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Screening for cervical cancer - UpToDate

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Screening for cervical cancer
Authors: Sarah Feldman, MD, MPH, Annekathryn Goodman, MD, MPH, Jeffrey F Peipert, MD, PhD Section Editors: Barbara Goff, MD, Joann G
Elmore, MD, MPH
Deputy Editor: Judith A Melin, MA, MD, FACP

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2019. |This
topic last updated: Feb 05, 2019.

INTRODUCTION

Cervical cancer is common among women worldwide. Most cases occur in developing countries [1]. In developed
countries, the decreases in cervical cancer incidence and mortality rates are related to the availability of screening and
to human papillomavirus (HPV) vaccination programs.

Screening can detect precursors and early-stage disease for both types of cervical cancer: squamous cell carcinoma
and adenocarcinoma. Treatment of precursors and early-stage disease can prevent the development of invasive
cervical cancer and reduce cervical cancer mortality.

Cervical cancer screening began with the development of the Papanicolaou (Pap) test. In countries that adopted Pap
test screening, the incidence and mortality of cervical cancer have decreased. In addition to the Pap test, screening
methods now include tests for high-risk strains of HPV, which are central to the pathogenesis of cervical cancer. Infection with
high-risk strains of HPV and persistence of HPV infection are the most important determinants of progression to cervical
cancer [2-6].

Recommendations for screening, as well as specific screening strategies, balance the benefits from early detection of
treatable lesions and reduction in incidence and mortality of cervical cancer with potential risks for false positives,
unnecessary procedures, and other harms. Potential benefits and risks vary with age, medical history, and risk factors.

There is debate about whom to screen, which testing methods are preferable (Pap test, HPV testing, or both), and how
often to screen.

This topic will discuss screening in developed countries, including appropriate ages to initiate and discontinue
screening, frequency of screening, and screening methods. Screening in resource-limited setting is described in detail
separately. (See "Screening for cervical cancer in resource-limited settings".)

Techniques for performing screening tests, interpreting tests, screening women who are HIV-positive, and
information about invasive cervical cancer are discussed in detail separately.

* (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)
*(See"Cervandivcagianallcytology:Interpretation ofresults(Paptestreport)".)
° (See "Screening for cervical cancer in HIV-inf women an | nts".)
* (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

SCREENING AVERAGE-RISK WOMEN

The age to initiate screening and the frequency of screening may vary depending on a patient’s screening history and
whether or not a patient is immunosuppressed.

Screening recommendations for women who are at average risk for cervical cancer apply to women who are
asymptomatic, immunocompetent, and had adequate screening starting at age 21 years with results that were al
normal.

However, women at higher risk due to a history of prior abnormal screening results or immunosuppression may need
more frequent testing, based on their prior results and treatment. (See ‘Screening in higher-risk women’ below and
‘Screening in other populations’ below.)

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Age less than 21 years — We suggest not screening asymptomatic immunocompetent women younger than age 21
years, regardless of the age of initiation of sexual activity.

Observational studies suggest that the potential harms outweigh the potential benefits in this age group, due to their
low incidence of cervical cancer [7]. The age-adjusted incidence of cervical cancer in women ages 15 to 19 years in
the United States is 0.1 per 100,000 (figur1e) [8]. Adolescents are also more likely to spontaneously clear human
papillomavirus (HPV) infection and associated abnormalities. While rates of atypical squamous cells of undetermined
significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) are consistently higher in adolescent
women than in adults, 90 to 95 percent of low-grade lesions in adolescent women, as well as many high-grade
lesions, regress spontaneously [9-13].

Age 21 to less than 30 years — We recommend cervical cancer screening in asymptomatic women age 21 years and
older. We suggest initiating screening at age 21 for women who are immunocompetent, regardless of the age of
initiation of sexual activity [14].

Guidelines in the United States recommend initiating screening at age 21 years (table 1) [6,15,16]. Other countries
may initiate screening at different ages (usually between 20 and 25 years) [17]. International guidelines vary.

Women should be screened even ifthey report sexual abstinence. Women may havea variety of reasons for not
disclosing prior sexual activity, including social, religious, or cultural norms or expectations regarding modesty,
virginity, and shame as well as reluctance to acknowledge prior sexual abuse or rape [18]. Women who have been
sexually abused or raped are often reluctant to acknowledge this history, and abuse may underlie the decision to
abstain and not engage in subsequent sexual activity. Furthermore, HPV can be transmitted in skin-to-skin genital
touching, which patients may not consider as sexual activity.

In women age 21 to <30 years with a normal immune system and prior results (if any) that are al normal:

* We suggest screening with Papanicolaou (Pap) testing. Some clinicians do Pap testing alone, whereas others do a
Pap test with reflex to HPV testing. Ifthe Pap test is negative, screening should be repeated at intervals of every three
years.

° We suggest not screening women <30 years with primary HPV testing or co-testing [14]. Each of these screening
strategies is described in detail below. (See 'Screening _strategies' below.)

Infection with HPV may be transient and cervical dysplasia may regress spontaneously, particularly in young women;
thus, the poor specificity and correspondingly poor positive predictive value of HPV testing limit its usefulness as a
screening modality in this age group [16]. Therefore, primary HPV testing is generally not used for screening under
age 25 years, and in United States guidelines it is not suggested until age 30 years. Randomized trials have
demonstrated that primary HPV testing in women <30 years of age results in substantial detection of transient HPV
infections and unnecessary colposcopies [19-21].

Guidelines in the United States recommend various screening strategies for women <30 years (table 1) [6,15,16].
International guidelines vary. World Health Organization (WHO) guidelines for screening for cervical cancer
prevention are available.

Age 30 years or older — We recommend ongoing cervical cancer screening in asymptomatic women in this age
group. Women who report sexual abstinence also require screening as discussed above.

There are several appropriate screening strategies for average-risk women age 230 years who are immunocompetent.
We suggest screening these women with one of the following strategies:

* Co-testing (Pap test and HPV testing) every five years; or ° Primary HPV testing every five years; or
° Pap test with reflex HPV testing every three years; or
* Pap test alone every three years

These strategies (specific testing and frequency) are described in detail below. (See 'Screening_strategies' below.)

The indicated frequency is for patients with normal results. Patients with abnormal, unsatisfactory, or satisfactory but
limited findings require further follow-up. (See ‘Follow-up results that are not normal’ below.)

There are not high-quality data that indicate that one screening strategy is clearly superior to another with regard to
clinical outcomes. HPV infection is more likely to be persistent in women 230 years than in younger women and hasa
greater likelihood of clinical significance than in younger age groups [22]. However, in this age group, it remains
important to consider both the higher

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rate of detection of cervical disease with HPV testing (alone or with Pap testing) compared with Pap testing alone as
well as the increase in false positives and in colposcopies associated with HPV testing. These are discussed in detail
below. (See 'Benefits and harms of screening’ below.)
The US Preventive Services Task Force (USPSTF) 2018 recommendations added primary HPV testing to Pap testing
alone or co- testing as another screening strategy for women aged 30 to 65 years and concluded that for primary HPV
testing alone, an interval of five years offers the best balance of benefits and harms [23]. Recommendations from
guideline-issuing organizations in the United States and specialty societies around the world vary and are summarized
in the table (table 1) and in the Society Guideline Links section [6,15,16,23-25]. (See "Society guideline links:
Cervical cancer screening and prevention".)

WHEN TO DISCONTINUE SCREENING

The decision to discontinue screening depends on the patient’s prior results, life expectancy, and preferences in a
shared decision- making discussion.

If adequate prior screening — Discontinuing screening is predicated upon having adequate prior screening and
having no previouslyabnormalresultsorimmunosuppression.
(See'Continuingsurveillanceafterprecaonrccaencrerbelowand!Other higher-risk patients’ below.)

* For women with adequate prior screening with normal results and a life expectancy >10 years, the optimal age to
discontinue screening isuncertain.

* For women who have adequate prior screening and no factors that warrant extended screening, we screen through
age 65 years. While data are limited and potential harms of screening need to be considered (eg, false positives),
some clinicians continue to offer screening through age 74 years.

Adequate prior screening takes into account the number and timing of consecutive screening tests done in the past 10
years and the results of those tests. To meet these criteria, Papanicolaou (Pap) tests must be negative (ie, not
abnormal, positive, unsatisfactory, or satisfactory but limited).

We consider adequate prior screening to be [15]:

* Two consecutive negative co-tests (Pap tests with human papillomavirus [HPV] testing) within the past 10 years,
with the most recent test within the previous five years; or

* Three consecutive negative Pap tests within the past 10 years, with the most recent test within the previous three
years; or * Two consecutive negative primary HPV tests within the past 10 years, with the most recent test within the
previous five years

Ifthe results of screening within the prior 10 years are not known, then prior screening is not considered adequate.

A patient with a history of high-grade cervical dysplasia (cervical intraepithelial neoplasia [CIN] 2/3 or
adenocarcinoma in situ [AIS]), cervical cancer, precancer or cancer of the vagina or vulva, or anal intraepithelial
neoplasia (AIN) should continue screening according to recommendations for surveillance after these precancerous or
cancerous findings. (See ‘Continuing surveillance after

recancer or cancer’below.)

In the United States, guideline-issuing organizations recommend discontinuing screening after age 65 for women who
are up to date on testing with normal results (table 1). However, guidelines from some countries use an older age at
which to stop screening. For example, in Australia, which has the lowest cervical cancer mortality rate in the world,
guidelines advise discontinuing screening after age 74 years [26]. The decision to discontinue screening should also
consider the patient's preferences in a shared decision- making discussion.

Data about stopping age for cervical cancer screening are limited. A 2013 systematic review of 24 studies found no
conclusive evidence to support a specific age to stop cervical cancer screening, as none of the reviewed studies
looked specifically at this question [27]. Observational studies suggest that continued screening in older women may
be efficacious [28-30].

Studies have reported an incidence of cervical cancer among women over age 65 years that is higher than previously
thought [31- 33]. In a study that corrected for the estimated prevalence of hysterectomy, cervical cancer incidence in
the United States peaked at ages 65 to 69 years (corrected rate of 27.4 cervical cancer cases per 100,000 women
versus uncorrected rate of 14.8 per 100,000 women). In one study based on the Massachusetts state cancer registry,
almost 24 percent of cervical cancers were diagnosed in
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women age 265 years [34]. These older women were more likely to have higher-stage disease (2stage I) than younger
women (72
versus 44 percent). In other studies, close to 20 percent of cervical cancers occurred in women ages 65 years and
above [31,32]; invasive cervical cancer incidence did not decline with increasing age until at least age 85 years [33].

One limitation among the aforementioned studies isthat itisuncertain whether the women who developed cervical
cancer atan older age had been adequately screened through age 65 years; thus, the studies’ implications are not
necessarily applicable to women over age 65 years whose prior screening was adequate and negative. In average-risk
women over age 65 years who have undergone adequate prior screening with normal results, the harms of screening
may outweigh the benefits [35,36]. Older women are less likely to realize the benefits of screening because of
competing causes of death. High-grade lesions are rare among older women who have been previously screened, and
Pap test abnormalities among previously screened older women may have poor positive predictive value for
significant pathology, while causing a need for follow-up testing [37,38]. A study in pre- and postmenopausal women
who had Pap tests showing “atypical squamous cells: cannot exclude high-grade lesion (ASC-H)” found high-grade
histology in 22 percent of premenopausal women, compared with 6 percent of postmenopausal women [39].

Ifprior screening inadequate or unknown — Women aged 65 years or older who have never been screened have the
highest incidence of and mortality from cervical cancer and benefit the most from screening [40-42]. Modeling
studies suggest that screening older women who have never been screened could reduce mortality by 74 percent [22].

Women aged 65 years and older who have not had adequate prior screening should undergo screening
(see‘Ifadequate prior screening! above). For such patients, we suggest co-testing annually for three years before
spreading out the interval to every five years. Some clinicians continue screening such women up to about age 80
years. The decision about how long to continue screening should be predicated onalife expectancy of at least 10 years
and an informed decision—making discussion with the patient. (See'If adequate prior screening’ above.)

For older women with inadequate or unknown prior screening, the US Preventive Services Task Force (USPSTF)
suggests that screening be continued until age 70 or 75 years [16].

A considerable proportion of older women have not had adequate prior screening [33]. In retrospective analysis of
United States survey data, 18 percent of women aged 61 to 65 years had not had a Pap test within the preceding five
years (including those who had never had a Pap test); thus, these women would not meet criteria for stopping
screening at age 65.

Other higher-risk patients — For most women who had prior abnormal screening results or are immunosuppressed
and who have a life expectancy >10 years, some contributors continue to offer screening until about age 80 years,
whereas others stop screening a few years earlier. The age to discontinue screening depends on the adequacy of prior
screening as well as on the patient's risk factors for cervical cancer.

Continuing surveillance may be warranted for women with a history of cervical, vaginal, or vulvar cancer or precancerous findings,
orAIN.(See‘Continuingsurveillanceafterprecaonrcaencrer’below.)

SCREENING IN HIGHER-RISK WOMEN

Factors that affect risk for cervical cancer and increase the recommended frequency and/or duration of screening
include persistence of infection with a high-risk strain of human papillomavirus (HPV), prior abnormal screening
results, a history of inadequate screening for cervical cancer, and immunosuppression that can hinder clearance of
HPV infection [43]. (See ‘Follow-up results that are not normal’ below and "Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis", section on ‘Risk factors’ and “Invasive cervical nocarcinoma",
section on ‘Epidemiology and risk factors’.)

HIV — Women with HIV are more likely to have persistent HPV infection and increased rates of high-grade cervical
dysplasia, and they are at increased risk for the development of cervical cancer. Screening for women infected with
HIV is described separately. (See "Screening for cervical cancer in HIV-infected women and adolescents".)

Immunosuppressive therapy — Women without HIV who are on long-term immunosuppressive therapy (eg, for
organ transplant or systemic disease) have decreased rates of clearance of HPV infection and increased rates of
cervical dysplasia and cancer [44].

For women who are immunocompromised from causes other than HIV, we initiate screening one year after the onset
of sexual activity or by age 21, whichever comes first, and screen for three years with a yearly Papanicolaou (Pap)
test for patients age <30 years and with a yearly Pap test, yearly reflex testing, or yearly co-testing for patients age
230 years. If al results are normal for

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three years, these patients may consider moving to a screening frequency of every three years but are not candidates
for screening every five years. Extending screening for cervical cancer is warranted beyond age 65 years in patients
who are on long-term immunosuppressive therapy, although data are limited. (See 'When to discontinue screening!
above.)
For example, rates of abnormal Pap tests, high-grade dysplasia, and persistence of high-risk HPV subtypes are
significantly higher in women with systemic lupus erythematosus who are receiving immunosuppressive therapy than
in patients on immunosuppressive treatment for other conditions or in those with milder forms of lupus who are not
on treatment [43,45-48].

Diethylstilbestrol-exposed women — Daughters of women who took diethylstilbestrol (DES) during pregnancy
should have more frequent screening for vaginal and cervical cancer. This is discussed elsewhere. (See "Outcome and
follow-up doifethylstilbestrol

(DES)expoisenddividsuectiaonlson‘D"ES, daughters’)

Continuing surveillance after precancer or cancer — Precancerous cervical abnormalities and carcinoma in situ may
require extended surveillance. Extended cervical testing may also be warranted as part of follow-up of HPV-related
diseases of other pelvic organs (ie, vagina, vulva, and anus)

® History of cervical intraepithelial neoplasia (CIN) 2, CIN 3, cervical adenocarcinoma in situ (AIS), vaginal
intraepithelial neoplasia (VaIN), vaginal cancer, vulvar intraepithelial neoplasia (VIN), vulvar cancer, or anal
intraepithelial neoplasia (AIN). Subsequent surveillance and follow-up for women who have a history of precancer or
cancer of the cervix, vagina, or vulva, or AIN isdiscussed elsewhere.

« (See "Cervical nocarcinoma in situ", section on 'Posthysterectomy follow-up". ) « (See "Cervical nocarcinoma in situ",
section on ‘Postconization follow-up’.)

« (See "Vaginal cancer", section on 'Post-treatment surveillance’.)

«(Seei"Vulvnartraepneioplatsiah",elsecitionona‘Followingtreatment.)

surveillance.)

° Prior hysterectomy for CIN — Posthysterectomy screening in women with a history of CIN 2 or CIN 3 is discussed
in detail separately. (See "Cervical intraepithelial neoplasia: Treatment and follow-up", section on 'Posthysterectomy’.)

° Invasive cervical cancer — Posttreatment surveillance is described in detail separately. (See "Invasive cervical
cancer: Patterns of recurrence and posttreatment surveillance".)

SCREENING INOTHER POPULATIONS

Prior benign hysterectomy — Women who haveahistory of cervical neoplasia require surveillance even after
hysterectomy. (See

For patients who have had a hysterectomy and have no history of cervical cancer or cervical intraepithelial neoplasia
(CIN) our recommendations are:

 *  Total hysterectomy (with cervix removed) — We recommend that women who have undergone total
hysterectomy and have no history of cervical cancer or CIN NOT undergo screening for cervical cancer or
screening for vaginal cancer.

Women who have undergone a hysterectomy in which the cervix was removed are at a vanishingly small
risk of cervical cancer [49]. Although itwas once believed that women without a uterus were at increased
risk for vaginal cancer [50-54], studies show no association between total hysterectomy for benign disease
and subsequent vaginal carcinoma [54-59].

 *  Subtotal hysterectomy (cervix intact) —-Women who have undergone subtotal hysterectomy and have
no history of CIN likely share the same risk of cervical cancer as women with an intact uterus and cervix,
and screening recommendations are the same. (See ‘Screening _average-risk women’ above and 'Screening
in higher-risk women’ above.)

Women who are uncertain iftheir cervix was removed at the time of a benign hysterectomy should undergo
an examination to determine ifthe cervix is present; ifso, there is ongoing need for cervical cancer
screening.

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Recipients of HPV vaccine — Until data from clinical trials are available, current standard screening
recommendations should be observed for women who have received human papillomavirus (HPV) vaccine
[6,15,16,60,61]. (See ‘Screening average-risk women’ aboveand‘Screinehnigihenr-rgiskwomen’above.)
The optimal approach to cervical cancer screening in women who have received HPV vaccine or whose male partners
received HPV vaccine remains uncertain [62]. HPV vaccination of female and male adolescents is anticipated to have
a significant impact on the risks for cervical abnormalities [63,64]. However, the vaccine does not provide immunity
against al HPV types responsible for cervical cancers; additionally, some vaccine recipients may have already been
infected with high-risk HPV [60].

Resource-limited settings — For women in resource-limited settings, screening recommendations may differ. This is
discussed separately. (See "Screening for cervical cancer in resource-limited settings".)

Symptomatic women — Women of any age, including age <21 years, who have signs or symptoms of cervical
disease (eg, abnormality on visualization or palpation of the cervix, abnormal or postmenopausal bleeding, abnormal
discharge, pelvic pain, or change in bowel or bladder function) should undergo appropriate diagnostic evaluation
regardless of prior screening history. This evaluation includes a diagnostic Papanicolaou (Pap) test and evaluation for
cervical biopsy; by definition, this diagnostic evaluation is not "screening" and may require additional follow-up.
(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on
'Clinical manifestations'.)

SCREENING METHODS

Available screening tests — The available methods for screening are the Papanicolaou (Pap) test (cytology) and
human papillomavirus (HPV) testing [65]. These are used alone or in combination. (See 'Screening strategies' below.)

* Pap test — The Pap test consists of cells sampled from the cervix and vagina. It can identify abnormal cells from
the transformation zone and the junction of the ecto- and endocervix, where cervical dysplasia and cancers arise.
Sample collection isdiscussedelsewhere.
(See"Cervicalcancerscreeningtests:Techfnoricerqvicualecytsologyandhumanpapillomavirus testing", section on ‘How
to obtain a sample’.)

The Pap test yields cytologic results, permitting examination of cells (picture 1 and picture 2) but not tissue structure.
Interpretation of Pap test results is discussed elsewhere. (See "Cervical and vaginal cytology: Interpretation of results
(Pap test report)".)

In a systematic review, sensitivity and specificity varied significantly [66]. There is considerable interobserver
variability in test interpretation, although variability decreases for tests with more severe abnormalities [67]. The Pap
test is more sensitive for detecting squamous malignancy than adenocarcinoma and adenocarcinoma in situ (AIS)
[68,69]. Squamous lesions are more likely to be visually apparent than adenocarcinoma. Also, adenocarcinoma
involves the glandular tissue of the internal cervical canal and may occur at several sites within the canal ("skip
lesions"). This makes it more difficult to detect by routine Pap screening.

Either conventional or liquid-based Pap tests are acceptable for cervical cancer screening [6]. These are described
separately. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus
testing", section on ‘Specfiormcyetolnogsy'.)

For a Pap test to be satisfactory for evaluation, an adequate number of squamous cells must be well-visualized (ie, not
limited by obscuring factors or interfering substances), and the Pap test must not have an absent endocervical
transformation zone. A Pap test that is satisfactory but limited by any of these factors warrants additional evaluation
and follow-up, which are described

separately. (See “Cerviacndalvaginal cytology: Interpretationofresults (Paptestreport)", section

on‘Specimenadequacy’.

HPV testing — HPV tests identify most, but not al, of the high-risk HPV types (table 2). Four HPV tests are
approved by the US Food and Drug Administration (FDA) (tabl3e) [70]. Within this topic review, "HPV testing"
refers to the approved tests. Some researchers and clinicians use the term “high-risk HPV” (“hrHPV”) testing when
describing this HPV testing. One test, the cobas HPV test, has been approved by the FDA for primary HPV testing
(without a Pap test) in women age 225 years [71]. Three additional tests are approved for use in co-testing or reflex
testing with a Pap test (table 3). Other HPV tests may be used by individual laboratories but are not approved by the
FDA and have not been validated adequately.

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Techniques for HPV testing are discussed separately. (See "Cervical cancer screening tests: Techniques for cervical
cytology and human papillomavirus testing", section on 'HPV testing’.)
The FDA approved the cobas test for primary HPV testing based on unpublished data from a large multicenter
prospective study in which women who had abnormal primary HPV testing were triaged to have a Pap test and then
colposcopy ifthe Pap test was abnormal [72,73].

Screening strategies — Screening strategies use the available screening tests (ie, Pap test, HPV testing) either alone
or in combination. (See ‘Available screening tests’ above.)

Management of screening results includes review of results of prior screening and any follow-up done; these are
needed to determine iffollow-up testing is due and to guide the frequency of screening.

If results from the most recent or prior tests are abnormal, unsatisfactory, or satisfactory but limited, additional
follow-up of the findings is needed. The timing of follow-up depends upon the results of the testing. (See ‘Follow-up
results that are not normal’ below.)

Ifthe most recent and al prior results are normal, and the patient is immunocompetent and up to date with screening,
screening strategies and frequencies include:

* Pap testing alone — In Pap testing alone, only a Pap test is done to assess cervical cytology for cellular
abnormalities. (See ‘Available screening tests’ above.)

When the Pap test is used as the only screening method and results of the Pap test and al prior results are normal, we
suggest screening every three years.

The incidence of high-grade cytologic abnormalities is very low within three years of a normal Pap test (10 to 66 per
10,000) [35], and modeling studies have suggested cancer detection rates to be similar with annual or triennial
screening, while doubling or tripling the number of downstream interventions, including colposcopies [74-76]. A
synthesis of several studies in women aged 21 to 29 years predicted that the lifetime risk of death due to cervical
cancer would be similar: 0.03, 0.05, and 0.05 per 1000 women with screening annually, every two years, and every
three years, respectively [15].

Reflex HPV testing (also called triage HPV testing) — In reflex testing, a Pap test is performed first. Ifthe Pap test
shows atypical squamous cells of undetermined significance (ASC-US), an HPV test is performed on a sample
collected at the same time as the cytology was obtained, typically using the same container.

With reflex HPV testing, ifthe Pap test is normal (thus HPV testing is not done) and al prior screening results are
normal, screening is suggested again in three years, as discussed above.

Co-testing — In co-testing, both a Pap test and HPV testing are performed on the sample collected, rather than using
the result of the Pap test to determine ifthe HPV test should be done.

Ifco-testing is used and results of both tests are negative, and al prior results have been normal, a co-testing screening
interval of five years provides a balance of benefits and risks that is comparable to cytology screening every three
years.

A US Preventive Services Task Force (USPSTF) review of four randomized trials found a similar number of detected
cancer cases with co-testing at a frequency of every five years compared with Pap testing alone every three years,
although differences in study methodology (colposcopy referral methods and thresholds) made interpretation
complex [16].

Primary HPV testing — In primary HPV testing, an HPV test alone is performed. In many countries, although not in
most United States settings, primary HPV testing is used, especially when Pap testing is not available and/or
resources are limited.

If HPV testing is used as the only screening method (primary HPV testing) and is negative (normal), Society of
Gynecologic Oncology (SGO)/American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines state
that rescreening should occur no sooner than every three years, whereas the USPSTF recommends screening every
five years.

In the Athena trial, with three-year follow-up, the cumulative incidence of cervical intraepithelial neoplasia (CIN) 3+
over three years was <1 percent [77].
* Reflex cytology (Pap) testing — In reflex cytology testing, when an HPV test is reported as positive, Pap testing is
performed to determine ifa patient should be sent for colposcopy. Availability of this technique using approved
testing is limited in some

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With reflex cytology (Pap) testing, ifthe HPV testing is normal (thus, Pap testing is not done) and al prior screening
results are normal, screening is suggested again in three to five years, as described above.

The recommended frequency of testing varies with the chosen test or combination of tests. In modeling studies of
screening at various time intervals, decreasing the frequency of screening is associated with a decrease in colposcopy
rates. In one modeling study of women age >30 years, a combination of Pap and HPV testing every five years was as
effective as screening with Pap testing alone every three years [16]. In another modeling study of women age 40
years, co-testing every five years was associated with decreased colposcopies compared with co-testing every three
years, with only a minimal change in lifetime cancer risk (0.39 versus 0.61 percent) [78]. However, some argue that
the increased risk for cancer with less frequent screening is not minimal and that annual Pap testing should be the
gold standard used for comparison in modeling studies [79].

Follow-up results that are not normal — Appropriate follow-up of abnormal tests is essential for effective cervical
cancer screening. Women who have abnormal Pap tests and/or HPV testing need appropriate follow-up and possibly
further subsequent evaluation, depending upon the results. Recommendations differ depending on the woman's age,
test results, and whether or not both Pap and HPV testing were done.

Inadequate follow-up of abnormal Pap tests performed months or years before the diagnosis of cancer was found in
up to 13 percent of women with invasive cervical cancer [80-83]. In one study, the median time from the date of the
"failed" follow-up for abnormal Pap test to the cancer diagnosis was 22 months; older age and poverty were
associated with greater likelihood of a failed follow-up process [84].

Interpretation of Pap (table4) and HPV test results is described separately. (See "Cervical and vaginal cytology:
Interpretatioonf

positive results’)
Subsequent follow-up for women who have an abnormal Pap test or HPV test is described in detail in the following
topic chapters:

° Pap test satisfactory for evaluation but limited — A Pap test may be reported as satisfactory for evaluation but
limited (eg, due to partially obscuring blood or inflammation). Management of a Pap test that is satisfactory but
limited is discussed

evaluation’.)

Pap test unsatisfactory — A Pap test may be reported as unsatisfactory for interpretation. An unsatisfactory Pap
specimen is not reliable for evaluation of epithelial abnormalities. Management of an unsatisfactory Pap test is
discussed separately. (See

“Cerviacndalvaginalcytology:Interpretation ofresults(Paptestreport)",sectionon‘Unsatisfactory
forevaluation’.) Abnormal HPV testing but normal Pap testing — Follow-up for abnormal HPV testing with
normal Pap testing is described

cytology’.)

Abnormal HPV testing without Pap test — Follow-up for abnormal HPV testing without Pap testing is described
separately [24.71,85]. (See "Human papillomavirus testing of the cervix: Management of abnormal results", section
on 'Hpv-positive results' and "Human papillomavirus testing of the cervix: Management of abnormal results", section
on 'HPV genotyping’.)

e Abnormal Pap results — Follow-up is necessary for a patient who has an abnormal Pap test result. Depending on
the Pap test findings, subsequent testing (eg, colposcopy) may be guided by the results of HPV testing, ifperformed
with the Pap test, as discussed in the following topics:

¢ Atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells (cannot exclude
high-grade lesion,ASC-H) (see"Cervicalcytology:Evaluationofatypicalsquamouscells(ASC-US
andASC-H)")

¢ Atypical and malignant glandular cells (see "Cervical cytology: Evaluation of atypical and malignant glandular
cells")
« Low-grade squamous intraepithelial lesions (LSIL) (see “Cervical cytology: Evaluation of low-grade squamous
intraepithelial lesions (LSIL)")

intraepitheliallesions (HSIL)")
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¢ Cervical intraepithelial neoplasia (CIN) (see "Cervical intraepithelial neoplasia: Management of low-grade and
high-grade lesions")

¢ Cervical cancer (see "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis",
section on "Diagnosis')

BENEFITS AND HARMS OF SCREENING

The benefits of cervical cancer screening in decreasing the mortality and incidence of cervical cancer need to be
weighed against the risks of false-positive screening results and overdiagnosis.

Mortality reduction — Systematic reviews and meta-analyses of observational studies provide consistent and
compelling evidence that screening leads to a decrease in mortality due to cervical cancer (figur2e) [27,65]. Multiple
observational studies showed reductions in cervical cancer mortality as Papanicolaou (Pap) screening was
implemented, leading to the adoption of screening programs [27,68,86-94]. In the United States, mortality due to
cervical cancer has continued to decrease since the 1970s (figure 3).

There are no clinical trials comparing mortality rates among the various screening strategies. However, a
microsimulation model for the US Preventive Services Task Force (USPSTF) found that screening strategies that
included human papillomavirus (HPV) testing (ie, primary HPV testing or co-testing [Pap test with HPV testing])
were associated with fewer cervical cancer deaths compared with screening strategies that included Pap testing (ie,
Pap testing alone every three years or co-testing every five years). In this model, cervical cancer deaths associated
with screening that included Pap testing ranged from 0.30 to 0.76 deaths per 1000 women versus 0.23 to 0.29 deaths
per 1000 women with screening that included HPV testing [95].

Cervical disease detection and incidence — Systematic reviews, meta-analyses, and observational studies
consistently show that screening is associated with a decreased incidence of cervical cancer (figure 2) [27,65].

The United States adopted Pap test screening in the 1950s, and by the mid-1980s cervical cancer incidence decreased
by 70 percent [96]. In observational studies, screening is also associated with higher cure rates for invasive cervical
cancer [97,98]. Ina meta-analysis of 12 case-control studies, Pap testing was associated with a decreased risk of
invasive cervical cancer (odds ratio [OR] 0.35, 95% Cl 0.30-0.41) [27]. (See “Invasive cervical cancer:
Epidemiology, risk factors, clinical manifestations, and diagnosis", section on ‘Incidence and mortality’.)

Primary HPV testing has been shown in several studies to be a very sensitive test for identifying potential precursors
of cervical cancer during an initial round of screening [65,77,99]. In a systematic review for the USPSTF, primary
HPV screening among women aged 25 to 65 years compared with Pap testing alone was associated with increased
detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening (relative risk (RR) range 1.61 [95% Cl
1.09-2.37] to 7.46 [95% Cl 1.02-54.66)), whereas co-testing was not associated with initial increased CIN3+ detection
compared with Pap testing alone [100].

A benefit of co-testing on the incidence of cervical cancer has been seen in several studies. In large cohort studies,
women who have negative co-testing have an extremely low risk (<1 percent) of developing CIN 3 or a higher-risk
lesion within the next 5 to 10 years [101-107]. In a large European meta-analysis, compared with Pap-based testing,
screening with HPV testing (largely as co- testing) was associated with a lower rate of incident cervical cancer at a
median of 6.5 years of follow-up (rate ratio 0.60, 95% Cl 0.40-0.89) [108]. In this well-screened population, the
overall incidence of invasive cervical cancer was low (107 cervical cancers found among 176,464 women followed
for 6.5 years [1.2 million person-years]).

After the initial round of screening, some studies have found a lower cumulative incidence of CIN 3+ associated with
HPV testing, whereas others found that including HPV testing (ie, primary HPV testing or co-testing) led to earlier
detection, but not reduced incidence, of high-grade cervical lesions including cancer. For example, at 48 months, the
large HPV FOCAL Study found a lower incidence of CIN 3+ associated with initial HPV testing (incidence ratio (IR)
2.3/1000 [95% Cl 1.5-3.5]) than with initial Pap testing (IR 5.5/1000 [95% Cl 4.2-7.2]; RR 0.42 [95% Cl, 0.25-0.69])
[109]. The relative risk of CIN 2+ was also lower with primary HPV testing than with initial Pap testing. By contrast,
in one trial comparing screening with co-testing or with Pap testing alone (co- testing), initially women who had co-
testing had fewer CIN 3+ lesions; however, over two rounds of screening, overall rates of CIN 3 or a higher-risk
lesion were equivalent in the two groups [99]. Similarly, in the Population-Based Screening Study Amsterdam, which
compared initial testing with either co-testing or with Pap alone, followed by rescreening at five years with co-testing,
those initially screened with co-testing had less CIN 3 or a higher-risk lesion (88 versus 122 cases, RR 0.73, 95% Cl
0.55-0.96) and less cervical cancer (4 versus 14 cancers, RR 0.29, 95% Cl 0.10-0.87) [110]. However, the cumulative
detection of CIN 3 or a higher-risk lesion
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and cervical cancer over the two testing rounds did not differ between the two groups. The reduction in second-round
lesions appeared to be directly attributable to a reduction in HPV 16-positive lesions.
False-positive and colposcopy rates — Studies have found that primary HPV testing is associated with an increased
number of positive results, although outcomes of these results were uncertain [19,20,65,72,100]. Some detected
abnormalities can lead to unnecessary diagnostic procedures and treatment, especially because HPV often regresses
over time, contributing to the rate of false positives and thus to unnecessary colposcopies, particularly in younger
women.

Both HPV testing and Pap testing are associated with false-positive results that lead to subsequent testing and follow-
up examinations. Screening strategies that include HPV testing have been associated with more false-positive results
than screening with Pap testing alone [100]. In a USPSTF systematic review that compared methods that include
HPV testing versus Pap testing alone, during first-round screening, false-positive rates with primary HPV testing
were 6.6 to 7.4 percent compared with 2.6 to 6.5 percent for Pap testing alone. In separate studies, false-positive rates
with co-testing were 5.8 to 19.9 percent compared with 2.6 to 10.9 percent for Pap testing alone. In one European
study in women aged 25 to 60 years, HPV screening increased the detection of CIN 2 and 3; however, many of these
lesions spontaneously regressed, particularly in women aged <30 years [19,20]. (See "Cervical intraepithelial
neoplasia: Management of low-grade and high-grade lesions", section on 'High-grade lesions: CIN 2,3'.)

A consequence of higher rate of positive tests is a higher rate of follow-up examinations including colposcopy.
Higher colposcopy rates have been associated with use of HPV testing rather than Pap testing alone. In the USPSTF
systematic review, the colposcopy rate after primary HPV testing was 1.2 to 7.9 percent compared with 1.1 to 3.1
percent for Pap alone. Among studies that compared co-testing with Pap testing, the colposcopy rates were 6.8 to
10.9 percent versus 3.3 to 5.2 percent respectively [100]. Other studies have similarly found that primary HPV testing
is associated with an increased number of colposcopies performed [19,20,65, 72,10]. Primary HPV testing with reflex
Pap testing has been associated with a substantial increase in various types of follow-up, including colposcopies
[21,77]. For example, in a randomized trial of over 100,000 women, compared with Pap test screening, HPV testing
with reflex Pap testing resulted in 27 percent more colposcopies in women aged 25 to 35 years as well as increased
rates of recommendation for intensified follow-up in women 25 to 29 years (22 versus 10 percent) [21].

Modeling studies have shown variations in colposcopy rates depending upon the screening method used. In one
study, primary HPV testing was associated with increased life-years; however, itwas also associated with more
colposcopies compared with no screening, Pap testing, and co-testing [95]. In that model, switching at age 30 years to
HPV testing with cytology triage (reflex Pap testing) every five years was associated with 73 colposcopies per life-
year gained, whereas Pap testing alone every three years from ages 21 to 65 years was associated with three
colposcopies per life-year gained compared with no screening. Another modeling study predicted that co-testing
would result in nearly three times as many colposcopies as Pap testing, Pap with reflex HPV testing, or HPV testing with
reflex Pap testing [78].

Other potential harms — Adverse health outcomes related to cervical cancer screening include the potential for
adverse effects on reproduction, as well as the discomfort, psychosocial consequences, and costs of procedures used
to diagnose and treat cervical abnormalities. The harmful effects of treatment on fertility (eg, cervical stenosis) and
on pregnancy outcomes (eg, increased risk of second-trimester pregnancy loss, preterm premature rupture of
membranes, preterm delivery, and perinatal mortality) are discussed separately. (See “Cervicalintraepithelial
neoplasia: Reproductive effects of treatment.)

The discomforts and inconveniences of Pap test screening are apparent. They increase with the frequency and
duration of screening and may be particularly relevant for adolescents and older adults.

Screening also has psychosocial consequences. High levels of anxiety are associated with colposcopy referral for
women with high- or low-grade abnormalities as well as with surveillance for mild test abnormalities [111-113].
Anxiety is heightened in women with a positive HPV test and in younger women [112,114].

The costs of cervical cancer screening include both monetary and opportunity costs. Monetary costs relate to
screening and to procedures that result from screening. Opportunity costs relate to the possibility of overdooking
more immediate health care issues during medical visits in which cervical cancer screening is discussed and
performed.

IMPROVING SCREENING RATES

More than one-half of women who develop cervical cancer have not been screened appropriately [80,115-117].
Furthermore, among women diagnosed with invasive cervical carcinoma, one-half have never had a Papanicolaou
(Pap) test; another 10 percent have

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not hadatest in the past five years [115]. In a survey of screening in the United States in 2015, 83 percent of women
aged 21 to 65 years with a cervix reported having had a Pap test within the preceding three years or co-testing within
five years. [118].
In United States surveillance, never-screened and under-screened women tend to be older women and those with no
usual source of health care, the uninsured, and women who immigrated to the United States within the past 10 years
[119-121]. In Canada, screening rates are low in women with disability and those with chronic conditions [122].

Various strategies can be used to increase screening rates. Actively inviting women to schedule an appointment for
cervical cancer screening is an effective way to increase participation in a screening program [123], though even
active solicitation resulted in less than a 20 percent increase in screening in one systematic review [124]. The most
effective single intervention used a dedicated nurse practitioner and offered same-day screening (33 percent increase
in screening).

Urgent care clinic visits can be used as an opportunity to screen women who are unlikely to otherwise comply with
cervical cancer screening recommendations [125]. However, patient follow-up in this setting can be more difficult
than in the longitudinal care setting.

Initiating a reminder system is helpful for ensuring compliance with follow-up [126,127]. A systematic review of 38
randomized trials of interventions to promote screening for cervical cancer found good evidence that invitation letters
can increase cancer screening uptake, and more limited evidence that educational interventions are also effective
[128].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Cervical cancer screening _and prevention".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5“ to 6" grade reading level, and they answer the four or five
key questions a patient might have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to- read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10" to 12" grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

*Basicstopic(see"ePatidentucatPapitestos(Tnhe:Basics)")

* Beyond the Basics topics (see "Patient education: Cervical cancer screening (Beyond the Basics)" and “Patient
education: Managementceofravicbiaopsylwithprecacenllsc(BeyorndotheuBsasics)"and “Patient
education:Follow-upoflow-grade

(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

© There is consistent and compelling evidence that screening leads to a decrease in mortality due to cervical cancer.
(See ‘Benefits and harms of screening’ above.)

e For women age 221 years, we recommend cervical cancer screening (Grade 1A).

« We suggest not screening asymptomatic immunocompetent women younger than age 21 years. (See 'Age less than
21 years’ above.)

¢ For average-risk women who are asymptomatic and immunocompetent, we initiate screening at age 21 years. Some
experts and guideline groups recommend initiating screening at different ages (usually between 20 and 25 years).
(See

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REFERENCES
‘Age 21 to less than 30 years' above.)

e For higher-risk patients (eg, those with prior abnormal screening results or with immunosuppression),
recommendations for what ages to start and discontinue screening and which screening strategy to choose may differ.
Recommendations may also differindifferentpatientpopulationsordifferentsettings.(See‘Scre_einhnigihenr-
rgiskwomen’aboveand‘Screeninginother populations’ above and "Screening for cervical cancer in resource-limited
settings".)

Symptomatic women should have Papanicolaou (Pap) testing as part of a diagnostic workup, regardless of prior
screening results. (See ‘Symptomatic women’ above.)

The age at which we discontinue screening takes into account whether the patient had adequate prior screening and
whether she had prior abnormal results and includes informed discussions of the potential benefits and harms of
screening. For older women, continuing screening is contingent ona life expectancy >10 years. (See ‘When iscontin
ning! above.)

¢ For women who have had adequate prior screening with normal results and no cervical cancer risk factors, the
optimal age to discontinue screening is uncertain. We screen through at least age 65 years. While data are limited and
potential harms of screening need to be considered (eg, false positives), some UpToDate authors and editors continue
to offer screening through age 74 years. (See'Ifadequate prior screening’ above.)

For women who have had adequate prior screening but have a history of abnormal results, are immunosuppressed, or
would like to continue screening, some contributors continue screening up to about age 80 years, whereas others stop
screening earlier depending on the risk factor and the patient's life expectancy. (See ‘Other higher-risk patients' above
and ‘Screienhnigihenr-rgiskwomen’above.)

For women older than age 65 years with inadequate prior screening, we suggest screening with co-testing annually
for three years before spreading out the interval to every five years. (See'If prior screening inadequate or unknown’
above.)

Screening strategies (choice of test or combination of tests) for cervical cancer include Pap testing alone; primary
human papillomavirus (HPV) testing; and different combinations or sequences of Pap and primary HPV testing. The
frequency of testing depends on the test(s) chosen and the patient's prior screening history. (See 'Screening methods’
above.)

Recommendations regarding the choice of screening strategy differ for younger versus older women, available
resources, and other risk factors, and the patient should be included in the decision about which approach to use,
depending on what's availableinthatsetting.
(See'Age21tolessthan30years'aboveand'Age30yearsorolderaboveand‘Screeinhiignhegr- risk women’ above and
‘Screening in other populations’ above.)

For average-risk women age 21 to <30 years, we suggest Pap testing alone every three years. Some clinicians suggest
Pap testing with reflex to HPV testing every three years. (See 'Age 21 to less than 30 years’ above and ‘Benefits and
harms of screening! above.)

« For average-risk women age 230 years who are immunocompetent and whose prior screening results (if any) are al
normal, we suggest screening with one of the following strategies, and at the frequency shown, as long as all results
are normal: co-testing (Pap test and HPV testing) every five years, primary HPV testing every five years. Pap test
with reflex HPVtestingeverythreeyears,orPaptestaloneeverythreeyears.(See'Age30yeaorrolsderabove.)

Use of UpToDate is subject to the Subscription and License Agreement.

worldwide. J Pathol 1999; 189:12.

3. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation of human papillomavir consequencesforcervical-
cancerscreaeprnospiectnivegs:tudy.Lancet1999:354:20.

rvical lesions an

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high grade cervical squamous intraepithelial lesions in young women: population based prospecti