Pap Test Update

by David B. Troxel, M.D., Board of Governors

New diagnostic strategies have emerged to detect cervical cancer and its precursor lesions. They are characterized by greater sensitivity than the conventional Pap smear with correspondingly lower false-negative rates. Most are based on the fact that human papillomavirus (HPV) infection is the underlying cause of cervical cancer and its precursors. Carcinogenic high-risk HPV types can be identified in liquid-based cytology (LBC) specimens or in specimens obtained subsequent to collecting a conventional Pap smear.

The National Cancer Institute’s ASC-US/LSIL Triage Study (ALTS) involved 3,488 women with atypical squamous cells of undetermined significance (ASC-US) and 1,572 women with low-grade squamous intraepithelial lesions (LSIL) and evaluated three alternative methods of management: immediate colposcopy, cytologic follow-up, and triage by HPV DNA testing (for 13 oncogenic HPV types utilizing liquid-based cytology). These women were followed for two years. The study conclusions were:

1. In women with a diagnosis of ASC-US, HPV DNA testing is as sensitive as colposcopy in detecting high-grade squamous intraepithelial lesions (HSIL) and carcinomas, particularly in women 30 years of age or older. When ASC-US is diagnosed, reflex testing for HPV permits triaging those who are HPV positive to colposcopy (55 percent), while those who are HPV negative can be followed with a repeat Pap test in 12 months (45 percent).
2. Reflex HPV testing is notan effective triage method for LSIL due to the high prevalence of high-risk HPV types. Most women with LSIL should be referred for colposcopic examination—although management options may differ for adolescent, pregnant, and postmenopausal women.
3. Both HPV-positive ASC-US patients and LSIL patients can be followed after colposcopy with HPV testing at 12 months. Their risk of developing HSIL is approximately 26 percent at two years.
4. HPV testing shows promise as a primary screening test, since its sensitivity exceeds that of cytology alone. Its specificity is somewhat lower, however, especially in women younger than 30 years.
5. HPV DNA testing (using Digene’s High-Risk HPV DNA Hybrid Capture 2 test) combinedwith cytology testing (DNAwithPap test) is now FDA approved as a cervical screening test for women 30 years and older. Its sensitivity for detecting HSIL/carcinoma approaches 100 percent, and it has the potential to eliminate screening false negatives. These ALTS conclusions were the basis for the Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities developed by the American Society for Colposcopy and Cervical Pathology. Pathologists and clinicians should become familiar with these guidelines, and pathologists should consider making follow-up recommendations in their Pap reports, particularly for liquid-based cytology ASC-US cases, e.g.,“consider immediate HPV DNA testing, diagnostic colposcopy, or a repeat Pap test in four to six months.”

Over the past seven years, there has been an increase in the proportion of cervical cancers that are adenocarcinomas (circa 1/3). The conventional Pap test is noteffective in detecting cervical adenocarcinoma; the abnormal cells are often interpreted as atypical glandular cells of undetermined significance (AGUS) or reactive endocervical cells. HPV DNA testing shows promise in detecting a high percentage of these cases as well.

Finally, the American Cancer Society revised its cervical cancer screening guidelines in 2002 as follows:

• Screening should begin three years after becoming sexually active, but no later than 21 years of age.
• A conventional Pap test should be done annually, or a liquid-based cytology test should be obtained every two years until age 30.
• If there have been three consecutive negative cytology tests, screening should continue every two to three years thereafter.

Recommendations

(if third-party reimbursement and/or practice guidelines permit):

1. The use of a liquid-based cytology Pap test is recommended. LBC is more sensitive than the conventional Pap smear in detecting significant lesions (LSIL or higher).
   
   
2. DNA testing for high-risk HPV is recommended whenever a Pap test shows ASC-US. Reflex DNA testing is facilitated by the use of LBC.
   
   
3. The DNAwithPap test is recommended for women 30 years of age or older. Use either liquid-based cytology or a conventional Pap smear combined with DNA testing for high-risk HPV.
   
   
4. Use the 2001 Bethesda System terminology for reporting gynecologic cytology results. This terminology is part of the cytology standard of practice. The continued use of “class” systems is not acceptable.
   
   
5. Assure laboratory compliance with the new cytology regulations published in the Clinical Laboratory Improvement Act (CLIA) modifications of January 2003. These can be found at www.phppo.cdc.gov/clia/pdf/CMS-2226-F.pdf. CLIA compliance is also part of the cytology standard of practice.