The Tahoe Study: Bias in the Interpretation of Papanicolaou Test Results When Human Papillomavirus Status Is Known

Moriarty, Ann; Nayar, Ritu; Arnold, Terry; Gearries, Lisa; Renshaw, Andrew A.; Thomas, Nicole; Souers, Rhona J.

doi:10.5858/arpa.2012-0115-cp

Cited by 38 publications

(42 citation statements)

References 18 publications

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“…This more objective nature might also be of value, in particular in the triage of high-risk HPV-positive women, in which prior knowledge of high-risk HPV presence could result in a scoring 'bias' that likely will decrease specificity of Pap cytology, 32,33 as was also observed in the present study. Yet, it should be realized that p16/Ki-67 dual-stained cytology remains microscopy-based, in contrast to other suggested molecular triage tests.…”

Section: Discussionmentioning

confidence: 59%

“…Besides the use of an outpatient population, the prior knowledge of high-risk HPV presence to the cytotechnicians and cytopathologists might be an explanation for the high sensitivity of cytology in the current study. 32,33 By adjusting the threshold of abnormal cytology from ≥ ASC-US to ≥ LSIL in our study, sensitivity would decrease from 87.7 to 77.8%, with a corresponding increase in specificity from 44.9 to 72.3%. A similar finding was recently described by Ebisch et al (in press).…”

Section: Discussionmentioning

confidence: 78%

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p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

et al. 2016

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Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥ CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n = 446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥ CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopybased triage tool for high-risk HPV-positive women. Persistent infection with a high-risk type of the human papillomavirus (HPV) is essential for the development of almost all cervical cancers. 1,2 Testing for high-risk HPV has been shown to provide superior protection against cervical intraepithelial neoplasia grade 3 and cervical cancer (together referred to as ≥ CIN3) compared with cervical cytology (Pap cytology). 3 However, most women who test positive for high-risk HPV clear the virus spontaneously and do not develop clinically relevant cervical disease. Therefore, additional triage testing is required to identify the subgroup of high-risk HPVpositive women who actually have ≥ CIN3, thereby Correspondence: Professor CJLM Meijer, MD PhD,

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 78%

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

et al. 2016

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“…Another aspect is that within the POBASCAM trial cytology and HPV testing were performed without knowledge of the other test result. It is known that guided cytological screening performed with prior knowledge of HPV status results in an improved detection of cervical (pre)cancer at the cost of a loss in specificity 15. Accordingly, sensitivity figures of cytology triage might be underestimated in our study, and the observed risk difference between methylation‐negative women and cytology‐negative women might be slightly overestimated.…”

Section: Discussionmentioning

confidence: 66%

“…At present, reflex cytology testing, which has been adopted in the Dutch HPV‐based screening program, is considered an appropriate triage test,1, 4, 8, 9, 14 although a short‐term repeat cytology is needed to assure a sufficiently low risk of cervical cancer for triage test‐negative women. Furthermore, cytology is subjective and prior knowledge of HPV presence, as is the case in the setting of primary HPV screening, will likely increase the false‐positivity rate 15. This problem could be overcome by using an objective triage test for HPV‐positive women.…”

Section: Introductionmentioning

confidence: 99%

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

Strooper

Berkhof

Steenbergen

et al. 2018

Intl Journal of Cancer

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DNA methylation analysis of cervical scrapes using FAM19A4 and mir124‐2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV‐positive women. To date, longitudinal data on the cancer risk of methylation test‐negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124‐2 methylation analysis in an HPV‐positive screening cohort with 14 years of follow‐up. Archived HPV‐positive cervical scrapes of 1,040 women (age 29–61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124‐2 methylation. By linkage with the nationwide network and registry of histo‐ and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow‐up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124‐2 methylation, including 24 women with cervical cancer in follow‐up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow‐up. Within screening round capability of FAM19A4/mir124‐2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5–100). Kaplan–Meier estimate of 14‐year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66–3.0) among baseline methylation‐negative and 2.4% (95% CI: 1.4–3.6) among baseline cytology‐negative women (risk difference: 0.71% [95% CI: 0.16–1.4]). In conclusion, a negative FAM19A4/mir124‐2 methylation test provides a low cervical cancer risk in HPV‐positive women of 30 years and older. FAM19A4/mir124‐2 methylation testing merits consideration as an objective triage test in HPV‐based cervical screening programs.

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“…Recently, it has been shown that providing cytologists with information on the hrHPV-positive status of participants increases the overall sensitivity of Pap cytology [48,49], probably due to the beneficial preselection of a population with a higher a priori cervical cancer risk. This is, however, at the cost of a significant decrease in specificity, which can be seen as the negative consequence of a more meticulous cytological evaluation [49,50]. In a hrHPV-positive gynecologic outpatient population, a sensitivity of 80.8% and a specificity of 63.3% of Pap cytology were found [51].…”

Section: Pap Cytologymentioning

confidence: 99%

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

Luttmer

Strooper

Steenbergen

et al. 2016

Expert Review of Molecular Diagnostics

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Introduction: Primary HPV-testing has been shown to provide a superior detection of women at risk of cervical (pre)cancer compared to cytology-based screening. However, as most high-risk HPV infections are harmless, additional triage testing of HPV-positive women is necessary to identify those with cervical (pre)cancer. In this paper, we compare the performance, advantages and limitations of clinically relevant available triage strategies for HPV-positive women. Areas covered: Many different colposcopy triage strategies, comprising both microscopy-based and molecular (virus/host-related) markers, have been suggested: Pap cytology, p16/Ki-67 dual-stained cytology, HPV16/18 genotyping, viral DNA methylation and host cell DNA methylation. Literature search was limited to triage strategies that have achieved at least phase 2 of the five-phase framework for biomarker development and studies including large cohorts (≥100 hrHPV-positive women). Triage markers were stratified by sample type (cervical scrape, self-collected sample) and by study population (screening, non-attendee, referral). Expert commentary: At present, repeat Pap cytology and Pap cytology combined with HPV16/18 genotyping are the only triage strategies that have been robustly shown to be ready for implementation. Other strategies such as p16/Ki-67 dual-stained cytology and host cell DNA methylation analysis, with or without additional HPV16/18 genotyping, are attractive options for the near future. ARTICLE HISTORY

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The Tahoe Study: Bias in the Interpretation of Papanicolaou Test Results When Human Papillomavirus Status Is Known

Cited by 38 publications

References 18 publications

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

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