Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections,...

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Published in:	JNCI : Journal of the National Cancer Institute 2013-10, Vol.105 (20), p.1550-1557
Main Authors:	IKENBERG, Hans, BERGERON, Christine, KELLER, Thomas, VON KNEBEL DOEBERITZ, Magnus, NEUMANN, Heinrich H, PUIG-TINTORE, Luis M, SIDERI, Mario, REHM, Susanne, RIDDER, Ruediger, SCHMIDT, Dietmar, GRIESSER, Henrik, ALAMEDA, Francisco, ANGELONI, Claudio, BOGERS, Johannes, DACHEZ, Roger, DENTON, Karin, HARIRI, Jalil
Format:	Article
Language:	eng
Subjects:	Adult Aged Biological and medical sciences Biomarkers Biomarkers, Tumor - analysis Cell Transformation, Neoplastic - chemistry Cellular biology Cervical cancer Cervical Intraepithelial Neoplasia - chemistry Cervical Intraepithelial Neoplasia - diagnosis Cervical Intraepithelial Neoplasia - pathology Colposcopy Cyclin-Dependent Kinase Inhibitor p16 Cytopathogenic Effect, Viral Early Detection of Cancer - methods Europe Female Female genital diseases Gynecology. Andrology. Obstetrics Human papillomavirus Humans Ki-67 Antigen - analysis Mass Screening - methods Medical sciences Medical screening Middle Aged Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasm Grading Neoplasm Proteins - analysis Papillomaviridae - isolation & purification Papillomavirus Infections - diagnosis Papillomavirus Infections - virology Prospective Studies Referral and Consultation Sensitivity and Specificity Tumors Uterine Cervical Neoplasms - chemistry Uterine Cervical Neoplasms - diagnosis Uterine Cervical Neoplasms - pathology Vaginal Smears
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Summary:	Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing. A total of 27,349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined. The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001). The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.
ISSN:	0027-8874 1460-2105