CORRESPONDENCE

Re: A Study of the Impact of Adding HPV Types to Cervical Cancer Screening and Triage Tests

Silvia Franceschi, Gary M. Clifford

Affiliations of authors: International Agency for Research on Cancer, Lyon, France

Correspondence to: Silvia Franceschi, MD International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France (e-mail: franceschi{at}iarc.fr).

In a recent article in the Journal, Schiffman et al. (1) showed that testing for more than about 10 human papillomavirus (HPV) types decreased specificity for detection of cervical intraepithelial neoplasia grade 3 (CIN3) and cancer more than it increased sensitivity in the ASCUS/LSIL Triage Study (ALTS) and, most notably, in the Proyecto Epidemiológico Guanacaste (PEG). To further elucidate which HPV types are the strongest predictors of the risk of CIN3 and cancer, we compared our three large systematic reviews on the distribution of HPV types in low-grade squamous intraepithelial lesions [LSILs; 8308 women from 50 studies (2)], high-grade squamous intraepithelial lesions [HSILs; 4338 women from 52 studies (3)], and squamous cell cervical carcinoma [SCC, 10 058 women from 85 studies (4)].

We compared the type-specific prevalences reported from our three systematic reviews, selecting the same HPV types highlighted by Schiffman et al. (1), namely 13 high-risk HPV types (i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) that are currently included in the DNA test approved by the Food and Drug Administration (FDA) as an adjunct to primary cytologic screening and for triage of women with equivocal cytology (5), as well as five additional types (i.e., HPV26, 53, 66, 73, and 82) that have been considered for inclusion in the DNA test (6). We found that HPV16 was twice as prevalent in HSILs as it was in LSILs. Other HPV types showed either a similar prevalence in LSILs and HSILs or a substantially higher prevalence in LSILs than in HSILs (Fig. 1).



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Fig. 1. Prevalence of human papillomavirus (HPV) types in cervical lesions of increasing severity. Prevalence estimates are derived from three published systematic reviews of type-specific HPV prevalence data in i) low-grade squamous intraepithelial lesions (LSILs) (2), ii) high-grade squamous intraepithelial lesions (HSILs) (3), and iii) squamous cell cervical carcinoma (SCC) (4). The 13 HPV types included in the Food and Drug Administration (FDA)–approved HPV test kit are shown in A–C: A) HPV16 and 18, B) HPV types present in 1%–5% of SCC (HPV31, 33, 35, 45, 52, and 58), and C) PV types present in less than 1% of SCC (HPV39, 51, 56, 59, and 68). The five HPV types not currently included in the FDA-approved test set, as discussed by Schiffman et al. (1) (HPV26, 53, 66, 73, and 82), are shown in D.

 
Most important, the comparison of our systematic reviews provides additional insight into the shift in HPV type distribution in SCC, which was found in only 39 women in ALTS and PEG (1). In the International Agency for Research on Cancer (IARC) reviews, only HPV16 and 18 were found more frequently in SCC than in LSILs, whereas HPV26, 39, 51, 56, and 73 were at least 10-fold more common, and HPV53 and 66 were approximately 30-fold more common in LSILs than in SCC. The low-risk HPV types HPV6, 11, and 70 were also approximately 10-fold more common in LSILs than in SCC (data not shown).

Comparisons of HPV distribution in cross-sectional studies, as herein reported, have several limitations, including inaccuracies in cytologic/histologicclassification and viral detection, as well as non-negligible heterogeneity in HPV type distribution across different populations. HPV35 (7), for instance, was recently reported to be relatively common in HSILs and SCC in Mozambique, but little information on HPV type distribution in SCC in sub-Saharan Africa was available at the time of our systematic review (4). Nevertheless, the picture that emerges from our analysis of the IARC systematic reviews is remarkably consistent with the findings of receiver operating characteristic curves in PEG and ALTS. This picture suggests that 1) HPV types not currently included in FDA-approved DNA tests have little to contribute to SCC prevention, although this may also be the case for some of the types that are currently included (e.g., HPV39, 51, and 56); 2) HPV16 and 18, which are substantially enriched in SCC compared with LSILs and those types that are found at approximately equal frequencies in SCC and LSILs (HPV33 and 45) or slightly under-represented in SCC compared with LSIL (HPV31, 52, and 58) probably have the best trade-offs between sensitivity and specificity for cervical cancer screening prevention.

REFERENCES

(1) Schiffman M, Khan MJ, Solomon D, Herrero R, Wacholder S, Hildesheim A, et al. A study of the impact of adding HPV types to cervical cancer screening and triage tests. J Natl Cancer Inst 2005;97:147–50.[Abstract/Free Full Text]

(2) Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. HPV genotype distribution in low-grade cervical lesions: comparison by geographical region with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157–64.[Abstract/Free Full Text]

(3) Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer 2003;89:101–5.[CrossRef][ISI][Medline]

(4) Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003;88:63–73.[CrossRef][ISI][Medline]

(5) Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304–9.[Abstract/Free Full Text]

(6) Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–27.[Abstract/Free Full Text]

(7) Naucler P, Da Costa FM, Ljungberg O, Bugalho A, Dillner J. Human papillomavirus genotypes in cervical cancers in Mozambique. J Gen Virol 2004;85:2189–90.[Abstract/Free Full Text]



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