ORIGINAL RESEARCH ARTICLE: CERVIX AND HPV

Risk Estimates Supporting the 2019 ASCCP Risk-Based

Management Consensus Guidelines
Didem Egemen, PhD,1 Li C. Cheung, PhD,1 Xiaojian Chen, MSc,1 Maria Demarco, PhD,1
Rebecca B. Perkins, MD, MSc,2 Walter Kinney, MD,3 Nancy Poitras, BSc,4 Brian Befano, BSc,5
Alexander Locke, MD,4 Richard S. Guido, MD,6 Amy L. Wiser, MD,7 Julia C. Gage, PhD, MPH,1
Hormuzd A. Katki, PhD,1 Nicolas Wentzensen, MD, PhD, MS,1 Philip E. Castle, PhD, MPH,8
Mark Schiffman, MD, MPH,1 and Thomas S. Lorey, MD3
estimates supporting guidelines are presented in this article. Comprehensive risk
Objective: The 2019 American Society for Colposcopy and Cervical estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.
Pathology Risk-Based Management Consensus Guidelines for the manage-
ment of cervical cancer screening abnormalities recommend 1 of 6 clinical Key Words: risk-based, management guidelines, cervical screening, HPV
actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/ (J Low Genit Tract Dis 2020;24: 132–143)
biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular
screening) based on the risk of cervical intraepithelial neoplasia grade 3, Risk Estimate and Management Tables
adenocarcinoma in situ, or cancer (CIN 3+) for the many different combi-
nations of current and recent past screening results. This article supports 1. Abnormal Screening Results
the main guidelines presentation1 by presenting and explaining the risk esti- a. Immediate and 5-year risks of CIN 3+ for abnormal
mates that supported the guidelines. screening results, when there are no known prior HPV
Methods: From 2003 to 2017 at Kaiser Permanente Northern California test results
(KPNC), 1.5 million individuals aged 25 to 65 years were screened with human b. Immediate and 5-year risks of CIN 3+ after a prior HPV-
papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We es- negative screen documented in the medical record
timated immediate and 5-year risks of CIN 3+ for combinations of current test 2. Surveillance following results not requiring immediate
results paired with history of screening test and colposcopy/biopsy results. colposcopic referral
Results: Risk tables are presented for different clinical scenarios. Exam- a. Immediate and 5-year risks of CIN 3+ for results obtained
ples of important results are highlighted; for example, the risk posed by in follow-up of HPV-negative ASC-US
most current abnormalities is greatly reduced if the prior screening round b. Immediate and 5-year risks of CIN 3+ for results obtained
was HPV-negative. The immediate and 5-year risks of CIN 3+ used to de- in follow-up of HPV-negative LSIL
cide clinical management are shown. c. Immediate and 5-year risks of CIN 3+ for results obtained
Conclusions: The new risk-based guidelines present recommendations for in follow-up of HPV-positive NILM
the management of abnormal screening test and histology results; the key risk 3. Receipt of colposcopy/biopsy results
4. Surveillance visit following colposcopy/biopsy finding less
than CIN 2 (no treatment)
1 a. Immediate and 5-year risks of CIN 3+ postcolposcopy at
Division of Cancer Epidemiology and Genetics, National Cancer Institute,
Rockville, MD; 2Department of Obstetrics and Gynecology, Boston University which CIN 2+ was not found, following referral for low-
School of Medicine/Boston Medical Center, Boston, MA; 3Division of Gyneco- grade results
logic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (con- b. Immediate and 5-year risks of CIN 3+ postcolposcopy at which
tributed before retirement); 4Regional Laboratory, Kaiser Permanente Northern CIN 2+ was not found, following referral for high-grade results
California, Berkeley, CA; 5Information Management Services Inc, Information
Management, Calverton, NY; 6Department of Obstetrics, Gynecology and Repro- 5. Follow-up after treatment for CIN 2 or CIN 3
ductive Sciences, UPMC Magee-Women's Hospital, Pittsburgh, PA; 7Department a. Immediate and 5-year risks after treatment for CIN 2 or CIN 3
of Family Medicine, Oregon Health and Science University, Portland, OR; and
8
b. Long-term follow-up when there are 2 or 3 negative
Albert Einstein College of Medicine, Bronx, NY follow-up test results after treatment of CIN 2 or CIN 3
Reprint requests to: Didem Egemen, PhD, Division of Cancer Epidemiology
and Genetics, National Cancer Institute, National Institutes of Health, 9609
Medical Center Dr, Rm 7E610 Rockville, MD 20892. E-mail:
INTRODUCTION
[email protected]. The 2019 American Society for Colposcopy and Cervical Pa-
The National Cancer Institute (including M.S. and N.W.) has received cervical thology (ASCCP) Risk-Based Management Consensus Guidelines
screening results at reduced or no cost from commercial research partners
(Qiagen, Roche, BD, MobileODT, Arbor Vita) for independent evaluations
describe 6 clinical actions that providers can use when managing pa-
of screening methods and strategies. P.E.C. has received HPV tests and tients with abnormal cervical cancer screening test results: treatment;
assays at a reduced or no cost from Roche, Becton Dickinson, Arbor Vita optional treatment or colposcopy/biopsy; colposcopy/biopsy; 1-year
Corporation, and Cepheid for research. R.S.G. reports that he was an surveillance; 3-year surveillance; and return to 5-year regular
ASCCP consultant for the guideline and a DSMB consultant for Ikonosys.
The other authors have declared they have no conflicts of interest.
screening.1 These clinical actions are recommended based on a
This study was partly supported by the Intramural Research Program of the US patient's risk of either currently having or subsequently developing cer-
National Institutes of Health (NIH)/National Cancer Institute (NCI). vical intraepithelial neoplasia grade 3 (CIN 3), adenocarcinoma in-situ
NCI-Kaiser Permanente Northern California (KPNC) Persistence and (AIS), or cancer (defined subsequently as CIN 3+). Exploration of nu-
Progression (PaP) study have been reapproved yearly by both KPNC and
NCI Institutional Review Board review committees.
merous potential risk factors led to the determination that a patient's
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on CIN 3+ risk can be estimated based on current human papilloma-
behalf of the ASCCP. This is an open-access article distributed under the virus (HPV) and cytology test results and recent history of test re-
terms of the Creative Commons Attribution-Non Commercial-No Derivatives sults, colposcopic evaluation and biopsy results, and treatments.
License 4.0 (CCBY-NC-ND), where it is permissible to download and share
the work provided it is properly cited. The work cannot be changed in any
The 2019 guidelines comprehensively use and expand upon
way or used commercially without permission from the journal. the principle of “equal management for equal risks” that was intro-
DOI: 10.1097/LGT.0000000000000529 duced in the 2012 guidelines.2 Specifically, management is based

132 Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

FIGURE 1. Frequency of women at their first cotest visit based on age groups: First visit age group 30- to 34-year frequency reflects initiation of
cotesting at 30 years and older starting in 2003. The 25- to 29-year age group frequency reflects KPNC initiation of cotesting starting at age
25 in 2013.

on a patient's risk of CIN 3+, regardless of what combination of inform the new guidelines for clinicians. The comprehensive risk
test results yields that risk level. The guidelines make recommen- database is stored at the National Institutes of Health, publicly
dations based on immediate CIN 3+ risk, which is the probability accessible through this link: https://CervixCa.nlm.nih.gov/RiskTables.
of patient currently having CIN 3+, and 5-year CIN 3+ risk, which A user-friendly, electronic presentation of these risk estimates
gives the probability of developing CIN 3+ over the ensuing and their related recommendations is available via a smartphone
5 years.1,3 We conducted an extensive data analysis effort to pro- app, and a web version (available via asccp.org).
duce risk estimates for all combinations of tests and recent screen-
ing history, considering 5 clinical scenarios: (a) current abnormal METHODS
screening results, (b) surveillance of past screening results not re-
quiring immediate colposcopic referral, (c) management based on Study Population
colposcopy/biopsy results, (d) postcolposcopy surveillance after Kaiser Permanente of Northern California (KPNC)/National
less than CIN 2 histology, and (e) posttreatment follow-up. This ar- Cancer Institute Guidelines Cohort has been previously described.3–5
ticle navigates the most relevant risk-based management tables that In brief, from 2003 to 2017, cervical cancer screening was

FIGURE 2. Determining suggested management based on calculated risk.

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 133
Egemen et al. Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020

conducted among individuals aged 25 to 65 years, using HPV was also centralized. Clinical outcomes were obtained by linkage
testing with Hybrid Capture 2 (HC2; Qiagen, Germantown, to KPNC cytology and histopathology electronic medical records.
MD) and cytology. The age distribution of the study cohort at
the first visit at which they received cotesting (i.e., enrollment) Variables
is shown in Figure 1. The largest age cohort included ages 30 Cytology results at KPNC were reported based on the 2001
to 34 years (25%), followed by 35 to 39 years (14%) and 25 to Bethesda System, categorized as: negative for intraepithelial lesion
29 years (13%). The accumulation of individuals in the 30- to or malignancy (NILM), atypical squamous cells of undetermined
34-year age group reflects the start of cotesting at 30 years and significance (ASC-US), low-grade squamous intraepithelial lesion
older from 2003 until KPNC guidelines changed in 2013 to rec- (LSIL), atypical squamous cells cannot exclude an high-grade
ommend beginning cotesting at age 25 years. As a result, every squamous intraepithelial lesion (ASC-H), atypical glandular
year in KPNC screening participants became age eligible for cells (AGC) (note, subcategorization of AGC is described in
cotesting resulting in a peak at the age group 30 to 34 years and, Perkins et al.1), high-grade squamous intraepithelial lesion or
starting in 2013, the same effect in those aged 25 to 29 years. worse (HSIL+), and inadequate.
We restricted the analytic sample to 1,546,462 screened individ- We reported HPV status as negative versus positive for infec-
uals with both HPV and cytology results, excluding those with a tion with any of the 13 pooled high-risk HPV types (16, 18, 31,
prior hysterectomy, histopathologic CIN 2+ diagnosis, missing 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), recognizing that HC2
HPV results or with cytology reports of missing, uncertain, or not also detects through cross-reaction a percentage of closely related
cervical. Cytology was performed at KPNC regional and local lab- HPV types (e.g., 53, 66, 67, 70, 82, and 82v).6 A subset of HC2-
oratories. The HPV status was based on HC2 testing performed on positive cervical specimens at KPNC had HPV typing, as part of
a second cervical specimen (collected at the same time as the cytol- the National Cancer Institute-KPNC Persistence and Progression
ogy specimen) at the KPNC regional laboratory. Histopathology Study. These results are reported separately by Demarco et al.7

TABLE 1A. Immediate and 5-Year Risks of CIN 3+ for Abnormal Screening Results, When There Are No Known Prior HPV Test Results

Current CIN 3+ Recommendation

Current cytology CIN 3+ immediate CIN 3+ 5-year Recommended confidence
History HPV result result n % cases risk, % risk, % Management score, %
Unknown HPV-negative NILM 1,388,153 90 1,246 0.00 0.12 5-y follow-up 100
Unknown HPV-negative ASC-US 25,331 1.6 83 0.04 0.40 3-y follow-up 100
Unknown HPV-negative LSIL 3,300 0.21 47 1.1 2.0 1-y follow-up 100
Unknown HPV-negative ASC-H 791 0.05 26 3.4 3.8 Colposcopya Special situation
Unknown HPV-negative AGC 2,275 0.15 27 1.1 1.5 Colposcopya Special situation
Unknown HPV-negative HSIL+ 183 0.01 43 25 27 Colposcopy/treatment 53
Unknown HPV-negative ALLb 1,420,033 92 1,472 0.01 0.14 5-y follow-up 95

Unknown HPV-positive NILM 63,541 4.1 1,798 2.1 4.8 1-y follow-up 100
Unknown HPV-positive ASC-US 30,506 2.0 1,378 4.4 7.3 Colposcopy 100
Unknown HPV-positive LSIL 23,659 1.5 1,008 4.3 6.9 Colposcopy 96
Unknown HPV-positive ASC-H 3,766 0.24 863 26 33 Colposcopy/treatment 82
Unknown HPV-positive AGC 977 0.06 254 26 35 Colposcopy/treatmenta 80
Unknown HPV-positive HSIL+ 3,980 0.26 1,700 49 53 Colposcopy/treatment 100
Unknown HPV-positive ALLb 126,429 8 7,001
Totalc 1,546,462 100 8,473
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
Who can be managed by Table 1A?
Patients without a prior HPV screening test result documented in the medical record can be managed by this table. It applies for cotest results, primary
HPV screens that are negative (represented as the HPV-negative “ALL” row) and for primary HPV tests with cytology triage for HPV-positive results.
The first column represents the past history which is unknown. The second and third columns represent current screening results. The following columns
show the total sample size (n) in each category and each screening result as a percentage (%) of total screened, number of observed CIN 3+ cases, CIN 3+
immediate and 5-year risks, recommended management, and “Recommendation confidence score” for corresponding management (for more detailed ex-
planation of each column refer to Methods Section).
HPV-negative ASC-H and AGC are referred to colposcopy although they do not exceed the 4% immediate colposcopy threshold (Sections G.1 and H.2 in
Perkins et al.1). This decision is made to be especially careful in terms of management of these rare high-grade findings when found; accordingly, in column
“Recommendation confidence score,” these cases are noted as “Special situation.” When cotesting is used, the uncommon findings of HPV negativity with
nonnormal cytology are observed (2.0% of the screened population, mainly HPV-negative ASC-US). Most importantly, HPV-negative HSIL+ is seen in only
0.01% of the population, with an immediate risk of 25% (management recommendation of colposcopy or treatment).
The risks associated with HPV-positive ALL are not presented in the table because all positive HPV screening results should have a reflex testing (e.g.,
cytology) for management (refer to Perkins et al.1).
a
Refer to Perkins et al.1 for special consideration of ASC-H and AGC.
b
ALL, e.g., primary HPV screening without cytology.
c
HPV-negative/positive ALL are excluded from the total to avoid duplication.

134 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

For the main analyses and consensus guidelines, precancer abnormal screening results. Table 1A addresses patients with-
was defined as a histopathologic diagnosis of CIN 3+ (CIN 3/ out a documented recent HPV test result. To qualify for Table 1B,
AIS/cancer). CIN 2 was de-emphasized because it is a less reliable a patient's current abnormal screening test result must be preceded
histopathologic definition of precancer. However, ancillary analyses by a negative HPV test documented in the medical record within
considered CIN 2+ (CIN 2/CIN 3/AIS/cancer) as an alternative the past approximately 5 years (e.g., a normal screening interval).
definition of precancer and cancer by itself as an alternative out- Scenario 2 describes surveillance after abnormal results not
come (please refer to the comprehensive tables available online requiring immediate colposcopic referral. Management of current
at https://CervixCa.nlm.nih.gov/RiskTables). cotest results is described after a previous result of HPV-negative
ASC-US (see Table 2A), HPV-negative LSIL (Table 2B), and
Statistical Analysis HPV-positive NILM (Table 2C).
Scenario 3, management upon receipt of colposcopy/biopsy
We used prevalence-incidence mixture models.8–10 The results, describes subsequent management based on the colposcopy/
model is a mixture of logistic regression for events present at the biopsy diagnosis (see Table 3). Scenario 4 describes management af-
time of the current visit (prevalent disease) and proportional haz- ter a colposcopy at which CIN 2+ was not found (i.e., colposcopy/
ards model for events occurring after the current visit (incident biopsy results were CIN 1 or normal). Table 4A describes CIN 3+
disease). We estimated risk of CIN 3+ at years 0, 1, 2, 3, 4, and risks when the index cotest was low grade (i.e., LSIL, ASC-US,
5; most decisions considered the immediate risks at year 0 and or HPV-positive NILM). Table 4B describes CIN 3+ risks when
the 5-year risks (see Figure 2 and Cheung et al. for details).3 the index cotest was high grade (i.e., ASC-H, AGC, HSIL+). Sce-
nario 5 addresses management after treatment for CIN 2 or CIN
Data Presentation: Clinical Scenarios 3, either short term (see Table 5A) or longer term (see Table 5B).
Risk-based management tables are organized under the 5
clinical scenarios. It is important to emphasize that for a given pa- Data Presentation: Current Results and History
tient over time, a clinician is likely to consult various tables as the Two central questions underlie risk estimations: (a) What
management scenarios are encountered, from initial abnormality are the current results? (b) What past results affect the risk es-
to resolution. Scenario 1 describes initial management of timate for the current results? The “current results” are those

TABLE 1B. Immediate and 5-Year Risks of CIN 3+ After a Prior HPV-Negative Screen Documented in the Medical Record

Current CIN 3+ CIN 3+ Recommendation

Current cytology CIN 3+ immediate 5-year Recommended confidence
History HPV result result n % cases risk, % risk, % management score, %
HPV-negative HPV-negative NILM 769,908 94 410 0.00 0.09 5-y follow-up 100
HPV-negative HPV-negative ASC-US 14,372 1.8 43 0.01 0.36 3-y follow-up 100
HPV-negative HPV-negative LSIL 1,553 0.19 9 0.44 0.79 1-y follow-up 82
HPV-negative HPV-negative ASC-H 558 0.07 16 2.8 3.3 Colposcopy Special situation
HPV-negative HPV-negative AGC 1,518 0.19 11 0.78 0.88 Colposcopy Special situation
HPV-negative HPV-negative HSIL+ 64 0.01 8 14 14 Colposcopy 98
HPV-negative HPV-negative ALLa 787,973 96 497 0.01 0.10 5-y follow-up 100

HPV-negative HPV-positive NILM 16,552 2.0 225 0.74 2.3 1-y follow-up 100
HPV-negative HPV-positive ASC-US 7,794 0.95 189 2.0 3.8 1-y follow-up 100
HPV-negative HPV-positive LSIL 5,990 0.73 143 2.1 3.8 1-y follow-up 100
HPV-negative HPV-positive ASC-H 633 0.08 77 14 18 Colposcopy 100
HPV-negative HPV-positive AGC 180 0.02 28 14 21 Colposcopyb 100
HPV-negative HPV-positive HSIL+ 411 0.05 117 32 34 Colposcopy/treatment 100
Totalc 819,533 100 1,276
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
Who can be managed by Table 1B?
New HPV-related abnormalities are less risky than prevalent/persistent abnormalities. Thus, patients with abnormal screening results that are preceded by
a documented negative HPV test result within an appropriate screening interval (approximately 5 years) can be managed by Table 1B rather than Table 1A.
Of note, the risks shown here refer specifically to a negative primary HPV test; management after a prior negative cotest is so similar that we do not show
them (interested readers should consult the full tables online).
The first column indicates that the most recent HPV test obtained before the current visit was negative. The second and third columns represent current
screening results. The following columns show the total sample size (n) in each category and each screening result as a percentage (%) of total screened,
number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence score” for corre-
sponding management (for more detailed explanation of each column, refer to Methods Section).
The 2012 guidelines did not address abnormalities after a negative HPV-based screen. HPV–positive ASC-US and LSIL preceded by a negative HPV test
are now recommended to be followed-up in 1-year rather than immediately referred to colposcopy.
a
HPV-negative ALL, e.g., primary HPV screening.
b
Refer to Perkins et al.1 for additional management of AGC.
c
HPV-negative ALL is excluded from the total to avoid duplication.

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 135
Egemen et al. Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020

TABLE 2A. Immediate and 5-Year Risks of CIN 3+ for Results Obtained in Follow-up of HPV-Negative ASC-US

Current CIN 3+ Recommendation

Current cytology CIN 3+ immediate CIN 3+ 5-y Recommended confidence
History HPV result result n % cases risk, % risk (%) management score, %
HPV-negative ASC-US HPV-negative NILM 13,918 82 14 0.00 0.14 5-y follow-up 58
HPV-negative ASC-US HPV-negative ASC-US 1,701 10 11 0.06 0.78 1-y follow-up 82
HPV-negative ASC-US HPV-negative LSIL 193 1.1 5 2.4 3.1 1-y follow-up 80
HPV-negative ASC-US HPV-negative ASC-H 57 0.34 3 5.7 5.7 Colposcopya 65
HPV-negative ASC-US HPV-negative AGC 59 0.35 0 0.00 0.00 Colposcopya Special situation
HPV-negative ASC-US HPV-negative HSIL+ 11 0.07 1 11 11 Colposcopy 36
HPV-negative ASC-US HPV-negative ALLd 15,939 94 34 0.06 0.27 b
Special situation

HPV-negative ASC-US HPV-positive NILM 392 2.3 6 0.96 2.4 1-y follow-up 97
HPV-negative ASC-US HPV-positive ASC-US 288 1.7 13 2.1 6.6 1-y follow-up 97
HPV-negative ASC-US HPV-positive LSIL 228 1.4 5 2.6 2.6 1-y follow-up 85
HPV-negative ASC-US HPV-positive ASC-H 25 0.15 5 24 24 Colposcopya 53
HPV-negative ASC-US HPV-positive AGC 5 0.03 0 0.00 0.00 Colposcopya Special situation
HPV-negative ASC-US HPV-positive HSIL+ 26 0.15 8 36 36 Colposcopy/treatment 86
Totalc 16,903 100 71
The risk determining the recommended management is bolded.
Who can be managed by Table 2A?
Patients who are under surveillance after a prior HPV-negative ASC-US test result can be managed by Table 2A. A current cotest result or primary HPV
test with cytology triage for HPV-positive tests are addressed in the table.
The first column indicates that the most recent HPV test obtained before the current visit was HPV-negative ASC-US. The second and third columns
represent current screening results. The following columns show the total sample size (n) in each category and each screening result as a percentage (%)
of total screened, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence
score” for corresponding management (for more detailed explanation of each column refer to Methods Section).
A prior HPV-negative ASC-US result provides nearly the same level of reassurance as a prior negative cotest, so that a negative cotest after HPV-negative
ASC-US can safely return to screening in 5 years. In addition, minor abnormalities after HPV-negative ASC-US are recommended to be followed-up in
1 year, such as HPV-positive ASC-US and HPV-positive LSIL.
a
Refer to Perkins et al.1 for additional management of ASC-H and AGC.
b
HPV-negative ASC-US should be followed-up with cotest rather than primary HPV test.
c
HPV-negative ALL is excluded from the total to avoid duplication.
d
HPV-negative ALL, e.g., primary HPV screening.

for which the clinician is seeking guidance, either an HPV test test result at the follow-up visit after treatment. The risk remains
or cotest result (see Tables 1A–2C 4A–5B) or a colposcopy/biopsy higher for treated CIN 3 compared with CIN 2 scenarios. However,
result (see Table 3). The past results that impact risk estimates to maximize safety after treatment of precancer, management is rec-
are noted under “history.” Table 1A refers to patients without ommended based on the risks of patients treated for CIN 3. Thus,
a recent documented HPV test or cotest result, so the history is the management recommendations apply to both treated CIN 2
simply “unknown.” In Table 1B, “history” refers to recent docu- and CIN 3.
mented negative HPV test (management after a prior negative
cotest is so similar that we do not show them, interested readers
can consult the full tables online). However, documented negative Data Presentation: Total Numbers, Risks Estimates,
cytology provides relatively less reduction in risk compared and Recommended Management
with a negative HPV or cotest as history. Therefore, patients We report the total number of patients and the number of CIN
with a negative cytology history will still be managed by Table 1A. 3+ cases reported among those patients for each combination of
In Tables 2A–C, “history” refers to the abnormal screening test “current results” and “history.” We present the number and per-
result preceding the current result: HPV-negative ASC-US centage of the population with corresponding current test results
(Table 2A), HPV-negative LSIL (Table 2B), and HPV-positive in columns “n” and “%,” respectively. The total number of CIN
NILM (Table 2C). In Table 3, “history” refers to the precolposcopy 3+ detected from the initial screen until the end of follow-up is
test results. In Table 4A, “history” refers to both the colposcopy presented in column “CIN 3+ cases.” Columns “CIN 3+ immedi-
result (<CIN 2) and a low-grade test result preceding colposcopy. ate risk, %” and “CIN 3+ 5-y risk, %” give the estimated immedi-
In Table 4B, “history” again refers to both the colposcopy result ate and 5-year CIN 3+ risks (as percent probabilities). CIN 3+
(<CIN 2) and preceding test result but addresses when a high- immediate risk is the estimated probability of observing CIN 3+
grade test result preceded the colposcopy. if the patient were referred to colposcopy based on the current
In Tables 5A and 5B, “history” refers to treatment for CIN 2 or visit. CIN 3+ 5-year risk is the probability of observing CIN 3+
CIN 3, and “current results” are HPV test results or cotest results after within 5 years after the current visit. The following column “Rec-
treatment. For Tables 5A and 5B, the risk estimation in this scenario ommended management” gives the recommendation for clinical
(i.e., posttreatment) derives specifically from treated CIN 3 and the management based on the clinical action thresholds decided by

136 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

TABLE 2B. Immediate and 5-Year Risks of CIN 3+ for Results Obtained in Follow-up of HPV-Negative LSIL

Current CIN 3+ Recommendation

Current cytology CIN 3+ immediate CIN 3+ 5-y Recommended confidence
history HPV result result n % cases risk, % risk, % management score, %
HPV-negative LSIL HPV-negative NILM 1,547 70 3 0.00 0.40 3-y follow-up 57
HPV-negative LSIL HPV-negative ASC-US 258 12 5 0.00 4.0 1-y follow-up 100
HPV-negative LSIL HPV-negative LSIL 133 6.0 2 0.00 4.4 1-y follow-up 96
HPV-negative LSIL HPV-negative ASC-H 6 0.27 0 0.00 0.00 Colposcopya Special situation
HPV-negative LSIL HPV-negative AGC 5 0.23 0 0.00 0.00 Colposcopya Special situation
HPV-negative LSIL HPV-negative HSIL+ 4 0.18 0 0.00 0.00 Colposcopy Special situation
HPV-negative LSIL HPV-negative ALLd 1,953 88 10 0.00 1.1 b
Special situation

HPV-negative LSIL HPV-positive NILM 71 3.2 4 0.00 8.6 1-y follow-up 97

HPV-negative LSIL HPV-positive ASC-US 88 4.0 5 5.3 6.9 Colposcopy 69
HPV-negative LSIL HPV-positive LSIL 87 3.9 5 7.9 7.9 Colposcopy 88
HPV-negative LSIL HPV-positive ASC-H 8 0.36 3 50 50 Colposcopya Special situation
HPV-negative LSIL HPV-positive AGC 1 0.05 0 0.00 0.00 Colposcopya Special situation
HPV-negative LSIL HPV-positive HSIL+ 3 0.14 1 33 33 Colposcopy/treatment Special situation

HPV-negative LSIL Cotest negative 2 693 1 0.00 0.27 3-y follow-up 52

Totalc 2,211 100 28
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
Who can be managed by Table 2B?
Patients who are under surveillance after a prior HPV-negative LSIL test result can be managed by Table 2B. A current cotest result or primary HPV test
with cytology triage for HPV-positive tests are addressed in the table.
The first column indicates that the most recent HPV test obtained before the current visit was HPV-negative LSIL. The second and third columns rep-
resent current screening results. The following columns show the total sample size (n) in each category and each screening result as a percentage (%) of total
screened, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence score” for
corresponding management (for more detailed explanation of each column, refer to Methods Section).
In the 2012 guidelines, repeat cotesting at 3 years was recommended for HPV-negative NILM after HPV-negative LSIL; this recommendation does not
change in the new guidelines. However, management recommendations for HPV-negative ASC-US, HPV-negative LSIL, and HPV-positive NILM after
HPV-negative LSIL are different from the previous guidelines, as they all lead to 1-year surveillance rather than immediate colposcopy.
To assess when the patients can return back to regular screening after HPV-negative LSIL, we calculated risks after 2 cotest negative. The results indicate
that 2 negative cotests after HPV-negative LSIL do not provide enough reassurance to safely return back to 5-year regular screening. The data are sparse and
the recommendations may change in the future as more data accrue.
a
Refer to Perkins et al.1 for special consideration of ASC-H and AGC.
b
HPV-negative LSIL should be followed-up with cotest rather than primary HPV test.
c
HPV-negative ALL and cotest negative 2 are excluded from the total to avoid duplication.
d
HPV-negative ALL, e.g., primary HPV screening.

the consensus group. Certain high-risk situations are managed events to generate a stable risk estimate and confidence that the es-
based on factors other than risk estimates and denoted as “Special timate is yielding the correct recommendation based on the KPNC
Situations.” These included rare result combinations for which in- data. It is the percent probability that the estimated risk, from a
sufficient data caused risk estimates to be unstable and those for random sample of that size, would support the determined manage-
which the cancer risk estimates and/or scientific literature indi- ment option, rather than the neighboring options. For instance, a
cated disproportionately high cancer risks relative to CIN 3+ risks, “Recommendation confidence score” of 95% for a recommendation
leading to recommendations for more aggressive management. of 1-year surveillance means 95% statistical confidence that the
Special situations are covered in Sections H and I of Perkins et al.1 recommended management is correct when considering the
and explained in the footnotes of the tables. KPNC data, rather than colposcopy or 3-year surveillance. Gener-
alizability to other clinical settings/populations is thought to be
good, as outlined in the methods article.3 Nonetheless, the rec-
Data Presentation: Recommendation ommendation confidence score should not be misinterpreted
Confidence Score as the true probability that a recommendation is absolutely cor-
The column named “Recommendation confidence score, %” rect. No such perfect prediction is possible or implied; the mea-
indicates the percent probability that the KPNC risk estimates fall sure is given more as a warning when the percentage is low,
within the risk range dictating the recommended management signifying lack of confidence in the recommendation. With this
(based on the sample size and how close the estimated risks are strong caveat, a recommendation confidence score above 80%
to clinical action thresholds, Cheung et al.3). A high percent sug- is suggested as a helpful guide by the statisticians directing the
gests statistical precision, defined as adequate numbers of CIN 3+ analyses to represent good reassurance for the recommended

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 137
Egemen et al. Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020

TABLE 2C. Immediate and 5-year risks of CIN 3+ for results obtained in follow-up of HPV-positive NILM

Current CIN 3+ Recommendation

Current cytology CIN 3+ immediate CIN 3+ 5-y Recommended confidence
History HPV result result n % cases risk, % risk, % management score, %
HPV-positive NILM HPV-negative NILM 22,625 51 113 0.01 0.90 1-y follow-up 100
HPV-positive NILM HPV-negative ASC-US 585 1.3 11 0.35 2.6 1-y follow-up 100
HPV-positive NILM HPV-negative LSIL 114 0.26 2 2.3 2.3 1-y follow-up 71
HPV-positive NILM HPV-negative ASC-H 17 0.04 0 NA NA Colposcopy Special situation
HPV-positive NILM HPV-negative AGC 41 0.09 3 8.3 8.3 Colposcopya 83
HPV-positive NILM HPV-negative HSIL+ 9 0.02 4 44 44 Colposcopy/treatment 71
HPV-positive NILM HPV-negative ALLb 23,391 53 133 0.06 0.99 1-y follow-up 100

HPV-positive NILM HPV-positive NILM 11,990 27 608 4.1 7.2 Colposcopy 60

HPV-positive NILM HPV-positive ASC-US 4,953 11 310 5.4 9.5 Colposcopy 100
HPV-positive NILM HPV-positive LSIL 2,733 6.2 153 5.0 8.5 Colposcopy 98
HPV-positive NILM HPV-positive ASC-H 654 1.5 134 22 29 Colposcopy 95
HPV-positive NILM HPV-positive AGC 204 0.46 67 33 40 Colposcopya 99
HPV-positive NILM HPV-positive HSIL+ 466 1.0 185 44 50 Colposcopy/treatment 100

HPV-positive NILM Cotest negative 2 10,522 16 0.0 0.29 3-y follow-up 84

HPV-positive NILM Cotest negative 3 5,457 5 0.0 0.17 3-y follow-up 56
Totalc 44,391 100 1,590
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
Who can be managed by Table 2C?
Patients who are under surveillance after a prior HPV-positive NILM test result can be managed by Table 2C. A current cotest result or primary HPV test
with cytology triage for HPV-positive tests are addressed in the table.
The first column indicates that the most recent HPV test obtained before the current visit was HPV-positive NILM. The second and third columns rep-
resent current screening results. The following columns show the total sample size (n) in each category and each screening result as a percentage (%) of total
screened, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence score” for
corresponding management (for more detailed explanation of each column, refer to Methods Section).
2012 guidelines recommended immediate colposcopy for screening results of ASC-US or worse cytology or positive HPV testing after HPV-positive
NILM. New guidelines continue to recommend colposcopy for HPV-positive, regardless of cytology, after HPV-positive NILM. However, HPV-negative
ASC-US and HPV-negative LSIL after HPV-positive NILM are recommended to have a deferred management of 1-year surveillance. Another change from
the 2012 guidelines is cotest negative after HPV-positive NILM is recommended to be followed-up in 1 year rather than repeating cotesting in 3 years.
After 2 negative cotests, the screening interval can be safely extended to 3 years. Data after 3 cotests are sparse, and recommendations may change in the
future as more data accrue (see Section J.4 main article for discussion).
a
Refer to Perkins et al.1 for additional management of AGC.
b
HPV-negative ALL, e.g., primary HPV screening without cytology.
c
HPV-negative ALL, cotest negative 2, and cotest negative 3 are excluded from the total to avoid duplication.
NA indicated not applicable. Due to small sample size and zero observed CIN 3+ cases, CIN 3+ risks couldn't be obtained for these cells.

management, although again there is no absolute threshold for risk 0.55% or greater (but under the colposcopy threshold of
such a statistical intuition. 4.0% immediate risk), 3-year follow-up for risk 0.15% or greater
and less than 0.55%, and return to routine screening at 5-year in-
tervals for risk less than 0.15%.
RESULTS To apply these clinical action thresholds using the tables in
this article, the first step is to determine whether the risk denoted
Using the Risk Tables to Determine in the “CIN 3+ immediate risk” column is greater than or less than
Clinical Management 4%. For immediate risks greater than 4%, the recommended man-
Suggested management is determined by matching a patient's agement is determined by the immediate CIN 3+ risk. For imme-
risk estimate to a clinical action threshold (see Figure 2). Expe- diate risks less than 4%, the “CIN 3+ 5-year risk” column is used
dited treatment (i.e., without preceding colposcopy/biopsy) is to determine recommended follow-up interval. In the tables, the
preferred for patients with immediate CIN 3+ risk 60% or greater, risk used to determine the recommended management is bolded.
treatment or colposcopy/biopsy is acceptable for risk 25% or We will illustrate how risk estimates are used to determine man-
greater and less than 60%, and colposcopy/biopsy is recom- agement using hypothetical patient examples.
mended for risk 4.0% or greater and less than 25%. Patients with Patient 1: A 32-year-old woman presents for screening, she
immediate CIN 3+ risks of less than 4.0% are recommended to denies having colposcopy or treatment in the past, but her medical
have follow-up surveillance, and their deferred clinical manage- records are not available so her history is unknown. Her current
ment is guided by 5-year risks of CIN 3+: 1-year follow-up for test results are HPV-positive ASC-US.

138 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

TABLE 3. CIN 3+ 1-Year and 5-Year Risks Upon Receipt of Colposcopy/Biopsy Result

History: Precolposcopy Colposcopic biopsy CIN 3+ CIN 3+ CIN 3+ 5-y Recommended

test result diagnosis n % cases 1-y risk, % risk, % management
HPV-positive NILM 2 <CIN 1 7,082 6.9 120 0.56 2.7 1-y follow-up
HPV-positive ASC-US <CIN 1 15,601 15 251 0.49 3.2 1-y follow-up
HPV-positive LSIL <CIN 1 7,129 6.9 94 0.59 2.1 1-y follow-upa (special situation)
ASC-H <CIN 1 1,644 1.6 51 2.4 4.4 1-y follow-upa (special situation)
AGC <CIN 1 3,213 3.1 55 1.2 1.6 1-y follow-upa (special situation)
HSIL+ <CIN 1 338 0.33 16 2.9 4.8 1-y follow-upa (special situation)

HPV-positive NILM 2 CIN 1 5,732 5.6 102 0.74 2.8 1-y follow-up
HPV-positive ASC-US CIN 1 20,131 20 296 0.53 2.6 1-y follow-up
HPV-positive LSIL CIN 1 18,254 18 242 0.74 2.3 1-y follow-up
ASC-H CIN 1 2,131 2.1 70 1.4 5.6 1-y follow-upa (special situation)
AGC CIN 1 947 0.92 22 1.3 3.8 1-y follow-upa (special situation)
HSIL+ CIN 1 809 0.78 33 3.9 6.5 1-y follow-upa (special situation)

— CIN 2 12,094 12 NA NA Treatment

— CIN 3 6,836 6.6 NA NA Treatment
— AIS 531 0.51 NA NA Treatment
— Cancer 656 0.64 NA NA Treatment
Total 103,128 100 1,352
The risk determining the recommended management is bolded.
Who can be managed by Table 3?
Patients who have undergone a recent colposcopy with biopsy can be managed by this table. Colposcopy not leading to biopsy was excluded from cal-
culations, because the KPNC protocol recommended biopsy for all patients; thus, absence of biopsy has unclear meaning. However, deferral of biopsy is
allowed for extremely low-risk patients under the colposcopy standards recommendations, and they may be managed with 1-year follow-up.
The first column represents the screening test result leading to referral for colposcopy (precolposcopy test result), whereas the second column gives the
colposcopy finding (colposcopic biopsy diagnosis). The following columns show the total sample size (n) in each category and each screening result as a
percentage (%) of total screened, number of observed CIN 3+ cases, CIN 3+ 1-year risk (rather than immediate risk), CIN 3+ 5-year risk, and recommended
management (for more detailed explanation of each column, refer to Methods Section). “Recommendation confidence score” cannot be obtained for this analysis.
In summary, the management of colposcopy biopsy results of normal or CIN 1, regardless of results preceding colposcopy referral, including high-grade
cytology, is 1-y follow-up. However, patients with high-grade findings on cytology but low-grade findings on histology represent a higher-risk group, with
more intensive short- and long-term management outlined in the Perkins et al.1 Section I.4. Individuals in the KPNC cohort with CIN 2 or 3, AIS, or cancer
colposcopy results are typically referred for treatment; therefore, we cannot obtain CIN 3+ risks for these cases.
a
For management of these special situations refer to Perkins et al.1
NA indicated not applicable. Due to small sample size and zero observed CIN 3+ cases, CIN 3+ risks couldn't be obtained for these cells.

This patient has an abnormal current result and an unknown/ result combination, among whom 189 had CIN 3+, leading to a
undocumented history, therefore consult Table 1A. Her immediate recommendation confidence score of 100%.
CIN 3+ risk is 4.4%. The recommended management is colpos- Patient 3: A 32-year-old woman presents for follow-up. Her
copy because her immediate estimated risk is greater than 4% (the history is a cotest result 1 year ago that was HPV-positive NILM.
colposcopy threshold) and less than 25% (the treatment or colpos- Her result today is HPV-negative ASC-US.
copy threshold). In the KPNC database, 30,506 women had this This patient has a history of an abnormal result that did not
result combination, among whom 1,378 had CIN 3+ (detected require colposcopy, therefore consult the Tables 2A–C section
from initial screen through the end of follow-up), leading to a rec- corresponding to her initial abnormal result. For HPV-positive
ommendation confidence score rounding to 100%. NILM, this is Table 2C (use Tables 2A, B for HPV-negative
Patient 2: A 35-year-old woman presents for screening, ASC-US and LSIL, respectively). This patient's immediate CIN
she denies having colposcopy or treatment in the past, and 3+ risk is less than 4%, so the 5-year risk is used to determine
medical record documentation shows that her last result was the recommended management. Her 5-year risk is 2.6%, which
an HPV-negative NILM screening result 5 years ago. Her current is above the 0.55% threshold for a 3-year return, so the recom-
test results are HPV-positive ASC-US. mended management is 1-year follow-up. In the KPNC database,
This patient has an abnormal current result and history of a 585 women had this result combination, among whom 11 had
documented negative HPV and cytology cotest, therefore con- CIN 3+, leading to a recommendation confidence score of 100%.
sult Table 1B (although Table 1B is for negative HPV— Patient 4: A 32-year-old woman has a history of an HPV-
without cytology—history, the CIN 3+ risks are very similar positive LSIL result. Her colposcopic biopsy shows CIN 1.
with cotest negative history). Her immediate CIN 3+ risk is less This patient has colposcopy/biopsy result, therefore consult
than 4%, so the 5-year risk is used to determine management. Table 3. Because we know the colposcopy/biopsy results of the pa-
Her 5-year risk is 3.8%, which is above the 0.55% threshold tient, calculating immediate CIN 3+ risks is meaningless. Therefore,
for a 3-year return, so the recommended management is in this scenario, we are rather interested in 1- and 5-year CIN 3+ risks
1-year follow-up. In the KPNC database, 7,794 women had this of the patients. For this patient, 1-year CIN 3+ risk is less than 4%, so

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 139
Egemen et al. Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020

TABLE 4A. Immediate and 5-Year Risks of CIN 3+ Postcolposcopy at Which CIN 2+ Was Not Found, After Referral for Low-Grade Results

History: History: Current Current CIN 3+ Recommendation

precolposcopy colposcopy HPV cytology CIN 3+ immediate CIN 3 + 5-y Recommended confidence
test result result result result n % cases risk, % risk, % management score, %
Low gradeª <CIN 2 HPV-negative NILM 32,361 55 56 0.00 0.42 3-y follow-up 99
Low gradeª <CIN 2 HPV-negative ASC-US/LSIL 2,937 5.0 14 0.05 0.92 1-y follow-up 93
Low gradeª <CIN 2 HPV-negative High gradeb 149 0.25 4 1.6 4.1 Colposcopy Special situation
Low gradeª <CIN 2 HPV-negative ALLc 35,603 60 74 0.01 0.51 3-y follow-up 73

Low gradeª <CIN 2 HPV-positive NILM 9,352 16 272 2.1 5.2 1-y follow-up 100
Low gradeª <CIN 2 HPV-positive ASC-US/LSIL 12,843 22 445 3.1 6.0 1-y follow-up 100
Low gradeª <CIN 2 HPV-positive High gradeb 1,294 2.2 276 23 31 Colposcopy 94
Totald 58,936 100 1,067
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
Who can be managed by Table 4A?
Patients who are recommended for 1-year follow-up surveillance after less than CIN 2 colposcopy results following a low-grade (i.e., ASC-US, LSIL
regardless of HPV test result or HPV-positive NILM) screening result can be managed by Table 4A. This table addresses both a current cotest result or pri-
mary HPV test with cytology triage for HPV-positive tests.
The first column indicates that the HPV test referring the patient to colposcopy was low-grade (i.e., HPV-positive NILM, or ASC-US or LSIL cytology
regardless of HPV test result) and the second column presents the colposcopic biopsy diagnosis. The third and fourth columns represent current screening
results obtained at the surveillance visit. The following columns show the total sample size (n) in each category and each screening result as a percentage (%)
of total screened, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence
score” for corresponding management (for more detailed explanation of each column, refer to Methods Section).
In summary, patients followed-up after a <CIN 2 finding after low-grade screening result can be managed as follows: those with high-grade cytology are recom-
mended to have colposcopy, those with low-grade abnormalities are recommended to be followed-up in 1 year, and those with a negative cotest can return in 3 years.
ªPrecolposcopy low-grade test result corresponds to either ASC-US/LSIL (regardless of HPV test result) or HPV-positive NILM.
b
High grade corresponds to ASC-H/AGC/HSIL+.
c
HPV-negative ALL, e.g., primary HPV screening.
d
HPV-negative ALL is excluded from the total to avoid duplication.

the 5-year risk is used. Her 5-year risk is 2.3%, which is above the (LEEP), followed by 1 negative HPV test. She presents for follow-up
0.55% threshold for a 3-year return, so the recommended man- and her second HPV test result is also negative.
agement is 1-year follow-up. In the KPNC database, 18,254 This patient has a history of treated CIN 3 and more than 1
women had this result combination, among whom 242 had CIN 3+. negative follow-up test, therefore consult Table 5B. Her immedi-
Patient 5: A 32-year-old woman has a history of an HPV- ate CIN 3+ risk is less than 4%, so the 5-year risk is used. Her
positive LSIL result, followed by a colposcopic biopsy showing 5-year risk is 0.91%, which is above the 0.55% threshold for a
CIN 1. She presents for follow-up at 1 year and her cotest result 3-year return, so the recommended management is 1-year
is HPV-positive ASC-US. follow-up. In the KPNC database, 2,379 women had this result
This patient has a history of a low-grade screening test result, combination, among whom 12 had CIN 3+, leading to a recom-
followed by a colposcopy where CIN 2+ was not found, and now mendation confidence score of 91%.
presents with new follow-up test results, therefore consult the
Table 4A. Her immediate CIN 3+ risk is less than 4%, so the Summary of Concepts Underlying Changes From
5-year risk is used. Her 5-year risk is 6.0%, which is above the 2012 Guidelines1
0.55% threshold for a 3-year return, so the recommended manage- Negative HPV tests reduce risk. An HPV-negative test is vir-
ment is 1-year follow-up. In the KPNC database, 12,843 women tually as reassuring as a negative cotest. The only instance in
had this result combination, among whom 445 had CIN 3+, lead- which HPV-negative is not reassuring is when cytology is HSIL+.
ing to a recommendation confidence score of 100%. However, this test combination is extremely rare (0.01% of overall
Patient 6: A 32-year-old woman has a history of CIN 3 screens in Tables 1A, B).
that was treated with a diagnostic excisional procedure (loop As history, a negative HPV test followed by a positive HPV
electrosurgical excision procedure). She presents for follow-up test suggests a new or reappearing infection, which is lower risk
at 6 months and her cotest result is HPV-positive NILM. than a persistent infection. Therefore, a prior HPV-negative test
This patient has a history of treated CIN 3, therefore consult leads to lower risks (see Table 1B) than unknown history (see
Table 5A. Her immediate CIN 3+ risk is 5.6%. This exceeds the Table 1A). For HPV-positive ASC-US and LSIL, this reduction
4% colposcopy threshold but is below the threshold for offering in risks leads to a change of recommended management. A doc-
colposcopy or treatment (25%), so the recommended manage- umented negative HPV test result before HPV-positive ASC-US
ment is colposcopy. In the KPNC database, 290 women had this and LSIL almost halves the immediate CIN 3+ risk (4.4%, 4.3%–
result combination, among whom 21 had CIN 3+, leading to a rec- 2.0%, 2.1%, respectively) and changes the recommended manage-
ommendation confidence score of 86%. ment from immediate colposcopy to 1-year follow-up (see Table 1B).
Patient 7: A 32-year-old woman has a history of CIN 3 that The HPV–negative ASC-US is also a reassuring history result
was treated with diagnostic loop electrosurgical excisional procedure (see Table 2A). A negative cotest after HPV-negative ASC-US

140 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

TABLE 4B. Immediate and 5-Year Risks of CIN 3+ Postcolposcopy at Which CIN 2+ Was Not Found, After Referral for High-Grade Results

History: History: Current Current CIN 3+ Recommendation

precolposcopy colposcopy HPV cytology CIN 3+ immediate CIN 3+ 5-y Recommended confidence
test result result result result n % cases risk, % risk, % management score, %
High gradeª <CIN 2 HPV-negative NILM 4,650 70 12 0.02 0.48 1-y follow-upb Special situation
High gradeª <CIN 2 HPV-negative ASC-US/LSIL 379 5.7 3 0.28 1.3 1-y follow-up 84
High gradeª <CIN 2 HPV-negative High gradeª 109 1.6 9 5.6 14 Look at footnotec 75
High gradeª <CIN 2 HPV-negative ALLd 5,161 77 24 0.14 0.80 1-y follow-up 93

High gradeª <CIN 2 HPV-positive NILM 510 7.6 36 5.0 12 Colposcopy 80

High gradeª <CIN 2 HPV-positive ASC-US/LSIL 689 10 61 6.6 17 Colposcopy 99
High gradeª <CIN 2 HPV-positive High gradeª 346 5.2 95 28 38 Look at footnotec Special situation
Totale 6,683 100 216
The risk determining the recommended management is bolded.
Who can be managed by Table 4B?
Patients who are recommended for 1-year follow-up surveillance after less than CIN 2 examination after a high-grade (i.e., ASC-H, AGC, or HSIL+)
screening result can be managed by Table 4B. A current cotest result or primary HPV test with cytology triage for HPV-positive tests is addressed by this table.
The first column indicates that the HPV test referring the patient to colposcopy was high-grade (i.e., ASC-H, AGC, or HSIL+ cytology regardless of HPV
test result) and the second column presents the colposcopic biopsy diagnosis. The third and fourth columns represent current screening results obtained at the
surveillance visit. The following columns show the total sample size (n) in each category and each screening result as a percentage (%) of total screened,
number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation confidence score” for corre-
sponding management (for more detailed explanation of each column, refer to Methods Section).
ASC-H, AGC, and HSIL+ are rare diagnoses, and CIN 2+ is found in most cases. Therefore, a relatively small number of patients are available for risk
estimation in follow-up after these results, requiring ASC-H, AGC, and HSIL+ to be combined in longer-term follow-up analyses. Because of the concern
for occult disease after any high-grade cytology, results are managed cautiously. Specifically, when a risk estimate is close to a clinical action threshold after a
high-grade result, a more aggressive management strategy is preferred.
a
High grade corresponds to ASC-H/AGC/HSIL+.
b
This case has a low “recommendation confidence score” and should be managed cautiously. Therefore, the recommended management is 1-year follow-up
rather than 3-year follow-up.
c
High grade: Management differs based on cytology, ASC-H/AGC recommended management is “colposcopy”, HSIL+ recommended management is
“treatment preferred” (for more details, refer to Perkins et al.1)
d
HPV-negative ALL, e.g., primary HPV screening.
e
HPV-negative ALL is excluded from the total to avoid duplication.

warrants return to screening at 5-year intervals (5-year CIN 3+ A history of HPV-positive results increases risk, even when
risk is 0.14%, which is less than the 0.15% 5-year surveillance the current result is negative. After HPV-positive NILM, a nega-
threshold). Minor abnormalities (e.g., HPV-positive ASC-US tive cotest is recommended to be followed-up in 1 year rather than
and HPV-positive LSIL) after HPV-negative ASC-US are rec- 3 years (since 5-year CIN 3+ risk is 0.9%, higher than the 0.55%
ommended to be followed in 1 year, rather than proceed imme- 3-year surveillance threshold, see Table 2C), as was recommended
diately to colposcopy (see Table 2A). Though higher risk than in 2012 guidelines.2 Only after 2 negative cotests can the screen-
HPV-negative ASC-US, HPV-negative LSIL is less risky than pre- ing interval can be safely extended to 3 years because the 5-year
viously thought, allowing minor abnormalities after HPV-negative CIN 3+ risk drops to 0.29% (see Table 2C). Data after 3 negative
LSIL (i.e., HPV-negative ASC-US, HPV-negative LSIL, and cotests continue to support a 3-year interval, although data are
HPV-positive NILM) to be followed in 1 year, rather than proceed sparse and recommendations may change in the future as more
immediately to colposcopy (see Table 2B). In addition, HPV- data accrue (See Section J.4 main article for discussion).
negative ASC-US and HPV-negative LSIL after HPV-positive NILM Prior treatment for CIN 2 or CIN 3 increases risk. After
are recommended to have a deferred management of 1-year sur- treatment for CIN 2 or CIN 3, most treated patients (82.3%, in
veillance (see Table 2C). total 4,695) have a negative HPV test result on the first
Colposcopy performed for low-grade abnormalities, which follow-up screening, with immediate and 5-year CIN 3+ risks
confirms the absence of CIN 2+ reduces risk. After a colposcopic of 0.34% and 2.0% leading to 1-year follow-up (see Table 5A).
examination performed for low-grade abnormalities (e.g.; HPV- Any abnormality on any follow-up test leads to re-referral to col-
positive NILM  2, HPV-positive ASC-US, or HPV-positive LSIL) poscopy, including HPV-negative ASC-US/LSIL cytology, HPV-
at which CIN 1 or less was confirmed via biopsy, minor abnor- negative high-grade cytology, and all HPV-positive results (see
malities (e.g., HPV-positive ASC-US and HPV-positive LSIL) Table 5A). Two negative HPV tests (HPV negative  1 followed
found on the first follow-up test are recommended to be followed by HPV negative in Table 5B) after a treated CIN 2 or CIN 3 will
in 1 year, rather than proceed immediately to colposcopy (see give a 5-year CIN 3+ risk of 0.91% resulting in 1-year follow-up
Table 4A). Because all repeat abnormalities were referred back (see Table 5B). Observing one more negative HPV test result de-
to colposcopy at KPNC, we cannot estimate risks for additional creases this risk to 0.44%, which leads to 3-year follow-up (see
rounds of follow-up. Therefore, the 2019 guidelines recom- Table 5B). Results are similar when cotesting is considered rather
mend referral for colposcopy for abnormal results occurring than primary HPV testing. Even after 3 negative HPV tests or
on subsequent rounds of follow-up testing. cotests, risks remain well above the 0.15% 5-year CIN 3+ risk

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 141
Egemen et al. Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020

TABLE 5A. Immediate and 5-Year Risks After Treatment for CIN 2 or CIN 3

CIN 3+
History: CIN Current Current CIN 3+ immediate CIN 3+ 5-y Recommended Recommendation
2 or 3 (treated) HPV result cytology result n % cases risk, % risk, % management confidence score, %
CIN 2 or 3 HPV-negative NILM 3,525 75 29 0.03 1.7 1-y follow-up 100
CIN 2 or 3 HPV-negative ASC-US/LSIL 280 6 6 0.75 3.8 1-y follow-up 98
CIN 2 or 3 HPV-negative High gradeª 59 1.3 10 18 18 Colposcopy 93
CIN 2 or 3 HPV-negative ALLb 3,876 45 0.34 2.0 1-y follow-up 100

CIN 2 or 3 HPV-positive NILM 290 6.2 21 5.8 12 Colposcopy 86

CIN 2 or 3 HPV-positive ASC-US/LSIL 342 7.3 41 10 21 Colposcopy 100
CIN 2 or 3 HPV-positive High gradeª 199 4.2 98 53 63 Colposcopy/treatment 97
Totalc 4,695 100 205
100% recommendation confidence score is not exact but rounds to 100%.
The risk determining the recommended management is bolded.
The risk varies substantially for treated CIN 2 and treated CIN 3 scenarios. However, to maximize safety after treatment of precancer management is
recommended based on treated CIN 3 cases. The Table 5A present risks at follow-up visit after being treated for CIN 3, but the corresponding managements
will apply to both treated CIN 2 and CIN 3. The prior test result that triggered the colposcopy and subsequent treatment is not included as a predictor in these
tables as it did not change the recommended management.
Who can be managed by Table 5A?
Patients being followed after a treatment for CIN 2 or CIN 3 can be managed by Table 5A. Current cotest results or primary HPV tests with cytology
triage for HPV-positive tests are addressed.
The first column represents the history of the patient whose treatment is for CIN 2 or CIN 3. The second and third columns represent current screening
results obtained at the surveillance visit after treatment. The following columns show the total sample size (n) in each category and each screening result as a
percentage (%) of total screened, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommenda-
tion confidence score” for corresponding management (for more detailed explanation of each column, refer to Methods Section).
After treatment for CIN 2 or CIN 3, 75% of the 4,695 patients have a negative cotest result on the first follow-up cotest, with immediate and 5-year
CIN 3+ risks of 0.03% and 1.7% leading to 1-year follow-up.
In summary, all of the HPV-positive results lead to immediate referral back to repeat colposcopy. Cotest and HPV-negative results as well as HPV-negative
ASC-US/LSIL have a deferred management of 1-year surveillance while HPV-negative high-grade cytology lead to referral back to colposcopy.
ªHigh Grade corresponds to ASC-H/AGC/HSIL+.
b
HPV-negative ALL, e.g., primary HPV screening.
c
HPV-negative ALL is excluded from the total to avoid duplication.

TABLE 5B. Long-Term Follow-up When There Are 2 or 3 Negative Follow-up Test Results After Treatment of CIN 2 or CIN 3

History: CIN History: cotest or Current CIN 3+ CIN 3+ CIN 3 5-y Recommended Recommendation
2 or 3 (treated) HPV test negative test result n cases immediate risk, % risk, % management confidence score, %
CIN 2 or 3 Cotest negative 1 Cotest negative 2,087 7 0.00 0.68 1-y follow-up 68
CIN 2 or 3 HPV-negative 1 HPV-negative 2,379 12 0.05 0.91 1-y follow-up 91
CIN 2 or 3 Cotest negative 2 Cotest negative 1,099 2 0.00 0.35 3-y follow-up 58
CIN 2 or 3 HPV-negative 2 HPV-negative 1,314 4 0.15 0.44 3-y follow-up 59
The risk varies substantially for treated CIN 2 and treated CIN 3 scenarios. However, to maximize safety after treatment of precancer management is
recommended based on treated CIN 3 cases. The Table 5B present risks at follow-up visit after being treated for CIN 3, but the corresponding managements
will apply to both treated CIN 2 and CIN 3. The prior test result that triggered the colposcopy and subsequent treatment is not included as a predictor in these
tables as it did not change the recommended management.
The risk determining the recommended management is bolded.
Who can be managed by Table 5B?
Patients who are followed up after a CIN 2 or CIN 3 treatment with more than 1 cotest or primary HPV-negative results can be managed by Table 5B.
The first column represents the history of the patient whose treatment is for CIN 2 or CIN 3. The second column represents the follow-up screening re-
sults in the past surveillance visits after treatment. The third column represents the current screening results. The following columns show the total sample
size (n) in each category, number of observed CIN 3+ cases, CIN 3+ immediate and 5-year risks, recommended management, and “Recommendation con-
fidence score” for corresponding management (for more detailed explanation of each column, refer Methods Section).
Table 5B is created to assess the number of negative tests needed to return the patient back to regular screening from post-treatment surveillance. Two
cotest negatives (cotest negative 1 followed by cotest negative) after a treated CIN 2 or CIN 3 will give a 5-year CIN 3+ risk of 0.68% resulting in
1-year follow-up. Observing one more cotest negative decreases this risk to 0.35%, which leads to 3-year follow-up (Figure 2). The results are similar when
primary HPV testing is considered rather than cotesting.
In summary, as a result of the presented data, multiple negative cotest results after a CIN 2 or CIN 3 treatment are not enough to exit after treatment sur-
veillance rather, a continuation of 3-year follow-up is recommended.

142 © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.
Journal of Lower Genital Tract Disease • Volume 24, Number 2, April 2020 Risk Estimates for Consensus Guidelines

threshold needed to return to screening at 5-year intervals, leading Therefore, risk estimation subsequent to diagnoses of CIN 1 or
to a recommendation of continued follow-up at 3-year intervals. less after these cytologic results were less reliable, and because
of the concern for occult disease after any high-grade cytology,
DISCUSSION results are managed cautiously. In other situations, some current cy-
We detail how risk estimates are used for clinical manage- tologic results are grouped together to avoid small categories with
ment according to the principles laid out by the 2019 ASCCP almost zero CIN 3+ cases, allowing for calculation of risk estimates.
Risk-Based Management Guidelines. We also lay out basic princi-
ples underlying risk-based management: (a) HPV-negative test re- CONCLUSIONS
sults reduce risk; (b) colposcopic examinations at which CIN 2+ The unique KPNC screening experience, and the long-term
is not found reduce risk; (c) HPV-positive test results increase risk; collaborative dedication of our KPNC colleagues, permitted this
and (d) prior treatment for CIN 2 or CIN 3 increases risk. Although detailed examination of risks. The length and size of the program,
these principles are intuitive, their ramifications are far-reaching. At and its indisputable high quality, lend confidence to the internal
a population level, the risk of CIN 3+ for screening participants at comparisons of risk after different test results. The question of
any given age is highest at the time of the initial HPV-based screen external validity of KPNC data-based management guidelines
(0.45% immediate CIN 3+ risk for patients new to HPV testing in is addressed elsewhere in this issue.3 The generalizability of
KPNC aged 25–65 years). The first screening round will detect risk estimates and clinical action thresholds seems high based
most prevalent CIN 3+ and reduce the risk of CIN 3+ in future on comparison with 4 other data sets from varied populations.
screening rounds. This situation is exemplified by patients entering As other large prospective data sets become available, additional
an HPV-based screening program for the first time. checks on external validity will be conducted as part of the pro-
Among 1,546,462 people at the first visit, 92% had a primary posed plan for ongoing updates to the guidelines.
HPV-negative test result. Individuals with a negative HPV screen- The risk-based management tables shown in abbreviated
ing results are at very low risk of developing CIN 3+ within the form in this article underlie the 2019 ASCCP Risk-Based Consen-
next 5 years (0.14%); thus, a 5-year screening interval is recom- sus Management Guidelines. Moving from result-based to risk-
mended. As populations begin screening with HPV testing, most based guidelines, it is important for the clinician to understand
individuals will test negative, reducing their need for colposcopy how these risk estimates were obtained and how to use them in
in subsequent screening rounds. clinical management of cervical screening. This article explains
Among the 8% of the population that initially tested HPV risk-based management tables under 5 different clinical scenarios
positive, immediate CIN 3+ risks ranged from 2.1% for HPV-posi- that comprise most management visits and decisions.
tive NILM (below the colposcopy threshold), to 4.3% and 4.4% for A more extensive version of these tables (which include risk
HPV-positive ASC-US and LSIL, respectively (defining the colpos- estimates with CIN 2+, CIN 3+, and cancer end points, as well as
copy threshold), to 25% and 26% for HPV-negative HSIL+ and risk estimates for 0, 1, 2, 3, 4, and 5 years under each end point together
HPV-positive ASC-H, respectively (defining the treatment or colpos- with the standard error and CI for each risk estimate) can be found at a
copy threshold), to 49% for HPV-positive HSIL+. Reaching the 60% database stored at the National Institutes of Health, publicly acces-
threshold for preferring treatment requires an additional risk factor, sible through this link: https://CervixCa.nlm.nih.gov/RiskTables.
such as HPV-16 infection7 or a history of not having been screened.
Management recommendations are similar to the 2012 guide-
lines2 for patients with an unknown screening history but are mod- REFERENCES
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© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 143