1 Department of Obstetrics and Gynecology, University of Munich, Munich, Germany; 2 Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, USA
Received 21 August 2003; revised 25 January 2004; accepted 29 January 2004
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ABSTRACT |
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We determined whether testing of self-collected vaginal swabs for human papillomavirus (HPV) DNA can be used to screen for cervical disease within internal medicine outpatient clinics.
Patients and methods:
In this prospective study, 560 patients visiting two referral outpatient clinics for internal medicine were asked to take an HPV self-sample. Acceptability of self sampling, HPV prevalence and cervical intraepithelial neoplasia (CIN) detection rate were evaluated.
Results:
435 women (78%) performed HPV self-sampling; 1.5% considered self-sampling to be difficult. 134 women (31%) tested positive for high-risk type of HPV. There were significant differences between HPV-positive and -negative women with respect to the following: mean age (42 versus 46 years), number of women aged <16 years at first coitus (35% versus 23%) and history of drug abuse (8.3% versus 2.6%). Colposcopy could be performed for 70 HPV positive women: CIN 13 was identified in 24%. Two of 52 women with HPV-negative results undergoing colposcopy had biopsy-confirmed CIN 1. Test performance for detection of CIN 23 after correction for verification bias: sensitivity, 100%; specificity, 71%; negative predictive value, 100%; positive predictive value, 10%. HPV persistence was associated with a 5.7-fold risk of CIN 23 detection at follow-up.
Conclusions:
Self-assessment for HPV DNA is an easy, feasible and well-accepted method for HPV testing and for cervical cancer screening in internal medicine outpatient clinics.
Key words: cervical cancer screening, HPV, self-sampling
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Introduction |
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Previous studies have demonstrated the usefulness of adjunctive human papillomavirus DNA testing as a complement to cytology in primary screening [710]. Patient-obtained vaginal samples (self-sampling) for analysis of HPV DNA has a sensitivity for detection of high-grade cervical lesions and invasive cancer that is equivalent or even superior to that of a Pap smear [11, 12]. In addition, self-sampling has the advantage of not requiring a vaginal speculum examination, thus reducing the discomfort that may make screening unattractive even among women who have access to health care.
In our study we evaluated patient-obtained vaginal samples to determine the feasibility and effectiveness of self-sampling for HPV DNA as a screening tool for cervical cancer in tertiary referral internal medicine outpatient clinics. We analyzed the acceptability of self-sampling, the HPV prevalence and persistence within this population, important demographic and sexual characteristics, CIN detection rate and HPV self-sampling test performance.
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Patients and methods |
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Participants were informed about their HPV test results and the possible clinical significance by letter. The option of an appointment in our colposcopy clinic was offered to all participants when desired by the women.
Follow-up consisted of a postal questionnaire and a thorough gynecological examination including colposcopy: to all participants a questionnaire with 35 items was sent that included questions on demographic characteristics, sexual behavior (Table 1) and acceptability of self-sampling (Table 2). If no response was obtained after 12 months, a reminder letter was sent. Analysis of the questionnaire was performed with regard to the HPV status (HPV-positive versus HPV-negative). Analysis of the questions with regard to the acceptability of self-sampling differentiated between women <35 and 35 years of age. All HPV-positive participants were contacted by telephone and recalled for a gynecological examination and colposcopy. To enable calculations on test performance (sensitivity, specificity, positive and negative predictive value) of HPV self-sampling, an appropriate number of randomly selected (blinded to demographic characteristics) HPV-negative women were recalled as well (n = 52).
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Cervical smears were classified according to the cytological classification most widely used in Germany (Münchner Nomenklatur) [13]: I, normal cytology; II, mild to moderate inflammatory, metaplastic or degenerative changes; III, squamous or glandular cells of unclear significance; IIID, mild to moderate dysplasia; IVa, severe dysplasia or carcinoma in situ; IVb, carcinoma in situ, invasion cannot be ruled out; V, invasive carcinoma. Histology was classified as CIN: CIN 1, mild dysplasia; CIN 2, moderate dysplasia; CIN 3, severe dysplasia/carcinoma in situ.
Statistical analysis
The sensitivity, specificity, positive and negative predictive value of the hybrid capture II results (self-assessment) were calculated using three different cut points for being test positive: (i) cytological smear IIID or CIN
1; (ii) CIN 1/2/3; and (iii) CIN 2/3. As gold standard cytology results and colposcopy directed biopsy results were used. As probability for verification by gold standard differed between HPV-positive and -negative women, the correction for verification bias was performed [14]. Proportions were compared using the Chi-squared tests or Fishers exact test when appropriate. The t-test or MannWhitney U-test were used for continuous variables. The agreement between HPV-doctor, HPV-patient and HPV test results at recruitment and at follow-up was calculated using the
statistic reflecting the overall agreement beyond chance. The relative risk (RR) for CIN in women with HPV persistence versus no persistence was determined. For proportions and relative risks, 95% confidence intervals (95% CI) were calculated.
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Results |
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There was good agreement between HPV-doctor and HPV-patient for 52 consecutive participants at the follow-up visit ( = 0.71; Table 3). Nine women were HPV-positive in the self-taken sample and six were positive in the doctors sample. HPV DNA test results were concordant in 48 of 52 women (92%). Six were positive and 42 were negative on both tests. One woman testing negative by her self-obtained sample tested positive with the doctors sample. Three women had a positive self-attained HPV sample and a negative doctors sample.
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Detection rate for CIN
Adequate follow-up with regard to the gynecological examination and colposcopy (and directed biopsies if required) could be performed in 70 (52%) of 134 HPV-positive women (Figure 1). There were no differences between women with and without follow-up with regard to any of the demographic characteristics listed in Table 1, with the exception of number of smears within the last 3 years (2.9 with follow-up versus 3.5 without follow-up; P = 0.038). Fifty-two (17%) of the 301 HPV-negative women served as a negative control group and were assessed by colposcopy in the same way as HPV-positive women. In the HPV-positive group (n = 70), a biopsy confirming CIN of any grade was identified in 17 women (24%), CIN 2/3 in seven women (10%) and CIN 1 in 10 (14%). Cytology grade IIID was identified in 16 (23%) women. In the HPV-negative group (n = 50), only two histologically confirmed cases of CIN 1 (3.8%) were identified, both of them belonged to the cytological group IIID. There were no women with CIN 2 or 3 in the HPV-negative group. Table 5 shows the test performance before and after correction for verification bias. These values adjust for different probabilities of cytological and/or histological verification in HPV-positive versus HPV-negative women, and reflect the values that would be expected if follow-up had been performed in all women.
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On average, women participating in our study had one Pap smear per year, indicating that a well screened population had been analyzed in the care of an established health service. This is consistent with reports that 57% of women with invasive disease had a normal cytology result within 5 years prior to diagnosis, and that 47% of patients <70 years of age diagnosed with invasive cancer greater or equal to FIGO stage IB1 disease had a history of adequate cytology-based screening [18, 19].
With regard to detection of CIN 2 or 3 via self-sampling, our study demonstrated both an excellent sensitivity and negative predictive value (each 100%). We used a cytobrush for self-sampling that has demonstrated a good sensitivity (92%) in detecting CIN 23 in an earlier study [12]. Other techniques (cervicovaginal lavage, tampon, Dacron swab) have shown lower sensitivities [11, 20]. Self-sampling with a cotton tip swab even missed 50% more cancers than did physician sampling, indicating that the cotton tip technique is not a safe method for the collection of samples aimed at primary cervical cancer screening [21]. The high negative predictive value associated with a high sensitivity supports the suggestion that screening intervals for women negative for high-risk HPV could safely be lengthened [5]. This offers possible cost-saving effects that could compensate for the increased screening expenditures caused by HPV testing. Such cost-saving effects have been demonstrated recently by several investigators [2225].
Analysis of the participants answers with regard to acceptability of self-sampling by a cytobrush reflected ease of use: only 1.5% of 333 women considered self-sampling to be difficult, 97% were willing to perform self-sampling at home and 57% of the participants would pay for the HPV self-test if it was available over the counter. The high acceptance of self-sampling could further decrease cervical cancer mortality, bearing in mind that most cases of cervical cancers are associated with absent or deficient screening [4].
This study has several limitations. Not all women received verification by histology or cytology; however, a substantial fraction of verified results were available in both groups and a formal correction for verification bias could be performed. In the HPV- positive group the only difference between women with and without follow-up was the higher number of smears within the last 3 years in the group not followed up. This indicates that the groups that have been followed up are representative for the whole study population. The results of this study, however, cannot easily be generalized to the normal population, because in our study screening took place in tertiary centers. Positive and negative predictive values are dependent on the prevalence of CIN, which is expected to be higher in the study population compared with the general population. Therefore, PPV may be lower and NPV higher in the general population compared to the reported values.
For HPV (self-)testing to be cost effective in primary screening, it is necessary to develop an effective policy for the management of women who test positive for high-risk HPV types.
Taking into account our and related findings [26] we would like to propose the following algorithm for cervical cancer screening: for women between 25 and 30 years of age, cytology screening every second year should be the preferred screening method, because HPV testing in this age group would detect too many transient HPV infections that are not associated with high-grade CIN. For women over 30 years of age we recommend HPV testing every 3 years. This can be accomplished by a gynecologist or, alternatively, as self-sampling. In case of a test result positive for a high-risk HPV type it should be repeated after 6 months. Again, surveillance reduces the detection of transient HPV infections, and of low-grade lesions, which have a high spontaneous regression rate. If the second HPV test also detects a high-risk HPV type then colposcopy with cytology and directed biopsies is indicated. One aim of cervical cancer screening is to include as many women as possible. Regarding this, HPV self-sampling could contribute to the improvement of our screening. However, these suggestions have to be tested in future studies with regard to costs and outcomes.
Our data show that self-sampling offers the chance of cervical cancer screening not only in gynecological office practices, but also in other medical fields such as internal medicine. Self-assessment for HPV DNA is an easy, feasible and well-accepted method of testing for HPV and for cervical cancer in tertiary referral internal medicine outpatient clinics.
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Acknowledgements |
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FOOTNOTES |
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