Informed Cytology for Triaging HPV-Positive Women: Substudy Nested in the NTCC Randomized Controlled Trial

Bergeron, Christine; Rossi, Paolo Giorgi; Cas, Frederic; Schiboni, Maria Luisa; Ghiringhello, Bruno; Palma, Paolo Dalla; Minucci, D; Rosso, Stefano; Zorzi, Manuel; Naldoni, Carlo; Segnan, Nereo; Confortini, Massimo; Ronco, Guglielmo

doi:10.1093/jnci/dju423

Cited by 70 publications

(64 citation statements)

References 25 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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“…However, cytology comes with some limitations, including its subjective nature and the required repeated cytology to ensure sufficient safety in the screening program. Moreover, prior knowledge of hrHPV-positivity influences cytology reading, which may result in an increase of false-positive referrals with simultaneously higher costs for the healthcare system [47–49]. Recent clinical validation studies in screening populations have shown that DNA methylation markers provide a good alternative for cytology [14,50–54].…”

Section: Discussionmentioning

confidence: 99%

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

et al. 2018

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Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis. DNA methylation analysis was performed by quantitative methylation-specific PCR (qMSP) and relative qMSP values were used to analyze the data. The majority of genes displayed a comparable DNA methylation pattern in both cell lines and clinical specimens. DNA methylation onset occurred at early or late immortal passage, and DNA methylation levels gradually increased towards tumorigenic cells. Subsequently, we defined a so-called cancer-like methylation-high pattern based on the DNA methylation levels observed in cervical scrapings from women with cervical cancer. This cancer-like methylation-high pattern was observed in 72% (38/53) of CIN3 and 55% (11/20) of CIN2, whereas it was virtually absent in hrHPV-positive controls (1/26). In conclusion, hrHPV-induced carcinogenesis is characterized by early onset of DNA methylation, typically occurring at the pre-tumorigenic stage and with highest DNA methylation levels at the cancer stage. Host-cell DNA methylation patterns in cervical scrapings from women with CIN2 and CIN3 are heterogeneous, with a subset displaying a cancer-like methylation-high pattern, suggestive for a higher cancer risk.

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“…Of note, these estimates were obtained in study settings where cytologists were blinded to hrHPV-test results. 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].…”

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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Informed Cytology for Triaging HPV-Positive Women: Substudy Nested in the NTCC Randomized Controlled Trial

Cited by 70 publications

References 25 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

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer

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

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