Cervical cancer is the second most common cancer in women worldwide
and is the most common female cancer in developing countries. In 2000,
more than 450,000 women around the world developed cervical cancer, and
more than 200,000 died from the disease.34 These figures are less gloomy for American women: 10,370 cases of cervical carcinoma were diagnosed in 2005 with about 3,710 related deaths.8 Countries with well established cervical cancer screening programs have been extremely successful in lowering the incidence of and mortality from cervical cancer, thanks to the enormous success of the Pap test. However, this test is imperfect and prone to a fairly high false-negative rate. Yet finally, for the first time in the year 2006, the American Cancer Society estimated that fewer than 10,000 women would be diagnosed with cervical cancer in the United States.
Why are there cervical cancer screening failures in the U.S.?
- While more than 50 percent of cervical
cancer patients were never screened, and 10 percent to 20 percent
of patients were not screened in at least the previous five years,
there still are 30 percent false-negative screening events (that
is, the patient has disease but it is not detected).1–3
- Of those false-negatives, 50 percent are
due to sampling errors, and the remainder are due to screening or interpretive
- Any single Pap test event is only 50
percent sensitive for disease prevalence.4
- Recurring independent Pap test events
make a screening program successful. Nevertheless, even with perfect
compliance, this system is flawed because of less than ideal sensitivity,
interpretive variance, and morphological subjectivity.6,7
How do we reduce false-negatives
and increase accuracy?
There are at least four major lines of attack1: enriching the sample, increasing the detection of abnormal cells, refining the accuracy of the morphologic interpretation, and eliminating morphology from the entire equation.
The first two approaches are addressed by the introduction of thin-layer cytology, which has increased the sensitivity and specificity of the Pap test. New automation systems are designed to help locate abnormal cells, lessening fatigue and lowering false-negative rates due to screening errors.9 Quality
improvement programs and continuing medical education courses improve
the morphologic acumen of cytotechnologists and cytopathologists. All
of these strategies have had a minimal impact on the rate of false-negative
cytology. So what about removing morphology entirely from our “hands”?
Removal of the reliable, but imperfect, morphologic analysis should
be addressed by a test that does not require the subjectivity of the
cytological process but would improve the performance of cervical cancer
screening. HPV testing is the best contender for that role at this
point in time.
What do we know so far
about human papillomavirus?
- HPV has been shown to be the causative agent
of about 95 percent of all cervical carcinomas worldwide.10,
- The vast majority of HPV infections with
both high-risk and low-risk types are benign in nature and will regress
spontaneously with no serious sequelae.29
- Cervical cancer is an unusual complication
of a persistent cervical infection with a high-risk HPV type.
- Women younger than age 30 have a high
rate of infection with high-risk HPV (15–46 percent), and most infections
will be transient.29
- The clearance time reported for transient
HPV infection is about six to 18 months.
- A significant drop in HPV prevalence
is noted in patients after the third decade of life (10 percent or
- High-risk HPV types are HPV 16, 18, 31,
33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Since these types are
known to be oncogenic, they are the only clinically relevant types
that should be tested for. The only FDA-approved test is Hybrid Capture
2 (HC2, Digene, Gaithersburg, Md.).17, 20, 21
- Persistence of high-risk HPV infection
is essential for the development, continuation, and progression to
Is HPV testing a useful tool to identify patients at risk for developing cervical neoplasia?13–17
- Several studies have demonstrated that
HPV testing is more sensitive and more reproducible and has a better
predictive and prognostic value than cytology alone.
- The addition of HPV testing to cytology
screening has achieved sensitivities of over 95 percent with specificity
analogous to or only slightly less than cytology alone (90 percent).
- These studies have led the way to revised
practice guidelines with the addition of HPV testing as an adjunct
to the Pap test in the primary screening of women age 30 and older.
- This strategy may reduce the false-negative
rate to nearly zero, allowing for an increase in the screening interval
to up to three years for women who are negative on both Pap and high-risk
What are the current uses of HPV testing?18
- HPV testing is recommended as a reflex
test in women of any age for the triage of those with equivocal cytological
- HPV testing is recommended as an adjunct
to cervical cytology in the screening of women more than 30 years
- HPV testing may be used in the post-colposcopy
followup of women with HPV-positive ASC-US, ASC-H, or LSIL, without
histological confirmation of CIN 2/3.
- HPV testing is recommended for the initial
followup of treated CIN 2/3, replacing colposcopy or cytology or
- HPV testing is not recommended as a screening
tool in conjunction with the Pap in women younger than 30 years of
- Negative Pap and HPV tests in women older
than 30 years allow for a longer interval between cervical screenings
What is the management of women who are screened with a combination of cytology and HPV testing?19
- Normal Pap test and negative HPV-DNA (double negative):
Negative results on combined screening have a high negative predictive
value (99.1–100 percent) for cervical cancer. A repeat Pap and HPV
is recommended within three years. The risk of unidentified CIN 2/3
is approximately one in 1,000.
- Normal Pap test and positive HPV-DNA: These cases constitute three percent to five percent of the population screened, and have a 20-fold increased chance of developing CIN 2/3 than women with negative HPV-DNA tests. It is recommended to re-test with a combination of Pap and HPV in six to 12 months. Approximately 40 to 60 percent of these patients will clear their HPV infection over this short followup. The risk for CIN 2/3 is 2.8 to 4.2 percent.
- ASC-US Pap and negative HPV-DNA: The recommendation is for retesting with both Pap and HPV combination in 12 months. The risk for CIN 2/3 is six percent to 12 percent, recognizing that even HPV testing is imperfect.
- ASC-US Pap and positive HPV-DNA: The risk for CIN 2/3 is 15 to 20 percent within a two-year period, justifying the recommendation of colposcopic evaluation.
- ASC-H and LSIL cases have a high frequency
of high-risk HPV-DNA detection, thus diminishing the value of HPV
testing as a colposcopic triage test.
What are the major concerns of adding HPV testing as a tool for cervical cancer screening in clinical practice?
Laboratory-related issues23, 25, 26
- HPV testing should be clinically validated
to ensure that results are objective and highly reproducible.
- It is potentially clinically deleterious
to attain the highest analytical sensitivity for the detection of
HR-HPV molecules. HPV presence does not equate to clinical evidence
of disease. Therefore, an issue vital to the validation question
is the need for an equilibrium between analytical sensitivity and
clinical sensitivity. Maximal sensitivity has the potential of detecting
clinically insignificant infection and thus increasing the false-positive
rate. Hence, the current FDA-approved HPV Hybrid Capture 2 has been
calibrated to balance sensitivity and specificity toward the detection
of a significant copy number of HPV DNA molecules, which is more
likely to correlate with a clinically significant disease state.
- The need for counseling and educating
patients about the significance of HPV as a sexually transmitted
infection, and the significance of its presence in the setting of
a negative cytology.
- The change in practice due to the lengthening
of screening intervals to every three years.
- The potential for drastic increases in
cervical cancer screening costs.
- The risk of expanding superfluous interventions
and treatment, thus diminishing the quality of life.
Public health issue27, 28
- The high prevalence of HPV infection
will have the effect of large numbers of women in need of advice
and support. This requires a well-organized, accessible, and massive
public health education for women and health care providers.
- Cost-effectiveness analyses models indicate
promising outcome by providing increased protection against cervical
cancer while reducing the average woman lifetime costs associated
with screening, opening the horizon for a significant positive impact
- By improving the clinical performance
of screening and enhancing the efficiency and cost-effectiveness
of the test, it will be possible to direct assets toward efforts
to lessen disparities and increase screening coverage.
What is the future of cervical
cancer screening?30–33, 35–38
- HPV screening as the primary screening
modality could be implemented in countries with high-quality cytology
labs, with cytology reserved for triage of HPV-positive cases. This
approach has the following benefits: (1) HPV assays are automated,
objective, and highly sensitive, allowing for improved quality control
and reducing false-negative rates; (2) cytology may be used for HPV-positive
women as a reflex test; (3) the longer screening intervals proposed
may prove to be safer due to fewer false-positives; and (4) primary
screening with HPV-DNA testing needs to be evaluated in large trials
to understand and predict its full impact on cancer incidence and
- Screen-and-treat method: HPV as a standalone
test (self-sampled or physician-collected) may be used in developing
countries where cytology-based screening programs are not available.
A positive result would be followed by immediate treatment, maximizing
the use of sparse health care resources and patient compliance. Field
testing of this process will begin this year in China and India.
There are two issues related to this screening method: (1) Large-scale trials must concentrate on the optimal time to initiate screening, intervals between visits, and management of positive HPV results; and (2) if the premise of this program is that all HPV-positive women should be treated, the risk of overtreatment with its serious and potentially permanent adverse effects must be examined closely.
- Increase HPV specificity: The need to
increase the lower specificity of HPV testing vis-à-vis cytology screening may
be tackled by several methods: (1) HPV typing, especially for HPV types
16 and 18, may increase the correlation of a positive test with true
disease; (2) viral loads may separate clinically relevant infections
from cases unlikely to be linked with CIN 2/3; (3) surrogate markers,
such as proliferative markers (p16 and mRNA) or cell cycle markers
(cdc6 and mcm5 proteins), may help distinguish those infections that
have the potential to progress toward cancer; and (4) host-cell biomarkers
may be detected by comparative genomic hybridization, or CGH, microarray
analyses, possibly aiding in a superior risk stratification of HPV-positive
What is the current state of cervical cancer screening?
- Women now have improved cervical cancer
- There are clearer and more meaningful
cytological interpretations because of standardization by the 2001
- There are coherent and easier evidence-based
- There are powerful molecular diagnostics,
such as HPV testing, that improve outcomes and potentially reduce
- A newly approved HPV vaccine may prevent
98 percent of persistent infections with high-risk HPV types 16 and
18, potentially reducing cervical cancer by up to 51 percent even
in the absence of cytological screening.
What is the path of success?
- Patients must come in for the test (most
important reason for “missed” diagnoses).
- Clinicians must take adequate, representative,
- Cytologists must correctly identify dysplastic
- Results must reach the clinicians.
- Clinicians must act appropriately on
results based on published evidence-based guidelines.
- Patients must return for therapy or appropriate
Overall, our approach to cervical cancer screening has been a major success. In the last decade or so, advances in the understanding of the role of HPV in the pathogenesis of cervical cancer have started to revolutionize this approach. Primary screening with molecular diagnostic tests for HPV and other potentially specific markers are on the horizon, and they promise to provide even better prevention of cervical cancer to women worldwide.
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Drs. Wasserman, Schwartz, and Darragh are members of the CAP Cytopathology Committee. Dr. Wasserman is with Long Island Jewish Medical Center, New Hyde Park, NY; Dr. Schwartz with The Methodist Hospital, Houston; and Dr. Darragh with the University of California San Francisco.