Meta‐analysis of the accuracy of p16 or p16/Ki‐67 immunocytochemistry versus HPV testing for the detection of CIN2+/CIN3+ in triage of women with minor abnormal cytology

Abstract

BACKGROUND: Women with atypical squamous cells of undetermined significance (ASC-US) can be triaged accurately with a high-risk human papillomavirus (hrHPV) test to identify those who need a referral. However, the triage of lowgrade squamous intraepithelial lesion (LSIL) with hrHPV testing has very low specificity. Overexpression of p16, with or without Ki-67, indicates neoplastic transformation of human papillomavirus-infected cervical cells and may more accurately predict underlying cervical intraepithelial neoplasia of grade 3 or worse (CIN3+). METHODS: A literature search was conducted in 3 bibliographic databases. Studies were selected if they included women with ASC-US or LSIL who were triaged with dual staining (p16/Ki-67) and/or p16 staining and, if available, with a comparator hrHPV test to detect cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or CIN3+. RESULTS: Thirty-eight studies were eligible. The sensitivity of p16 staining for CIN3+ was significantly lower than that of hrHPV DNA testing (ratio for ASC-US, 0.87; 95% confidence interval [CI], 0.78-0.97; ratio for LSIL, 0.86; 95% CI, 0.80-0.93). In contrast, the specificity of p16 staining was substantially higher with relative specificities of 1.60 (95% CI, 1.35-1.88) and 2.29 (95% CI, 2.05-2.56) for ASC-US and LSIL respectively. Dual staining was as sensitive as hrHPV DNA testing but was more specific (ratio for ASC-US, 1.65; 95% CI, 1.42-1.92; ratio for LSIL, 2.45; 95% CI, 2.17-2.77). CONCLUSIONS: This meta-analysis confirms that p16 staining and p16/Ki-67 staining are more specific for CIN2+/CIN3+ than hrHPV DNA testing. Although p16 staining is less sensitive for CIN3+ than hrHPV DNA testing, dual staining has similar sensitivity.

Dual staining for p16/Ki‐67 to detect high‐grade cervical lesions: Results from the Screening Triage Ascertaining Intraepithelial Neoplasia by Immunostain Testing study

“…populations. A recent meta-analysis 6 of studies published between 2012 and 2017 demonstrated that dual-stained cytology was more specific than high-risk HPV testing for the identification of CIN2+; the relative specificity was 1.65 (95% CI: 1.42-1.92, P < .0001, n = 11 studies 8,14,15,[18][19][20][21][22][23][24][25] for the triage of ASC-US and 2.45 (95% CI:…”

“…Importantly, our finding that dual‐stained cytology performed significantly better than HPV testing in terms of specificity substantiate previous reports in different geographic regions and populations. A recent meta‐analysis 6 of studies published between 2012 and 2017 demonstrated that dual‐stained cytology was more specific than high‐risk HPV testing for the identification of CIN2+; the relative specificity was 1.65 (95% CI: 1.42‐1.92, P < .0001, n = 11 studies 8,14,15,18‐25 ) for the triage of ASC‐US and 2.45 (95% CI: 2.17‐2.77, P < .0001, n = 13 studies 7,8,14,15,18,20‐27 ) for the triage of LSIL. Equivalent values for CIN3+ were 1.48 (95% CI: 1.29‐1.72, P < .0001) and 2.56 (95% CI: 2.20‐2.98, P < .0001) based on five studies.…”

“…In normal cells, the expression of p16 and Ki‐67 is mutually exclusive. A recent meta‐analysis reported the higher specificity of dual‐stained cytology compared to high‐risk HPV testing for the identification of high‐grade lesions (CIN of Grade 2 or worse, CIN2+ and CIN of Grade 3 or worse, CIN3+) 6 . The sample size of the original studies ranged from a low of 45 women 7 to a high of 1104 women, 8 with none of the studies conducted in Canada.…”

Triage options to manage high‐risk human papillomavirus‐positive women: A population‐based cross‐sectional study from rural China

“…and Ki-67 might improve the accuracy especially enhance the specificity of staining method by allowing to discriminate between p16-positive normal and dysplastic cells. 30 Wentzensen et al 31 reported the 87% sensitivity and 59% specificity of dual staining for CIN3+ detection among HPV-positive women (n = 1509) in KPNC trial, which 33 it remains merited to study the epidemiological characteristics and appropriate screening algorithms for elder population. Considering that the HPV infections in older women are likely to be more persistent and have a higher risk of progressing to (pre)cancer, the effectiveness of screening could be enhanced.…”

Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection

“…The researchers also pointed out that, although p16 staining is less sensitive for CIN3+ than hrHPV DNA testing, dual staining has similar sensitivity. In addition, the sensitivity of the co-staining in cervical samples was higher than the cytology test, presenting a similar specificity [134][135][136].…”