Association of p16 and Ki-67 with Risk of Recurrence in Previously Treated Cervical High-Grade Squamous Intraepithelial Lesions

Abstract

<b><i>Objective:</i></b> Our main objective was to assess the association between the markers p16 and Ki-67 and recurrence of disease in patients previously treated for cervical high-grade squamous intraepithelial lesion (HSIL). <b><i>Design:</i></b> This is a case-control study at the National Cancer Institute conducted between 2005 and 2015. Of the patients with a pathologically confirmed diagnosis of HSIL, 107 cases were selected. They were divided into 2 groups: 28 cases with recurrence after treatment and a control group of 79 patients without recurrence. We identified clinical, pathological, and treatment variables. <b><i>Methods:</i></b> Two experienced pathologists performed immunohistochemical analysis of biomarkers; they agreed on their interpretation, and we calculated the odds ratios (ORs) associated with recurrence. For group comparisons, we used the Wilcoxon signed-rank, χ<sup>2</sup>, or Fisher’s exact test, depending on the type of variable. We conducted logistic regression models to estimate ORs and determine the factors associated with recurrence. The recurrence-free period was defined as the time frame between conization and either recurrence of disease or the last date the patient was seen. We used Kaplan-Meier plots to visualize survival curves and log-rank tests to compare the curves. We established a <i>p</i> value <0.05 as statistically significant. <b><i>Results:</i></b> After pathologists performed immunohistochemical analysis, they achieved an agreement level of 83.7% for p16 and 60% for Ki-67. We did not find an association between recurrence and either p16 expression (<i>p</i> = 0.69) or the percentage of Ki-67 expression (<i>p</i> = 0.71). The recurrence-free period analysis did not reveal a difference in p16 expression (<i>p</i> = 0.57) nor in the percentage of Ki-67 expression in the 3-tiered scale (<i>p</i> = 0.56). <b><i>Limitations:</i></b> Our main limitation was a reduced sample size. <b><i>Conclusion:</i></b> We found no association between p16 and Ki-67 positivity and the risk of recurrence in previously treated HSIL.

P16 expression and recurrent cervical intraepithelial neoplasia after cryotherapy among women living with HIV

“…The role of p16 as a predictor of recurrent cervical disease is inconclusive, with limited and contradictory results. A large study in China reported a significant association between p16 and recurrent CIN2+ disease after conization and two-year follow-up (25). Compared with our study, the women were on average 10 years older and both their HIV and hrHPV status at baseline treatment were not disclosed, thus we cannot directly compare our findings.…”

“…In a smaller study of HIV-uninfected women with CIN2+, cervical disease recurrence was 37% at 18 months and the positive predictive value of p16 for recurrent CIN2+ disease was 42% ( 24 ). Similarly, in a study in Mexico, there was no association between the CIN2+ recurrence-free period and p16 expression ( p = 0.57) and few women were living with HIV (5%) ( 26 ). Moreover, p16 expression has been shown to be less sensitive than insulin-like growth factor II mRNA-binding protein (IMP3) expression at predicting progression and recurrence of HSIL among women living with HIV ( 28 ).…”

“…Few studies have investigated the role of p16 in predicting CIN2+ recurrence after surgical treatment and the findings are equivocal (24)(25)(26). We evaluated the correlates of p16 expression in women with HIV and CIN2/3 at treatment with cryotherapy and the diagnostic utility of p16 immunohistochemistry in predicting recurrence of CIN2+ in the two-years following treatment.…”