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American Cancer Society Guideline for the Early Detection of Cervical Neoplasia and
Cancer
Debbie Saslow, Carolyn D. Runowicz, Diane Solomon, Anna-Barbara Moscicki, Robert A.
Smith, Harmon J. Eyre and Carmel Cohen
CA Cancer J Clin 2002;52;342-362
ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
American Cancer Society Guideline
for the Early Detection of Cervical
Neoplasia and Cancer
Dr. Saslow is Director, Breast and
Gynecologic Cancer, American
Cancer Society, Atlanta, GA.
Dr. Runowicz is Vice Chairman,
Department of Obstetrics and
Gynecology, St. Lukes-Roosevelt
Hospital Center, New York, NY.
ABSTRACT An update to the American Cancer Society (ACS) guideline regarding screening
for the early detection of cervical neoplasia and cancer, based on recommendations from a
formal review and recent workshop, is presented. The new screening recommendations
address when to begin screening, when screening may be discontinued, whether to screen
women who have had a hysterectomy, appropriate screening intervals, and new screening
technologies, including liquid-based cytology and HPV DNA testing. (CA Cancer J Clin
Dr. Solomon is Project Officer,
ASCUS/LSIL Triage Study, National
Cancer Institute, Rockville, MD.
Dr. Moscicki is Director, Teen
Colposcopy Clinic and Associate
Director, Division of Adolescent
Medicine, University of California,
San Francisco, CA.
Dr. Smith is Director of Cancer
Screening, American Cancer Society, Atlanta, GA.
Dr. Eyre is Chief Medical Officer and
Executive Vice President for
Research and Cancer Control,
American Cancer Society, Atlanta,
GA, and Editor in Chief of CA.
Dr. Cohen is Professor and Director,
Division of Gynecologic Oncology,
and Vice Chairman, Department of
Obstetrics, Gynecology, and Reproductive Science, The Mount Sinai
Medical Center, New York, NY.
This article is available online at
http://CAonline.AmCancerSoc.org
2002;52:342-362.)
INTRODUCTION
Cervical cancer mortality in the United States has decreased over the last five
decades by over 70 percent in large part attributable to the introduction of the
Papanicolaou (Pap) test. Cervical cancer, once the number one cancer killer of
women, now ranks 13th in cancer deaths for women in the United States.1 As
cervical cytology screening has become more prevalent, preinvasive lesions of the
cervix are detected far more frequently than invasive cancers. In 2002, an estimated
13,000 cases of invasive cervical cancer will be diagnosed, and an estimated 4,100
women will die from this disease.Women with preinvasive lesions have a five-year
survival rate of nearly 100 percent.When cervical cancers are detected at an early
stage, the five-year survival rate is approximately 92 percent.1
Between 93 and 100 percent of squamous cell carcinomas of the cervix contain
DNA from high-risk types of human papillomavirus (HPV), which are transmitted
during sexual activity.2,3 Studies of the natural history of cervical cancer have shown
that infection with high-risk HPV types may lead to low-grade or high-grade
intraepithelial lesions. High-grade lesions may progress to cervical carcinoma if not
Author disclosures: R. Marshall Austin, MD, PhD, has served as a consultant and/or speaker without accepting personal compensation for AutoCyte Inc., Cytyc
Corporation, Digene Corporation, Morphometrix Technologies Inc., NeoPath, Inc., Neuromedical Sciences Inc., and Veracel Inc. J.Thomas Cox, MD, has consulted for Cytyc Corporation, Digene Corporation, 3M Pharmaceuticals, Inc., and Merck & Co., Inc., and is on the speaker’s bureau of Cytyc Corporation,
and 3M Pharmaceuticals, Inc. Jack Cuzick, PhD, is a consultant to Digene Corporation. Eduardo Franco, MPH, DrPH, has occasionally been invited by 3M
Pharmaceuticals, Inc., GlaxoSmithKline, Digene Corporation, and F. Hoffmann-La Roche Ltd. to serve as a temporary consultant or visiting speaker. Walter
Kinney, MD, has received research support from 3M Pharmaceuticals and serves on the speaker’s bureau for Cytyc Corporation and Digene Corporation. Evan
Myers, MD, MPH, has received research support from and is a consultant to Merck Research Laboratories. Ellen Sheets, MD, was appointed as a vice president
of Cytyc Corporation in May 2002, following the ACS guideline workshop.Thomas C.Wright, Jr., MD, has received research support from Digene Corporation
and Cytyc Corporation and is on the speaker’s bureau of Cytyc Corporation and TriPath Imaging, Inc.
342
CA A Cancer Journal for Clinicians
Downloaded from caonline.amcancersoc.org by guest on January 18, 2007 (©American Cancer Society, Inc.)
Debbie Saslow, PhD; Carolyn D. Runowicz, MD; Diane Solomon, MD;
Anna-Barbara Moscicki, MD; Robert A. Smith, PhD; Harmon J. Eyre, MD; Carmel Cohen, MD
CA Cancer J Clin 2002;52:342-362
Guideline Development
The ACS guideline for the early detection
of cervical cancer was last reviewed in 1987.At
that time it was recommended that all women
who are or have been sexually active, or have
reached the age of 18, have an annual Pap test
and pelvic examination; after a woman has had
three or more consecutive, technically
satisfactory, normal annual examinations, the
Pap test may be performed less frequently at
the discretion of her physician.11 This
recommendation was accepted as policy in
identical or similar wording by the National
Cancer Institute, the American College of
Obstetricians and Gynecologists, the American
Medical Association, the American Academy of
Family Physicians, the American Medical
Women’s Association, and the American
Nurses Association.
In 2001 to 2002, the ACS convened an
expert panel to review the existing guideline in
the context of evidence that has accumulated
since the last revision. The panel was divided
into working groups to review the evidence
and develop recommendations regarding (1)
when to start screening; (2) when to discontinue screening; (3) screening of women
who have had a hysterectomy; (4) screening
intervals; and (5) screening tests.
During the current guideline review,
published articles related to cervical cancer
screening, including new screening tests, were
identified using MEDLINE (National Library
of Medicine), bibliographies of identified
articles, personal files of panel members,
and unpublished manuscripts. Expert panel
members reviewed articles using specified
criteria (Appendix A) and discussed them
during a series of conference calls. Each work
group developed recommendations, rationale,
and evidence summaries, and reviewed the
summaries developed by the other work
groups prior to an April 2002 workshop.When
evidence was insufficient or lacking, the final
recommendations incorporated the expert
opinions of the panel members. Relevant
unpublished manuscripts were distributed to
workshop attendees prior to the meeting.
During the conference calls and workshop,
Downloaded from caonline.amcancersoc.org by guest on January 18, 2007 (©American Cancer Society, Inc.)
treated.4,5 Most HPV* infections, however, are
transient, resulting either in no symptoms or
cellular changes or producing low-grade
intraepithelial lesions.6,7,8 The purpose of
screening, in addition to detecting cervical
cancers at an early stage, is to detect and
remove high-grade lesions and thus prevent
potential progression to cervical carcinoma.
The very success of the Pap test in cervical
cancer screening has fostered an unrealistic
expectation that the test is perfect. It is not. Pap
test sensitivity for high-grade cervical
intraepithelial neoplasia (CIN) is in the range
of 70 to 80 percent.9 Factors that limit test
sensitivity include: small size of a lesion,
inaccessible location of the lesion, the lesion
not being sampled, the presence of only a few
abnormal cells on the slide, small size of the
abnormal cells, or the presence of
inflammation and/or blood obscuring cell
visualization. False-negative results occur even
in optimized screening programs and cannot
be entirely eliminated.
Approximately half of the cervical cancers
diagnosed in the United States are in women
who have never been screened, and an
additional 10 percent of cancers occur in
women who have not been screened within
the past five years.10 While the new American
Cancer Society screening guideline includes a
review of new cervical cancer screening tests,
perhaps the largest gain in reducing cervical
cancer incidence and mortality could be
attained by increasing screening rates
(regardless of the test used) among women
who are currently unscreened or screened only
infrequently. However, new technologies may
offer advantages over what is already a
successful screening test, when utilized.
*Unless otherwise specified, HPV refers to high-risk types only throughout this document.
Volume 52 • Number 6 • November/December 2002
343
ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
344
consensus was reached on the
key issues within the
guideline recommendations.
Following the workshop,
ACS Gynecologic Cancer
Advisory Group members
deliberated over the guideline
modifications. Each work
group member and workshop
attendee reviewed the draft of
this manuscript.
Several organizations reviewed this manuscript, provided comments, and indicated their support of the
new recommendations. These
organizations include the
American College of Obstetricians and Gynecologists,
the American Social Health
Association, the American
Society of Colposcopy and
Cervical Pathology, the
Association of Reproductive
Health Professionals, the
Gynecologic Cancer Foundation, the National Association of Nurse Practitioners
in Women’s Health, and the
Society of Gynecologic Oncologists.
RECOMMENDATIONS,
RATIONALE, AND EVIDENCE
When to Start Screening
Recommendation
Cervical cancer screening
should begin approximately
three years after the onset of
vaginal intercourse. Screening
should begin no later than 21
years of age. It is critical that
adolescents who may not
need a cervical cytology test
CA A Cancer Journal for Clinicians
obtain appropriate preventive health care,
including assessment of health risks,
contraception, and prevention counseling,
screening and treatment of sexually transmitted
diseases.The need for cervical cancer screening
should not be the basis for the onset of
gynecologic care.
Rationale
The published and unpublished data on the
incidence of cervical cancer and the natural
history of HPV infection and of low- and
high-grade cervical lesions suggest that there is
little risk of missing an important cervical
lesion until three to five years after initial
exposure to HPV (Evidence section). Thus,
cervical cytology screening in adolescents is
unlikely to add appreciable benefits within the
first three years following onset of vaginal
intercourse. It is the intent of the ACS that
offering screening “approximately” three years
after the onset of sexual intercourse will avoid
denial of health insurance coverage for teens
and young women who undergo their first
cytology test prior to the suggested three years.
However, the concern is that screening before
the three-year-period may result in an
overdiagnosis of cervical lesions that will
regress spontaneously, leading to inappropriate
intervention, which may result in more harm
than good. Because the risk of HPV
transmission to the cervix is low for other
types of sexual activity, the onset of vaginal
sexual intercourse has been selected as the
historical marker for initiating cervical
cytology screening.
An upper age limit for when to initiate
screening is needed for providers who don’t
ask patients about their sexual history and for
adolescents who are unable or unwilling to
disclose prior consensual and/or nonconsensual intercourse. Such an upper age limit
ensures that young women, including victims
of sexual abuse, are protected.
In cases where a history of sexual abuse has
been established, there is a lack of evidence to
support earlier cervical screening for victims of
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Gynecologic Cancer Advisory Group:
Carmel Cohen, MD, (Chair), Professor and Director,
Division of Gynecologic Oncology, and Vice
Chairman, Department of Obstetrics, Gynecology,
and Reproductive Science, The Mount Sinai Medical
Center, New York, NY; Diane M. Harper, MD, MPH,
Associate Professor, Departments of Community and
Family Medicine and Obstetrics and Gynecology,
Dartmouth Medical School, Lebanon, NH; Joan G.
Jones, MD, Professor of Pathology and Clinical
Obstetrics, Gynecology, and Women's Health, Albert
Einstein College of Medicine, and Director of
Surgical Pathology, Weiler-Einstein Division,
Montefiore Medical Center, Bronx, NY; Heyoung Lee
McBride, MD, Radiation Oncologist, John Stoddard
Cancer Center, Iowa Methodist Medical Center, Des
Moines, IA; William McGuire, MD, Director, Franklin
Square Hospital Cancer Center, Baltimore, MD;
Edward Partridge, MD, Professor and Vice Chairman,
Department of Obstetrics and Gynecology, Division of
Gynecologic Oncology, The University of Alabama at
Birmingham, Birmingham, AL; Stephen Rubin, MD,
Professor and Director, Department of Obstetrics and
Gynecology, Division of Gynecologic Oncology,
University of Pennsylvania Medical Center,
Philadelphia, PA; Carolyn D. Runowicz, MD, Vice
Chairman, Department of Obstetrics and Gynecology,
St. Lukes-Roosevelt Hospital Center, New York, NY;
Debbie Saslow, PhD, Director, Breast and
Gynecologic Cancer, American Cancer Society,
Atlanta, GA; Diane Solomon, MD, Project Officer,
ASCUS/LSIL Triage Study, National Cancer Institute,
Rockville, MD.
When to Start Screening Work Group:
Anna-Barbara Moscicki, MD, (Chair), Director Teen
Colposcopy Clinic and Associate Director, Division of
Adolescent Medicine, University of California, San
Francisco, CA; S. Jean Emans, MD, Chief, Division of
Adolescent Medicine, Children’s Hospital, Boston,
and Professor of Pediatrics, Harvard Medical School,
Boston, MA; Sue J. Goldie, MD, MPH, Associate
Professor of Health Policy and Decision Science,
Harvard Center for Risk Analysis, Department of
Health Policy and Management, Harvard School of
Public Health, Boston, MA; Paula Adams Hillard, MD,
Professor, Departments of Obstetrics/Gynecology
and Pediatrics, Division of Adolescent Medicine,
Children’s Hospital Medical Center, and Director,
Women’s Health, University of Cincinnati College of
Medicine, Cincinnati, OH; Luella Klein, MD, Professor,
Department of Gynecology and Obstetrics, Emory
University, Atlanta, GA; Mary-Ann Shafer, MD,
Professor, Department of Pediatrics, and Associate
Director, Division of Adolescent Medicine, University
of California, San Francisco, CA; Debbie Saslow, PhD,
Director, Breast and Gynecologic Cancer, American
Cancer Society, Atlanta, GA; Robert A. Smith, PhD,
Director of Cancer Screening, American Cancer
Society, Atlanta, GA.
Work Group on Interval, Older Women,
and Hysterectomy:
Carolyn D. Runowicz, MD, (Chair), Vice Chairman,
Department of Obstetrics and Gynecology, St. LukesRoosevelt Hospital Center, New York, NY; Carol Ann
Armenti, Executive Director, Center for Cervical
Health, Toms River, NJ; David Atkins, MD, MPH, Chief
Medical Officer, Center for Practice and Technology
Assessment, Agency for Healthcare Research and
Quality, Rockville, MD; R. Marshall Austin, MD, PhD,
Medical Director and Director of Cytopathology and
Gynecologic Pathology Services, Coastal Pathology
Laboratories, SC, and Clinical Associate Professor of
Pathology, Medical University of South Carolina, Mt.
Pleasant, SC; J. Thomas Cox, MD, Director,
Colposcopy and Gynecologic Clinic, Health Services
Department, University of California, Santa Barbara,
CA; Jack Cuzick, PhD, Head, Department of
Mathematics, Statistics, and Epidemiology, Cancer
CA Cancer J Clin 2002;52:342-362
Evidence
Cervical cancer in women less than 19 years
of age is rare. Mount, et al.13 provided the
highest reported prevalence (3.77 percent) of
squamous intraepithelial lesions (SIL) among
10,296 cytology smears from patients aged 10
to 19 years, 18 percent of SILs were high grade,
and no cases of invasive cancer were detected.
The National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER)
program reported that the incidence rate of
invasive cervical cancer was 0/100,000/year
for ages 10 to 14 years; 0/100,000/year for ages
15 to 19 years and 1.7/100,000/year for ages
20 to 24 years from 1995 to 1999.14 Based on
the SEER data, the potential implied cost of
missing high-grade SIL (HSIL) in 15- to 19year-olds (by not screening or treating these
lesions) is at most 1.7 cases of cervical cancer
per 100,000/year (the incidence rate for 20- to
24-year-olds). It is not known, however, how
many cervical cancer cases among the 20- to
24-age group were found in women who were
immunosuppressed and/or HIV positive, how
many of the women were
screened, or at what stage the
cancers were diagnosed.
The goal of cervical
screening in the United States
is to identify and remove
significant precancerous lesions
in addition to preventing
mortality from invasive cancer.
HSIL is considered a significant
precancerous lesion, whereas
low-grade SIL (LSIL) is
considered a much more
benign lesion since most of
these lesions regress. Data on
regression and the natural
history of LSIL and HPV
infection in young women
aged 13 to 22 have shown that
most HPV infections are
transient, with 70% regression
rates of high-risk HPV types
within three years and over
90% regression for low-risk
types.7 HPV regression rates of
over 90 percent within two
years have been reported in
college
populations.8 Regression of LSIL is more
common in adolescents than in
adults. Fifty to eighty percent
of LSIL in adult women will
whereas
90
regress,15,16,17
percent of LSIL in adolescents
and young women (aged 13 to
21) will regress.18 In one study,
when HPV type was known,
81 percent of LSIL in young
women with a high-risk HPV
DNA type regressed, whereas
six percent progressed.18 This
discrepancy may reflect a more
benign natural history for HPV
infection in adolescents or
reflect an increased accuracy of
cytological diagnosis at entry,
since LSIL greatly outnumbers
HSIL in adolescents, reducing
Research UK, London, United Kingdom; Diane Fink,
MD, Chief Cancer Control Officer, American Cancer
Society, California Division, Inc., Oakland, CA; Diane
M. Harper, MD, MPH, Associate Professor,
Departments of Community and Family Medicine and
Obstetrics and Gynecology, Dartmouth Medical
School, Lebanon, NH; Ira Horowitz, MD, the Willaford
Ransom Leach Professor and Vice Chairman,
Department of Gynecology and Obstetrics, and
Director, Division of Gynecologic Oncology, Emory
University, Atlanta, GA; Herschel W. Lawson, MD,
Medical Advisor, Program Services Branch, DCPC,
NCCDPHP, Centers for Disease Control and
Prevention, Atlanta, GA; Martin C. Mahoney, MD,
PhD, Director, Cancer Prevention and Detection
Center, Division of Cancer Prevention and Population
Sciences, Roswell Park Cancer Institute, Buffalo, NY;
Jeanne Mandelblatt, MD, MPH, Director, Cancer
Control Program, Lombardi Cancer Center,
Georgetown University Medical Center, Washington,
DC; Kenneth L. Noller, MD, Obstetrician-in-Chief,
Department of Obstetrics and Gynecology, Tufts-New
England Medical Center, Boston, MA; George F.
Sawaya, MD, Assistant Professor, Departments of
Obstetrics, Gynecology, and Reproductive Sciences,
Epidemiology and Statistics, University of California,
San Francisco, CA; Debbie Saslow, PhD, Director,
Breast and Gynecologic Cancer, American Cancer
Society, Atlanta, GA; Robert A. Smith, PhD, Director of
Cancer Screening, American Cancer Society, Atlanta,
GA.
Work Group on Technologies:
Diane Solomon, MD (Chair), Project Officer,
ASCUS/LSIL Triage Study, National Cancer Institute,
Rockville, MD; Diane D. Davey, MD, Professor,
Department of Pathology and Laboratory Medicine,
and Director, Cytopathology, University of Kentucky
Medical Center, Lexington, KY; Eduardo L. Franco,
MPH, DrPH, Professor of Epidemiology and Oncology,
and Director, Division of Cancer Epidemiology, McGill
University, Montreal, Canada; Katherine Hartmann,
MD, PhD, Director, North Carolina Program for
Women’s Health Research, and Assistant Professor
of Obstetrics and Gynecology and Epidemiology,
University of North Carolina, Chapel Hill, NC; Ira
Horowitz, MD, the Willaford Ransom Leach Professor
and Vice Chairman, Department of Gynecology and
Obstetrics, and Director, Division of Gynecologic
Oncology, Emory University, Atlanta, GA; Joan G.
Jones, MD, Professor of Pathology and Clinical
Obstetrics, Gynecology, and Women's Health, Albert
Einstein College of Medicine, and Director of Surgical
Pathology, Weiler-Einstein Division, Montefiore
Medical Center, Bronx, NY; Walter Kinney, MD,
Gynecologic Oncologist, Division of Gynecologic
Oncology, The Permanente Medical Group, Inc.,
Sacramento, CA, and Associate Clinical Professor of
Obstetrics and Gynecology, University of California,
Davis, CA; Evan Myers, MD, MPH, Associate
Professor, Department of Obstetrics and Gynecology,
Duke University Medical Center, Durham, NC; Mark
Schiffman, MD, MPH, Chief, Interdisciplinary Studies
Section, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, Department of
Health and Human Services, Rockville, MD; Ellen
Sheets, MD, Associate Professor, Department of
Obstetrics, Gynecology, and Reproductive Biology,
Harvard Medical School, and Vice President, Cytyc,
Corp., Boston, MA; Edward J. Wilkinson, MD,
Professor, Department of Pathology and Laboratory
Medicine, University of Florida College of Medicine,
Gainesville, FL; Thomas C. Wright, Jr., MD, Associate
Professor of Pathology, College of Physicians and
Surgeons, Columbia University, New York, NY; Debbie
Saslow, PhD, Director, Breast and Gynecologic
Cancer, American Cancer Society, Atlanta, GA; Robert
A. Smith, PhD, Director of Cancer Screening,
American Cancer Society, Atlanta, GA.
Volume 52 • Number 6 • November/December 2002
345
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prepubescent sexual abuse. Abuse victims who
have had vaginal intercourse, especially postpuberty, may be at increased risk of HPV
infection and cervical lesions and should be
referred for screening once they are
psychologically and physically ready (i.e., postpuberty) by a provider who has experience
and sensitivity for working with abused
adolescents.
Provider discretion and patient choice
following counseling should be used to guide
the initiation of cervical cytology screening in
young women aged 21 and older who have
never had vaginal sexual intercourse and for
whom the absence of a history of sexual abuse
is certain.
Young women who are infected with HIV
and/or are immunocompromised should
follow the US Public Health System Guidelines, i.e., obtain a Pap test twice in the first
year after diagnosis of HIV infection and, if the
results are normal, annually thereafter.12
ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
346
CA A Cancer Journal for Clinicians
of onset of vaginal intercourse, with an age cap
at 25 (this modeling used the assumption that
cytology would be performed every three years
following three annual, consecutive, technically
satisfactory normal/negative cytology results).
This strategy was modified to reflect the
opinion of an expert panel of clinicians, which
held that an age cap of 25 might result in a
proportion of women not being screened until
their late 20s in the absence of initiation based
on an accurate sexual history. Consequently
some high-grade lesions could progress.
Furthermore, the SEER data indicate that
invasive cervical cancer does occur in women
under 25 years of age. The revised policy
analysis showed that a sexual activity-based
strategy with an age cap of 21 was also costeffective, and particularly more cost-effective
than universal age-based screening at age 18.
The expert panel suggested that an age cap of
21 would represent a more practical and
realistic age than 25 for compliance and access
to patients, and would be more acceptable than
postponing screening until age 25 in the
United States. Of note, a sexual activity-based
screening initiation criterion rather that an
age-based criterion was superior even when
screening was conducted every two years or
every year.
When to Discontinue Screening
Recommendation
Women who are age 70 and older with an
intact cervix and who have had three or more
documented, consecutive, technically satisfactory normal/negative cervical cytology
tests, and no abnormal/positive cytology tests
within the 10-year period prior to age 70 may
elect to cease cervical cancer screening.
Screening is recommended for women who
have not been previously screened, women for
whom information about previous screening
is unavailable, and for whom past screening is
unlikely. Women who have a history of
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the misclassification rate compared to adult
women. The high regression rate of LSIL
parallels the high regression rates reported for
HPV DNA detection, supporting the benign
nature of most LSIL in adolescents and young
women.
There are limited data on the progression
rate of LSIL in adolescents. Moscicki, et al.18
found that only three percent of adolescents
with LSIL progressed to HSIL within three
years. On the other hand, five percent of
adolescents who developed an HPV infection
in an earlier study developed a HSIL, half of
whom did not have a preceding detectable
LSIL.7 Based on the prevalence of HSIL on
cytology smears and the number of patients
with HSIL (CIN2/3) found on histology who
had only LSIL on cytology, approximately 1.7
percent of adolescents are estimated to harbor
an HSIL. However, the risk of progression of
these high-grade lesions among adolescents
remains unknown. Nasiell, et al.19 observed that
the time of progression for women with CIN2
to a carcinoma in situ or cancer over age 51
was 70 to 80 months, 41 to 42 months for
women aged 26 to 50 years, and 54 to 60
months for women under 25 years of age.The
relevance of these findings to young women
today is unclear given that sexual behavior,
contraceptive use, and smoking habits have all
changed from the time when this and other
cohort studies were performed in the 1960s to
1980s. The 54- to 60-month estimated
progression for women under 25 years of age is
the only available data.The difference from 41
months (for women aged 26 to 50) could be
the result of study design rather than biology.
Therefore the more conservative period of 41
months was used as the basis for
recommending
that
screening
begin
approximately three years from potential
exposure to HPV.
In support of this recommendation,
mathematical modeling20 suggests that the most
cost-effective strategy (excluding HPV DNA
testing) is to start screening three years after age
CA Cancer J Clin 2002;52:342-362
and higher health care costs due to falsepositive cytology results.
The choice of exact age at which to cease
screening is arbitrary. The choice of age 70 is
based on the opinions of the expert panel
members in an effort to balance the benefits
and harms of screening older women. While
some organizations have chosen the age of 65
(which is also arbitrary) in their guidelines, the
ACS set the age at 70 based on mathematical
modeling21 (Jeanne Mandelblatt, MD, MPH,
unpublished data.) and demographic trends
that may increase the likelihood of older
women having new sexual partners and thus
new exposures to HPV. Older women who
choose to discontinue screening should
continue to obtain appropriate preventive
health care.
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cervical cancer, in utero exposure to
diethylstilbestrol (DES), and/or who are
immunocompromised (including HIV+)
should continue cervical cancer screening for
as long as they are in reasonably good health
and do not have a life-limiting chronic
condition. Until more data are available,
women aged 70 and older who have tested
positive for HPV DNA should continue
screening at the discretion of their health care
provider. Women over the age of 70 should
discuss their need for cervical cancer screening
with their health care provider based on their
individual circumstances (including the
potential benefits, harms, and limitations of
screening) and make informed decisions about
whether to continue screening. Women with
severe comorbid or life-threatening illnesses
may forego cervical cancer screening.
Evidence
Rationale
There is general consensus that the
incidence of cervical cancer in older women is
almost entirely confined to the unscreened and
underscreened. Screening in the unscreened
population can reduce morbidity and mortality
from cervical cancer.
Evidence suggests there is very low risk of
cervical cancer for women aged 50 and older
in countries with organized screening
programs. Data do not exist to support
screening over age 65 to 70 in women who
have been regularly screened. Since screening
the unscreened has been shown to affect
mortality rates, there is rationale to screen the
elderly unscreened population.
In the United States, cervical cancer is rare
among older screened women. Furthermore, it
may be difficult to get satisfactory samples from
older women due to conditions such as
atrophy and cervical stenosis.There is evidence
that screening is associated with potential
harms, including anxiety and discomfort
during cytology sampling of some older
women, and the invasive procedures, anxiety,
Several studies have shown a low efficiency
of cytological screening in women over the age
of 50; the vast majority of cervical cancers in
older women occurred in those who were not
previously screened or who did not have three
consecutive normal cytology results.22,23,24,25,26,27,28
Few studies provide data on women aged 65
and older. Sigurdsson24 reported decreasing
rates of high-grade intraepithelial lesions in
women aged 60 to 69 with increasing number
of prior normal cytology tests. Sawaya, et al.28
observed low rates of LSIL and HSIL in
women aged 65 and over with at least one
previous normal cytology result within the last
three years.
Screening After Hysterectomy
Recommendation
Screening with vaginal cytology tests
following total hysterectomy (with removal of
the cervix) for benign gynecologic disease is
not indicated. Efforts should be made to
confirm and/or document via physical exam
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ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
Rationale
Use of cytology tests in women who have
had their cervix removed for benign reasons
screens the vaginal cuff. Vaginal cancer is an
uncommon gynecologic malignancy with an
incidence rate of 1 to 2/100,000/year.1
Abnormal vaginal cytologic smears are
uncommon and rarely of clinical importance.
However, women with a history of in utero
DES exposure are at increased risk for vaginal as
well as cervical cancer.Women who have had a
hysterectomy for cervical intraepithelial lesions
may be at increased risk of vaginal cancer, but
the data are limited. Women who have had a
subtotal hysterectomy retain their cervix and
should continue cervical screening. Women
who discontinue screening should continue to
obtain appropriate preventive health care.
For women in whom CIN2/3 was the
indication for the hysterectomy, follow-up
cytology is recommended every four to six
months. Three documented, consecutive,
technically satisfactory normal/negative
vaginal cytology tests and no abnor-
348
CA A Cancer Journal for Clinicians
mal/positive cytology tests should be achieved
within an 18- to 24-month period following
hysterectomy before discontinuing cytology
screening. Women with a history of CIN2/3
prior to/but not as the indication for
hysterectomy should be screened until
three documented, consecutive, technically
satisfactory normal/negative vaginal cytology
tests and no abnormal/positive cytology tests
(within a 10-year period) are achieved.
Evidence
A retrospective cohort study of vaginal cuff
cytologic smears (VCS) in 5,862 women who
had undergone a hysterectomy for benign
disease found abnormal VCS among 79
women (1.1 percent of all smears). The mean
length of time from hysterectomy to abnormal
cytology result was 19 years. The positive
predictive value for detection of vaginal cancer
was 0 (95 percent CI 0 to 33 percent).29 A 10year retrospective study among 697 women
after hysterectomy for benign disease found
that 663 VCS were needed to detect one case
of vaginal dysplasia.30 A retrospective study of
220 women selected at random from 2,066
women who had a previous hysterectomy for
benign conditions and followed for an average
of 89 months identified seven patients (three
percent) who had intraepithelial cytologic
abnormalities, but no vaginal cancers. Four of
these patients underwent successful excision or
laser treatment of the lesions, and dysplastic
lesions in the remaining three patients
regressed without any treatment. No benefit in
patient outcomes was observed.31 A crosssectional study of 5,330 screening cytology
tests in women who had had a hysterectomy
found one case of dysplasia and no cancers.32
Videlefsky, et al.31 reported two cases of
severe dysplasia among 44 women (4.5
percent) after hysterectomies for HSIL. The
difference in risk compared with women
without a history of abnormal cytology prior
to hysterectomy (3.6 percent) was not
statistically significant. In a study of 193
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and review of the pathology report (when
available) that the hysterectomy was performed
for benign reasons (the presence of CIN2/3 is
not considered benign) and that the cervix was
completely removed. Women who have had a
subtotal hysterectomy should continue cervical
cancer screening as per current guidelines.
Women with a history of CIN2/3 or for
whom it is not possible to document the
absence of CIN2/3 prior to/or as the
indication for the hysterectomy should be
screened until three documented, consecutive,
technically satisfactory normal/negative
cervical cytology tests and no abnormal/positive cytology tests within a 10-year
period are achieved. Women with a history of
in utero DES exposure and/or with a history
of cervical carcinoma should continue
screening after hysterectomy for as long as they
are in reasonably good health and do not have
a life-limiting chronic condition.
CA Cancer J Clin 2002;52:342-362
women with CIN at hysterectomy, the
incidence of abnormal vaginal cuff cytologic
smears at least two years after hysterectomy was
0.7 per 1,000, and at 20 years 96.5 percent of
the women continued to have normal smears.33
Recommendation
After initiation of screening, cervical
screening should be performed annually with
conventional cervical cytology smears OR
every two years using liquid-based cytology; at
or after age 30, women who have had three
consecutive, technically satisfactory normal/
negative cytology results may be screened
every two to three years (unless they have a
history of in utero DES exposure, are HIV+,
or are immunocompromised by organ
transplantation, chemotherapy, or chronic
corticosteriod treatment).
Rationale (for Conventional Cervical Cytology)
The difference in absolute risk of an
important lesion progressing to invasive disease
is small when comparing one-, two-, and
three-year
screening
intervals
with
conventional cervical cytology. While most
data in this area come from countries with
organized screening programs, data from the
United States are similar. The difference in
relative risk of an important lesion progressing
to invasive disease between two- or three-year
screening intervals compared with a one-year
interval is significant; however, it is important
to note that the probability of disease is quite
small even among women screened every three
years. The number of high-grade lesions that
might progress during a screening interval
longer than three years is considered to be
unacceptably high in the United States. While
more frequent screening increases sensitivity,
it also increases patient harm and costs.
Sensitivity, patient harm, and cost were all
factors in determining the ACS guideline.
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Screening Interval
Screening interval recommendations apply
to women who have been screened previously
and received a technically satisfactory
normal/negative result. Specimen adequacy
and quality indicators should be considered
when determining the timing of repeat
screening for both conventional Pap smears
and liquid Pap tests. If endocervical
cells/transformation zone elements are absent
or if there are partially obscuring factors, an
annual repeat may be considered, and selected
women may benefit from an earlier repeat
test.34,35 Women who have had a recent
abnormal cytology result would be classified as
under surveillance rather than undergoing
screening. A history of consecutive
normal/negative cytology results has been
associated with decreased risk of HSIL and
cervical carcinoma.
Preliminary data suggest the most
appropriate screening interval is agedependent and younger women may benefit
more from a shorter screening interval (Jack
Cuzick, PhD, unpublished data.) e.g., one-year
intervals rather than two- to three-year
intervals for women under the age of 30.
Women who are immunocompromised should
follow the CDC guideline on screening HIVinfected women.12 Women who have been
exposed to DES in utero have an increased risk
of cervical and vaginal cancers and should be
screened annually. Other risk factors, such as
early age of onset of sexual activity or multiple
sexual partners, should not be used as a
rationale for more frequent screening.36 There
are insufficient data to support recommendations for or against a more frequent
screening interval (i.e., annual screening even
after age 30) for women who smoke cigarettes,
although one small study suggests that there
would not be a benefit.37
There is some concern that screening less
than annually with conventional cytology will
miss a proportion of endocervical adenocarcinomas. There is little data on the efficacy
of cervical cytology as a screening and
detection tool for nonsquamous cell
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ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
carcinomas. Use of the endocervical brush as
well as new technologies including liquidbased cytology tests may increase the sensitivity
to detect this type of cervical cancer.
The rigorous criteria established for the
ACS guideline review process (Appendix A)
resulted in exclusion of many studies. In most
cases, excluded studies did not address whether
the subjects had any prior history of cytology
tests. Most of the case-series studies did not
include information about prior screening nor
did they have controls. Some measured
incident cancer cases three to six years after the
last screening test; however, the guideline
review panel agreed that the risk of screening
less frequently than three-year intervals was
unacceptable, and therefore the panel was
interested only in cases identified within three
years. The number of such cases is very small
even over a long period of time. Negative or
normal results as presented across the studies
were not consistent, standardized, or defined.
While the format and definitions employed
in measuring relative risk of invasive cervical
cancer for one-, two-, and three-year screening
intervals were often inconsistent, most studies
suggest that compared to annual screening, the
relative risks with a two-year or a three-year
screening interval are in the range of one to
two and two to three, respectively, above annual
screening.38,39,40,41,42,43 Risk increases with longer
screening intervals of 4 to 10 years.38,39,40,41,42,44
Because most studies do not provide data on
the number of women screened, measurements
of absolute risk are even more limited. Sawaya,
et al.28 provided data from a prospective cohort
study of 128,805 women in the United States
and determined the age-adjusted incidence
rate of HSIL, carcinoma-in situ, or invasive
carcinoma within three years of normal
cytology results to be 25 per 10,000 for
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Evidence for Screening With Conventional
Cytology
women screened at 9 to 12 months, 29 per
10,000 for women screened at 13 to 24
months, and 33 per 10,000 for women
screened at 25 to 36 months following a
normal cytology result. The differences in
incidence were not statistically significant.28 A
case control study reported that a two-year or
three-year interval led to doubling the relative
risk of being diagnosed with invasive cancer,
but only a slight increase in absolute risk.43 This
finding was based on 482 cases observed over
13 years in a health maintenance organization
with an enrollment of about one million
women each year. Fifty-three of the cases
occurred within three years of three or more
negative/normal Pap smears. In this
population, the absolute risk of invasive
squamous cell cancer within the three years
following three or more normal Pap smears
was estimated at less than 5 per 100,000
women per year.
Several studies have shown that a history of
normal/negative results has a protective effect
on cervical cancer incidence.39,40,45,46 One case
control study in Italy found a decrease in the
risk of invasive cervical cancer of 90 percent
among women with three or more
normal/negative cytology smears compared to
women with no previous cytology test.45 A
cohort study in Denmark found that women
with two- to four-previous normal/negative
cytology results had a negligible risk of
developing cancer within two years, and a
slower increase in risk compared to women
with only one previous negative result.40
Sawaya, et al.46 estimated the absolute risks of
cervical cancer (within 18 months of the last
negative smear) following one, two, and three
or more consecutive negative cytology smears
as 3.09, 2.56, and 1.43 per 100,000 women,
respectively, based on 2.4 million long-term
members of a prepaid health plan. Further, it is
important to note that there is an irreducible
risk of cervical cancer in the United States. If
all women in the United States were screened
CA Cancer J Clin 2002;52:342-362
NEW TECHNOLOGIES
Recently, interest has been focused on new
technologies that enhance the accuracy of
cervical cancer screening. The expert review
panel considered several cervical screening
technologies with sufficient published clinical
data and with potential application within the
United States.The panel excluded technologies
that are currently under development or that
may have utility only in low-cost screening
settings, i.e., aided visualization, cervicography,
computer-assisted screening devices, optical
probe devices, self-collected vaginal samples for
HPV DNA testing, and spectroscopy/electronic
detection devices.
When evaluating and comparing the utility
of the technologies, several points must be
emphasized. Data on sensitivity are generally
derived from research settings with optimized
testing conditions; the same results may not be
achievable in actual practice. Certain research
designs by their nature may also over- or
underestimate test sensitivity.
Test sensitivity must be distinguished from
program sensitivity. Test sensitivity is the
probability that a single test performed at a
specified point in time will detect the presence
of underlying disease. Program sensitivity is the
probability that tests repeated at specified
intervals will detect underlying disease over a
period of time. Repeat screening at regular
intervals therefore compensates somewhat for
the limitations of the sensitivity of the technique.
For any test, sensitivity for detection of
disease can be improved by lowering the test
threshold for a “positive” result but only with
concomitant loss in specificity, resulting in
more false-positive results. When screening a
population for a very low-prevalence disease,
even a small percentage change in specificity
affects a large number of women because the
vast majority of women screened do not have
disease. For example, if disease prevalence is 10
percent and test specificity is 95 percent, then a
five percent decrement of specificity for 50
million screening tests represents an increase of
2.25 million women (from 2.25 million to 4.5
million) who will receive a “false-positive”
result.
Prevailing management paradigms, medicolegal issues, economic factors, and societal
expectations are all factors in determining the
balance between sensitivity and specificity for
a screening program. Risk perception,
understanding, and acceptability all vary
among individual patients, care providers, and
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annually, it is estimated that there would be 1.5
cases of cervical cancer per 100,000 women
having a negative cytology result within 0 to
18 months and at least three prior consecutive
normal/negative results.47
Patient harm is very difficult to measure, and
studying patient harm resulting from screening
for a rare outcome such as cervical cancer
poses particular challenges. Sawaya, et al.27
reported that in approximately 2,561 postmenopausal screened women, 110 required
diagnostic work ups for incident abnormalities
(one or two years after a negative smear)
involving 231 total interventions, and one
woman was found to have a mild to moderate
intraepithelial lesion.
The recommended screening interval for
older women is rarely addressed in the available
published literature. One exception is the
Heart and Estrogen/Progestin Replacement
Study (HERS) study,27 which included women
up to age 80. This study concluded that
cervical cytology screening of previouslyscreened postmenopausal women at a rate
more often than every two years had a positive
predictive value of 0 to 2.7 percent (PPV
varied depending on whether women without
available biopsy results were included or
excluded) and therefore supports not screening
postmenopausal women within two years of
normal cytologic results.
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ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
policy makers.48,49,50,51 Criteria for the ACS
review and evaluation of new technology
articles are summarized in Appendix B.
Liquid-based Pap Technology
As an alternative to conventional cervical
cytology smears, cervical screening may be
performed every two years using liquid-based
cytology; at or after age 30, women who have
had three consecutive, technically satisfactory
normal/negative cytology results may be
screened every two to three years (unless they
have a history of in utero DES exposure, are
HIV+, or are immunocompromised).
Rationale
Currently, two liquid-based Pap (LBP)
technologies have been approved by the FDA
as being at least equivalent to the conventional
Pap smear in their ability to detect cervical
precancerous lesions and cancers. Most studies
have shown improved sensitivity for LBP
compared to conventional smears. LBP
specificity has been difficult to calculate but
generally is thought to be comparable or
moderately
decreased
compared
to
conventional cytology when performed less
frequently. Although the ACS and others have
recommended since before 1980 that
conventional cytology can be safely performed
up to every three years for most women, in the
United States, annual screening is expected by
most women and health care providers. A
longer interval for LBP, i.e., every two to three
years, compared to annual conventional Pap
testing compensates for the decrease in
specificity. Conversely, screening with LBP at
the same interval as conventional cytology will
likely lead to significant increases in the
detection of atypical squamous cells uncertain significance (ASC-US) and lowgrade abnormalities, with subsequent increases
in referral of women to colposcopy
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CA A Cancer Journal for Clinicians
Evidence
Compared with conventional cytology, LBP
provides at least equivalent percentages of
satisfactory specimens.54,55,56 The key criteria for
evaluating the available published literature
were the sample size of the study, the type
of population utilized (with a screening
population similar in risk to the US population
preferred), comparable medical practices to
those of the United States, comparable patient
demographics for historical cohort studies, an
acceptable method of addressing inter/intraobserver variability, a way to address falsenegative outcomes, and histology outcomes in
a significant portion of the patients screened
(Appendix B).
All of the available studies have important
flaws, and the results are all presented in
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Recommendation
unnecessarily, risking the potential for
overtreatment and increased health care costs.
Several problems with conventional
cytology smears are addressed by liquid-based
methods. With LBP, the sampling device is
directly placed into a liquid fixative instead of
being spread onto a glass slide providing
immediate fixation, thereby decreasing airdrying artifact and thus improving specimen
adequacy. Additionally, LBP are felt to improve
cellular sampling, distribute the cells more
evenly over the slide and reduce cell
overlapping, and
decrease
obscuring
background factors (such as blood and
inflammatory cells) often seen in conventional
cytology (factors that may also affect test
accuracy). Another advantage of LBP is the
availability of residual material, which
potentially may be used for ancillary testing
(e.g., for oncogenic HPV DNA).
There are currently no data to support a
particular screening interval for LBP. This
recommendation was based on modeling by
two independent researchers52,53 (Evan Myers,
MD, MPH, unpublished data.) as well as expert
opinion based on the existing data described
below.
CA Cancer J Clin 2002;52:342-362
an overall rise in the rate of invasive cervical
adenocarcinoma.
The preponderance of the data considered
in this review of LBP utilized the first of the
two FDA-approved techniques (ThinPrep).
The studies and abstracts of the other LBP
method (SurePath, previously Autocyte)
suggest equivalent performance, but the few
studies limit opportunities for comparison.
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different ways. Taken as a whole, the available
evidence supports the conclusion that LBP is
an acceptable option for cervical screening,
that LBP is somewhat more sensitive but less
specific for high-grade lesions, and that it may
increase the number of ASC-US referrals and
possibly the proportion of samples lacking an
endocervical component. Of the studies
reviewed54,55,56,57,58,59,60 all but one60 showed
increased sensitivity. Three studies showed a
significant increase in the ASC-US detection
rate,57,58,59 while others showed similar or
slightly decreased rates.54,55,56,60 In the studies
that provided data on specificity, the specificity
was significantly decreased in two,57,58 was
similar in two,56,60 and was uncertain in one.59
One study found improved sample adequacy56
while three found an increased rate of samples
lacking an endocervical component.54,55,60
Importantly, in the one study that found no
significant differences in sensitivity between
LBP and conventional cytology, sampling for
conventional testing was greatly enhanced by
use of a specialized collection device, removal
of mucus and cellular debris from the cervical
surface prior to sampling, and colposcopicallyguided sampling to verify harvesting of cells
from the endocervical canal and full circumference of the cervical surface.60
Although there have been questions
regarding the detection of glandular lesions by
LBP, recent studies62,63,64 have shown an
improvement in sensitivity and specificity for
biopsy-proven adenocarcinoma. Ashfaq, et al.62
demonstrated similar rates of glandular
abnormalities on LBP as conventional
cytology; however, the positive predictive value
for LBP was higher and there were fewer falsenegative LPB reports preceding biopsyconfirmed adenocarcinomas and adenocarcinoma in situ (AIS). Bai, et al.63 reported a
50 percent lower rate for glandular atypia on
LBP, but the positive predictive value for AIS
was five-fold higher.Thus it is felt that LBP are
capable of more precisely predicting
AIS/adenocarcinoma. This is particularly
important given the recent literature indicating
HPV DNA Testing With Cytology for the Screening
of Cervical Cancer and Its Precursor Lesions
Preliminary Recommendation
HPV DNA testing with cytology for
primary cervical cancer screening has not been
approved by the FDA. Based on the available
data, both published and unpublished, the ACS
guideline review panel found this technology
to be promising. Should the FDA approve
HPV DNA testing for this purpose, it would
be reasonable to consider that for women aged
30 and over, as an alternative to cervical
cytology testing alone, cervical screening may
be performed every three years using
conventional or liquid-based cytology
combined with a test for DNA from high-risk
HPV types. Frequency of combined cytology
and HPV DNA testing should NOT be more
often than every three years. Counseling and
education related to HPV infection is a critical
need. Consensus guidelines for the
management of women with a technically
satisfactory normal/negative cytology result
and a HPV DNA test result that is positive for
high-risk HPV types would need to be
developed.
Rationale
Since the mid-1990s there has been
substantial interest in the use of HPV DNA
testing as a cervical cancer screening tool based
on the premise that standardized molecular
testing of exfoliated cervical cells for the
causative agent of cervical cancer could have
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CA A Cancer Journal for Clinicians
evaluation and potential overtreatment of
many women for transient HPV infections.53
Only testing for high-risk HPV types would
be of value. Testing for low-risk HPV types
is not useful, and may have a negative
psychological impact on the patient.
HPV DNA testing for the triage of patients
with a cytology result of ASC-US was
considered outside the scope of this screening
guideline review. Consensus recommendations
for the management of women with abnormal
cytology tests were developed through a
process sponsored by the American Society for
Colposcopy and Cervical Pathology, and
published in April 2002.65
Evidence
Only studies using the HC2 test were taken
into account for the purpose of this guideline
review.59,66,67,68,69,70,71,72,73 All of them assessed the
diagnostic performance for existing lesions
using cross-sectional or short-term follow-up
investigations of European,59,66,67 African,69,72,73
Asian,68 Latin American,71 and North American
(Canada)70 populations. Lesion definition
varied across studies and included either CIN
of all grades or CIN2/3 or worse lesions,
diagnosed by histology on specimens obtained
by colposcopy-guided biopsy. In some studies,
the colposcopic result was used if no biopsy
was taken. None of these studies were based on
long-term follow-up for more relevant
endpoints, such as incidence of/or mortality
from invasive cervical cancer. No results from
randomized controlled trials have yet been
published; all studies were based on
concomitant testing. The review panel took
into account the statistical issues that make it
necessary to use different criteria to judge
sensitivity and specificity when two tests are
used together.
HPV DNA testing at the manufacturer’s
recommended threshold of positivity of one
pg/ml (equivalent to 5,000 viral copies) has
been shown to have greater sensitivity than
cytology (on average, 25 percent higher in
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acceptable diagnostic performance while being
more reproducible and more easily adapted for
clinical practice than conventional cytology.
There have been several studies assessing the
relative utility of both a cytology test and HPV
DNA testing compared to the cytology test
alone as a primary cervical cancer screening
tool. Most studies have used the Hybrid
Capture ® (HC) system, the only HPV DNA
test currently approved by the FDA. The
currently marketed system is Hybrid Capture
II ® (HC2). It detects the presence of 13 types
of HPV that have been associated with cervical
cancer. Most of the studies reviewed by our
panel indicate that women with a concurrent
normal cytology test and a negative HC2 result
have substantially decreased risk of high-grade
lesions on colposcopy relative to those for
whom the only screening information is a
normal conventional cytology result. On the
other hand, a positive HC2 result is not an
absolute indicator that high-grade lesions exist
or will develop; the prognostic value of a
positive test result, especially in the absence of
a cytologic abnormality, has not been fully
validated in prospective studies.
HPV DNA testing has greater sensitivity
than cytology for detecting clinically relevant
lesions. Restricting screening to women aged
30 and older reduces the number of women to
be referred to colposcopy due to transient
HPV infection. The high negative predictive
value resulting from concomitant screening
with cytology and HPV DNA testing could
safely permit increasing screening intervals,
thus lowering costs. While definitive evidence
of efficacy is still needed from long-term
follow-up studies with CIN2/3 as an outcome
and from randomized controlled trials, the
opinion of the majority of expert panel
members was that the available evidence
supports consideration of the use of HPV
DNA testing as an adjunct to cervical cytology
with a screening interval no more frequently
than every three years. More frequent
screening would not significantly improve
sensitivity, but would likely result in over-
CA Cancer J Clin 2002;52:342-362
ADDITIONAL RECOMMENDATIONS
The expert panel made several additional
recommendations: (1) The ACS and others
should educate women, particularly teens and
young women, that a pelvic exam does not
equate with a cytology (Pap) test, and that
women who may not need a cytology test still
need regular health care visits, including
gynecologic care and STD screening and
prevention. (2) The current guideline review
did not address the potential usefulness of
pelvic and/or rectal examinations. Pelvic
exams are not effective in detecting cervical
cancer, however both pelvic and rectal exams
may facilitate identification of other types of
cancer and of other gynecologic conditions.
Women should discuss the need for these
exams with their provider. (3) Referrals of
women with low-grade lesions for colposcopy
may be less necessary for adolescents given the
self-limited nature of many LSILs in this age
group. Detection and treatment of HSIL
should be the goal of adolescent screening and
referral. (4) Health insurance payers should not
exclude adolescents or women of any age from
coverage for cervical health on the basis of
false-positive cytology results and/or mild
abnormalities on cervical cytology. (5) Health
insurance coverage for new cervical screening
technologies is not uniform. Providers should
confirm coverage before ordering tests such as
LBP and HPV DNA testing, including use for
triage of patients with ASC-US.
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absolute terms) but lower specificity (on
average, 10 percent lower in absolute terms) for
detecting high-grade lesions.59,66,67,68,69,70,71,72,73
Screening of women aged 30 or older or 35 or
older tended to improve the specificity of HPV
DNA testing considerably because viral
infections in this age group are less common
and are less likely to be of a transient nature
than those in younger women. An important
finding of most studies was the realization that
the combination of cytology and HPV DNA
testing attained very high negative predictive
values (approaching 100 percent). Although
none of these studies has been on an American
population, it is reassuring that ongoing
analyses from the NIH-funded Portland cohort
corroborate the enhanced value of HPV DNA
testing in screening for high-grade cervical
lesions as compared with cytology.74
CONCLUSION
Compared to the previous ACS guideline
published in 1988,11 this guideline represents
more comprehensive recommendations based
on the body of accumulated evidence. Changes
were made concerning what age to start
screening and, to a lesser extent, the screening
intervals. New recommendations were
developed to address when screening may be
discontinued, screening of women who have
had a hysterectomy, and the use of new
screening technologies. Changes to the
screening recommendations are unlikely to
have a significant impact on the relatively low
incidence and mortality associated with
cervical cancer in the United States. Yet the
large number of women currently being
screened each year (50 million) who receive an
abnormal result (two million ASC-US and
ASC-H, 1.25 million LSIL, 300,000 HSIL, in
addition to 13,000 cancers) and undergo
additional procedures represents a potential for
a large impact in reducing patient discomfort,
anxiety, and inconvenience as well as health
care costs.
The guideline continues to emphasize the
importance of flexibility for women and their
providers in the context of informed decisionmaking. Individual patients will have different
perceptions of risk and risk tolerance that may
affect their choice of screening interval,
screening test, and whether to discontinue
screening after a certain age. Ideally these
decisions should be based on discussions of the
benefits, risks, and limitations of cervical cancer
screening between women and their providers.
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ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
Screening interval remains a controversial
issue in the United States. While the evidence
supports the conclusion that conventional
cytology can be safely performed at two- to
three-year intervals, many women and
providers in the United States may be more
comfortable with annual screening. A key
factor is the limited sensitivity of the
conventional Pap test. A significant proportion
of false-negative conventional cytology results
Evidence Grading
1 = Strong evidence.
2 = Limited evidence.
3 = No evidence/exclude.
Study Type Code (from US Preventive Services Task Force)
Primary Reports of
New Data Collection
Class A:
Class B:
Class C:
Class D:
Reports That Synthesize or Reflect Upon
Collections of Primary Reports
Randomized, controlled trial.
Prospective cohort study; Case-control study
nested within a prospective cohort study.
Non-randomized trial with concurrent or
historical controls; Case-control study (except
for the preceding); Retrospective cohort
study; Study of sensitivity and specificity of
a diagnostic test; Population-based descriptive
study.
Cross-sectional study; Case series;
Case reports.
Class M:
Class R:
Class X:
Meta-analysis; Decision analysis; Cost-benefit
analysis; Cost-effectiveness study.
Review article; Consensus statement;
Consensus report.
Medical opinion.
Criteria for Evidence Grading
(1) Strong Evidence
• Evidence is useful to our task
(reviewer’s conclusion may be
different from authors’).
• Sample size is adequate to give
statistical power.
• Unbiased or biases addressed.
• Endpoint defined as CIN2/3.
(2) Limited Evidence
• Conclusions/assumptions are not
supported by data, but some
useful data is provided.
• Sample size insufficient to give
statistical power to observe a true
effect.
• Flaws or biases that could negate
conclusions.
• Study design weakens conclusions
(reviewer should provide
explanation).
• Review article with a new
perspective.
(3) No Evidence/Exclude
• No relevant data (e.g., review
article).
• Symptomatic women.
• Shortcomings negate conclusions.
• Articles not in English.
Key Data to Abstract for Each Article that Meets Inclusion Criteria
Country
Sample size
Sample description (age, risk,
ethnicity, screening history)
Time period
356
Biases (selection, verification,
observer)
Issue addressed
Endpoints
Length of follow up (e.g., average,
individual, person-years)
CA A Cancer Journal for Clinicians
Major flaws
Major strengths
Authors’ conclusions
Reviewer’s conclusions
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APPENDIX A
CA Cancer J Clin 2002;52:342-362
APPENDIX B
Criteria for Evaluating Studies of Cervical
Screening Technologies
The purpose of these suggested criteria is
not to exclude any study because it is missing
any of the following criteria, nor to grade a
particular study based on the criteria, but to
give a sense of weight of the evidence for a
given technology. At least one study should
provide evidence that supports use of the
technology, and meet the individual evidence
criteria. For example, if every study of
Technology A suggests it is more sensitive than
Technology B, and at least one study addresses
at least one of these methodological issues,
then Technology A would be considered more
sensitive. Issues of study design come into play
in trying to estimate how much more sensitive,
but trying to come up with quantitative
estimates was beyond the scope of this
guideline review.
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are due to inadequate sampling; improvements
in the ability to obtain an adequate sample
would increase the sensitivity and effectiveness
of conventional cytology. In addition, many
experts believe that the use of new
technologies such as liquid-based Pap tests and
HPV DNA testing (in combination with
cytology), when performed at a less frequent
interval, offers several advantages over
conventional cytology smears alone. These
advantages may include increased sensitivity,
lower long-term costs, and facilitation of the
triage of ASC-US results. If used at the same
interval though (e.g., annual LBP compared to
annual convention cytology), new technologies
would significantly increase the number of
women referred for colposcopy unnecessarily,
greatly increasing health care costs and harms
to patients, with little or no benefit.
It is important to reiterate that the biggest
gain in reducing cervical cancer incidence and
mortality would be achieved by increasing
screening rates among women who have not
been screened or who have not been screened
regularly. Missed opportunities for screening
abound, particularly among unscreened older
women, women of low income and/or low
education, and women who are uninsured or
underinsured. Clinicians, hospitals, health
plans, and public health officials should seek to
identify and screen these women, and to ensure
continued screening at regular intervals.
Reference Standard Specified
The minimum criteria for inclusion is that
the reference standard is explicitly stated.
Timing is an important issue to be considered
(e.g., how soon after the cytology was the
colposcopy done). Suggested acceptable
reference
standards
included
cone
biopsy/hysterectomy specimen, colposcopy/
biopsy, and (under defined circumstances)
comparison of cytological results.
Test Results Directly Comparable: Should Be
Applied to the Same Patient/Specimen or Be
Randomly Assigned
Studies that do not involve direct comparison
of the results of two or more tests in either the
same patients, or in patients drawn from the
same population and randomly assigned to a
particular test, are less preferable than studies
where either the new technology was randomly
assigned or where it was applied to the same
population of patients and/or slides.
Tests Performed in the Context of Screening,
Not Follow-up of Abnormal Results
When an imperfect reference standard
(colposcopy/histology)
is
used,
test
characteristics are dependent on the prevalence
of the disease. Studies that report test
performance in a general screening population
are preferable. Any study should provide
adequate characterization of the study
population.
Volume 52 • Number 6 • November/December 2002
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ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
Study Reports Results of Detection of
HSIL/CIN2/3
Verification Bias Addressed
If the reference standard is applied only to
positive screening tests, then the sensitivity will
always be overestimated. Ideally, at least one
study of a technology will have a design that
avoids verification bias.
Chance Gains in Sensitivity Have Been
Considered
Adding an adjunct screening test in parallel
to Pap cytology will always yield an increased
combined sensitivity that may not be greater
than that contributed by an unrelated adjunct
test in the same screening setting. Ideally,
studies should consider sensitivity gains of
combined testing only after taking into
account this chance increase in sensitivity.75
Observer Variability Addressed
Inter- and intraobserver variability may have
significant impacts on the consistency of test
sensitivity and specificity.All other things being
equal, a more consistent test is preferable.
Ideally, at least one study of a technology will
address inter- and intraobserver variability in
the interpretation of results.
Statistical/Sample Size Issues Addressed
Because most comparisons of cervical
screening tests are based on categorical
outcomes, statistical power is inherently
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CA A Cancer Journal for Clinicians
APPENDIX C
Collection of Cervical Cytology Samples
It is estimated that at least one third or more
of false-negative cytology tests (negative results
when a woman has a high-grade cervical
lesion) are related to sampling issues—
specifically that abnormal cells are not present
on the cytologic slide examined in the
laboratory.76,77,78,79 Sampling problems can occur
if abnormal cells are not collected onto the
sampling instrument or if collected cells are
not transferred to the slide to be examined, but
rather remain on the sampling instrument.
Regardless of the collection device, only a
relatively small percentage of cells are
transferred to the slide to be submitted as
compared to the total number of cells collected
on the device.80,76,81
Obtaining an Adequate Cervical Cytologic
Sample
An adequate cervical cytologic specimen
involves circumferential sampling of the
ectocervix adjacent to the transformation
zone, the endocervix, and the cervical
transformation zone (T-zone). A vaginal
cytologic sample is not necessary for cervical
cytologic sampling, and is not recommended
for cervical cytologic sampling.Vaginal samples
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Because no study will be able to
demonstrate reduction in the incidence of
cervical cancer, the next best alternative is the
ability to improve detection of high-grade
precursors. In order to infer that a new
technology will result in a decrease in cervical
cancer, evidence about its ability to detect
CIN2/3 must be provided.
somewhat reduced compared to continuous
outcomes. Sample size can also affect study
interpretation in other ways. In addition, use of
multivariate analytic techniques invariably
results in some loss of power. Power
calculations, preferably a priori, should be
stated. Studies that present results that allow
quantification of uncertainty (point estimates
of sensitivity and specificity with 95%
confidence limits) are in general preferable to
studies that provide only the results of
significance testing (chi-square comparison of
two different sensitivities).
CA Cancer J Clin 2002;52:342-362
are recommended for the detection of vaginal
carcinoma in women exposed to DES in utero.
Collection Instruments
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Using a combination of the extended tip
spatula and the endocervical brush provides
sampling of the ectocervix, T-zone, and
endocervix, and has the lowest false-negative
rate when compared to less thorough
sampling.82,83,84 Both samples are usually placed
on a single slide, rather than using two slides.85
The extended tip spatula is superior to the
conventional Ayres spatula for sampling the
ectocervix and the T-zone.81 The spatula has
been traditionally made of wood; however,
plastic spatulas perform equally well for
conventional smears and perform better when
used in liquid-based systems because the cells
can be washed from the plastic more readily
than from wood spatulas.
To collect the endocervical cytologic
sample, it is necessary to insert the collection
device within the endocervical canal and
collect cells by gently scraping or brushing the
endocervical mucosa. When using the
endocervical brush, the brush should be
inserted until it has moved into the endocervix
and until the bristles most proximal to the
handle are approximately even with the
apparent external cervical os.The brush is then
rotated 180 degrees (one-half turn) in the
canal. Additional rotation does not improve
sampling and may cause bleeding. In the nonpregnant patient, the use of an endocervical
brush provides a cellular sample that is
generally rich in endocervical and/or high Tzone cervical cells.This device is used after the
spatula sampling of the ectocervix and T-zone.
The endocervical brush can be used to prepare
conventional cervical smears, as well as with
liquid-based cervical cytology. The endocervical brush collects more diagnostic cellular
material than the swab, as studied in patients
who had undergone prior treatment to the Tzone, including cryotherapy, laser ablation, and
conization.84,86,87 Although the endocervical
brush is not generally recommended by the
manufacturer for use in pregnant women
because of the potential risk of inadvertent
perforation of the amniotic sac, there is
considerable clinical experience with the use
of the brush in pregnant women with no
apparent complications.88
Cervical broom instruments and other
single sampling instruments are designed to
simultaneously sample the ectocervix, T-zone,
and endocervical areas, and are fairly
comparable to the combination of extended
tip spatula and endocervical brush.The cervical
broom may be used for conventional cytology
smear samples as well as for liquid-based
systems, and may be used in pregnant women.
Use of a Small Swab for Endocervical Sampling
An endocervical swab is less sensitive than
the endocervical brush and its use is
discouraged for endocervical cytologic
sampling.81 It may be considered for pregnant
women when there is concern about using
other endocervical sampling devices. It should
be used in combination with an ectocervical
and T-zone sampling instrument such as the
extended tip spatula. The swab should be
moistened with a small amount of saline prior
to use in order to prevent cellular desiccation
on contact with the swab, and to release cells
from the swab more easily when making a
smear. A swab is not recommended with
liquid-based systems. For liquid-based systems,
the cervical broom is recommended in the
pregnant patient, rather than the spatula and
swab collection method.
Patient Advice Prior to a Cytology Test
The patient can be advised that there are
several actions she can take to optimize the
cytology test (based on American Society of
Cytopathology 2001 guidelines available at:
http://www.cytopathology.org/guidelines/cer
vical-cytologyiii.php).These include:
1.Try to schedule the appointment when it
Volume 52 • Number 6 • November/December 2002
359
ACS Guideline for the Early Detection of Cervical Neoplasia and Cancer
Collection of a Specimen With the Cervical
Broom Device
There are a number of single-sampling
devices that sample both the endocervix and
the T-zone at the same time, with one
collection scraping of the cervix. The cervical
broom is the most commonly used among
such devices. It can be used instead of the
extended tip spatula and the endocervical
brush, and can be used in pregnant women.
The long central bristles of the broom are
inserted into the endocervical os while the
broom is pressed against the cervix so that the
outer bristles bend. The broom is then rotated
in one direction for five complete rotations.
(Rotating in one direction, and then the other
is not recommended because it can result in
loss of cells.) The cervical broom can be used
with conventional cervical cytology, as well as
with liquid-based cervical cytology. For
conventional cytology, the broom sample is
smeared on a slide (labeled with the patient’s
name) by stroking the broom on the usable
surface of the slide (excluding the frosted label)
from the label margin toward the other end of
the slide.The sample is then quickly fixed with
a spray fixative or by immersing the slide in
95% ethanol. For liquid cytology, one
360
CA A Cancer Journal for Clinicians
manufacturer recommends that the broom be
rinsed as free of cells as possible in the
preservative medium. Another manufacturer
recommends snapping off the handle of the
instrument and leaving the broom end of the
instrument in the fixative solution to be sent to
the laboratory.
Typical Procedure for Making the Cervical
Cytologic Smear When Employing the
Extended Tip Spatula and the Endocervical
Brush Using a Single Slide Technique
Using a glass slide labeled with the patient’s
name (a slide with a frosted label space on one
end is preferred, so the patient’s name can be
written on the slide with pencil) the
endocervical brush with the cellular sample is
rolled onto the surface of the glass slide. The
brush sample can be rolled on the slide
immediately adjacent to the frosted label area,
usually using about a two cm portion of the
slide.The extended tip spatula sample can then
be smeared on the same slide, smearing the
sample immediately adjacent to the
endocervical sample and, using a circular
motion, smearing the cellular sample onto the
glass slide.The slide is then rapidly fixed with a
spray fixative, or immersed in 95% ethanol. If a
liquid-based Pap test is used, the brush and the
extended tip spatula are carefully rinsed in a
vial of preservative, and the container is labeled
with the patient’s name.
Submitting Samples Using Liquid-based
Techniques
For liquid cytology, both the endocervical
brush sample and the extended tip spatula
cytologic sample are submitted in a single
container with appropriate fixative solution and
labeled with the patient’s name. A plastic
extended tip spatula is recommended for
liquid-based techniques. One manufacturer
recommends that the spatula and the
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is not during the menstrual period.
2. Do not douche 48 hours prior to the
cytology test.
3. Refrain from intercourse 48 hours prior
to the test.
4. Do not use tampons, birth control foams,
jellies, or other vaginal creams or vaginal
medications for 48 hours prior to the test.
Schedule the test to avoid menses if possible.
Ideally, screening is best performed in the
absence of heavy menstrual flow but should
not be deferred in the event of abnormal
bleeding (i.e., bleeding between periods, post
coital bleeding, postmenopausal bleeding) or if
accessibility for return examination is difficult.
CA Cancer J Clin 2002;52:342-362
endocervical brush (or the cervical broom, if
used) be rinsed as free of cells as possible in the
fixative solution. Another manufacturer recommends the sampling devices be separated or cut
from the handle and placed into the fixative
CA
Acknowledgments: The authors thank Kim Andrews Sawyer
and Connie Lim for their assistance in the preparation of this
manuscript.
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Errata
Errata
(pages 330 and 331, respectively). Table 2 and
Table 3 have been modified with the corrected
data and are reproduced here.We apologize for
these errors and any confusion they may have
caused.
TABLE 2
African American to White Incidence Rate Ratios, US, 1995 to 1999*
Males
Cancer Type†
Females
African American
White
African
American/White
Rate
Rate
Ratio
Myeloma
13.1
Stomach
19.3
Esophagus
12.8
Larynx
12.2
Prostate
266.8
Liver and
Intrahepatic Bile Duct 10.3
Lung and Bronchus
125.6
Pancreas
18.2
Oral Cavity and Pharynx 21.8
Kidney and Renal Pelvis 18.4
Colon and Rectum
69.0
Non-Hodgkin’s
Lymphoma
19.9
Leukemia
12.6
Myeloid Leukemia
5.7
Acute Myeloid Leukemia
3.4
Hodgkin’s Lymphoma
2.7
Lymphocytic Leukemia
5.3
Chronic Lymphocytic
Leukemia
4.1
Brain
4.6
Urinary Bladder
19.3
6.5
10.7
7.6
7.1
163.2
2.0
1.8
1.7
1.7
1.6
6.4
84.4
12.3
16.5
15.6
65.0
1.6
1.5
1.5
1.3
1.2
1.1
24.5
16.7
6.9
4.5
3.4
7.4
0.8
0.8
0.8
0.8
0.8
0.7
5.5
8.3
39.8
0.7
0.6
0.5
All Cancers
560.1
1.2
695.3
Cancer Type†
White
African
American/White
Rate
Rate
Ratio
Myeloma
10.3
Stomach
10.3
Esophagus
4.4
Small Intestine
2.9
Larynx
2.9
Uterine Cervix
13.6
Pancreas
15.2
Liver and
Intrahepatic Bile Duct
4.0
Kidney and Renal Pelvis
9.8
Colon and Rectum
56.1
Soft Tissue (including heart) 2.6
Lung and Bronchus
54.4
Breast
123.7
Urinary Bladder
7.7
Leukemia
7.6
Uterine Corpus
17.3
Hodgkin’s Lymphoma
2.0
Ovary
12.0
Non-Hodgkin’s
Lymphoma
11.2
Thyroid
5.6
4.2
4.6
2.0
1.5
1.6
8.1
9.5
2.5
2.2
2.2
1.9
1.8
1.7
1.6
2.5
7.8
47.1
2.4
53.3
140.9
10.2
9.8
26.1
2.8
18.1
1.6
1.3
1.2
1.1
1.0
0.9
0.8
0.8
0.7
0.7
0.7
16.5
10.0
0.7
0.6
433.5
1.0
All Cancers
African American
412.9
*Rates are per 100,000 and age adjusted to the 2000 US standard population.
†Site selected if cases greater than 100.
Source: Surveillance, Epidemiology, and End Results program, Division of Cancer Control and Population Sciences, National Cancer Institute,
2002.
126
CA A Cancer Journal for Clinicians
Downloaded from caonline.amcancersoc.org by guest on January 18, 2007 (©American Cancer Society, Inc.)
In the November/December 2002 issue, in
the article “Cancer Statistics for African
Americans” (Ghafoor A, Jemal A, Cokkinides V,
et al. CA Cancer J Clin 2002:52;326-341), an
error appeared in the data for Tables 2 and 3
CA Cancer J Clin 2003;53:126-127
TABLE 3
African American to White Mortality Rate Ratios, US, 1995 to 1999*
Males
Cancer Type†
Females
White
African
American/White
Rate
Rate
Ratio
Larynx
5.8
Prostate
72.8
Stomach
14.2
Myeloma
9.2
Oral Cavity and Pharynx
8.3
Esophagus
12.9
Liver and
Intrahepatic Bile Duct
9.2
Lung and Bronchus
109.1
Pancreas
16.2
Small Intestine
0.5
Colon and Rectum
34.4
Kidney and
Renal Pelvis
6.2
Leukemia
9.3
Hodgkin’s Lymphoma
0.7
Lymphocytic Leukemia
3.0
Myeloid Leukemia
3.7
Non-Hodgkin’s Lymphoma 7.8
Urinary Bladder
5.7
Brain
3.2
Melanoma
0.5
2.4
31.2
6.3
4.5
4.2
7.2
2.4
2.3
2.3
2.0
2.0
1.8
5.9
79.7
12.0
0.7
25.8
1.6
1.4
1.4
1.4
1.3
6.2
10.6
0.7
3.3
4.5
11.2
8.0
6.0
4.4
253.0
All Cancers
359.2
Cancer Type†
African American
White
African
American/White
Rate
Rate
Ratio
3.0
3.0
2.8
1.7
0.5
2.0
2.3
2.3
2.2
2.1
1.8
1.6
1.3
18.0
9.0
1.5
1.4
1.4
1.0
0.9
1.0
0.9
0.8
0.7
0.7
0.5
0.1
Stomach
6.8
Myeloma
6.8
Uterine Cervix
6.2
Esophagus
3.5
Larynx
0.9
Uterine Corpus
3.2
Soft Tissue
(including heart)
1.9
Colon and Rectum
25.4
Pancreas
13.0
Liver and
Intrahepatic Bile Duct
3.9
Breast
37.1
Urinary Bladder
3.1
Lung and Bronchus
40.2
Kidney and Renal Pelvis
2.9
Leukemia
5.6
Myeloid Leukemia
2.5
Ovary
7.6
Non-Hodgkin’s Lymphoma 4.7
Brain
2.3
Melanoma
0.5
2.8
28.2
2.3
41.7
2.9
6.1
2.8
9.3
7.5
4.1
2.1
1.4
1.3
1.3
1.0
1.0
0.9
0.9
0.8
0.6
0.6
0.2
1.4
All Cancers
169.8
1.2
203.5
Downloaded from caonline.amcancersoc.org by guest on January 18, 2007 (©American Cancer Society, Inc.)
African American
*Rates are per 100,000 and age adjusted to the 2000 US standard population.
†Site selected if number of deaths is greater than 100.
Source: Underlying mortality data provided by the National Center for Health Statistics. Available at: http://www.cdc.gov/nchs.
In the November/December 2002 issue, in
the article “American Cancer Society
Guideline for the Early Detection of Cervical
Neoplasia and Cancer” (Saslow D, Runowicz
CD, Solomon D, et al. CA Cancer J Clin
2002:52;342-362), an error appeared in the
author byline on page 342.
The byline should have read “Debbie Saslow,
PhD; Carolyn D. Runowicz, MD (for the Work
Group on Interval, Older Women, and
Hysterectomy); Diane Solomon, MD (for the
Work Group on Technologies); Anna-Barbara
Moscicki, MD (for the When to Start Screening
Work Group); Robert A. Smith, PhD; Harmon
J. Eyre, MD; Carmel Cohen, MD (for the
Gynecologic Cancer Advisory Group).”
We apologize for this error and any
confusion it may have caused.
Volume 53 • Number 2 • March/April 2003
127