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

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

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

Introduction Randomized clinical trial; India; 130,000 women 30-59 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

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

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

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

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

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)

Results 5,194 30+ women double-screened HPV DNA testing: Negative (90%) Positive (7%) Insufficient material (3%) 5,025 30+ women with combined morphology and HPV result

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

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

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

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).

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

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

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

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.

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