HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears

Zielinski, G. Denise; Snijders, Peter J.F.; Rozendaal, Lawrence; Voorhorst, Feja J.; Linden, Hans van der; Runsink, Arnold P.; Schipper, Frits A. de; Meijer, Chris J.L.M.

doi:10.1054/bjoc.2001.1926

Cited by 106 publications

(91 citation statements)

References 16 publications

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“…To solve the uncertainty on the confounding of regressive CIN III lesions, this prospective analysis with CIN III as end point should be accompanied by archival studies, in which retrospectively the HPV status of smears preceding a diagnosis of cervical cancer, is assessed. Zielinski et al (2001) concluded in a retrospective study of 57 women with invasive cervical cancer that the detectable preclinical stage could be prolonged by at least 2 years by adding HPV testing, which corroborates our results. This type of study, however, is susceptible to confounding biases such as selection and length time bias, which may result in an underestimation of the extension of the detectable preclinical stage as cervical cancers found after participation in a screening programme may be selective towards fast-growing cancers.…”

Section: Discussionsupporting

confidence: 90%

“…For Pap smear screening, the preclinical duration was the combined duration of CIN and microinvasive cervical cancer, a period estimated at 15 years on average (Gustafsson and Adami, 1989;Habbema, 1991, 1995;van Oortmarssen et al, 1992;Zielinski et al, 2001). Consequently, adding the HPV test to primary screening leads to duration of the detectable preclinical stage of almost 20 years in women aged 34 -54 years.…”

Section: Discussionmentioning

confidence: 99%

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Extended duration of the detectable stage by adding HPV test in cervical cancer screening

et al. 2003

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The human papillomavirus test (HPV) test could improve the (costÀ) effectiveness of cervical screening by selecting women with a very low risk for cervical cancer during a long period. An analysis of a longitudinal study suggests that women with a negative Pap smear and a negative HPV test have a strongly reduced risk of developing cervical abnormalities in the years following the test, and that HPV testing lengthens the detectable stage by 2 -5 years, compared to Pap smear detection alone. One of the possible uses of the human papillomavirus test (HPV) is in primary cervical cancer screening in addition to or instead of the current Pap smear (Cuzick et al, 1999a;Cuzick, 2000;Meijer and Walboomers, 2000).Introduction of HPV screening should be based on established (cost-) effectiveness. The (cost-) effectiveness of HPV testing is primarily determined by the duration of the detectable preclinical stage (the period from the HPV infection to clinical disease), and the sensitivity and costs of HPV testing. To estimate preclinical duration and sensitivity, longitudinal studies on the association between HPV infection and the development of neoplasias are necessary. Several large longitudinal screening studies have started, but no longterm results have been reported yet, although smaller longitudinal studies have been published (Rozendaal et al, 1996(Rozendaal et al, , 2000Ho et al, 1998;Liaw et al, 1999). These studies differ with respect to HPV test used, age range of women, study design, and cytological or histological endpoint, which complicates the comparison and interpretation of these results. It is therefore too early for definite answers on the value of HPV testing in primary screening (Myers et al, 2000;Kim et al, 2002;Mandelblatt et al, 2002). However, available data can be explored to derive preliminary estimates for parameters that determine the cost-effectiveness of HPV testing. This study investigates the duration of the detectable preclinical stage using the results of Rozendaal et al (2000). For these estimates, the 5-year cumulative incidence of cervical intraepithelial neoplasia (CIN) III after a negative Pap smear, the current screening interval in the Netherlands, is compared with the cumulative incidence within a doubled screening interval of 10 years (Meijer and Walboomers, 2000) in case of a negative Pap smear and a negative HPV test. MATERIAL AND METHODSThe study population, and screening and follow-up results are described in Rozendaal et al (1996Rozendaal et al ( , 2000. Briefly, the smears obtained during routine screening from 1988 to 1991, from a cohort of 2250 women aged 34 -54 years, who were either normal or who showed borderline nuclear changes were tested for a highrisk HPV. The women were followed during a mean period of 6.4 years, using screen-detected (histologically confirmed) CIN III as end point. Among the 2129 (95%) women with a negative HPV test at baseline, one case of CIN III was diagnosed at a following screening round. Of the 121 women with a positive HPV test result at b...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Extended duration of the detectable stage by adding HPV test in cervical cancer screening

et al. 2003

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“…7,14,19 Triage with HPV-testing as an adjunct to cytology has been proposed for women with minimal cytological changes. 15,17,23 Several studies have used different classifications of mildly abnormal cytology.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Consequently, HPV-testing may play an important role in clinical practice, i.e., in triage of women with BMD cytology, as an adjunct to cytology in primary screening and in posttreatment protocols. [15][16][17] The prevalence of hrHPV in women with BMD smears is about 35% 18,19 and it is likely that hrHPV negative BMD women are not at risk for development of high-grade CIN lesions or carcinoma. Hence, triage with hrHPV testing may improve the selection of women at risk for development of cervical cancer and consequently the management of women with BMD smears.…”

mentioning

confidence: 99%

“…Hence, triage with hrHPV testing may improve the selection of women at risk for development of cervical cancer and consequently the management of women with BMD smears. 15,[19][20][21][22][23] This would not only have the advantage of improving the efficiency of the screening program through fewer referrals but also would reduce unnecessary anxiety among the majority of women with BMD who are not at risk for high-grade CIN. 3,5,24 In this prospective study, triage with hrHPV testing was performed in the follow-up of women referred with a repeated BMD established in the screening program.…”

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Triage using HPV‐testing in persistent borderline and mildly dyskaryotic smears: Proposal for new guidelines

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et al. 2005

Intl Journal of Cancer

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In the Netherlands 2% of cervical smears in the cervical cancer screening program are read as borderline or mildly dyskaryotic cytology (BMD smear). Only in about 10% of these women a highgrade CIN lesion (CIN II-III) is present; therefore referral is for the majority unnecessary. In our study triage with high-risk HPV (hrHPV) testing was used to identify women at risk for development of high-grade CIN lesions after a repeat BMD smear. A ''wait-and-see'' period was incorporated allowing clearance of HPV and regression of the lesion. Women with a low-grade lesion, irrespective of their HPV status, were monitored at 12 months; women with a high-grade lesion were monitored at 6 and 12 months. Fifty-one of the 105 women (49%) were hrHPV negative at baseline; none of them showed progression of the lesion within the first year of follow-up (NPV 100%). High-grade CIN was present in 1 patient who was HPV negative at baseline (2%); she demonstrated regression after 12 months. Nineteen of the hrHPV positive women (35%) demonstrated a high-grade CIN lesion at baseline and 3 cleared hrHPV after 6 months, with a subsequent regression of CIN. Ten women remained hrHPV positive with persistence of high-grade CIN and were eventually treated. At baseline, 35 hrHPV positive women demonstrated a low-grade lesion, 19 remained hrHPV positive after 12 months and 5 developed high-grade CIN. Sixteen out of the 35 cleared the hrHPV infection without progression of the lesion. In conclusion, triage, using hrHPV testing for women with persistent BMD cytology, can select women who are not at risk for development of high-grade CIN. We recommend return to the screening program without referral for colposcopic examination if hrHPV is absent. For hrHPV positive women, a repeat hrHPV test after another 6 months is suggested. Referral is only required if persistence of hrHPV is established. ' 2005 Wiley-Liss, Inc.Key words: HPV; triage; borderline or mild dyskaryosis; guidelinesIn the Dutch population-based cervical cancer-screening program, women between 30 and 60 years of age undergo a cytological smear every 5th year. Recent surveys showed that about 2% of these smears contained borderline or mildly dyskaryotic (BMD) changes. 1,2 According to current screening guidelines, in these cases cytology is repeated after 6 months and (if negative) after 12 months. When cytology is persistently abnormal, women are referred to the gynaecologist where colposcopic examination is performed and a biopsy is taken for histological examination. When histology shows no or low-grade dysplasia ( CIN I) women will be kept under cytological surveillance without immediate treatment. High-grade dysplasia (CIN II-III) or a worse lesion will be treated. Only 10% of women with a single BMD smear show a high-grade CIN lesion. [3][4][5][6] Consequently, there is a need for an improved risk assessment of women with BMD.Infection with high-risk HPV (hrHPV) has been established as an important etiological factor in the carcinogenesis of cervical cancer. 7,8 Persistence of hr...

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Identification of reference genes for circulating long noncoding RNA analysis in serum of cervical cancer patients

et al. 2018

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Circulating lnc RNAs have attracted considerable attention as potential noninvasive biomarkers for diagnosing cancers. RT ‐ qPCR is the canonical technique for detecting circulating RNA and depends largely on stable reference genes for data normalization. However, no systematic evaluation of reference genes for serum lnc RNA has been reported for cervical cancer. Here, we profiled and validated lnc RNA expression from serum of cervical cancer patients and controls using microarrays and RT ‐ qPCR . We identified lnc RNA RP 11‐204K16.1, XLOC _012542, and U6 small nuclear RNA as the most stable reference genes based on geNorm, NormFinder, BestKeeper, delta Ct, and RefFinder. These genes were suitable also for samples from different age groups or with hemolysis. Additionally, we discovered lnc RNA AC 017078.1 and XLOC _011152 as candidate biomarkers, whose expression was down‐regulated in cervical cancer. Our findings could aid research on circulating lnc RNA and the discovery of blood‐based biomarkers for cervical cancer diagnosis.

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HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears

Cited by 106 publications

References 16 publications

Extended duration of the detectable stage by adding HPV test in cervical cancer screening

Extended duration of the detectable stage by adding HPV test in cervical cancer screening

Triage using HPV‐testing in persistent borderline and mildly dyskaryotic smears: Proposal for new guidelines

Identification of reference genes for circulating long noncoding RNA analysis in serum of cervical cancer patients

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