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

Ikenberg H, Bergeron C, Schmidt D, Griesser H, Alameda F, Angeloni C, Bogers J, Dachez R, Denton K, Hariri J, Keller T, von Knebel Doeberitz M, Neumann HH, Puig-Tintore LM, Sideri M, Rehm S, Ridder R, PALMS Study Gro - J. Natl. Cancer Inst. (2013)

Bottom Line: 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.The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older.

View Article: PubMed Central - PubMed

Affiliation: 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).

ABSTRACT

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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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Related in: MedlinePlus

Diagnostic performance for detecting CIN2+ (Reference standard H&E). Receiver operating characteristic graph is shown for Pap cytology (squares), dual-stained cytology (circles), and HPV (triangle) for women 18–65 years of age (gray fill), younger than 30 years (white fill), and 30 years or older (black fill).
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Figure 2: Diagnostic performance for detecting CIN2+ (Reference standard H&E). Receiver operating characteristic graph is shown for Pap cytology (squares), dual-stained cytology (circles), and HPV (triangle) for women 18–65 years of age (gray fill), younger than 30 years (white fill), and 30 years or older (black fill).

Mentions: Among women of all ages, sensitivity for biopsy-confirmed CIN2+ (reference standard H&E) of dual-stained cytology was 86.7%, statistically significantly higher than Pap cytology (68.5%; ratio of true-positive fractions = 1.265, P < .001) (Tables 2 and 3). Specificity rates for both tests were comparable (95.2% vs 95.4%; ratio of false-positive fractions = 1.049; P = 0.15). A similar statistically significant effect of increased sensitivity of dual-stained cytology over Pap cytology was observed when analyzing data for women 18–29 years or women 30 years or older (Tables 2 and 3). HPV testing in screening of women 30 years or older was more sensitive for CIN2+ than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001). Figure 2 summarizes the diagnostic performance as a receiver operating characteristic graph.


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

Ikenberg H, Bergeron C, Schmidt D, Griesser H, Alameda F, Angeloni C, Bogers J, Dachez R, Denton K, Hariri J, Keller T, von Knebel Doeberitz M, Neumann HH, Puig-Tintore LM, Sideri M, Rehm S, Ridder R, PALMS Study Gro - J. Natl. Cancer Inst. (2013)

Diagnostic performance for detecting CIN2+ (Reference standard H&E). Receiver operating characteristic graph is shown for Pap cytology (squares), dual-stained cytology (circles), and HPV (triangle) for women 18–65 years of age (gray fill), younger than 30 years (white fill), and 30 years or older (black fill).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3814411&req=5

Figure 2: Diagnostic performance for detecting CIN2+ (Reference standard H&E). Receiver operating characteristic graph is shown for Pap cytology (squares), dual-stained cytology (circles), and HPV (triangle) for women 18–65 years of age (gray fill), younger than 30 years (white fill), and 30 years or older (black fill).
Mentions: Among women of all ages, sensitivity for biopsy-confirmed CIN2+ (reference standard H&E) of dual-stained cytology was 86.7%, statistically significantly higher than Pap cytology (68.5%; ratio of true-positive fractions = 1.265, P < .001) (Tables 2 and 3). Specificity rates for both tests were comparable (95.2% vs 95.4%; ratio of false-positive fractions = 1.049; P = 0.15). A similar statistically significant effect of increased sensitivity of dual-stained cytology over Pap cytology was observed when analyzing data for women 18–29 years or women 30 years or older (Tables 2 and 3). HPV testing in screening of women 30 years or older was more sensitive for CIN2+ than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001). Figure 2 summarizes the diagnostic performance as a receiver operating characteristic graph.

Bottom Line: 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.The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older.

View Article: PubMed Central - PubMed

Affiliation: 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).

ABSTRACT

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Show MeSH
Related in: MedlinePlus