Application of p16/Ki-67 dual-staining cytology in cervical cancers

Abstract

Cytology-based Papanicolaou test on and primary HPV screening have been widely used in the identification of cervical cancer and precancerous lesions, which is of great significance for the prevention and treatment of cervical cancer. Patients diagnosed as ASCUS/LSIL usually need follow-up because some of them may develop into CIN2+. The consequences of women positive for HPV vary from person to person; some of them may progress into cervical dysplasia, reversible forms of precancerous lesions, and eventually invasive cervical cancer. Therefore, it is necessary to establish an effective biomarker to triage different patients according to the preliminary screening results. p16 acts as a cell cycle regulatory protein that induces cell cycle arrest, and Ki-67 is a cell proliferation marker. Under physiological conditions, they could not co-express in the same cervical epithelial cells. The co-expression of these two molecules suggests a deregulation of the cell cycle mediated by HR-HPV infection and predicts the presence of high-grade cervical epithelial lesions. There is increasing evidence that p16/Ki-67 dual-staining cytology can be used as an alternative biomarker, showing overall high sensitivity and specificity for identifying high-grade CIN and cervical cancer. In this review, we discuss the significance of p16/Ki-67 dual-staining and summarize its application in the screening and triaging of cervical cancer and precancerous lesions.

Keywords: CIN; HPV; cervical cancer screening; cytology; p16/Ki-67 dual-staining.

Fig 1

p16/Ki-67 dual-staining positive cells with morphological features of HSIL. A, Liquid-based cytology (SurePath). B, Slide A was dual-stained with p16/Ki-67. Cell with p16 staining alone (blue arrow) is characterized by a brown cytoplasmic/nuclear signal and cell with Ki-67 staining alone (red arrow) is presented in red nuclear signal. The positive p16/Ki-67 dual-staining cells (dark arrow) are characterized by a brown cytoplasmic signal for p16 overexpression and a dark red nuclear signal for p16/Ki-67 co-expression in the same cell. (45-year-old woman, CIN3, HPV16+, p16/Ki-67+).

Fig 2

Screening and triaging of cervical cancer and the application of p16/Ki-67 dual-staining. The women diagnosed as ASCUS/LSIL, or positive for HR-HPV and free of cytological abnormalities, or positive for other 12 types of HR-HPV and negative for HPV 16 and 18 are recommended for the triage by p16/Ki-67 dual-staining.