The n e w e ng l a n d j o u r na l of
clinical practice
From the Division of Cancer Epidemiology
and Genetics (M.S.) and the Division of
Cancer Prevention (D.S.), National Cancer
Institute, National Institutes of Health,
Rockville, MD. Address reprint requests
to Dr. Schiffman at the Division of Cancer
Epidemiology and Genetics, National
Cancer Institute, 9609 Medical Center Dr.,
Rockville, MD 20850, or at schiffmm@
exchange.nih.gov.
N Engl J Med 2013;369:2324-31.
DOI: 10.1056/NEJMcp1210379
Copyright 2013 Massachusetts Medical Society.
An audio version
of this article is
available at
NEJM.org
2324
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Copyright 2013 Massachusetts Medical Society. All rights reserved.
m e dic i n e
Caren G. Solomon, M.D., M.P.H., Editor
Cervical-Cancer Screening with Human
Papillomavirus and Cytologic Cotesting
Mark Schiffman, M.D., M.P.H., and Diane Solomon, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
A healthy 35-year-old woman wants to discuss cervical-cancer screening. She reports
no symptoms and has a negative screening history except for an abnormal Pap
about 10 years previously that did not require treatment. She has two children, is
currently taking oral contraceptives, and does not smoke. She is interested in human
papillomavirus (HPV) testing because of an article she read in a magazine, which
suggested that testing with HPV and Pap is better than just Pap alone. What
would you advise?
The Cl inic a l Probl em
Cervical cancer is the third leading type of cancer in women worldwide. There are
approximately 530,000 new cases and 275,000 associated deaths annually.1 The
disease burden is highest in resource-poor countries, where more than 80% of
cases occur.1 In the United States and other countries that have developed wide-
spread programs for cervical cytologic screening (Papanicolaou [Pap] tests), mor-
bidity and mortality from cervical cancer have been greatly reduced. Nevertheless,
approximately 4000 women die from cervical cancer each year in the United States.2
A single Pap test has limited sensitivity for the detection of cervical cancer and
its immediate precursors. Strategies routinely used in the past to compensate for
the limited sensitivity included repeat screening at short intervals and a low cyto-
logic threshold for additional follow-up. However, this approach is costly and
generates many unnecessary follow-up tests, such as colposcopic examinations.
Expenditures in the United States total $6 billion annually for more than 50 million
screening tests and for the clinical care of women with mainly minor screening
abnormalities.3
Virtually all cases of cervical cancer are caused by persistent infection with one
of about a dozen carcinogenic HPV genotypes specifically, HPV types 16, 18, 31,
33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.4,5 The carcinogenic HPV types are evo-
lutionarily related and belong to the alphapapillomavirus genus; they are distantly
related to the viruses associated with common skin warts.6-8 HPV-16 is the most
carcinogenic type, accounting for half of cervical-cancer cases.9 HPV-18, which is
implicated in many cases of endocervical adenocarcinoma,10 is the second most
carcinogenic type, accounting for approximately 15% of all cervical cancers.11
An understanding of the central role of HPV in the development of cervical
cancer has led to the following two effective preventive strategies, in addition to
Pap tests: primary prevention by vaccination,12-14 and enhanced secondary preven-
tion (screening) with the use of HPV-based molecular assays that detect viral DNA
n engl j med 369;24nejm.orgdecember 12, 2013
The New England Journal of Medicine
 clinical pr actice

key Clinical points

cervical-cancer screening with human papillomavirus and cytologic cotesting

Cervical cancer screening in the United States should not start until the age of 21 years, since
adolescents are at extremely low risk for cervical cancer but have high rates of transient human
papillomavirus (HPV) infections and associated minor cytologic abnormalities.

The risk of cervical precancer and cancer is very low in the years after a negative HPV test.

For women in the United States who are 30 years of age or older (past the age at which new HPV
infections peak), cotesting with HPV and cytologic tests every 5 years is an accepted alternative to
cytologic testing alone every 3 years.

Molecular testing for HPV, together with cytologic testing, yields multiple possible combinations of
results, with varying associated risks of precancer and cancer; management strategies are guided by
the magnitude of risk.

or RNA.15 Owing to incomplete coverage of the
HPV types and partial population uptake (ap-
proximately one third of adolescent girls at the
target ages have completed the three-dose vac-
cination regimen), the advent of vaccination has
not yet altered screening recommendations in the
United States.16
Molecular testing for the pool of carcinogenic
types of HPV was initially introduced as a second-
ary test (so-called reflex HPV testing, used as a
triage tool) for clarifying whether women with
equivocal lesions (atypical squamous cells of un-
determined significance [ASC-US]) on cytologic
screening require colposcopy. More recently, the
number of assays for HPV that have been ap-
proved by the Food and Drug Administration has
increased,15,17-19 and the use of testing for carci-
nogenic HPV types in women 30 years of age or
older has been expanded to include HPV testing
in combination with cytologic evaluation (HPV
cotesting).16,20,21 Stand-alone HPV screening22 is
not currently recommended in the United States,
although it has been adopted elsewhere. This ar-
ticle discusses the rationale for HPV cotesting, as
well as the benefits and challenges of cotesting.
S t r ategie s a nd E v idence
The many cytologic and histologic terms used in
cervical screening to describe the natural history
of cervical cancer have recently been consolidat-
ed in the United States (Table 1 in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). For squamous disease,
accounting for the great majority of cancer cases,
the stages consist of low-grade squamous intra
epithelial lesions (LSIL), indicating microscopi-
cal evidence of acute HPV infection; high-grade
squamous intraepithelial lesions (HSIL), indicat-
ing precancer; and cancer.9 Histologically, HSIL
correlates with cervical intraepithelial neoplasia
grade 3 (CIN 3) and most cases of cervical intra
epithelial neoplasia grade 2 (CIN 2).23
The introduction of HPV testing into the
screening protocol for women 30 to 65 years of
age was prompted by prospective observational
studies showing the high sensitivity of HPV test-
ing, as well as the corollary reassurance that a
negative test confers a very low risk of cancer.
Several long-term, prospective studies (lasting
more than 10 years) have shown that the risk of
CIN 3 or cancer is approximately 1% among
women with a negative test for HPV, as com-
pared with 5 to 10% among women with a
positive test.24-27 Randomized trials comparing
HPV testing alone with cytologic testing
alone28-32 have shown that more cases of CIN 3
or cancer are detected with the use of HPV test-
ing than with the use of cytologic testing in the
first round of screening, with a commensurate
decrease in the number of cases at the subse-
quent screening. A large trial of HPV testing,
which was conducted in India among women
who had never before been screened, convinc-
ingly showed during an 8-year follow-up period
that deaths from cervical cancer were extremely
rare among women who had a single negative
HPV screening test.33

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Approximately
10 yr
CIN 3
100 100
90 90
Percentage of Carcinogenic 80 Persistence Invasion 80

Percentage of CIN 3
HPV Infections 70 70
60 60
50 50
40 Clearance 40
30 Persistence 30
or regression
20 20
10 10
0 0
0 1 2 3 0 5 10 20 30
Years since Infection with Carcinogenic HPV Years since Diagnosis with CIN 3

Figure 1. Typical Time Course of Infection with Carcinogenic Human Papillomavirus, from Acquisition to the
Development of Squamous-Cell Cancer.
Regardless of a womans age at acquisition, most new human papillomavirus (HPV) infections tend to clear (become
undetectable) quickly. Those that persist pose an increasing risk of highgrade squamous intraepithelial lesions (HSIL).
The typical time course for each stage is shown. The rates are based on cervical intraepithelial neoplasia grade 3 (CIN 3),
the most severe type of HSIL. Adapted from Schiffman et al.15

penetrative sexual intercourse. Peak transmis-

Infection Progression Invasion sion is in adolescence and young adulthood.9
HPV Most infections, including the minority that
Normal HSIL Cancer
Infection
Clearance Regression
cause microscopically evident equivocal abnor-
malities (ASC-US) or definite abnormalities
Relative Population Prevalence

(LSIL), clear (i.e., become undetectable on sensi-

0 10 20 30 40
Age (yr)
Figure 2. Age at Peak Prevalence for Each Stage in Cervical Carcinogenesis.
In the United States, the peak in the prevalence of HPV infection, as mea
sured by DNA testing, occurs in late adolescence and early adulthood, soon
after the initiation of sexual intercourse. The peak in HSIL or precancer occurs
5 to 10 years after infection, when women are approximately 25 to 35 years
of age, depending on the intensity of screening (more intensive screening
leads to earlier detection of smaller HSIL). The rise in the incidence of cer
vical cancer typically occurs many years later; the median age at diagnosis
is 49 years. Adapted from Schiffman et al.15
Proper use of HPV testing is guided by the
typical time course (Fig. 1) and age at diagnosis
(Fig. 2) for each step in cervical carcinogene-
sis.9,15 Cervical HPV is transmitted by direct
sexual contact; transmission does not require
tive molecular assays) in 1 to 2 years.34 Those
infections that remain detectable are considered
to be persistent. Only persistently infected cervi-
cal cells have a substantial likelihood of grad-
ually growing into diagnosable HSIL. Cohort
studies have shown that most diagnoses of HSIL
are made 5 to 10 years after infection.9 The long
50 60 70
time frame, typically at least one decade and
possibly more than three decades,35 between the
development of HSIL and the development of
invasive cancer explains why screening is usually
effective treatment of HSIL at any time during
this interval can prevent cancer.
Since adolescents are at extremely low risk for
cervical cancer but have high rates of transient
HPV infections, current guidelines (Table 1)
recommend that cervical-cancer screening start
at the age of 21 years, regardless of the age at
first intercourse.16,20,21 For women who are 21 to
29 years of age, the prevalence of HPV remains
very high, but the risk of cancer increases only
slightly; as a result, cytologic screening alone
every 3 years is recommended. Decision model-
ing suggests that starting at 21 years of age,

2326 n engl j med 369;24 nejm.org december 12, 2013

The New England Journal of Medicine

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 clinical pr actice
screening at a 3-year interval as compared with
annual screening results in a small difference
in the predicted lifetime risk of cervical cancer
(8.5 cases per 1000 women vs. 2.5 cases per
1000 women) and a substantial reduction in the
number of lifetime colposcopic examinations
(approximately 760 per 1000 women vs. 1930 per
1000 women).36 Cotesting is not used for primary
screening in this age group, since the positive pre-
dictive value of the HPV test is low. However, if the
cytologic result is ASC-US, then reflex HPV testing
is used as a triage test; among women 25 years of
age or older, reflex HPV testing is preferred over
repeat cytologic testing or immediate colposcopy.37
For women 30 to 65 years of age, the current
strategy in the United States is cotesting every 5
years or cytologic testing alone every 3years.16,20,21
Either conventional or liquid-based cytologic
tests are acceptable, given their similar results
when they are well performed.38 A major advan-
tage of cotesting in women 30 years of age or
older (i.e., past the age at which the prevalence
of HPV infection peaks) is that both cytologic
testing and HPV testing will be negative in the
great majority of women, indicating reassuringly
low risk and permitting lengthened screening
intervals. A large-scale study at Kaiser Permanente
Northern California,39 which adopted cotesting
in 2003, has shown a low risk of cervical cancer
among women who have had negative results of
HPV and cytologic cotesting. Among approxi-
mately 300,000 women in the Kaiser Permanente
database who were 30 years of age or older and
had negative cotests, the 5-year cumulative inci-
dence of CIN 3 or cancer was less than 2 cases
per 1000 women, and the 5-year incidence of
cancer was less than 2 cases per 10,000 women
less than half the cancer risk associated with
negative results of cytologic testing alone.39 The
improved negative predictive value of cotesting
over that of cytologic testing alone is the basis
for the current recommendation to extend the
screening interval from every 3 years (if cyto-
logic screening alone is negative) to every 5 years
(if cotesting is negative).16
In populations with a low risk of cervical
cancer, screening is not recommended. These
populations include women older than 65 years
of age who have had an adequate number of
negative screening results previously16 and wom-
en who have had a hysterectomy with removal of
the cervix and have no history of HSIL.16
n engl j med 369;24nejm.orgdecember 12, 2013
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Table 1. Cervical-Cancer Screening Guidelines.*
Population Screening Recommendation
Age group
<21 yr Do not screen.
2129 yr Perform cytologic testing alone every 3 years.
3065 yr Perform cytologic and HPV cotesting every 5 years (pre
ferred), or perform cytologic testing alone every
3years (acceptable).
>65 yr Discontinue screening if there has been an adequate
number of negative screening results previously
(3consecutive negative cytologic tests or 2 consec
utive negative cotests in the past 10 years, with the
most recent test in the past 5 years) and if there is no
history of HSIL, adenocarcinoma in situ, or cancer.
Women who have Discontinue screening if the patient has undergone a total
undergone hysterectomy with removal of cervix and if there is no
hysterectomy history of HSIL, adenocarcinoma in situ, or cancer.
* The three major sets of screening guidelines were issued by the American
Cancer Society, American Society for Colposcopy and Cervical Pathology, and
American Society for Clinical Pathology Multisociety Guidelines Group16; the
American College of Obstetricians and Gynecologists21; and the U.S. Preven
tive Services Task Force (USPSTF).20 The guidelines agree on most recommen
dations, including the recommended age at the start of screening (21 years),
the age at which screening can be discontinued if the history of negative screen
ing is adequate (>65 years), and the recommended interval between tests.
Specifically, cotesting at a 5-year interval is either preferred or acceptable for
women 30 to 65 years of age, whereas cytologic testing alone every 3 years is
acceptable for women 21 to 65 years of age. HSIL denotes high-grade squamous
intraepithelial lesions.
The terms preferred and acceptable are not included in the USPSTF Recom
mendation Statement.
HSIL includes cervical intraepithelial neoplasia grade 3 and cases of grade 2
that stain positive for p16.23
Among women with HPV infection, the risk
of cervical cancer is increased in association
with multiparity,40 prolonged use of oral contra-
ceptives,41 and smoking,42 but the effect of these
cofactors is not strong enough to affect clinical
management. Immunosuppression, in contrast,
is associated with a risk of HSIL that is high
enough to warrant distinct screening guide-
lines,16 although the care of women who have
abnormal screening results is not altered.37
A r e a s of Uncer ta in t y
Cost-Effectiveness of Various Screening
Strategies
There has been insufficient comparison of the
cost-effectiveness of various screening options
(in particular, cytologic and HPV cotesting vs.
HPV testing alone). The addition of cytologic
testing to HPV testing is much more expensive
than HPV testing alone and provides limited ad-
2327
 The n e w e ng l a n d j o u r na l
ditional reassurance that cancer is neither present
nor about to develop. Among the women involved
in the Kaiser Permanente Northern California
study, the 5-year risk of CIN 3 or cancer after neg-
ative cotests was estimated to be 0.16%, which
was not meaningfully lower than the risk after a
negative HPV test alone (0.17%).39
It is unclear whether U.S. clinicians and wom-
en who are accustomed to more frequent Pap
tests will accept the extended screening interval
warranted by more sensitive screening. If cotest-
ing were performed at more frequent intervals,
new tests with positive results in women with
previously negative test results would most likely
represent incident HPV infections, with a low as-
sociated risk of HSIL or cancer43; thus, the iden-
tification of HPV infections would be likely to
increase costs and downstream testing without
improving outcomes.
management of Positive Screening Cotests
Less than 10% of women will have a positive
screening result on cotesting. The various com-
binations of positive cytologic categories and
HPV test results are associated with different
risks of HSIL or cancer. Management options
include continued regular screening, increased
surveillance (shorter screening intervals), or col-
poscopic assessment, depending on the risk.
For high-risk combinations (e.g., cytologic
HSIL, regardless of the HPV test result), imme-
diate colposcopy is warranted. However, for some
very common combinations associated with lower
risk, the best methods of management are un-
certain. The incidence of various combinations
of cotest results, the associated 5-year risks of
histologic HSIL (approximated by data for CIN 2
and CIN 3) and cancer and the currently recom-
mended management are shown in Table 2. Risk-
based management guidelines were developed to
ensure that women at equal risk for cancer re-
ceive similar care according to existing and ac-
cepted practice. However, randomized trials of
various management options have not been con-
ducted, and many recommendations are based
on observational data or expert opinion.37
The most common combination of positive
screening cotests is a positive HPV test and a
negative cytologic test; approximately 4% of
women 30 years of age or older who undergo
cotesting have this combination of results.44
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of m e dic i n e
Among such women, the 5-year risk of HSIL or
cancer is approximately 10%, which is not quite
high enough to justify immediate referral for
colposcopy45; moreover, referral would triple the
number of colposcopic examinations. Intensified
surveillance is recommended, but the best tim-
ing for repeat testing is uncertain; longer inter-
vals allow a higher proportion of infections to
clear but result in a greater, though still small,
risk of cancer. The most recent guidelines16,37
recommend repeat cotesting in 1 year, with re-
ferral for colposcopy if cytologic testing is posi-
tive or if HPV testing remains positive, suggest-
ing persistent infection.
An alternative is genotyping DNA or RNA
specifically for HPV-16 and HPV-18, with imme-
diate colposcopy if either of these highest-risk
types is found and repeat cotesting in 1 year if
neither type is found. This is currently the only
recommended use of genotyping to determine
individual HPV types. Biomarkers have also
been proposed to help identify women who are
at particularly high risk for HSIL and cervical
cancer and require colposcopy. One proposed
biomarker measured in a cytologic specimen is
p16, which if positive indicates an increased
risk of HSIL or cancer.46 Further evaluation of
the p16 assay is needed, as are definitive com-
parisons of alternative options for women who
have positive HPV test results and negative cyto-
logic test results.
Data are also lacking to guide the care of the
very small percentage of HPV-positive women
who have persistently positive HPV tests for years
without evident progression to HSIL. The ques-
tion is whether to choose indefinitely heightened
surveillance with repeated testing and perhaps
colposcopy or presumptive treatment with loop
electrosurgical excision.
Another combination of screening cotest re-
sults, affecting approximately 1 million women
a year in the United States, is a negative HPV test
with a cytologic test showing ASC-US.47 ASC-US
is by far the most common abnormal cytologic
finding (representing approximately 5% of cyto-
logic test results) but is an equivocal or border-
line result. At least half of women with a cyto-
logic test result of ASC-US have a negative test
for carcinogenic HPV, and theoretically, such
women should not be at increased risk for cervi-
cal cancer4; however, in the Kaiser Permanente
 clinical pr actice

Table 2. Ranked 5-Year Risk of HSIL and Cancer and Suggested Management According to Test Results.*

Frequency Risk of
Result on Cytologic Testing of Screening Histologic HSIL
or Cotesting Result and Cancer Suggested Management
percent
SCC 0.0048 84 Immediate colposcopy
HPV+/HSIL 0.20 71 Immediate colposcopy
HSIL 0.21 69 Immediate colposcopy
HPV/HSIL 0.013 49 Immediate colposcopy
HPV+/AGC 0.054 45 Immediate colposcopy
HPV+/ASC-H 0.12 45 Immediate colposcopy
ASC-H 0.17 35 Immediate colposcopy
HPV+/LSIL 0.81 19 Immediate colposcopy
HPV+/ASC-US 1.1 18 Immediate colposcopy
LSIL 0.97 16 Immediate colposcopy
AGC 0.21 13 Immediate colposcopy
HPV/ASC-H 0.051 12 Immediate colposcopy
HPV+/Pap 3.6 10 Repeat testing in 6 to 12 mo
ASC-US 2.8 6.9 Repeat testing in 6 to 12 mo
HPV/LSIL 0.19 5.1 Repeat testing in 6 to 12 mo
HPV/AGC 0.16 2.2 Immediate colposcopy
HPV/ASC-US 1.8 1.1 Repeat testing in 3 yr
Pap 96 0.68 Repeat testing in 3 yr
HPV/Pap 92 0.27 Repeat testing in 5 yr

* The data are based on cytologic testing and cotesting performed by Kaiser Permanente Northern California. Under the
principle of similar management of similar risks, the management guidelines for cotesting results were benchmarked
to the current management of cytologic-testing-only results. In accordance with the Bethesda System, AGC denotes
atypical glandular cells, ASC-H atypical squamous cells (cannot rule out high-grade lesion), ASC-US atypical squamous
cells of undetermined significance, LSIL low-grade squamous intraepithelial lesion, Pap Papanicolaou test, and SCC
squamous-cell carcinoma. Minus signs denote negative, and plus signs positive.
The frequencies of cytologic-testing-only results are derived from data for all women with cytologic testing results, and
the frequencies of cotesting results are derived from data for all women with cotesting results.
The frequency of HSIL and cancer was estimated by the Kaiser histologic diagnoses of CIN 2, CIN 3, adenocarcinoma
in situ, and cancer.
For HPV/AGC, the cancer risk remained high, justifying immediate colposcopy.

Northern California study, the 5-year risk of cancer
among these women (0.05%) was meaningfully
higher than the risk among women with dual
negative cotests (0.01%).47 Owing to this ambi-
guity, current guidelines provide different recom-
mendations for the timing of repeat cotesting; the
recommended interval is currently 3 years in one
set of guidelines37 and 5 years in another.16 There
is a delicate balance between tailoring follow-up
screening intervals to gradations of demonstrated
risk and issuing overly complex guidelines that
are impractical for clinical implementation.
By identifying women without definite abnor-
malities on cytologic tests but with positive HPV
tests, cotesting will lead to colposcopy in many
women in whom HPV infection would be likely
to clear. Other women will have very small HSIL
that are difficult to visualize colposcopically and
that are probably more likely to regress sponta-
neously than are larger HSIL identified on Pap
testing.48 Obtaining more than one biopsy spec-
imen, targeting even faintly visible aceto-white
lesions (lesions that turn white with the applica-
tion of acetic acid), substantially increases the
sensitivity of colposcopy49 for the detection of
small HSIL.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Guidel ine s particular findings used to determine the level

In 2011, the American Cancer Society, together
with two dozen other organizations, developed
evidence-based screening guidelines for the pre-
vention and early detection of cervical cancer.16
Separately, the American College of Obstetricians
and Gynecologists21 and the U.S. Preventive Ser-
vices Task Force20 convened different sets of ex-
perts to develop guidelines. To minimize the po-
tential for confusion associated with multiple
guidelines, the groups agreed to harmonize word-
ing when their conclusions were concordant. The
recommendations issued by the three groups
are largely identical (Table 1). The central points
are that cytologic screening at 3-year intervals is ac-
cepted as the standard of care in the United
States, and cotesting at 5-year intervals is judged
to result in equivalent or even greater reductions
in the incidence of cervical cancer and in mortal-
ity associated with cervical cancer.
In 2013, a multisociety group led by the
American Society for Colposcopy and Cervical
Pathology (ASCCP) published updated guidelines
for managing abnormal cervical findings.37 To
the extent practicable, similar management strat-
egies are recommended for women at similar
risk for HSIL and cancer, regardless of the
of risk (Table 2).
C onclusions a nd
R ec om mendat ions
For women 30 years of age or older, such as the
woman described in the vignette, we would recom-
mend HPV and cytologic cotesting over cytologic
testing alone (although cytologic testing alone is
acceptable). Cotesting is associated with greater
sensitivity, greater reassurance if both tests are
negative, and longer screening intervals. Our rec-
ommendation is not changed by the womans his-
tory of apparently minor abnormalities on a Pap
test in the distant past. The great majority of wom-
en who undergo cotesting will have normal results
and can reasonably wait 5 years for repeat screen-
ing. For the 5 to 10% of women with positive cotest
results, management guidelines are tailored to the
level of risk associated with the specific combina-
tion of cytologic and HPV test results.
Dr. Schiffman reports receiving, at no charge, HPV DNA testing
of specimens from Roche Molecular Systems for a cytologicHPV
cotesting study with Kaiser Permanente, as well as equipment
and reagents from Qiagen for the evaluation of the careHPV test
method in Nigeria. No other potential conflict of interest rele-
vant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Ferlay J, Shin H, Bray F, Forman D,
Mathers C, Parkin D. GLOBOCAN 2008:
cancer incidence and mortality worldwide:
Lyon, France: International Agency for
Research on Cancer, 2008.
2. Siegel R, Naishadham D, Jemal A.
Cancer statistics, 2013. CA Cancer J Clin
2013;63:11-30.
3. Solomon D, Breen N, McNeel T. Cervi-
cal cancer screening rates in the United
States and the potential impact of imple-
mentation of screening guidelines. CA
Cancer J Clin 2007;57:105-11.
4. Bosch FX, Lorincz A, Muoz N, Meijer
CJ, Shah KV. The causal relation between
human papillomavirus and cervical cancer.
J Clin Pathol 2002;55:244-65.
5. Bouvard V, Baan R, Straif K, et al.
A review of human carcinogens part B:
biological agents. Lancet Oncol 2009;10:
321-2.
6. Schiffman M, Herrero R, Desalle R,
et al. The carcinogenicity of human papil-
lomavirus types reflects viral evolution.
Virology 2005;337:76-84.
7. Doorbar J. Molecular biology of hu-
man papillomavirus infection and cervical
cancer. Clin Sci (Lond) 2006;110:525-41.
8. zur Hausen H. Papillomaviruses in the
causation of human cancers a brief his-
torical account. Virology 2009;384:260-5.
9. Schiffman M, Castle PE, Jeronimo J,
Rodriguez AC, Wacholder S. Human papil-
lomavirus and cervical cancer. Lancet
2007;370:890-907.
10. Castellsagu X, Daz M, de Sanjos S,
et al. Worldwide human papillomavirus
etiology of cervical adenocarcinoma and
its cofactors: implications for screening
and prevention. J Natl Cancer Inst 2006;
98:303-15.
11. Guan P, Howell-Jones R, Li N, et al.
Human papillomavirus types in 115,789
HPV-positive women: a meta-analysis from
cervical infection to cancer. Int J Cancer
2012;131:2349-59.
12. Garland SM, Hernandez-Avila M,
Wheeler CM, et al. Quadrivalent vaccine
against human papillomavirus to prevent
anogenital diseases. N Engl J Med 2007;
356:1928-43.
13. Herrero R, Wacholder S, Rodrguez
AC, et al. Prevention of persistent human
papillomavirus infection by an HPV16/18
vaccine: a community-based randomized
clinical trial in Guanacaste, Costa Rica.
Cancer Discov 2011;1:408-19.
14. Lehtinen M, Paavonen J, Wheeler CM,
et al. Overall efficacy of HPV-16/18 AS04-
adjuvanted vaccine against grade 3 or
greater cervical intraepithelial neoplasia:
4-year end-of-study analysis of the random
ised, double-blind PATRICIA trial. Lancet
Oncol 2012;13:89-99. [Erratum, Lancet
Oncol 2012;13(1):e1.]
15. Schiffman M, Wentzensen N, Wachold
er S, Kinney W, Gage JC, Castle PE. Hu-
man papillomavirus testing in the preven-
tion of cervical cancer. J Natl Cancer Inst
2011;103:368-83.
16. Saslow D, Solomon D, Lawson HW,
et al. American Cancer Society, American
Society for Colposcopy and Cervical Pa-
thology, and American Society for Clini-
cal Pathology screening guidelines for the
prevention and early detection of cervical
cancer. CA Cancer J Clin 2012;62:147-72.
17. Monsonego J, Hudgens MG, Zerat L,
et al. Evaluation of oncogenic human papil-
lomavirus RNA and DNA tests with liquid-
based cytology in primary cervical cancer
screening: the FASE study. Int J Cancer
2011;129:691-701.
18. Castle PE, Stoler MH, Wright TC Jr,
Sharma A, Wright TL, Behrens CM. Perfor-
mance of carcinogenic human papilloma-
virus (HPV) testing and HPV16 or HPV18

2330 n engl j med 369;24nejm.orgdecember 12, 2013

The New England Journal of Medicine

Downloaded from nejm.org by HECTOR GARCIA on February 7, 2014. For personal use only. No other uses without permission.
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 clinical pr actice

genotyping for cervical cancer screening
of women aged 25 years and older: a sub-
analysis of the ATHENA study. Lancet
Oncol 2011;12:880-90.
19. Einstein MH, Martens MG, Garcia FA,
et al. Clinical validation of the Cervista
HPV HR and 16/18 genotyping tests for
use in women with ASC-US cytology. Gy-
necol Oncol 2010;118:116-22.
20. Moyer VA. Screening for cervical can-
cer: U.S. Preventive Services Task Force
recommendation statement. Ann Intern
Med 2012;156:880-91.
21. ACOG Practice Bulletin number 131:
screening for cervical cancer. Obstet Gy-
necol 2012;120:1222-38.
22. Rijkaart DC, Berkhof J, van Kemenade
FJ, et al. HPV DNA testing in population-
based cervical screening (VUSA-Screen
study): results and implications. Br J Can-
cer 2012;106:975-81.
23. Darragh TM, Colgan TJ, Cox JT, et al.
The Lower Anogenital Squamous Termi-
nology Standardization Project for HPV-
Associated Lesions: background and con-
sensus recommendations from the College
of American Pathologists and the Ameri-
can Society for Colposcopy and Cervical
Pathology. J Low Genit Tract Dis 2012;16:
205-42. [Erratum, J Low Genit Tract Dis
2013;17:368.]
24. Chen HC, Schiffman M, Lin CY, et al.
Persistence of type-specific human papil-
lomavirus infection and increased long-
term risk of cervical cancer. J Natl Cancer
Inst 2011;103:1387-96.
25. Dillner J, Rebolj M, Birembaut P, et al.
Long term predictive values of cytology
and human papillomavirus testing in cer-
vical cancer screening: joint European
cohort study. BMJ 2008;337:a1754.
26. Khan MJ, Castle PE, Lorincz AT, et al.
The elevated 10-year risk of cervical pre-
cancer and cancer in women with human
papillomavirus (HPV) type 16 or 18 and
the possible utility of type-specific HPV
testing in clinical practice. J Natl Cancer
Inst 2005;97:1072-9.
27. Kjr SK, Frederiksen K, Munk C,
Iftner T. Long-term absolute risk of cervi-
cal intraepithelial neoplasia grade 3 or
worse following human papillomavirus
infection: role of persistence. J Natl Can-
cer Inst 2010;102:1478-88.
28. Bulkmans NW, Berkhof J, Rozendaal L,
et al. Human papillomavirus DNA testing
for the detection of cervical intraepithelial
neoplasia grade 3 and cancer: 5-year fol-
low-up of a randomised controlled imple-
mentation trial. Lancet 2007;370:1764-72.
29. Mayrand MH, Duarte-Franco E, Ro-
drigues I, et al. Human papillomavirus
DNA versus Papanicolaou screening tests
for cervical cancer. N Engl J Med 2007;357:
1579-88.
30. Naucler P, Ryd W, Trnberg S, et al.
Human papillomavirus and Papanicolaou
tests to screen for cervical cancer. N Engl
J Med 2007;357:1589-97.
31. Ronco G, Giorgi-Rossi P, Carozzi F, et
al. Efficacy of human papillomavirus test-
ing for the detection of invasive cervical
cancers and cervical intraepithelial neo-
plasia: a randomised controlled trial.
Lancet Oncol 2010;11:249-57.
32. Ronco G, Dillner J, Elfstrm KM, et al.
Efficacy of HPV-based screening for pre-
vention of invasive cervical cancer: follow-
up of four European randomised con-
trolled trials. Lancet 2013 November 1
(Epub ahead of print).
33. Sankaranarayanan R, Nene BM, Shas-
tri SS, et al. HPV screening for cervical
cancer in rural India. N Engl J Med 2009;
360:1385-94.
34. Rodrguez AC, Schiffman M, Herrero
R, et al. Longitudinal study of human
papillomavirus persistence and cervical
intraepithelial neoplasia grade 2/3: critical
role of duration of infection. J Natl Cancer
Inst 2010;102:315-24.
35. McCredie MR, Sharples KJ, Paul C, et
al. Natural history of cervical neoplasia
and risk of invasive cancer in women with
cervical intraepithelial neoplasia 3: a retro-
spective cohort study. Lancet Oncol 2008;
9:425-34.
36. Kulasingam SL, Havrilesky LJ, Ghebre
R, Myers ER. Screening for cervical can-
cer: a modeling study for the US Preven-
tive Services Task Force. J Low Genit Tract
Dis 2013;172:193-202.
37. Massad LS, Einstein MH, Huh WK, et
al. 2012 Updated consensus guidelines
for the management of abnormal cervical
cancer screening tests and cancer precur-
sors. J Low Genit Tract Dis 2013;17:Suppl 1:
S1-S27. [Erratum, J Low Genit Tract Dis
2013;17:367.]
38. Siebers AG, Klinkhamer PJ, Grefte JM,
et al. Comparison of liquid-based cytology
with conventional cytology for detection
of cervical cancer precursors: a random-
ized controlled trial. JAMA 2009;302:1757-
64. [Erratum, JAMA 2009;302:2322.]
39. Katki HA, Kinney WK, Fetterman B,
et al. Cervical cancer risk for women un-
dergoing concurrent testing for human
papillomavirus and cervical cytology:
a population-based study in routine clinical
practice. Lancet Oncol 2011;12:663-72.
[Erratum, Lancet Oncol 2011;12:722.]
40. International Collaboration of Epide-
miological Studies of Cervical Cancer.
Comparison of risk factors for invasive
squamous cell carcinoma and adenocarci-
noma of the cervix: collaborative reanaly-
sis of individual data on 8,097 women
with squamous cell carcinoma and 1,374
women with adenocarcinoma from 12 epi-
demiological studies. Int J Cancer 2007;
120:885-91.
41. Idem. Cervical cancer and hormonal
contraceptives: collaborative reanalysis of
individual data for 16,573 women with cer-
vical cancer and 35,509 women without
cervical cancer from 24 epidemiological
studies. Lancet 2007;370:1609-21.
42. Idem. Carcinoma of the cervix and to-
bacco smoking: collaborative reanalysis
of individual data on 13,541 women with
carcinoma of the cervix and 23,017 women
without carcinoma of the cervix from 23
epidemiological studies. Int J Cancer 2006;
118:1481-95.
43. Rodrguez AC, Schiffman M, Herrero
R, et al. Low risk of type-specific carcino-
genic HPV re-appearance with subsequent
cervical intraepithelial neoplasia grade
2/3. Int J Cancer 2012;131:1874-81.
44. Katki HA, Schiffman M, Castle PE, et
al. Five-year risks of CIN 3+ and cervical
cancer among women with HPV-positive
and HPV-negative high-grade Pap results.
J Low Genit Tract Dis 2013;17:Suppl 1:
S50-S55.
45. Idem. Benchmarking CIN 3+ risk as the
basis for incorporating HPV and Pap co-
testing into cervical screening and man-
agement guidelines. J Low Genit Tract Dis
2013;17:Suppl 1:S28-S35.
46. Tsoumpou I, Arbyn M, Kyrgiou M, et
al. p16(INK4a) immunostaining in cyto-
logical and histological specimens from
the uterine cervix: a systematic review and
meta-analysis. Cancer Treat Rev 2009;35:
210-20.
47. Katki HA, Schiffman M, Castle PE,
et al. Five-year risks of CIN 3+ and cervical
cancer among women with HPV testing of
ASC-US Pap results. J Low Genit Tract Dis
2013;17:Suppl 1:S36-S42.
48. Schiffman M, Rodrguez AC. Hetero-
geneity in CIN3 diagnosis. Lancet Oncol
2008;9:404-6.
49. Gage JC, Hanson VW, Abbey K, et al.
Number of cervical biopsies and sensitiv-
ity of colposcopy. Obstet Gynecol 2006;108:
264-72.
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