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ORIGINAL ARTICLES |
From the Departments of Surgery (TWB, FRS, LSC, IB, DLF, BJC), Nuclear Medicine (AA), Radiology (SPW), and Biostatistics and Epidemiology (RM), School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Surgery (TLB), York Hospital, York, Pennsylvania.
Correspondence: Address correspondence and reprint requests to: Brian J. Czerniecki, MD, PhD, Department of Surgery, 4 Silverstein, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104; Fax: 215-662-7476; E-mail: czerniec{at}mail.med.upenn.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Three hundred thirty-two patients with biopsy-proven operable breast cancer or ductal carcinoma in situ at two institutions underwent SLN mapping. Eighty-three patients had PT injection of blue dye (group 1), and 249 patients had SA injection of blue dye (group 2). All patients underwent PT injection of 99mTc-labeled sulfur colloid.
Results: The two groups were similar in age, previous biopsy type, and tumor size, location, and histology. The mean number of SLNs identified was 2.4 (range, 0–9) in group 1 and 2.5 (range, 0–11) in group 2. The SLN identification rate was 95% for group 1 and 97% for group 2. The isotope success rate was 94% for both groups. The blue dye success rate was 84% for group 1 and 90% for group 2. The isotope/blue dye concordance rate was 87% for group 1 and 90% for group 2. At a median follow-up of 28 months (range, 14 to 40), there were no axillary recurrences in any of the 332 patients.
Conclusions: These data suggest that delivery of mapping reagents in the SA and PT locations identifies similar lymph nodes. Because of simplicity and the similarity in node identification between SA and PT injection, further investigation of the SA site for delivery of SLN mapping reagents for breast cancer is warranted.
Key Words: Sentinel lymph node mapping • Subareolar injection • Blue dye • Radioisotope • Breast cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gould et al.9 first used the term "sentinel node" in 1960 to describe the lymph node consistently located at the confluence of the anterior and posterior facial veins which predicted the status of the lymph nodes in the neck of patients with cancer of the parotid gland. Cabanas10 in 1977 reported the first series of SLN mapping with lymphangiography in 46 patients with penile cancer. The SLN, as he described it, was the lymph node that represented the primary site of metastasis from penile carcinoma. In 1992, Morton et al.11 popularized SLN mapping for patients with melanoma of the trunk and extremities by using lymphoscintigraphy (LSG) to localize the draining lymph node basins and then using blue dye to identify the SLN. In 1993, Krag et al.12 were the first to report SLN mapping for breast carcinoma by use of a radioisotope. Giuliano et al.13 first reported SLN mapping for breast carcinoma with blue dye alone, and Albertini et al.14 first reported the combination of radioisotope and blue dye.
There have been many variations in the technique of SLN mapping, such as choice of localizing agent (blue dye, radioisotope, or both); particle size of the radioisotope; volume of agent; timing of injection, scintigraphic imaging, and surgery; and, more recently, site of injection (peritumoral [PT],12–21 subdermal [sd],21,22 intradermal [ID],21,23–25 and subareolar [SA] or periareolar [PA]21,26–30). The majority of investigators have used PT injection, with varying success. With PT injection of blue dye alone, Giuliano et al.13 reported a 94% success rate in SLN localization, with a 0% false-negative (FN) rate and an accuracy of 100% in 107 patients. However, others have reported identification rates as low16 as 71% and FN rates as high31 as 16.7%. Some studies using PT injection of radioisotope alone have reported a 91% to 94% SLN localization rate with a 0% to 11% FN rate and 97% to 100% accuracy,15,17,32 whereas others have reported identification rates as low33 as 68% and FN rates as high34 as 14%. With use of the combination of PT blue dye and radioisotope, SLN identification rates of 88% to 99% with 0% to 15% FN rates have been reported14,18–21,35–37; however, identification rates as low38 as 81% have been reported with this technique. There have been several published series of SLN mapping for breast cancer with use of sd or ID injection (Table 1), all with SLN identification rates of 98% to 100% and FN rates21–25 of 0% to 9%. Veronesi et al.39 reported on 376 patients by using radioisotope by sd injection for superficial tumors and PT injection for deep tumors, with a 98.7% identification rate, a 6.7% FN rate, and 96.8% accuracy.
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The findings of Sappey43 and Turner-Warwick,46 although slightly different, are both consistent with our knowledge of the embryological development of the breast. The breast develops from an ectodermal primitive milk streak, which later becomes the nipple-areolar complex.40,41 The lymphatics of the breast elongate as the lactiferous duct system develops, maintaining their connection to the SA lymphatic plexus.42 The SA lymphatic plexus of the mature breast consists of an extensive network of lymphatic channels that originate in the nipple/areolar complex and communicate with deep and superficial intramammary lymphatics that terminate in regional lymph nodes. This direct connection between the SA plexus and the axillary lymph nodes via collecting lymphatic channels is illustrated in Fig. 1. This image was obtained during an attempted ductogram in which the duct was perforated and contrast leaked into the SA lymphatic plexus. The dye drains from the SA plexus to two collectors, which each drain to an axillary lymph node. With this rich SA lymphatic plexus as the origin of the lymphatics in the breast, we chose to evaluate SA injection of blue dye for SLN mapping in breast cancer.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Radiotracer Injection and LSG
For patients with palpable breast tumors, 99mTc-labeled sulfur colloid (1 mCi in 6 ml of saline at the University of Pennsylvania and 450 µCi in 8 ml of saline at York Hospital) was injected into the breast tissue around the primary tumor on the day of surgery. 99mTc-labeled sulfur colloid was filtered through a .22-µm filter before administration. Patients at the University of Pennsylvania underwent injection by ultrasound guidance for lesions visible by ultrasound. Lesions not visible by ultrasound were injected by palpation or by needle localization if they were nonpalpable. At York Hospital, ultrasound guidance was used in patients who had a previous excisional biopsy to avoid injection of radiotracer into the biopsy cavity, whereas patients with nonpalpable needle-localized tumors underwent PT injection without ultrasound guidance.
All patients at the University of Pennsylvania underwent LSG with a large-field-of-view gamma camera with a high-resolution collimator (Model 2000TM; General Electric Medical Systems, Waukesha, WI). Static images were taken for 1 to 2 hours after the injection of radiotracer. After localization of the tracer, anterior/posterior and lateral images were taken to document the site of the radiographically identified draining lymph nodes. All such lymph nodes were marked on the overlying skin with indelible ink. Patients were then transported to the operating room.
Blue Dye Injection and Surgery
This was a sequential study in which 83 patients were injected with 1% LymphazurinTM blue dye (US Surgical Corp., Norwalk, CT) in the PT location from April to November 1998 (group 1), and 249 patients were injected in the SA location from November 1998 to July 2000 (group 2). The patients undergoing PT blue dye injection were injected with 4 to 6 ml of blue dye in four quadrants around the primary tumor site. Breast massage was used in some patients. For patients with prior excisional biopsy, blue dye was injected adjacent to the biopsy cavity. Ultrasound localization was not used for injection of the blue dye. Patients undergoing SA blue dye injection were injected with 3 to 4 ml of blue dye in the SA location without breast massage.
The SLN procedure was performed before removal of the breast tumor in patients undergoing lumpectomy or re-excision. Patients undergoing modified radical mastectomy had the SLN removed either before or after mastectomy. An axillary skin incision was made, and careful dissection was performed, searching for blue lymphatics draining to a blue-stained lymph node. An intraoperative gamma-detecting probe (US Surgical Corp.) was used to identify the SLN. An SLN was positively identified if it was blue, if the lymph node had in vivo radioactive counts at least three times the background counts of the axilla, or both, and radioactive nodes were removed until the background radioactivity of the axilla was <10% of the hottest node removed, as previously defined.37,48,49 A level I and II ALND was performed if no SLN was identified or if an SLN was positive for tumor metastasis.
Pathologic Evaluation
Lymph nodes were marked as sentinel or nonsentinel. The lymph nodes were formalin fixed, paraffin embedded, and evaluated with hematoxylin and eosin and cytokeratin antibody (AE1/3TM, monoclonal antibody, 1:250; Boehringer Mannheim, Indianapolis, IN) with a negative control. All non-SLNs were evaluated with standard hematoxylin and eosin–stained sections. Primary tumors or re-excision specimens were evaluated by routine histology.
Statistical Evaluation
The 95% exact confidence intervals were estimated with Stata 6.0 (Stata Corp., College Station, TX).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We previously reported a 90% identification rate and a 6.7% FN rate in 52 patients (T. L. Bauer, unpublished data), a 95% SLN identification rate with a 0% FN rate in 43 patients,47 and a 99% SLN identification rate with a 2% FN rate in 104 patients37 by using PT injection of radioisotope and blue dye. Thus, our previously reported data are consistent with the reported series of SLN mapping for breast cancer.13–15,17–20,22–24,32,35,36,39 In addition, this argues that the surgeons in this study had reached the plateau of their respective learning curves and that an increase in surgeon experience was probably not a factor during this sequential study. In this series with PT injection of blue dye and radioisotope in 83 patients, the SLN identification rate was 95%, with an 87% isotope/blue dye concordance rate and a blue dye success rate of 84%, consistent with our previously reported series. In this series, by using SA injection of blue dye and PT injection of radioisotope in 249 patients, we achieved a 97% SLN identification rate and a 90% isotope/blue dye concordance rate and a 90% blue dye success rate. The PT and SA techniques were also similar in mean number of SLNs identified per patient and isotope success rate.
This is the largest series, to our knowledge, of SA injection for SLN mapping for breast cancer reported in the literature, and the results we achieved with SA injection are similar to those of the other six reported series with SA injection, four of which were validated with complete ALND (Table 1). Klimberg et al.,28 using SA radioisotope injection and PT blue dye injection, reported a 94% SLN identification rate and a 95% isotope/blue dye concordance rate for 69 breast tumors. Mertz et al.27 reported SLN mapping with SA injection of radioisotope only in 47 patients (31 with unifocal tumors and 16 with multifocal tumors) followed by complete ALND, with an SLN identification rate of 98% and a 0% FN rate. Kern26 performed SA blue dye injection only, SLN mapping, and complete ALND in 40 patients, with a 98% SLN identification rate and a 0% FN rate. In another study, Kern and Rosenberg30 performed SA injection of both isotope and blue dye in 30 patients, with a 96.7% identification rate. Borgstein et al.29 performed PT isotope and PA blue dye injection in 130 patients, with a 96.9% identification rate and a 0% FN rate. McMasters et al.21 reported on a multi-institution series in which 85 patients underwent PT blue dye and either SA or PA isotope injection, with a 98.8% identification rate and a 5.9% FN rate. These studies with SA or PA injection have all achieved a high SLN identification rate (94.2% to 98.8%), and the two studies with SA-only injection had 0 of 22 FNs and 0 of 15 FNs. Although this review is not a meta-analysis and these studies were small and all performed differently, the results obtained seem to be similar. On the basis of this study and the previously reported series, SA injection seems to be an accurate and reliable technique for mapping breast carcinoma.
A major limitation of this study is that FN rates cannot be assessed because complete ALND was not performed in the majority of patients. Although the gold-standard validation is ALND in every patient, we believe that our data suggest that the SA injection technique is mapping to the same lymph nodes as the PT technique. The similar SLN identification rates, mean number of SLNs identified per patient, percentage of nodes that were both hot and blue, the blue dye/isotope concordance rate, and blue dye success rate all suggest that the SA injection technique is probably mapping to the same axillary lymph nodes as the PT technique. If the SA blue dye injections were mapping to different nodes than the PT blue dye injections (with PT isotope as a constant in both groups), then these results could not, by definition, be obtained. However, the SA technique can be truly validated only by performing complete ALND in every patient.
The concern in breast cancer SLN mapping for FN mapping is probably unrelated to the site of injection because FN mappings are seen in all of the different locations where reagents are administered, including PT, sd, ID, SA, and PA (Table 1). In contrast, the FN rate may be related to surgeon experience and to tumor replacement of the SLN. There are two determinants of the sentinel status of the lymph nodes that drain the breast. The first of these is the lymphatic drainage pattern of the breast. This has been shown to occur from superficial to deep in the breast and from the SA plexus to the regional lymph node basins via lymphatic collecting channels43–46 (Fig. 1). This drainage pattern is determined by the embryological development of the breast and is constant regardless of the tumor location. Thus, with the various injection sites mapping similar nodes, the site of injection alone is not likely to prevent all FN mappings. The second determinant of the sentinel status of the lymph nodes is immunological. Faries et al.50 have shown that SLNs are responsible for immunologically screening lymph. They demonstrated that antigen-presenting cells located in the interfollicular region of the SLN take up mapping radiotracers by macropinocytosis, whereas this does not occur in non-SLNs. This phenomenon of active antigen trapping of mapping reagents in the SLN explains why grossly replaced lymph nodes often do not take up radioisotope or blue dye.51 That is, progressive tumor growth in the lymph node results in loss of antigen-presenting cells in the lymph node, and, therefore, there will not be uptake and retention of tracers, resulting in FN mapping. Because these two determinants of the sentinel status of the lymph nodes are independent of the tumor location in the breast, PT, sd, ID, and SA injection of tracers all map to the same SLN. Therefore, the location of injection for SLN mapping in breast cancer should be the easiest and most convenient site regardless of tumor location.
SA injection would have several advantages over the other techniques. Ultrasound guidance is not needed for patients with nonpalpable lesions or those with previous excisional biopsy cavities (together comprising 66 [80%] of 83 patients for group 1). There is a lesser risk of injecting the previous biopsy cavity, which could result in failure to identify the SLN, with SA injection. SA injection avoids operating in a field of blue dye. The entire breast can be mapped with a single injection, which is important for multifocal or multicentric lesions that are fairly common. Tracers are more rapidly visualized in the axilla after SA injection (our unpublished observation).30 Because the tracers are rapidly and efficiently taken up by the dense SA plexus, there is no need for breast massage, which theoretically may result in tumor metastasis. Finally, because most breast cancers occur in the upper outer quadrant, SA injection of isotope moves the background interference further from the axilla, making localization with the handheld gamma probe theoretically easier. On the basis of the results obtained in this study and the previously reported SA injection series, we believe that the ideal technique is SA injection of both blue dye and isotope, as reported by Kern and Rosenberg.30
SA injection for SLN mapping in breast cancer has an embryological basis. This technique is simpler and has several logistical advantages over other techniques. The series reported to date with high SLN identification rates and low FN rates are very promising. A multi-institutional validation study with SA injection of both agents and complete ALND is warranted to investigate this technique.
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Acknowledgments |
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Footnotes |
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Received for publication May 18, 2001. Accepted for publication October 25, 2001.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), isotope only (
), and isotope and blue dye (
). PT, peritumoral (n = 83); SA, subareolar (n = 249).