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J Natl Cancer Inst. 2013 Oct 16;105(20):1550-7. doi: 10.1093/jnci/djt235. Epub 2013 Oct 4.

Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study.

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Affiliations of authors: Cytomol, Frankfurt, Germany (HI); Laboratoire Cerba, Cergy Pontoise, France (CB); Institute for Pathology, Mannheim, Germany (DS); Center for Pathology and Cytodiagnostics, Cologne, Germany (HG); Hospital del Mar, Barcelona, Spain (FA); Unità Gestionale Screening Regionale, Ospedale Atri, Italy (CA); Labo Lokeren - Campus Riatol, Antwerp, Belgium (JB); Institute Alfred Fournier, Paris, France (RD); North Bristol NHS Trust, Bristol, United Kingdom (KD); Sønderborg Hospital, Sønderborg, Denmark (JH); Acomed statistik, Leipzig, Germany (TK); Institute for Pathology, University of Heidelberg, Heidelberg, Germany (MvkD); Institute for Pathology, Nordhorn, Germany (HHN); University of Barcelona, Barcelona, Spain (LMP-T); European Institute of Oncology, Milan, Italy (MS); Roche mtm laboratories, Mannheim, Germany (SR, RR).



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.

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