Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis

Mamiko Onuki; Koji Matsumoto; Manabu Sakurai; Hiroyuki Ochi; Takeo Minaguchi; Toyomi Satoh; Hiroyuki Yoshikawa

doi:10.3802/jgo.2016.27.e3

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

Original Article

J Gynecol Oncol 2016;27(1):e3.

Published online: 4 January 2016

DOI: https://doi.org/10.3802/jgo.2016.27.e3

Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis

Mamiko Onuki, Koji Matsumoto, Manabu Sakurai, Hiroyuki Ochi, Takeo Minaguchi, Toyomi Satoh, Hiroyuki Yoshikawa

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Correspondence to Koji Matsumoto Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. E-mail: matsumok@mui.biglobe.ne.jp

Received 23 March 2015 Revised 29 July 2015 Accepted 19 August 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: Cell Biology, Cervical Intraepithelial Neoplasia, Human Papillomavirus, Posttreatment Surveillance

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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.

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.

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.

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
Testing methods	No. of women included in analysis	No. of test-positive women (colposcopy referral rate, %)	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).

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