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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 4  |  Page : 613-620

The clinical application of HPV E6/E7 mRNA testing in triaging women with atypical squamous cells of undetermined significance or low-grade squamous intra-epithelial lesion Pap smear: A meta-analysis


1 Department of Gynecology and Obstetrics, The Third Affiliate Hospital of Zhengzhou University, Zhengzhou, Henan, China
2 Department of Radiology, The Third Affiliate Hospital of Zhengzhou University, Zhengzhou, Henan, China

Date of Web Publication13-Sep-2017

Correspondence Address:
Chenchen Ren
Department of Gynecology and Obstetrics, The Third Affiliate Hospital of Zhengzhou University, No. 7 Kangfuqian Street, Zhengzhou, Henan 450052
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_56_17

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 > Abstract 

Objective: The aim is to evaluate the clinical application value and correlation with cervical lesions' progression of human papillomavirus (HPV) E6/E7 mRNA test in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intraepithelial lesions (LSILs/mild dyskaryosis) cytological abnormalities.
Methods: A meta-analysis was conduct by searching China National Knowledge Infrastructure (1979–2016), Wanfang Date (1998–2016), VIP (1989–2016), PubMed (1950–2016), Web of Science (1950–2016) and Elsevier Science Direct (1998–2016), for studies on effect of HPV E6/E7 mRNA detection in women with ASCUS/LSIL/dyskaryosis. Study selection and appraisal were conducted independently by three authors, according to inclusive and exclusive criteria. Then, a meta-analysis was performed using the RevMan4.2 software. The subgroups analysis was conducted according to women's initial HPV DNA test results.
Results: Six articles with a total of 1024 subjects were included in the study. It was concluded that a positive HPV E6/E7 mRNA tested result have a higher risk of progressing to CIN2+ in future 2 years than a negative result. The pooled relative risk (RR) is 3.08, (95% confidence interval [CI] = 1.57–6.07, P < 0.05). The same situation was also observed in the subgroup of HPV DNA tested positive group and HPV DNA tested unlimited group. The pooled RR value of the two subgroups was, respectively, 1.98, (95% CI = 1.19–1.19, P < 0.05) and 7.58, (95% CI = 3.64–3.64, P < 0.05).
Conclusion: A positive HPV E6/E7 mRNA testing result suggested the women with ASCUS, or LSIL Pap smear was in a truly dangerous position, which is an adverse prognostic factor. It suggested that cervical lesions stay in a progressing status and these women should be referred for colposcopy and strengthen follow-up promptly. Whereas, women with a negative HPV E6/E7 mRNA testing result can increase follow-up interval, by comprehensively considering their situation, thus, avoiding unnecessary colposcopy and reducing the rate of colposcopy and biopsy.

Keywords: Atypical squamous cells of undetermined significance, diagnostic value, E6/E7, human papilloma virus, low-grade squamous intra-epithelial lesion, meta-analysis, mRNA


How to cite this article:
Yang L, Zhu Y, Bai Y, Zhang X, Ren C. The clinical application of HPV E6/E7 mRNA testing in triaging women with atypical squamous cells of undetermined significance or low-grade squamous intra-epithelial lesion Pap smear: A meta-analysis. J Can Res Ther 2017;13:613-20

How to cite this URL:
Yang L, Zhu Y, Bai Y, Zhang X, Ren C. The clinical application of HPV E6/E7 mRNA testing in triaging women with atypical squamous cells of undetermined significance or low-grade squamous intra-epithelial lesion Pap smear: A meta-analysis. J Can Res Ther [serial online] 2017 [cited 2017 Sep 21];13:613-20. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/613/214479

Li Yang and Yuanhang Zhu contributed equally to this work and they are the co-first authors.



 > Introduction Top


With the popularity of screening for cervical cancer and precancer, cervical cancer morbidity and mortality have decreased steadily in recent decades. However, cervical cancer remains the third most common malignant disease among women worldwide.[1] According to the World Health Organization statistical date, about 75,000 of the annual new cervical cancer cases were estimated to occur in China, where cervical cancer was responsible for 33,000 deaths in 2008. Hence, early detection of cervical cancer and precancerous lesions is very important to the reduction of cervical cancer mortality and protect women's reproductive health. Current clinical common methods for cervical cancer screening are cervical cytological examination, human papillomavirus (HPV) DNA testing, aimed at screening out high-level cervical intraepithelial lesion or cervical cancer (CIN2+). Moreover, there is a research shows that combination of HPV testing and cytology may be appropriate for screening cervical cancer compared to isolated cytology.[2] Cytological outcome of borderline or mild dyskaryosis (BMD), which contains atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL). These women with ASCUS or LSIL have similar clinical outcomes, account for a large proportion, and the treatment of them is controversial.[3],[4],[5] It is difficult to confirm that the pathological results of ASCUS or LSIL is normal or will progress to CIN2+, which is the biggest confusion for the clinicians, cytopathologists and these women with ASCUS or LSIL. Conducting colposcopy/biopsy blindly for these women with ASCUS or LSIL will increase the rate of colposcopy and biopsies, especially for those without the risk of progressing to CIN2+, because that have a great influence on women's physical and mental health. At present, additional triage is recommended for women with ASCUS or LSIL. High risk (HR) HPV DNA testing is a preferred triage option, with colposcopic evaluation for women who are HPV positive and with repeat cytology at 12 months for women who are HPV negative.[6],[7],[8] However, some people point out it is generally not effective to triage these women with a HPV DNA assay because of lack of specificity for high-grade lesions and a high colposcopic referral rate, which may increase the risk of excessive treatment.[9] What's more, some studies found that about 70% of ASCUS and low grade lesions regress spontaneously.[10]

Therefore, it is essential to find an effective biomarker to be used in triaging women with ASCUS or LSIL to enhance the overall diagnostic accuracy. It is pleasing to say there is a new detection method, HPV E6/E7 mRNA testing, which can not only detect the HPV infection, also predict the change of cervical lesions. Because, in the process of cervical epithelial cell carcinogenesis, HPV integrates its E6/E7 DNA into the genome of cervical epithelial cells, which made the epithelial cells obtain the oncogene E6/E7 DNA, which was activated in the external carcinogenic factors and transcribed into E6/E7 mRNA and further translated into oncoprotein E6/E7, which are combined with tumor suppressor protein P53 and PRB, respectively, resulting in P53 and PRB inactivation, eventually leading to cervical cancer. Therefore, HPV E6/E7 mRNA assay can not only detect HPV infection, but also to a certain extent, reflect E6/E7 gene's expression and lesions' activity. HPV E6/E7 mRNA testing of cervical exfoliated cells is expected to accurately detect HSIL.[11],[12],[13],[14],[15],[16] Existing literature have compared the accuracy about HPV E6/E7 mRNA detection and HPV DNA testing.[6],[17],[18] However, the numbers of literature about clinical application value of HPV E6/E7 mRNA testing is small. Moreover, although the study found that compared with HPV E6/E7 mRNA testing negative patients, HPV E6/E7 mRNA testing positive patients were more likely to develop CIN2+, the results were comparatively large difference and there is study had denied this viewpoint.[19] Therefore, we carried on this systematic analysis to confirm the clinical value of HPV E6/E7 mRNA testing and better applied to clinical.


 > Methods Top


Information retrieval

Study selection and appraisal were conducted independently by three authors (Zhu YH, Bai Y, Zhang XA). Differences in opinion between reviewers were resolved by discussion. A systematic search was conducted to identify published literature on the effect of HPV E6/E7 mRNA detection in women with a cytological outcome of BMD. The China National Knowledge Infrastructure (CNKI) database (1979–2016), Wanfang database (1998–2016), VIP (1989–2016), PubMed (1950–2016), Web of Science (1950–2016) and Elsevier Science Direct (1998–2016) were searched, with Chinese and English language only. We used “cervical intraepithelial lesions,” “HPV,” “ASCUS,” “LSILs,” “cervical cancer,” “E6/E7 mRNA,” “CIN,” “HPV,” “ASCUS” and “LSIL” as search themes in the article titles, abstracts, and keywords. To expand the scope of the retrieval, the reference lists of relevant articles obtained were also screened. If related literatures have defective or missing information, we will contact the corresponding author to get complete information. Taking CNKI as an example, the retrieval strategy is shown in [Figure 1].
Figure 1: China National Knowledge Infrastructure search strategy

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Quality assessment

Although there is no unified international gold standard and the existing checklists and quality assessment scales in observational studies is controversial, the Newcastle–Ottawa Scale were adapted for this analysis. We defined two categories: The study was considered to have high quality if it scored seven points or above. The study was considered to have low quality if it scored six points or less. Any disagreements with raters were resolved by discussion and the involvement of another.

Inclusion and exclusion criteria

  1. Inclusion criteria: (1) Female patients with a cytology of ASCUS or/and LSIL or BMD; (2) the study given formal and complete HPV E6/E7 mRNA detection method and the positive judgment standard; (3) the research shows the cervical histopathological detection standard and the follow-up endpoint is histopathologically verified CIN2+; (4) type of study design must be cohort study; (5) follow-up data should be integrity, clear and follow-up time should be at least 1 year; (6) women have a HPV DNA test
  2. Exclusion criteria: (1) The number of lost to follow-up is too much (more than 20%); (2) nonrandom obtained samples; (3) a single study's sample size is <10; (4) we cannot get raw data through any channels.


Statistical analysis methods

Before conducting meta-analysis, heterogeneity was evaluated with the Q statistic and I2 statistic. The Q statistic is used to assess whether differences in result are compatible with chance alone. If the P value is above 0.1, it indicates that there is no significant heterogeneity. To complement the Q statistic, the I2 statistic which denotes the variance among studies as a proportion of the total variance was also calculated and reported, because I2 is not sensitive to the number of studies. An I2 of 0% indicated no observed heterogeneity, whereas 25% indicated shows slow, 50% moderate, and 75% high levels of heterogeneity. When the hypothesis of homogeneity was rejected by the Q statistic and I2 statistic (P < 0.1, I2 >50%), subgroup analysis was conducted to explore potential moderating factors for heterogeneity. In this study, subgroup analysis was conducted for moderate factors, including women's HPV DNA status when they enter the study and detection methods. However, due to a few of study (the number is ≤3) using the PreTect HPV - Proofer method, and other reason (this two articles which have different initial HPV DNA tested results), the subgroup comparison of risk of CIN2+ in different types of detection method were not analyzed. Classification variables use relative risk (RR) as pooled effect. An RR >1 indicates that CIN2+ is more likely to occur in HPV E6/E7 mRNA tested positive (HPV E6/E7 mRNA+) than negative (HPV E6/E7 mRNA−), while an RR <1 indicated that CIN2+ is less likely to occur in HPV E6/E7 mRNA+ than HPV E6/E7 mRNA−. The pooled random-effects estimates of RR and 95% confidence intervals (CIs) were calculated by standard methods using the fixed effect model. A random effect model was used because it involves the assumption of statistical heterogeneity between studies. RevMan4.2 (Nordic Cochrane Center) meta-analysis software was used to analyze overall effects.


 > Results Top


Study selection

A flowchart describing the inclusion and exclusion process is presented. As shown in [Figure 2], we identified the possibly eligible articles through CNKI database (n = 2255), Wangfang database (n = 541), VIP database (n = 46), PubMed (n = 384), Web of Science (n = 2), and Elsevier Science Direct (n = 1940). To expand searches, the reference lists of relevant articles obtained (n = 102) were also screened. The titles and abstracts of these possible eligible papers were respectively studied by the three authors and the full-text articles without duplicates (n = 18) were selected for further examination. Based on the full-text of these studies, we finally selected six studies for the present meta-analysis.[19],[20],[21],[22],[23],[24] We exclude 12 articles, because the women in the study (n = 6)[25],[26],[27],[28],[29],[30] without a cytology of ASCUS or LSIL or BMD, the follow-up ending is not histopathologically verified CIN2+ (n = 2),[14],[31] articles do not have complete follow-up data (n = 3),[32],[33],[34] and we cannot find original data through anyway (n = 1).[35]
Figure 2: A flowchart of study screening and selection process

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Characteristic of included studies

In this study, there are two kinds of detection methods. There are two articles using the PreTect HPV - Proofer method to detect HPV E6/E7 mRNA and four articles using APTIMA method. Respectively, the PreTect HPV - Proofer test is a real-time multiplex NASBA assay for isothermal amplification of full-length mRNA transcripts from five HR-HPV types (HPV 16, 18, 31, 33, and 45) in addition to the U1A as an internal control for sample validity. The APTIMA is based on target capture transcription-mediated amplification of E6/E7 mRNA from 14 HR HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) in a single tube. According to the original HPV DNA status, HPV DNA testing positive (HPV DNA+) (n = 4) versus HPV DNA testing results unlimited (just conducted HPV DNA test) (n = 2). Study characteristics are listed in [Table 1].
Table 1: Characteristics of the included studies

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Risk of bias assessment

Ratings of study quality for each of the Newcastle–Ottawa criteria are presented in [Table 2]. Higher scores reflect the better study quality. In this study, five articles were scored seven points or above, and they were high quality. However, there was one article scored six points, and hence its quality is relatively low.
Table 2: Assessment of study quality

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Relative risk of CIN2 + in women with cytology of atypical squamous cells of undetermined significance or low-grade squamous intra-epithelial lesion abnormality

A pooled random effect meta-analysis was conducted using date from six studies, which estimated the levels of CIN2+ in women with a virology of HPV E6/E7 mRNA+ versus HPV E6/E7 mRNA−. This analysis included date for 732 women with HPV E6/E7 mRNA+ and 292 women with HPV E6/E7 mRNA−. As shown in [Figure 3], the RR value was associated with a 3.08-fold increased risk of HPV E6/E7 mRNA+ compare with HPV E6/E7 mRNA− (RR = 3.08, 95% CI = 1.57–6.07; P < 0.05). However, the heterogeneity analysis of the effect sizes of CIN2+ (P = 0.001, I2 = 80.3%) showed that there was a relatively high amount of heterogeneity in our meta-analysis.
Figure 3: Forest plot for the meta-analysis of CIN2+ in women with human papillomavirus E6/E7 mRNA+ and human papillomavirus E6/E7 mRNA−

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Subgroup analyses

As shown in [Figure 4], RR value was obtained for studies using different HPV DNA status. Although no difference of CIN2+ was observed in studies asking the initial HPV DNA positive and unlimited HPV DNA test, a significant smaller RR of CIN2+ was observed in studies for the former (RR = 1.98, 95% CI = 1.19–3.30, I2 = 62.4%) compared with the latter (RR = 7.58, 95% CI = 3.64–15.78, I2 = 9.5%).
Figure 4: Subgroup meta-analysis according to the initial status of human papillomavirus DNA. (a) Forest plot for the meta-analysis of CIN2+ in women with human papillomavirus E6/E7 mRNA+ and human papillomavirus E6/E7 mRNA− in the group of human papillomavirus DNA+. (b) Forest plot for the meta-analysis of CIN2+ in women with human papillomavirus E6/E7 mRNA+ and human papillomavirus E6/E7 mRNA− in the group of human papillomavirus DNA tested uncertain

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As shown in [Figure 5] and [Figure 6], there are two articles which compare the difference between HPV E6/E7 mRNA and HPV DNA testing. The RR value indicate there were no difference of risk of CIN2+ among HPV E6/E7 mRNA+ compared with HPV DNA+ (RR = 1.30, 95% CI = 0.97–1.75; I2 = 48.1%), among HPV E6/E7 mRNA− compared with HPV DNA− (RR = 1.19, 95% CI = 0.34, 4.21; I2 = 0%).
Figure 5: Forest plot for the meta-analysis of CIN2+ in women with human papillomavirus E6/E7 mRNA+ and human papillomavirus DNA+

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Figure 6: Forest plot for the meta-analysis of CIN2+ in women with human papillomavirus E6/E7 mRNA− and human papillomavirus DNA−

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 > Discussion Top


At the beginning of the discussion, we would assess the heterogeneity and study quality in this meta-analysis. First, we perform strict inclusion criteria, random effects models and subgroup analyses to control and reduce the heterogeneity. However, the heterogeneity was still relatively higher, and the conclusion should be considered with some caution. Second the Newcastle–Ottawa Scale was used to assess the study quality. Five articles were high quality, but one article is relatively low because the follow-up is at least 15 months not more than 24 months, but there are articles indicated that almost all HPV infection disappeared within 6–24 months.[36],[37] Some studies found that most of the HPV infection removed within 12 months.[38]

In this study, there was a total of 1024 cases, 732 cases with virology of HPV E6/E7 mRNA+ versus 285 cases with a biopsy of CIN2+, however 292 cases with HPV E6/E7 mRNA− versus 44 cases with CIN2+ in the process of follow-up. The level of CIN2+ was significantly higher in women with an HPV E6/E7 mRNA+ compared with those with an HPV E6/E7 mRNA−. This is the first meta-analysis reporting the clinical application of HPV E6/E7 mRNA testing risk of CIN2+ in women with a mild abnormal cytology. Our studies indicate that the risk of CIN2+ in women with a positive HPV E6/E7 mRNA testing is about three-fold than a negative result. This result can fully show the HPV E6/E7 mRNA testing can predict the progress of the cervical lesions and can screen out women who may have CIN2+ in the future. Due to the heterogeneity analysis is unsuccessful (P = 0.001, I2 = 80.3%), we perform subgroup analysis. The different literature has different requirements of HPV DNA test results before following up, that is to say, when women with a test of HPV DNA positive, the HPV E6/E7 mRNA test results are more likely to be positive and in the future, she is more likely to suffer from high-level cervical lesions. Hence, we based on the initial status of HPV DNA-conducting subgroup analysis, divided into groups of HPV DNA positive group and HPV DNA unlimited group. In the group of HPV DNA testing positive, we found that there is still heterogeneity. After analyzing, we found that in this group there is one article using PreTect HPV - Proofer assay to detect HPV E6/E7 mRNA, whereas other articles using APTIMA assay to detect E6/E7 mRNA. In one study, we found that women with a cytology for ASCUS or LSIL, PreTect HPV - Proofer assay's sensitivity and specificity were, respectively, 53%, (95% CI = 38.1–67.9) and 76%, (95% CI = 65.4–85.1); APTIMA assay's sensitivity and specificity were, respectively, 98%,(95% CI = 88.7–99.9) and 38%, (95% CI = 26.9–49.0),[34] and hence the difference of detection method can also be the cause of heterogeneity. After removing this article, the heterogeneity still existed. Therefore, we use random effect model to analyze. In the group of HPV DNA testing unlimited, there is no heterogeneity. Meta-analysis for these two groups found HPV E6/E7 mRNA test positive represent a higher risk of CIN2+ than a negative HPV E6/E7 mRNA test. In HPV DNA positive group, although all women with a positive HPV DNA, in the process of follow-up, only a few of women developed into CIN2+, which is consistent with some studies. In one systematic analysis compared the sensitivity and specificity of HPV E6/E7 mRNA in women with a cytology of LSIL, results shown the sensitivity and specificity were, respectively, 91.0%, (95% CI = 85.2–94.7), 42.5%, (95% CI = 33.3–52.3),[39] whereas HPV DNA testing were respectively 97.2%, (95% CI = 95.6–98.9), 28.6%, (95% CI = 22.2–35.0).[5] In Rijkaart et al.'s study,[19] he suggests for those women with HPV E6/E7 mRNA tested and HPV DNA tested positive, a biopsy can perform directly, thus saving the time of follow-up. However for HPV E6/E7 mRNA negative and HPV DNA positive, just performing a follow-up is enough. So, the HPV DNA test combined with HPV E6/E7 mRNA can better predict the development of cervical lesions. In this study where Rijkaart also explored whether HPV E6/E7 mRNA detection can be used in triaging women with HPV DNA positive, he pointed out that HPV E6/E7 mRNA tested positive represent that these women were infected with HPV and may suffer from CIN2+ in the future; HPV E6/E7 mRNA tested negative, but HPV DNA tested negative represent that these women were more likely to regress in the future. In an article [40] where we cannot found the original data through anyway, we found that women with a cytology of ASCUS or LSIL, the three years' cumulative incidence for HPV E6/E7 mRNA positive group was 43.4% (95% CI = 28.9–55.0), while the negative group was 4.5% (95% CI = 0.5–8.3).[35] This suggested that compared with HPV E6/E7 mRNA tested negative, tested positive are more likely to develop to CIN2+ over the next 3 years. Thus, for those women with a positive HPV E6/E7 mRNA should have a relatively more rigorous follow-up project, while for those women with a negative result can appropriately extend the follow-up interval. However, at the same time, we also found some women with a negative HPV E6/E7 mRNA test can also progress to high-level cervical lesions in the follow-up. Therefore for those women with a negative HPV E6/E7 mRNA should be taken some clinical, biologic factors into account, such as age, smoking, sex behavior, delivery times, and so on, thus making reasonable follow-up plan.

There were two articles which compare the clinical performance of an HPV E6/E7 mRNA test and an HPV DNA test in the triage of ASCUS or LSIL. Although the number of article is little, the cases were enough (>200 cases). From our result, we found whether the result of HPV E6/E7 mRNA detection and HPV DNA testing is positive or negative, there was no difference in the risk of CIN2 + in the next 2 years (HPV E6/E7 mRNA+ vs. HPV DNA+: RR = 1.30, 95% CI = 0.97–1.75, P = 0.08 and HPV E6/E7 mRNA − vs. HPV DNA−: RR = 1.19, 95% CI = 0.34–4.21, P = 0.78). However, this result is inconsistent with other articles. Molden et al.[24] thought that HPV E6/E7 mRNA detection as an adjunct to cytology is of great value to the screening of cervical cancer, because compared with HPV DNA testing, HPV E6/E7 mRNA detected positive have a 5.7 times risk of CIN2+ in the next 2 years. In a study carried out a 2-year follow-up of cytological normal women, the researchers found that compared with HPV DNA testing, HPV E6/E7 mRNA test possess a low sensitivity in predicting disease, but a high specificity.[14] Due to the number of selected research is less, our results lacking of persuasion, a larger sample size are needed to confirm our results.

It is worth mentioning that of six retrieved studies, there are 732 women with HPV E6/E7 mRNA+ and 292 women with HPV E6/E7 mRNA−. This study is represented by relatively limited sample size, and bigger data are needed. What's more, although there are no new different finding that supports HPV DNA testing is more suitable in triaging ASCUS, more high-quality randomized controlled trials are required for assessing the effects of HPV E6/E7 mRNA test in triaging ASCUS.


 > Conclusion Top


We concluded that HPV E6/E7 mRNA tested positive suggested an HR of CIN2+, and the same situation is observed in subgroup analysis. The findings support that HPV E6/E7 mRNA test can act as a new method to triage women with cytology of BMD. However, due to the little study comparing the clinical application of HPV E6/E7 mRNA and HPV DNA, we could not conclude HPV E6/E7 mRNA can triage women with cytology equivocal or low-grade cytological abnormalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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    Tables

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