Efficacy and Safety of Vacuum-Assisted Excision for Benign Breast Mass Lesion: A Meta-Analysis

Background and Objective: Breast mass lesions are common; however, determining the malignant potential of the lesion can be ambiguous. Recently, to evaluate breast mass lesions, vacuum-assisted excision (VAE) biopsy has been widely used for both diagnostic and therapeutic purposes. This study aimed to investigate the therapeutic role of VAE. Materials and Methods: Relevant articles were obtained by searching PubMed and EMBASE on 3 September 2021. Meta-analyses were performed using odds ratios and proportions. To assess heterogeneity, we conducted a subgroup analysis and meta-regression tests. Results: Finally, 26 studies comprising 18,170 patients were included. All of these were observational studies. The meta-analysis showed that the complete resection rate of VAE was 0.930. In the meta-regression test, there was no significant difference. The meta-analysis showed a recurrence rate of 0.039 in the VAE group. The meta-regression test showed no statistical significance. Postoperative hematoma, pain, and ecchymosis after VAE were 0.092, 0.082, and 0.075, respectively. Conclusion: VAE for benign breast lesions showed favorable outcomes with respect to complete resection and complications. This meta-analysis suggested that VAE for low-risk benign breast lesions is a reasonable option for both diagnostic and therapeutic purposes.


Introduction
Breast mass lesions are very common, but it can be difficult to determine their malignant potential [1]. Because breast cancer is one of the leading causes of mortality worldwide, it is crucial to detect malignant lesions [1,2]. Although the performance of the imaging system to evaluate the potential of malignancy has increased, biopsy is the final informative method for diagnosis [3]. Histologic confirmation is enabled by fine-needle aspiration, core needle biopsy, open excision, and vacuum-assisted excision (VAE) biopsy. Among these modalities, fine-needle aspiration and core needle biopsy can only be used for diagnostic purposes, but it has some limitations [3]. Fine-needle aspiration and core needle biopsy cannot examine the whole mass, whereas VAE can perform a full examination of the entire mass. Owing to the advantage that VAE can remove the entire mass region, VAE has recently been widely used for both diagnostic and therapeutic purposes [3][4][5]. In 2002, the US Food and Drug Administration (FDA) approved VAE for the removal of benign lesions. Although VAE can remove a large amount of tissue, open surgical excision remains the gold standard for large palpable masses [6]. Thus, the indications and efficacy of VAE remain controversial. Although traditional open excision is the most effective method for removing all mass lesions, it results in scarring, which is not preferred by women. Most surgeons would respect this patient's preference if the procedure is secure.

Data Extraction
Data from all eligible studies were extracted by two investigators. Extracted data from each of the eligible studies included the following: the first author's name, year of publication, study location, study design, study period, number of patients analyzed, age, number of lesions, indication of vacuum-assisted biopsy, complete resection rate, recurrence rate, and complications.

Quality Assessment
We used the Newcastle-Ottawa quality assessment scale (NOS) to assess the risk of bias in observational studies [8]. NOS uses a star system that includes three domains: selection, comparability, and exposure/outcome. All studies were independently reviewed by two investigators. Any disagreement concerning study selection and data extraction was resolved by consensus.

Statistical Analysis
To obtain the estimated effect sizes, a meta-analysis was performed using the Comprehensive Meta-Analysis software package (Biostat, Englewood, NJ, USA). We computed the point estimate by combining single descriptive statistics to pool the overall proportions [9]. Pooled proportion of event was estimated using fixed-effect and random-effect model of meta-analysis. To pool the proportion (complete resection, recurrence, and complications), we used logit-transformed values to avoid the squeezing of variance effect [10,11]. Confidence interval was calculated using the exact confidence limits for a binominal proportion [11]. To pool the odds ratio for binary data, we used the inverse variance method with random effects weighing for meta-analysis of outcomes. As the eligible studies used populations with heterogeneity, a random-effects model was more appropriate than a fixed-effects model. Heterogeneity between eligible studies was checked using Cochran's Q (Chi-square test) (p-value < 0.10 were considered significant). Egger's test was conducted to evaluate the publication bias.
We performed a subgroup analysis to assess the heterogeneity across the studies. The pooled incidence of complete resection, recurrence, and complications was calculated according to study-level characteristics as follows: (1) mass removal technique (VAE or surgical open excision) (2) breast tumor size. We also conducted a meta-regression test for each moderator to assess heterogeneity.

Selection and Characteristics
A total of 509 studies were identified through a database search. Among the searched studies, 236 were excluded. Studies were excluded because they were non-original (n = 31), studied other diseases (n = 24), or were written in a non-English language (n = 39). Finally, 26 studies  comprising 18,170 patients were included in the present meta-analysis (Figure 1), and detailed information about the eligible studies is shown in Table 1. We performed a subgroup analysis to assess the heterogeneity across the studies. The pooled incidence of complete resection, recurrence, and complications was calculated according to study-level characteristics as follows: (1) mass removal technique (VAE or surgical open excision) (2) breast tumor size. We also conducted a meta-regression test for each moderator to assess heterogeneity.

Quality Assessment
The quality assessment and risk of bias for each eligible study are summarized in Table 2. All the included studies were observational. The NOS score of 11 studies (42.3%) was 4 points (lowest) and that of nine studies (34.6%) was 7 points (highest). We found that all studies had insufficient selection of controls in the selection domain and non-response rate in the exposure domain. Overall, substantial confounding factors may exist with respect to selection and exposure. Particularly, only four studies directly compared VAE with open excision.

Pooled Incidence of Postoperative Hematoma, Pain, and Ecchymosis
Postoperative hematomas, pain, and ecchymosis are summarized in

Discussion
Our analysis suggested that benign breast masses could be safely removed using VAE. The estimated complete resection rate is sufficiently high. Indeed, the estimated rates of recurrence and complications after VAE were sufficiently low. The complete resection and recurrence rate are critical to the use of both diagnostic and therapeutic procedures. However, a limited number of comparative studies and high heterogeneity indicate that more prospective comparative studies are warranted. Nonetheless, our study indicates that VAE is a useful option for successfully removing benign breast masses. However, in terms of high-risk lesions such as phyllodes tumor or atypical ductal hyperplasia, there have been insufficient studies to demonstrate oncologic safety. VAE was approved by the FDA in 2002 for the removal of benign lesions and by the National Institute for Health and Care Excellence in the United Kingdom in 2006 [5]. However, it is still controversial for some high-risk lesions, such as phyllodes tumors or atypical lesions [5]. To date, several guidelines recommend VAE as an alternative to conventional open excision for benign breast lesions. The international consensus reference in Swiss [6] recommends minimally invasive management of selected B3 lesions with therapeutic VAE. However, according to this consensus, open surgery is still the gold standard for atypical ductal hyperplasia and phyllodes tumors. The study group of breast ultrasonography in Germany [38] stated that VAE allows the resection of breast tissue up to 8 cm 3 (volume). However, it has not been formulated as a nationwide guideline. In the statement of the American Society of Breast Surgeons, it was recommended that easily visualized, confirmed histologically prior to treatment, and less than 4 cm are indications of VAE for fibroadenoma [39]. All these guidelines allow the use of VAE for breast masses that are limited to low-risk lesions.
During our literature search, we found four comparative studies, in which VAE was compared to open excision [14,20,31,32]. All of these studies were observational. Two studies [31,32] comprised benign phyllodes tumors, whereas two [14,20] comprised other benign breast masses such as fibroadenoma, fibrocystic change, papilloma, atypical ductal hyperplasia, or fibrocystic nodule. However, Chen et al. [14] did not report the complete resection rate of all benign masses, in which the complete excision rate of breast carcinomas was reported. Wang et al. [20] reported a 3.4% incomplete removal rate in the VAE group, which was not significantly different from that of open excision. Two studies [31,32] [31]). Complete excision and recurrence rates of VAE were favorable. Although VAE for phyllodes tumors is still controversial [38], our review suggests that the curability of VAE as an alternative to surgery is promising.
Recently, a meta-analysis of 15 studies involving 5256 patients reported the efficacy and safety of VAE [40]. This study showed no significant difference in tumor size, postoperative hematomas, ecchymosis, or residual disease between VAE and open excision. However, the authors used the Chinese database, and many studies are written in the Chinese language. All eligible studies were conducted in China. Only two studies could be searched using the Medline database. This may induce substantial language or location bias [41]. We excluded Chinese-written literature from our analysis. Our study is an updated meta-analysis comprising more recent studies. Another systematic review was conducted without a meta-analysis that aimed to investigate VAE for fibroadenoma [42]. However, this study has some crucial limitations, including the small number of studies (n = 4), no assessment of risk of bias, and no pooling estimates.
Our analysis has several limitations. First, all eligible studies were not randomized trials but were observational. There was no prospective study. Selection bias was inevitable. Second, we used single descriptive statistics because there were limited comparative studies. This may have resulted in substantial heterogeneity. To overcome this issue, we conducted subgroup analysis and meta-regression. Third, among the eligible studies, the indication of VAE was substantially heterogeneous, and high-risk or moderate-risk masses were not excluded. Fourth, we included limited a number of studies with open excision because there was a limited number of comparative studies between VAE and open excision. Therefore, the certainty of the comparison of effect size was limited in our meta-analysis. Instead, we noted the single proportional effect size of VAE. Fifth, in Egger's test, publication bias existed regarding two outcomes of pain and ecchymosis. However, other crucial outcomes such as complete resection or recurrence had no publication bias in Egger's Test. In our study, we did not include unpublished studies such as grey literature, dissertation, or conference presentation. In general, studies with significance are more likely to be published [9]. This may contribute to publication bias. Nevertheless, studies that have not been in peer-reviewed journals tend to be of lower quality [9]. We acknowledge that our study may have potential publication bias regarding pain and ecchymosis, but we believe these complications have a less clinical impact than other outcomes. Finally, only articles written in English were included. Overall, our study has a substantial risk of bias due to the nature of a non-randomized study and non-comparative study. The publication bias implies that there might exist more complications. The limitation of our studies emphasizes the need for future study that is comparative with open excision prospectively. Furthermore, it is needed to compare other minimally invasive procedures to remove breast mass. Recently, some procedures such as cryoablation, microwave ablation, highintensity focused ultrasonography, or laser therapy were introduced and some have shown promising results [5]. However, they have still limited evidence and only cryoablation and VAE have received FDA approval [5]. In the future study, systematic review for these procedures would be needed.

Conclusions
In conclusion, VAE for benign breast lesions showed favorable outcomes with respect to complete resection and complications. This meta-analysis suggested that VAE for low-risk benign breast lesions is a reasonable option for both diagnostic and therapeutic purposes. However, a limited number of comparative studies on open excision have weakened the strength of evidence. More comparative prospective studies are required to estimate the true effect size.