Journal List > J Gynecol Oncol > v.27(1) > 1148286

Onuki, Matsumoto, Sakurai, Ochi, Minaguchi, Satoh, and Yoshikawa: Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis

Abstract

Objective

We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3).

Methods

Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013.

Results

The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001).

Conclusion

Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.

References

1. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine. 2006; 24(Suppl 3):S3/78–89.
crossref
2. Chan BK, Melnikow J, Slee CA, Arellanes R, Sawaya GF. Posttreatment human papillomavirus testing for recurrent cervical intraepithelial neoplasia: a systematic review. Am J Obstet Gynecol. 2009; 200:422. e1–9.
crossref
3. Kocken M, Uijterwaal MH, de Vries AL, Berkhof J, Ket JC, Helmerhorst TJ, et al. High-risk human papillomavirus testing versus cytology in predicting posttreatment disease in women treated for high-grade cervical disease: a systematic review and meta-analysis. Gynecol Oncol. 2012; 125:500–7.
crossref
4. Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia. Int J Cancer. 2006; 118:2048–55.
crossref
5. Takeda T, Wong TF, Adachi T, Ito K, Uehara S, Kanaoka Y, et al. Japan Society of Obstetrics and Gynecolo-gyJapan Association of Obstetricians and Gynecologists. Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2011 edition. J Obstet Gynaecol Res. 2012; 38:615–31.
crossref
6. IKNL. (integraal kankercentrum Nederland) Oncoline. National Guideline “Cervical Intraepithelial Neoplasia” 2004 [Internet]. Utrecht, ND: Comprehensive Cancer Centre the Netherlands;c2015. [cited 2015 Nov 4]. Available from:. http://www.oncoline.nl/index.php?pagina=/richtlijn/item/pagina.php&richt-lijn_id=220.
7. NHS (National Health Service) Cancer Screening Programmes. Colposcopy and programme management: guideline for the NHS cervical cancer screening progamme: second edition [Internet]. Sheffield, UK: NHS Cancer Screening Programmes;2010. [cited 2015 Nov 4]. Available from:. http://www.cancerscreening.nhs.uk/cervical/publications/nhscsp20.html.
8. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013; 121:829–46.
crossref
9. Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014; 383:524–32.
crossref
10. Bollen LJ, Tjong-A-Hung SP, van der Velden J, Mol BW, ten Kate FW, ter Schegget J, et al. Prediction of recurrent and residual cervical dysplasia by human papillomavirus detection among patients with abnormal cytology. Gynecol Oncol. 1999; 72:199–201.
crossref
11. Hernádi Z, Szoke K, Sápy T, Krasznai ZT, Soós G, Veress G, et al. Role of human papillomavirus (HPV) testing in the follow-up of patients after treatment for cervical precancerous lesions. Eur J Obstet Gynecol Reprod Biol. 2005; 118:229–34.
crossref
12. Almog B, Gamzu R, Kuperminc MJ, Levin I, Fainaru O, Niv J, et al. Human papilloma virus testing in patient follow-up post cone biopsy due to high-grade cervical intraepithelial neoplasia. Gynecol Oncol. 2003; 88:345–50.
crossref
13. Elfgren K, Bistoletti P, Dillner L, Walboomers JM, Meijer CJ, Dillner J. Conization for cervical intraepithelial neoplasia is followed by disappearance of human papillomavirus deoxyribonucleic acid and a decline in serum and cervical mucus antibodies against human papillomavirus antigens. Am J Obstet Gynecol 1996;174:937–42.
crossref
14. Distéfano AL, Picconi MA, Alonio LV, Dalbert D, Mural J, Bartt O, et al. Persistence of human papillomavirus DNA in cervical lesions after treatment with diathermic large loop excision. Infect Dis Obstet Gynecol. 1998; 6:214–9.
crossref
15. Bekkers RL, Melchers WJ, Bakkers JM, Hanselaar AG, Quint WG, Boonstra H, et al. The role of geno-type-specific human papillomavirus detection in diagnosing residual cervical intraepithelial neoplasia. Int J Cancer. 2002; 102:148–51.
crossref
16. Kreimer AR, Guido RS, Solomon D, Schiffman M, Wacholder S, Jeronimo J, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol Biomarkers Prev. 2006; 15:908–14.
crossref
17. Brismar S, Johansson B, Borjesson M, Arbyn M, Andersson S. Follow-up after treatment of cervical intraepithelial neoplasia by human papillomavirus genotyping. Am J Obstet Gynecol. 2009; 201:17. e1–8.
crossref
18. Kang WD, Oh MJ, Kim SM, Nam JH, Park CS, Choi HS. Significance of human papillomavirus genotyping with high-grade cervical intraepithelial neoplasia treated by a loop electrosurgical excision procedure. Am J Obstet Gynecol. 2010; 203:72. e1–6.
crossref
19. Heymans J, Benoy IH, Poppe W, Depuydt CE. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer. 2011; 129:903–9.
crossref
20. Valasoulis G, Koliopoulos G, Founta C, Kyrgiou M, Tsoumpou I, Valari O, et al. Alterations in human papillomavirus-related biomarkers after treatment of cervical intraepithelial neoplasia. Gynecol Oncol 2011;121:43–8.
crossref
21. Söderlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol. 2014; 86:634–41.
crossref
22. Chua KL, Hjerpe A. Human papillomavirus analysis as a prognostic marker following conization of the cervix uteri. Gynecol Oncol. 1997; 66:108–13.
crossref
23. Jain S, Tseng CJ, Horng SG, Soong YK, Pao CC. Negative predictive value of human papillomavirus test following conization of the cervix uteri. Gynecol Oncol. 2001; 82:177–80.
crossref
24. Bodner K, Bodner-Adler B, Wierrani F, Kimberger O, Denk C, Grünberger W. Is therapeutic conization sufficient to eliminate a high-risk HPV infection of the uterine cervix? A clinicopathological analysis. Anticancer Res. 2002; 22(6B):3733–6.
25. Nagai N, Mukai K, Oshita T, Shiroyama Y, Ohama K. Human papillomavirus DNA status after loop excision for cervical intraepithelial neoplasia grade III – A prospective study. Int J Mol Med. 2004; 13:589–93.
crossref
26. Verguts J, Bronselaer B, Donders G, Arbyn M, Van Eldere J, Drijkoningen M, et al. Prediction of recurrence after treatment for high-grade cervical intraepithelial neoplasia: the role of human papillomavirus testing and age at conisation. BJOG. 2006; 113:1303–7.
crossref
27. Bae JH, Kim CJ, Park TC, Namkoong SE, Park JS. Persistence of human papillomavirus as a predictor for treatment failure after loop electrosurgical excision procedure. Int J Gynecol Cancer. 2007; 17:1271–7.
crossref
28. Gallwas J, Ditsch N, Hillemanns P, Friese K, Thaler C, Dannecker C. The significance of HPV in the follow-up period after treatment for CIN. Eur J Gynaecol Oncol. 2010; 31:27–30.
29. Torné A, Fusté P, Rodríguez-Carunchio L, Alonso I, del Pino M, Nonell R, et al. Intraoperative post-coni-sation human papillomavirus testing for early detection of treatment failure in patients with cervical intraepithelial neoplasia: a pilot study. BJOG. 2013; 120:392–9.
crossref
30. Ribaldone R, Boldorini R, Capuano A, Arrigoni S, Di Oto A, Surico N. Role of HPV testing in the follow-up of women treated for cervical dysplasia. Arch Gynecol Obstet. 2010; 282:193–7.
crossref
31. Leguevaque P, Motton S, Decharme A, Soulé-Tholy M, Escourrou G, Hoff J. Predictors of recurrence in high-grade cervical lesions and a plan of management. Eur J Surg Oncol. 2010; 36:1073–9.
crossref
32. Ryu A, Nam K, Kwak J, Kim J, Jeon S. Early human papillomavirus testing predicts residual/recurrent disease after LEEP. J Gynecol Oncol. 2012; 23:217–25.
crossref
33. Fallani MG, Penna C, Marchionni M, Bussani C, Pieralli A, Andersson KL, et al. Prognostic significance of high-risk HPV persistence after laser CO2 conization for high-grade CIN: a prospective clinical study. Eur J Gynaecol Oncol. 2008; 29:378–82.
34. Nagai Y, Maehama T, Asato T, Kanazawa K. Persistence of human papillomavirus infection after therapeutic conization for CIN 3: is it an alarm for disease recurrence? Gynecol Oncol. 2000; 79:294–9.
crossref
35. Nobbenhuis MA, Meijer CJ, van den Brule AJ, Rozendaal L, Voorhorst FJ, Risse EK, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer. 2001; 84:796–801.
crossref
36. Zielinski GD, Rozendaal L, Voorhorst FJ, Berkhof J, Snijders PJ, Risse EJ, et al. HPV testing can reduce the number of follow-up visits in women treated for cervical intraepithelial neoplasia grade 3. Gynecol Oncol. 2003; 91:67–73.
crossref
37. Cecchini S, Carozzi F, Confortini M, Zappa M, Ciatto S. Persistent human papilloma virus infection as an indicator of risk of recurrence of high-grade cervical intraepithelial neoplasia treated by the loop electrosurgical excision procedure. Tumori. 2004; 90:225–8.
crossref
38. Sarian LO, Derchain SF, Andrade LA, Tambascia J, Morais SS, Syrjänen KJ. HPV DNA test and Pap smear in detection of residual and recurrent disease following loop electrosurgical excision procedure of high-grade cervical intraepithelial neoplasia. Gynecol Oncol. 2004; 94:181–6.
crossref
39. Kitchener HC, Walker PG, Nelson L, Hadwin R, Patnick J, Anthony GB, et al. HPV testing as an adjunct to cytology in the follow up of women treated for cervical intraepithelial neoplasia. BJOG. 2008; 115:1001–7.
crossref
40. Smart OC, Sykes P, Macnab H, Jennings L. Testing for high risk human papilloma virus in the initial follow-up of women treated for high-grade squamous intraepithelial lesions. Aust N Z J Obstet Gynaecol. 2010; 50:164–7.
crossref
41. Bar-Am A, Gamzu R, Levin I, Fainaru O, Niv J, Almog B. Follow-up by combined cytology and human papillomavirus testing for patients post-cone biopsy: results of a long-term follow-up. Gynecol Oncol. 2003; 91:149–53.
crossref
42. Alonso I, Torné A, Puig-Tintoré LM, Esteve R, Quinto L, Campo E, et al. Pre- and post-conization high-risk HPV testing predicts residual/recurrent disease in patients treated for CIN 2–3. Gynecol Oncol. 2006; 103:631–6.
crossref
43. Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 2011; 12:441–50.
crossref

Fig. 1.
Literature search. Initial search through PubMed identified 1,143 articles for our systematic review. After reviews of titles, abstracts and full texts, 33 eligible articles were included in our analysis [10–42]. CIN 2, cervical intraepithelial neoplasia grade 2; HPV, human papillomavirus.
jgo-27-e3f1.tif
Fig. 2.
Risk stratification of posttreatment cervical intraepithelial neoplasia grade 2+ (CIN 2+) provided by carcinogenic human papillomavirus (HPV) testing, cytology, and surgical margin histology. In each test method of high-risk HPV testing, cytology (atypical squamous cells of undetermined significance+) or surgical margin histology, the absolute risks of having recurrent or residual CIN 2+ lesions (■) and 95% confidence intervals (error bars) were calculated for women testing positive or negative for each test. HPV testing provided the greatest risk stratification between test-positive and -negative women.
jgo-27-e3f2.tif
Fig. 3.
Further risk stratification of posttreatment cervical intraepithelial neoplasia grade 2+ (CIN 2+) provided by the addition of carcinogenic human papillomavirus (HPV) testing to cytology and surgical margin histology. Carcinogenic HPV testing provided additional risk stratification for posttreatment CIN 2+ lesions according to cytology results (atypical squamous cells of undetermined significance+) or surgical margin status. The absolute risks of having recurrent or residual CIN 2+ lesions and 95% confidence intervals (error bars) were calculated for HPV-positive (■) and -negative women (■) in each category group.
jgo-27-e3f3.tif
Table 1.
Test performance of HPV testing and cytology for detection of posttreatment CIN 2 or worse
Testing methods No. of women included in analysis No. of test-positive women (colposcopy referral rate, %) Detection of recurrent or residual CIN 2 or worse
Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI)
High-risk HPV test* 5,322 1,119 (21.0) 0.91 (0.88–0.94) 0.83 (0.82–0.84) 0.28 (0.26–0.31) 0.99 (0.99–1.00)
HPV genotyping 1,667 399 (23.9) 0.89 (0.82–0.94) 0.83 (0.81–0.85) 0.28 (0.24–0.33) 0.99 (0.98–0.99)
Cytology 3,656 813 (22.2) 0.74 (0.68–0.79) 0.85 (0.83–0.86) 0.25 (0.22–0.28) 0.98 (0.97–0.98)
Co-testing§ 2,287 645 (28.2) 0.92 (0.87–0.96) 0.76 (0.74–0.78) 0.20 (0.17–0.23) 0.99 (0.99–1.00)

CIN 2, cervical intraepithelial neoplasia grade 2; HPV, human papillomavirus; NPV, negative predictive value; PPV, positive predictive value.

* High-risk HPV tests, all HPV DNA detection assays detecting at least 13 carcinogenic HPV genotypes.

HPV genotyping, detection of HPV persistence between pre- and posttreatments.

Cytology, atypical squamous cells of undetermined significance threshold.

§ Co-testing, combination test of both high-risk HPV test and cytology.

Appendix 1.
Studies included in the pooled analysis of the performance of posttreatment human papillomavirus testing*
Author (Reference No.) Journal Publicatio Year on Country HPV test Time from treatment to first HPV test (mo) N Follow-up (mo) (mean or median [range]) Treatment Cytology
Elfgren K et al. [13] Am J Obstet Gynecol 1996 Sweden PCR (GP5+6+) 6 22 16–27 Cone LBC
Chua KL et al. [22] Gynecol Oncol 1997 Sweden PCR (GP5+6+) <12 48 1–98 Cone conventional
Distefano AL et al. [14] Infect Dis Obstet Gynecol 1998 Argentina PCR (GP5+6+) 6–12 36 6–12 LEEP NA
Bollen LJ et al. [10] Gynecol Oncol 1999 Netherlands PCR (CPI/IIG) <24 43 13–206 Cone/LEEP/ Cryo/laser LBC
Nagai Y et al. [25] Gynecol Oncol 2000 Japan PCR (L1C1/ L1C2) 6–12 58 31.8 (12–73) LEEP NA
Jain S et al. [23] Gynecol Oncol 2001 Taiwan HC2 6 wk 79 6–8 wk LEEP LBC
Nobbenhuis MA et al. [35] Br J Cancer 2001 Netherlands PCR (GP5+6+) 6 184 24 (3–76) LEEP conventional
Bodner K et al. [24] Anticancer Res 2002 Austria HC2 3 37 24 Cone LBC
Bekkers RL et al. [15] Int J Cancer 2002 Netherlands PCR (SPF10) 6 90 24–47 LEEP LBC+conventional
Bar-Am A et al. [41] Gynecol Oncol 2003 Israel HC2 6 67 63 (50–72) LEEP NA
Almog B et al. [12] Gynecol Oncol 2003 Israel HC1 6 96 47 (36–60) Cone NA
Zielinski GD et al. [36] Gynecol Oncol 2003 Netherlands HC2 3 108 29 (2–65) Cone/LEEP NA
Cecchini S et al. [37] Tumori 2004 Italy PCR (pU1/U2) 6 84 22.8 (11–40) LEEP NA
Sarian LO et al. [38] Gynecol Oncol 2004 Brazil HC2 6 88 17 LEEP conventional
Nagai N et al. [25] Int J Mol Med 2004 Japan PCR (L1C1/ L1C2) <12 161 78 (48–118) LEEP LBC
Hernádii Z et al. [11] Eur J Obstet Gynecol Reprod Biol 2005 Hungary HC2 5 61 25 (3–62) LEEP NA
Verguts J et al. [26] BJOG 2006 Belgium HC2 3–6 72 24 LEEP LBC
Alonso I et al. [42] Gynecol Oncol 2006 Spain HC2 6 203 20±13 LEEP conventional
Kreimer AR et al. [16] Cancer Epidemiol Biomarkers Prev 2006 USA HC2 6 610 24 LEEP LBC
Fallani MG et al. [33] Eur J Gynaecol Oncol 2007 Italy PCR (Nanogen) 3–6 66 24 Cone NA
Bae JH et al. [27] Int J Gynecol Cancer 2007 Korea HC2 6–12 114 30.7±13.5 LEEP NA
Kitchener HC et al. [39] BJOG 2008 UK HC2 6 917 24 NA LBC
Brismar S et al. [17] Am J Obstet Gynecol 2009 Sweden PCR (Linear Array) 12 84 34 (4–115) LEEP conventional
Ribaldone R et al. [30] Arch Gynecol Obste 2010 Italy PCR (INNO-LiPA) 4 78 35.7 Cone NA
Smart OC et al. [40] Aust N Z J Obstet Gynaecol 2010 New Zealand HC2 <18 100 9 (3–18) Cone/LEEP/ laser LBC
Gallwas J et al. [28] Eur J Gynaecol Oncol 2010 Germany HC2 <12 107 21.4 (2–76) Cone conventional
Leguevaque P et al. [31] Eur J Surg Oncol 2010 France PCR (GP5+6+) 6 352 73 LEEP NA
Kang WD et al. [18] Int J Gynecol Cancer 2010 Korea HC2,PCR (HDC) ) 3–24 672 >24 LEEP NA
Heymans J et al. [19] Int J Cancer 2011 Belgium PCR (E6/E7) 6 63 24 Cone LBC
Valasoulis G et al. [20] Gynecol Oncol 2011 Greece PCR (MY09/11) ) 6 188 14 LEEP LBC
Torne A et al. [29] BJOG 2012 Spain HC2 6 109 24 LEEP LBC
Ryu A et al. [32] J Gynecol Oncol 2012 Korea HC2 3 183 25.3±13.3 LEEP LBC
Söderlund-Strand A et al. [21] J Med Virol 2013 Sweden PCR (GP5+6+) 6 142 36 LEEP conventional

HC, hybrid capture; LBC, liquid based cytology; LEEP, loop electrosurgical excision procedure; NA, not available; PCR, polymerase chain reaction.

* These studies were included in the pooled analysis to compare the performance of HPV testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2 or CIN 3).

TOOLS
Similar articles