|Year : 2015 | Volume
| Issue : 4 | Page : 697-703
Contrast-enhanced ultrasonography in qualitative diagnosis of sentinel lymph node metastasis in breast cancer: A meta-analysis
Yi-Xia Zhang, Xue-Mei Wang, Shu Kang, Xiang Li, Jing Geng
Department of Ultrasonography, The First Affiliated Hospital of China Medical University, Shenyang, China
|Date of Web Publication||15-Feb-2016|
Department of Ultrasonography, The First Affiliated Hospital of China Medical University, Nanjing Street No. 155, Heping District, Shenyang - 110 001
Source of Support: None, Conflict of Interest: None
Aim: This meta-analysis aims to determine the accuracy of contrast-enhanced ultrasonography (CEUS) in the qualitative diagnosis of metastatic sentinel lymph node (SLN) for patients with breast cancer.
Materials and Methods: We screened PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases. All analyses were calculated using the STATA software, version 12.0 (Stata Corp, College Station, TX, USA). We calculated the summary statistics for sensitivity (Sen), specificity (Spe), positive and negative likelihood ratios (LR + /LR-), diagnostic odds ratio (DOR) and receiver operating characteristic (SROC) curve. Thirteen articles that met all inclusion criteria were included in this meta-analysis.
Results: A total of 876 breast cancer patients were assessed, including 372 patients with metastatic SLN and 504 patients without metastatic SLN. All SLN were histologically confirmed after conducting CEUS. The pooled Sen was 0.80 (95%CI = 0.76-0.84); the pooled Spe was 0.94 (95% CI = 0.91-0.96). The pooled LR + was 6.28 (95%CI = 3.61-10.92); the pooled negative LR - was 0.218 (95% CI = 0.10-0.31). The pooled DOR of CEUS in qualitative diagnosis of SLN metastasis was 49.10 (95% CI = 27.89-86.45). The area under the SROC curve was 0.937 (standard error [SE] =0.0128).
Conclusions: Our meta-analysis suggests that CEUS may have high a diagnostic accuracy in testing for metastatic SLN in breast cancer. Thus, CEUS may be a good tool for differential diagnosis between metastatic and non-metastatic SLN.
Keywords: Breast cancer, contrast-enhanced ultrasonography, metastasis, meta-analysis, sentinel lymph node
|How to cite this article:|
Zhang YX, Wang XM, Kang S, Li X, Geng J. Contrast-enhanced ultrasonography in qualitative diagnosis of sentinel lymph node metastasis in breast cancer: A meta-analysis. J Can Res Ther 2015;11:697-703
|How to cite this URL:|
Zhang YX, Wang XM, Kang S, Li X, Geng J. Contrast-enhanced ultrasonography in qualitative diagnosis of sentinel lymph node metastasis in breast cancer: A meta-analysis. J Can Res Ther [serial online] 2015 [cited 2020 May 28];11:697-703. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/697/146129
| > Introduction|| |
Breast cancer is the primary cause of cancer death among women in both the developing and developed world.  It is estimated that there is more than one million women newly diagnosed with breast cancer every year worldwide.  The sentinel lymph node (SLN) is the hypothetical first lymph node or group of nodes draining a cancer.  It has been well established that the use of SLN detection may help to determine the stage of breast cancer to see if it has spread to any lymph nodes, thus decreasing unnecessary lymph node dissections and thereby reducing the risk of certain complication such as lymphedema. , Notably, previous studies have documented that lymph node metastasis, especially the metastasis of the SLN, has been one of the most important prognostic signs and has proven to be beneficial for the clinical development of breast cancer treatment plans. , Thus, the detection of SLN metastasis may benefit prognosis of breast cancer patients. Ultrasonography (US) has been widely used for the early diagnosis of SLN metastasis in breast cancer and is relative non-invasiveness and low cost.  However, it is usually difficult for conventional US to distinguish between malignant and benign SLNs. 
Contrast-enhanced ultrasound (CEUS), based on standard gray scale ultrasound imaging, is performed in diagnostic and experimental settings in various institutions around the world and it has become a standard diagnostic tool. , With microbubble contrast agents, CEUS imaging has created a significant opportunity for visualizing microcirculation and thus can overcome the disadvantages of traditional US techniques. , In breast imaging, CEUS can add diagnostic value by characterizing mass lesions, staging invasive cancer, detecting tumor recurrence assessing response to neoadjuvant chemotherapy, and providing abundant information on the tumor vasculature and blood perfusion.  These techniques are able to improve the visualization of blood flow in the microvasculature by detecting every single microbubble.  Several previous studies have found that CEUS can accurately discriminate metastatic from non-metastatic SLNs in patients with breast cancer but the results of these studies have been contradictory. ,, Therefore, we performed the present meta-analysis to assess the accuracy of CEUS for differential diagnosis between metastatic and non-metastatic SLN in breast cancer.
| > Materials and methods|| |
Related articles were identified by searching PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases comprehensively from their inception through August 1, 2013 without language restrictions. The following keywords and MeSH terms were used: ["breast cancer" or "breast carcinoma" or "breast neoplasm" or "breast tumor"] and ["sentinel lymph node" or "sentinel LN" or "SLN"] and ["contrast-enhanced ultrasound" or "contrast-enhanced ultrasonography" or "contrast ultrasonography" or "ultrasound contrast imaging" or "CEUS"]. We also performed a manual search to find other potential articles.
The included studies must meet all five of the following criteria: (1) the study design must be clinical cohort study or diagnostic test; (2) the study must address the accuracy of CEUS for differential diagnosis between metastatic and non-metastatic SLN in breast cancer; (3) all patients diagnosed with breast cancer must have been confirmed by histopathological examinations; (4) all SLN diagnoses must have been histologically confirmed after CEUS; (5) published data in the four-fold (2 × 2) tables must be sufficient. If the study failed to meet the inclusion criteria, it was excluded. When authors published several studies using the same subjects, the one with the most recent publication date or with the largest sample size was included.
Titles, abstracts, and full-text articles screening as well as study quality evaluation were completed independently by two investigators who reached a consensus on all the items through discussion and reexamination. The following relevant data were extracted from prospective eligible studies: Language of publication, year of publication, first author, geographical location, design of study, sample size, the source of the subjects, number of lesions, contrast agent, diagnostic accuracy, etc., Data on true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) published in the four-fold (2 × 2) tables were also collected.
Methodological quality was independently assessed by two researchers according to the tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS).  The QUADAS criteria include 14 assessment items. Each of these items is scored as "yes" (2), "no" (0), or "unclear" (1). QUADAS scores range from 0 to 28 with a score greater than or equal to 22 indicating good quality.
The STATA version 12.0 (Stata Corp, College Station, TX, USA) and Meta-Disc version 1.4 (Universidad Complutense, Madrid, Spain) were used for meta-analysis. We calculated the pooled summary statistics for sensitivity (Sen), specificity (Spe), positive and negative likelihood ratios (LR + /LR− ), diagnostic odds ratio (DOR) with their 95% confidence intervals (CIs). Summary receiver operating characteristic (SROC) curve and the corresponding area under the curve (AUC) were obtained.  Threshold effect was assessed using Spearman correlation coefficients. Power and sample size calculations were performed using PS software.  The Cochran's Q-statistic and I 2 test were used to evaluate potential heterogeneity between studies.  If a Q-test showing a P < 0.05 or I 2 test exhibiting a value greater than 50% indicating significant heterogeneity, the random-effect model was conducted; otherwise, the fixed-effects model was used. We also performed subgroup and meta-regression analyses to investigate potential sources of heterogeneity. In order to evaluate the influence of single studies on the overall estimate, a sensitivity analysis was performed. We also used Begger's funnel plots and Egger's linear regression test to investigate publication bias. 
| > Results|| |
Characteristics of included studies
The original search yielded 127 papers related to the searched keywords. We reviewed the titles and abstracts of all articles and excluded 128 articles. Full texts and data integrity were then reviewed and another 81 articles were excluded. Finally, 13 studies that met all inclusion criteria were included in this meta-analysis. ,[ 24],,,,,,,,,,, The publication years of eligible studies range from 2008 to 2013. [Figure 1] shows the selection process of eligible articles. The distribution of the number of articles selected from those electronic databases is shown in [Figure 2]. In total, this meta-analysis assessed 876 breast cancer patients, of which 372 patients were with metastatic SLN and 504 patients were without metastatic SLN. The statistical power for the sample size of every included study was higher than 0.50. The sonographic contrast agent SonoVue was used in all studies. The subcutaneous administration of SonoVue was performed in 11 studies and the intravenous administration was performed in 4 studies. The Siemens ultrasound was used in 6 studies; the Phillips ultrasound was used in 4 studies; and the Esaote ultrasound was used in the remaining 3 studies. The QUADAS scores of all included studies were greater than or equal to 22. Study characteristics and methodological quality are summarized in [Table 1].
Quantitative data synthesis
|Figure 1: Flow chart of literature search and study selection. Thirteen studies were included in this meta-analysis|
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|Figure 2: The distribution of the number of topic-related literatures in electronic databases during the last decade|
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|Table 1: Baseline characteristics and methodological quality of all included studies |
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Meta-analysis findings on the accuracy of CEUS for differential diagnosis between metastatic and non-metastatic SLN in breast cancer are shown in [Table 2]. The random effects model was used due to obvious heterogeneity among studies. The diagnostic accuracy of CEUS was measured as pooled Sen, Spe, LR + , LR− , and DOR [Figure 3]. Our meta-analysis revealed that the pooled Sen was 0.80 (95%CI = 0.76-0.84) and the pooled Spe was 0.94 (95%CI = 0.91-0.96). There was no significant correlation (r = -0.118, P = 0.417) between sensitivity and specificity, which indicates the absence of the threshold effect. In addition, we observed that the pooled LR + and LR − were 6.28 (95%CI = 3.61-10.92) and 0.218 (95%CI = 0.10-0.31), respectively. The pooled DOR of CEUS in the qualitative diagnosis of SLN metastasis was 49.10 (95% CI = 27.89-86.45). The results were plotted as a symmetrical SROC curve [Figure 4], and the corresponding AUC was 0.937 (standard error [SE] =0.0128).
|Figure 3: Forest plots for the diagnostic accuracy of CEUS for the diagnosis of SLN metastasis in patients with breast cancer. (a) Sensitivity; (b) Specificity; (c) Positive likelihood ratio; (d) Negative likelihood ratio|
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|Figure 4: Forest plot of DOR and SROC curve on the diagnostic accuracy of CEUS in diagnosing SLN metastasis in patients with breast cancer. DOR, diagnostic odds ratio; SROC, summary receiver operator characteristic; AUC, area under curve; SE, standard error|
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|Table 2: Meta - analysis of the diagnostic accuracy of contrast - enhanced ultrasonography for the diagnosis of axillary lymph node metastasis in breast cancer |
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Subgroup and meta-regression analyses were conducted based on language, sample size, route of administration, and instrument type to investigate potential sources of heterogeneity. Subgroup analysis results revealed that CEUS exhibited high diagnostic performance in various subgroups. Meta-regression analysis results confirmed that no one factor could explain potential sources of heterogeneity [Table 3]. We found no evidence of obvious asymmetry in the Begger's funnel plots [Figure 5]. Egger's test also did not display strong statistical evidence for publication bias (t = -1.14, P = 0.277).
|Figure 5: Begger's funnel plot of publication bias on the pooled DOR of CEUS for the diagnosis of SLN metastasis in patients with breast cancer. No publication bias was detected in this meta-analysis. DOR, diagnostic odds ratio|
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|Table 3: Meta - regression analyses of potential source of heterogeneity |
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| > Discussion|| |
The importance of US examination in the diagnosis of breast cancer has been widely demonstrated and US is the first choice for screening patients with suspected breast cancer because of its relatively low cost, non-invasiveness, and ready availability.  However, it has a lower sensitivity and specificity than CT and MRI. , During the last few years, the introduction of ultrasound contrast agents has been considered to be a promising tool for studying the vascular pattern of lymph nodes in breast cancer.  It has been repeatedly shown that CEUS could improve the accuracy of conventional US in the assessment of SLN metastasis in breast cancer and could be useful for predicting the response of breast cancer to therapy. ,, Previous studies have indicated that CEUS may be generally applicable to the diagnosis of SLN metastasis in breast cancer, ,,, while other studies failed to provide any evidence that CEUS is an accurate diagnostic tool. ,
In the present meta-analysis, we systematically evaluated the technical performance and accuracy of CEUS for differential diagnosis between metastatic and non-metastatic SLN in breast cancer. Thirteen independent studies were included with 372 patients with metastatic SLN and 504 patients without metastatic SLN. Our results showed that the pooled sensitivity, specificity and DOR of CEUS in diagnosing SLN metastasis were 80%, 94%, and 49.10%, respectively. These results were consistent with the view that CEUS has a high diagnostic accuracy for metastatic SLN in breast cancer, which suggests that CEUS may be a good tool for differentially diagnosing between metastatic and non-metastatic SLN. Generally, the parametric imaging of CEUS combines the high sensitivity and specificity that enables the reliable prediction of non-SLN status in breast cancer patients with metastatic SLN. This could be explained by the fact that CEUS employs micro-bubble contrast agents, which combined with nonlinear imaging techniques result in the enhancement of backscattering light from blood models where the echo is more uniform than from the heart wall. In addition, the contrast agent is accompanied by blood flow, which helps prevent the occurrence of false images, thereby improving diagnostic accuracy. ,, Our findings showed no significant relationship between sensitivity and specificity within studies, revealing no evidence of the threshold effect. The threshold effect is usually interpreted as a sudden and radical change in a phenomenon and often occurs after surpassing a quantitative limit. In the study of genetics, the threshold effect is used to represent the necessary minimum number of disease susceptibility genes in certain environmental conditions. Significantly, the existence of a threshold may promote the division of a group into healthy subjects and patients, in which those above the threshold are susceptible and those below are not. , Since heterogeneity existed in previous individual studies, subgroup analyses were carried out. Similar results were found in these subgroup analyses. CEUS exhibited a high diagnostic performance in different subgroups for the diagnosis of SLN metastasis, suggesting that differences in language, sample size, route of administration, and instrument type did not directly influence the diagnostic accuracy of CEUS. Furthermore, our results found no direct evidence of publication bias. Consistent with previous studies, our findings strongly suggest that CEUS is a high-accuracy and non-invasive tool for qualitatively diagnosing metastatic SLN in breast cancer.
While this is the first meta-analysis focused on the diagnostic accuracy of CEUS for metastatic SLN in breast cancer, our study has some limitations. Firstly, our results lacked sufficient statistical power to assess the accuracy of CEUS due to a relatively small sample size. Secondly, meta-analysis is a retrospective study that may lead to subject selection bias. In addition, this meta-analysis failed to obtain original data from the included studies, which limited a further clinical assessment of CEUS for the diagnosis of breast cancer. Importantly, the inclusion criteria of cases and controls were not well defined in all included studies and thus might have influenced our results.
In conclusion, our meta-analysis suggests that CEUS may have a high diagnostic accuracy for metastatic SLN in breast cancer. Thus, CEUS may be a good tool for differential diagnosis between metastatic and non-metastatic SLN. However, due to the limitations mentioned above, further detailed studies are still required to confirm our findings.
| > Acknowledgment|| |
We would like to acknowledge the helpful comments on this paper received from our reviewers. Also, we would like to thank all our colleagues working in the Department of Ultrasonography, the First Affiliated Hospital of China Medical University.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]