Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program.

We evaluated the performance of cytologic p16(INK4a) (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test. Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3. All samples had histological follow-up. In the ASC-US category, p16 sensitivity was 91% for CIN2+ and 100% for CIN3, while specificity was 64 and 58%, respectively, negative predictive value (NPV) was 96 and 100%, respectively, and PPV was 39%. In the LSIL category, sensitivity was 77 and 75%, respectively, for CIN2+ and CIN3, while specificity was 64 and 57%, NPV was 93 and 98% and PPV was 30%. Sensitivity for ASC-H and HSIL-CIN3 was 100% for CIN2+ and CIN3, while for HSIL-CIN2 it was 91 and 95%, respectively; NPV for ASC-H was 100%, and for HSIL-CIN2 it was 43 and 86%, respectively. Follow-up examinations of 8 cases diagnosed as p16+ ASC-H and HSIL-CIN3, but histologically negative or CIN1 on the first biopsy, showed 4 CIN2 and 4 CIN3 lesions. Sensitivity, specificity, PPV and NPV confirm the importance of the utilization of p16 in the categories ASC-US and LSIL after triage with an HR-HPV test. In the ASC-H and HSIL-CIN3 lesions, p16 was shown to be an excellent marker for picking up CIN2+ lesions, especially in cases with cytohistological discordance.

Gustinucci D ，Passamonti B ，Cesarini E ，Butera D ，Palmieri EA ，Bulletti S ，Carlani A ，Staiano M ，D'Amico MR ，D'Angelo V ，Di Dato E ，Martinelli N ，Malaspina M ，Spita N ，Tintori B ，Fulciniti F ... -  《ACTA CYTOLOGICA》

p16 Immunohistochemistry is useful in confirming high-grade squamous intraepithelial lesions (HSIL) in women with negative HPV testing.

Zhang G ，Yang B ，Abdul-Karim FW 《-》

[Clinical value of p16(INK4a) immunocytochemistry in cervical cancer screening].

Song FB ，Du H ，Xiao AM ，Wang C ，Huang X ，Yan PS ，Liu ZH ，Qu XF ，Belinson JEROMEL ，Wu RF ... -  《-》

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

We compared clinical performance of p16/Ki-67 dual-stained cytology and human papillomavirus (HPV) genotyping, via different algorithms-alone, or in combination with cytology-to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) in women referred to as colposcopy. We included 492 cervical specimens (134 normal, 130 CIN1, 99 CIN2, 121 CIN3, 8 cancers) randomly selected from 1158 specimens with valid conventional cytology, HPV (cobas 4800 HPV test) and biopsy results. Dual-stained cytology was retrospectively performed (CINtec PLUS assay) on PreservCyt material; slides were read by a cytologist and confirmed by two pathologists, blinded to cytology, biopsy and genotyping results. Sensitivity and specificity (95% confidence intervals in parentheses) of dual-stained cytology to detect CIN2+ and CIN3+ were compared to other screening tests available for the same women. Positivity rate for dual-stained cytology increased with histological severity: 30.6% in normal, 41.5% in CIN1, 72.7% in CIN2, 86.8% in CIN3 and 87.5% in cancer. Dual-stained cytology alone had lower sensitivity than HPV testing for CIN2+ [80.7% (75.0-85.6) vs 89.9% (85.3-93.5)] and CIN3+ [86.8% (79.7-92.1) vs 92.3% (86.2-96.2)]. However, corresponding specificity values were higher [64.0% (57.9-69.8) vs 56.1% (49.8-62.1) for CIN2+; 54.0% (48.7-59.2) vs 44.4% (39.2-49.6) for CIN3+]. Combining dual-stained cytology with an ASC-US abnormality threshold decreased specificity to 31.4% (25.9-37.4) for CIN2+ and 24.2% (19.9-29.0) for CIN3+. The corresponding values considering low squamous intraepithelial lesion threshold values were 42.8% (36.8-49.0) and 35.0% (30.1-40.1). Dual-stained cytology and HPV testing exhibited similar performance, although the former improved the specificity by 7.9% and 9.6% for CIN2+ and CIN3+, respectively.

El-Zein M ，Gotlieb W ，Gilbert L ，Hemmings R ，Behr MA ，Franco EL ，STAIN-IT Study Group ... -  《-》

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.

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 low-grade 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+). 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+. 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). 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.

Peeters E ，Wentzensen N ，Bergeron C ，Arbyn M ... -  《-》