Clinical Review

Atypical squamous cells: The case for HPV testing

OBG Manag. 2004 March;16(3):52-69

References

1. Kurman RJ, Henson DE, Berbst AL, Noller KL, Schiffman MH. Interim guidelines for the management of abnormal cervical cytology. JAMA. 1994;271:1866-1869.

2. Ferenczy A. Viral testing for genital human papillomavirus infections: recent progress and clinical potentials. Int J Gynecol Cancer. 1995;5:321-328.

3. Schiffman M, Adrianza ME. ASCUS-LSIL Triage Study. Design, methods and characteristics of trial participants. Acta Cytol. 2000;44:726-742.

4. Solomon D, Schiffman M, Tarone R, et al. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst. 2001;93:293-299.

5. Sherman ME, Schiffman M, Cox JT, et al. Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst. 2002;94(2):102-107.

6. Cox JT, Lorincz AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 1995;172:946-954.

7. Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA. 1999;281:1605-1610.

8. Cox JT, Schiffman M, Solomon D, et al. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol. 2003;188:1406-1412.

9. Kinney WK, Manos MM, Hurley LB, Ransley JE. Where’s the high-grade cervical neoplasia? The importance of the minimally abnormal Papanicolaou diagnosis. Obstet Gynecol. 1998;91:973-976.

10. Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.

11. Wright TC, Jr, Cox JT, Massad LS, et al. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

12. Jones MH, Singer A, Jenkins D. The mildly abnormal cervical smear: patient awareness and choice of management. J Royal Soc Med. 1996;89:257.-

13. Wright TC, Lorincz AT, Ferris DG, et al. Reflex human papillomavirus deoxyribonucleic acid testing in women with abnormal Pap smears. Am J Obstet Gynecol. 1998;178:926-966.

14. Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol. 1995;141:680-689.

15. Agency for Health Care Policy and Research. Evidence Report/Technology Assessment #5: Evaluation of Cervical Cytology. Rockville, Md: AHCPR; January 1999.

16. Stoler MH, Schiffman M. Atypical Squamous Cells of Undetermined Significance—Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA. 2001;285:1500-1505.

17. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383-1392.

18. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946-949.

19. Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. JAMA. 2002;287:2382-2390.

20. Guido R, Schiffman M, Solomon D, et al. 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;188:1401-1405.

21. Nobbenhuis M, Walboomers JM, Helmerhorst TI, Rozendaal L. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet. 1999;354:20.-

22. Wright TC, Jr, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

23. Paraskevaidis E, Koliopoulos G, Alamanos Y, Malamou-Mitsi V, Lolis ED, Kitchener HC. Human papillomavirus testing and the outcome of treatment for cervical intraepithelial neoplasia. Obstet Gynecol. 2001;98:833-836.

24. Nobbenhuis MA, Meijer CJ, van den Brule AJ, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer. 2001;84:796-801.

25. Jain S, Tseng CJ, Horng SG, Soong YK, Pao CC. Negative predictive value of human papillomavirus test following conization of the cervix uteri. Gynecol Oncol. 2001;82:177-180.

26. Massad LS, Ahdieh L, Benning L, et al. Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women’s interagency HIV study. J Acquir Immune Defic Syndr. 2001;27:432-442.

27. Selvaggi SM. Reporting of atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion (ASC-H) on cervical samples: is it significant? Diagn Cytopathol. 2003;29:38-41.

28. Alli PM, Ali SZ. Atypical squamous cells of undetermined significance—rule out high-grade squamous intraepithelial lesion: cytopathologic characteristics and clinical correlates. Diagn Cytopathol. 2003;28:308-312.

29. Sherman ME, Solomon D, Schiffman M, et al. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study. Am J Clin Pathol. 2001;116:386-394.

2 repeat cytologies: Sensitivity, cost issues. This approach requires at least 2 repeat, optimized (liquid-based) Pap tests to equal the sensitivity of a single HPV test. This, compounded with the high rate of repeat abnormal cytology requiring colposcopic evaluation, means repeat cytology is unlikely to be cost-competitive with HPV testing.^4,13

Cervical cytology as a triage option. Cytology has been a good screening test, but its comparatively low sensitivity (51% to 83%) and poor reproducibility reduces its value as a triage test.^13-17 For example, in ALTS, of 1,473 repeat Paps originally read as ASCUS by good clinical pathologists, only 633 were reread as ASCUS when 2-of-3 agreement was obtained in a blinded review by an expert panel of pathologists.¹⁶ In other words, 840 (57%) were reread as something other than ASCUS. Most were downgraded to normal.
The sensitivity of the HPV test in detecting CIN 2,3 was 92.4%. This rate was matched only by 2 repeat Pap tests, provided the threshold for referral to colposcopy was ASCUS or greater.¹⁷ At this threshold, 95% of the CIN 2,3 was detected with repeat Pap testing, but only after an average of 8 to 12 months. This contrasts with the immediate reassurance provided by the initial HPV test.
ALTS did not evaluate repeat conventional Pap smears. Nor do the guidelines differentiate between conventional and liquid-based methods in the number of follow-up Pap tests required for reassurance, despite consensus that the sensitivity of liquid-based cytology is better than that of the conventional “dry slide.”
Any woman with a repeat Pap result of ASC-US or greater should be referred to colposcopy. Referral at a threshold of LSIL or greater would result in far fewer colposcopies, but has not been shown to be sufficiently sensitive for CIN 2,3.¹⁷

HPV testing identifies clear risk. Any objective test that initially indicates which women with ASC-US are at risk for CIN 2,3 and which are not—either now or in the future—should confer a major advantage.

HPV-positive women are clearly at risk, justifying the anxiety and cost of colposcopic referral, while HPV-negative women may be reassured (FIGURE 2). Also, ALTS data showed HPV triage is essentially equivalent to immediate colposcopy in sensitivity for high-grade CIN, while halving colposcopic referrals.^17,18

Because low-risk HPV types do not cause CIN 3 or cancer, the HPV test should document only high-risk types.¹¹ The only HPV test approved by the US Food and Drug Administration (Hybrid Capture 2, Digene, Gaithersburg, Md) includes both low- and high-risk HPV panels. For cost savings, the laboratory can be asked to use only the high-risk panel. All positive high-risk HPV cases should be referred to colposcopy.

FIGURE 1 3 triage options for management of ASC-US

FIGURE 2 Management of atypical squamous cells–cannot exclude high–grade squamous intraepithelial lesions (ASC-H)

Some high-grade lesions are still overlooked

A single HPV test or 2 repeat liquid-based Pap tests with a colposcopy-referral threshold of any findings of ASC-US or greater have similar sensitivity for CIN 2,3.^17,18

The guidelines state that women who undergo immediate colposcopy with negative results or who have a negative initial HPV test should undergo a follow-up Pap test in 12 months. Note that the guidelines do not state that these women can return directly to routine screening. The reason: In some settings, “routine” screening is at 2- or 3-year intervals, and some risk still exists—albeit minimal—for missed CIN 2,3.

For example, 1 of 83 cases of CIN 2,3 were missed by HPV testing in the study by Manos et al.⁷ In ALTS, that number was 1 in 90,⁴ and in the study by Cox et al⁶ it was 1 in 136. Further, colposcopy did not initially detect 25% of the cumulative high-grade lesions detected over 2 years of follow-up in ALTS.¹⁷

In contrast, the recommendation for women with 2 repeat normal Pap tests is to return to “routine screening.” This inexplicably departs from the 12-month repeat Pap testing urged for women with negative results on the other 2 triage options, despite a similar risk of missed high-grade disease.

In my opinion, all 3 scenarios should be managed by repeat Pap testing in 12 months.

Reducing referrals to colposcopy

If all women returned as directed for repeat cytology, more of them would be referred to colposcopy by repeat abnormal Pap tests at the ASC-US threshold than by testing positive for high-risk HPV types. In ALTS, 53% tested positive for high-risk HPV and were referred to colposcopy, compared with 67% who had an abnormal Pap test on the first or second repeat (these women also had 1 or 2 more office visits prior to referral to colposcopy.).