1. Morphologic Pap Test Findings in HPV Negative Women Age 30 Years and Older: What Information Will Be Lost with HPV Only Primary Screening?
Brooke Henninger, MD; Maryanne Hornish, CT(ASCP), MBA;
Q. Jackie Cao MD, PhD; Liron Pantanowitz, MD; and Robert Goulart, MD
Baystate Medical Center/Tufts University Medical Center
Springfield, Massachusetts

2. Conflict of Interest
The authors have no financial arrangements to disclose which could represent a potential conflict of interest.

3. Introduction ASCCP 2006 consensus guidelines
Double screening in women age 30+
If both tests NEG, repeat every 3 yrs
For women age 30+, HPV testing:
More sensitive than cytology for detection of CIN
Bulkmans et al., Lancet 2007; Mayrand et al., NEJM 2007
Naucler et al., NEJM 2007; Shi et al., Am J of Epidemiology 2009
Small reduction of PPV
Some authors suggest HPV testing at extended intervals for primary cervical cancer screening, with cytology (or other test) as triage

4. Introduction
Randomized clinical trial; India; 130,000 women years of age
Sankaranarayanan et al., NEJM 2009
Single HPV screen reduced the incidence of advanced cervical cancer and cervical-cancer mortality
Greater than single conventional Pap smear or visual cervical inspection
Although detection rates were similar
No cancer deaths among HPV-negative women

5. Introduction Controversial and debated conclusions:
Unidentified follow-up care differences
Further study of VIA arm required (visual inspection with acetic acid) Suba et al., NEJM 2009
Longer-term cohort follow-up ongoing
Screening implications for low-resource regions and cost-conscious developed countries
Decades until benefits of prophylactic HPV vaccines
Affordable and accurate HPV DNA testing exists
Simpler and less expensive test to likely follow
Schiffman and Wacholder, NEJM 2009

6. Objective
To examine the added yield of cytology by retrospectively determining the frequency and types of morphologic Pap test findings in double screened 30+ HPV-negative women
In a large, hospital-based laboratory

7. Methods 12-month period (2008) HPV-Neg cases stratified by:
Morphologic interpretation
Using TBS 2001
Rates and findings of subsequent follow-up (Pap test and/or biopsy) were recorded
Endometrial cells, 40+ yrs old
Biopsy follow-up for atypical endometrial hyperplasia/carcinoma
Trichomonas
Herpes

8. Clinically significant “end point” lesions defined as:
CIN 3+
Atypical endometrial hyperplasia/carcinoma
Trichomonas
Herpes

9. Methods (continued)
ALTS trial data used to estimate rate of CIN 3+ for HPV-Neg with ASC-US
ThinPrep; with 100% Imager review
Qiagen HCII (RCS platform)

10. Results 5,194 30+ women double-screened HPV DNA testing:
Negative (90%)
Positive (7%)
Insufficient material (3%)
5, women with combined morphology and HPV result

11. Results: HPV Test Results by Patient Age (Decade) (n=5,025)

12. Results: HPV-Negative Patients (n = 4,666)
Pap Morphologic Interpretations

13. Results: HPV-Negative Patients (n = 4,666)
Pap Morphologic Interpretations
Non-NILM Pap Interpretations for HPV-Neg (n = 233)

14. Results: Follow-up of Epithelial Abnormalities in HPV-Neg Women
Pap Test Interpretation
HPV-Neg Women (n=4,666)
Follow-Up (Pap Test and/or Biopsy)
Cases with CIN 3+
ASC-US
202 (4.3%)
N/A* 3*
ASC-H
9 (0.2%)
5 (55%)
LSIL
15 (0.3%)
9 (60%)
LSIL; cannot exclude HSIL
2 (0.04%)
2 (100%)
HSIL
1 (0.02%)
1 (100%) 1
AGC
4 (0.1%)
4 (100%)
Overall %
233/4666 (4.9%)
21/31 (68%)
*Estimated using ALTS follow-up data, which showed a 1.4% rate of CIN 3+
in ASC-US HPV-N women (all ages).

15. Results: Other Significant Findings and Follow-up
Clinically Significant Finding
Endometrial Cells, 40+ yrs
n= 124 (2.6%)
No*
Trichomonas
38 (0.8%)
Herpes Simplex Virus
0 (0%)
*No atypical endometrial hyperplasia/carcinoma identified
during follow-up for identification of endometrial cells, 40+ yrs

16. Results:
Information that would be lost with HPV only primary screening for HPV-Neg, 30+ yr old women:
4 clinically significant epithelial lesions, CIN 3+ (0.09%)
Trichomonas (0.8%)
Additional 6 months of data yielded similar results

17. What Did It Cost To Find What Would Have Potentially Been Lost?
Finding
Cost per finding*
CIN 3+ (1 case)
$233,300
CIN 3+ (4 cases)
$58,325
Trichomonas identifications
$6,139
*Based on $50/Pap test x 4,666 tests

18. Conclusion
Our data further supports minimal yield for morphologic Pap test review in HPV-Negative women age 30+.
The identification of significant morphologic findings in this cohort come at great expense.

19. Thank You