Abstract
Cervical cancer screening saves lives. Secondary prevention in cervical cancer screening
relies on the results of primary cytology and/or HPV testing. However, primary screening
with cytology has a low sensitivity, and HPV screening has a low specificity. This
means that either cancers are missed, or women are over-treated. To improve performance
outcomes, the concept of dual-stain cytology (CINtec® PLUS Cytology test) has been introduced. In this approach, additional staining with
p16/Ki-67 is performed in cases where cytology results are abnormal (LSIL or ASCUS)
and/or HPV-positive. Another way to describe this approach might be “diagnostic” cytology.
In order to assess the value of this “diagnostic cytology”, a systematic literature
review was conducted of dual-stain cytology performance across multiple studies until
May 2016. In a Belgian screening population (women age 25–65 years), dual-stain cytology
was significantly more sensitive (66%) and slightly less specific (−1.0%) than cytology.
In the population referred to colposcopy or with abnormal cytology (ASCUS, LSIL),
dual-staining showed a significantly higher increase in specificity, and a slightly
lower sensitivity than HPV testing. Specificity gains resulted in fewer false positives
and an increase in the number of correct referrals to colposcopy. Dual-staining with
p16/Ki-67 cytology is an attractive biomarker approach for triage in cervical cancer
screening.
Keywords
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References
- The ideal cervical cancer screening recommendation for Belgium, an industrialized country in Europe.Eur J Gynaecol Oncol. 2014; 35: 211-218
- ANOVA model for network meta-analysis of diagnostic test accuracy data.Stat Methods Med Res Sep. 2016; 20
- Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.PLoS Med. 2009; 6: e1000097https://doi.org/10.1371/journal.pmed.1000097
- Systematic reviews of diagnostic test accuracy.Ann Intern Med (Ann Intern Med). 2008; 149 (149/12/889 [pii]): 889-897
- p16/ki-67 dual-stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study.Cancer Cytopathol. 2011; 119: 158-166https://doi.org/10.1002/cncy.20140
- Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews.J Clin Epidemiol. 2005; 58: 982-990
R Development Core Team RF for SC. R: a Language and Environment for statistical computing. 2008.
- Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study.J Natl Cancer Inst. 2013; 105: 1550-1557https://doi.org/10.1093/jnci/djt235
- Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology.Gynecol Oncol. 2011; 121: 505-509https://doi.org/10.1016/j.ygyno.2011.02.033
- Usefulness of p16/Ki67 immunostaining in the triage of women referred to colposcopy.Cancer Cytopathol. 2014; 122: 227-235https://doi.org/10.1002/cncy.21366
- Dual immunostaining of cervical cytology specimens with atypical squamous cells for p16/Ki-67 does not exclude the existence of a high-grade squamous intraepithelial lesion.Virchows Arch. 2013; 463: 689-696https://doi.org/10.1007/s00428-013-1483-4
- p16/Ki-67 dual staining in cervico-vaginal cytology: correlation with histology, Human Papillomavirus detection and genotyping in women undergoing colposcopy.Gynecol Oncol. 2012; 126: 198-202https://doi.org/10.1016/j.ygyno.2012.05.004
- Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population.Clin Cancer Res. 2012; 18: 4154-4162https://doi.org/10.1158/1078-0432.CCR-12-0270
- Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: cross-sectional and longitudinal outcome study.Br J Cancer. 2014; 110: 1579-1586https://doi.org/10.1038/bjc.2014.34
- Immunostaining of p16(INK4a)/Ki-67 and L1 capsid protein on liquid-based cytology specimens obtained from ASC-H and LSIL-H cases.Int J Med Sci. 2013; 10: 1602-1607https://doi.org/10.7150/ijms.6526
- CINtec® plus dual immunostain: a triage tool for cervical pap smears with atypical squamous cells of undetermined significance and low grade squamous.Diagn Cytopathol. 2013; 41https://doi.org/10.1002/dc
- Immunocytochemistry of p16INK4a and Ki-67 as adjunctive method for routine gynecological cytology of mild and moderate dysplasia.Pathologe. 2012; 34: 323-328https://doi.org/10.1007/s00292-012-1613-9
- Evaluation of p16(INK4a)/Ki-67 dual stain in comparison with an mRNA human papillomavirus test on liquid-based cytology samples with low-grade squamous intraepithelial lesion.Cancer Cytopathol. 2013; 121: 136-145https://doi.org/10.1002/cncy.21233
- Implementing specificity of HPV-DNA primary screening in a successful organised cervical cancer prevention programme.Gynecol Oncol. 2013; 128: 427-432https://doi.org/10.1016/j.ygyno.2012.11.030
- Chromogenic in situ hybridization and p16/Ki67 dual staining on formalin-fixed paraffin-embedded cervical specimens: correlation with HPV-DNA test, E6/E7 mRNA test, and potential clinical applications.Biomed Res Int. 2013; 2013: 453606https://doi.org/10.1155/2013/453606
- Immunocytochemical colocalization of P16(INK4a) and Ki-67 predicts CIN2/3 and AIS/adenocarcinoma.Cancer Cytopathol. 2012; 120: 26-34https://doi.org/10.1002/cncy.20188
- Improved abnormal pap smear triage using cervical cancer biomarkers.J Low Genit Tract Dis. 2014; 18: 1-7https://doi.org/10.1097/LGT.0b013e31828aeb39
- There are two prophylactic human papillomavirus vaccines against cancer, and they are different.J Clin Oncol. 2015; 33: 964-965
- New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections.Eur Cancer. 2002; 38: 2229-2242
- Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia.Cancer Epidemiol Biomarkers Prev. 2008; 17: 2536-2545
- The impact on women’s health and the cervical cancer screening budget when the screening is based on primary HPV screening with dual stain cytology triage.Eur J Obstet Gynecol. 2017;
Article info
Publication history
Published online: January 07, 2017
Accepted:
January 4,
2017
Received in revised form:
December 30,
2016
Received:
October 29,
2016
Identification
Copyright
© 2017 Elsevier B.V. All rights reserved.
