Neoadjuvant chemotherapy (NAC) is widely considered in breast cancer patients who are potential candidates for adjuvant chemotherapy [1]. NAC has been proven to increase overall survival and disease-free survival, while providing an increased chance of being able to perform breast-conserving surgery (BCS) [2]. The safety and efficacy of breast tissue marker insertion before NAC are now also commonly accepted. Markers are used to demarcate the biopsy area because a residual tumor after NAC may be clinically occult and further surgery may be required pending a margin status review by pathology. The placement of these markers is more accurately done under ultrasound (US) guidance than under stereotactic guidance [3,4].

When BCS is considered, needle localization is necessary for marker insertion prior to surgery. A marker may be clearly visible on US if it is present within a hypoechoic lesion, and US-guided localization is preferred because US-guided biopsy has several advantages over stereotactic biopsy [5]. However, in patients with pathologically complete response (pCR), the lesions might have dramatically shrunk to the point of not being visible on US. Well-visible breast tissue markers need to be placed in these lesions in order to enable better surgical options and outcomes [3,6].

While Fajardo et al. [7] introduced the benefits of the microcoil as a breast marker, Thomassin-Naggara et al. [8] introduced surgical clips inserted with an 18-gauge spinal needle. Before many types of commercial breast tissue markers were available for patients undergoing NAC, surgical clips were used as breast markers. Breast tissue markers can be categorized into commercial metallic markers and markers with surrounding material. Commercial metallic markers are simply made of 2- to 3-mm pieces of titanium or stainless steel, and are the most commonly used markers today. Markers with surrounding material were developed for long-term visibility, and the embedding materials can be collagen, polylactic acid, polyglycolic acid or starch pellets, or hydrogel. These markers have several advantages. First, they fill the space cavity, thereby decreasing the risk of marker migration. Second, the markers have a hemostatic effect because they place direct pressure on adjacent tissue. Third, they enhance visibility on US. However, a previous study reported that although markers with a microfiber pad were clearly seen on US just after insertion, visibility greatly decreased after 6-8 weeks, making them ineffective as breast markers for patients who have undergone NAC [8]. The effectiveness of surgical clip placement has been studied before for breast cancer, but insufficient studies have compared different types of breast tissue markers after NAC [9]. It is necessary to investigate which types of breast tissue markers are more visible on specific imaging modalities, because such knowledge would help radiologists determine the most suitable type of breast tissue marker for each patient before insertion.

The objective of this study was to compare the visibility of breast tissue markers after NAC on US and to analyze whether the type of breast tissue marker affected the choice of localization method.

This retrospective study was approved by the Institutional Review Board of our institution with a waiver of informed consent.

In 148 patients (median age, 51 years; range, 26 to 72 years) who underwent BCS after localization, three types of breast tissue markers were inserted in 153 breast lesions that demonstrated pCR at surgery: 56 LigaClip markers, 61 Cormark markers, and 36 UltraClip markers. At the US evaluations after NAC, a residual tumor lesion was seen in 111 cases (72.5%), but not in the remaining 42 cases (27.5%). Markers were seen on US in 127 cases overall (83.0%), and in 30 cases (71.4%) with no residual lesion visible on US.

NAC is an internationally recognized treatment option for breast cancer. The effect of NAC is dramatic in some patients, and the proportion of patients achieving pCR has been reported to be as high as 32.9% in some studies [10]. However, an excellent response to NAC can cause difficulties in localization because residual lesions are not clearly visible on images [3,11-13]. Dash et al. [11] reported that no residual tumors were visible on 35.7% of mammograms (10 of 28). Furthermore, Edeiken et al. [3] reported that 46.9% of lesions (23 of 49) were not visualized on US or mammography after NAC. In such cases, localization is almost impossible without a breast tissue marker. As localization is needed to decide the extent of surgery and to help the pathologist identify the main lesion, the implantation of breast tissue markers is important for breast cancer patients who undergo NAC.

The visibility of the breast tissue marker is important for localization. US, mammography, and magnetic resonance imaging (MRI) can all be used for localization, and almost all markers are visible on mammography and MRI. However, radiation hazards need to be considered with regard to mammogram-guided localization, and MRI-guided localization is difficult to perform due to excessive time and cost. Thus, US is the most feasible method for localization, but breast tissue markers have relatively inferior visibility on US compared to their visibility on mammography and MRI. In our study, 28.6% of the markers (12 of 42) were not seen on US when no residual tumor was visible on US. This kind of non-visibility of breast tissue markers poses a clinical challenge.

As far as we know, very few studies have compared the visibility of different types of breast tissue markers [14]. Our study shows that the visibility of LigaClip and Cormark may be superior to that of UltraClip, although the use of surgical clips has decreased in recent years due to the introduction of commercial breast markers. LigaClip is thicker than other markers, which might be why it is clearly visible on US (Fig. 3). Cormark is a marker in which a metal clip is surrounded by collagen. The surrounding collagen provides extra contrast, allowing better visibility of the marker (Fig. 4). UltraClip is a marker composed of a non-absorbable polyvinyl alcohol (PVA) polymer with a metallic clip. Our results are broadly similar to those reported by Sakamoto et al. [15], who indicated that 60% of UltraClip markers were visible. The PVA polymer does not help enhance visibility, so fewer than 50% of UltraClip markers were visible on US when residual lesions were not visible on US in our study (Fig. 5). However, the surrounding collagen helps enhance visibility, so more than 80% of Cormark markers were visible. Therefore, radiologists should consider the fact that some markers may not be visible after NAC if the tumors show a good response to NAC before inserting the marker. In our study, only 34% of cancers (246 of 717) reached pCR status, and among them, only 42 cases (27.5%, 42 of 153) were not visible on US after NAC. Because of the relatively small number of cases with no visible residual tumors, our study might not have an immediate clinical impact at this time, but continuing developments and improvements in NAC and targeted therapy may increase the number of pCR cases, so that our findings may gain more clinical importance in the future.

There are several limitations of this study. First, our study was retrospective, so selection bias may have been present. Second, the number of cases with no visible residual tumors was relatively small, although marker visibility was especially important in those cases. Finally, the visibility of the markers was evaluated on the basis of imaging reading reports written by many radiologists, so interobserver variability may have been present.

In conclusion, the type of breast tissue marker affected the visibility of the marker on US, and more importantly, the localization method used in breast cancer patients who underwent NAC. Thus, the type of breast tissue marker should be considered before clip insertion.