Theoretically p Ki co expression is related to HPV infection
Theoretically, p16/Ki-67 co-expression is related to HPV infection. HPV virus—especially HPV 16/18—interferes with the cell regulation mechanism through Diphenylterazine (DTZ) of its DNA into the DNA of the host cell [25,26]. The abnormal cell then expresses p16 and Ki-67 simultaneously, transforming the activity of the E7 oncoprotein through inactivation of the tumor-suppressor function of the retinoblastoma protein [27,28]. The results of our study showed that the p16/Ki-67 positivity rate in women infected with HR-HPV was six-fold higher than in HPV negatives, and three-fold higher in women infected with HPV16/18 than in negatives. This is consistent with the findings of other studies [29,30], and indicates a strong relationship between p16/Ki-67 co-expression and HR-HPV infection, especially for women infected with HPV16/18. In our study we also observed that positivity rates of p16/Ki-67 increased with the grade of histological severity; this is in agreement with the findings of previous studies [31,32].
Many studies have recommended HR-HPV testing as the primary cervical screening method for developing countries [17,33]. Our study shows that p16/Ki-67 dual staining can detect most cervical precancers (88.10% for CIN2+, 91.30% for CIN3+) similarly to HR-HPV (95.71% for CIN2+, 88.10% for CIN3+), and also demonstrates specificities (85.02% for CIN2+ and 76.86% CIN3+) similar to those of LBC (84.71% for CIN2+, 80.05% for CIN3+). This is in accordance with previous studies [31,34]. However, the previous studies differed from our study in that they showed no significant difference between sensitivities and specificities of p16/Ki-67 and HR-HPV as well as LBC. This may be due to a different study design and a different population. Higher specificities can decrease the burden of colposcopy. If p16/Ki-67 dual staining were used as the triage strategy, colposcopy referral rates would decrease by 11.36%; 16 women with CIN2+ would be missed compared to all HR-HPV after triage, but the detection rate for CIN2+ would increase by 10.92%.
HPV is common in young women, but most infections are temporary and will be cleared . Therefore, practice bulletin No.157 regarding the prevention and early detection of cervical cancer recommends that women <30 years old need only cytology . Results of this study were stratified by age group and showed that sensitivities and specificities of p16/Ki-67 dual staining in detecting CIN2+ or CIN3+ were similar to those of LBC in women aged <30 years. It suggests that young women can receive p16/Ki-67 dual staining to avoid the subjectivity of diagnosis by cytology. Hence, under the current circumstances, p16/Ki-67 dual staining is a promising alternative method for cervical screening. A systematic literature review also showed that p16/Ki-67 dual staining is more sensitive but slightly less specific than cytology .
Performance of p16/Ki-67 for triage in women diagnosed with ASC-US was also analyzed in this study. Women diagnosed with ASC-US make up a large burden for the colposcopy doctor. Recently, HPV DNA testing as a management measure was used to triage these women attending for colposcopy . However, it can still lead to over-referral because of its low specificity. In these women, sensitivities of p16/Ki-67 in detecting CIN2+ and CIN3+ were similar to those of HR-HPV, and specificities were 85.96% (for CIN2+) and 79.84% (for CIN3+) respectively, higher than those for HR-HPV (p<0.05). This supports the idea that p16/Ki-67 dual staining could be applied to triage women with undefined and abnormal LBC results, which is consistent with the findings of previous studies [, , ].