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Randomized Prospective Evaluation of a Novel Technique for Biopsy or Lumpectomy of Nonpalpable Breast Lesions: Radioactive Seed Versus Wire Localization

From the Departments of Surgery (RJG, CS, KN, ED, JF, EP, GW, LB, CEC) and Radiology (CB), Comprehensive Breast Cancer Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, Florida.

Correspondence: Address correspondence and reprint requests to: Charles E. Cox, MD, Director, Breast Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612; Fax: 813-979-9779.

	ABSTRACT

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Background: Standard wire localization (WL) and excision of nonpalpable breast lesions has several shortcomings.

Methods: Ninety-seven women with nonpalpable breast lesions were prospectively randomized to radioactive seed localization (RSL) or WL. For RSL, a titanium seed containing ¹²⁵I was placed at the site of the lesion by using radiographical guidance. The surgeon used a handheld gamma detector to locate and excise the seed and lesion.

Results: Both techniques resulted in 100% retrieval of the lesions. Fewer RSL patients required resection of additional margins than WL patients (26% vs. 57%, respectively; P = .02). There were no significant differences in mean times for operative excision (5.4 vs. 6.1 minutes) or radiographical localization (13.9 vs. 13.2 minutes). There were also no significant differences in the subjective ease of the procedures as rated by surgeons, radiologists, and patients. All WLs were carried out on the same day as the excision, whereas RSL was performed up to 5 days before the operative procedure.

Conclusions: RSL is as effective as WL for the excision of nonpalpable breast lesions and reduces the incidence of pathologically involved margins of excision. RSL also reduces scheduling conflicts and may allow elimination of intraoperative specimen mammography. RSL is an attractive alternative to WL.

Key Words: Wire localization • Breast biopsy • Radioguided surgery

	INTRODUCTION

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Because of increased mammographical screening and improved imaging techniques, there has been a rapid increase in the detection of nonpalpable breast lesions. This has resulted in a greater proportion of lumpectomies and operative breast biopsies requiring radiographical localization. The current standard technique for preoperative localization of these lesions is wire localization (WL), whereby a thin, hooked wire is guided through the skin to the lesion and the surgeon uses the wire to help guide the excision. This technique has several problematic features. First, the ideal skin entry site for the wire so the radiologist can accurately position its tip at the lesion is often distant from the ideal skin incision site for the surgeon. This results in extensive dissection or perhaps compromise in the positioning of the incision. In addition, the surgeon must base the incision site and the direction of dissection on the mammographs, with the wire serving mainly to confirm that he or she has not judged incorrectly. Another reported downside is that the thin wire can be transected,¹ in which case all guidance to the lesion is lost and foreign bodies can be left within the breast. Finally, because the wire comes outside the patient’s body, displacement of the wire has occurred during confirmatory mammography or patient transfers,^2–4 and the excision must occur on the same day as the localization.

Several modifications of the WL technique have been proposed to help minimize some of these problems,^5–8 and some have used intraoperative ultrasound in select cases.⁹ Gennari et al.¹⁰ reported radioguided breast biopsy with ^99mTc-labeled albumin. Unfortunately, this technique is cumbersome because the entire marker is not detectable by mammography or ultrasound, and it uses the same radioactive marker as that used for sentinel lymph node (SLN) biopsy. The aim of this study was to perform a randomized, prospective trial to evaluate a new technique that eliminates the disadvantages of WL and these alternative techniques.

	METHODS

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Patients
After an initial pilot study of 25 cases with seed localization,¹¹ a randomized prospective trial was initiated. Between November 1999 and February 2001, 106 women with nonpalpable breast lesions detected by mammography, ultrasonography, or both were randomized to WL or radioactive seed localization (RSL). During randomization of the first 30 patients, only women undergoing biopsy for an undiagnosed lesion were included. Subsequently, patients with a carcinoma diagnosed by percutaneous techniques were also included in the study population. Written informed consent was obtained before the procedures from all patients, and the local institutional review board approved the protocol. Four women were excluded after randomization because at the time of localization, the lesion was no longer visible on mammogram or ultrasound. Five women were excluded because of missing data items. This left 97 assessable women in the final study group: 51 in the RSL group and 46 in the WL group.

Fifty-six patients (58%) had suspicious lesions that were believed to be inappropriate for percutaneous biopsy techniques and therefore underwent localization for excisional biopsy. Forty-one patients (42%) had a confirmed diagnosis of breast cancer by core needle biopsy and underwent localization for lumpectomy. The radiographical lesions were calcifications in 42 patients (43%) and a density in 55 (57%).

Radioactive Seed
RSL was carried out with a titanium seed containing .29 mCi of ¹²⁵I. This amount of radioactivity is significantly less than that of a standard mammogram or chest radiograph. In a pilot study performed at our institution, the radiation exposure to the patient and medical staff was determined by radiation badges and rings and was found to comply with radiation exposure regulations. The titanium seed used is 4.5 x .8 mm and passes through a standard 18-gauge needle. It is the most widely used seed for prostate brachytherapy. Titanium combines low radiation absorption with excellent strength and tissue tolerance.^{12 125}I has a half-life of 60 days and is a 27-keV source of gamma radiation.¹³ Because of these characteristics, ¹²⁵I is an excellent gamma source to use in combination with the ^99mTc used for SLN biopsy. The 27-keV ¹²⁵I gamma source can be detected as a separate signal from the 140-keV ^99mTc source as long as there is sufficient energy to overcome the Compton effect scatter from the 140-keV source. We determined in a mastectomy specimen that .05 mCi or more of ¹²⁵I was sufficient to overcome the Compton effect from the standard injection of .45 mCi of ^99mTc-labeled sulfur colloid used for SLN biopsy.

Technique
WL was performed with standard techniques and used either mammographical or ultrasound guidance as deemed appropriate. For RSL, the nonpalpable lesion was likewise visualized with mammography or ultrasonography. The radioactive seed was placed within an 18-gauge needle that has had its tip occluded with sterile bone wax. The needle was then guided to the lesion, and a stilette was used to displace the radioactive seed through the bone wax and into the breast parenchyma at the site of the lesion. The needle was withdrawn, and the position of the seed was confirmed with mammography.

Up to 5 days later, the patient was taken to the operating room for excision of the lesion. A handheld gamma probe was set to detect a 27-keV source and was then placed over the anterior surface of the breast. The point of greatest activity marked the skin location directly overlying the seed and lesion. The incision was made at this site, and the gamma probe was used to guide the excision of the seed and lesion. Seed removal within the specimen was ensured by detecting the ¹²⁵I source of radioactivity within the excised specimen. Complete excision was confirmed by detecting no ¹²⁵I source remaining within the wound.

For purposes of this study, all specimens were taken to the radiology suite for specimen radiographs. The specimen was then transported to the surgical pathology suite, where imprint cytology was obtained for margin evaluation. All margins were marked with ink, and the seed and lesion were localized with a handheld gamma probe. The specimen was sectioned across the point of highest radioactivity to identify the seed and lesion. The seed was placed in a lead container and sent to a lead-lined storage site. The remaining specimen was then processed routinely.

SLN Biopsy
Those patients in both groups who underwent localization for a lumpectomy had an SLN biopsy performed at the same operation. This included patients with ductal carcinoma in situ. In all cases, a combined ^99mTc-labeled sulfur colloid and vital blue dye technique was used as previously described.¹⁴ The SLN biopsy was performed before excision of the primary lesion.

Data Collection and Analysis
All patients were randomly assigned to RSL or WL. Data were collected prospectively and entered into a computer database. The subjective difficulty of each procedure was ranked on a Likert scale from 1 (easiest) to 10 (most difficult) by the radiologist at the completion of localization, by the patient at the completion of localization, and by the surgeon at the completion of the excision. The margins of excision were considered pathologically involved by tumor if imprint cytology of the margins demonstrated malignant cells or if final histology demonstrated malignant cells <1 mm from any margin. Only lesions that proved to be malignant were included in the analysis of the rates of involved margins. All results for each group were compared by using the two-tailed t-test.

	RESULTS

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Fifty-one patients underwent RSL and 46 underwent WL. Among RSL patients, 27 (53%) had their localization for a breast biopsy and 24 (47%) for a lumpectomy. Twenty-nine WL patients (63.0%) underwent breast biopsy, and 17 (37%) underwent lumpectomy. The radiographical abnormalities and final pathologic diagnoses of the patients are listed in Table 1.

The suspicious lesion was retrieved in 100% of patients in each group. No significant migration of the localization device was observed in either group. The pathology staff was able to retrieve the radioactive seed and demonstrate the lesion in 51 of 51 (100%) RSL patients without the aid of a specimen radiograph, but with the use of a gamma probe, in a mean of 2.2 minutes. Among the WL patients, 46 of 46 (100%) lesions were identified with the aid of the specimen radiograph in a mean of 1.7 minutes (P = .12). The mean time required for radiographical localization was 14.0 minutes (range, 4–27 minutes) for RSL and 13.1 minutes (range, 3–25 minutes) for WL (P = .49). The mean time for operative excision of the lesion was 5.4 minutes (range, 2–15 minutes) for RSL and 6.1 minutes (range, 3–18 minutes) for WL (P = .28; Fig. 1). Fewer patients undergoing RSL had pathologically involved margins of excision than did those who had WL (26% vs. 57%, P = .02), despite the mean volume of tissue excised in the initial specimen’s being similar in both groups (55.7 ml for RSL, 73.5 ml for WL; P = .48; Fig. 2). The subjective ease of the procedure was not different between RSL and WL as ranked by the surgeons (2.95 vs. 2.97, P = .96), the radiologists (1.98 vs. 1.75, P = .63), or the patients (2.59 vs. 2.61, P = .97; Fig. 3).

View larger version (72K): [in this window] [in a new window]   FIG. 1. Mean times for radiographical guidance and operative excision in minutes. RSL, radioactive seed localization; WL, wire localization.

View larger version (74K): [in this window] [in a new window]   FIG. 2. Percentage of patients needing margin re-excision and mean volume of tissue excised in initial specimen (ml). RSL, radioactive seed localization; WL, wire localization.

View larger version (66K): [in this window] [in a new window]   FIG. 3. Mean ranking of the ease of the procedures (1–10; 1 = easiest, 10 = most difficult). RSL, radioactive seed localization; WL, wire localization.

The SLN was successfully identified in 30 of 31 RSL patients (97%) and in 22 of 22 WL patients (100%, P = .33). The single mapping failure patient in the RSL group failed to manifest any blue dye or detectable radioactivity within the axilla. There was a blue lymphatic vessel that was mapped to an internal mammary node, and this was collected. The node had no detectable radioactivity and was considered unreliable as the only SLN. Therefore, the patient was considered a mapping failure, and a complete axillary lymph node dissection was performed. The mean number of SLNs removed was 1.73 in the RSL group and 1.82 in the WL group (P = .81). Metastatic breast cancer was detected in the SLNs in 3 of 30 RSL patients (10.0%) and in 4 of 22 WL patients (18.2%, P = .42; Table 2).

	DISCUSSION

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The excision of nonpalpable breast lesions has become an increasingly prominent component of the practice of surgical oncologists. Because of the many disadvantages of WL, we developed a new technique to localize these lesions before excisional biopsy or lumpectomy. RSL has many logistical advantages over WL. Because the entry site of the seed is not an issue in the excision, the radiologist can choose the site that is best for precise placement without consideration of the surgical incision site. Likewise, because the surgeon can precisely locate the seed through the skin, the incision can be made at the point closest the lesion and thus avoid excessive dissection and tissue loss. The gamma probe also allows for constant reorientation to the seed and lesion throughout the procedure to help ensure that the lesion is centrally located within the specimen. Avoidance of dissection along a fine wire eliminates the possibility of wire transection or dislodgment and loss of localization. Finally, because the seed is entirely contained within the breast parenchyma, the localization procedure can be performed days in advance of the operative excision, thus reducing scheduling conflicts.

The results of this study position RSL as an attractive alternative to WL. RSL is more reliable than WL for the excision of nonpalpable breast lesions because fewer patients require re-excision of involved margins. The 57% rate of patients requiring excision of additional margins in the WL group is consistent with the rate in a recent report of WLs¹⁵ and reported residual tumor after diagnostic biopsy,¹⁶ but this was decreased by more than half among our RSL group. This finding is probably because of the ability of the surgeon to constantly reorient to the position of the seed by using the gamma probe; this allows for a more central positioning of the lesion within the specimen. This conclusion is strengthened by the fact that the RSL group had significantly fewer pathologically involved margins despite the mean volume of tissue initially removed being similar between the two groups (Fig. 2). Avoiding resection of additional margins is an advantage not to be underestimated. Each re-excision of a margin requires, at a minimum, expensive additional operating room and pathology time. On occasion, it involves an additional procedure at a later date, which is not only expensive but also traumatic for the patient.

The RSL procedure was easy to learn. Although it was a new technique, radiologists, surgeons, and patients found it subjectively no more difficult than the familiar WL. It is important to note that we found that SLN biopsy was able to be successfully performed in association with RSL lumpectomy, with 30 of 31 patients (97%) having successful lymphatic mapping. Because the one patient with unsuccessful SLN biopsy failed to map with both blue dye and radiocolloid, this was considered an anatomical mapping failure unrelated to the RSL. There certainly was no interference from the radioactive seed that contributed to this mapping failure.

During this study, the pathology technicians were able to locate and retrieve both the seed and the lesion in 100% of RSL patients by using a handheld gamma probe without the aid of a specimen radiograph. This suggests the possibility of completing the operation with immediate pathologic confirmation of lesion excision without the time and expense of an intraoperative specimen radiograph. Radiographical documentation of complete lesion excision remains the standard of care, but for many well-defined lesions RSL could allow this to be performed after simple pathologic confirmation that the lesion is within the specimen. A significant amount of expensive operating room time could be saved by performing specimen radiography after the completion of the procedure, as demonstrated by the 2.2-minute mean time to locate the seed and lesion without a specimen radiograph in this study. Additional study of the reliability of this technique for confirming the excision of select lesions is required, however, before elimination of intraoperative specimen radiographs can be recommended.

In conclusion, RSL allows the reliable excision of nonpalpable breast lesions with fewer patients having pathologically involved margins of resection, thus saving time and breast tissue. RSL is intuitive to learn and allows improved logistics.

	Footnotes

 
Presented in part at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 15, 2001. Accepted for publication June 25, 2001.

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