Clinical practice guidelines for visualized percutaneous breast tissue clips: Chinese Society of Breast Surgery (CSBrS) practice guideline 2021



## Indications of tissue clips
Level of evidence Strength of recommendation 1. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Indications for primary breast lesion 1.1. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Non-palpable suspicious breast lesion, for surgical biopsy [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] II A 1.1.2 Non-palpable breast cancer, for breastconserving surgery [bib_ref] Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical..., Rahusen [/bib_ref] [bib_ref] Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection..., Corsi [/bib_ref] I A

## 1.1.3
Breast cancer for neoadjuvant therapy and breastconserving surgery [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] I A 1.2 Indications for axilla lymph node 1.2. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Pathologically confirmed metastatic axillary LN (pN1), for neoadjuvant therapy [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] I A

# Discussion
With the widespread screening for breast cancer, detected nonpalpable breast lesions have been increased. [bib_ref] Intraoperative margin management in breast-conserving surgery: a systematic review of the literature, Gray [/bib_ref] Clip placement in nonpalpable suspicious breast lesions could provide help in follow-up and surgical biopsy. [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] The expert panel recommended the clip placement in nonpalpable breast suspicious lesions as one indication.
Accurate localization of nonpalpable breast cancer is a prerequisite for breast-conserving surgery, whereas clip placement and localization could increase negative margin rate to 90%, [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] and reduce the secondary resection. [bib_ref] Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical..., Rahusen [/bib_ref] [bib_ref] Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection..., Corsi [/bib_ref] The expert panel recommended the clip placement and perioperative poisoning in nonpalpable breast cancer intended for breast-conserving surgery as one indication.
In breast cancer neoadjuvant therapy, the clinical complete remission rate could reach 20% to 57%. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] Therefore, residual lesion re-localization after neoadjuvant therapy is important. Retrospective studies showed that clip placement at primary breast cancer before neoadjuvant therapy helped localize tumor intraoperatively and improve the negative surgical margin rate. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] Besides, the 5-year local recurrence rate was lower in the clipped group than in the control. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] The expert panel recommends the clip placement for primary breast cancer in neoadjuvant patients, especially planned for breast-conserving surgery.
Functional axillary LN dissection has received increasing attention recently. The ACOSOG Z1071, MARI, and ILINA trials have shown the feasibility of the targeted axillary dissection (TAD) technique, suggesting that the removal of sentinel and clipped LNs could reflect the axillary LNs status (false negative rate/FNR 2%-7%) and reduce the incidence of postoperative upper limb lymphedema. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] [bib_ref] Improving the accuracy of axillary lymph node surgery in breast cancer with..., Plecha [/bib_ref] The expert panel recommends clip placement to label the pathologically confirmed metastatic axillary LN (pN1) before neoadjuvant therapy, providing an opportunity for TAD.
The contraindications to US or MMG-guided clip placement for breast lesion and axillary LN should be based on the preoperative evaluation principles of breast lesion and regional LN biopsy, with reference to published exclusion criteria in clinical trials. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] The expert panel recommends the contraindications for clip placemen at Recommendation 2.
US-guided clip placement has been reported to be more accurate than X-ray-guided placement. [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] The expert panel preferred US-guided clip placement, with X-rayguided placement as an optional method. Regarding the number of clips to be placed, which should balance localization accuracy and medical cost, [bib_ref] Intraoperative ultrasound guidance with an ultrasound-visible clip: a practical and cost-effective option..., Konen [/bib_ref] [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] the expert panel recommended one clip for each primary breast lesion or metastatic axillary LN.
Due to the small size of clips, intraoperative position failure and loss of clips have been reported in 5% to 20% of cases. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] Considering the clinical operability and accessibility in China, the expert panel recommended the use of guide wires or dyes for preoperative assisted clip localization, and isotopic tracers could be used when available. Intraoperative resected specimens need to be reexamined, and the expert panel recommends the use of radiographic imaging for intraoperative clip confirmation.
Regarding the timing of clip placement, delayed clip placement in primary breast lesions after 2-cycle of effective neoadjuvant therapy may achieve some health- [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A 2.2 Concomitant severe bleeding or coagulation disorders [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A

## 2.3
The presence of breast local infection or adjacent to the breast prosthesis [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A Number of clips placed 3.1.1 One placed in the center of primary breast lesion [bib_ref] Intraoperative ultrasound guidance with an ultrasound-visible clip: a practical and cost-effective option..., Konen [/bib_ref] [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] II A 3.1.2 One placed in the center of metastatic axillary LN [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A 3.2 Imaging-guided approaches for clip placement 3.2.1 Ultrasound-guided placement [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] [bib_ref] Ultrasound-guided segmental mastectomy and excisional biopsy using hydrogel-encapsulated clip localization as an..., Gentile [/bib_ref] I A 3.2.2 X-ray-guided placement [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] I A

## 3.3
Preoperative clip localization methods 3.3.1 Guide wire [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] [bib_ref] Wire guided localisation for targeted axillary node dissection is accurate in axillary..., Balasubramanian [/bib_ref] I A 3.3.2 Dye [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] I A 3.3.3 Isotopic tracer [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] I A 3.4
Intraoperative clip confirmation 3.4.1 Intraoperative radiography [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] I A

## 3.5
Timing of clip placement in neoadjuvant therapy 3.5.1 Before neoadjuvant therapy following pathological confirmation of primary breast cancer lesion [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] I A 3.5.2 Before neoadjuvant therapy following pathological confirmation of metastatic axillary LN [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A LN: Lymph nodes.
Chinese Medical Journal 2021;134 [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] www.cmj.org economics advantages, [bib_ref] Influencing factors of placement and removal of breast tissue marker clips in..., Yizhou [/bib_ref] but further confirmation is needed from prospective studies. For metastatic axillary LN, published studies indicated that clip placement needed before neoadjuvant therapy. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] The expert panel recommends clip placement in pathologically confirmed primary breast cancer and metastatic axillary LN before neoadjuvant therapy.
Appendix 1: Technical guidelines for visualized percutaneous breast tissue clip placement, http://links.lww.com/ CM9/A624.

## Conflicts of interest
The expert committee for these guidelines declares no conflict of interest.
These guidelines are a reference for breast disease specialists in clinical practice. However, the guidelines are not to be used as the basis for medical evaluation, and do not play an arbitrating role in the handling of any medical disputes. The guidelines are not a reference for patients or nonbreast specialists. The Chinese Society of Breast Surgery assumes no responsibility for results involving the inappropriate application of these guidelines and reserves the right to interpret and revise the guidelines.
List of Committee members (In alphabetical order by surname): Zhong-Wei Cao, Yuan-Jia Cheng, De-Tian