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. 2021 Jun 11;16(6):e0253045.
doi: 10.1371/journal.pone.0253045. eCollection 2021.

The p16/ki-67 assay is a safe, effective and rapid approach to triage women with mild cervical lesions

Maria Magkana  1   2 , Panagiota Mentzelopoulou  2 , Ekaterini Magkana  2 , Andreas Pampanos  3 , Georgios Daskalakis  4 , Ekaterini Domali  4 , Alexandros Rodolakis  4 , Kalliopi Pappa  4   5
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Free PMC article

The p16/ki-67 assay is a safe, effective and rapid approach to triage women with mild cervical lesions

Maria Magkana et al. PLoS One. .
Free PMC article

Abstract

Objective: The aim of this study was to evaluate the diagnostic accuracy and efficiency of p16/ki-67 dual stain in the identification of CIN2+ lesions, in Greek women with ASCUS or LSIL cytology.

Methods: A total of 200 women, 20 to 60 years old, were enrolled in the study. All samples were cytologically evaluated and performed for p16/ki-67 and high-risk HPV (HR-HPV) test. All patients were referred to colposcopy for biopsy and histological evaluation. Three cervical cancer (CC) screening strategies were designed and the total direct medical costs of the procedures during our clinical trial were evaluated, from a healthcare perspective.

Results: HPV 16 as expected was the most common HR-HPV type followed by HPV 31 and HPV 51. The risk for CIN2+ was significantly higher in HPV 16/18 positive cases. p16/ki-67 demonstrated a high sensitivity for CIN2+ identification in both ASCUS and LSIL groups (90.4% and 95%, respectively). HR-HPV test with sensitivity 52.3% and 65.5%, as well as colposcopy with sensitivity 14.3% and 36% respectively in ASCUS and LSIL group, showed inferior results compared to p16/ki-67. The specificity of p16/ki-67 for ASCUS and LSIL was 97.2% and 95.2% respectively, inferior only to colposcopy: 100% and 100%, lacking however statistical significance. HR-HPV test instead, presented the lowest specificity: 76.4% and 71.4% respectively in comparison to the other two methods. From a healthcare perspective, the costs and benefits of the tests implementation for the annual screening and triaging, in three CC screening strategies, were also calculated and discussed.

Conclusions: The results of the study indicate that p16/ki-67 is a safe and rapid assay that could be used to detect CIN2+ among women with mild cervical lesions, presenting both high sensitivity and specificity and could minimize the psychological and economic burden of HPV screening.

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Conflict of interest statement

The authors have declared that no competing interests exist. Roche Diagnostics (Hellas) S.A partially supported the statistical analysis of the current study (No 16742). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Examples of p16/ki-67 dual stained cells.
Fig 2
Fig 2. First strategy: Cytology as primary screening test.
Triage with a) HPV test with 16/18 genotyping and b) p16/ki-67 dual stain. Cytology, LBC; Costs in Euros (€), direct medical costs (screening tests, colposcopy with biopsy and office visit) per woman screened; costs for annual follow-ups and treatments for CIN were not included. *Colposcopy with biopsy.
Fig 3
Fig 3. Second strategy: HPV test as primary screening test with 16/18 genotyping.
Triage with a) Cytology b) p16/ki-67dual stain. Cytology, LBC; Costs in Euros (€), direct medical costs (screening tests, colposcopy with biopsy and office visit) per woman screened; costs for annual follow-ups and treatments for CIN were not included. *Colposcopy with biopsy.
Fig 4
Fig 4. Third strategy: Co-testing as primary screening.
Triage with p16/ki-67 dual stain. Cytology, LBC; Costs in Euros (€), direct medical costs (screening tests, colposcopy with biopsy and office visit) per woman screened; costs for annual follow-ups and treatments for CIN were not included. *Colposcopy with biopsy.
Fig 5
Fig 5. HR-HPV genotypes distribution in the study population.
The bars represent a single or multiple type infection, whilst in multiple types the case is classified according to the highest risk type for its constituents.
Fig 6
Fig 6. Evaluation of the two methods, HR-HPV test and p16/ki-67 by ROC curve analysis.
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Grants and funding

This research is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ); Roche Diagnostics (Hellas) S.A partially supported the statistical analysis of the current study (No 16742). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.