|Year : 2016 | Volume
| Issue : 1 | Page : 283-289
Diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer: A meta-analysis
Tong Li, Yan Li, Guo-Xian Yang, Peng Shi, Xiao-Ying Sun, Yu Yang, Ying-Ying Li, Yang Liu
Department of Gynecology and Obstetrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, China
|Date of Web Publication||13-Apr-2016|
Gynecology Ward, Central Hospital Affiliated to Shenyang Medical College, No. 5, South Seventh West Road, Tiexi, Shenyang - 110 024
Source of Support: None, Conflict of Interest: None
Objectives: The objective of this study was to assess the diagnostic value of combination of human papillomavirus (HPV) testing and cytology as compared to isolated cytology in screening cervical cancer.
Materials and Methods: We searched public databases including PubMed and Embase before September 30, 2014. Sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR) of the two methods from included studies were meta-analyzed. The summary receiver operating characteristic (SROC) curve was constructed, and the area under curve (AUC) and an index Q* were summarized. Besides, a two-sample Z-test was conducted to evaluate the differences of the two diagnostic modalities.
Results: Totally eight studies were involved. The included studies showed significant heterogeneity in estimating sensitivity, specificity, positive LR, negative LR, and DOR in both methods. The results of the above indexes in combination method were 0.937 (95% confidence interval (CI): 0.925–0.948), 0.858 (95% CI: 0.855–0.860), 3.924 (95% CI: 2.037–7.559), 0.083 (95% CI: 0.033–0.210), and 51.563 (95% CI: 14.682–181.09), respectively. The AUC and Q* index were 0.8841 and 0.8763, respectively. The results for isolated method were 0.743 (95% CI: 0.716–0.768), 0.951 (95% CI: 0.949–0.953), 6.408 (95% CI: 2.322–17.683), 0.226 (95% CI: 0.112–0.460), and 30.897 (95% CI: 7.170–133.15), respectively. The AUC and Q* index were 0.8550 and 0.7859, respectively. Combination method was superior to isolated method (Z = 13.375, P < 0.01) in sensitivity, while was inferior to isolated method (Z = 56.935, P < 0.01) in specificity.
Conclusion: Combination of HPV testing and cytology may be appropriate for screening cervical cancer if conditions allow.
Keywords: Cervical cancer, combination of human papillomavirus testing and cytology, diagnostic value, isolated cytology, meta-analysis
|How to cite this article:|
Li T, Li Y, Yang GX, Shi P, Sun XY, Yang Y, Li YY, Liu Y. Diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer: A meta-analysis. J Can Res Ther 2016;12:283-9
|How to cite this URL:|
Li T, Li Y, Yang GX, Shi P, Sun XY, Yang Y, Li YY, Liu Y. Diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Nov 13];12:283-9. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/283/154032
| > Introduction|| |
Cervical cancer is heralded as being the third most common cancer in women followed by breast and colorectal cancer. World Health Organization (WHO) has reported that approximately 530,000 women worldwide are diagnosed with cervical cancer, and the mortality of incidence ratio ranged from 52 to 88% in developing countries. Although cervical cancer screening programs by cytology tests (e.g., conventional Pap smear More Detailss, liquid-based cytology) has decreased the incidence and death rate in many countries in the past few decades, cervical cancer still remains a leading cause of death in women due to the high rate of false positive results and limited reproducibility of cytology tests. Besides, the sensitivity and specificity of the test have been questioned. The low sensitivity of cytology tests would put women at risk of developing invasive cervical cancer. Thus, much concern has arisen recently to develop a better screening test for the disease prevention, especially the role of human papillomavirus (HPV) testing.
The major cause of cervical cancer is the infection with HPV, and persistent HPV infection precedes the onset of cytologic abnormalities in the natural history of the disease. HPV testing has been adopted as an adjunct to cytologic testing for women over 30 years of age in the USA. The HPV testing has greater sensitivity (approximately 90%) and reproducibility. However, it has slightly decreased specificity for cervical intraepithelial neoplasia (CIN) 2 and 3 when compared with cytology. Besides, this test in women less than 30 years can lead to unneeded evaluation and overtreatment because these women have a high prevalence of transient infection and a low prevalence of underlying high-grade lesions., In recent years, a large number studies involving the addition of HPV testing to screening cytology have been reported., However, studies concerning the diagnostic value of comparison with HPV testing plus cytology with isolated cytology have been rarely reported.
In order to comprehensively assess the diagnostic value of combination of HPV testing and cytology as compared to isolated cytology method in screening cervical cancer, we systematically reviewed the published findings and quantitatively combined the results using meta-analysis.
| > Materials and Methods|| |
We systematically searched electronic databases of PubMed and Excerpta Medica Database (Embase). The keywords search using (''cervical cancer” or “cervical carcinoma” or “uterine cervix cancer” or “Carcinoma of cervix” or “cervical neoplasm'') AND (''Pap test” or “Pap Smear” or “Papanicolaou test” or “Papanicolaou smear'') AND (''TCT” or “Thinprep” or “liquid-based” or “Thinprep Liquid-based Cytology Test” or “cytology” or “cytological techniques”) AND (''HPV” or “human papilloma virus”). The deadline for the search was September 30, 2014.
The inclusion criteria were as follows: (i) The published researches contained cytology techniques (Pap test and Thin Prep) and combination of cytology techniques with HPV testing; (ii) the studies provided the number of true positive, false positive, false negative, and true negative, or the results could be acquired according to the known related indicators; and (iii) the diagnostic tests should contain clinically diagnostic criteria (mainly histopathological examination). Cervical cancer is diagnosed when CIN ≥ 2.
The exclusion criteria were listed as below: (i) non-original article, such as abstract, reviews, editorials, conference proceedings, letters, or comments, were excluded; (ii) studies that contained duplicate publication; (iii) studies that were the same article with different focal points; and (iv) studies that did not offer control group.
Data extraction and quality assessment
Systematic assessment of quality and documentation of relevant data of the selected researches were performed by independent two investigators (Tong Li and Xiao-Ying Sun) using a standardized form. The information was extracted included the first author's name, year of publication, region and duration of the study carried out, research type, age, source of subjects, gold standard, exclusion criteria for subjects, and index of diagnostic test including the number of true positive, false positive, false negative, and true negative, etc., Disagreements or inconsistency were resolved by discussion with the third investigator (Guo-Xian Yang).
In the present study, the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) was performed to assess the quality of studies. It is a validated consensus method including 14 items for study characteristics investigation of the diagnostic accuracy of the enrolled studies. Reviewers recorded a score of “1” for “yes” and “0” for “no” or unclear for each of the 14 items. If the score met on average 10 of the 14 QUADAS criteria was considered as high quality. Any disagreements in QUADAS scores were resolved by discussion until a consensus was obtained.
Meta-DiSc (Version 1.4) was employed in the diagnostic meta-analysis. The effect index, such as sensitivity, specificity, positive likelihood ratio (LR), negative LR, diagnostic odds ratio (DOR), 95% confidence intervals (CIs), and summary receiver operating characteristic (SROC) curve were selected. The Cochrane-Q statistic and the I 2 test were utilized to assess the heterogeneity. Heterogeneity was found when P - value < 0.05 (Q statistic) and/or I 2 > 50%, and then a random effects model of DerSimonian–Laird was performed to calculate the pooled effect, otherwise a fixed effect model of Mantel–Haenszel would be used. A two-sample Z-test was conducted to evaluate the differences between the two diagnostic modalities.
| > Results|| |
Characteristics of the eligible studies
A flow diagram of the search process for the study was showed in [Figure 1]. Based on the keywords screening, totally 1,675 articles were found. By reviewing titles and abstracts; 1,395 studies were eliminated. The duplicate documents (103) and the studies with no available or wrong data (169) were then also excluded. Finally, eight articles were included in the final review.,,,,,,, [Table 1] and [Table 2] show the basic information for the meta-analysis. The publication year ranged from 2003 to 2012. Of the eight articles, two studies were randomized controlled trial (RCT) and six articles were cross-sectional study. The region of these studies included France, America, Canada, Italy, Brazil, etc., The source of subjects was mainly conventional census. The histopathological examination was considered as gold standard. Pregnant women or women with a history of cervical disease were excluded. Besides, two studies reached 11 of the 14 QUADAS criteria, four studies met 12 of the 14 QUADAS criteria, and two studies achieved 13 of the 14 QUADAS criteria, which all showed high quality [Table 3].
Pooled diagnostic performance for isolated cytology
The pooled results of isolated cytology are showed in [Figure 2]. The included studies showed significant heterogeneity in estimating of sensitivity (I 2 = 96.6%, P < 0.01), specificity (I 2 = 99.5%, P < 0.01), positive LR (I 2 = 99.8%, P < 0.01), negative LR (I 2 = 97.7%, P < 0.01), and DOR (I 2 = 98.4%, P < 0.01), respectively. Therefore, a random-effects model was performed. The pooled sensitivity, specificity, positive LR, negative LR, and DOR were 0.743 (95% CI: 0.716–0.768), 0.951 (95% CI: 0.949–0.953), 6.408 (95% CI: 2.322–17.683), 0.226 (95% CI: 0.112–0.460), and 30.897 (95% CI: 7.170–133.15), respectively.
|Figure 2: Results of pooled diagnostic performance for isolated cytology. (a) Sensitivity, (b) specificity, (c) positive LR, (d) negative LR, and (e) DOR. LR = Likelihood ratio, DOR = diagnostic odds ratio|
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In addition, the SROC curve showed that there was no threshold effect (P = 0.3453), thus a fixed effect model of Mantel–Haenszel was employed. The results showed that the area under curve (AUC) and Q* index were 0.8550 (95% CI: 0.842–0.868) and 0.7859 (95% CI: 0.774–0.798), respectively [Figure 3]a.
|Figure 3: Results of SROC for both methods. (a) Results of SROC for isolated cytology, and (b) results of SROC for combination of HPV testing and cytology. SROC = Summary receiver operating characteristic|
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Pooled diagnostic performance for combination of HPV testing and cytology
The pooled results of combination of HPV testing and cytology were showed in [Figure 4]. The included studies showed statistical heterogeneity in their estimate of sensitivity (I 2: 93.8%, P < 0.01), specificity (I 2: 99.8%, P < 0.01), positive LR (I 2: 99.9%, P < 0.01), negative LR (I 2: 95.1%, P < 0.01), and DOR (I 2: 96.4%, P < 0.01), respectively. Hence, a random-effects model was performed. The pooled sensitivity, specificity, positive LR, negative LR, and DOR were 0.937 (95% CI: 0.925–0.948), 0.858 (95% CI: 0.855–0.860), 3.924 (95% CI: 2.037–7.559), 0.083 (95% CI: 0.033–0.210) and 51.563 (95% CI: 14.682–181.09), respectively.
|Figure 4: The results of pooled diagnostic performance for combination of human papillomavirus testing and cytology. (a) Sensitivity, (b) specificity, (c) positive LR, (d) negative LR, and (E) DOR. LR = Likelihood ratio, DOR = diagnostic odds ratio|
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In addition, we conducted the SROC curve analysis and found that there was no threshold effect (P = 0.3462), hence a fixed effect model of Mantel–Haenszel was performed. The results showed that the AUC and Q* index were 0.8841 (95% CI: 0.690–1.000) and 0.8763 (95% CI: 0.678–1.000), respectively [Figure 3]b.
Evaluation the differences of the two diagnostic modalities
We compared the two diagnostic modalities via sensitivity, specificity, positive LR, negative LR, and DOR [Table 4]. The results indicated that combination of HPV testing and cytology methods was superior to isolated cytology method (Z = 13.375, P < 0.01) in sensitivity, while was inferior to isolated cytology method (Z = 56.935, P < 0.01) in specificity. In addition, there were no significant differences in other indexes.
|Table 4: Pairwise comparison between cytology method and combination of HPV and cytology method|
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| > Discussion|| |
In the present study, we comprehensively assessed the diagnostic value of combination of HPV testing and cytology as compared to isolated cytology method in screening cervical cancer using a meta-analysis. The result of AUC indicated that the diagnostic value of the two methods was both high, and no significant differences were observed. However, combination method was superior to isolated cytology method in sensitivity, while was inferior to isolated method in specificity. Therefore, we demonstrated that combination of HPV testing and cytology might be appropriate for screening cervical cancer if conditions allow.
Screening is the best method to prevent cervical cancer, which aims to detect high-grade cancer precursor lesions or early asymptomatic invasive disease. Currently, there are three main screening methods for cervical cancer: Cervical cytology tests, HPV testing, and visual inspection with acetic acid (VIA). Cervical cytology tests, commonly referred to as the Pap smear, have two main forms: Conventional and liquid-based cytology. The difference between conventional and liquid-based cytology is the spread of cells. However, there were no clinically significant differences in sensitivity or specificity between the two methods. Although cervical cytology has been proven an extremely successful public health intervention and achieved reductions in incidence of up to 80%, it has significant limitations  and the sensitivity of a single Pap test to screen CIN or invasive cervical cancer is less than 60%. Epidemiological studies have convincingly established that the correlation between HPV and cervical cancer, which might promote the development of HPV molecular tests for cervical cancer. The HPV testing is a potentially valuable tool, which could amplify the DNA signal in the assays of the 13 HPV high-risk types. It is recommended for follow-up of abnormal cytology in women aged over 30 and for the surveillance of patients after colposcopic treatment for CIN. Although HPV testing has a higher sensitivity and negative predictive value for high-grade CIN detection than either the conventional Pap smear or liquid-based cytology, a lower specificity and positive predictive value still existed.,,,, Therefore, HPV testing has been additionally be utilized with Pap smears for optimal diagnosis of high-grade CIN. Combination of the Pap smear with HPV testing may be better for women with mild or borderline abnormal Pap results. Because a negative HPV testing has the potential to guarantee women whose Pap smear result is probably incorrect. Besides, the treatment for a positive HPV testing may be started earlier in the women owing to the high sensitivity of the test. Naucler et al., found that the addition of an HPV test to the Pap test for women in their mid-30s decreased the incidence of grade 2 or 3 CIN or cervical cancer detected by subsequent screening examinations. Cox et al., showed that HPV testing in combination with Pap tests are 96–100% sensitive for detection of CIN 2/3 and cancer, respectively. Similarly, the results in our study indicated that combination of HPV testing and cytology method was superior to isolated cytology method in sensitivity (Z = 13.375, P < 0.01), while was inferior to isolated method (Z = 56.935, P < 0.01) in specificity. Because most infections with HPV are benign, and the infections are common in young women and most are transient.
There are several strengths of the present meta-analysis. We explored the diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer, and found that there were distinctions in sensitivity and specificity. The results in our study may provide theoretical basis for diagnosing cervical cancer.
However, there are also some limitations in our study. Heterogeneity in our study was substantial. The reasons and sources might be diverse. It is noteworthy that the regions of these studies included France, America, Canada, Italy, Brazil, etc., The differences among races, countries, living habit, cultural exchange, living conditions, the ages of women, or the sample size of each study may contribute to the results. Besides, only published researches were included, hence, publication bias may exist. What is more, subgroup analyses were not performed. Furthermore, other factors could be not underwent meta-analysis due to the relatively incomplete hierarchical information in the included study.
In summary, results from this systematic review and meta-analysis demonstrate that combination of HPV testing and cytology method in screening cervical cancer was superior to isolated cytology method in sensitivity, while was inferior in specificity. Given the harms caused by cervical cancer, combination of HPV testing and cytology may be appropriate for screening cervical cancer if conditions allow.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]