Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program

Wentzensen, Nicolas; Clarke, Megan A.; Bremer, Renee; Poitras, Nancy; Tokugawa, Diane; Goldhoff, Patricia; Castle, Philip E.; Schiffman, Mark; Kingery, Julie D; Grewal, Kiranjit; Locke, Alex; Kinney, Walter; Lorey, Thomas

doi:10.1001/jamainternmed.2019.0306

Cited by 113 publications

(163 citation statements)

References 25 publications

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“…21 In ATHENA, and other studies, DS testing demonstrated better performance (improved sensitivity and at least equal specificity) compared to cytology for the cross-sectional detection of ≥CIN3 in hrHPV-positive women. 20,[22][23][24][25][26][27][28][29][30][31] However, like Pap cytology, DS testing is not integrated into the first-line HPV screening test, and both Pap cytology and DS testing require the preparation of a slide for subjective microscopic assessment by highly trained professionals.…”

Section: Introductionmentioning

confidence: 99%

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

Stoler

Baker

Boyle

et al. 2019

Intl Journal of Cancer

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The objective of our study was to assess the performance of different triage strategies for high‐risk human papillomavirus (hrHPV)‐positive results utilizing either extended genotyping or a p16/Ki‐67 dual‐stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single‐genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)‐approved algorithm (HPV16/18 positive, or 12‐other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA‐approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV‐positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

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Section: Introductionmentioning

confidence: 99%

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

Stoler

Baker

Boyle

et al. 2019

Intl Journal of Cancer

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“…The second batch (N = 383) was tested at AML laboratory, Antwerp, Belgium, using the TaqMan-based qPCR assay (RIATOL, Sonic Healthcare Benelux, Antwerp, Belgium) which detects 17 HPV genotypes and β -globin in seven multiplex reactions. These HPV types include all 12 high-risk types (HPV16, 18,31,33,35,39,45,51,52,56,58,59), three probably high-risk types (HPV53, 66 and 68), one low-risk type (HPV6) and one undetermined risk type (HPV67) [32]. All HC2 positive and a subset of HC2 negatives samples were retested using the TaqMan-based qPCR assay.…”

Section: Laboratory Testingmentioning

confidence: 99%

“…Dual stain cytology is currently the most extensively studied molecular triage test [31,[68][69][70], that shows superior performance compared to other disease markers [71,72]. In centralized laboratories the assay is performed on automated platforms offering high sample throughput.…”

Section: Evaluation Of Screening Technologiesmentioning

confidence: 99%

Novel concepts in cervical cancer screening: a comparison of VIA, HPV DNA test and p16INK4a/Ki-67 dual stain cytology in Western Kenya

Orang’o

Were

Rode

et al. 2020

Infect Agents Cancer

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Background Screening of unvaccinated women remains essential to mitigate the high morbidity/mortality of cervical cancer. Here, we compared visual inspection with acetic acid (VIA), recommended by WHO as the most cost-effective screening approach in LMICs, with HPV-based screening, and usage of p16INK4a/Ki-67 dual stain cytology. Methods We prospectively enrolled women participating in a VIA-based cervical cancer screening program in two peri-urban health centers of Kenya. Consenting women had a VIA examination preceded by collection of a liquid-based cytology sample from the cervix stored in PreservCyt medium (Hologic®). Analysis of all samples included a hrHPV DNA test and evaluation of a p16INK4a /Ki-67 (CINtecPLUS®) dual stained slide that was prepared using the ThinPrep® 2000 Processor and evaluated by a pathologist trained in the methodology. Results In 701 of a total of 800 women aged 18–64 years, all three investigations were performed and data could be analyzed. The HPV, VIA and dual stain cytology positivity were 33%, 7%, and 2% respectively. The HPV positivity rate of VIA positive cases was 32%. The five most common HPV types were HPV16, 52, 68, 58 and 35. The OR among HIV infected women of an HPV infection, VIA positivity and positive dual stain cytology were 2.6 (95%CI 1.5–4.3), 1.9 (95%CI 0.89–4.4) and 3.4 (95%CI 1.07–10.9) respectively. The sensitivity of VIA to detect a p16INK4a/Ki-67 positive transforming infection was 13% (95%CI 2–38). Conclusions Primary HPV testing appears feasible and should be considered as a primary screening test also in LMICs. The poor sensitivity of VIA renders it unsuitable as a triage test for HPV positive women. The utility of p16INK4a/Ki-67 dual stain cytology as a triage test for HPV positive women in LMICs should be further studied.

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“…This immunocytochemistry test detects cells that have undergone neoplastic transformation in the course of a persistent HPV infection, a stage in the HPVmediated cervcial carcinogenesis that is also called a transforming infection and that correlates morphologically with a CIN2/3 lesion 28 29 30 . Its high speci city in the diagnosis of cervical intraepithelial neoplasia of grade 2 or higher (CIN2+) has been demonstrated in large organized screening programs 31 and has been widely approved as a triage test for HPV-infected.…”

Section: Introductionmentioning

confidence: 99%

Novel Concepts in Cervical Cancer Screening. A Comparison of VIA, HPV DNA Test and p16ink4a/Ki-67 Dual-Stain Cytology in Western Kenya.

Orang’o

Were

Rode

et al. 2020

Preprint

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Abstract Background: Screening of unvaccinated women remains essential to mitigate the high morbidity/mortality of cervical cancer. Here, we compared visual inspection with acetic acid (VIA), recommended by WHO as the most cost-effective screening approach in LMICs, with HPV-based screening, and usage of p16INK4a/Ki-67 dual stain cytology.Methods: We prospectively enrolled women participating in a VIA-based cervical cancer screening program in two peri-urban health centers of Kenya. Consenting women had a VIA examination preceded by collection of a liquid-based cytology sample from the cervix stored in PreservCyt medium (Hologic®). Analysis of all samples included a hrHPV DNA test and evaluation of a p16 INK4a /Ki-67 (CINtecPLUS®) dual-stained slide that was prepared using the ThinPrep® 2000 Processor and evaluated by a pathologist trained in the methodology.Results: In 701 of a total of 800 women aged 18-64 years, all three investigations were performed and data could be analyzed. The HPV, VIA and dual-stain cytology positivity were 33%, 7%, and 2% respectively. The HPV positivity rate of VIA positive cases was 32%. The five most common HPV types were HPV16, 52, 68, 58 and 35. The OR among HIV infected women of an HPV infection, VIA positivity and positive dual stain cytology were 2.6 (95%CI 1.5-4.3), 1.9 (95%CI 0.89-4.4) and 3.4 (95%CI 1.07-10.9) respectively. The sensitivity of VIA to detect a p16INK4a/Ki-67 positive transforming infection was 13% (95%CI 2-38). Conclusions: Primary HPV testing appears feasible and should be considered as a primary screening test also in LMICs. The poor sensitivity of VIA renders it unsuitable as a triage test for HPV positive women. The utility of p16ink4a/Ki-67 dual-stain cytology as a triage test for HPV positive women in LMICs should be further studied.

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Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program

Cited by 113 publications

References 25 publications

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA

Novel concepts in cervical cancer screening: a comparison of VIA, HPV DNA test and p16INK4a/Ki-67 dual stain cytology in Western Kenya

Novel Concepts in Cervical Cancer Screening. A Comparison of VIA, HPV DNA Test and p16ink4a/Ki-67 Dual-Stain Cytology in Western Kenya.

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