Evaluation of the p16 and Ki-67 Biomarkers as Predictors of the Recurrence of Premalignant Cervical Cancer Lesions after LEEP Conization

Abstract

Objective To evaluate the expressions of biomarkers p16 and K i -67 in low-grade (LG) or high-grade (HG) lesions, and to relate them to risk factors and the recurrence of these lesions. Methods A retrospective case-control study of 86 patients with LG and HG lesions who underwent a loop electrosurgical excision procedure (LEEP) between 1999 and 2004. The control group was composed of 69 women with no recurrence, and the study group, of 17 patients with recurrence. All patients were followed-up over a two-year period after surgery, and screened every six months, including cytology and colposcopy. Biopsy samples collected from LEEP were submitted to immunohistochemical analysis for p16 and K i -67. The statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS, IBM-SPSS, Inc., Chicago, IL, US), with a significant p < 0.05. Results The biomarkers p16 and K i -67, separately or combined, showed no relation to recurrence on the total analysis. However, evaluating specifically HG lesions, the positive expression (2þ and 3 þ ) of p16/K i -67 was associated with recurrence (0.010). In addition, p16 isolated was also more expressive in HG lesions (2þ and 3 þ , p ¼ 0.018), but it was unrelated to recurrence. Conclusion Proteins p16 and K i -67, both isolated and combined, are not reliable primary markers for the recurrence of cervical lesions in the majority of LG lesions. However, analyzing only the group with prior diagnosis of HG lesions, the expressions of p16 and of p16/K i -67 were associated with recurrence, and they may be useful in monitoring these cases. IntroductionThe search for markers to facilitate the diagnosis of diseases is a constant in scientific research to save resources, time and to prevent unnecessary treatments. Cervical cancer is the most common cancer among women in 45 countries of the world and, worldwide, 266 thousand women die of it each year; 1 it is preceded by cervical lesions that may or may not progress to invasion. They are associated with infection and with the persistence of the human papillomavirus (HPV) to progress to invasive carcinoma. 2 Through this process, the cells infected with high-risk oncogenic HPV alter the cell cycle, modifying the production of proteins p16 and K i -67. The most common treatment for high grade (HG) lesions is cervical cone resection using the loop electrosurgical excision procedure (LEEP). A major concern of the treatment is the recurrence of the lesion, as it may reappear without symptoms and more severely. Proteins p16 and K i -67 are, respectively, cell progression and proliferation markers. Protein p16 is a tumor suppressor from the Ink4a family that induces the hyperphosphorylation of the retinoblastoma protein (pRb), and has low expression in normal tissues.3 K i -67 is a nuclear protein present in cells during the active proliferation stage, but it is not expressed when cells are in the quiescent state. 3 The expression of both molecules simultaneously already denotes some problem in the cell c...

Assessment of p16 and Ki67 Immunohistochemistry Expression in Squamous Intraepithelial Lesion with Cytohistomorphological Correlation

“…In the study by Leite P. et al p16 positivity observed was 12.8% and 72.1% for LSIL and HSIL respectively. They also observed a significant relation between p16 positivity and recurrence with P-value of 0.018 (30). Comparative analysis of p16 and Ki67 with various recent studies and the present study is depicted in Table 4.…”

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

“…However, after specifically analyzing HSIL with p16 and Ki-67 positivity and comparing the presence or absence of recurrence, the authors observed a significant difference (OR: 0.19, 95% CI 0.054–0.662, p = 0.010). The percentage of positive cells was higher in the nonrecurrence group, thus showing that the presence of these biomarkers could be useful in managing patients with HSIL, which differs from the findings of our study [26].…”

“…A Brazilian study published in 2016 by Leite et al [26] examined the relationship between p16 and Ki-67 expression in LSIL and HSIL and the risk of recurrence after conization. They retrospectively assessed 86 patients divided into a control and a recurrence group (69 vs. 17) for 2 years after surgery, with a 6-month follow-up including cytology and colposcopy.…”

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

“…14 Several studies have shown increased sensitivity and specificity for cervical cancer screening using p16 staining in conjunction with other biomarkers, such as p16/Ki-67 15,16,[24][25][26] and Survivin, the inhibitor of apoptosis. 27 …”