P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri

Abstract

The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (< or = 25%) and as diffuse positive (> 25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P < 0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.

Impact of utilizing p16INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

“…One prospective study of women with CIN 1 demonstrated a higher rate of regression of p16 INK4A -negative CIN 1 lesions (71%) compared to p16-positive CIN 1 lesions (38%). 20 Although some p16-negative CIN 1 lesions progressed to CIN 3 in that study, the p16-positive lesions were much more likely to progress. Another prospective study demonstrated that 44% of women with p16 INK4A -positive biopsies that were classified as ''not CIN 2,3'' by consensus pathology were subsequently diagnosed with CIN 2,3.…”

“…23 Moreover, women with cervical biopsies that are p16 INK4a -positive but not diagnosed as CIN 2,3 are at greatly elevated risk for subsequently being diagnosed with CIN 2,3 and women with p16 INK4a -negative CIN 1 lesions are less likely to progress to CIN 3 than those with p16 INK4a -positive CIN 1. 16,20 Numbers do not add up to totals due to missing data and are as shown. Cases of invasive cervical cancer are not included.-2 v 2 test for trend except for median RLU value that is by Kruskall-Wallace test.-3 P0 is ''warrants colposcopy'' diagnosis.- 4 If high-risk HPV DNA positive by hc2, RLU is relative light units that is an indicator of HPV DNA content or viral load.…”

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

“…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. 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.…”

“…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.…”

“…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.…”