Percutaneous Biopsy and Sentinel Lymphadenectomy: Minimally Invasive. he diagnosis and treatment of nonpalpable. Breast Cancer

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1 Laura Liberman 1 Hiram S. Cody III 2 Received January 30, 2001; accepted after revision April 3, Supported by a grant from the New York State Department of Health (C015709). 1 Department of Radiology, Breast Imaging Section, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY Address correspondence to L. Liberman. 2 Breast Service, Department of Surgery, Memorial Sloan- Kettering Cancer Center, New York, NY AJR 2001;177: X/01/ American Roentgen Ray Society Percutaneous Biopsy and Sentinel Lymphadenectomy: Minimally Invasive Diagnosis and Treatment of Nonpalpable Breast Cancer OBJECTIVE. The purpose of this study was to determine the usefulness of the combination of percutaneous imaging-guided large-core breast biopsy and sentinel lymphadenectomy in the diagnosis and treatment of nonpalpable invasive breast cancer. MATERIALS AND METHODS. Retrospective review revealed 200 consecutive nonpalpable breast cancers diagnosed by percutaneous imaging-guided large-core biopsy and treated with surgery that included sentinel lymphadenectomy. Percutaneous breast biopsy was performed with stereotactic or sonographic guidance with an automated core needle or vacuum-assisted biopsy probe. Sentinel lymphadenectomy was performed with intradermal injection of a radioisotope and intraparenchymal injection of blue contrast agent. Technical success was defined as identification of sentinel nodes at surgery. Medical records were reviewed. RESULTS. Technical success rate was 200 (100%) of 200. In 158 (79%) of 200 cancers, sentinel nodes were tumor-free, and axillary dissection was avoided. In three (2%) of 200 carcinomas, the sentinel nodes were negative for tumor, but nonsentinel nodes suspicious on intraoperative palpation were excised and found by frozen section analysis to contain tumor. Tumor was found in sentinel nodes in 39 (20%) of 200 carcinomas; axillary dissection, performed in 31 of these 39 women, revealed additional tumor in nonsentinel nodes in seven (23%). A single surgical procedure was performed for 164 (82%) of 200 carcinomas; the breast was preserved in 191 (96%) of these 200 carcinomas. CONCLUSION. Percutaneous imaging-guided large-core breast biopsy and sentinel lymphadenectomy provide a minimally invasive approach to the diagnosis and treatment of women with nonpalpable invasive breast cancers. T he diagnosis and treatment of nonpalpable invasive breast cancer has traditionally involved at least two surgical procedures: diagnostic surgical biopsy, followed by a separate operation to provide definitive surgical treatment. Axillary dissection has traditionally been part of the therapeutic surgery for these lesions. Although the information from axillary lymph node dissection is of prognostic importance and impacts on treatment decisions, axillary dissection has associated morbidity, and the survival benefit remains uncertain. Recent advances allow us to reassess the traditional two-stage surgical approach. Percutaneous large-core biopsy with stereotactic or sonographic guidance is an alternative to surgical biopsy for the diagnosis of nonpalpable breast lesions [1 5]. Sentinel lymphadenectomy with a radioisotope [6], blue contrast agent [7], or a combination of methods [8] can be used to determine the histologic status of the axilla. Although a previous small series suggested that the combination of percutaneous breast biopsy and sentinel lymphadenectomy was potentially useful in the diagnosis and treatment of nonpalpable breast cancers [9], some investigators have excluded women with nonpalpable breast cancer from sentinel lymphadenectomy [10 12]. Our study was undertaken to evaluate the usefulness of percutaneous imaging-guided large-core breast biopsy and sentinel lymphadenectomy in women with nonpalpable breast cancer. Materials and Methods Retrospective review of surgical records at our institution from August 28, 1998, to June 8, 2000, revealed 200 breast carcinomas that had sentinel lymph node biopsy after percutaneous imaging- AJR:177, October

2 Liberman and Cody guided core-biopsy diagnosis of nonpalpable infiltrating breast carcinoma. These 200 breast carcinomas, which occurred in 197 women who were years old (median age, 59 years), constitute the basis of this study. Informed consent was obtained from all women. All women had mammographically detected nonpalpable carcinomas and findings negative for tumor in axillae on preoperative physical examination. Percutaneous biopsy was performed with sonographic (n = 108) or stereotactic (n = 92) guidance, with a 14-gauge automated needle (n = 136), vacuum-assisted biopsy probe (n = 63), or large biopsy cannula (n = 1). The median time from percutaneous biopsy to surgery was 24 days (range, days). Sentinel lymph nodes were identified with a combination of intradermal radioisotope and intraparenchymal blue contrast agent. Radioisotope injection was accomplished with the following technique: for women who underwent lumpectomy and sentinel lymph node biopsy, preoperative needle localization was performed with a modified Kopans wire (Cook, Bloomington, IN). After needle localization, 0.1 mci (3.7 ΜBq) of unfiltered technetium- 99m sulfur colloid in 0.05 ml of saline solution was injected intradermally via a 28-gauge needle superolateral to the site of the primary tumor in the breast (Fig. 1). For women who underwent mastectomy and sentinel lymph node biopsy, we injected the radioisotope intradermally superolateral to the primary tumor site before surgery, using the same technique, without preoperative needle localization. We performed preoperative lymphoscintigraphy, using a large field-of-view dual-head gamma camera with a low-energy high-resolution collimator. Transmission images in the anterior and lateral projections were obtained with a cobalt-57 flood source. Lymphoscintigraphic imaging began approximately 20 min after injection (Fig. 2). The time between injection and surgery ranged from 2 to 4 hr. The handheld C-Trak gamma probe (Care-Wise Medical, Morgan, CA) was used intraoperatively to obtain counts of room background, the breast injection site, and the hottest spot in the axilla. Four milliliters of isosulfan blue contrast agent (Lymphazurin; Zenith Parenterals, Rosemont, IL) was injected in one to three aliquots around the tumor site into the parenchyma of the breast. Within 5-10 min after administration of blue dye contrast agent, an axillary incision was made, and sentinel node biopsy was performed, guided by the gamma probe and by the appearance of blue contrast agent in lymphatic channels and nodes (Fig. 3). In situ and ex vivo node counts were taken, and axillary background counts were taken after removal of the node. Technical success was defined as identification of the sentinel nodes at surgery. A node was considered to be a sentinel node if it exhibited blue staining at surgery, its removal resulted in a fourfold or greater reduction in axillary counts, or both. If sentinel nodes were not found, axillary dissection was performed. All sentinel nodes were excised and analyzed by frozen and paraffin sections. If frozen section and the initial H and E stained paraffin section of the sentinel node were negative for tumor, immunohistochemical stains and deeper sections were obtained as per the following protocol: two immediately adjacent sections were evaluated with cytokeratin immunohistochemistry with AE1/3 and CAM 5.2 antibodies, and three deeper levels 50 µm apart were evaluated by H and E stain. The protocol was to perform axillary lymph node dissection if frozen section, paraffin section, or immunohistochemical analysis of the sentinel nodes yielded carcinoma. Nonsentinel axillary lymph nodes were examined with a single H and E section, according to the standard procedure used for axillary dissections at our institution. If the sentinel nodes were free of tumor by all methods and the axilla was clinically negative for tumor on intraoperative examination, no further axillary surgery was performed. Medical records and histologic findings were reviewed to determine the technical success rate of sentinel lymph node biopsy and to determine the frequency of performing a single surgical procedure, sparing axillary lymph node dissection and preserving the breast. Exact 95% confidence intervals (CIs) were calculated around relevant frequencies with statistical software (version 8.0; SAS Institute, Cary, NC). Results were entered on a computerized spreadsheet (Excel 97; Microsoft, Redmond, WA) for analysis. Results The median histologic size of infiltrating carcinoma was 1.1 cm (range, cm). Histologic findings in these 200 cancers were infiltrating ductal carcinoma in 161 (including 143 with ductal carcinoma in situ), mixed infiltrating ductal and infiltrating lobular carcinoma in 27 (including 21 with ductal carcinoma in situ), and infiltrating lobular carcinoma in 12 (including three with ductal carcinoma in situ). Tumor was located in the upper outer quadrant in 125 carcinomas, lower outer quadrant in 19, upper inner quadrant in 31, and lower inner quadrant in 25. Sentinel nodes were found at surgery in 200 of 200 carcinomas, indicating a technical success rate of 100% (95% CI, %). The median number of sentinel Fig. 1. Asymptomatic 58-year-old woman with nonpalpable cancer proven at percutaneous imagingguided core biopsy. Before surgery, radioisotope is injected intradermally superolateral to localizing wire. Fig year-old woman with nonpalpable breast cancer. Frontal lymphoscintigraphic image shows intense radiotracer uptake (straight arrow) at injection site adjacent to tumor in upper outer quadrant, blast zone. Separate focus of radiotracer uptake is present in axilla, corresponding to sentinel node (curved arrow). Fig year-old woman with nonpalpable breast cancer. Intraoperative photograph obtained after intraparenchymal injection of blue contrast medium and axillary incision shows blue sentinel node (arrow). Two blue afferent lymphatics (arrowheads) are also identified. 888 AJR:177, October 2001

3 Percutaneous Biopsy and Sentinel Lymphadenectomy in Breast Cancer nodes was 2.0, and the mean was 2.0 (range, 1 9). In 158 (79%; 95% CI, 73 84%) of 200 carcinomas, the sentinel nodes were free of tumor, and axillary lymph node dissection was averted. In three (2%) of 200 carcinomas, the sentinel lymph nodes were negative for tumor, but nonsentinel nodes, suspicious on intraoperative palpation, were excised and found to contain tumor by frozen section analysis. Axillary lymph node dissection revealed additional axillary metastases in all three of these women. Tumor was present in sentinel nodes in 39 (20%; 95% CI, 14 25%) of 200 carcinomas. Tumor was found in sentinel nodes by frozen section analysis in 22 (56%) of these 39 patients, by paraffin analysis in three (8%), and by immunohistochemical analysis after frozen and paraffin sections were negative for tumor in 14 (36%). Axillary lymph node dissection, performed in 31 of 39 women with sentinel node metastases, revealed additional tumor in nonsentinel nodes in seven (23%), including four (19%) of 21 women with sentinel node metastases found by frozen section, one (33%) of three women with sentinel node metastases found by paraffin section, and two (29%) of seven women with sentinel node metastases found by immunohistochemistry. In the 200 nonpalpable breast cancers in this study, axillary dissection was spared in 158 (79%; 95% CI, 73-84%) with no tumor in sentinel nodes. Axillary dissection was performed for 34 carcinomas (17%) on the day of the first surgery in 24 (because of sentinel node metastases identified on frozen section in 22 and suspicious nonsentinel node on intraoperative palpation that contained tumor at frozen section in two) and at a later date in 10 (because of tumor found on immunohistochemical analysis of sentinel nodes in six, tumor found at paraffin analysis of sentinel nodes in three, and tumor found at frozen and paraffin analysis of a suspicious nonsentinel node found at intraoperative palpation in one). Axillary dissection was not performed because of patient or physician choice for eight carcinomas with tumor in sentinel nodes, including seven with sentinel node metastases found by immunohistochemistry and one with sentinel node metastases found at frozen and paraffin sections. A single surgical procedure was performed for 164 (82%; 95% CI, 76 87%) of 200 carcinomas. The median number of surgeries performed was one, and the mean was 1.2 (range, 1 4). The initial breast surgery performed at the time of sentinel lymphadenectomy was wide excision in 197 women (99%) and mastectomy in three women (2%). Two or more surgical procedures were performed for 36 carcinomas; subsequent surgeries included reexcision (n = 22), mastectomy (n = 4), axillary dissection (n = 6), reexcision and axillary dissection (n = 2), mastectomy and axillary dissection (n = 1), and two reexcisions followed by mastectomy and axillary dissection (n = 1). Among these 200 carcinomas, the breast was preserved in 191 (96%; 95% CI, 92 98%); of these, 167 (87%; 95% CI, 82 92%) achieved clear histologic margins of resection during the first operation. Discussion Progress in the field of breast cancer has been marked by development of less invasive, but highly effective, methods for diagnosis and treatment. For years, the radical mastectomy as described by Halsted [13], was the standard of care for the surgical treatment of invasive breast cancer. The advent of breast-conserving surgery created a revolution in breast cancer treatment, offering effective therapy while preserving the breast [14]. The last decade has witnessed two more revolutions: percutaneous imaging-guided large-core breast biopsy (for diagnosis) [15] and sentinel lymphadenectomy (for treatment) [16]. Percutaneous imaging-guided large-core breast biopsy was pioneered by Parker et al. [1] in Early validation studies showed % concordance between the results of 14-gauge automated percutaneous core biopsy and surgery, with the best results achieved by obtaining multiple specimens with a long-excursion gun [1 5]. Percutaneous biopsy is less invasive and less expensive than surgery, can be performed quickly, and does not deform the breast [17]. For women with benign breast lesions, who account for 70 80% of all women undergoing breast biopsy, percutaneous biopsy can obviate surgery. Percutaneous biopsy is also advantageous for women with breast cancer. Women whose cancers are diagnosed by percutaneous rather than surgical biopsy undergo fewer surgical procedures and are more likely to obtain clear histologic margins of resection at the first operation [18 21]. Sentinel lymphadenectomy was first applied to breast cancer by Krag et al. [6] using a radioisotope in 1993 and by Giuliano et al. [7] using blue contrast agent in The sentinel node hypothesis states that the sentinel nodes are the first nodes draining a tumor and that the histologic status of the sentinel nodes predicts the status of the regional lymphatic basin. Studies correlating the results of sentinel lymphadenectomy with axillary lymph node dissection in more than 3000 women with breast cancer have shown a technical success rate of 88%, sensitivity of 93%, and accuracy of 97% [22]. On the basis of these data, some medical centers have begun to offer sentinel lymphadenectomy as an alternative to axillary dissection for women with small infiltrating breast carcinomas and lymph nodes clinically negative for tumor. Axillary dissection is performed if sentinel nodes are not found, if tumor is present in sentinel nodes, or if axillary nodes are suspicious on palpation. In our study, we found the combination of percutaneous breast biopsy and sentinel lymphadenectomy provided a minimally invasive approach to the diagnosis and treatment of nonpalpable invasive breast cancer. Ninety-six percent of the women in our study had breastconserving surgery. Eighty-two percent of these women had a single surgical procedure. The high frequency of achieving clear histologic margins at the first surgery likely reflects the fact that the surgeon, knowing that the diagnosis was cancer from the percutaneous biopsy results, intentionally excised a larger volume of tissue to resect the cancer with clear histologic margins [18, 20, 21]. For 158 (79%) of the 200 carcinomas analyzed in our study, sentinel nodes were free of tumor, and axillary dissection was averted. The high technical success of sentinel lymphadenectomy in our study likely reflects several factors. First, we used a combination of radioisotope and blue contrast agent, an approach shown to be successful more often than either method individually [11]. Second, the radioisotope was injected intradermally. Linehan et al. [23] showed a significantly higher technical success rate for sentinel lymph node biopsy using intradermal rather than intraparenchymal radioisotope injection, perhaps because the higher interstitial pressure that can be obtained with the intradermal method favors lymphatic uptake. In addition to having a high technical success rate, intradermal radioisotope injection has high accuracy. In a validation study, Boolbol et al. [24] reported an accuracy of 100% in 44 women who had sentinel lymphadenectomy after intradermal injection of radioisotope and intraparenchymal blue contrast agent. Other researchers have shown that intraparenchymal and intradermal injections resulted in labeling the same sentinel nodes in % of patients [10]. AJR:177, October

4 Liberman and Cody A third reason accounting for our high technical success rate may be the use of percutaneous biopsy rather than surgical biopsy for diagnosis. Some investigators have reported higher technical success rates for sentinel lymphadenectomy in women who did not have prior surgical biopsy, perhaps due to disruption of normal lymphatic drainage pathways at surgical biopsy [16]. Finally, our previous experience with sentinel lymph node biopsy likely contributed to our high success rate. In the patients in this study, percutaneous biopsy was performed after a preliminary validation study of 60 patients with backup axillary dissection and after additional clinical experience with more than 500 patients. The literature indicates that sentinel lymph node biopsy has a learning curve, with higher technical success and lower false-negative rates achieved with experience [25]. Our study does not address the false-negative rate of either percutaneous biopsy or sentinel lymphadenectomy. Other investigators have reported that an average of 2.8% (range, %) of cancers were missed at percutaneous biopsy, comparable to the average cancer miss rate of 2.0% (range, 0 8%) reported at needle localization and diagnostic surgical biopsy [26, 27]. The false-negative rate of percutaneous breast biopsy can be reduced by use of appropriate tissue-acquisition devices such as directional vacuum-assisted biopsy for calcifications [28, 29] and by meticulous attention to technique, particularly with respect to lesion targeting [30]. Furthermore, the impact of a false-negative percutaneous diagnosis can be minimized by careful correlation of imaging and histologic findings after biopsy; imaging histologic discordance may allow prospective identification of a missed cancer, avoiding deleterious delay in diagnosis [31]. Studies of sentinel lymphadenectomy have reported an average false-negative rate of 7% (range, 0 22%), but there are several factors that can reduce this. First, the false-negative rate of sentinel lymph node biopsy decreases with experience. Cody et al. [25] reported that among 104 patients who had sentinel node biopsy with planned backup axillary dissection, the false-negative rate was 10.6%; eliminating the first six or the first 15 patients of each surgeon reduced the false-negative rate to 5.2% and 2%, respectively. Second, the false-negative rate of sentinel lymphadenectomy is lower if the combination of radioisotope and blue contrast agent is used rather than either method individually [32]. Third, intraoperative palpation is important: a node replaced by tumor may not take up contrast agent or radioisotope, as illustrated in three (2%) of the 200 carcinomas in our study and in four (3%) of 130 cases reported by Borgstein et al. [10]. If nodes are of clinical concern, they should be excised. Finally, immunohistochemical analysis of sentinel nodes significantly reduces the false-negative rate from 8% to 3% [33]. In 1998, McMasters et al. [34] suggested that sentinel lymphadenectomy was not yet the standard of care. A paucity of long-term follow-up data is an inherent limitation of all new technologies, and that of sentinel lymphadenectomy is no exception. However, validation studies in more than 3000 women suggest that sentinel lymphadenectomy is a viable alternative to axillary dissection for women with small invasive breast cancers and clinically negative nodes. It can be estimated that of approximately 200,000 women who will be diagnosed with invasive breast cancer in the year 2001 [35], at least 50,000 (25%) will have nonpalpable lesions identified at screening mammography. Percutaneous biopsy combined with sentinel lymphadenectomy can provide a minimally invasive approach to the diagnosis and treatment of nonpalpable breast cancer in such women. Continued refinement of these techniques may allow us to transcend the traditional two-stage surgical approach and set a new minimally invasive standard. Acknowledgment We thank David C. Perlman for invaluable assistance. References 1. Parker SH, Lovin JD, Jobe WE, et al. Stereotactic breast biopsy with a biopsy gun. Radiology 1990; 176: Parker SH, Lovin JD, Jobe WE, Burke BJ, Hopper KD, Yakes WF. Nonpalpable breast lesions: stereotactic automated large-core biopsies. Radiology 1991;180: Elvecrog EL, Lechner MC, Nelson MT. Nonpalpable breast lesions: correlation of stereotaxic largecore needle biopsy and surgical biopsy results. Radiology 1993;188: Parker SH, Jobe WE, Dennis MA, et al. US-guided automated large-core breast biopsy. Radiology 1993;187: Gisvold JJ, Goellner JR, Grant CS, et al. 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