The Negative Predictive Value of p16INK4a to Assess the Outcome of Cervical Intraepithelial Neoplasia 1 in the Uterine Cervix

Abstract

The immunohistochemical expression of p16 in formalin-fixed and paraffin-embedded histological sections was evaluated in a retrospective study comprising a low-grade group of 100 cases of cervical intraepithelial neoplasia (CIN) 1, a high-grade group of 50 cases of CIN 2 to 3, and a benign group of 50 cases of normal tissue or benign lesions in the uterine cervix. The cases were consecutive within each group and had a minimum follow-up period of 5 years. Positive reaction for p16 was detected in all cases in the high-grade group and in only 3 cases in the benign group. In the low-grade group, a total of 9 cases had to be excluded. The remaining 91 cases in the low-grade group showed positive reaction for p16 in 65 cases (71%), including 23 cases that progressed to a high-grade lesion, 36 cases that revealed normal cytological and/or histological picture during the follow-up period, and 6 cases that persisted as CIN 1. A total of 26 cases (29%) in the low-grade group showed negative reaction for p16. All but one of these p16 negative cases in the low-grade group had a benign or normal outcome. This case showed a high-grade lesion in the follow-up period and was probably a high-grade lesion from the beginning and so underestimated as CIN 1. These results reveal that the negative predictive value of p16 to predict the outcome of the cases of CIN 1 is as high as 96%, which strongly suggest an important role of p16 in the assessment of this type of lesion.

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.…”

“…23 hrHPV testing was performed in the cervical specimens collected in PreservCyt solution using the commercially available Hybrid Capture 2 (HC2) system (Qiagen, Gaithersburg, MD, USA). All the samples were analyzed for the presence of hrHPV types (16,18,31,33,35,39,45, 51, 52, 56, 58, 59, and 68). A relative light units value of 1 (1.0 pg/ml) was used as the cutoff to classify and record each specimen as positive or negative.…”

“…In the last decade, a number of studies have addressed this issue and have suggested that p16-positive LSIL/CIN1 lesions are at higher risk of showing a HSIL/CIN2-3 outcome diagnosis. 4,5,16,17 However, the number of cases included in these series was very small and consequently, the true value of p16 as a marker of 'progression' in these women remains uncertain. Thus, prospective, longitudinal studies focused on the prognostic value of p16 immunostaining in patients with biopsies showing LSIL/CIN1 are needed before definitive conclusions can be drawn.…”

“…Thus, prospective, longitudinal studies focused on the prognostic value of p16 immunostaining in patients with biopsies showing LSIL/CIN1 are needed before definitive conclusions can be drawn. 5,16,[18][19][20][21][22] The aim of this study was to evaluate the usefulness of p16 staining in predicting the outcome of biopsy proven LSIL/CIN1 lesions, in a large prospective series of patients recruited at a single institution and who were strictly followed over a long period of time.…”

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

“…There is extensive evidence showing that CDKN2A/p16 staining in histological sections increases the detection of HSIL 13,16 and can identify LSIL at higher risk of progression. 10,17 Recently, the combination of p16 and Ki67 detected by immunohistochemistry has been used in cytological samples to identify patients with high-grade cervical lesions. 18,19 In our study, the analysis of these biomarkers in biopsy material by immunohistochemistry showed that all were positive in a high proportion of the HSIL lesions, which is consistent with current evidence.…”