Getting the most out of Pap
and HPV DNA co-testing
Austin, MD, PhD
The Food and Drug Administration announced on March 31 its
approval of Digene’s High-Risk HPV DNA Hybrid Capture 2 test
as a cervical screening test to be used in conjunction with the
Pap test for human papillomavirus infection in women age 30 and
older.1 The landscape of cervical screening risk management
and patient safety advocacy has been permanently altered, given
findings in published2,3 and unpublished studies4
that co-testing with cytological Pap screening and HPV DNA testing
can, for the first time, approach entrenched but previously unrealistic
public and professional expectations5,6 of 100 percent
effectiveness for detection of clinically significant cervical lesions.
Whether the full promise of “DNAwithPap”7
co-testing is realized may now depend on the ability of patient
safety advocates to communicate clearly to diverse audiences not
only the advantages but also the limitations of HPV DNA testing
in cervical cancer screening. This communication is important, since
financially driven pressures and messages are already growing to
tempt cost-conscious payers to move prematurely toward unproven
lengthened screening intervals and a primary screening role for
a high-risk HPV DNA test.
the “DNAwithPap” test was based on a review of international
cervical screening studies on more than 77,000 women and more than
1,000 cases of detected high-grade squamous intraepithelial lesions
and cancer spanning four continents and 11 countries.4 For most
studies, the sensitivity of the Pap test and the Hybrid Capture
2 (HC2) HPV DNA test combined was higher than for either test alone.
The negative predictive values were also higher with co-testing:
They were consistently over 99 percent, and they reached 100 percent
in several studies. Significantly, in the above review there was
not a single study in which the sensitivity of the Pap test exceeded
or fully equaled the HPV DNA test.
In the only
study2 in which verification bias concerns were fully
addressed by 100 percent colposcopy and cervical biopsy of almost
2,000 previously unscreened high-risk Chinese women, 95 percent
of HSIL and invasive cancer (HSIL+) lesions were detected from residual
vial fluid by HC2 HPV DNA testing, 94 percent of HSIL+ lesions were
detected using direct-to-vial ThinPrep liquid-based cytology (LBC),
and virtually all 86 HSIL+ lesions (including 12 invasive cancers)
were detected by co-testing. In another significant comparison study
of almost 8,000 screened women from Reims, France, HC2 HPV DNA testing
detected 100 percent of HSIL+ lesions compared with 58 percent for
the conventional Pap smear and 84 percent for direct-to-vial ThinPrep
LBC.8 Overall, the reviewed studies indicated that HPV
DNA testing on average detected 92 percent of HSIL+ lesions compared
with an average of only 58 percent HSIL+ detection for conventional
Pap smear screening.4
several important longitudinal studies have also become available.3,4,9
These studies indicate that women who are HPV DNA positive but who
do not have an abnormal Pap test or suspicious clinical findings
should not necessarily be viewed as having a “false-positive”
test; rather, they are at significantly increased risk for subsequent
development of a significant cervical lesion (HSIL+). Therefore,
such women need to be followed closely with repeat testing for persistence
of high-risk HPV DNA or development of detectible cytologic abnormality,
or both, and subsequent appropriate referral for diagnostic colposcopic
and possible tissue biopsy evaluations.7
In the United
States, previously unrealistic but entrenched public and professional
expectations of near 100 percent effectiveness for cervical screening
have established a breathtakingly high standard for expected test
effectiveness. These expectations have been reflected in significantly
rising costs to cover liability exposure from Pap test litigation
and an alarming decline in the number of insurers in the indemnity
market willing to insure cytotechnologists and pathologists for
Pap testing at any price.10 At the same time, these unrealistic
expectations have been further complicated by the significant rising
relative and absolute prevalence of endocervical adenocarcinomas.11
Although no conclusive evidence is available from population studies
to prove that conventional Pap smear screening has been able in
any location to decrease substantially the incidence of or the morbidity
and mortality due to endocervical adenocarcinoma,12 recent
reports suggest that enhanced screening with HPV DNA testing13,14
and ThinPrep LBC15-17 could improve previously disappointing
The lack of
data on the impact of the rising incidence of endocervical adenocarcinoma
in the most commonly cited cervical cancer models18 and
experience suggesting a diminished screening window of opportunity
for detecting cervical adenocarcinoma19 call into question
the prudence of new guideline recommendations for triennial Pap
and HPV co-testing.20,21 In a similar spirit, some international
cost-efficiency models have implied that as much as 30 percent of
cervical cancer is unavoidable with “efficient” screening
policies,22 and in the U.S. some experts have discounted
even halving of existing cancer rates in screened populations as
perhaps insignificant “small decreases in absolute risk.”23
Nevertheless, informed individual patients and their legal representatives
in the U.S. tort system have not so far consented to the concept
of “acceptable cervical cancer rates” in screened patients.
This conundrum is exacerbated by the ability of third-party payers
to actually improve their bottom lines and decrease their costs
by paying only for less-than-optimal screening practices, even while
transferring risk without accountability to patients and professionals
involved in testing.
and manufacturer-funded model studies indicate that elusive U.S.
Healthy People 2010 cervical cancer goals could be met or even exceeded
by using more sensitive new screening technologies at existing rates
of recruitment to screening.24,25 Achieving and exceeding
these model projections now appears feasible with Pap and HPV DNA
co-testing at existing rates of screening. The models and common
sense do not, however, suggest that telling women to present themselves
less frequently for screening will be helpful in meeting national
cervical cancer goals. Co-testing with Pap and HPV DNA tests at
existing rates of screening is the policy most consistent with public
expectations for high screening effectiveness and the challenge
of early detection and treatment of increasingly prevalent, difficult-to-detect
endocervical adenocarcinomas. Exhortations to economically justify
longer screening intervals and to consider primary HPV testing should
rely on accumulation of longitudinal population studies that include
substantial numbers of cases of endocervical adenocarcinoma. Assertions
that certain rates of cervical cancer may be “irreducible”20
and, by implication, acceptable should await the completion of well-designed
U.S. population studies and “informed consent” from
credible consumer representatives.
a member of the CAP Cytopathology Committee, is medical director and
director of cytopathology and gynecologic pathology, Coastal Pathology
Laboratories, Charleston, SC.
- U.S. Food and Drug Administration. FDA News: FDA approves expanded
use of HPV test. Available at: www.fda.gov/bbs/topics/news/2003/new00890.html.
Accessed July 14, 2003.
- Belinson JH, Qiao YI, Pretorius R, et al. Shanxi Province Cervical
Cancer Screening Study: a cross-sectional comparative trial of
multiple techniques to detect cervical neoplasia. Gynecol
Oncol. 2001; 83: 439–444.
- Bory JP, Cucherousset J, Lorenzato M, et al. Recurrent human
papillomavirus infection detected with the hybrid capture II assay
selects women with normal cervical smears at risk for developing
high grade cervical lesions: a longitudinal study of 3,091 women.
Int J Cancer. 2002; 102:519–525.
- Lorincz AT, Richart RM. Human papillomavirus DNA testing as
an adjunct to cytology in cervical screening programs. Arch
Pathol Lab Med. 2003;127:959–968.
- Austin RM. Human papillomavirus reporting: minimizing patient
and laboratory risk. Arch Pathol Lab Med. 2003;127:973–977.
- Austin RM. Public expectations, reliable screening sensitivity,
and the standard of practice. Cancer Cytopathol. 2003;
- Digene. Clinical Information: With DNAwithPap, now you can be
more certain. Available at: www.digene.com/clinician_1_3.html.
Accessed July 14, 2003.
- Clavel C, Masure M, Bory JP, et al. Human papillomavirus testing
in primary screening for the detection of high grade cervical
lesions: a study of 7,932 women. Br J Cancer. 2001;84:1616–1623.
- Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology,
human papillomavirus testing, and risk for cervical neoplasia:
a 10-year cohort analysis. JNatl Cancer Inst. 2003;95:46–52.
- Austin RM. In: Allen KA, Holladay EB, eds. Preface. Risk
Management for the Cytology Laboratory. Raleigh, NC: American
Society for Cytotechnology; 2002:6–9.
- Smith HO, Tiffany MF, Qualls CR, et al. The rising incidence
of adenocarcinoma relative to squamous cell carcinoma of the uterine
cervix in the United States—a 24-year population-based study.
Gynecol Oncol. 2000; 78: 97–105.
- Kinney W, Sawaya G, Sung HY, et al. Stage at diagnosis and mortality
in patients with adenocarcinoma and adenosquamous carcinoma of
the uterine cervix diagnosed as a consequence of cytologic screening.
Acta Cytol. 2003; 47: 167–171.
- Ronnett BM, Manos MM, Ransley JE, et al. Atypical glandular
cells of undetermined significance: cytopathologic features, histopathologic
results, and human papillomavirus DNA detection. Human Pathol.
- Andersson S, Rylander E, Larsson B, et al. The role of human
papillomavirus in cervical adenocarcinoma carcinogenesis. Eur
J Cancer. 2001;37:246–250.
- Bai H, Sung CJ, Steinhoff MM. ThinPrep Pap test promotes detection
of glandular lesions of the endocervix. Diagn Cytopathol.
- Ashfaq R, Gibbons D, Vela C, et al. ThinPrep Pap test. Accuracy
for glandular disease. Acta Cytol. 1999; 43: 81–85.
- Schorge JO, Hossein SM, Hynan L, et al. ThinPrep detection of
cervical and endometrial adenocarcinomas: a retrospective cohort
study. Cancer Cytopathol. 2002; 96: 338–343.
- McCrory DC, Mather DB, Bastian L, et al. Evaluation of Cervical
Cytology, Evidence Report/Technology Assessment No. 5, Rockville,
Md: Agency for Health Care Policy and Research; 1999. AHCPR publication
- Janerich DT, Hadjimichael O, Schwartz PE, et al. The screening
histories of women with invasive cervical carcinoma, Connecticut.
Am J Publ Health. 1995;7 9: 791–794.
- 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: 342–362.
- Austin RM. Too much emphasis on screening interval, too little
on safety. CAP TODAY. 2003;17(5):12–15.
- Van den Akker-van Marle ME, van Ballegooijen MV, van Oartmarssen
GJ, et al. Cost-effectiveness of cervical cancer screening: comparison
of screening policies. JNatl Cancer Inst. 2002;94:193–204.
- Miller GM, Sung HY, Sawaya GF, et al. Screening interval and
risk of invasive squamous cell cervical cancer. Obstet Gynecol.
- Hutchinson ML, Berger BM, Farber FL. Clinical and cost implications
of new technologies for cervical cancer screening: the impact
of test sensitivity. Am J Managed Care. 2000;6:766–780.
- Montz FJ, Farber FL, Bristow RE, et al. Impact of increasing
Papanicolaou test sensitivity and compliance: a modeled cost and
outcomes analysis. Obstet Gynecol. 2001; 97:781–788.