Triage of HPV-positive women in cervical cancer screening

Wentzensen, Nicolas

doi:10.1016/s1470-2045(12)70568-5

Cited by 127 publications

(184 citation statements)

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“…Recent data from a multicenter randomized trial (New Technologies for Cervical Cancer, NTCC, in Italy) comparing HPV testing with Pap cytology and using p16 cytology to triage positive HPV results suggest that immediate follow-up can be avoided in HPV-positive p16 cytology-negative women, who may be safely managed with follow-up testing within 2–3 years (15,16). The high sensitivity levels of dual-stained cytology for the detection of prevalent HGCIN (especially CIN3+) shown in several cross-sectional studies may hint at a comparable negative predictive value for negative test results of the dual-stained cytology assay when used for triaging HPV-positive women, as compared with the p16 cytology assay used in the NTCC trial (15–22,27). …”

Section: Discussionmentioning

confidence: 99%

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Ikenberg¹,

Bergeron²,

Schmidt³

et al. 2013

JNCI: Journal of the National Cancer Institute

190

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BackgroundPap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing.MethodsA total of 27349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined.ResultsThe p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001).ConclusionsThe p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.

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Section: Discussionmentioning

confidence: 99%

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Ikenberg¹,

Bergeron²,

Schmidt³

et al. 2013

JNCI: Journal of the National Cancer Institute

190

186

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“…However, since HPV infections are very widespread especially in younger women, HPV tests do not have a high positive predictive value for the presence of HSILs. Women who test positive for HPV therefore require a further triage test as for example a Pap cytology test or more recently developed biomarker‐based triage tests …”

Section: Pathogenesis Of Hpv‐triggered Neoplastic Lesions: the Detectmentioning

confidence: 99%

The clinical impact of using p16^INK4a immunochemistry in cervical histopathology and cytology: An update of recent developments

Bergeron¹,

Ronco

Reuschenbach

et al. 2014

Intl Journal of Cancer

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Cervical cancer screening test performance has been hampered by either lack of sensitivity of Pap cytology or lack of specificity of Human Papillomavirus (HPV) testing. This uncertainty can lead to unnecessary referral and treatment, which is disturbing for patients and increases costs for health care providers. The identification of p16 INK4a as a marker for neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV-transformed cells in histopathology or cytopathology specimens. Diagnostic studies have demonstrated that the use of p16 INK4a immunohistochemistry substantially improves the reproducibility and diagnostic accuracy of histopathologic diagnoses. p16 INK4a cytology has substantially higher sensitivity for detection of cervical precancer in comparison to conventional Pap tests. Compared to HPV DNA tests, immunochemical detection of p16 INK4a -stained cells demonstrates a significantly improved specificity with remarkably good sensitivity. About 15 years after the initial observation that p16 INK4a is overexpressed in HPV-transformed cells we review the accumulated clinical evidence suggesting that p16 INK4a can serve as a useful biomarker in the routine diagnostic work up of patients with HPV infections and associated lesions of the female anogenital tract.

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“…The goal of cervical screening is to detect and treat precancers and early cancers in order to reduce cancer mortality and morbidity, while minimizing intervention in women that do not need it . Because of the sensitivity of HPV tests, women screening HPV‐negative using any of the well‐validated DNA or RNA assays can be reassured of very low risk of cervical cancer for several years until the next screen .…”

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confidence: 99%

“…An intermediate step called “triage” is introduced when affordable, meant to divide HPV‐positive women according to their chance of having treatable precancer, if colposcopy is performed. The highest‐risk women are referred to colposcopy directly while lower‐risk women are retested, often after approximately 6 to 12 months, in the hope of clearance of infection . A 1‐year delay permits viral clearance and return to routine screening intervals in approximately half the women; persistent infection (monitored either by repeat HPV testing or, less directly, by cytology) indicates an elevated risk and mandates reconsideration of colposcopy referral …”

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confidence: 99%

Proof-of-principle study of a novel cervical screening and triage strategy: Computer-analyzed cytology to decide which HPV-positive women are likely to have ≥CIN2

Schiffman

Dunn

et al. 2016

Int. J. Cancer

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A challenge in implementation of sensitive HPV-based screening is limiting unnecessary referrals to colposcopic biopsy. We combined 2 commonly recommended triage methods: partial HPV typing and “reflex” cytology, evaluating the possibility of automated cytology. This investigation was based on 1,178 exfoliated cervical specimens collected during the enrollment phase of The Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED, Oklahoma City, Oklahoma). We chose a colposcopy clinic population to maximize number of outcomes, for this proof-of-principle cross-sectional study. Residual aliquots of PreservCyt were HPV-typed using Linear Array (LA, Roche Molecular Systems, Pleasanton, CA). High-risk HPV typing data and cytologic results (conventional and automated) were used jointly to predict risk of histologically defined ≥CIN2. We developed a novel computer algorithm that uses the same optical scanning features that are generated by the FocalPoint Slide Profiler (BD, Burlington, NC). We used the LASSO (Least Absolute Shrinkage and Selection Operator) method to build the prediction model based on a training dataset (n=600). In the validation set (n=578), for triage of all HPV-positive women, a cytologic threshold of ≥ASC-US had a sensitivity of 0.94, and specificity of 0.30, in this colposcopy clinic setting. When we chose a threshold for the severity score (generated by the computer algorithm) that had an equal specificity of 0.30, the sensitivity was 0.91. Automated cytology also matched ≥ASC-US when partial HPV typing was added to the triage strategy, and when we re-defined cases as ≥CIN3. If this strategy works in a prospective screening setting, a totally automated screening and triage technology might be possible.

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Triage of HPV-positive women in cervical cancer screening

Cited by 127 publications

References 9 publications

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

The clinical impact of using p16^INK4a immunochemistry in cervical histopathology and cytology: An update of recent developments

Proof-of-principle study of a novel cervical screening and triage strategy: Computer-analyzed cytology to decide which HPV-positive women are likely to have ≥CIN2

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Triage of HPV-positive women in cervical cancer screening

Cited by 127 publications

References 9 publications

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

The clinical impact of using p16INK4a immunochemistry in cervical histopathology and cytology: An update of recent developments

Proof-of-principle study of a novel cervical screening and triage strategy: Computer-analyzed cytology to decide which HPV-positive women are likely to have ≥CIN2

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Product

Resources

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The clinical impact of using p16^INK4a immunochemistry in cervical histopathology and cytology: An update of recent developments