ASC-H, AGC, AIS)
or if low-grade cytology persists at the 2-year follow-up visit (BII). If reflex HPV
testing for ASC-US is performed and the results are negative, repeat cytology in 3
years is recommended (BII). After 2 consecutive negative cytology results, return
to routine age-based screening is recommended (BII). If colposcopy is performed and
the results are less than CIN 2 (i.e., histologic LSIL [CIN 1] or less), repeat cytology
in 1 year (BII), and manage as above (e.g., repeat cytology for ASC-US/LSIL, colposcopy
for ASC-H or higher). Clinicians should switch to using risk estimates when patients
reach the age of 25 years (see Figures 12, 13).
FIGURE 12
This figure describes management of cytologic abnormalities in patients younger than
25 years.
FIGURE 13
This figure describes management of histologic LSIL (CIN 1) in patients younger than
25 years.
Rationale: HPV vaccination became available in the United States in 2006, and patients
at the target age for vaccination have now entered the younger than 25-year age group.
130
Consequently, population-level risks of CIN 3+ for a given screening results are expected
to decrease through a combination of individual and herd immunity. Observation is
indicated for low-grade cytology results (ASC-US, LSIL), which are likely to represent
non-16/18 HPV infections with a high probability for regression and low risk for rapid
progression to cancer. Accurate risk estimation for this age group is very difficult
because vaccination is rapidly changing population-level CIN 3+ risk and the conservative
2012 management guidelines recommend against colposcopy/biopsy for lesser cytology
abnormalities, which limits the ability to accurately measure CIN 3+ rates in this
age group. Therefore, in the absence of new compelling data to change management in
this age group, the 2012 algorithms are carried forward. The guidelines outlined in
this document are designed to adapt to changes in population vaccination coverage
as well as new technologies, and we anticipate that incorporating HPV vaccination
effects on the population-level prevalence of HPV infections will affect management
recommendations in the near future.
Management of Cytology ASC-H and HSIL in Patients Younger Than 25 Years
Guideline: Colposcopy is recommended for patients younger than 25 years with ASC-H
or HSIL cytology (AII). Immediate treatment without histologic confirmation is not
recommended (see Figure 13).
Rationale: Although overall CIN 3+ prevalence is lower, cytology results of ASC-H
are associated with higher risks of CIN 3+ than ASC-US, even in patients younger than
25.
3
Therefore, colposcopy is warranted to evaluate the cervix for CIN 3+. Immediate treatment
without histologic confirmation is not warranted in this population because of the
high rate of resolution of CIN 2+ and the potential harms of treatment.
Management of Histology of Less Than CIN 2 Preceded by Cytology ASC-H and HSIL in
Patients Younger Than 25 Years
Guideline: Observation is recommended and diagnostic excisional procedures are not
recommended for patients younger than 25 years with a preceding cytology of ASC-H
or HSIL and a colposcopy with biopsy of CIN 1 or less as long as the squamocolumnar
junction and the upper limit of all lesions are fully visualized, the endocervical
sampling is less than CIN 2, and review of histology/cytology does not change the
diagnosis. Observation with colposcopy and cytology in 1 and 2 years is recommended
for those with HSIL cytology. Cytology at 1 and 2 years is recommended for those with
ASC-H cytology, with colposcopy recommended for ASC-US or above on repeat testing.
If CIN 2+ is diagnosed, this is managed per guidelines described in the following
section. If a high-grade cytologic abnormality (HSIL, ASC-H) without histologic HSIL
persists for 2 years, a diagnostic excisional procedure is recommended (unless the
patient is pregnant). A diagnostic excisional procedure is recommended in patients
when the squamocolumnar junction or the upper limit of all lesions are not fully visualized
(see Figures 9, 10).
Rationale: CIN 1 or less preceded by cytologic ASC-H or HSIL is a rare diagnosis and
not well represented in the KPNC population. The rationale for conservative management
of this clinical situation is discussed in Section I.4.
Management of Histologic HSIL (CIN 2 or CIN 3) for Patients Younger Than 25 Years
Guideline: In patients younger than 25 years with histologic HSIL (CIN 3), treatment
is recommended, and observation is unacceptable (EII). In patients younger than 25
years with histologic HSIL (CIN 2), observation is preferred, and treatment is acceptable
(BII). In patients younger than 25 years with histologic HSIL unspecified as CIN 2
or CIN 3, observation or treatment is acceptable. Observation includes colposcopy
and cytology at 6-month intervals. If during surveillance of histologic HSIL, all
cytology results are less than ASC-H and histology results are less than CIN 2 at
6 and 12 months, subsequent surveillance should be at 1 year after the second evaluation.
If CIN 2 or unspecified histologic HSIL persists for a 2-year period, treatment is
recommended. Excisional treatment is recommended when the squamocolumnar junction
or the lesion(s) are not fully visualized (see Figure 8).
Rationale: Cervical cancer is uncommon in patients younger than 25 years despite the
high prevalence of HPV infections and high-grade histologic lesions (especially CIN
2).
16,131
Younger patients have higher rates of regression for histologic HSIL (particularly
CIN 2) and lower risks of progression to invasive cancer.
26,27,132,133
Therefore, less intensive management strategies that do not include HPV testing are
appropriate for this population. The exception is CIN 3, which is considered a direct
cervical cancer precursor and should be treated at any age.
K.2 Managing Patients During Pregnancy
Guideline: In pregnancy, management of abnormal screening results using the same Clinical
Action Thresholds for surveillance and colposcopy established for nonpregnant patients
is recommended (CIII). Endocervical curettage, endometrial biopsy, and treatment without
biopsy are unacceptable during pregnancy (EIII). A diagnostic excisional procedure
or repeat biopsy is recommended only if cancer is suspected based on cytology, colposcopy,
or histology (BII). If histologic HSIL (CIN 2 or CIN 3) is diagnosed at the first
colposcopy examination during pregnancy, surveillance colposcopy and testing (diagnostic
cytology/HPV depending on age) is preferred every 12 to 24 weeks, but deferring colposcopy
to the postpartum period is acceptable (BII). Repeat biopsy is recommended if invasion
is suspected or the appearance of the lesion worsens (BII). Treatment of histologic
HSIL (CIN 2 or CIN 3) during pregnancy is not recommended (DII). If AIS is diagnosed
during pregnancy, referral to a gynecologic oncologist is preferred, but management
by a gynecologist skilled in the colposcopic diagnosis and treatment of AIS is acceptable
(CIII).
In the postpartum period, colposcopy is recommended no earlier than 4 weeks after
delivery (BII). In patients diagnosed with histologic HSIL (CIN2 or CIN3) during pregnancy,
if a lesion is detected at postpartum colposcopy, an excisional treatment procedure
or full diagnostic evaluation (cervical cytology, HPV, and biopsy) is acceptable (BII).
In the absence of a lesion on colposcopy, a full diagnostic evaluation is recommended;
expedited treatment is not recommended (BII).
Rationale: Pregnancy was considered as a special population in which to consider management
and treatment options that weigh the risk to fetus and mother versus the risk of missing
cancer. Rate of progression to cancer is not thought to be different in pregnancy.
The 2012 management guidelines for pregnant patients were considered,
3
and literature published since 2012 was reviewed.
134–139
The adoption of Clinical Action Thresholds in 2019 necessitated modification of the
2012 guidelines, which were based on test results. Although the risk of precancer
is not known to be elevated among pregnant patients, cervical hyperemia and other
physiologic changes of pregnancy may impact the likelihood of precancer and cancer
detection. Colposcopist experience, specifically in the evaluation of the pregnant
patient, is known to affect the ability to visually distinguish cancers from pregnancy-related
changes, increasing the risk of a missed cancer diagnosis. Colposcopy by an experienced
provider during pregnancy is preferred.
The intervals recommended for follow-up are relatively wide taking into consideration
the experience and comfort level of the colposcopist, gestational age of the fetus,
and the potential for loss to follow-up. Pregnancy does not seem to alter the risk
for or rate of progression from cervical precancer to cancer, and colposcopy-directed
biopsies in pregnant patients seem to be safe. The 2019 guidelines allow deferral
of colposcopy for minor abnormalities in women with prior negative HPV testing or
colposcopic examinations at which CIN2+ was not found. Therefore, women referred for
colposcopy under the 2019 guidelines will have higher risk of prevalent CIN3+ due
to either lack of prior screening or persistent HPV infections. In general, data in
pregnancy are limited, however, and shared decision-making taking into account both
the pregnant patient and the fetus is critical for management.
Although the risk for progression to cancer during a pregnancy is low, an estimated
11% of new mothers lose their health insurance in the postpartum period. This loss
of healthcare access disproportionately affects those most at risk for cervical cancer;
rates of noninsurance may be 2 to 3 times as high among low-income and minority patients,
as well as those living in states that did not expand Medicaid.
140
For individuals who do not qualify for health insurance before pregnancy, pregnancy
care is a unique event that facilitates entry into health care coverage. However,
Medicaid coverage often terminates at the end of the calendar month in which the delivery
occurred or at 6 to 8 weeks postpartum. Because most deliveries in the United States
are to individuals with Medicaid, pregnancy may provide an opportunity to identify
cancer precursors and even cancer in this population. Healthcare access was considered
when developing guidelines. Individuals who are screened infrequently or are unable
to complete appropriate follow-up are at increased risk for developing cervical cancer.
141
K.3 Managing Patients With Immunosuppression
Immunocompromised patients include those with HIV, solid organ transplant, or allogeneic
hematopoietic stem cell transplant, as well as those with systemic lupus erythematous,
and those with inflammatory bowel disease or rheumatologic disease requiring current
immunosuppressive treatments. The cervical cancer screening guidelines for persons
living with HIV have been supported by an increasing number of publications, including
prospective studies. Although the literature for other immunosuppressed populations
remains limited, these other conditions that suppress cell-mediated immunity have
also been associated with virally induced cancers, including cervical cancer.
142,143
Therefore, cervical cancer screening and abnormal result management recommendations
for immunocompromised individuals without HIV use the guidelines developed for people
living with HIV
144
: screening should begin within 1 year of first insertional sexual activity and continue
throughout a patient's lifetime: annually for 3 years, then every 3 years (cytology
only) until the age of 30 years, and then either continuing with cytology alone or
cotesting every 3 years after the age of 30 years.
Guideline: In immunocompromised patients of any age, colposcopy referral is recommended
for all results cytology results of HPV-positive ASC-US or higher. If HPV testing
is not performed on ASC-US results, then repeat cytology in 6 to 12 months is recommended,
with colposcopy referral for ASC-US or higher. For any result of ASC-US or higher
on repeat cytology or if HPV positive, referral to colposcopy is recommended. For
all cytology results of LSIL or worse (including ASC-H, AGC, AIS, and HSIL), referral
to colposcopy is recommended regardless of HPV test result if done.
Rationale: Because of higher risk of CIN 3+ with low-grade cytologic abnormalities
among HIV+ individuals, colposcopic referral is recommended for HPV-positive ASC-US.
145
Lack of data at KPNC precludes risk estimation for immunosuppressed patients. Sexually
active patients with HIV infection who are younger than 21 years may have a high rate
of progression to precancer. No similar prospective data are available for adolescents
who acquired HIV during the perinatal period, but as many as 30% of adolescents perinatally
infected had ASC-US or greater on their first cervical cytology. Because of the relatively
high HPV prevalence before age 30 years, HPV cotesting is not recommended for patients
younger than 30 years of age with HIV.
144
K.4 Managing Patients After Hysterectomy
Guideline: After a diagnosis of high-grade histology or cytology, patients may undergo
hysterectomy for reasons related or unrelated to their cervical abnormalities. If
hysterectomy is performed for treatment, patients should have 3 consecutive annual
HPV-based tests before entering long-term surveillance. Long-term surveillance after
treatment for histologic HSIL (CIN 2 or CIN 3) or AIS involves HPV-based testing at
3-year intervals for 25 years, regardless of whether the patient has had a hysterectomy
either for treatment or at any point during the surveillance period (CIII). Among
patients who have undergone hysterectomy but either have no previous diagnosis of
CIN 2+ within the previous 25 years or have completed the 25 year surveillance period,
screening is generally not recommended. However, if performed, abnormal vaginal screening
test results should be managed according to published recommendations (BII).
146
Rationale: The risk of high-grade vaginal intraepithelial neoplasia is elevated among
patients who have had a hysterectomy for treatment of histologic HSIL.
146
Although HPV testing is not FDA approved for vaginal samples, sensitivity of HPV-based
testing in the setting of posthysterectomy for histologic HSIL seems superior to cytology
alone.
147
For patients who have undergone a hysterectomy for benign disease and are screened
with cytology and/or HPV testing, ASC-US HPV-positive and LSIL cytology should be
managed with follow-up in 12 months and only those with high-grade cytology (HSIL,
ASC-H, AGC) should be referred immediately for vaginal colposcopy.
148
K.5 Managing Patients Older Than 65 Years With a History of Prior Abnormalities
Guideline: If patients over age 65 years undergo HPV testing, cotesting, or cytology,
management according to guidelines for patients aged 25 to 65 years is recommended
(CII). If surveillance testing is recommended for either a history of abnormal screening
results or treatment for precancer, discontinuing surveillance is unacceptable if
the patient is in reasonably good health and testing is feasible (DII). Discontinuation
of surveillance is recommended for patients with a limited life expectancy (EIII).
Rationale: Screening for patients older than 65 years should follow national guidelines.
14,149
However, approximately 20% of cervical cancers occur in patients older than 65 years.
150,151
To mitigate cancer risk in patients older than age 65 years, previous consensus management
guidelines included continued testing in patients with abnormal results as well as
those who do not meet exit criteria.
13,14,152
Although the sensitivity of cytology, HPV testing, and colposcopy seem to be higher
in premenopausal than postmenopausal patients, evidence indicates that screening in
patients older than 65 years is associated with a lower risk of the subsequent development
of cervical cancer.
153
Because cessation of routine screening is recommended in adequately screened patients
at the age of 65 years, data on the prognostic value of specific screening test results
in older patients are limited. However, as cancer rates remain appreciable beyond
the age of 65 years,
150,151
and cancer diagnostic procedures such as mammography, breast biopsy, and colonoscopy
are recommended beyond the age of 65 years,
154–156
the consensus decision was to use the guidelines for patients aged 25 to 65 years
in evaluating older individuals with abnormal results but without limited life expectancy.
Patients with previous CIN 3+ seem to have an elevated lifetime risk of developing
cervical or vaginal cancer and thus may require surveillance testing beyond the age
of 65 years.
123
However, patient comfort and the limitations of positioning and examining older patients
should enter into the shared decision-making conversation about when to discontinue
screening. Vaginal estrogen use for a limited time (3 weeks) can be considered to
obtain adequate sampling.
157
L. CURRENT CONSIDERATIONS AND FUTURE DIRECTIONS
L.1 Current Considerations
The 2019 guidelines are designed to take into account factors that influence Clinical
Action Thresholds. Working groups considered risk factors to determine their importance
for inclusion in clinical applications of the guidelines, taking into account both
the magnitude of effect on the estimated risk, as well as the feasibility of collecting
accurate data in clinical practice to inform management. Screening history profoundly
influenced risk estimates, specifically current HPV and cytology test results, previous
HPV test results, and history of histologic HSIL. Patient screening history is often
not known; therefore, unknown history is considered separately as a risk factor. Additional
factors were considered because of their association with cervical cancer in the literature:
HPV vaccination, age, hormonal contraception use, history of sexually transmitted
infection, parity, cigarette smoking, obesity, and sexual behaviors including age
of first intercourse and multiple partners. HPV vaccination in adolescence (generally
before the age of 18 years) does seem to reduce the risk of HPV 16/18 infections and
associated histologic HSIL.
158,159
However, HPV vaccination status was omitted from this revision of the guidelines because
(a) management guidelines are already very conservative in the population younger
than 25 years, (b) the population prevalence of on-time HPV vaccination in the 25-
to 29-year-old population is currently lower than that needed for herd immunity,
160
thus changing recommendations for this population as a whole is not yet warranted,
and (c) making person-specific recommendations based on age at vaccine series initiation
and number of doses received is impractical in the United States in the absence of
linkable, comprehensive, state-based immunization registries. Overall, none of the
other factors contributed clinically meaningful risk beyond that afforded by the screening
factors noted previously. Therefore, additional factors were not included in risk
estimates. Analyses were limited for heavy smoking history and younger than 30 years.
L.2 Future Directions
A successor to the new technologies group will be proposed to continue the consensus
process, and to provide continuous future updates to guidelines as new tests become
available for management. Decreases in the overall population prevalence of HPV infection,
especially HPV 16/18 genotypes, are expected as individuals vaccinated as adolescents
reach screening age. The guidelines outlined in this document are designed to adapt
to decreases in oncogenic HPV prevalence because of HPV vaccination as well as new
screening and management technologies. As data on the CIN 3+ risks associated with
screening test results become available for individuals aged 25 to 29 years who received
timely vaccination, we anticipate that decreases in population-level prevalence of
HPV infections will affect management recommendations for this age group in the near
future. In addition, new technologies that enter the market will be evaluated for
their utility in improving the diagnosis and management of CIN 3+. Examples of clinically
useful products would be those with increased specificity for detecting high-grade
abnormalities or the ability during longitudinal follow-up to distinguish incident
(new) from prevalent (persistent) HPV infections. No specific new technologies are
listed as creating a comprehensive list of products in development is beyond the scope
of this article.
In the near future, we will also complete analyses related to costs, benefits, and
effectiveness. The high value care group laid out a future research agenda that includes
simulation modeling to estimate the quality-of life and economic effects of proposed
changes to managing those with abnormal cervical cancer screening test results over
multiple rounds of screening.
Finally, we are tasked with disseminating these guidelines within the United States
to create a new national standard of care for management of abnormal cervical cancer
screening test results. Changing from recommendations that could be easily memorized
by clinicians to guidelines that incorporate both current results and history is a
major undertaking. However, the result of successful adoption should be reduction
of unnecessary testing and invasive procedures in low-risk patients and identification
of high-risk patients who will benefit from more intensive surveillance. Maximizing
cancer prevention benefits while minimizing the harms of overtesting and overtreatment
is a worthwhile but lofty goal, and these guidelines require more robust implementation
plans than previous iterations. The process of guidelines dissemination will involve
a comprehensive communications and dissemination plan using best practices for risk
communication and health promotion. Components include the following: presentations
at national, regional and local meetings, social media outreach to engage clinicians
and medical societies, and development of promotional materials to answer frequently
asked questions. Additional areas for future research include development of an evaluation
and impact process for these new recommendations on clinical practices. Because low-income
and minority women bear the greatest burden of cervical cancer, particular emphasis
will be placed on working with these communities and the providers who serve them.
GLOSSARY
CIN 2+: this term includes CIN 2, CIN 3, AIS, and cancer
CIN 3+: this term includes CIN 3, AIS, and cancer
Clinical Action Threshold: this term refers to risk levels that prompt different clinical
management strategies. For example, an immediate CIN 3+ risk of 4% is the Clinical
Action Threshold for colposcopy; risks below this threshold undergo surveillance,
whereas risks above this threshold, but below the expedited treatment threshold, undergo
colposcopy.
Colposcopy Standards: this term refers to the ASCCP Colposcopy Standards that provide
evidence-based recommendations for the practice of colposcopy
Cotesting: this term refers to screening or surveillance performed with both cytology
and HPV testing.
Expedited treatment: this term means treatment without confirmatory colposcopic biopsy
(e.g., see and treat).
Excisional treatment: this term includes procedures that remove the transformation
zone and produce a specimen for histologic analysis, such as loop electrosurgical
excision procedure (LEEP), laser cone biopsy, large loop excision of the transformation
zone (LLETZ), and cold knife conization.
HPV: this term refers to human papillomavirus. Within this text, HPV refers specifically
to high-risk HPV as defined by IARC, including the 12 types that are considered class
1 carcinogens, plus type 68 which is considered a class 2A carcinogen (i.e., HPV types
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68).
HPV-based testing: this term is used in this document to describe the use of either
cotesting or primary HPV screening for surveillance after abnormalities. It does not
apply to reflex HPV testing for triage of ASC-US cytology in this document. The HPV
testing and positive HPV results discussed throughout this document refer to high-risk
HPV types only.
Lower Anogenital Squamous Terminology (LAST): this term refers to 2-tiered pathology
criteria for evaluating histologic specimens obtained via colposcopic biopsy
Primary HPV testing: testing with HPV testing alone as a screening or surveillance
test.
Reflex testing: this means that laboratories should perform a specific additional
triage test in the setting of a positive screening test to inform the next steps in
management. For example, an ASC-US cytology should trigger a reflex HPV test. New
for these guidelines, a positive a positive primary HPV screening test should trigger
both a reflex genotyping test (to determine the presence/absence of HPV 16/18 if that
information is not included in the initial primary test result) and also a reflex
cytology test to determine whether the patient would be a candidate for expedited
management.
Surveillance: this term refers to repeat testing (HPV primary screening, cotesting,
or cytology alone) that occurs at shorter intervals than those recommended for routine
screening. For example, HPV primary testing or cotesting at intervals of less than
5 years, or cytology alone at intervals of less than 3 years.
Additional contributing authors for the ASCCP Risk Based Management Consensus Guidelines
Committee
Deborah Arrindell, Washington DC
Pelin Batur, MD, Cleveland OH
Alicia Carter, MD, Burlington NC
Patty Cason, MS, FNP, Los Angeles, CA
Xiaojian Chen MS, Bethesda, MD
Li Cheung PhD, Bethesda, MD
Kim Choma, DNP, Teaneck NJ
Megan Clarke, PhD, MHS, Rockville MD
Christine Conageski, MD, Aurora CO
Miriam Cremer, MD, MPH, Cleveland, OH
Barbara Crothers, DO, Silver Spring MD
Teresa Darragh, MD, San Francisco CA
Maria Demarco, PhD, Rockville MD
Eileen Duffey-Lind, MSN, Boston, MA
Ysabel Duron, BA, San Jose CA
Didem Egemen PhD, Bethesda, MD
Carol Eisenhut, MD, MBA, Indianapolis IN
Tamika Felder, Upper Marlboro MD
Sarah Feldman, MD, MPH, Boston MA
Michael Gold, MD, Tulsa OK
Robert Goulart, MD, Springfield MA
Paul Han, MD, Portland ME
Sally Hersh, DNP, Portland OR
Aimee Holland, DNP, Birmingham AL
Eric Huang, MD, Seattle, WA
Michelle Khan, MD, MPH, San Leandro CA
Rachel Kupets, MD, Toronto ON, Canada
Margaret Long, MD, Rochester MN
Thomas Lorey MD, Berkeley, CA
Jennifer Loukissas, MPP, Bethesda MD
Jeanne Murphy, PhD, Washington DC
Amber Naresh, MD, MPH, New Orleans LA
Erin Nelson, MD, San Antonio TX
Akiva Novetsky, MD, MS, Newark NJ
Jeffrey Quinlan, MD, Bethesda, MD
Debbie Saslow, PhD, Atlanta GA
Kathryn Sharpless, MD, PhD, Portland ME
Katie Smith, MD, MS, Oklahoma City OK
Elizabeth Stier, MD, Boston MA
Colleen Stockdale, MD, MS, Iowa City IA
Sana Tabbara, MD, Washington DC
Deanna Teoh, MD, MS, Minneapolis MN
Elizabeth Unger, PhD, MD, Atlanta GA
Alan Waxman, MD, MPH, Albuquerque NM
Kelly Welch, North Falmouth, MA
Claudia Werner, MD, Dallas TX
Amy Wiser, MD, Portland OR
Rosemary Zuna, MD, Oklahoma City OK