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

Abstract

In order to evaluate the usefulness of p16 staining in predicting the outcome of histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 (LSIL/CIN1) we prospectively recruited all the patients referred to colposcopy from 2003 to 2011 due to abnormal screening test results and diagnosed with LSIL/CIN1 at biopsy (n = 507). All biopsies were stained for p16 and re-evaluated after three years by the same gynecological pathologist using the LAST criteria. Follow-up was conducted every 6 months and included a Pap test (liquid-based cytology), high-risk human papillomavirus testing (Hybrid Capture 2 test), and colposcopy. The mean follow-up was 28 months. An outcome diagnosis of HSIL was defined as a histological diagnosis of highgrade SIL/CIN (HSIL/CIN2-3). The diagnosis of LSIL/CIN1 was confirmed in 416 out of 507 biopsies (82%), whereas 58 (11%) were reclassified as negative and 33 (6%) as HSIL/CIN2-3. During follow-up, 86/507 women initially diagnosed with LSIL/CIN1 (17%) showed an outcome diagnosis of HSIL/CIN2-3, with the rate of HSIL final diagnosis of 3% (2/58) in the women with biopsies reclassified as negative, 17% (70/416) in the group with confirmed LSIL and 42% (14/33) in the women with biopsies reclassified as HSIL (Po 0.001). p16 was positive in 245/507 patients (48%) and in 210/416 patients (50%) with confirmed LSIL/CIN1 at re-evaluation. Although positive p16 immunostaining was associated with risk of HSIL/CIN2-3 outcome in the multivariate analysis (Hazard ratio (HR) 1.9; 95% confidence interval (CI): 1.2-3.1; P = 0.009) in the overall group of patients with LSIL/CIN1, this association was not verified in the subset of patients with confirmed LSIL/CIN1 after re-evaluation (HR: 1.6; 95% CI: 0.9-2.6; P = 0.095). In conclusion, in LSIL/CIN1 lesions p16 should be limited to equivocal cases in which HSIL/CIN2 is included in the differential diagnosis since it has low value in clinical practice as a marker of progression of LSIL/CIN1.

Progression of Precancerous Cervical Lesion Predicted by p16 Protein Immunohistochemistry in Rajavithi Hospital

“…Factor Associated with Recurrent to CIN2 or Worse in HSIL from those studies were inconclusive. The statistical difference was obvious in 2 studies (Liao et al, 2014;Razmpoosh et al, 2014) whereas not statistically different in another 2 studies (Pacchiarotti et al, 2014;Sagasta et al, 2016). In the present study, high-grade lesion with positive p16 staining had recurrence to CIN2+ about 2.13 times than those with negative p16 staining but it was not significantly different.…”

Predictive value of p16INK4a, Ki‑67 and ProExC immuno‑qualitative features in LSIL progression into HSIL

“…Liao et al (19) conducted a prospective population-based study to evaluate if the overexpression of p16 INK4a in LSIL biopsies can accurately predict HSIL progression and found that p16 INK4a expression in LSIL on initial diagnosis was associated with an increased risk of HSIL in 2 years (OR=1.43; 95% CI, 0.52-3.91). However, Sagasta et al (20) showed that HSIL/CIN2-3 exhibited higher positive rates for p16 INK4a staining compared with persistent or regressing LSIL/CIN1 lesions (71 vs. 44%), but found that p16 INK4a immunostaining was not associated with risk of HSIL [hazard ratio 1.6 (95% CI, 0.9-2.6); P=0.095]. Sagasta et al (20) subsequently concluded that p16 INK4a overexpression in biopsies from women with LSIL was a poor predictor in LSIL progression, with little or no value as a marker in clinical practice.…”

“…It is therefore possible that p16 INK4a , Ki-67 and ProExC can be applied as early HSIL and cervical cancer risk indicators in early cervical lesions. However, to the best of our knowledge, there have been limited studies on the predictive value of p16 INK4a and Ki-67 for LSIL prognosis with inconsistent results (19)(20)(21), whilst the use of ProExC staining as a biomarker for LSIL prognosis has not been previously reported.…”

Deciphering the Multifactorial Susceptibility of Mucosal Junction Cells to HPV Infection and Related Carcinogenesis

“…Among these latter, p16 ink4 , the HPV viral load and genotyping were the most investigated. Although, all gave some indications on high-risk patients, a lack of concordance has been extensively reported and all failed to precisely predict CIN, which will finally progress to cancer [68,69,70,71,72,73,74,75]. …”