Good performance of p16/ki‐67 dual‐stained cytology for surveillance of women treated for high‐grade CIN

• Published in: International journal of cancer Vol. 140; no. 2; pp. 423 - 430
• Main Authors: Polman, Nicole J., Uijterwaal, Margot H., Witte, Birgit I., Berkhof, Johannes, van Kemenade, Folkert J., Spruijt, Johan W.M., van Baal, W. Marchien, Graziosi, Peppino G.C.M., van Dijken, Dorenda K.E., Verheijen, René H.M., Helmerhorst, Theo J.M., Steenbergen, Renske D.M., Heideman, Daniëlle A.M., Ridder, Ruediger, Snijders, Peter J.F., Meijer, Chris J.L.M.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15-01-2017
• Subjects: Adult; Cancer; Cell cycle; Cellular biology; Cervical cancer; cervical cytology; Cervical Intraepithelial Neoplasia - metabolism; Cervical Intraepithelial Neoplasia - pathology; Cervical Intraepithelial Neoplasia - virology; Colposcopy - methods; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cytodiagnosis - methods; DNA methylation; Early Detection of Cancer - methods; Female; human papillomavirus; Humans; Ki-67 Antigen - metabolism; Medical research; Middle Aged; p16/Ki‐67 dual‐stained cytology; Papillomaviridae; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; posttreatment; Pregnancy; Prospective Studies; recurrent cervical intraepithelial neoplasia; Sensitivity and Specificity; Surveillance; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Young Adult; cervical cytology; recurrent cervical intraepithelial neoplasia; p16/Ki-67 dual-stained cytology; posttreatment; human papillomavirus
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30449

Women treated for high‐grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high‐risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki‐67 dual‐stained cytology (p16/Ki‐67) for posttreatment monitoring. Three hundred and twenty‐three women treated for high‐grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki‐67 dual‐staining was performed on residual liquid‐based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki‐67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki‐67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71–1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68–0.99). Specificity of p16/Ki‐67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19–1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12–1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki‐67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92–1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19–1.38). Thus, when considered in combination with hrHPV, p16/Ki‐67 might be an attractive approach for surveillance of women treated for high‐grade CIN.
What's new?
Normally the cell‐cycle regulator p16 and the proliferation marker Ki‐67 are not expressed in the same epithelial cell unless the cell is dysregulated after infection with a high‐risk human papilloma virus (hrHPV). Here the authors used p16/Ki‐67 dual‐stained cytology in combination with hrHPV testing in women treated for high‐grade intraepithelial cervical neoplasia (CIN2/3). They show that this test is as sensitive as conventional cytology/hrHPV co‐testing to detect recurrence. However, it results in lower colposcopy referrals due to higher specificity and positive predictive value, making it an interesting approach to monitor women for recurrent CIN2/3.