Division of Adolescent Medicine, Cincinnati Childrens Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. E-mail: jessica.kahn@cchmc.org
Although the implementation of cervical cytology (Pap) screening has been responsible for a dramatic decline in the incidence of cervical cancer over the past 50 years in developed countries [1], its limitations are evidenced by the fact that cervical cancer remains a leading cause of death among women worldwide [24]. The primary limitation of the Pap test is its low sensitivity for detection of cervical intraepithelial neoplasia (CIN), necessitating frequent screening intervals [5]. Furthermore, many women do not participate in screening programs or adhere to recommendations for follow-up of abnormal results, perhaps because they do not understand the rationale for screening or find the pelvic examination to be painful or embarrassing [68]. In developing countries additional barriers to screening include a lack of trained providers and the infrastructure necessary to perform testing, as well as the prohibitively high cost of cervical cancer screening and follow-up procedures [9, 10].
The limitations of Pap testing have generated much interest in alternative screening techniques that could improve sensitivity for detection of CIN and rates of screening. Research has focused on the role of human papillomavirus (HPV) testing, given that persistent infection with high-risk HPV types is the primary risk factor for the development of cervical carcinoma and that testing for high-risk HPV is highly sensitive for the detection of moderate to severe CIN [1113]. Proposed roles for HPV testing in cervical cancer screening programs include triage of patients with mild cytological abnormalities such as atypical cells of undetermined significance or low-grade squamous intraepithelial lesion, surveillance of women with confirmed CIN, and primary screening for cervical cancer [1424]. The main drawbacks to HPV testing as a primary screening test are that relative to the Pap test, the cost is higher and specificity lower for detection of CIN; thus, HPV testing may result in higher colposcopy referral rates than Pap screening. These limitations might be overcome if HPV testing allowed for longer screening intervals and if high volume use decreased the cost of testing [21, 25, 26]. A benefit of HPV testing with potentially far-reaching implications is that a speculum examination is not needed for collection of vaginal specimens, which appear to be as accurate as cervical specimens for HPV detection [2729]. Women who avoid the speculum examination may be more likely to adhere to screening protocols if clinician- or self-collected vaginal samples can be collected instead of a Pap test, and self-collected samples may enhance access to screening in low-resource settings.
The critical questions concerning the utility of self-collected HPV specimens are whether the self-collected specimen is as sensitive as clinician testing for the detection of CIN and whether it is acceptable to patients. The study published in this issue of Annals of Oncology by Dannecker et al. [30] addresses both issues. This prospective study enrolled women (mean age 45 years) from hematology/oncology and gastroenterology clinics at a University hospital: 435 (78%) agreed to participate and performed HPV self-sampling. Of the 134 (30.8%) who were high-risk HPV positive, 70 (52%) underwent colposcopy and clinician testing for HPV; a sample of 52 HPV-negative women also underwent colposcopy. At the colposcopy visit, a consecutive sample of 52 women collected another self-obtained HPV specimen. Agreement was high at the colposcopy visit between the results of self- and clinician-collected samples ( = 0.71, test results concordant in 92%). However, agreement was only fair between the results of self-testing at the baseline visit and clinician testing at the follow-up visit (
= 0.24, test results concordant in 59%), perhaps reflecting the transient nature of many HPV infections [31]. After correction for verification bias, the sensitivity of self-testing for detection of CIN 2/3 (identified in seven women) was 100%, specificity 45%, positive predictive value 10%, and negative predictive value 100%. Although virtually all of the women
35 years of age did not consider self-testing to be difficult, only 24% would prefer self-testing over a gynecological examination and 61% preferred both. The findings by Dannecker et al. suggest that HPV self-testing is sensitive for the detection of CIN 2/3 and feasible in a sample of adult women with a high prevalence of HPV infection.
Data from previous studies regarding agreement between clinician- and self-collected vaginal swabs for HPV are inconsistent. While some investigators have found good agreement ( = >0.70) [3235], others have reported poor or fair agreement (
= 0.090.62) [28, 3638]. Similarly, while some investigators have reported that the sensitivity of HPV clinician testing and self-testing are similar for detection of abnormal cytology or CIN [32, 34, 35], others have found that the sensitivity of clinician testing is substantially higher than self-testing [28, 3638]. In considering the implications of these findings for general screening, it is important to recognize that in research settings self-sampling occurs under optimal conditions and sensitivity may be lower in clinical settings. The findings of previous studies concerning acceptability of self-testing similarly are inconsistent. Most suggest that women find self-collected samples for HPV DNA more acceptable than clinician-collected samples, and prefer self- to clinician testing [3234, 36, 39]. However, the majority of adolescent and young adult women in one study preferred clinician to self-testing, primarily because of concerns about self-collection technique and the accuracy of the self-test result [40]; adult women also may have poor confidence in the results of self-testing [39].
Discrepancies between the findings of the studies described above may be due to differences in recruitment and data collection procedures, study populations, analytic methods and outcome measures. For instance, in the study by Dannecker et al. [30], a subset of 52 participants was used to evaluate concordance between the results of self- and clinician testing and the remaining 508 women either did not agree to participate, did not return for colposcopy, or were not recalled for colposcopy. If those who participated were more likely than those who did not to possess the skills or self-confidence necessary to self-collect specimens correctly, estimates of the agreement between self- and clinician testing may be inflated. Similarly, studies of acceptability may be subject to selection bias. A woman who enrolls in a study of self-testing, particularly one who already participates actively in screening programs as is probably true for this study sample, may be more likely to find self-testing acceptable. The authors suggest that the cytology brush technique used for HPV self-collection in this and a previous study may account for the high concordance noted between self- and clinician testing [30, 32]. However, the sensitivity of HPV self-testing for detection of CIN was significantly lower than clinician testing (49% versus 82%) in a recently published study that utilized a similar collection technique [38], indicating that self-collection methods must be tested further in order to determine the optimal technique. Finally, the participants in the study by Dannecker et al. [30] demonstrated a remarkably high prevalence of high-risk HPV (three to six times higher than the expected prevalence in women of comparable age); thus, the positive predictive value of 10% that is reported may be lower in the general population. Another reason for caution in generalizing these results to other women is that the estimates of sensitivity and specificity are based on a total of only seven cases of CIN. While the sensitivity of 100% is encouraging, larger studies are needed to confirm this finding.
The fundamental question raised by the study of Dannecker et al. [30] is whether patient-obtained samples for HPV DNA may be used as a primary screen for cervical cancer. Self-testing has tremendous potential to expand access to screening in low-resource settings and increase adherence to screening and follow-up protocols. While an increasing body of evidence suggests that clinician-collected swabs for HPV DNA may be useful as a primary screening test for CIN or cervical cancer [1619, 21], the data currently available do not convincingly support a recommendation that self-testing for HPV may be used for screening. Research priorities should include the design of optimal collection techniques for self-testing as well as the implementation of sufficiently large clinical trials that compare the sensitivity, specificity and costs of HPV self-testing, HPV clinician testing and Pap testing. Ultimately, we must determine which screening strategies are the most effective in decreasing cervical cancer incidence and mortality.
J. A. Kahn
Division of Adolescent Medicine, Cincinnati Childrens Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (E-mail: jessica.kahn@cchmc.org)
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