We read with great interest the systematic review published by Verdoodt et al regarding the use of testing for E6-E7 messenger ribonucleic acid (mRNA) overexpression of 5 high-risk human papillomaviruses (HPVs) to triage minor cytology abnormalities in cervical cancer screening.[1] This summary of the available evidence was needed and surely will be useful in evaluating whether to introduce this biomarker in ongoing cervical cancer screening. Nevertheless, we are convinced that to fully understand the clinical usefulness of the biomarker, the positive predictive value (PPV) and the percentage of women with a positive test result (ie, a colposcopy referral) should have also been given. In fact, the main accuracy measures in the article are sensitivity and specificity.[1] However, when we assess the clinical validity of biomarkers that are causal risk factors for the disease and not, instead, the symptoms, specificity is just a direct expression of the percentage of women testing positive, whereas the PPV tends to be more constant.[2] Although the population is very well defined (ie, women with low-grade squamous intraepithelial lesions [LSILs] or atypical squamous cells of undetermined significance [ASC-US] cytology), the prevalence of HPV DNA and mRNA positivity among these women varies strongly according to the specificity of the cytological classification in each context.[3] This is evident if we consider what to our knowledge are the 4 largest studies of the 5 included in the review by Verdoodt et al comparing HPV DNA and mRNA (ie, excluding the study by Halfon et al[4]), along with another large study with a similar design[5] that was excluded from the review for its incomplete ascertainment of mRNA-negative women (which is not relevant for calculating PPV and colposcopy referral). In these 5 studies, considering ASC-US and LSIL together, mRNA positivity ranged from 27% to 41% and HybridCapture2 positivity ranged from 12% to 37%; the pooled estimate for relative positivity (ie, a direct measure of the reduction in colposcopy workload) was 0.44 (95% confidence interval, 0.38-0.52) and the relative PPV was 1.55 (95% confidence interval, 1.37-1.76).

Unfortunately, using published data, we could only calculate the indicators for ASC-US and LSIL together and for a subset of the included articles, but we are convinced that the authors can provide this vital information for decision-making in a more detailed way.


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Dr. Giorgi Rossi is Principal Investigator of a project sponsored by the Italian Ministry of Health (data owner) and is in contact for reagents at a reduced price or free of cost from Roche Diagnostics, Hologic Gen-Probe, Abbott, and Qiagen.

  • Maria Benevolo, PhD

  • Pathology Department

  • Regina Elena National Cancer Institute

  • Rome, Italy

  • Paolo Giorgi-Rossi, PhD

  • Epidemiology Unit

  • Local Health Unit (AUSL)

  • Reggio Emilia, Italy


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  • 1
    Verdoodt F, Szarewski A, Halfon P, Cuschieri K, Arbyn M. 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 [published online ahead of print July 23, 2013]. Cancer (Cancer Cytopathol). doi: 10.1002/cncy.21325.
  • 2
    Giorgi-Rossi P, Franceschi S, Ronco G. HPV prevalence and accuracy of HPV testing to detect high-grade cervical intraepithelial neoplasia. Int J Cancer. 2012;130:1387-1394.
  • 3
    Ronco G, van Ballegooijen M, Becker N, et al. Process performance of cervical screening programmes in Europe. Eur J Cancer. 2009;45:2659-2670.
  • 4
    Halfon P, Benmoura D, Agostini A, et al. Relevance of HPV mRNA detection in a population of ASCUS plus women using the NucliSENS EasyQ HPV assay. J Clin Virol. 2010;47:177-181.
  • 5
    Benevolo M, Vocaturo A, Caraceni D, et al. Sensitivity, specificity, and clinical value of human papillomavirus (HPV) E6/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test. J Clin Microbiol. 2011;49:2643-2650.