The Egyptian Journal of Radiology and Nuclear Medicine 49 (2018) 1163–1168

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The Egyptian Journal of Radiology and Nuclear Medicine

journal homepage: www.elsevier.com/locate/ejrnm

Original Article

Cost-effectiveness of ultrasound-guided surgical clips placement for breast T

cancer localization prior to neoadjuvant chemotherapy
⁎
Ahmed H. Soliman, Ahmed M. Osman
Radiology Department – Faculty of Medicine, Ain Shams University, Cairo, Egypt

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: To evaluate the outcome and the cost value of surgical clips use as guidance for breast cancer loca-
Surgical clips lization in patients prepared for neoadjuvant chemotherapy (NAC).
Ultrasound-guided Methods: A prospective study of 43 patients confirmed histopathologically to have breast cancer and prepared to
Breast cancer receive pre-operative NAC. Surgical clips were inserted via US guidance. The patients were followed up by
Neoadjuvant chemotherapy
mammography and US before surgery to evaluate the treatment response meanwhile, assessment of clips lo-
cation, migration and complications. The overall cost of clips was also calculated.
Results: Only 32 patients completed the study; the mean time interval was 32 weeks ± 2 weeks between the clip
insertion date and the surgery. The number of the inserted clips was 34 surgical clips. Only two cases showed
positive migration yet with no evidence of other complications occurred in our study patients. The average cost
of the surgical clips was 145 ± 20 Egyptian pounds (average 8–9 US$).
Conclusion: Surgical clips can be used safely to replace the usual commercial markers in the localization of breast
cancer before NAC. They showed effective results with no complications, don't interfere with the patients'
imaging and of the significant low cost compared to the commercial ones.

1. Introduction
Breast malignancy is one of commonest tumor affecting the women,
representing 31% of overall tumors affecting the female population.
Also, 10% of the females have the risk of developing breast cancer at
some stage in their life. The incidence and mortality of breast cancer are
directly related to the female age [1,2].
The increase in breast cancer incidence is accompanied by an in-
crease in the clinician and researchers concerns regarding the im-
provement of diagnostic and therapeutic tools [3].
The treatment options and the characteristics determining the
therapy choice in patients with primary advanced breast cancer are
becoming variable. New targeted therapies are now available in com-
bination with the usual chemotherapy exerting dramatic change in the
treatment strategy of breast cancer over the last 10 years [4].
Neoadjuvant chemotherapy (NAC) made a revolution in the man-
agement of patients with operable and inoperable breast cancer.
Multiple studies demonstrated the significant response of the primary
breast lesion to the NAC with success rates reaching to about 80–90%
[5,6].
The value of NAC appeared in decreasing the mortality incidence,
changing the surgical approach as the use of breast conservative sur-
gery and convert the inoperable lesions into operable ones [5,7,8].
The response of breast cancer to NAC assessed using pathologic
complete remission (pCR). The American Food and Drug
Administration (FDA) made a worldwide large meta-analysis study on
approximately 12,000 patients. The prognostic relevance of pCR for
recurrence-free survival and overall survival (HR 0.48, p < 0.001) was
confirmed. So, the NAC now becomes a new challenging concept for the
surgeons and the radiologists as this dramatic pCR hinder proper lo-
calization of any residual tissue by the surgeon or even make a sa-
tisfactory reconstructive surgery [9].
To avoid these complications, the international breast cancer spe-
cialist panel in 2006 and 2010 alarming the importance of radiopaque
marker localization into the breast tumor before NAC start. The
radiopaque marker implant in the tumor bed became a safe and re-
commended method for tumor localization before surgical resection or
even reconstructive surgery in patients who received NAC [10,11].
In a study by Edeiken et al., the metallic markers were only re-
maining with a complete absence of the original tumor in 47% of the
studied patients with cancer breast [12].
Application of breast markers adds more progress in the field of

Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine.
⁎
Corresponding author.
E-mail address: dr_aosman@med.asu.edu.eg (A.M. Osman).

https://doi.org/10.1016/j.ejrnm.2018.06.010
Received 14 November 2017; Accepted 20 June 2018
Available online 15 September 2018
0378-603X/ © 2018 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
A.H. Soliman, A.M. Osman The Egyptian Journal of Radiology and Nuclear Medicine 49 (2018) 1163–1168

Fig. 1. CONSORT flow diagram showing number of patients at each phase of the study.

Table 1
Demonstrates the number and the percentage of the patients according to the
ACR classification as well as the response to the NAC.
Number of patients Incidence (%)

ACR classification:
ACR 1 11 34.38
ACR 2 15 46.87
ACR 3 6 18.75
Response to NAC:
Partial 12 37.50
Complete 14 43.75
Stationary 6 18.75

interventional radiology in concerns with breast cancer as such clips are

inserted using the ultrasound-guided technique [13]. Many types of
commercial clips and markers are widely available and used prior to
NAC. However, they are relatively expensive encouraging the re-
searchers to study less expensive alternatives such as standard titanium
Fig. 2. A female patient 38 years old presented with left breast upper outer
surgical clips especially in the third world contraries where the health
quadrant malignant mass lesion as seen in A and B and diagnosed histopatho-
expenses are of high load for the patients [14].
logically to have invasive duct carcinoma (IDC) grade II. The decision was to
Our study aimed to investigate the feasibility of using surgical clips take NAC before conservative surgery with the positive clinical response made
as tumor localizations markers studying their effectiveness, complica- the mass not more palpable for the surgeon indicating wire application. C image
tions, and influence on the imaging assessment after NAC, and finally shows the excised malignant specimen with the wire noticed inside (black
the cost of such procedure. arrow indicating the wire and the black star indicating the mass) (the nipple is
covered by white color tag).

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Fig. 3. A female patient 53 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and
diagnosed histopathologically to have invasive duct carcinoma (IDC) grade II with no ductal carcinoma in situ (DCIS). The decision was to take NAC before
conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C
images representing the mammography images after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive
response to the NAC. The rest of the breast categorized as ACR 1.

2. Patients & Methods 2.3. US-guided clip placement:

2.1. Patients • Ultrasound machine: we used Logic P5 ultrasound machine (GE –

A prospective study conducted on 43 patients who came to the
Radiology Department – Intervention unit - Ain Shams University
Hospital presented with pathologically proved malignant breast lesion
(BIRAD VI). They were prepared to receive NAC before surgery and in
need for clip placement for tumor localization over the period from
January 2016 to August 2017. Informed written consents were taken
from all patients according to the ethical committee regulations.
The decision of clip placement was made by a multidisciplinary
team including a surgeon, oncologist, radiologist and pathologist after
patients' agreement. The maneuver was done by consultant radiologist
with 3 years experience in the interventional radiology field.
2.2. Patient preparation
No specific preparation needed apart from bleeding profile. Patients
with a high bleeding profile or patients with no available histopatho-
logical data for the breast lesions were excluded from the study.
General Electric Healthcare - USA) during the surgical clip insertion
and during the follow-up.
• Mammography machine: we used Mammomat 1000 mammography
machine (Siemens Medical Solutions Company - Germany) during
follow up.
• Technique: All patients were placed in adequate position according
to the site of the lesion with both arms elevated uncovering the neck
and breast regions. Adequate localization of the breast lesion was
done using the US followed by skin sterilization of the affected
breast and the expected site of entrance in a circumferential manner.
Local anesthesia (Lidocaine 1%) was applied with a dose 10 ml/kg
being infiltrated along the skin, epidermal layer as well as along the
expected track of needle entrance. A small skin incision was done
using scalpel blade size 10. Disposable Guillotine biopsy needle 16 G
x 20 cm GTA® was used, where we removed the needle stylet and fit
single GRENA® surgical titanium ligation clips into the bore of the
needle transducer. The needle was advanced along the anesthetized
track directed to the targeted mass, then the stylet was used to di-
ploy the titanium clip 2–4 mm after initial penetration of the mass
into the center of the lesion, followed by removal of the whole
biopsy needle with the stylet. The sonomammography examination

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o The surgical clips location in relation to the breast lesion either

“within” or “outside” the tumor with an assessment of the degree of
migration compared to the last mammography done before NAC.
o The degree of artifact exerted by the inserted clips and to what
extent interfering with the image interpretation and judgment.

The patients were sent back to the Intervention radiology

Fig. 4. The ultrasound of the same case of Fig. 2 done after clip insertion
showing the surgical clips within the tumor mass (white arrow) with no sig-
nificant artifact interfering with the image interpretation.
Department prior to surgery to assess whether the lesion disappeared or
shrunken and not more palpable to the surgeon for wire localization
over the already placed clips after confirmation no migration.
The surgical specimens were examined by frozen section intra-op-
eratively and paraffin block post surgery with an assessment of the clips
localization. The feedback from the surgeons and pathologist were
collected for all patients about the adequate localization of the surgical
clips and presence of migration in any case.

was done after finishing to ensure the adequate location of the clips.
The wound was covered using Steristrips cover. The whole cost of
the procedure was calculated and recorded.
2.4. Follow up after NAC
The patients were followed up after finishing the course of the NAC
and before the surgery by both US and mammography with the calcu-
lation of the time gap between clip placement and the time of surgery.
The follow up was done via two experts radiologist in the field of breast
imaging with experience at least five years and not involved in the
study. The following were assessed during the pre-operative follow up:
2.5. Analysis of data
the analysis of data was done using IBM SPSS statistics (V. 24.0, IBM
Corp., USA, 2016). Quantitative and qualitative data are expressed as
mean ± SD, frequencies, and percentages. The cost of surgical clips
was compared to the commercial clips.
3. Results
32 cases out of 43 cases completed the study till the surgery level
(Fig. 1). 2 patients were excluded from the study due to inadequate
bleeding profile and nonavailable histopathological data about the

Fig. 5. A female patient 48 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and
diagnosed histopathologically to have infiltrative ductal carcinoma grade II with decision was to take NAC before conservative surgery. B images show the CC (B1)
and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images
after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive response to the NAC. The rest of the breast
categorized as ACR 1.

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Fig. 6. A female patient 40 years old presented with right breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and
diagnosed histopathologically to have lobular carcinoma with decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views
of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed
complete response of the tumor to the NAC with radiological disappearance of the tumor. C images shows the surgical clips are still seen in the same site compared to
the previous studies (B).

breast lesion. 4 patients refused to participate in such study and another
2 didn't attend the date of US-guided clip placement. 3 patients were
lost during the follow-up stage.
The age of the patients ranged from 28 to 76 years old with the
mean age ± SD was 51.28 ± 12.2 years. ACR classification of patients
revealed that 15 patients classified as ACR 2 representing 46.87% of the
cases (Table 1). Two cases showed bilateral malignant breast lesions
while the others showed one lesion in both breasts.
We used 34 surgical clips to localize 34 lesions within 32 patients.
The mean time interval between the insertion date to the time of sur-
gery was 32 weeks ± 2 week. 14 cases showed pCR between the stu-
died patients representing 43.75% while only 6 cases showed stationary
course after NAC representing 18.75% (Table 1). 26 patients showed
clinical improvement and lesions became no more palpable after NAC
representing 81.25% underwent guide wire application before the time
of surgery (Fig. 2).
Only two cases representing 6.25% showed positive migration on
preoperative follows diagnosed when comparing the follow-up mam-
mogram with the old one done before the start of NAC. This is also
confirmed by the surgeons' and pathologists' feedback who recorded
absent of migration in any other cases. These two cases were categor-
ized as patients with breast type ACR 1 with predominant fatty ele-
ments (Figs. 3–6). The radiologists responsible for follow up recorded 3
cases with ultrasound artifacts representing 9.4% yet not interfering
with images interpretation. No other complications recorded.
The mean cost of surgical clips application was 145 ± 20 LE
Egyptian pounds (about 8–9 US $) with the average cost of the
needle = 130 LE Egyptian pounds and the clip = 15 LE Egyptian
pounds
4. Discussion
This study demonstrates the significant value of using metallic
surgical clips in breast tumor localization in patients undergoing NAC
before surgical treatment with a significant reduction in total cost when
compared to the commercial clips without significant complications.
NAC is a standard pre-operative treatment for breast cancer, espe-
cially in locally advanced cases. It is used to convert the inoperable
masses into operable one with fewer complications and better cosmetic
outcome [14].
Because the unexpected response of the tumor to the NAC which
may be adequate up to complete radiological response associated with
difficult identification of the tumor site by the surgeon during surgery
raises the use of radiopaque markers before NAC start [7,11,15]. In our
study, there were 14 cases had a complete radiological response after
NAC. This is close to Edeiken et al, who found 47% complete response
yet considered high in controversy to other studies such as Dash et al.
who found 21.4% out of 28 patients [12,16].

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A.H. Soliman, A.M. Osman
In this study, we tried to use the surgical clips instead of the com-
mercial breast markers trying to reduce the cost of this procedure. This
was done using US-guided semi-automated technique using a guiding
needle (Disposable Guillotine biopsy needle). Multiple studies used the
similar semi-automated technique [14,15] which is considered a safe
and easy procedure similar to the core needle biopsy done completely
under real-time ultrasound and accurately identifying the desired lo-
cation for the surgical clips insertion with an estimated time of the
whole procedure about 7–10 min. This is in controversy to Lee et al.
(2005) and Uematsu (2007) who used an automated gun for clip pla-
cement [17,18]. The disadvantage of the automated technique is the
relatively high cost when compared with the use of disposable biopsy
needle.
No complications occurred among our study group apart from 2
cases reported having positive migration during preoperative follow up
when comparing the preoperative mammogram with the one done
before the start of NAC. These two cases observed to have partial re-
sponse to the NAC and categorized as patients with breast type ACR 1
with predominant fatty elements which may be an explanation for the
occurrence of this complication due to redundant breast tissue inter-
fering with the fixation of surgical clips especially after decrease in the
size of the mass soft tissue which is an important factor for clip fixation
and stability. This result wasn't in agreement with Masroor et al and
Youn et al who studied the feasibility of surgical clips use as breast
marker and found no cases with clip migration [14,15]. The incidence
and occurrence of clip and breast marker migration were discussed in a
lot of research works [19,20,21].
During follow up, only 3 cases recorded artifact in the US yet not
interfering with the judgment upon the tumor assessment and response
to NAC. This is similar to a lot of studies which concluded that the
application of surgical clips does not interfere with the radiological
assessment of the lesion [11,16,22,23].
Our study revealed that the average cost of the single surgical clip
for each patient was 145 ± 20 LE Egyptian pounds at the time of the
study which is almost equal to 8–9 US$. This is was almost in agreement
with Masroor et al study done in Aga Khan University Hospital,
Pakistan since 2014 who found the cost of surgical clips about 9 US$
[14]. Also, this result was close to the study done in South Korea since
2015 with estimated cost was 10 US$ per clip [15].
This is of much low cost when compared to the commercial breast
markers of different companies with an estimated price range for
clip = 75–200 US$ (average 90 US$) [15]. So, using surgical clips in
our study saved about 80–82 US$ for each clip placement when cal-
culated to our study group (34 × 80 US$ = 2720 US$). So, the use of
surgical clips of the highly significant low cost compared to the com-
mercial breast marker especially in developing countries as Egypt.
Finally due to the adequate response to NAC, 26 cases in our study
represented 81.25% had nonpalpable breast masses as mentioned in
result section after NAC and subsequently, the decision was to apply
breast wire localization for the surgeon over the previously inserted
surgical clips. This is the same technique explained by multiple authors
as Corsi et al and Sajid et al. [24,25].
5. Conclusion
The use of breast marker is mandatory before NAC start with the use
of surgical clips is of high value being effective with no evidence of
complication and of course of the significant low cost compared with
the commercial breast clips.
6. Limitations
We didn't follow up the patients using MRI to study the artifact
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The Egyptian Journal of Radiology and Nuclear Medicine 49 (2018) 1163–1168
effect of the surgical clips on the MRI image and whether it will in-
terfere with the image quality and the judgment of the response to the
NAC. The non-use of MRI was due to the high cost as well as the long
waiting lists. So, further studies needed including the MRI during pre-
operative follow up after clip placement. Also, multi-centric study is
needed to study this technique over larger number of patients.
References
[1] Guraly M, Sahin A. Benign breast diseases: Classification, Diagnosis, and
Management. Oncologist 2006;11(5):435–49.
[2] VanderWalde A, Hurria A. Early breast cancer in the older woman. Clin Geriatr Med
2012;28:73–91.
[3] Guo Y, Cai Y, Cai Z. Differentiation of clinically benign and malignant breast lesions
using diffusion-weighted imaging. J Magn Reson Imaging 2002;16(2):172–8.
[4] Gerber D. Targeted therapies: A new generation of cancer treatments. Am Fam
Physician 2008;77(3):311–9.
[5] Adel-Razeq H, Marei L. Current neoadjuvant treatment options for HER2-positive
breast cancer. Biologics 2011;5:87–94.
[6] Lobbes MB, Prevos R, Smidt M, et al. The role of magnetic resonance imaging in
assessing residual disease and pathologic complete response in breast cancer pa-
tients receiving neoadjuvant chemotherapy: a systematic review. Insights Imaging
2013;4:163–75.
[7] Kaufmann M, Von Minckwitz G, Bear H, et al. Recommendations from an interna-
tional expert panel on the use of neoadjuvant (primary) systemic treatment of op-
erable breast cancer: new perspectives 2006. Ann Oncol 2007;18:1927–34.
[8] Kim Z, Min SY, Cs Yoon, et al. The basic facts of Korean breast cancer in 2011:
results of a nationwide survey and breast cancer registry database. J Breast Cancer
2014;17:99–106.
[9] Wang-Lopez Q, Chalabi N, Abrial C, et al. Can pathologic complete response (pCR)
be used as a surrogate marker of survival after neoadjuvant therapy for breast
cancer? Critic Rev Oncol/Hematol 2015;95:88–104.
[10] Cardoso F, Loibl S, Pagani O, et al. The European society of breast cancer specialists
recommendations for the management of young women with breast cancer. Eur J
Cancer 2012;48(18):3355–77.
[11] Oh JL, Nguyen G, Whitman G, et al. Placement of radiopaque clips for tumor lo-
calization in patients undergoing neoadjuvant chemotherapy and breast conserva-
tion therapy. Cancer 2007;110(11):2420–7.
[12] Edeiken BS, Fornage BD, Bedi DG, et al. US-guided implantation of metallic markers
for permanent localization of the tumor bed in patients with breast cancer who
undergo preoperative chemotherapy. Radiology 1999;213:895–900.
[13] Plantade R. Interventional radiology: the corner-stone of breast management. Diagn
Interventional Imaging 2013;94(6):575–91.
[14] Masroor I, Zeeshan S, Afzal S, et al. Outcome and cost-effectiveness of ultra-
sonographically guided surgical clip placement for tumor localization in patients
undergoing neoadjuvant chemotherapy for breast cancer. Asian Pac J Cancer Prev
2016;16(18):8339–43.
[15] Youn I, Choi SH, Kook SH, et al. Ultrasonography-guided surgical clip placement for
tumor localization in patients undergoing neoadjuvant chemotherapy for breast
cancer. J Breast Cancer 2015;18(1):44–9.
[16] Dash N, Chafin S, Johnson R, et al. Usefulness of tissue marker clips in patients
undergoing neoadjuvant chemotherapy for breast cancer. Am J Roentgenol
1999;173:911–7.
[17] Lee SY, Kook SH, Kwag HJ. The results and usefulness of marker clip placement
after ultrasound-guided mammotome excision of breast lesion. J Korean Radiol Soc
2005;52:207–13.
[18] Uematsu T. Commercially available titanium clip placement following a sono-
graphically guided core needle biopsy of breast. Breast J 2007;13:624–6.
[19] Esserman L, Cura M, DaCosta D. Recognizing pitfalls in early and late migration of
clip markers after imaging-guided directional vacuum-assisted biopsy.
Radiographics 2004;24(1):147–56.
[20] Le-Petross H, Hess K, Knudtson J, et al. Effect of mammography on marker clip
migration after stereotactic-guided core needle breast biopsy. Curr Probl Diagn
Radiol 2017;46(6):410–4.
[21] Jain A, Khalid M, Qureshi M, et al. Stereotactic core needle breast biopsy marker
migration: an analysis of factors contributing to immediate marker migration. Eur
Radiol 2017;27(11):4797–803.
[22] Baron LF, Baron PL, Ackerman SJ, et al. Sonographically guided clip placement
facilitates localization of breast cancer after neoadjuvant chemotherapy. Am J
Roentgenol 2000;174:539–40.
[23] Genson CC, Blane CE, et al. Effects on breast MRI of artifacts caused by metallic
tissue marker clips. Am J Roentgenol 2007;188:372–6.
[24] Corsi F, Sorrentino L, Sartani A, et al. Preoperative localization and surgical margins
in conservative breast surgery.
[25] Sajid MS, Parampalli U, Haider Z, et al. Comparison of radioguided occult lesion
localization (ROLL) and wire localization for non-palpable breast cancers: a meta-
analysis. J Surg Oncol 105(8):852–8.