Usefulness of CINtec® PLUS p16INK4a/Ki-67 Double-Staining in Cytological Screening of Cervical Cancer

Abstract

Objective: This study evaluated the usefulness of p16^INK4a/Ki-67 as a new biomarker in the diagnosis of human papillomavirus (HPV)-related cervical lesions. Study Design: From 69 women with previous positive cytology, clinician-collected (CC) samples were obtained using a Cervex-Brush®. One month later, self-collected (SC) material was acquired using a Rovers® Viba-Brush. Liquid-based cytology specimens were prepared from both samples, and then the grades of squamous intraepithelial lesions (SIL) were determined; following immunostaining with CINtec® PLUS, HPV status was analyzed using a linear array. Results: The mean double-positive cell scores (SCORE) in the CC samples were 3.2 in samples negative for intraepithelial lesions or malignancy, 1.3 in atypical squamous cells of undetermined significance, 87.1 in low-grade SIL, and 367 in high-grade SIL. According to HPV risk type, the mean SCORE was 16 in samples negative for HPV, 8.4 in low-risk HPV, 143 in high-risk HPV other than type 16, and 420 in HPV16 – with a statistical significance between high-risk HPV and type 16 (p < 0.05). The SCORE of the SC group was lower than that of the CC group because of the limited number of cells collected. Conclusions: The SCORE showed a significant correlation with HPV16 compared with lesser-degree lesions. CINtec PLUS is useful as a diagnostic marker of progression of lesions and a surrogate marker of an elevated risk of high-grade lesions with HPV16.

HPV16 genotype, p16/Ki‐67 dual staining and koilocytic morphology as potential predictors of the clinical outcome for cervical low‐grade squamous intraepithelial lesions

“…Various studies have evaluated the usefulness of the immunocytochemical detection of the biomarkers p16 and Ki-67 as potential indicators of an underlying high-grade cervical lesion. [29][30][31][32] In our study, dual staining was expressed in 36.1% of LSIL cases, which is consistent with the result of 36.4% reported by Singh et al 35 However, higher p16/Ki-67 positivity rates of 52.5%, 66.5% and almost 70% were detected in other studies. [30][31][32][33] In those studies, immediate or subsequent clinical outcome was more frequently CIN2+ compared with our results.…”

“…In recent studies, it has been shown that the sensitivity of p16/Ki-67 dual staining for the detection of CIN2+ is close to that of hrHPV positivity, and ranges from 81.8% to 97%; the specificity ranges from 53% to 81.8% and, in all studies, is higher for p16/Ki-67 dual staining than for hrHPV DNA tests (specificity of about 40%). [30][31][32][33][34][35] Similarly, in our study, the sensitivity of p16/Ki-67 dual staining was comparable to that of the hrHPV test, and the specificity was substantially higher. The highest specificity was found for presence of the HPV16 genotype (91%), but with low sensitivity.…”

“…Previous studies have already shown that p16/Ki-67 might serve as an important marker for the detection of high-grade cervical lesions in patients with negative, ASC-US and LSIL cytology. [29][30][31][32][33][34][35] According to our results, p16/Ki-67-positive cases showed a 30.8% progression rate, compared with only 4.3% of p16/Ki-67-negative cases, and progression was more prominent in hrHPV-positive cases. The prediction of underlying CIN2+ or progression to CIN2+ in other studies showed similar results.…”

“…It is considered to be even better than HPV DNA testing in triage and in the prediction of the clinical outcome of ASC-US and LSILs. [29][30][31][32][33][34][35] The aim of this study was to evaluate the HPV DNA test result, HPV genotype, p16/Ki-67 dual immunostaining and the presence of koilocytosis in LSIL, and their association with its clinical outcome.…”

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

“…The threshold for positivity of the assay is the presence of p16 and Ki-67 in one single cell [57-60,65,67,69], which emphasizes the need for sufficient cellularity of specimens with sufficient intact abnormal cells to guarantee the clinical applicability of this triage strategy. Concordantly, p16/Ki-67 dual-stained cytology is not reliably applicable to self-sampled material [70]. Although data on the long-term ≥CIN3 risk in p16/Ki-67 dual-stain negative women are currently lacking, results from the studies with short-term follow-up (up to 2 years) [65] are promising, reporting NPVs of a single p16/Ki-67 dual-stained cytology test between 97.4% and 99.4% [65,67].…”