New cervical cancer prevention strategies are arising from rapidly improving insight into human papillomavirus (HPV) natural history and cervical carcinogenesis, challenging the coventional roles of cytology and colposcopically directed biopsy as the reference standards of screening and diagnosis, respectively. HPV testing has high sensitivity but mediocre specificity and positive predictive value, making the role of colposcopy for the accurate identification of patients requiring treatment even more important. We believe that deficiencies of the colposcopically guided biopsy must be addressed, in particular, the inaccuracy of biopsy placement leading to low sensitivity for detection of CIN3. This opinion outlines our concerns and summarizes new data, suggesting posssible steps that may lead to improvement in colposcopic accuracy.

Colposcopy at a Crossroads

Background
Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman.

Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management.

This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer.

Objectives
Main objective

To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+).

Secondary objective

To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done.

Search methods
We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011).  Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.

More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review.

Selection criteria
Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification.

Data collection and analysis
The review authors independently extracted data from the selected studies, and obtained additional data from report authors.

Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL.  

The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests.

Main results
The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001).

Authors' conclusions
HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology.

When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account.

/pdf/human-papillomavirus-testing-versus-repeat-cytology-for-4a25yqn3yp.pdf

Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions.

Since the introduction of biomolecular testing for the identification of high-risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA testing has been demonstrated to have better sensitivity than conventional cytology in several settings: screening, triage of ASC-US and in follow-up after treatment. Despite this, some limitations of these new technologies have also been underlined: the major issue is the low specificity of the tests, which cannot discriminate between regressive and progressive infections. Thus, recent research has moved the attention towards novel markers of progression that could more precisely detect cases at real risk of cancer development. In view of the fact that progression to cancer is dependable of the E6/E7 proteins integration and transforming action, the overexpression of E6/E7 transcripts has been seen as a valuable marker of this risk. This review aims to summarise the literature data on this topic and to provide a clear view of the emerging perspectives.

E6/E7 mRNA testing for human papilloma virus-induced high-grade cervical intraepithelial disease (CIN2/CIN3): a promising perspective

BACKGROUND

High-risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US). However, no consensus has been reached on the optimal management of low-grade squamous intraepithelial lesions (LSIL).



METHODS

In this meta-analysis, the diagnostic accuracy of nucleic acid sequence-based amplification (NASBA) detection of messenger ribonucleic acid (mRNA) of 5 hrHPV types (the PreTect HPV-Proofer and NucliSENS EasyQ tests) for detecting grade 2 cervical intraepithelial neoplasia or worse (CIN2+) and CIN3+ was assessed in women who had a diagnosis of ASC-US and LSIL. The results were compared with the Hybrid Capture-2 (HC2) assay, which detects the DNA of 13 hrHPV types. A bivariate random-effect model that incorporated the intrinsic correlation between the true-positive and false-positive rates was used for a pooled meta-analysis.



RESULTS

Considering underlying CIN2+, the pooled absolute sensitivity of the 10 included studies was 75.4% (95% confidence interval [CI], 68.1%-82.7%) and 76.2% (95% CI, 68.3%-76.9%) for the triage of ASC-US and LSIL, respectively. The pooled absolute specificity to exclude CIN2+ was 77.9% (95% CI, 70.1%-85.7%) and 74.2% (95% CI, 69.5%-78.8%) in women with ASC-US and LSIL, respectively. Five studies allowed direct comparison of the mRNA assays with HC2. Considering CIN2+ in women with ASC-US and LSIL, mRNA testing was substantially more specific than the HC2 assay (ratio: 1.98 and 3.36, respectively; P < .001) but was less sensitive (ratio: 0.80 and 0.74, respectively; P < .001).



CONCLUSIONS

HPV assays for detecting the mRNA of 5 hrHPV types may reduce the over-diagnosis of women who have minor cytologic abnormalities. However, given the lower sensitivity, women with negative mRNA test results cannot be considered free of CIN2+ and require further surveillance. Cancer (Cancer Cytopathol) 2013;121:675–687. © 2013 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncy.21359

Triage of women with minor abnormal cervical cytology: meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types.

High risk types of human papillomaviruses E6/E7 oncogenes and their association with tumor suppressor genes products are the key factors of cervical carcinogenesis. This study proposed them as specific markers for cervical dysplasia screening. The aim of the study is to compare the clinical and prognostic significance of HPV E6/E7 mRNA as an early biomarker versus HPV DNA detection and cytology in triage of woman for cervical cancer. The study group consists of 413 women: 258 NILM, 26 ASC-US, 81 LSIL, 41 HSIL, and 7 unsatisfactory cytology. HPV4AACE screening, real-time multiplex PCR and MY09/11 consensus PCR primers methods were used for the HPV DNA detection. The real-time multiplex nucleic acid sequence-based assay (NucliSENS EasyQ HPV assay) was used for HPV E6/E7 mRNA detection of the five most common high risk HPV types in cervical cancer (16, 18, 31, 33, and 45). The results show that HPV E6/E7 mRNA testing had a higher specificity 50% (95% CI 32-67) and positive predictive value (PPV) 62% (95% CI 46-76) for CIN2+ compared to HPV DNA testing that had specificity of 18% (95% CI 7-37) and PPV 52% (95% CI 39-76) respectively. The higher specificity and PPV of HPV E6/E7 mRNA testing are valuable in predicting insignificant HPV DNA infection among cases with borderline cytological finding. It can help in avoiding aggressive procedures (biopsies and over-referral of transient HPV infections) as well as lowering patient's anxiety and follow up period.

HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women.

Objective To examine the diagnostic accuracy of nucleic acid sequence based amplification (NASBA) and flow cytometry for E6&7 human papillomavirus (HPV) mRNA detection in the triage of minor cytological abnormalities. Design Prospective diagnostic accuracy study. Setting Gynecology outpatient clinics of a university hospital. Population 472 women with low-grade squamous intraepithelial lesion (LSIL) or atypical squamous cells of undetermined significance (ASCUS). Methods Residual material of the liquid-based smears was tested by NASBA and by flow cytometry for E6E Fisher's exact test). In the LSIL group the NASBA accuracy indices for CIN3+ were: sensitivity 75%, specificity 78.7% and positivity rate 20.8%, and for flow 77.8%, 64.5% and 35.9%, respectively. Conclusions NASBA has favorable specificity and positivity rates for triaging LSIL prior to colposcopy. A relatively low sensitivity warrants cytological surveillance of the NASBA-negative LSILs. Flow cytometry does not perform as well overall.

The diagnostic accuracy of two methods for E6&7 mRNA detection in women with minor cytological abnormalities.

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The diagnostic accuracy of two methods for E6&7 mRNA detection in women with minor cytological abnormalities.