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Improved Abnormal Pap Smear Triage Using Cervical Cancer Biomarkers

Killeen, Jeffrey L. MD; Dye, Timothy PhD; Grace, Chelestes MD; Hiraoka, Mark MD

Journal of Lower Genital Tract Disease: January 2014 - Volume 18 - Issue 1 - p 1–7
doi: 10.1097/LGT.0b013e31828aeb39

Objective The current system of Pap smear screening and management of abnormal cytology has resulted in a marked reduction in invasive cervical cancer. Many women, however, are not found to have significant precursor lesions. This is due to the poor specificity of high-risk human papillomavirus (HPV) triage. More specific cervical cancer biomarkers may be more effective triage tools than hr-HPV. We evaluated whether a dual stain for p16 and Ki-67 might improve the triage of abnormal Pap smears.

Materials and Methods p16/Ki-67 immunostaining was performed on additional slides prepared from 515 women with abnormal Pap smears (301 atypical squamous cells of undetermined significance [ASCUS], 169 low-grade squamous intraepithelial lesion [LSIL], 29 atypical squamous cells-cannot exclude high-grade lesion [ASC-H], 16 high-grade squamous intraepithelial lesion [HSIL]). High-risk HPV typing was performed on all cases. Immunostaining and hr-HPV were compared in relation to their diagnostic accuracy for the detection of biopsy-proven cervical intraepithelial neoplasia (CIN) 2/3. A cost analysis comparing hr-HPV versus immunostaining as the initial triage tool used for abnormal Pap smears was also performed.

Results High-risk HPV was positive in 127 (42.2%) ASCUS, 129 (76.3%) LSIL, 20 (69.0%) ASC-H, and 15 (93.8%) HSIL. p16/Ki-67 was positive in 54 (17.9%) ASCUS, 73 (43.2%) LSIL, 19 (65.5%) ASC-H, and 15 (93.8%) HSIL. For detection of CIN 2/3, sensitivity/specificity of hr-HPV and p16/Ki-67 was 89.29%/14.94% and 96.43%/60.92%, respectively. Overall, diagnostic accuracy was statistically significantly higher for p16/Ki-67 compared with hr-HPV. Compared to HPV, immunostain triage could have generated approximately $46,000 savings in the study population.

Conclusions The triage of abnormal Pap smears by p16/Ki-67 immunostaining shows comparable sensitivity, improved specificity, and significantly improved diagnostic performance when compared to hr-HPV. Immunostaining is of value in triaging LSIL and ASC-H Pap smears in addition to ASCUS. The widespread utilization of biomarker triage could result in significant health care cost savings without compromising the detection of significant cervical cancer precursors.

Triage of abnormal Pap smears using biomarkers is more effective than high-risk human papillomavirus triage.

Kapi’olani Medical Center for Women and Children, Honolulu, HI

Reprint requests to: Jeffrey L. Killeen, MD, Department of Pathology, Kapi’olani Medical Center for Women and Children, 1319 Punahou St, Honolulu, HI 96826. E-mail:

The authors have declared they have no conflicts of interest.

The authors received funding from the Hawaii Medical Services Association Foundation, the Kapi’olani Foundation, and the Pacific Medical Administrative Group.

Copyright © 2014 by the American Society for Colposcopy and Cervical Pathology