Elsevier

Gynecologic Oncology

Volume 104, Issue 1, January 2007, Pages 232-246
Gynecologic Oncology

Review
Diagnostic accuracy of human papillomavirus testing in primary cervical screening: A systematic review and meta-analysis of non-randomized studies

https://doi.org/10.1016/j.ygyno.2006.08.053Get rights and content

Abstract

Objective

This is a meta-analysis of studies comparing HPV testing to cytology with regard to their accuracy in the detection of underlying high grade cervical intraepithelial neoplasia in primary cervical cancer screening.

Methods

A systematic review was conducted following the Cochrane Collaboration Guidelines. A systematic search was performed in 8 electronic databases. Strict selection criteria were applied in terms of types of participants, types of interventions and methods to limit verification bias. Where possible we calculated the sensitivity, specificity, positive and negative predictive value of cytology and the HPV test, as well as sensitivity and specificity ratios for the detection of CIN2 or worse. Random effect models were used for pooling accuracy parameters. The results were displayed using forest plots.

Results

We identified 25 studies fulfilling the inclusion criteria. The pooled sensitivity of HC2, PCR, cytology (ASCUS or worse) and cytology (LSIL or worse) was 90%, 80.9%, 72.7% and 61.6%, respectively, and the pooled specificity was 86.5%, 94.7%, 91.9% and 96.0%, respectively. The ratio of the sensitivity of HC2 to cytology (ASCUS) was 1.25 (95% CI = 1.20–1.29), and the corresponding specificity ratio was 0.97 (95% CI = 0.96–0.98). The ratio of the sensitivity of combination of HC2 and cytology (ASCUS) to HC2 alone was 1.05 (95% CI = 1.04–1.06) and the ratio of the specificity 0.95 (95% CI = 0.94–0.96). For women over 30 years, the sensitivity of HC2 was 94.8% and the specificity 86.0%.

Conclusions

Compared to cytology, the HC2 and PCR are substantially more sensitive for prevalent CIN2 or worse but significantly less specific. The combination of HC2 and cytology has the highest sensitivity and lowest specificity. However, reduction of the incidence of or mortality from invasive cervical cancer among HPV screened subjects compared to cytologically screened subjects has not yet been demonstrated.

Introduction

Organized cervical screening programs are currently essentially based on exfoliative cytology as a screening test. Screening for cervical cancer has arguably met many of the prerequisites that would seem to be necessary for mass screening [1]. The disease is common enough to justify mass screening, is associated with significant mortality, effective treatment is available for pre-invasive or early invasive disease and finally detection and treatment of pre-symptomatic state results in benefits beyond those obtained through treatment of early symptomatic disease. Cervical cytological screening has resulted in a substantial reduction in both the morbidity and mortality of cervical cancer [2], [3]. However, in recent years, the sensitivity and specificity of this test have been questioned, especially with respect to false negative results, in which disease has been missed, as well as the false positive rates that emanate from over-interpretation of benign conditions. Both false negative and false positive tests have important medical, financial, psychological and occasionally legal implications. A low sensitivity of the cervical screening program would put women at risk of developing invasive disease [4]. There are also concerns about the test's reproducibility as there is considerable variation in smear interpretation between cytopathologists [5]. These issues have raised doubts on the appropriateness of the whole process of cervical cytology sampling and interpretation as a screening test. There is therefore considerable pressure to develop a better screening test for cervical cancer prevention and in particular to exploit the role of HPV testing.

Epidemiological studies convincingly demonstrate that the causal factor for development of cervical cancer or its precursors is persistent infection with high-risk HPV types. There are a number of cofactors which modify the risk among women infected with high-risk HPV, such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status, prolonged use of combined oral contraceptives and positive smoking history [6]. A large number of studies exploring the role of HPV testing in primary screening settings have been published employing differing methodologies with sometimes conflicting results. A comprehensive systematic review would be useful to synthesize the currently available bulk of information. Structured critical analysis of evidence and appropriate pooling of results has greater power and subsequently would be expected to reduce the likelihood of type I and II statistical errors. A meta-analysis would also study the geographical consistency of the studies so that we can assess whether the results can be generalized to a wider population. The results of the ongoing longitudinal randomized studies in this field are expected for 2007–2008, targeting more public-health-relevant outcomes. Thus, the best level of evidence on this subject so far would be provided by a systematic review and meta-analysis of existing non-randomized screening accuracy publications.

The objective of this review is to determine the value of HPV testing in a primary cervical cancer screening program for the general population with respect to performance, validity or accuracy to detect cervical cancer precursors or even early invasive disease. The review will not cover other potential applications of HPV testing which have been the subject of other systematic reviews. A recent meta-analysis of the use of HPV testing in the triage of women with an ASCUS Pap smear has shown that the Hybrid Capture 2 (HC2) has superior accuracy to repeat cytology [7], [8]. Another meta-analysis of the role of HPV testing in the follow up after surgical treatment of cervical intraepithelial neoplasia has suggested that it has higher sensitivity in predicting treatment failure than cytology [9], [10].

Section snippets

Research question

In this meta-analysis, we addressed the following question: what is the accuracy (sensitivity, specificity, predictive values) of HPV DNA testing to detect histologically confirmed CIN2 or worse disease in women participating in cervical cancer screening and how it compares to the accuracy of cytological testing.

Data sources

A systematic literature search identified articles published between 1994 and 2005 that contained quantitative data. Articles were retrieved from the electronic bibliographic databases

Study characteristics

We identified 25 studies fulfilling the inclusion criteria [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. A list of other studies that were initially considered but eventually excluded along with the reasons for their exclusion can be provided upon request. In twenty-three of the included studies, the design was cross-sectional with concomitant cytology and HPV testing. In one study, the

Discussion

In this meta-analysis, we evaluated the accuracy of two cervical cancer screening methods: cervical cytology and HPV testing. We focused mainly on the sensitivity and the specificity of the tests. Predictive values depend on the local disease prevalence, and therefore generalization of the results is usually of limited value, although this might not be the case in this review as all the included studies were done in primary screening populations. There was large interstudy variation in the

Acknowledgments

We would like to thank Professor Sean Kehoe and Mr. Mark Charnock from Oxford for their encouragement and beneficial comments. Financial support was received from (1) the European Commission (Directorate of SANCO, Luxembourg, Grand-Duché du Luxembourg), through the European Cancer Network and (2) the DWTC/SSTC (Federal Services for Scientific, Cultural and Technical Affairs, Brussels, Belgium) and (3) the Gynaecological Cancer Cochrane Review Collaboration (Bath, UK).

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