Prognostic value of p16‐INK4A protein in women with negative or CIN1 histology result: A follow‐up study

Abstract

P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN21). This study measures the relative risk (RR) of CIN21 of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity.Cervical cancer is the third most common cancer in women worldwide, and the seventh overall, with an estimated 530,000 new cases in 2008. However, while persistent infection of the cervix with oncogenic human papillomavirus types-the most common sexually contracted infection in humans-is its necessary cause, 1-3 cervical cancer is in fact rare; only a very small proportion of infected women will develop a high-grade intraepithelial lesion (CIN21) and even fewer will develop cancer. 4More than 85% of the global cervical cancer burden occurs in developing countries, where it accounts for 13% of all female cancers. 5 In fact, cervical cancer is a wellKey words: cervical cancer, screening, cervical intraepithelial neoplasia, p16, colposcopy, cohort study, prognostic value Novelty and impact: P16 overexpression has been proposed as a prognostic marker for CIN progression, but a few prospective studies tested the prognostic value of histological p16 in post-colposcopy follow up. In a 2 years cohort study, we found low prognostic sensitivity for CIN21 (6/13), but a 5.5 relative risk (95% CI 1.7-17.4) for women p16 positive at baseline compared to negative. P16 overexpression is a good candidate for modulating follow up intensity after a negative colposcopy.

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

“…13 Women have a range of approximately two years of stable CIN development and rarely progress to cancer. 14 Additionally, p16 can be useful for identifying high grade lesion when histological features are equivocal but p16 utility in screening and in conjunction with other markers…”

p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix

“…Some of these studies do not include hrHPV testing, 4,16 have a short follow-up, 21 or include a very limited number of patients with LSIL/CIN1. 25,26 Other studies analyze specific groups, which were retrospectively selected based on the outcome. 17,27 Independently of their design, all these studies show that patients with LSIL/CIN1 with diffuse p16 staining are at higher risk of progression to HSIL/CIN2-3 and suggest the need for closer follow-up.…”

“…17,27 Independently of their design, all these studies show that patients with LSIL/CIN1 with diffuse p16 staining are at higher risk of progression to HSIL/CIN2-3 and suggest the need for closer follow-up. 5,16,17,25,26 However, all these studies reported a relative inaccuracy of p16 to predict the outcome of LSIL/CIN1, thereby questioning the usefulness of follow-up strategies modulated by p16. 5,22,26 The main strength of our study is that it includes a large series of women with LSIL/CIN1.…”

“…5,16,17,25,26 However, all these studies reported a relative inaccuracy of p16 to predict the outcome of LSIL/CIN1, thereby questioning the usefulness of follow-up strategies modulated by p16. 5,22,26 The main strength of our study is that it includes a large series of women with LSIL/CIN1. Moreover, all the patients were prospectively recruited and followed over a long period of time.…”

Cervical intraepithelial neoplasia in pregnancy: Interference of pregnancy status with p16 and Ki-67 protein expression

“…In a study by Benevolo et al, none of the normal cervical tissues analyzed exhibited p16 positive staining, whereas a constant and significant increase in protein overexpression was observed in CIN1 (30%), CIN2 (90%), CIN3 (100%) and carcinoma (100%) tissues (36). More recently, p16 was evaluated as a prognostic marker of progression and regression in series of prospectively recruited patients with CIN1, suggesting that a negative result for p16 may exclude the possibility of progression during follow-up (37). The Ki-67 protein is a human nuclear antigen strictly associated with cell proliferation.…”