The natural history of cervical intraepithelial neoplasia I and the clinical significance of p16(INK4a) protein as a marker of progression in cervical intraepithelial neoplasia I

Abstract

To describe the natural history of cervical intraepithelial neoplasia (CIN) I and the biologic factors associated with the progression of CIN I and to analyze the predictive values of p16(INK4a) protein for the progression of CIN I. From August 2010 to July 2013, 104 patients referred for abnormal cytology [≤ low-grade squamous intraepithelial lesion (LSIL); including negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASCUS), LSIL] and high-risk (HR) HPV positive, and were diagnosed CIN I by colposcopy-assisted biopsy and followed at 1-year intervals in the First Affiliated Hospital of Nanjing Medical University. In order to analyze the relationship between the progression of CIN I with clinical biologic factors, including patient age, cervical cytology before colposcopy, loads of HR HPV, HPV L1 capsid protein, p16(INK4a) protein, χ(2) tests was used to compare the different frequencies of factors in groups of progressed and persisted/regressed CIN I, then five factors with progressed CIN I were processed into binary logistic regression analysis. (1) In the first year of follow-up, among 104 patients (including 15 cases NILM, 78 cases ASCUS, 11 cases LSIL), 52 cases of them were NILM and HR HPV negative, 30 cases were negative for intraepithelial lesion, 10 cases were CIN I, 5 cases were CIN II and 7 cases were CIN III. In total, 82 cases (78.8%, 82/104) cases had regressed, 10 cases (9.6%, 10/104) persisted, 12 cases (11.5%, 12/104) progressed [including 5 cases (4.8% , 5/104) progressed to CIN II, 7 cases (6.7% , 7/104) progressed to CIN III, none progressed to invasive cancer]. (2) All patients, 88 cases of them accepted immunohistochemical detection the expression of p16(INK4a) protein. The result shown that 30 cases (34%, 30/88) were positive and 58 cases (66%, 58/88) were negative. And 94 cases accepted immunocytochemical detection the expression of HPV L1 capsid protein, 49 cases (52% , 49/94) were positive and 45 cases (48% , 45/94) were negative. (3) Univariate analysis showed that age of the patient, loads of HR HPV, cervical cytology before colposcopy and the expression of HPV L1 capsid protein were not risk factors of the progression of CIN I (all P>0.05) except for the expression of p16(INK4a) protein (P<0.05). Multivariable analysis found that p16(INK4a) protein positive was associated with progression of CIN I (OR=5.1, 95%CI: 1.162-22.387, P=0.031). (4) Thirty-one cases were p16(INK4a) protein positive, 8 cases (27%, 8/30) of them progressed, while 4 cases (7%, 4/58) of 58 cases with p16(INK4a) protein negative progressed,in which there were significant difference (P<0.05). The sensitivity was 75%, the specificity was 71%, the positive predictive value was 27% and the negative predictive value was 93% for progression to CIN II-III of p16(INK4a) protein staining. The progression rate of CIN I with abnormal cytology (≤LSIL) and HR HPV positive was lower, and there was no progression to invasion at 1-year intervals. Immunostaining of p16(INK4a) protein as the risk factors of CIN I progression could have a role in prediction of CIN I and the management of high-risk CIN I.