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Comparison of detection rate of high risk HPV infection between self-collected HPV testing and clinician-collected HPV testing in cervical cancer screening
Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 477e481
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Comparison of detection rate of high risk HPV infection between self-collected HPV testing and clinician-collected HPV testing in cervical cancer screening Pattiya Nutthachote a, Shina Oranratanaphan a, *, Wichai Termrungruanglert a, Surang Triratanachat a, Arkom Chaiwongkot b, Fern Baedyananda b, Parvapan Bhattarakosol b a b
Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand Department of Microbiology, Faculty of Medicine, Chulalongkorn University, 10330, Thailand
a r t i c l e i n f o
a b s t r a c t s
Article history: Accepted 8 January 2019
Objective: to correlate the detection rate of high risk HPV (HR-HPV) DNA between self-collected and clinician-collected testing. Materials and methods: A cross-sectional analytic study was conducted in 400 women undergoing cervical cancer screening program during February and May 2015. The procedure began with self-collected method and then clinician-collected method. Then, the specimens were processed and interpreted with the same technique. If the results from either methods were positive for HPV genotype 16 or 18, colposcopy was performed. We also conducted cytology testing for the participants. If the results were abnormal (ASC-USþ), colposcopy was also performed. Results: The detection rate of HR-HPV DNA was 10.0% and 7.5% by self-collected and clinician-collected specimen, respectively (kappa ¼ 0.73). HR-HPV positive rate in cytology ASC-USþ was no significantly different between groups. HR-HPV DNAs were positive in every HSIL (100% detection rate). HPV DNA test positive for detection CINþ was not significantly different between self-collected and clinician-collected testing. Conclusion: self-collected HPV testing can be used as an alternative option for primary cervical screening program. Detection rate of high grade lesion is similar to clinician-collected test. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cervical cancer screening Clinician-collected HPV testing Correlation Self-collected HPV DNA testing Self-sampling
Introduction Cervical cancer is the most common gynecologic cancer in Thailand [1]. The objective of cervical cancer screening program is to reduce the incidence, morbidity and mortality of cervical cancer [2]. Cervical cancer screening program, such as conventional cytology (Papanicolaou (Pap) smear), liquid based cytology, are used to detect precancerous lesions and treat before progress to cancer. The main screening method in Thailand is conventional Pap
* Corresponding author. Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand. E-mail addresses: [email protected] (P. Nutthachote), dr_shina@hotmail. com (S. Oranratanaphan), [email protected] (W. Termrungruanglert), t_surang@ hotmail.co.th (S. Triratanachat), [email protected] (A. Chaiwongkot), [email protected] (F. Baedyananda), [email protected] (P. Bhattarakosol).
smear. Although cervical cancer screening program can reduce the incidence, morbidity and mortality of cervical cancer, the incidence of cervical cancer in Thailand is still high. The main reason of persistent high incidence of cervical cancer in Thailand is low coverage of cervical cancer screening. Only 25e38% of women in Thailand had ever been screened [3e5]. The reasons for patients' refusing Pap test were embarrassment, fear of pain, fear of cancer, unavailability and lack of understanding regards to the test importance [4]. Primary HPV DNA testing has been approved by USFDA and proposed as an alternative cervical cancer screening method in women older than 25 years [6]. HPV DNA testing has been confirmed as a high sensitivity method to detect precancerous lesions because persistent high-risk HPV (HR-HPV) infection is considered as a cause of invasive cervical cancer. Therefore, self ecollected HPV DNA testing (self-HPV) which is a method that patients can collect specimen by themselves and send to the lab for
https://doi.org/10.1016/j.tjog.2019.05.008 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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HR-HPV DNA testing may enhance the screening rate for women who were not comfortable with pelvic examination. Currently, using self-collected vaginal sampling to detect HRHPV has been applied in some European countries to improve the coverage of the screening. The screening coverage was significantly increased by using self-sampling method comparing to other methods in previous study [7e10]. The consistency of the results between self-collected and clinician-collected sampling were controversy. Some studies revealed almost 80e90% consistency between self-collected and clinician-collected specimens [11e13]. The other studies revealed that the self-collected sampling detection rate were lower than the clinician-collected sampling. Detection rates of CIN2þ lesions with self-collected and clinician-collected HPV testing were 50e88% and 63e100%, respectively [14e17]. Nowadays, Self-sampling method is not widely used in Thailand and Asian countries. Therefore, the data of self-sampling method for cervical cancer screening in Thai and Asian population is still limited. Our study was designed to determine the correlation between self-collected and clinician-collected HPV DNA testing. Our secondary objective was to evaluate the accuracy of self-collected HPV DNA testing to detect cervical precancerous lesions. Materials and methods A cross-sectional analytic study was conducted. After approval from the Institutional Review Board (IRB) was achieved, women who were screened for cervical cancer at King Chulalongkorn Memorial Hospital during 1st January 2015 and 31st May 2015 were recruited to this study. A total number of 400 women were recruited at outpatient clinic in King Chulalongkorn Memorial Hospital. We included women attending for routine cervical cancer screening. Patients who had a history of hysterectomy, cervical cancer, previous radiation therapy or chemotherapy were excluded from the study. Information regarding self-collected and cliniciancollected tests was advised. After the participants were clearly understand about the procedures, all of the participants signed inform consent voluntarily. Self collected instruments were given to the participants at outpatient clinic and the participant collected the vaginal sample with brush type collecting system (QIAGEN Gaithersburg, Inc.) at the private rest room in outpatient clinic by themselves. The specimens were collected in a transport medium tube for HPV DNA testing (QIAGEN Gaithersburg, Inc). After complete the self-collected sampling collection, speculum examination was performed by physician. Cervical sampling was collected for HPV testing and liquid based cytology with broom type cervical brush (Surepath®). To avoid invalid of the test results, the specimens were stored in 4 degree Celsius, and analyzed within 4 weeks. The collected samples were analyzed by using Hybrid capture II method (QIAGEN Gaithersburg, Inc) to detect HR-HPV DNA. All HRHPV DNA positive specimens were further specify HPV DNA genotype for HPV genotype type 16, 18 and other high risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) (QIAGEN Gaithersburg, Inc). According to ASCCP guideline for management of abnormal Pap smear, the cases that results were positive for HR-HPV type 16 or 18 either from self-collected or clinician-collected methods, colposcopy was performed. In non 16, 18 HR-HPV, colposcopy would be performed when coexisting with abnormal cytology results. For that reason, we also conducted liquid based cytology for all the participants. Liquid based slides were evaluated by the professional cytologists and interpreted based on Bethesda classification system. If the results were abnormal, atypical cells of undetermined significance (ASC-US) or more severe abnormal cytology, colposcopy was also performed. Colposcopic diagnosis is based on American Society for colposcopy and Cervical Pathology
(ASCCP) recommendation. Biopsies or endocervical curettage (ECC) were taken to confirm the diagnosis. The patients whose biopsy result was CIN 2 or more were treated according to ASCCP guideline. The main objective of this study is to determine the agreement of HPV detection rate between self-collected and clinician-collected method. The secondary outcome is to assess the accuracy of selfcollected HPV DNA testing in the participants who had cervical precancerous lesions. Statistical analysis Mc Nemar and Kappa test were used to assess the consistency between self- and clinician-collected HPV testing. The detection rate of HPV from each method was presented as percentage. We considered p-value of <0.05 as statistically significant. Positive predictive value for abnormal cytology in both HPV collecting methods was calculated by chi-square test. Agreement between self collected and clinician collected specimens was evaluated by Kappa (k) statistics. All statistical analysis was performed by using the Statistical Package for Social Sciences (SPSS) versions 17 for Windows (SPSS, Chicago, IL, USA). The data was presented in percentage, mean and standard deviation as appropriate. Results After all the data from 400 participants were collected and analyzed, demographic data and patients' characteristic were presented in Table 1. Mean age of participants was 46.48 years. Sixty percent of the participants had performed cervical cancer screening test within 2 years. While, 25.8% of the participants had never performed Pap smear and 3% of the participants had not performed Pap test in last 5 years. The detection rate of HR-HPV DNA in self-collected samples was slightly higher than clinician-collected method [40 (10.0%) vs. 30 (7.5%)]. Kappa value for HR-HPV DNA test between two methods was 0.73 (Table 2). The comparison between HPV DNA testing and liquid based cytology were demonstrated in Table 3. Among selfcollected group (40 cases), Majority of HR-HPV detected was non 16, 18 genotype which was 87.5% (35 from 40 cases). HPV type 16 was found in 7.5% (3 cases). The other 5% (2 cases) was positive for HPV type 18. On the other hands, from 30 HPV positive samples in clinician-collected HPV samples, 90% (27 from 30 cases) was positive for non 16, 18 HR- HPV, 3.3% (1 case) was HPV type 16 and 6.7% (2 cases) was positive for HPV type 18. When we focused on the participants who had abnormal cytology, HPV positive rate was no significantly different between patient collected and physician collected specimens (p ¼ 1.0). From total 40 HR-HPV positive cases, 14 of them (35%) had ASC-US or more abnormal cervical cytology. In HSIL cytology patients, HRHPV detection rate was as high as 100%. The Colposcopy was performed in 15 patients who had abnormal cytology (7 cases of ASC-US, 5 cases of LSIL and 2 cases of HSIL) with HR-HPV detection and one case of LSIL with HR-HPV negative from self collected group. All of the HPV 16, 18 positive
Table 1 General characteristics of participants. Age (yr) (mean ± SD)
46.48 ± 11.6
Last pap smear Never (N (%)) <2 yr (N (%)) 2e5 yr (N (%)) >5 yr (N (%))
103 (25.75) 242 (60.5) 43 (10.75) 12 (3)
N ¼ number.
P. Nutthachote et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 477e481 Table 2 Correlation between clinician-collected and self-collected specimens. Clinician-collected HPV DNA test HR-HPV-N (%) Self-collected HR-HPV e N (%) HR HPV þ N (%) Total N (%)
Agreement (Kappa)
HR-HPVþ N (%)
Total N (%)
HPV DNA test 356 (89)
4 (1)
360 (90)
14 (3.5)
26 (6.5)
40 (10)
370 (92.5)
30 (7.5)
400 (100)
0.73
479
participants in this group were NILM. There was only one reported LSIL. Colposcopy was performed in that participant and the result revealed normal. No high grade cervical lesion was identified in the participants who had discordance result between self-collected and physician collected method. For high grade lesion, our study found 3 participants had CIN2þ from final pathology. All of them had positive both self collected and physician collected specimen. One of them had positive result for HPV type 18 and the other 2 participants were positive for other HR-HPV. Therefore, the detection rate for CIN 2 þ from both self collected and physician collected specimen were not different. Discussion
Table 3 Correlation between cervical cytology and HPV DNA testing results. HPV DNA results
Self-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV clinician-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV
Cervical cytology results (N) NILM (N)
ASC-US (N)
LSIL (N)
HSIL (N)
Total (N)
359 26 2 0 24
0 7 1 1 5
1 5 0 1 4
0 2 0 0 2
360 40 3 2 35
369 16 0 0 16
1 6 1 1 4
0 6 0 1 5
0 2 0 0 2
370 30 1 2 27
cases from clinician collected specimens had abnormal cytology which was already included for colposcopy. Therefore the total cases to perform colposcopy were 15 cases. The details of colposcopic results were demonstrated in Table 4. HR-HPV positive rate in CIN þ patients was no significantly different between selfcollected and clinician-collected testing (p ¼ 1.0). In this study we found some discordance results between patient collected and physician collected specimens. Fourteen patients had HPV positive in self-collected specimens but negative in clinician-collected specimen (Table 2). Cytology of these patients reported NILM in 13 specimens and ASC-US in 1 specimen. In these 14 specimens, 13 specimens were positive for other HR-HPV and HPV type 16 was identified in only 1 specimen. After Colposcopic examination was performed, all the examination result was normal. For the four patients who had HPV DNA positive in cliniciancollected but negative in self-collected, Cytologic results of the 3
Table 4 Comparing pathological results from colposcopic directed biopsy and HPV results. HPV DNA results
Self-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV clinician-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV
Cervical pathological results (N) Benign (N)
CIN1 (N)
CIN2-3 (N)
Total (N)
2 9 3 1 6
0 1 0 0 1
0 3 0 1 2
2 13 3 2 9
3 8 1 1 6
0 1 0 0 1
0 3 0 1 2
3 12 1 2 9
Persistent HPV infection is a major cause of cervical cancer. HPV type 16, 18 involve in 70% of invasive cervical cancer. Moreover, previous study showed that HPV DNA testing has been high sensitivity strategy for cervical cancer screening more than cervical cytology [5]. Furthermore, a new algorithm that uses HPV DNA testing for primary cervical cancer screening in women age more than 25 years is approved by the US-FDA. . Many studies proved that self sampling HPV DNA testing can improve coverage of cervical cancer screening in the specific population who avoid doing the Pap test with the physician by several reasons [18e23]. The acceptability rate of self-collected HPV DNA testing is high in many countries including in Thailand [24]. We demonstrated that self-collected HR-HPV testing is an accuracy method for cervical cancer screening. The accuracy of selfcollected HPV DNA testing is comparable with clinician-collected HR-HPV testing and liquid based cytology especially in the patients who had abnormal cytology result. Our study found that selfcollecting HR-HPV testing had higher detection rate than cliniciancollected HR-HPV testing (10% VS 7.5%). The finding is concordance with the previous study conducted by Haguenoer K et al. [19]. Their study found HR-HPV detection rate was higher in patient/selfcollected samples (177/722, 24.5%) compared with cliniciancollected samples (151/722, 20.9%) (p ¼ 0.0008). However, there are some studies that had concordance and discordance result comparing to this study. We summarized those studies result and presented in Table 5. Moreover, we found that HPV positive rate in abnormal cytology (ASC-USþ) subgroup was not different between self collected and physician collected specimen. While a previous meta-analysis showed that self-collected HPV testing has lower sensitive and specificity than cervical cytology test, we found that self-collected HPV DNA testing had a high sensitivity for high grade lesion detection (100%). Therefore, self-collecting HR-HPV testing can be used as an alternative option for cervical cancer screening. We also found the discrepancy of some result between self collected and physician collected specimens. However, after full investigations were performed, there was no precancerous lesion detected in the participants who had discrepancy result. That means the discrepancy of the result may not be clinically significant. Moreover, in the cases that had precancerous lesion, both patient collected and physician collected method can demonstrate HR-HPV infection. For those results, we can trust that the results of patient collected method is no clinically different from physician collected method. There are some limitations in our study. First, the study environment is not the real life situation because this study was performed in clinical setting. Some transportation system may be different between real life and clinical based situation. In real live situation, there may be some environment effect on the interpretation results such as damaging of the specimen from the transportation method or other reasons. The study to evaluate the
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References
Table 5 Comparing the results of previous studies with this studies. Study
Sample Detection rate of Detection rate of clinician collected size self collected method method
Kappa Agreement (%)
Bathal et al. [13] Zhao et al. [14] Hagurnoer et al. [19] Ajenifuja et al. [25] Twu et al.[26] Chang et al. [27] This study
446
13.1
12.3
0.76
93.8
13,140
15.3
14.7
NA
moderate
734
24.5
20.9
0.76
91.7
194
7.2
6.8
0.47
93.8
1717
24.7
30.2
0.37
NA
1194
12.1
13
NA
93
400
10
7.5
0.73
95.5
*NA: not available data.
accuracy of patient collected specimen in real life situation may be conducted in the next project. Second limitation is the obstacle for evaluation of positive predictive value (PPV) and negative predictive value (NPV) of the test. It is unethical to perform Colposcopy and cervical biopsy to the participants with negative HRHPV test and normal cytology test. Therefore, the comparison among histological finding of the cervix, HPV testing and cytology result was limited. For Colposcopic diagnosis, we used American Society for Colposcopy and Cervical Pathology (ASCCP) as a guideline for management. Colposcopic examination was performed in either abnormal cytology such as ASC-US, LSIL or HSIL. The participants who had positive for HPV type 16, 18 cases were also investigated. Biopsies or endocervical curettage (ECC) was taken in patients who had any suspected lesion. A meta-analysis that conducted by Arbyn M et al. [17] revealed that HPV DNA testing by self-collecting and clinician-collecting HR-HPV testing had similar accuracy for diagnose CIN2þ detection. Besides the high detection rate, concordance agreement of HPV DNA detection rate between self-collected and physician-collected in our study is also high (Kappa 0.73). Another limitation of this study is the screened population. The participants in our study were recruited mainly in tertiary hospital which may not represent for all Thai people in some aspects. In conclusion, the self-collected HPV DNA testing is correlated with clinician-collected HPV DNA testing. Although self-collected HPV testing has a higher detection rate for HR-HPV infection. There is similar detection rate for high grade lesion between two methods. Therefore, self-collected HPV testing could be an alternative tool for cervical screening program.
Conflict of interest The instrument and HPV analysis kits were supported by Louis T. Leonowens Limited (Thailand). However, the company did not involve in protocol design, result analysis and manuscript preparation. All of the authors declare no conflict of the interest.
Acknowledgement This study was supported by the Ratchadapiseksompotch Research Fund, Faculty of Medicine, Chulalongkorn University.
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[6] FDA Advisory Committee unanimously recommends Roche's HPV Test as primary screening tool for detection of women at high risk for cervical cancer [media release]. http://www.roche.com/media/media_releases/med-cor2014-03-13.htm. nic E, Hortlund M, Dillner J, et al. Com[7] Darlin L, Borgfeldt C, Forslund O, He parison of use of vaginal HPV self-sampling and offering flexible appointments as strategies to reach long-term non-attending women in organized cervical screening. J Clin Virol 2013;58:155e60. s-Palacio IC, Partridge EE, Castle PE. Acceptability [8] Scarinci IC, Litton AG, Garce and usability of self-collected sampling for HPV testing among AfricanAmerican women living in the Mississippi Delta. Womens Health Issues 2013;23:e123e30. [9] Szarewski A, Cadman L, Ashdown-Barr L, Waller J. Exploring the acceptability of two self-sampling devices for human papillomavirus testing in the cervical screening context: a qualitative study of Muslim women in London. J Med Screen 2009;16:193e8. [10] Anhang R, Nelson JA, Telerant R, Chiasson MA, Wright Jr TC. Acceptability of self-collection of specimens for HPV DNA testing in an urban population. J Women's Health (Larchmt) 2005;14:721e8. nic E, Dillner J, Kannisto P. Vaginal self[11] Darlin L, Borgfeldt C, Forslund O, He sampling without preservative for human papillomavirus testing shows good sensitivity. J Clin Virol 2013;56:52e6. [12] Wu R, Du H, Belinson SE, Pretorius RG, Zou J, Yang B, et al. Secondary screening after primary self-sampling for human papillomavirus from SHENCCAST II. J Low Genit Tract Dis 2012;16:416e20. [13] Bhatla N, Dar L, Patro AR, Kumar P, Kriplani A, Gulati A, et al. Can human papillomavirus DNA testing of self-collected vaginal samples compare with physician-collected cervical samples and cytology for cervical cancer screening in developing countries? Cancer Epidemiol 2009;33: 446e50. [14] Zhao FH, Lewkowitz AK, Chen F, Lin MJ, Hu SY, Zhang X, et al. 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HPV self-sampling or the Pap-smear: a randomized study among cervical screening nonattenders from lower socioeconomic groups in France. Int J Cancer 2013;133:2681e7. [19] Haguenoer K, Giraudeau B, Gaudy-Grsffin C, de-Pinieux I, Dubois F, TrignolViguier N, et al. Accuracy of dry vaginal self-sampling for detecting high-risk human papillomavirus infection in cervical cancer screening: a cross-sectional study. Gynecol Oncol 2014;134:302e8. [20] Untiet S, Vassilakos P, McCarey C, Tebeu PM, Kengne-Fosso G, Menoud PA, et al. HPV self-sampling as primary screening test in sub-Saharan Africa: implication for a triaging strategy. Int J Cancer 2014;135:1911e7. [21] Rosenbaum AJ, Gage JC, Alfaro KM, Ditzian LR, Maza M, Scarinci IC, et al. Acceptability of self-collected versus provider-collected sampling for HPV DNA testing among women in rural El Salvador. Int J Gynecol Obstet 2014;126:156e60. [22] Canda MT, Demir N, Sezer O, Doganay L, Ortac R. Clinical results of the liquidbased cervical cytology tool, Liqui-PREP, in comparison with conventional smears for detection of squamous cell abnormalities. Asian Pac J Cancer Prev 2009;10:399e402. [23] Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, et al. Cervical cancer risk for women undergoing concurrent testing for human
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Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Comparison of detection rate of high risk HPV infection between self-collected HPV testing and clinician-collected HPV testing in cervical cancer screening Pattiya Nutthachote a, Shina Oranratanaphan a, *, Wichai Termrungruanglert a, Surang Triratanachat a, Arkom Chaiwongkot b, Fern Baedyananda b, Parvapan Bhattarakosol b a b
Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand Department of Microbiology, Faculty of Medicine, Chulalongkorn University, 10330, Thailand
a r t i c l e i n f o
a b s t r a c t s
Article history: Accepted 8 January 2019
Objective: to correlate the detection rate of high risk HPV (HR-HPV) DNA between self-collected and clinician-collected testing. Materials and methods: A cross-sectional analytic study was conducted in 400 women undergoing cervical cancer screening program during February and May 2015. The procedure began with self-collected method and then clinician-collected method. Then, the specimens were processed and interpreted with the same technique. If the results from either methods were positive for HPV genotype 16 or 18, colposcopy was performed. We also conducted cytology testing for the participants. If the results were abnormal (ASC-USþ), colposcopy was also performed. Results: The detection rate of HR-HPV DNA was 10.0% and 7.5% by self-collected and clinician-collected specimen, respectively (kappa ¼ 0.73). HR-HPV positive rate in cytology ASC-USþ was no significantly different between groups. HR-HPV DNAs were positive in every HSIL (100% detection rate). HPV DNA test positive for detection CINþ was not significantly different between self-collected and clinician-collected testing. Conclusion: self-collected HPV testing can be used as an alternative option for primary cervical screening program. Detection rate of high grade lesion is similar to clinician-collected test. © 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cervical cancer screening Clinician-collected HPV testing Correlation Self-collected HPV DNA testing Self-sampling
Introduction Cervical cancer is the most common gynecologic cancer in Thailand [1]. The objective of cervical cancer screening program is to reduce the incidence, morbidity and mortality of cervical cancer [2]. Cervical cancer screening program, such as conventional cytology (Papanicolaou (Pap) smear), liquid based cytology, are used to detect precancerous lesions and treat before progress to cancer. The main screening method in Thailand is conventional Pap
* Corresponding author. Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand. E-mail addresses: [email protected] (P. Nutthachote), dr_shina@hotmail. com (S. Oranratanaphan), [email protected] (W. Termrungruanglert), t_surang@ hotmail.co.th (S. Triratanachat), [email protected] (A. Chaiwongkot), [email protected] (F. Baedyananda), [email protected] (P. Bhattarakosol).
smear. Although cervical cancer screening program can reduce the incidence, morbidity and mortality of cervical cancer, the incidence of cervical cancer in Thailand is still high. The main reason of persistent high incidence of cervical cancer in Thailand is low coverage of cervical cancer screening. Only 25e38% of women in Thailand had ever been screened [3e5]. The reasons for patients' refusing Pap test were embarrassment, fear of pain, fear of cancer, unavailability and lack of understanding regards to the test importance [4]. Primary HPV DNA testing has been approved by USFDA and proposed as an alternative cervical cancer screening method in women older than 25 years [6]. HPV DNA testing has been confirmed as a high sensitivity method to detect precancerous lesions because persistent high-risk HPV (HR-HPV) infection is considered as a cause of invasive cervical cancer. Therefore, self ecollected HPV DNA testing (self-HPV) which is a method that patients can collect specimen by themselves and send to the lab for
https://doi.org/10.1016/j.tjog.2019.05.008 1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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HR-HPV DNA testing may enhance the screening rate for women who were not comfortable with pelvic examination. Currently, using self-collected vaginal sampling to detect HRHPV has been applied in some European countries to improve the coverage of the screening. The screening coverage was significantly increased by using self-sampling method comparing to other methods in previous study [7e10]. The consistency of the results between self-collected and clinician-collected sampling were controversy. Some studies revealed almost 80e90% consistency between self-collected and clinician-collected specimens [11e13]. The other studies revealed that the self-collected sampling detection rate were lower than the clinician-collected sampling. Detection rates of CIN2þ lesions with self-collected and clinician-collected HPV testing were 50e88% and 63e100%, respectively [14e17]. Nowadays, Self-sampling method is not widely used in Thailand and Asian countries. Therefore, the data of self-sampling method for cervical cancer screening in Thai and Asian population is still limited. Our study was designed to determine the correlation between self-collected and clinician-collected HPV DNA testing. Our secondary objective was to evaluate the accuracy of self-collected HPV DNA testing to detect cervical precancerous lesions. Materials and methods A cross-sectional analytic study was conducted. After approval from the Institutional Review Board (IRB) was achieved, women who were screened for cervical cancer at King Chulalongkorn Memorial Hospital during 1st January 2015 and 31st May 2015 were recruited to this study. A total number of 400 women were recruited at outpatient clinic in King Chulalongkorn Memorial Hospital. We included women attending for routine cervical cancer screening. Patients who had a history of hysterectomy, cervical cancer, previous radiation therapy or chemotherapy were excluded from the study. Information regarding self-collected and cliniciancollected tests was advised. After the participants were clearly understand about the procedures, all of the participants signed inform consent voluntarily. Self collected instruments were given to the participants at outpatient clinic and the participant collected the vaginal sample with brush type collecting system (QIAGEN Gaithersburg, Inc.) at the private rest room in outpatient clinic by themselves. The specimens were collected in a transport medium tube for HPV DNA testing (QIAGEN Gaithersburg, Inc). After complete the self-collected sampling collection, speculum examination was performed by physician. Cervical sampling was collected for HPV testing and liquid based cytology with broom type cervical brush (Surepath®). To avoid invalid of the test results, the specimens were stored in 4 degree Celsius, and analyzed within 4 weeks. The collected samples were analyzed by using Hybrid capture II method (QIAGEN Gaithersburg, Inc) to detect HR-HPV DNA. All HRHPV DNA positive specimens were further specify HPV DNA genotype for HPV genotype type 16, 18 and other high risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) (QIAGEN Gaithersburg, Inc). According to ASCCP guideline for management of abnormal Pap smear, the cases that results were positive for HR-HPV type 16 or 18 either from self-collected or clinician-collected methods, colposcopy was performed. In non 16, 18 HR-HPV, colposcopy would be performed when coexisting with abnormal cytology results. For that reason, we also conducted liquid based cytology for all the participants. Liquid based slides were evaluated by the professional cytologists and interpreted based on Bethesda classification system. If the results were abnormal, atypical cells of undetermined significance (ASC-US) or more severe abnormal cytology, colposcopy was also performed. Colposcopic diagnosis is based on American Society for colposcopy and Cervical Pathology
(ASCCP) recommendation. Biopsies or endocervical curettage (ECC) were taken to confirm the diagnosis. The patients whose biopsy result was CIN 2 or more were treated according to ASCCP guideline. The main objective of this study is to determine the agreement of HPV detection rate between self-collected and clinician-collected method. The secondary outcome is to assess the accuracy of selfcollected HPV DNA testing in the participants who had cervical precancerous lesions. Statistical analysis Mc Nemar and Kappa test were used to assess the consistency between self- and clinician-collected HPV testing. The detection rate of HPV from each method was presented as percentage. We considered p-value of <0.05 as statistically significant. Positive predictive value for abnormal cytology in both HPV collecting methods was calculated by chi-square test. Agreement between self collected and clinician collected specimens was evaluated by Kappa (k) statistics. All statistical analysis was performed by using the Statistical Package for Social Sciences (SPSS) versions 17 for Windows (SPSS, Chicago, IL, USA). The data was presented in percentage, mean and standard deviation as appropriate. Results After all the data from 400 participants were collected and analyzed, demographic data and patients' characteristic were presented in Table 1. Mean age of participants was 46.48 years. Sixty percent of the participants had performed cervical cancer screening test within 2 years. While, 25.8% of the participants had never performed Pap smear and 3% of the participants had not performed Pap test in last 5 years. The detection rate of HR-HPV DNA in self-collected samples was slightly higher than clinician-collected method [40 (10.0%) vs. 30 (7.5%)]. Kappa value for HR-HPV DNA test between two methods was 0.73 (Table 2). The comparison between HPV DNA testing and liquid based cytology were demonstrated in Table 3. Among selfcollected group (40 cases), Majority of HR-HPV detected was non 16, 18 genotype which was 87.5% (35 from 40 cases). HPV type 16 was found in 7.5% (3 cases). The other 5% (2 cases) was positive for HPV type 18. On the other hands, from 30 HPV positive samples in clinician-collected HPV samples, 90% (27 from 30 cases) was positive for non 16, 18 HR- HPV, 3.3% (1 case) was HPV type 16 and 6.7% (2 cases) was positive for HPV type 18. When we focused on the participants who had abnormal cytology, HPV positive rate was no significantly different between patient collected and physician collected specimens (p ¼ 1.0). From total 40 HR-HPV positive cases, 14 of them (35%) had ASC-US or more abnormal cervical cytology. In HSIL cytology patients, HRHPV detection rate was as high as 100%. The Colposcopy was performed in 15 patients who had abnormal cytology (7 cases of ASC-US, 5 cases of LSIL and 2 cases of HSIL) with HR-HPV detection and one case of LSIL with HR-HPV negative from self collected group. All of the HPV 16, 18 positive
Table 1 General characteristics of participants. Age (yr) (mean ± SD)
46.48 ± 11.6
Last pap smear Never (N (%)) <2 yr (N (%)) 2e5 yr (N (%)) >5 yr (N (%))
103 (25.75) 242 (60.5) 43 (10.75) 12 (3)
N ¼ number.
P. Nutthachote et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 477e481 Table 2 Correlation between clinician-collected and self-collected specimens. Clinician-collected HPV DNA test HR-HPV-N (%) Self-collected HR-HPV e N (%) HR HPV þ N (%) Total N (%)
Agreement (Kappa)
HR-HPVþ N (%)
Total N (%)
HPV DNA test 356 (89)
4 (1)
360 (90)
14 (3.5)
26 (6.5)
40 (10)
370 (92.5)
30 (7.5)
400 (100)
0.73
479
participants in this group were NILM. There was only one reported LSIL. Colposcopy was performed in that participant and the result revealed normal. No high grade cervical lesion was identified in the participants who had discordance result between self-collected and physician collected method. For high grade lesion, our study found 3 participants had CIN2þ from final pathology. All of them had positive both self collected and physician collected specimen. One of them had positive result for HPV type 18 and the other 2 participants were positive for other HR-HPV. Therefore, the detection rate for CIN 2 þ from both self collected and physician collected specimen were not different. Discussion
Table 3 Correlation between cervical cytology and HPV DNA testing results. HPV DNA results
Self-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV clinician-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV
Cervical cytology results (N) NILM (N)
ASC-US (N)
LSIL (N)
HSIL (N)
Total (N)
359 26 2 0 24
0 7 1 1 5
1 5 0 1 4
0 2 0 0 2
360 40 3 2 35
369 16 0 0 16
1 6 1 1 4
0 6 0 1 5
0 2 0 0 2
370 30 1 2 27
cases from clinician collected specimens had abnormal cytology which was already included for colposcopy. Therefore the total cases to perform colposcopy were 15 cases. The details of colposcopic results were demonstrated in Table 4. HR-HPV positive rate in CIN þ patients was no significantly different between selfcollected and clinician-collected testing (p ¼ 1.0). In this study we found some discordance results between patient collected and physician collected specimens. Fourteen patients had HPV positive in self-collected specimens but negative in clinician-collected specimen (Table 2). Cytology of these patients reported NILM in 13 specimens and ASC-US in 1 specimen. In these 14 specimens, 13 specimens were positive for other HR-HPV and HPV type 16 was identified in only 1 specimen. After Colposcopic examination was performed, all the examination result was normal. For the four patients who had HPV DNA positive in cliniciancollected but negative in self-collected, Cytologic results of the 3
Table 4 Comparing pathological results from colposcopic directed biopsy and HPV results. HPV DNA results
Self-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV clinician-collected HR HPV e HR HPV þ HPV type 16 HPV type 18 Other HR HPV
Cervical pathological results (N) Benign (N)
CIN1 (N)
CIN2-3 (N)
Total (N)
2 9 3 1 6
0 1 0 0 1
0 3 0 1 2
2 13 3 2 9
3 8 1 1 6
0 1 0 0 1
0 3 0 1 2
3 12 1 2 9
Persistent HPV infection is a major cause of cervical cancer. HPV type 16, 18 involve in 70% of invasive cervical cancer. Moreover, previous study showed that HPV DNA testing has been high sensitivity strategy for cervical cancer screening more than cervical cytology [5]. Furthermore, a new algorithm that uses HPV DNA testing for primary cervical cancer screening in women age more than 25 years is approved by the US-FDA. . Many studies proved that self sampling HPV DNA testing can improve coverage of cervical cancer screening in the specific population who avoid doing the Pap test with the physician by several reasons [18e23]. The acceptability rate of self-collected HPV DNA testing is high in many countries including in Thailand [24]. We demonstrated that self-collected HR-HPV testing is an accuracy method for cervical cancer screening. The accuracy of selfcollected HPV DNA testing is comparable with clinician-collected HR-HPV testing and liquid based cytology especially in the patients who had abnormal cytology result. Our study found that selfcollecting HR-HPV testing had higher detection rate than cliniciancollected HR-HPV testing (10% VS 7.5%). The finding is concordance with the previous study conducted by Haguenoer K et al. [19]. Their study found HR-HPV detection rate was higher in patient/selfcollected samples (177/722, 24.5%) compared with cliniciancollected samples (151/722, 20.9%) (p ¼ 0.0008). However, there are some studies that had concordance and discordance result comparing to this study. We summarized those studies result and presented in Table 5. Moreover, we found that HPV positive rate in abnormal cytology (ASC-USþ) subgroup was not different between self collected and physician collected specimen. While a previous meta-analysis showed that self-collected HPV testing has lower sensitive and specificity than cervical cytology test, we found that self-collected HPV DNA testing had a high sensitivity for high grade lesion detection (100%). Therefore, self-collecting HR-HPV testing can be used as an alternative option for cervical cancer screening. We also found the discrepancy of some result between self collected and physician collected specimens. However, after full investigations were performed, there was no precancerous lesion detected in the participants who had discrepancy result. That means the discrepancy of the result may not be clinically significant. Moreover, in the cases that had precancerous lesion, both patient collected and physician collected method can demonstrate HR-HPV infection. For those results, we can trust that the results of patient collected method is no clinically different from physician collected method. There are some limitations in our study. First, the study environment is not the real life situation because this study was performed in clinical setting. Some transportation system may be different between real life and clinical based situation. In real live situation, there may be some environment effect on the interpretation results such as damaging of the specimen from the transportation method or other reasons. The study to evaluate the
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References
Table 5 Comparing the results of previous studies with this studies. Study
Sample Detection rate of Detection rate of clinician collected size self collected method method
Kappa Agreement (%)
Bathal et al. [13] Zhao et al. [14] Hagurnoer et al. [19] Ajenifuja et al. [25] Twu et al.[26] Chang et al. [27] This study
446
13.1
12.3
0.76
93.8
13,140
15.3
14.7
NA
moderate
734
24.5
20.9
0.76
91.7
194
7.2
6.8
0.47
93.8
1717
24.7
30.2
0.37
NA
1194
12.1
13
NA
93
400
10
7.5
0.73
95.5
*NA: not available data.
accuracy of patient collected specimen in real life situation may be conducted in the next project. Second limitation is the obstacle for evaluation of positive predictive value (PPV) and negative predictive value (NPV) of the test. It is unethical to perform Colposcopy and cervical biopsy to the participants with negative HRHPV test and normal cytology test. Therefore, the comparison among histological finding of the cervix, HPV testing and cytology result was limited. For Colposcopic diagnosis, we used American Society for Colposcopy and Cervical Pathology (ASCCP) as a guideline for management. Colposcopic examination was performed in either abnormal cytology such as ASC-US, LSIL or HSIL. The participants who had positive for HPV type 16, 18 cases were also investigated. Biopsies or endocervical curettage (ECC) was taken in patients who had any suspected lesion. A meta-analysis that conducted by Arbyn M et al. [17] revealed that HPV DNA testing by self-collecting and clinician-collecting HR-HPV testing had similar accuracy for diagnose CIN2þ detection. Besides the high detection rate, concordance agreement of HPV DNA detection rate between self-collected and physician-collected in our study is also high (Kappa 0.73). Another limitation of this study is the screened population. The participants in our study were recruited mainly in tertiary hospital which may not represent for all Thai people in some aspects. In conclusion, the self-collected HPV DNA testing is correlated with clinician-collected HPV DNA testing. Although self-collected HPV testing has a higher detection rate for HR-HPV infection. There is similar detection rate for high grade lesion between two methods. Therefore, self-collected HPV testing could be an alternative tool for cervical screening program.
Conflict of interest The instrument and HPV analysis kits were supported by Louis T. Leonowens Limited (Thailand). However, the company did not involve in protocol design, result analysis and manuscript preparation. All of the authors declare no conflict of the interest.
Acknowledgement This study was supported by the Ratchadapiseksompotch Research Fund, Faculty of Medicine, Chulalongkorn University.
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