p16 is an early found tumor suppressor gene, which can inhibit the metastasis of various tumors. The product of p16 gene encoding, p16 protein, also known as p16, mainly exists in the nucleus and cytoplasm, and plays a tumor suppressor role by causing cell cycle arrest. Ki-67 protein is related to cell proliferation and is expressed in the nucleus. Ki-67 high expression indicates that cells are in a high growth stage, and the level of its marker index is related to the grade of cervical lesions.
In normal cells, the expression of p16 and Ki-67 antagonized each other. If the two proteins are expressed in the same cell, it indicates that the cell cycle is dysfunctional and cancerous. Therefore, p16/Ki-67 double staining can be used to detect cervical precancerous lesions.
p16: Nucleus, cytoplasm
Ki-67: Cytoplasm
Screening and monitoring of high-risk groups of cervical cancer
2015 edition of Bethesda(The Bethesda System for Reporting
Cervical Cytology) indicated that the sensitivity of p16/Ki-67 double-stain testing for HSIL was comparable to that of high-risk HPV, with higher sensitivity and comparable specificity compared with cytology. In young women, high-risk HPV testing has some limitations; However, studies have shown that double-dye screening can be used in younger women.
1.p16/Ki67 double staining compared with HPV
Studies have shown that when p16/Ki-67 double stain detection is used for cervical cancer primary screening, its specificity is significantly high HPV detection for women under 30 years old and over 30 years old. Most HPV infections are transient and can not directly indicate the disease situation, and the clinical need is more lesion results rather than HPV infection results. p16/Ki-67 double stain detection can reduce and avoid the waste of resources and potential harm caused by overdiagnosis.
Prigenzi, K. , Heinke, T., Salim, R.C., & Focchi, G..(2018). Dual p16 and Ki-67 expression in liquid-basedcervical cytological samples compared to pap cytology findings, biopsies, and hpv testing in cervical cancescreening: a diagnostic accuracy study. acta cytologica, 62(2), 104.
2. Specificity and predictive value of p16/Ki-67 double stain cytology and human papillomavirus detection in CIN2+ and CIN3+ screening
A large number of studies have shown that HPV testing has limited specificity in screening with histological CIN2+/CIN3+ as the endpoint, because most HPV infections are transient and only a very low percentage persist and progress to transform into infective lesions. Due to the high prevalence of HPV infection in younger women, HPV testing is not currently recommended for women under the age of 30. THE JOURNAL OF THE NATIONAL CANCER IN STITUTE (F=14.336) noted that in women 30 years of age or older, double staining specificity was greater than HPV testing (96.2 vs 93), with histological CIN2+ as the endpoint. With histological CIN3+ as the end point, double staining specificity was greater than HPV detection (95.9 vs 92.7). The positive predictive value of double-staining CIN2+ was greater than that of HPV detection (15.3 vs 9.3).
3. Sensitivity and predictive value of p16/Ki-67 double stain cytology and Pap staining in CIN2+ and CIN3+ screening
CIN2+(CIN3+), cervical intraepithelial neoplasia 2(3) grade;
HPV= Human papillomavirus;
CI= confidence interval;
PPV positive predictive value;
NPV= negative predictive value.
CIN2+ (CIN3+), cervical intraepithelial neoplasia 2 (3) grade;
C= confidence interval;
PPV= positive predictive value;
NPV= negative predictive value.
