Comparing triage algorithms using HPV DNA genotyping, HPV E7 mRNA detection and cytology in high-risk HPV DNA-positive women

Luttmer, Roosmarijn; Berkhof, Johannes; Dijkstra, Maaike G.; Kemenade, Folkert J. van; Snijders, Peter J.F.; Heideman, Daniëlle A.M.; Meijer, Chris J.L.M.

doi:10.1016/j.jcv.2015.04.004

Cited by 19 publications

(15 citation statements)

References 46 publications

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“…16,20 CISOE-A results were translated into the Bethesda classification, 21 in which borderline or mild dyskaryosis equals atypical squamous cells of undetermined significance (ASC-US)/ASCs, cannot exclude high-grade squamous intraepithelial lesion (ASC-H)/low-grade squamous intraepithelial lesion (LSIL), and worse than borderline or mild dyskariosis equals high-grade squamous intraepithelial lesion. Cytotechnicians were aware of the high-risk HPV-positive status of the cervical scrapes but not of the results of high-risk HPV genotyping.…”

Section: Pap Cytologymentioning

confidence: 99%

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: Pap Cytologymentioning

confidence: 99%

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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“…This side‐effect can be tackled by applying an adequate triage test for HPV‐positive women to discern those with clinically relevant disease. Various studies have evaluated triage strategies for HPV‐positive women in screening cohorts, including virus‐ and host cell‐based strategies, such as HPV16/18 genotyping,4, 5 HPV E7 mRNA analysis,6, 7 cytology,8, 9 p16/ki67 dual staining,10, 11 epigenetic changes in the host and/or viral genome,12, 13 and combinations thereof 8, 9. 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.…”

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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“…For example, the detection of specific microRNAs has shown promising results in one clinical study [109]. Furthermore, detection of the E6 protein [110,111], and E6/ E7 mRNA [66,[112][113][114] was evaluated in some clinical cohorts of hrHPV-positive women, however with disappointing results. These assays require a relatively complex genotype-specific approach and have not been shown to reach the desired NPV in hrHPV-positive women; others did not reach the required phase of marker validation and are therefore beyond the scope of this review [42,43].…”

Section: Combining Host Cell Dna Methylation Analysis With Other Markmentioning

confidence: 99%

“…The combination of Pap cytology and methylation analysis, which have been suggested to serve as complementary markers in terms of detection of early and advanced CIN [32], could serve as a sensitive strategy that, in contrast to Pap cytology alone, detects all carcinomas and virtually all CIN3. Table 5 provides an overview of test characteristics (that is, sensitivity, specificity, NPV, PPV) of Pap cytology, HPV16/18 genotyping, p16/Ki-67 dual-stained cytology, and methylation analysis in a single (outpatient) study population [51,67,100,114]. A general limitation of microscopy-based strategies is the fact that these can only be adequately performed on cervical scrapes collected by health-care professionals.…”

Section: Expert Commentarymentioning

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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Comparing triage algorithms using HPV DNA genotyping, HPV E7 mRNA detection and cytology in high-risk HPV DNA-positive women

Cited by 19 publications

References 46 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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