Interobserver reproducibility of cytologic p16<sup>INK4a</sup>/Ki‐67 dual immunostaining in human papillomavirus‐positive women

Benevolo, Maria; Allìa, Elena; Gustinucci, Daniela; Rollo, Francesca; Bulletti, Simonetta; Cesarini, Elena Nardi; Passamonti, Basilio; Giovagnoli, Maria Rosaria; Carico, Elisabetta; Carozzi, Francesca; Mongia, Alessandra; Fantacci, Giulia; Confortini, Massimo; Rubino, Teresa; Fodero, Cristina; Prandi, Sonia; Marchi, Natalina; Farruggio, Angelo; Coccia, Anna; Macrì, Luigia; Ghiringhello, Bruno; Ronco, Guglielmo; Bragantini, Emma; Polla, E; Maccallini, Vincenzo; Negri, Giovanni; Rossi, Paolo Giorgi

doi:10.1002/cncy.21800

Cited by 27 publications

(40 citation statements)

References 32 publications

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“…It has been previously shown that p16/Ki-67 dual-stain shows substantial to good reproducibility with almost identical performance by novice evaluators compared with reference evaluations, indicating that it can be implemented in clinical practice with limited training. 34,35 The Kappa found in this study was lower as expected, this might be caused by the overall low quality of the samples. A disadvantage of the technique is that it cannot be reliably used on self-sampled material, as cellularity of cervical indicator cells in these samples is too limited resulting in a low sensitivity.…”

Section: Discussionmentioning

confidence: 39%

“…Partial HPV genotyping was done by the Roche Cobas 4800 test, according to the manufacturer's recommendations in the laboratory of the Department of Medical Microbiology, Radboud university medical center 26. This test provides separate result for HPV16 and 18, and a pool of 12 other high-risk HPV types (ie,31,33,35,39, 45, 51, 52, 56, 58, 59, 66, and 68). The HPV genotyping results were…”

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confidence: 99%

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Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

et al. 2017

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The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (PROHTECT-3B study). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for ≥CIN2 and ≥CIN3, and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV negative and cytology negative follow-up at 6 months was used as gold standard. Pap cytology (threshold atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93% (95% confidence interval: 85-98) with a specificity of 49% (95% confidence interval: 41-56) for ≥CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity with similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92% (95% confidence interval: 84-97) and a specificity of 61% (95% confidence interval: 54-69) for ≥CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92% (95% confidence interval: 84-97), with a specificity for ≥CIN3 of 64% (95% confidence interval: 56-71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96% (95% confidence interval: 89-99), and a specificity of 58% (95% confidence interval: 50-65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for ≥CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. Because the quality of Pap cytology worldwide varies, and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the most reliable strategy in triage of high-risk HPV-positive women with an increased specificity and similar sensitivity compared with Pap cytology triage.

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Section: Discussionmentioning

confidence: 39%

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confidence: 99%

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

et al. 2017

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“…It has been argued that the dual stain can reduce the requirement for “expert” cytology through simplifying interpretation and may improve interoperator variability compared to traditional cytology . However, a recent study showed important differences in interobserver reproducibility according to a laboratory's experience highlighting the need for robust training and quality assurance . In summary p16/ki67 dual stain is a credible tool for risk stratification of HPV‐positive women and compares favorably to cytology .…”

Section: ±P16 ± Ki67mentioning

confidence: 99%

Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

Cuschieri

Ronco²,

Lörincz

et al. 2018

Intl Journal of Cancer

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139

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Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.

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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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Interobserver reproducibility of cytologic p16^INK4a/Ki‐67 dual immunostaining in human papillomavirus‐positive women

Cited by 27 publications

References 32 publications

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

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

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Interobserver reproducibility of cytologic p16INK4a/Ki‐67 dual immunostaining in human papillomavirus‐positive women

Cited by 27 publications

References 32 publications

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women

Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

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

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Interobserver reproducibility of cytologic p16^INK4a/Ki‐67 dual immunostaining in human papillomavirus‐positive women