p16INK4a (p16) tumor-suppressor protein is a biomarker of human papillomavirus 
(HPV) oncogenic activity that has revealed a high rate of positivity in 
histological high-gade squamous intraepithelial lesion/cervical intraepithelial 
neoplasia grade 2 (HSIL/CIN2) lesions. However, there is a paucity of data 
regarding p16 status as a surrogate marker of HSIL/CIN2 evolution. The aim of 
this study was to evaluate the outcome of HSIL/CIN2 patients followed up without 
treatment for 12 months according to p16 immunohistochemical staining. Patients 
diagnosed with HSIL/CIN2 colposcopy-directed biopsy, were recruited 
prospectively between December 2011 and October 2013. p16 staining was performed 
in all HSIL/CIN2 diagnostic biopsies. Follow-up was conducted every 4 months by 
cytology, colposcopy and biopsy if suspicion of progression and once the 12 
months of follow-up completed. Complete regression, partial regression, 
persistence, and progression rates of HSIL/CIN2 were defined as a final outcome. 
A total of 96 patients were included in the analysis. The rate of spontaneous 
regression was 64%, while 28% had persistent disease, and 8% progressed at 12 
months of follow-up. p16 was positive in 81 (84%) initial HSIL/CIN2 biopsies. 
Regression was observed in all 15 p16 negative cases and in 46 of 81 (57%) p16 
positive cases (P=0.001). In conclusion, patients with p16 negative HSIL/CIN2 
biopsy had a high rate of regression during first 12 months of follow-up. Status 
of p16 staining could be considered for HSIL/CIN2 management.