JNCI

DOI: 10.
1093/jnci/djq562
Advance Access publication on January 31, 2011.
Published by Oxford University Press 2011.
REVIEW
Human Papillomavirus Testing in the Prevention of Cervical

Cancer
MarkSchiffman, NicolasWentzensen, SholomWacholder, WalterKinney, Julia C.Gage, Philip E.Castle
Manuscript received June 25, 2010; revised November 24, 2010; accepted December 17, 2010.
Correspondence to: Mark Schiffman, MD, MPH, Rm 7012, 6120 Executive Blvd, Rockville, MD 20852 (e-mail: schiffmm@mail.nih.gov).
J Natl Cancer Inst 2011;103:368383
Cervical cytology (Papanicolaou test) screening programs have

greatly reduced the rates of cervical cancer over the past 50 years
(13). Evidence from randomized trials now supports the incorporation of prevention methods that explicitly focus on human papillomavirus (HPV), the cause of cervical cancer, into these
screening programs (46). Proper use of vaccines in adolescent
girls to prevent HPV infections, and the addition of HPV testing
to screening, can eliminate the need for tens of millions of
screening visits every year in the United States alone. Low-cost
HPV tests would allow excellent cervical cancer prevention to be
extended to low-income women throughout the world (7,8).
To inform an evidence-based transition to a new public health
approach for cervical cancer screening, we summarize HPV natural
history and cervical carcinogenicity, review the efficacy of currently available cervical cancer prevention methods, discuss how
optimal prevention strategies are guided by HPV biology and technology, and describe important remaining uncertainties and concerns regarding the possible misuse of new screening strategies.
HPV Natural History and Cervical

Carcinogenicity
HPV Causes Virtually All Cervical Cancer
Persistent HPV infections cause virtually all of the more than
500000 cases of invasive cervical cancer per year worldwide (9).
The 250000 deaths from cervical cancer reported in 2008 make it
the third leading cause of cancer death in women (10). In 2009, the
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annual rate of invasive cases of cervical cancer in the United States

had declined to approximately 11000 cases per year, with 4000
deaths (11). Nonetheless, billions of dollars are spent per year on
the 75 million screening visits and resultant diagnostic and treatment visits to address its precursors, and the many minor cervical
cytological abnormalities that are exceedingly unlikely to become
cancerous (12,13).
Cervical cancers occur primarily at the cervical transformation
zone. The transformation zone is a ring of tissue located where
the squamous epithelium of the vagina meets, undermines, and
replaces the glandular epithelium of the endocervical canal
(Figure 1).
In this review, we focus on squamous lesions, which are the
most common and best understood cervical lesions caused by
HPV; however, HPV also causes the less common adenocarcinomas and some even rarer histological types (14). In this context,
it is worth noting that HPV testing might be especially useful for
detection of adenocarcinomas, which can be difficult to find using
cytology (14).
Because of its central role in the etiology of virtually all cases of
cervical cancer, HPV is correctly called a (virtually) necessary but
(generally) not sufficient cause of cervical cancer. With the exception of rare HPV-negative cases, cervical cancer arises via the following distinct and sequential steps: acute infection with
carcinogenic HPV type(s), followed by detectable viral persistence
(rather than clearance) linked to the development of cervical precancer, and invasion.
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Strong evidence now supports the adoption of cervical cancer prevention strategies that explicitly focus on persistent infection
with the causal agent, human papillomavirus (HPV). To inform an evidence-based transition to a new public health approach for
cervical cancer screening, we summarize the natural history and cervical carcinogenicity of HPV and discuss the promise and
uncertainties of currently available screening methods. New HPV infections acquired at any age are virtually always benign, but
persistent infections with one of approximately 12 carcinogenic HPV types explain virtually all cases of cervical cancer. In the
absence of an overtly persistent HPV infection, the risk of cervical cancer is extremely low. Thus, HPV test results predict the risk
of cervical cancer and its precursors (cervical intraepithelial neoplasia grade 3) better and longer than cytological or colposcopic
abnormalities, which are signs of HPV infection. The logical and inevitable move to HPV-based cervical cancer prevention strategies will require longer screening intervals that will disrupt current gynecologic and cytology laboratory practices built on
frequent screening. A major challenge will be implementing programs that do not overtreat HPV-positive women who do not
have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. The greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost
HPV testing and treatment.
Figure 1.The cervical transformation zone and

uncertainty of colposcopic impression. A) The
tissue at risk of cervical cancer is the epithelial
transformation zone, where the squamous vaginal epithelium undermines and replaces the
glandular epithelium of the cervical canal. B)
Squamous metaplasia continues as women
age; effective screening, diagnosis, and treatment of the transformation zone become difficult. For women of any age, colposcopists
cannot easily diagnose or target the biopsy of
lesions of different underlying severity.
Photographs were taken using a Zeiss 150 FC
colposcope at 7.1-fold magnification. CIN13 =
cervical intraepithelial neoplasia grades 13.
Time Course of HPV Infection and Cervical Carcinogenesis

The natural history of HPV is the basis for the rational use of
preventive measures. We can best build an understanding of the
time course of HPV infection and cervical carcinogenesis from the
bottom up by discussing HPV at three levels: an individual infection, a womans experience with HPV during her lifetime, and
in a population.
jnci.oxfordjournals.org
The Natural History of an Individual Carcinogenic HPV

Infection. Cervical cancer is typically the culmination of a decades-
long process that begins with an infection with a carcinogenic

HPV type (Figure 3). We refer to the moment of infection as
time zero when discussing the subsequent course of infection
because the natural history of a truly new infection is fundamentally the same regardless of an individuals age at incident infection
(27,29); for example, neither newly infected teenagers nor 45-yearold women are at immediate risk of cervical cancer.
As shown in Figure 3, half of new HPV infections are undetectable within approximately 612 months, and more than 90% clear
within a few years (26). The rate of clearance is high within the
first months after infection but decreases over time (30).
When a carcinogenic HPV type is detected by HPV testing, a
concurrent cytological abnormality is present about one-quarter to
one-third of the time (31). Most of these abnormalities are equivocal or, at most, minor. Compared with infection with other carcinogenic HPV types, a woman with an HPV16 infection is most
likely to present with serious cytological abnormalities. In general,
compared with the cytological and histological changes that accompany a carcinogenic HPV infection, HPV DNA is detected
earlier and is detectable for a longer time (32). However, annual
screening often misses these subtle temporal differences.
Details regarding the cell-mediated immune response that
results in clearance of each HPV infection and its associated cytological abnormalities are largely unknown (33). HPV clearance
seemingly results in long-term humoral and/or cellular protection
against reinfection with the same HPV type; whether the protection is lifelong is not known. Although the term clearance is used
when an HPV infection can no longer be detected using sensitive
test methods, HPV might not be completely eliminated; the latent
state of HPV is poorly understood.
Reappearance of HPV from latency (analogous to recurrent
herpes or shingles from varicella), even in the absence of definite
immunosuppression (34), is common, especially as women age, but
probably benign: In one large prospective cohort, there were no
cases of HPV reappearance followed by subsequent overt persistence and CIN3 (27).
By contrast to HPV infections that clear, the cancer risk increases
dramatically for the 5% of HPV infections that persist detectably
for more than a few years. Such long duration HPV infections are
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Characteristics of HPV
Papillomaviruses are 8000-base pair, double-stranded, circular
DNA viruses that can cause warty changes in epithelia from many
host species. Papillomaviruses have at most six early genes
(involved in viral replication) and two late genes (involved in capsid
formation) (15,16). Of the more than 150 HPV types identified,
approximately 40 can infect the cervix (17). The varying carcinogenicity of these HPV types for the cervix is related, in part, to the
expression of two early genes, the E6 and E7 oncogenes. Among
other functions, the E6 and E7 oncoproteins interfere with the
functions of tumor suppressor proteins p53 and pRb, respectively.
During the carcinogenic process, the HPV genome may integrate
into the epithelial cell genome and, during integration, parts of the
HPV genome can be lost (18). But continued presence and expression of the E6 and E7 gene regions are needed to sustain cancers
and cancer cell lines.
The International Agency for Research on Cancer (IARC) has
classified 12 HPV types as group 1 carcinogens (ie, oncogenic or
high risk): HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and
59 (19). As shown in the evolutionary dendrogram in Figure 2,
these 12 HPV types belong to four species in a single evolutionary
branch of the alpha genus, and all 12 HPV types can infect the
cervix (17,19,21). The same evolutionary branch includes HPV68,
an IARC group 2A carcinogen (ie, probably carcinogenic to
humans), and several possibly (rarely) carcinogenic HPV types
(IARC group 2B). Of the 12 known carcinogenic HPV types,
HPV16 is by far the most carcinogenic in terms of numbers of
cases of cervical cancer and its immediate precursor, cervical
intraepithelial neoplasia grade 3 (CIN3) (22,23). HPV16 also
causes most cancers linked to HPV in other anogenital epithelia
and in the oropharynx, as discussed elsewhere (24,25). HPV18 is a
distant second in terms of etiologic importance (but is disproportionately important for adenocarcinomas) (22).
clade (which comprises species a2, a3, a4, and a15) cause commensal
infections. HPV types in the red clade (which comprises species a5, a6, a7,
a9, and a11) (shown in detail on the right) are associated to different
degrees with cervical cancer and cervical intraepithelial neoplasia grade
3. The eight types that most commonly cause cervical cancer everywhere
in the world belong to species alpha-9 or, to a lesser extent, to alpha-7.
The carcinogen group for each HPV type is according to the International
Agency for Research on Cancer (19): group 1 = carcinogenic, group 2A =
probably carcinogenic, and group 2B = possibly carcinogenic.
associated with a high absolute risk (eg, >40% for long duration
HPV16 infection) for later diagnosis of cancer precursors (ie, CIN3)
that span the full thickness of the cervical epithelium (3537).
The clinical emergence of CIN3 lesions among women with
molecularly detectable HPV persistence is gradual; CIN3 lesions
that are initially confined to just a few transformed cells are too
small for cytological and colposcopic diagnosis. The CIN3 lesions

gradually grow laterally within the epithelium over the course of
several years (38). Current testing methods and screening intervals
in longitudinal cohorts cannot pinpoint the exact moment that a
persistently infected cell transforms into CIN3 or exactly when it
becomes large enough to diagnosis.
Figure 3.Risks of human papillomavirus (HPV)

persistence and progression. Left graph:
Proportion of prevalent carcinogenic HPV infections that clear, persist, or progress to cervical intraepithelial neoplasia grade 3 (CIN3) in
the first 3 years after first detection, based on
all infections found at baseline screening in the
Guanacaste Natural History Study (26). The
great majority represented new infections
(27). Persistence without CIN3 is surprisingly
uncommon. Uncommon reappearances of
HPV types following clearance did not predict
risk of CIN3. Right graph: Proportion of untreated CIN3 lesions that invade to cancer
within 30 years following the initial diagnosis
[based on data from New Zealand (28)].
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Figure 2. The evolution of human papillomavirus (HPV) types predicts

carcinogenicity. The evolution of papillomaviruses is very slow. Tissue
specificity, natural history, and carcinogenicity of HPVs are generally consistent with evolutionary relationships. HPV species in the alpha genus
(left) infect mucosa, including the anogenital region and the oral cavity.
The phylogenetic tree is based on the alignment of concatenated early
and late open reading frames as described in Schiffman et al. (20). HPV
types in the blue clade (which comprises species a1, a8, a10, and a13)
include the HPV types that cause genital warts. HPV types in the green
We do know that CIN3 lesions typically grow slowly over

many years before invasion (28,38). It is now clear that the development of CIN3 following a new HPV infection occurs much
more quickly than does the development of invasive cancer invasion from CIN3 (38). However, it is not possible to predict if or
when CIN3 lesions will break through the epithelial basement
membrane into the underlying stroma. The time from infection to
invasive cancer is shorter for HPV16 than for other HPV types
(39), but determinants of invasion other than HPV type are
unknown. Because we know so little about the transition from
CIN3 to invasive cervical cancer, CIN3 is treated as soon as it is
diagnosed to maximize the safety of affected women (except for
delay in some pregnant women).
A Womans Lifetime Experience With HPV Infections. The
Figure 4. Cervical cancer progression model

and optimized prevention strategy. A) The
three steps in cervical carcinogenesis are acute
human papillomavirus (HPV) infection, HPV
persistence associated with the development
of cervical precancer (cervical intraepithelial
neoplasia grade 3 [CIN3] in particular, and invasion. B) Infection and clearance are extremely
common and together contribute to the sharp
peak of HPV prevalence in the years following
average age of first sexual intercourse in the
population. The average age at CIN3 diagnosis
depends on the intensity of the screening effort
in the population. Typically, it takes decades for
a CIN3 lesion to grow and eventually invade,
although there are rare and rapid exceptions.
Panel B schematically displays current and
future screening options integrating cytology
(C), HPV testing (H), and prophylactic vaccination (V). The current emphasis on repeated cytology screening is inefficient. Even cotesting
at 3-year intervals would not be optimal. At
some point, an ideal program could emphasize
HPV vaccination before average age at first
sexual intercourse and reliance on increasingly
spaced HPV tests for primary screening (or another equally sensitive method). Note: the
prevalence curves are not drawn to scale. The
graph shows age-related prevalence of HPV
infections (green), CIN2 and CIN3 (blue), and
cervical cancer (red) in the United States. Data
on HPV infections are based on a summary of US-based HPV prevalence studies (55). The age distribution of CIN2 and/or CIN3 is based on
data from Kaiser Permanente Northern California Health Maintenance
HPV at the Population Level. For public health planning of cervical cancer prevention efforts, an awareness of the average age
distributions of the three increasingly severe stages in cervical
carcinogenesisacute HPV infection, CIN3, and canceris
essential (Figure 4). The peaks of these distributions vary by
Organization (P. E. Castle, personal communication) and the data on

cancers are from the Surveillance, Epidemiology, and End Results 17
database (56).
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great majority of sexually active women and men have been

infected with HPV at least once in their lifetime (40,41). HPV
infections are easily (co-)transmitted by sexual contact. A woman
might be infected with two HPV types by one partner and become
infected with a third HPV type later. One infection could persist
after several others have cleared. Although the exact transmission
probability per sexual contact or partnership is not known precisely, it has been estimated at approximately 0.5 (42).
HPV persistence is uncommon and represents the critical distinction between benign HPV exposure and substantial risk of
cervical precancer. Infection with one HPV type does not influence the likelihood or duration of persistence of another HPV
infection in a clinically meaningful way. High rates of HPV persistence estimated (30) in several studies of HPV-induced cytological
abnormalities (4345) are not reliable because sequential infections
with different HPV types, each of which could cause morphological changes, were considered persistent in the absence of HPV
typespecific testing persistence. Thus, the normal rapid clearance
of concurrent and/or consecutive infections was conflated with
more serious single-type persistence.
The risk of cervical cancer is powerfully, and almost exclusively,
defined by HPV natural history. The risk factors for progression to
CIN3 and possible invasive cancer (hereafter referred to as CIN3+)
among HPV-infected women include a history of smoking, longterm oral contraceptive use, multiparity, and probably chronic inflammation (4650). The mechanisms by which these exposures increase
risk are not clear. None of the etiologic cofactors that are associated
with a two- to threefold increased risk of CIN3 or cervical cancer
among HPV-infected women causes cervical cancer in the absence of
HPV. Chlamydia infections are probably associated with the risk of
CIN3+ only because of coincident sexually transmitted HPV (51).
Host genetics and other influences on host immunity might
influence immune response to HPV infection; weak associations of
HLA with risk of CIN3+ have been noted (52). Coinfection with
HIV is important because HIV-induced immunosuppression
impairs cell-mediated immune control of HPV infections (53).
Even in the absence of severe immunosuppression, some women
might have difficulty clearing HPV infections due to inherited or
acquired deficiencies (54).
Use of HPV Testing in Cervical Cancer

Prevention
In this section, we present the evidence about the performance of
existing cervical cancer prevention technologies and discuss how
HPV testing can be integrated. We consider all screening and diagnostic tests, including HPV molecular tests, cervical cytology, and
colposcopy, as well as histology, to be biomarkers of risk of cervical
cancer. Ideally, an essential function at each stage of a screening
program, including screening, triage, diagnosis, treatment decisions,
and follow-up, should be risk stratification. The choice of tests used
is likely to change in the coming years as even newer technologies
and test combinations are shown to stratify risk more accurately.
Screening
Screening is a public health activity to detect disease among people
thought a priori to be well. In the United States, the major cervical
screening target is treatable CIN3 (or, to be especially cautious,
CIN2), not invasive cervical cancer, for which treatment causes far
more morbidity and is less certain to succeed. Therefore, cervical
screening distinguishes between the few women who might
become patients because they are at highest risk of cancer and the
overwhelming majority of women who are at far lower risk.
Screening that targets the common, minor, and typically benign
cytological and histological evidence of acute HPV infection
cannot be cost-effective because the risk of invasive cancer is so
low. However, finding a woman with CIN3 is considered a
screening success because she has a high risk of invasive cancer and
can be treated before cancer develops.
Screening Using Cervical Cytology. We will mention key
aspects of cervical cancer screening programs based on cytology, in
which exfoliated cervical cells are examined to predict the underlying risk of cervical cancer, as the referent against which other
biomarkers are compared. The consistently observed substantial
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reduction of cervical cancer incidence after introduction of cytology screening and the marked difference in cervical cancer
incidence between countries with and without screening programs
indicates that Pap testing does prevent cervical cancer (1).
Papanicolaou originally introduced cervical cytology with morphological classifications that were based on probability of underlying cancer (Supplementary Figure 1, available online). However,
the current US cytology classificationthe Bethesda system
incorporates a view of cervical carcinogenesis that is explicitly
based on the natural history of HPV (60). For example, the
classification of low-grade squamous intraepithelial lesion (LSIL) is
based on microscopic signs of an acute HPV infection, whereas
high-grade squamous intraepithelial lesion (HSIL) suggests the
possibility of an underlying CIN3 (or the more uncertain precancer
diagnosis, CIN2). The great majority of HSIL and approximately
two-thirds of LSIL are associated with carcinogenic HPV types
(61,62). Very common and equivocal cytological changes, which
are classified as atypical squamous cells of undetermined significance (ASC-US), form the boundary between normal and abnormal cytological interpretations; roughly half of changes classified as
ASC-US are positive for carcinogenic HPV (63). In the United
States, ASC-US is more common than all other abnormalities
combined. Because this finding is common and some represent true
abnormalities, a sizeable fraction of CIN3+ cases are detected by
ASC-US cytology, despite poor interobserver reproducibility (64).
With some noteworthy exceptions (65,66), typically a single
cervical cytological screen is insensitive for detecting CIN3; sensitivity estimates as low as 50%60% have been reported in various
settings (67). Although a single negative high-quality Papanicolaou
test does indicate a substantially lowered risk of cervical cancer
lasting multiple years, stronger reassurance of safety (ie, a high
negative predictive value) requires repeated rounds of screening to
detect growing CIN3 lesions (68,69).
In many countries, conventional Papanicolaou smears are still
the standard of care. In the United States and a few other countries, liquid-based cytology techniques that create more uniform
slides and computer-assisted cytology evaluation systems have been
adopted to achieve greater laboratory productivity, but there is no
evidence that they detect CIN3 more accurately than conventional
cytology (70,71); therefore, we do not distinguish among cytological techniques when considering the new role of HPV testing.
Screening Using HPV Tests. There is now overwhelming evidence from randomized clinical trials that carcinogenic HPV
DNA screening is more sensitive than cytological screening for
detecting histological CIN3 (7277). Even more important, a negative HPV test provides long-term risk stratification: 510 years of
reassurance (ie, a high negative predictive value) of not developing
CIN3 and even stronger reassurance of not developing invasive
cancer among HPV DNAnegative women. High negative predictive value permits safe and cost-effective lengthening of the cervical
screening interval when HPV testing is used (78,79) (Figure 5).
Because the vast majority of HPV infections represent acute
HPV infections that are destined to clear without causing cancer,
HPV testing has mediocre specificity and positive predictive value
for cervical cancer screening. Women who test positive for carcinogenic HPV DNA or RNA, especially the first time they are
Vol. 103, Issue 5 | March 2, 2011
geographic region (57,58) and reflect the local average age at first
sexual intercourse, given that HPV infection starts the clock for
the events that follow. A few years after the average age at which
women become sexually active, there is a high peak of incident
HPV infections usually followed by a gradual decline (57,59); a
lower peak of CIN3 occurs 515 years later (the peak of diagnosis
of CIN3 shifts to younger ages with increasing intensity of a
screening program); and the long drawn-out peak or plateau in
invasive cancers occurs over the subsequent decades.
The prolonged time typically required to transition from infection to invasive cancer has two important implications: extremely
few rapid-onset cases of cervical cancer occur before the age of 25
years and most cancer diagnoses are made after age 40 years (56).
The rapid-onset cases of cervical cancer are intrinsically difficult to
prevent by screening and are too rare to determine the starting age
and frequency of screening as a public health activity that will affect tens of millions of women. In addition, because of the steep
decline in HPV infection incidence and the prolonged time
required to develop cancer and with increasing age, new HPV infections that are acquired at older ages contribute little to cervical
cancer in populations.
(baseline) were tested for carcinogenic HPV types. The risk estimates, adjusted for loss to follow-up, show primarily that in this
older cohort (average age approximately 35 years), a negative HPV
test predicts very low risk of subsequent CIN3+. Baseline test positivity for HPV16, HPV18, or HPV31 was most strongly linked to subsequent CIN3+.
tested (when the infections might already be persistent), are at

sufficiently high risk of CIN3+ to merit intensified scrutiny and
follow-up. Current practice in the United States to restrict carcinogenic HPV testing to women aged 30 years or older, who are
past the peak of acute HPV infections (Figure 4), results in a
higher positive predictive value of HPV testing because a higher
proportion have HPV infections that are persistent (3).
Successful risk stratification based on HPV screening depends
on whether the infections found are already persistent (and thus
possibly high risk) or new (low risk), especially among older

women. In this context, proponents of HPV screening have paid
insufficient attention to the downstream course of such screening
programs. For example, women who test HPV positive 3 years
after a negative HPV test [the current recommendation for cotesting (80)] are at much lower risk of CIN2 or CIN3+ than women
who are HPV positive at their first screen and, therefore, may
already have a persistent infection (Figure 6). This important
fact mandates much longer HPV screening intervals than current
Figure 6.Negative impact of testing for HPV too frequently. We plot

the results of HPV testing performed at two time points (at enrollment [t = 0] and at year 3) in women enrolled in the Guanacaste
Natural History Study; disease ascertainment occurred annually. The
cumulative incidence rate of cervical intraepithelial neoplasia grade 2
or worse (CIN2+) is shown for women testing positive and negative
at enrollment and again for women testing positive and negative at
year 3 among those who tested negative at enrollment (27). The risk
stratification of the first HPV test is excellent, but the second test is
less effective in detecting prevalent disease if performed too soon.

Testing HPV positive for prevalent HPV infections predicts an elevated risk of CIN2+ (the treatment threshold) found before the
screening at year 3, whereas testing HPV negative predicts a very low
risk. Among women with an HPV-negative test at enrollment (t = 0),
those who test HPV positive 3 years later (ie, at the currently recommended interval) are at much lower risk of CIN2+ than women who
were HPV positive at the first screen and who may already have a
persistent infection.
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Figure 5. Cumulative incidence rate of cervical intraepithelial neoplasia grade 3 or invasive cervical cancer (CIN3+) over 15 years following a single human papillomavirus (HPV) test. A cohort of 20000
women from Kaiser Permanente (Portland, OR) was followed up by
conventional cytology screening for approximately 15 years (78).
Archived cervical specimens obtained from the women at enrollment
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visit) and not just cases detectable by colposcopy at the time of

testing.
Commonly used HPV tests have not completely optimized the
threshold for positivity in cervical screening of general populations. A slightly higher threshold for HC2 positivity would reduce
the influence of cross-reactivity with noncarcinogenic HPV types
(87) and eliminate the effect of lowviral load HPV infections that
bear little risk of clinical disease, thereby stratifying risk even more
efficiently than does the current threshold for positivity (88). In
this same regard, the limited available data on the second FDAapproved HPV testCervista (Hologic, Bedford, MA)are concerning. In the earliest comparisons of Cervista with HC2, two- to
threefold more women were called HPV positive with Cervista,
but without concomitant gain in sensitivity for CIN2+; the use of
Cervista in cervical cancer screening is questionable until this discrepancy can be understood and resolved (89).
HPV test results are interpreted as either positive or negative.
When the result is positive, there is a temptation to view the viral
load measurement as a kind of dose effect; however, the use of
higher HPV viral load measurements for clinical decision making
is not FDA approved and should be avoided. A higher HPV viral
load is only a weak predictor of CIN3 (90,91). Acute (productive) HPV infections tend to have a very high viral load, whereas
many women with small CIN3 lesions (in which the acute infection has cleared) have low viral loads (90,91).
Screening Using Cotesting With Cytology and HPV Tests:
the Kaiser Permanente of Northern California (KPNC)
Experience. To our knowledge, there is only one large US experi-
ence with HPV testing in primary cervical screening: the KPNC

experience (81,92). The basis of the KPNC approach is the recognition that, when both cytology and HPV tests are negative, the
high negative predictive value for subsequent risk of CIN3+ permits extension of screening intervals. In 20032005, KPNC
adopted the FDA-approved cotesting strategy of cytology with
HC2 as an alternative screening method to routine (annual or biennial) cervical cytology alone for women aged 30 years or older
(who are past the peak of acute infections), with a policy that
women who tested negative for both assays would not be rescreened
before 3 years. Subsequent experience with more than 1 million
cotests has shed light on the practicality, advantages, and potential
pitfalls of contesting (92).
The transition from annual cytology to cotesting at 3-year
intervals has proven to be acceptable to patients and providers.
Currently, 95% of women opt for cotesting. Determining how to
manage women with HPV-positive and cytology-negative
screening results, the most common discordant finding, is a major
remaining challenge to the widespread use of cotesting. The risk
of CIN3+ in women who are HPV positive and cytology negative
is much greater than it is among HPV-negative women but
remains low in absolute terms. The risk does not justify immediate
colposcopy; and, referring all HPV-positive women (4% of all
screened women aged 30 years or older in KPNC) would roughly
double the colposcopy rates compared with referral of only women
with ASC-US or worse. In an effort to avoid unnecessary procedures and overdiagnosis, KPNC defers colposcopic referral among
HPV-positive cytology-negative women in favor of repeated
Vol. 103, Issue 5 | March 2, 2011
cytology screening intervals of every 2 years and suggests that the

current 3-year interval for cotesting (see below) will still be too
frequent. The corollary of high sensitivity of HPV testing for incipient as well as prevalent CIN3+ is a high negative predictive
value that lasts for years. Although the ability to lengthen screening
intervals is a great advance, it poses a major challenge for transitioning from cervical screening programs that are based on repeated cytology. In particular, in the United States, the considerable
general reluctance to move to long-interval screening is due at
least in part to reasons unrelated to theoretical best public health
practice. By contrast, in some European settings, where cervical
cancer screening practices are dictated more directly by public
health considerations, detailed planning is underway for a transition to long-interval HPV testing (81).
The variety of HPV tests that are currently available is shown
in Table 1. HPV tests rely on detection of overt, current infection
through DNA or, more recently, RNA testing, because there is no
clinically useful serological assay of HPV exposure or susceptibility. The two major methods for detection of carcinogenic HPV
DNA are hybridization with signal amplification and genomic
amplification using polymerase chain reaction or other techniques.
Currently, the workhorse of HPV testing in the United States is a
Food and Drug Administration (FDA)approved hybridization
method, Hybrid Capture 2 (HC2; Qiagen Corporation,
Gaithersburg, MD) (82). To date, HPV DNA detection by polymerase chain reactionbased methods have been used mainly for
research. They typically have used a pool of primers for broadspectrum amplification of HPV DNA followed by specific detection of target HPV types using type-specific hybridization probes
(83). The best-validated HPV tests (Table 1) have reasonably comparable performance (ie, they are more reproducible than interpathologist comparisons of the distinction between normal and
abnormal cytology), but there are exceptions.
HPV testing has an apparently unavoidable trade-off between
sensitivity and specificity. Acute HPV infections are common and
usually benign; therefore, the sensitivityspecificity trade-off is far
different for HPV testing than it is for screening of pathogens like
HIV, for which the sensitivity of the first test (indicating the need
for confirmation assays) is paramount.
Optimizing the clinical specificity of HPV testing while maintaining its sensitivity for detecting CIN3+ requires careful choices
about which HPV types are targeted and the threshold for a positive result. First, inclusion of common HPV types that cause CIN3
and more minor lesions but rarely if ever cause cancer (eg, HPV53
and HPV66) in an HPV test increases the number of false positives
but has little population benefit (84). As an analogous point, HC2
cross-reacts with some noncarcinogenic HPV types, which decreases its specificity (85). Second, the threshold for a positive test
should be chosen in clinical validation studies to maximize the
sensitivityspecificity trade-off for CIN3+ rather than for a less
severe diagnostic reference. Because CIN3 lesions are initially tiny
and difficult to detect visually, positive HPV tests that appear to be
false positive when judged against cytology or same-day colposcopic biopsy tend to predict elevated risk (true positive results)
of subsequent CIN3+ over the following decade or more (86).
Therefore, the diagnostic reference should be CIN3+ diagnosable
during the subsequent interval (at least until the next screening
L1
E1
BioRad
Autogenomics
Innogenetics
Roche
Multimetrix
Greiner
Abbott
Becton Dickinson
HR-HPV Dx PCR
Infinity HPV
InnoLiPA
Linear Array
Multiplex HPV
Genotyping Kit
Papillocheck
RT HPV
n/a
Aptima
NucliSENS
EasyQ HPV
OncoTect
L1
Not Commercialized
QIAGEN
Autogenomics
GP5+/6+ EIA
HC2
HPV QUAD
CE
n/a
n/a
CE
IVD Class I
CE
CE
CE
CE
CE
n/a
CE
n/a
CE
CE
n/a
CE
n/a
FDA/CE/sFDA
CE
CE
n/a
CE
CE
FDA/CE
CE
Regulatory approval(s)
HPV types 16, 18, 31, 33, and 45

HPV types 16, 18, and 45
Carcinogenic types, not specified
n/a
n/a
n/a
13 carcinogenic
13 carcinogenic and HPV66

HPV types 16, 18, 31, 33, and 45

13 carcinogenic and
13 noncarcinogenic
13 carcinogenic and
15 noncarcinogenic
13 carcinogenic and
24 noncarcinogenic
13 carcinogenic and
11 noncarcinogenic
13 carcinogenic and
11 noncarcinogenic
13 carcinogenic
13 carcinogenic and
22 noncarcinogenic
13 carcinogenic, HPV66,
and HPV82
13 carcinogenic
Target HPV genotypes
Yes
n/a
n/a
n/a
n/a
n/a
n/a
Partial (HPV16 and HPV18)

Partial (HPV types 16, 18, 31,
45, 51, 52, and 59)
No
Yes
Yes
Yes
Yes
Yes

Partial (HPV types 16,
18, and 45)
No
No
Partial (HPV types 16, 18, 31,
33, and 45)
No
Yes
No
No
Yes
HPV genotyping
In situ
hybridization
NASBA
Immunoassay
Immunostain
Immunostain
Immunostain
FISH
TMA
NASBA
Real-time PCR
Real-time PCR
PCR
PCR
PCR
PCR
PCR
PCR
PCR
Hybridization
PCR
Real-time PCR
Hybridization
PCR
Hybridization
Hybridization
PCR
Technology
Cross-hybridization with noncarcinogenic HPV types described.
E6/E7 mRNA
E6
L1
p16INK4a/Ki-67
MCM2/Top2A
3q/TERC
E6/E7 mRNA
Invirion/InCellDx
Norchip
Arbor Vitae
cytoimmun
mtm Laboratories
Becton Dickinson
ikonisys
E6/E7 mRNA
E6/E7 mRNA
GenProbe
BioMerieux
L1
n/a
L1
n/a
E1
L1
Full genome
E1
L1
Full genome
Roche
QIAGEN
COBAS 4800
eHC
L1
Full genome
L1
L1
Target molecule
Roche
QIAGEN
Hologic
Genomica
Manufacturer
Amplicor
careHPV
Cervista
CLART
Test name
PreTect Proofer
HPV protein E6 protein
cytoactiv
Cellular
CINtec plus
protein
ProExC
FISH
oncoFISH
HPV RNA
HPV DNA
Marker
Table 1.Human papillomavirus (HPV)based tests*
JNCI
* CE = Conformit Europenne (European conformity); FDA = Food and Drug Administration; FISH = fluorescence in situ hybridization; IVD = in vitro device; n/a = not available; NASBA = nucleic acid sequencebased
amplification; PCR = polymerase chain reaction; sFDA = State Food and Drug Administration (China); TMA = transcription-mediated amplification.
Review 375
cotesting at 1 year. Many acute infections resolve without treatment, but some cases of CIN3+ are likely missed, especially if
women do not return for testing. Therefore, other biomarkers
besides cytology would be desirable as a triage test to identify which
women need immediate colposcopic (diagnostic) evaluation.
predictive value) of CIN3+ among HPV-positive women, but their

risk remains substantial after a negative cytology triage result.
Therefore, at least in the United States; HPV-positive cytologynegative women require some kind of intensified follow-up before
resumption of routine screening.
Triage
Triage is similar to cotesting except that a second test is performed
in the laboratory only if the first (screening) test gives an equivocal
result. Cost and logistics (eg, the feasibility of women returning for
a triage visit) are the determinants of whether cotesting is superior
to triage.
HPV Screening With Triage by Novel Biomarkers. Although
Cytology With Triage by HPV Testing. In its first FDA-
HPV Screening With Triage by Cytology. Primary HPV testing
without cytology will be nearly as sensitive as cotesting; however,

too many women would be sent for colposcopy because of the
mediocre specificity of HPV testing. Triage of women who have a
positive HPV test with cytology is more economical than cotesting
all women with both tests. However, cytology is also an imperfect
second test for triaging HPV-positive women; an abnormal cytology finding (especially HSIL) further increases risk (positive
376Review
JNCI
Diagnosis of Screen-Positive Women

Colposcopy and Biopsy. Diagnosis and treatment are intrinsic to
any screening program. Therefore, any review of HPV testing

should consider what happens to women who screen positive,
whether by a single test, cotesting, or triage. Currently, the magnified colposcopy examination and biopsy result determine how
screen-positive women are managed and treated (eg, excision of
the entire transformation zone thought to contain a CIN3).
The current poor performance of colposcopic impression,
colposcopically-guided biopsy, and histological diagnosis (56)
limits the potential benefit of very sensitive screening tests (eg,
primary HPV or other molecular tests) (86,106). The typical current practice of targeting the most worrisome lesion on magnified
visual inspection misses more than one-third of prevalent small
HPV-positive CIN3 lesions (107).
Like cytology, colposcopy was developed in an era when detection and diagnosis of larger CIN3 lesions and even cancer were
paramount. In the United States and similar settings today, due to
high screening coverage and treatment, sensitivity for very small
CIN3 lesions, which constitute most disease that is now found, is
considered important. The shift to less severe disease challenges
the performance of colposcopy. For example, some data have demonstrated the poor reproducibility and inaccuracy of colposcopic
Vol. 103, Issue 5 | March 2, 2011
approved clinical use, HPV testing was demonstrated to be an

effective triage option for ASC-US cytology results (93,94), which
account for approximately 3 million cytological interpretations
per year in the United States. Risks of CIN3+ in women with
HPV-negative ASC-US (approximately 50% of all women with
ASC-US are HPV negative, depending on the pathologist) and
women with negative cytology are similar (95). Appropriately, in
the United States, the majority of ASC-US cytology interpretations are now triaged using HPV testing. Nonetheless, standard
practice following HPV negativity at triage is annual rescreening
rather than a complete return to 2-year routine screening intervals
(68). The heightened clinical attention given to HPV-negative
ASC-US, despite the low risk of CIN3+, is an example of the
difficulty of doing less once a more intensive management
strategy is established and has become routine for patients and
providers.
Less certain is the utility of using HPV testing for triage of
cytological interpretations other than ASC-US, such as LSIL,
atypical squamous cells, cannot exclude HSIL (ASC-H), atypical
glandular cells, and HSIL. Although most women with LSIL are
positive for carcinogenic HPV types, triage of women older than
45 or 50 years who have LSIL cytology with HPV testing may be
effective because a high percentage of older women will be reassured after a negative HPV test indicates very low risk (63,96). The
risk of CIN3+ in women with ASC-H cytology who are HPV
negative is elevated enough that triage by HPV testing is rarely
done (92,97). HPV test results for women with atypical glandular
cells cytology may not be useful for triage but may guide clinicians
to the anatomical sitecervix or endometriumwhere a problem
may exist: for postmenopausal women with atypical glandular cells
cytology, those who test HPV positive have exceptionally high
risks of prevalent cervical precancerous lesions and cancer, whereas
those who test HPV negative have a high risk of prevalent endometrial neoplasia (98).
novel biomarkers measuring the interaction of HPV with cervical

cells may one day become the basis of primary screening tests, they
will first be used to triage women with positive cytology and/or
HPV tests. Most of the biomarkers identified thus far are markers
of HPV-associated transformation, which occurs after HPV infection, and they are more prevalent in CIN3 than in acute infection.
Because they indicate infections that have already led to CIN3,
they cannot provide quite as long a period of risk stratification
(particularly negative predictive value) as does HPV DNA.
Currently developed biomarkers can be grouped as follows: 1)
markers of increased HPV oncogene expression, such as HPV
oncogene mRNA and protein; 2) markers of increased cell proliferation, such as Ki-67, MCM2, TOP2a, and p16; and 3) markers
of chromosomal instability, such as a gain of chromosome arm 3q
and HPV DNA integration (99101).
At present, the most promising candidate as a biomarker for
triage after a positive HPV test is immunocytochemical staining of
cytology slides for p16 (102105) (Table 1). p16 overexpression is
associated with the disruption of the retinoblastoma cell cycle
pathway by HPV E7 (102,103). A combined stain for p16 and
Ki-67 that was recently introduced into the diagnostics market can
highlight rare transformed cells (105). Because its sensitivity for
CIN3 is far higher than cytologys and almost equal to that of
HPV testing and its specificity is comparable to cytologys, this
stain could be used as a triage following primary HPV testing if it
proves reliable and the cost for routine use is low (105).
grading using grading systems, such as the Reid Index (106,108,109),

for distinguishing between acute HPV infection and CIN3.
Intercolposcopist agreement as to where a cervical biopsy
sample should be taken is also mediocre (86,106). Gains in sensitivity of colposcopically directed biopsy can be obtained by increasing the number of biopsy samples that are taken (107,110,111),
regardless of the experience of the colposcopist. Biopsies should
target acetowhite areas; the only visual diagnostic criterion with
sufficient sensitivity for prevalent precancer is acetowhitening, but
the specificity of this visual finding is very low (106). Thus, colposcopy protocols based on biopsy samples from many if not all distinct acetowhite lesions on the cervix may improve the sensitivity
of colposcopy and the accuracy of diagnosis of CIN3+. For example, the difference between finding CIN1 and normal histology, or between finding CIN2 and CIN3, in an HPV-positive
woman might be due to misclassifications reflecting the technical
limitations of colposcopy.
in a cervical screening program, a negative HPV test, in contrast

to negative cytology, provides substantial and sustained negative
predictive value. Under current clinical guidelines (69), women
who are referred to colposcopy for minor HPV-related abnormalities should have repeat HPV testing at 1 year or cytology every 6
months if the colposcopy visit yields no CIN2 or worse (CIN2+)
histological lesion. As we emphasize elsewhere in this review, however, frequent HPV testing provides little value: HPV testing at 6
months is too soon to judge viral persistence or to evaluate risk of
subsequent CIN3+. Adding cytology to HPV testing at 1 year adds
cost but not sensitivity (115).
Treatment
Usual Threshold for and Mode of Treatment. A willingness to
avoid even small risks of invasive cancer has led to low diagnostic
thresholds for treatment (ie, CIN2+ or even persistent CIN1)
(69,116). More sensitive screening tests and more aggressive colposcopy protocols will increase the detection of the smallest, earliest (CIN2 and) CIN3 lesions, which have the highest likelihood
of spontaneous regression. Screening programs that exploit the
extra sensitivity for CIN3+ conferred by HPV testing must still
minimize treatment of women that is unnecessary on both public
health and individual grounds.
In the United States, the predominant mode of treatment for
CIN2 or CIN3 is the excision of the transformation zone using a
wire loop cautery, commonly known as loop electrosurgical excision procedure (LEEP) or large loop excision of the transformation zone. This office-based procedure has two advantages: it can
be performed under local anesthesia and it produces a tissue specimen. The concern over the risk of premature delivery following
this treatment (117) motivates recent efforts to reduce overscreening and overtreatment, especially among young women. However,
the societal trade-offs that come from trying to prevent every case
of cervical cancer, vs the desire to prevent overtreatment of many
women, should and will be debated.
Use of HPV Testing to Monitor Success of Treatment. HPV
testing following treatment with LEEP can identify women who

remain at high risk of recurrence (118). Successful treatment of the
transformation zone often leads to HPV negativity in cervicovaginal specimens for the causative HPV type (119), although HPV
infects the vagina (and vulva and anogenital skin) and not just the
cervix. The reason for viral clearance even when the excision heals,
thus creating a new transformation zone, is not certain. Nonetheless,
negative HPV tests after LEEP predict a high probability of cure
(118). Thus, an HPV test can be used to replace cytology for this
clinical role with greater sensitivity and negative predictive value
(reassurance).
Key Elements of Optimal Cervical Cancer Prevention
Panel B of Figure 4 summarizes optimal cervical cancer prevention
from a public health perspective based on our current understanding of HPV natural history, multistage cervical carcinogenesis, and the performance of preventive technologies. Vaccinating
girls against the carcinogenic HPV types a few years before the
median age of first sexual intercourse in the population should
JNCI
Review 377
Histology. Histology provides the reference standard for cervical

disease. At present, histology is based on morphology and does not
consider HPV biomarkers. Advancing grades of CIN (grades 13)
are distinguished mainly according to the amount of vertical extension of abnormal cells in the cervical epithelium. Abnormal cells
restricted to the lower third are designated CIN1, abnormal cells
restricted to the lower two-thirds are designated CIN2, and fullthickness extension of abnormal cells are designated CIN3. This
division is arbitrary. Currently, a histologically confirmed CIN3
lesion is a clear indication for surgical treatment. Because diagnosed CIN2 is known to be a mixture of acute infections and
evolving CIN3, its management is more heterogeneous. For example, a woman in her early 20s with a CIN2 lesion might be
managed with close follow-up (69).
The lack of reproducibility of cervical histological classifications is
an important source of error and poor performance because the distinctions guide treatment. Even when excision and processing of the
entire cervical transformation zone removes possible error due to
location of the colposcopic biopsy sample, CIN1 and CIN2 diagnoses are difficult to distinguish, leading to high inter- and intra
observer variability (112114). CIN1 is a poorly reproducible,
morphological correlate of acute HPV infection. CIN2 is biologically
heterogeneous and includes both acute HPV infections and incipient
CIN3. Because vertical extension of abnormal cells in the cervical
epithelium, and not lesion size, is the primary criterion for morphological grading, small CIN3 lesions are combined with the larger
CIN3 lesions at higher risk of invasion for patient management.
As another aspect of the heterogeneity of histopathologic diagnoses, it is worth noting that the diagnoses are summarized to give
the worst finding found on the examination of all cervical tissue
from a woman. However, the cervix may harbor multiple lesions of
various grades and sizes at the same time (see Figure 1).
The accumulated evidence regarding cervical histopathology
suggests that CIN3 is the most reliable surrogate of cancer risk,
especially when accompanied by a description of lesion size
because large lesions are most likely to invade (38). Eventually, we
should aim to triage CIN2 lesions and to phase out the use of the
term CIN1 in favor of molecular rather than histopathologic evidence of acute HPV infection.
Use of HPV Testing During the Diagnostic Phase. At any stage
Longer-Term Uncertainties in the Transition

to HPV-Based Screening Technologies
In the first section of this review, we presented the science of HPV
and cervical carcinogenicity. In the second section, we outlined the
technical performance of each of the cervical cancer prevention
technologies. On the basis of these facts, we outlined the currently
optimal design of cervical cancer prevention programs from a
public health perspective. However, cervical cancer prevention is
also a social and political process. In this final section, we describe
the remaining uncertainties and barriers to the adoption of HPVbased screening technologies.
Integration of HPV Screening With HPV Vaccination
The thoughtful introductions of HPV screening and HPV vaccination require consideration of how they complement each other.
The two licensed HPV prophylactic vaccinesGardasil (Merck)
and Cervarix (GlaxoSmithKline)have very high and proven efficacy against new infection with HPV16 and HPV18 and the resultant CIN2 and CIN3 lesions (122,123). They also confer partial
protection against HPV31 (which is closely related to HPV16) and
HPV45 (which is closely related to HPV18). Within the next few
years, augmented prophylactic vaccines that prevent virtually all
carcinogenic types of HPV infection may be licensed. The proven
duration of protection of a three-dose regimen of HPV vaccination is now approaching a decade based on follow-up of vaccine
trial participants. Thus, vaccination of girls before the median age
of first sexual intercourse in the population would eliminate much
of the peak transmission of HPV. High population coverage with
an effective multivalent HPV vaccine will be the best primary preventive strategy against CIN2+, including cervical cancer.
378Review
JNCI
However, HPV vaccination will not help older women who are
beyond the age of vaccination or women who have an HPV infection present at vaccination (124).
Meanwhile, in a world of increasingly restricted health
resources, cervical screening must be reduced in HPV-vaccinated
populations to maximize net public health benefits. As HPV vaccination increases, carcinogenic HPV infections and their associated
CIN3+ lesions will become rarer, and almost all abnormal cytological results will be ASC-US or LSIL predicting only a low risk of
cancer (125,126). As a matter of public health policy, we do not
screen for rare diseases even in the United States. HPV vaccination
will further strengthen the argument for less frequent screening
than occurs in routine practice today and for accelerating the
switch from increasingly ambiguous cytology to HPV testing.
Moving From Clinical Algorithms to Risk-Based
Management
In the United States, clinical guidelines from professional medical
organizations provide recommendations for cervical cancer
screening, the management of women with an abnormal screening
test, and treatment (68,69). These recommendations are usually
developed through consensus meetings that review the evidence
and, when possible, develop evidence-based guidelines. Of note, in
the United States, cervical cancer screening is often viewed as a
clinicianpatient decision, not as a public program as it is in
some other countries. Clinicians and patients may view a particular
level of risk and cost differently from public health planners who
are faced with limited resources.
In any case, the introduction of new HPV tests with varying test
performances, new biomarkers, and the HPV vaccine will eventually make clinical algorithms regarding cervical screening and
management of screening abnormalities untenably complex
(95,127) and quickly out of date. Each round of revised algorithms
will need to account for past virological, cytological, and histological test histories (27,128), as well as the results of any novel tests
that emerge.
Compared with branching algorithms, a properly constructed
and validated risk assessment tool would be more powerful and
easier to update and use for clinical decision making, even for clinicianpatient discussions (95,127). The estimated risk of CIN3+
(eg, if colposcopy were performed that day, or in 1 year, or at a
3-year follow-up) is the relatively objective, quantifiable outcome
that scientists can provide as the basis for cost-effective clinical and
public health decisions.
Initially, such risk estimates will be most helpful to clinicians in
practice settings with good continuity of care and long-term medical records. Risk-based screening and management (at the clinical
or population level) would be dictated by the risk range or risk
band into which the risk estimate falls (Figure 7). These risk bands,
which would be defined by the lower and upper thresholds of each
band, would be established by professional medical societies that
have considered the evidence related to the benefits and potential
harms for each level of intervention. Risk estimates, updated with
most recent test results, would be the basis for choosing the appropriate step to take after the most recent set of tests: 1) when the
woman should next be screened; 2) whether a woman should be
referred immediately for a colposcopically directed biopsy; and
Vol. 103, Issue 5 | March 2, 2011
eliminate the peak of HPV transmission that leads, eventually, in

some women to CIN3 and, in even fewer women, to cancer. The
cost-effectiveness of HPV vaccination at older ages decreases substantially because these women are more often exposed and immune to carcinogenic HPV types, more often have a prevalent
infection that will not be affected by a vaccine, and are less likely
to be exposed to HPV subsequently (120). Because HPV exposure
decreases with increasing age and new HPV infections are no more
dangerous among older women than among young women, vaccination of older women with such an expensive vaccine is not the
best public health practice; the maximum age for which vaccination should be indicated is debatable and specific to different settings. In the absence of accurate HPV serology, there is no way to
know which women have been exposed to HPV or who remains
susceptible to HPV infection (121).
The successful introduction of HPV testing into screening
would require that such screening begin at ages 2530 years rather
than at 21 years, as is the current practice for cytology in the United
States, and that screening intervals among women who are found
to be HPV negative increase substantially. The HPV screening
interval for women after repeated negative screens could, and eventually should, extend beyond 3 years. Screening could be stopped
altogether among women with a proven repeated history of HPV
negativity who reach an age still to be determined mainly by societal expectations when their risk of cancer is sufficiently low.
3) the best follow-up management strategy after biopsy. Some

women at sufficiently high risk of CIN3+, for example, those with
an 80% or 90% risk, may warrant immediate LEEP.
Public Health Perspective
We believe that cervical cancer prevention, with its core components of vaccination and screening, is a public health activity, not
a clinical activity. We have emphasized a risk-based rather than an
algorithm-based perspective, relying on a current understanding of
HPV natural history and cervical carcinogenesis. Framing public
health interventions in terms of well-defined risks (with CIN3
serving as the main surrogate of invasive cancer) permits very
useful and focused comparative effectiveness research structured
around specific risk-based questions, such as What would be the
Prevention of Cervical Cancer in the United States

From a scientific and public health perspective, we conclude that
cervical screening intervals can be safely extended by incorporation
of HPV testing. However, such a change is not likely to happen
soon in the United States, where cancer prevention policies are
only partly dictated by evidence regarding optimal practice. It is
notable that current evidence-based guidelines for cervical cancer
screening and management are being widely ignored in the United
States (13). Each interest group with input into policy, including
various government agencies, has its own mandates and constraints. Much of screening practice is dictated by clinical groups;
in considering clinical recommendations, we should not ignore
that the economic threat to practicing gynecologists and cytopathologists inherent in reducing the amount of screening is real.
Also, it is essential for all to acknowledge, when advocating an
extension of screening intervals or other incremental improvements, that no prevention strategy is perfect. Demanding perfect
safety would doom the rational introduction of HPV technology.
Prevention of Cervical Cancer in Low-Resource Settings
In this review, we have focused on the incorporation of HPV
testing in wealthy countries like the United States. However, cervical cancer is associated with poverty even in rich countries (119),
and 90% of deaths from cervical cancer worldwide occur in developing countries (10,129). Despite its high-technology roots, HPV
testing will likely save far more lives in low-resource high-risk
populations where no preventive health-care structure is in place
(76) than in rich nations. The high sensitivity of HPV DNA
JNCI
Review 379
Figure 7.The use of risk bands to guide clinical decisions. Use of risk
estimates simplifies a complex battery of test results over time into a
single risk score on which management can be based. The probability
of diagnosis of cervical intraepithelial neoplasia grade or cervical cancer (CIN3+) is a reasonable metric that can be calculated based on data
from a prospective study. Importantly, various combinations of current
test results, past test results, and human papillomavirus (HPV) vaccination history should result in similar management of women who, in
fact, are at a similar risk of CIN3+. For example, the risk of CIN3+ for a
woman who cotests HPV positive with atypical squamous cells of undetermined significance (ASC-US) equals that of a woman with low-grade
squamous intraepithelial lesion (LSIL) by cytology; these women are
referred to colposcopy. The risk of CIN3+ for a woman who tests HPV
negative with ASC-US is similar to that for a woman who is HPV negative and has a normal cytology; these women should have follow-up
screenings at similar intervals. New technologies, once validated in a
clinical trial, would be integrated into the risk-based model, without the
need for new consensus conferences on management. This graph is
modified from Castle et al. (95). HSIL = high-grade squamous intraepithelial lesion.
change in programmatic effectiveness of shifting from cytology

every 2 years to cotesting every 5 years?
The public health perspective necessarily must consider costs
and cost-effectiveness of cervical cancer prevention strategies, not
just comparative effectiveness (ie, benefits and harms). For comparably effective benign interventions, the question is simple: Does
one approach cost less for the health care system? However, there
is usually a trade-off between cost and effectiveness, given the
multiple outcomeslives saved, morbidity, age at cancer incidence
or death, economic or family impact, iatrogenic adverse events
one might consider. This trade-off forces a consideration of the
societal value of preventing a cancer or cancer death. Because the
proportion of women in the general population who are truly at
high lifetime risk of cervical cancer is so low, a screening test must
incorporate triage or follow-up before treatment to achieve the
high specificity necessary for a high positive predictive value. In
other words, any cervical cancer screening program must weigh
the impact of false-negative screens (ie, cancer risks associated with
a missed CIN2 or CIN3 lesion) vs the impact of many more false
positives (ie, the harm of telling someone her result is abnormal,
with adverse effects possibly including treatments that may
increase the risk of subsequent premature delivery).
Determining the specific value of a single life is a social issue
beyond the scope of this scientific review. Clearly, however,
assigning an infinite value to a single life regardless of the financial
cost, if extended broadly as a policy, will undermine any public
healthoriented consideration of the opportunity for other public
health benefits from the same financial investment.
testing indicates that one or two screens in a lifetime, between

approximately age 30 years and menopause, would be sufficient to
make a major impact on mortality (130). Most women (80%90%)
will test HPV negative and gain reassurance for at least 10 years
that they are at low risk of cervical cancer; women who test HPV
positive will be immediately treated. An expanded discussion of
HPV testing for low-resource settings, including information on
the first low-cost HPV test, is presented as Supplementary
Material (available online).
Conclusions
References
1. Gustafsson L, Pontn J, Bergstrm R, Adami HO. International incidence
rates of invasive cervical cancer before cytological screening. Int J Cancer.
1997;71(2):159165.
2. Gustafsson L, Pontn J, Zack M, Adami HO. International incidence rates
of invasive cervical cancer after introduction of cytological screening.
Cancer Causes Control. 1997;8(5):755763.
3. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society
guideline for the early detection of cervical neoplasia and cancer. CA
Cancer J Clin. 2002;52(6):342362.
4. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S.
Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):
890907.
5. International Agency for Research on Cancer. Cervix Cancer Screening.
Lyon, France: IARC Press; 2005.
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Vol. 103, Issue 5 | March 2, 2011
This review of the introduction of HPV testing technology into

cervical cancer prevention in the United States is a microcosm of
the health-care reform debate. In terms of cost-effectiveness
(pending definitive analyses), we could likely improve cervical cancer prevention by replacing frequent cytology examinations with
HPV vaccination and HPV screening. However, the societal issues
involved in such a change, which would affect tens of millions of
women per year, will likely take decades to sort out; meanwhile,
lives may be lost (even in the United States), innumerable women
will be overtreated, and billions of dollars will be spent unnecessarily. Now that the sensitivity of HPV tests is beyond question,
waiting for results of randomized clinical trials of the various possible HPV screening and management protocols relative to cytology would risk postponing health benefits for many women.
Where practical, and following proper regulatory approvals, we
advocate implementation of HPV tests as the primary cervical
screening test in a well-controlled and evaluable fashion that will
allow the best strategies to be sorted out as HPV-based screening
(and vaccination) methods continue to improve [eg (81,131)]. As
we start to use HPV testing for the key function of screeningrisk
stratificationwhat we need most is to determine how best to 1)
make use of negative HPV tests to lengthen screening intervals
substantially and 2) manage women with positive HPV tests while
avoiding overtreatment.
To save the most lives, HPV testing should be adopted worldwide, especially in low-resource settings where the burden of cervical cancer is the greatest. Now that practical tests are available,
the most pressing need is for simple and inexpensive treatments for
HPV infections to permit optimal screen-and-treat programs in
the poorest places, where women are most threatened by invasive
cervical cancer.
6. Franceschi S, Cuzick J, Herrero R, Dillner J, Wheeler CM. EUROGIN

2008 roadmap on cervical cancer prevention. Int J Cancer. 2009;125(10):
22462255.
7. Scarinci IC, Garcia FA, Kobetz E, et al. Cervical cancer prevention: new
tools and old barriers. Cancer. 2010;116(11):25312542.
8. Qiao YL, Sellors JW, Eder PS, et al. A new HPV-DNA test for cervicalcancer screening in developing regions: a cross-sectional study of clinical
accuracy in rural China. Lancet Oncol. 2008;9(10):929936.
9. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation
between human papillomavirus and cervical cancer. J Clin Pathol. 2002;
55(4):244265.
10. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer
in 2008: GLOBOCAN 2008 [published online ahead of print June 17,
2010]. Int J Cancer. 2010.
11. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin.
2009;59(4):225249.
12. Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the
United States and the potential impact of implementation of screening
guidelines. CA Cancer J Clin. 2007;57(2):105111.
13. Saraiya M, Berkowitz Z, Yabroff KR, et al. Cervical cancer screening with
both human papillomavirus and Papanicolaou testing vs Papanicolaou
testing alone: what screening intervals are physicians recommending? Arch
Intern Med. 2010;170(11):977985.
14. Sasieni P, Castanon A, Cuzick J. Screening and adenocarcinoma of the
cervix. Int J Cancer. 2009;125(3):525529.
15. Doorbar J. Papillomavirus life cycle organization and biomarker selection.
Dis Markers. 2007;23(4):297313.
16. Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical
application. Nat Rev Cancer. 2002;2(5):342350.
17. Bernard HU, Burk RD, Chen Z, et al. Classification of papillomaviruses
(PVs) based on 189 PV types and proposal of taxonomic amendments.
Virology. 2010;401(1):7079.
18. Wentzensen N, Vinokurova S, Von Knebel Doeberitz M. Systematic
review of genomic integration sites of human papillomavirus genomes in
epithelial dysplasia and invasive cancer of the female lower genital tract.
Cancer Res. 2004;64(11):38783884.
19. Bouvard V, Baan R, Straif K, et al. A review of human carcinogenspart
B: biological agents. Lancet Oncol. 2009;10(4):321322.
20. Schiffman M, Herrero R, Desalle R, et al. The carcinogenicity of human
papillomavirus types reflects viral evolution. Virology. 2005;337(1):7684.
21. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer. 2009;4:8.
22. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human
papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer. 2011;128(4):927935.
23. Bosch FX, Burchell AN, Schiffman M, et al. Epidemiology and natural
history of human papillomavirus infections and type-specific implications
in cervical neoplasia. Vaccine. 2008;26(suppl 10):K1K16.
24. Parkin DM, Bray F. Chapter 2: the burden of HPV-related cancers.
Vaccine. 2006;24(suppl 3):S3/1125.
25. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in
head and neck cancers. J Clin Oncol. 2006;24(17):26062611.
26. Rodrguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human
papillomavirus and implications for clinical focus on persistent infections.
J Natl Cancer Inst. 2008;100(7):513517.
27. Rodriguez 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(5):315324.
28. 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 retrospective cohort study. Lancet Oncol. 2008;9(5):
425434.
29. Munoz N, Hernandez-Suarez G, Mendez F, et al. Persistence of HPV
infection and risk of high-grade cervical intraepithelial neoplasia in a
cohort of Colombian women. Br J Cancer. 2009;100(7):11841190.
human papillomavirus (HPV). Cancer Epidemiol Biomarkers Prev. 2001;

10(10):10211027.
51. Safaeian M, Quint K, Schiffman M, et al. Chlamydia trachomatis and Risk
of Prevalent and Incident Cervical Premalignancy in a Population-Based
Cohort. J Natl Cancer Inst. 2010;102(23):17941804.
52. Hildesheim A, Wang SS. Host and viral genetics and risk of cervical cancer: a review. Virus Res. 2002;89(2):229240.
53. Palefsky J. Human papillomavirus-related disease in people with HIV.
Curr Opin HIV AIDS. 2009;4(1):5256.
54. Garca-Pieres AJ, Hildesheim A, Herrero R, et al. Persistent human
papillomavirus infection is associated with a generalized decrease in
immune responsiveness in older women. Cancer Res. 2006;66(22):
1107011076.
55. Smith JS, Melendy A, Rana RK, Pimenta JM. Age-specific prevalence of
infection with human papillomavirus in females: a global review. J Adolesc
Health. 2008;43(4 suppl):S5S25. S25 e141.
56. Altekruse SF, Kosary CE, Krapcho M, et al. SEER Cancer Statistics Review,
19752007. Bethesda, MD: National Cancer Institute. http://seer.cancer.
gov/csr/1975_2007/, based on November 2009 SEER data submission,
posted to the SEER Web site, 2010.
57. Franceschi S, Herrero R, Clifford GM, et al. Variations in the age-specific
curves of human papillomavirus prevalence in women worldwide. Int
J Cancer. 2006;119(11):26772684.
58. Kjaer SK, Teisen C, Haugaard BJ, et al. Risk factors for cervical cancer in
Greenland and Denmark: a population-based cross-sectional study. Int
J Cancer. 1989;44(1):4047.
59. Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of typespecific human papillomavirus infection and cervical neoplasia in
Guanacaste, Costa Rica. J Infect Dis. 2005;191(11):17961807.
60. Solomon D, Nayar R. The Bethesda System for Reporting Cervical Cytology.
2nd ed. New York, NY: Springer-Verlag; 2004.
61. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type
distribution in invasive cervical cancer and high-grade cervical lesions: a
meta-analysis update. Int J Cancer. 2007;121(3):621632.
62. Clifford GM, Rana RK, Franceschi S, et al. Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic
region and with cervical cancer. Cancer Epidemiol Biomarkers Prev.
2005;14(5):11571164.
63. The Atypical Squamous Cells of Undetermined Significance/Low-Grade
Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human
papillomavirus testing for triage of women with cytologic evidence of lowgrade squamous intraepithelial lesions: baseline data from a randomized
trial. The Atypical Squamous Cells of Undetermined Significance/LowGrade Squamous Intraepithelial Lesions Triage Study (ALTS) Group.
J Natl Cancer Inst. 2000;92(5):397402.
64. Kinney WK, Manos MM, Hurley LB, Ransley JE. Wheres the highgrade cervical neoplasia? The importance of minimally abnormal
Papanicolaou diagnoses. Obstet Gynecol. 1998;91(6):973976.
65. Hutchinson ML, Zahniser DJ, Sherman ME, et al. Utility of liquid-based
cytology for cervical carcinoma screening: results of a population-based
study conducted in a region of Costa Rica with a high incidence of cervical
carcinoma. Cancer. 1999;87(2):4855.
66. Kitchener HC, Almonte M, Thomson C, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC):
a randomised controlled trial. Lancet Oncol. 2009;10(7):672682.
67. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou
test in screening for and follow-up of cervical cytologic abnormalities: a
systematic review. Ann Intern Med. 2000;132(10):810819.
68. Wright TCJr., Massad LS, Dunton CJ, et al. 2006 consensus guidelines
for the management of women with abnormal cervical cancer screening
tests. Am J Obstet Gynecol. 2007;197(4):346355.
69. Wright TCJr., Massad LS, Dunton CJ, et al. 2006 consensus guidelines
for the management of women with cervical intraepithelial neoplasia or
adenocarcinoma in situ. Am J Obstet Gynecol. 2007;197(4):340345.
70. Siebers AG, Klinkhamer PJ, Grefte JM, et al. Comparison of liquidbased cytology with conventional cytology for detection of cervical cancer
precursors: a randomized controlled trial. JAMA. 2009;302(16):
17571764.
JNCI
Review 381
30. Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM.

A 2-year prospective study of human papillomavirus persistence among
women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect
Dis. 2007;195(11):15821589.
31. Kovacic MB, Castle PE, Herrero R, et al. Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality.
Cancer Res. 2006;66(20):1011210119.
32. Schiffman M, Wheeler CM, Castle PE. Human papillomavirus DNA
remains detectable longer than related cervical cytologic abnormalities.
J Infect Dis. 2002;186(8):11691172.
33. Stanley M. Immune responses to human papillomavirus. Vaccine. 2006;
24(suppl 1):S16S22.
34. Gonzalez PA, Heildesheim A, Rodriguez AC, et al. Behavioral/lifestyle
and immunological factors associated with HPV infection among women
older than 45 years of age. Cancer Epidemiol Biomarkers Prev. 2010;19(12):
30443054.
35. Castle PE, Solomon D, Schiffman M, Wheeler CM. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in
women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst.
2005;97(14):10661071.
36. Trottier H, Mahmud SM, Lindsay L, et al. Persistence of an incident human
papillomavirus infection and timing of cervical lesions in previously unexposed young women. Cancer Epidemiol Biomarkers Prev. 2009;18(3):854862.
37. Schlecht NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA.
2001;286(24):31063114.
38. Schiffman M, Rodriguez AC. Heterogeneity in CIN3 diagnosis. Lancet
Oncol. 2008;9(5):404406.
39. Wheeler CM, Hunt WC, Joste NE, et al. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the
United States. J Natl Cancer Inst. 2009;101(7):475487.
40. Burchell AN, Winer RL, de Sanjos S, Franco EL. Chapter 6: epidemiology and transmission dynamics of genital HPV infection. Vaccine.
2006;24(suppl 3):S3/5261.
41. Winer RL, Feng Q, Hughes JP, et al. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis. 2008;
197(2):279282.
42. Barnabas RV, Laukkanen P, Koskela P, et al. Epidemiology of HPV 16
and cervical cancer in Finland and the potential impact of vaccination:
mathematical modelling analyses. PLoS Med. 2006;3(5):e138.
43. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical
review. Int J Gynecol Pathol. 1993;12(2):186192.
44. Nasiell K, Roger V, Nasiell M. Behavior of mild cervical dysplasia during
long-term follow-up. Obstet Gynecol. 1986;67(5):665669.
45. Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. Am J Obstet Gynecol. 1969;105(3):386393.
46. Cervical carcinoma and sexual behavior: collaborative reanalysis of individual data on 15,461 women with cervical carcinoma and 29,164 women
without cervical carcinoma from 21 epidemiological studies. Cancer
Epidemiol Biomarkers Prev. 2009;18(4):10601069.
47. Appleby P, Beral V, Berrington de Gonzalez A, et al. Cervical cancer and
hormonal contraceptives: collaborative reanalysis of individual data
for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet. 2007;370(9599):
16091621.
48. Appleby P, Beral V, Berrington de Gonzalez A, et al. Carcinoma of the
cervix and tobacco 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(6):14811495.
49. International Collaboration of Epidemiological Studies of Cervical
Cancer. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and
33,542 women without cervical carcinoma from 25 epidemiological
studies. Int J Cancer. 2006;119(5):11081124.
50. Castle PE, Hillier SL, Rabe LK, et al. An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic
382Review
JNCI
of undetermined significance. Am J Obstet Gynecol. 2003;188(6):

13831392.
94. Arbyn M, Buntinx F, van Ranst M, et al. Virologic versus cytologic triage
of women with equivocal pap smears: a meta-analysis of the accuracy to
detect high-grade intraepithelial neoplasia. J Natl Cancer Inst. 2004;
96(4):280293.
95. Castle PE, Sideri M, Jeronimo J, Solomon D, Schiffman M. Risk assessment to guide the prevention of cervical cancer. Am J Obstet Gynecol.
2007;197(4):356 e1e6.
96. Ronco G, Cuzick J, Segnan N, et al. HPV triage for low grade (L-SIL)
cytology is appropriate for women over 35 in mass cervical cancer
screening using liquid based cytology. Eur J Cancer. 2007;43(3):476480.
97. Sherman ME, Castle PE, Solomon D. Cervical cytology of atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion
(ASC-H): characteristics and histologic outcomes. Cancer. 2006;108(5):
298305.
98. Castle PE, Fetterman B, Poitras N, et al. Relationship of atypical glandular cell cytology, age, and human papillomavirus detection to cervical and
endometrial cancer risks. Obstet Gynecol. 2010;115(2, pt 1):243248.
99. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV-mediated
cervical carcinogenesis: concepts and clinical implications. J Pathol.
2006;208(2):152164.
100. Wentzensen N, von Knebel Doeberitz M. Biomarkers in cervical cancer
screening. Dis Markers. 2007;23(4):315330.
101. Cuschieri K, Wentzensen N. Human papillomavirus mRNA and p16
detection as biomarkers for the improved diagnosis of cervical neoplasia.
Cancer Epidemiol Biomarkers Prev. 2008;17(10):25362545.
102. Wentzensen N, Bergeron C, Cas F, Vinokurova S, von Knebel Doeberitz
M. Triage of women with ASCUS and LSIL cytology: use of qualitative
assessment of p16INK4a positive cells to identify patients with high-grade
cervical intraepithelial neoplasia. Cancer. 2007;111(1):5866.
103. Tsoumpou I, Arbyn M, Kyrgiou M, et al. p16(INK4a) immunostaining in
cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2009;35(3):210220.
104. Carozzi F, Confortini M, Dalla Palma P, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a
nested substudy of the NTCC randomised controlled trial. Lancet Oncol.
2008;9(10):937945.
105. Denton KJ, Bergeron C, Klement P, et al. The sensitivity and specificity
of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical
disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin
Pathol. 2010;134(1):1221.
106. Massad LS, Jeronimo J, Katki HA, Schiffman M. The accuracy of
colposcopic grading for detection of high-grade cervical intraepithelial
neoplasia. J Low Genit Tract Dis. 2009;13(3):137144.
107. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and
sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264272.
108. Jeronimo J, Massad LS, Schiffman M. Visual appearance of the uterine
cervix: correlation with human papillomavirus detection and type. Am
J Obstet Gynecol. 2007;197(1):47.e1e8.
109. Massad LS, Jeronimo J, Schiffman M. Interobserver agreement in the assessment of components of colposcopic grading. Obstet Gynecol. 2008;
111(6):12791284.
110. Pretorius RG, Bao YP, Belinson JL, et al. Inappropriate gold standard
bias in cervical cancer screening studies. Int J Cancer. 2007;121(10):
22182224.
111. Stoler MH, Vichnin MD, Ferenczy A, et al. The accuracy of colposcopic
biopsy: analyses from the placebo arm of the gardasil clinical trials [published online ahead of print May 20, 2010]. Int J Cancer. 2010.
112. Carreon JD, Sherman ME, Guillen D, et al. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological
review of population-based cervical samples. Int J Gynecol Pathol. 2007;
26(4):441446.
113. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUSLSIL Triage Study. JAMA. 2001;285(11):15001505.
114. Dalla Palma P, Giorgi Rossi P, Collina G, et al. The reproducibility of
CIN diagnoses among different pathologists: data from histology reviews
Vol. 103, Issue 5 | March 2, 2011
71. Ronco G, Cuzick J, Pierotti P, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer
screening: randomised controlled trial. BMJ. 2007;335(7609):2831.
72. Ronco G, Giorgi-Rossi P, Carozzi F, et al. Efficacy of human papillomavirus
testing for the detection of invasive cervical cancers and cervical intraepithelial
neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11(3):249257.
73. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl
J Med. 2007;357(16):15791588.
74. Bulk S, Bulkmans NW, Berkhof J, et al. Risk of high-grade cervical
intra-epithelial neoplasia based on cytology and high-risk HPV testing at
baseline and at 6-months. Int J Cancer. 2007;121(2):361367.
75. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and
Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;
357(16):15891597.
76. Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for
cervical cancer in rural India. N Engl J Med. 2009;360(14):13851394.
77. 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 follow-up of a randomised controlled implementation
trial. Lancet. 2007;370(9601):17641772.
78. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer 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(14):10721079.
79. Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of
cytology and human papillomavirus testing in cervical cancer screening:
joint European cohort study. BMJ. 2008;337:a1754.
80. Waxman AG. Cervical cancer screening in the early post vaccine era.
Obstet Gynecol Clin North Am. 2008;35(4):537548; vii.
81. Naucler P, Ryd W, Tornberg S, et al. Efficacy of HPV DNA testing with
cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009;101(2):8899.
82. Cuzick J, Arbyn M, Sankaranarayanan R, et al. Overview of human
papillomavirus-based and other novel options for cervical cancer screening
in developed and developing countries. Vaccine. 2008;26(suppl 10):K29K41.
83. Gravitt PE, Coutlee F, Iftner T, et al. New technologies in cervical cancer
screening. Vaccine. 2008;26(suppl 10):K42K52.
84. Schiffman M, Khan MJ, Solomon D, et al. A study of the impact of adding
HPV types to cervical cancer screening and triage test. J Natl Cancer Inst.
2005;97(2):147150.
85. Castle PE, Solomon D, Wheeler CM, et al. Human papillomavirus genotype
specificity of hybrid capture 2. J Clin Microbiol. 2008;46(8):25952604.
86. Jeronimo J, Schiffman M. Colposcopy at a crossroads. Am J Obstet Gynecol.
2006;195(2):349353.
87. Gravitt PE, Schiffman M, Solomon D, Wheeler CM, Castle PE. A comparison of linear array and hybrid capture 2 for detection of carcinogenic
human papillomavirus and cervical precancer in ASCUS-LSIL triage
study. Cancer Epidemiol Biomarkers Prev. 2008;17(5):12481254.
88. Lorincz AT, Castle PE, Sherman ME, et al. Viral load of human
papillomavirus and risk of CIN3 or cervical cancer. Lancet. 2002;360(9328):
228229.
89. Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and
the next generation of HPV DNA tests. Am J Clin Pathol. 2010;134(2):
193199.
90. Gravitt PE, Kovacic MB, Herrero R, et al. High load for most high risk
human papillomavirus genotypes is associated with prevalent cervical
cancer precursors but only HPV16 load predicts the development of incident disease. Int J Cancer. 2007;121(12):27872793.
91. Hesselink AT, Berkhof J, Heideman DA, et al. High-risk human papillomavirus DNA load in a population-based cervical screening cohort in relation to the detection of high-grade cervical intraepithelial neoplasia and
cervical cancer. Int J Cancer. 2009;124(2):381386.
92. Castle PE, Fetterman B, Thomas Cox J, et al. The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the
risk of cervical precancer and cancer. Obstet Gynecol. 2010;116(1):7684.
93. ASCUS-LSIL Traige Study (ALTS) Group. Results of a randomized trial
on the management of cytology interpretations of atypical squamous cells
126. Schiffman M. Integration of human papillomavirus vaccination, cytology,

and human papillomavirus testing. Cancer. 2007;111(3):145153.
127. Katki HA, Wacholder S, Solomon D, Castle PE, Schiffman M. Risk estimation for the next generation of prevention programmes for cervical
cancer. Lancet Oncol. 2009;10(11):10221023.
128. Castle PE, Rodriguez AC, Burk RD, et al. Short term persistence of
human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ. 2009;339:b2569.
129. Clegg LX, Reichman ME, Miller BA, et al. Impact of socioeconomic
status on cancer incidence and stage at diagnosis: selected findings from
the surveillance, epidemiology, and end results: National Longitudinal
Mortality Study. Cancer Causes Control. 2009;20(4):417435.
130. Kim JJ, Brisson M, Edmunds WJ, Goldie SJ. Modeling cervical cancer
prevention in developed countries. Vaccine. 2008;26(suppl. 10):K76K86.
131. Ogilvie GS, van Niekerk DJ, Krajden M, et al. A randomized controlled
trial of human papillomavirus (HPV) testing for cervical cancer screening:
trial design and preliminary results (HPV FOCAL Trial). BMC Cancer.
2010;10:111.
Funding
This work was supported in part by the Intramural Research Program of the
National Cancer Institute.
Notes
Drs Schiffman and Wacholder participate in the Costa Rican HPV Vaccine
Trial, a long-standing collaboration between investigators in Costa Rica and
the National Cancer Institute (NCI). The trial is sponsored and funded by the
NCI (grant N01-CP-11005), with funding support from the National Institutes
of Health Office for Research on Womens Health, and conducted with support from the Ministry of Health of Costa Rica. Vaccine was provided for the
trial by GSK Biologicals, under a Clinical Trials Agreement with the NCI.
GlaxoSmithKline also provided support for aspects of the trial associated with
regulatory submission needs of the company. GSK had no role in this review.
Dr Castle has a formal agreement with Roche Diagnostics to help analyze its
Food and Drug Administration clinical trial data, without compensation. The
funding source has not dictated the comment of this review.
Affiliations of authors: Division of Cancer Epidemiology and Genetics,
National Cancer Institute, Bethesda, MD (MS, NW, SW, JCG, PEC); Division
of Gynecologic Oncology, Kaiser Permanente Medical Care Program,
Oakland, CA (WK); American Society for Clinical Pathology, Washington, DC
(PEC).
JNCI
Review 383
from a multicenter randomized study. Am J Clin Pathol. 2009;132(1):

125132.
115. Guido R, Schiffman M, Solomon D, Burke L. Postcolposcopy management
strategies for women referred with low-grade squamous intraepithelial
lesions or human papillomavirus DNA-positive atypical squamous cells of
undetermined significance: a two-year prospective study. Am J Obstet
Gynecol. 2003;188(6):14011405.
116. Kyrgiou M, Tsoumpou I, Vrekoussis T, et al. The up-to-date evidence on
colposcopy practice and treatment of cervical intraepithelial neoplasia:
the Cochrane colposcopy and cervical cytopathology collaborative group
(C5 group) approach. Cancer Treat Rev. 2006;32(7):516523.
117. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. Obstetric outcomes
after conservative treatment for intraepithelial or early invasive cervical
lesions: systematic review and meta-analysis. Lancet. 2006;367(9509):
489498.
118. Kreimer AR, Guido RS, Solomon D, et al. Human papillomavirus testing
following loop electrosurgical excision procedure identifies women at risk
for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease.
Cancer Epidemiol Biomarkers Prev. 2006;15(5):908914.
119. Kreimer AR, Katki HA, Schiffman M, et al. Viral determinants of human
papillomavirus persistence following loop electrical excision procedure
treatment for cervical intraepithelial neoplasia grade 2 or 3. Cancer
Epidemiol Biomarkers Prev. 2007;16(1):1116.
120. Kim JJ, Ortendahl J, Goldie SJ. Cost-effectiveness of human papillomavirus vaccination and cervical cancer screening in women older than 30
years in the United States. Ann Intern Med. 2009;151(8):538545.
121. Schiffman M, Safaeian M, Wentzensen N. The use of human papillomavirus seroepidemiology to inform vaccine policy. Sex Transm Dis.
2009;36(11):675679.
122. Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued
prophylactic efficacy of quadrivalent human papillomavirus (Types
6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila). 2009;2(10):868878.
123. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus
(HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a
double-blind, randomised study in young women. Lancet. 2009;374(9686):
301314.
124. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;298(7):743753.
125. Franco EL, Mahmud SM, Tota J, Ferenczy A, Coutlee F. The expected
impact of HPV vaccination on the accuracy of cervical cancer screening:
the need for a paradigm change. Arch Med Res. 2009;40(6):478485.

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DOI: 10.

Published by Oxford University Press 2011.

Human Papillomavirus Testing in the Prevention of Cervical

J Natl Cancer Inst 2011;103:368383

Cervical cytology (Papanicolaou test) screening programs have

HPV Natural History and Cervical

annual rate of invasive cases of cervical cancer in the United States

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Figure 1.The cervical transformation zone and

Time Course of HPV Infection and Cervical Carcinogenesis

The Natural History of an Individual Carcinogenic HPV

long process that begins with an infection with a carcinogenic

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small for cytological and colposcopic diagnosis. The CIN3 lesions

Figure 3.Risks of human papillomavirus (HPV)

Vol. 103, Issue 5 | March 2, 2011

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Figure 2. The evolution of human papillomavirus (HPV) types predicts

We do know that CIN3 lesions typically grow slowly over

Figure 4. Cervical cancer progression model

Organization (P. E. Castle, personal communication) and the data on

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great majority of sexually active women and men have been

Use of HPV Testing in Cervical Cancer

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tested (when the infections might already be persistent), are at

possibly high risk) or new (low risk), especially among older

Figure 6.Negative impact of testing for HPV too frequently. We plot

less effective in detecting prevalent disease if performed too soon.

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visit) and not just cases detectable by colposcopy at the time of

ence with HPV testing in primary cervical screening: the KPNC

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cytology screening intervals of every 2 years and suggests that the

HPV types 16, 18, 31, 33, and 45

13 carcinogenic and HPV66

13 carcinogenic and HPV66

Target HPV genotypes

Partial (HPV16 and HPV18)

Partial (HPV16 and HPV18)

Cross-hybridization with noncarcinogenic HPV types described.

Table 1.Human papillomavirus (HPV)based tests*

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predictive value) of CIN3+ among HPV-positive women, but their

HPV Screening With Triage by Novel Biomarkers. Although

Cytology With Triage by HPV Testing. In its first FDA-

HPV Screening With Triage by Cytology. Primary HPV testing

without cytology will be nearly as sensitive as cotesting; however,

Diagnosis of Screen-Positive Women

any screening program. Therefore, any review of HPV testing

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approved clinical use, HPV testing was demonstrated to be an

novel biomarkers measuring the interaction of HPV with cervical

grading using grading systems, such as the Reid Index (106,108,109),

in a cervical screening program, a negative HPV test, in contrast

testing following treatment with LEEP can identify women who

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Histology. Histology provides the reference standard for cervical

Use of HPV Testing During the Diagnostic Phase. At any stage

Longer-Term Uncertainties in the Transition

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eliminate the peak of HPV transmission that leads, eventually, in

3) the best follow-up management strategy after biopsy. Some

Prevention of Cervical Cancer in the United States