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Original Article |
1 John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, California 90404
2 Park Nicollet Methodist Hospital, 6500 Excelsior Boulevard, St. Louis Park, Minnesota 55426
3 United Hospital, 333 North Smith Avenue, St. Paul, Minnesota 55102
4 Department of Surgery, University of Minnesota, 420 Delaware St. S.E., Minneapolis, Minnesota 55455
Correspondence: Address correspondence and reprint requests to: Todd M. Tuttle, MD; E-mail: tuttl006{at}umn.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: One hundred twenty-two women with invasive breast cancer were enrolled onto this prospective study. Immediately after the induction of general anesthesia, patients were injected with 1 to 2 mCi of filtered TcSC in the SA location. Then, 5 mL of 1% isosulfan blue dye was injected into the PT location. The SLN or SLNs were identified as radioactive, blue, or both and removed for pathologic evaluation.
Results: The mean patient age was 56 years. The mean tumor size was 1.5 cm. In 86.1% of patients, a transcutaneous axillary "hot spot" was identified by handheld gamma probe. The mean time from TcSC injection to axillary incision was 17.6 minutes. At least one SLN was identified in 99.2% of patients. The mean number of SLNs identified per patient was 1.83. The mean count of radioactive SLNs was 2715 cps. In 97.2% of patients, blue SLNs were also radioactive.
Conclusions: TcSC injected into the SA lymphatics rapidly drains to the SLN. The radioactive SLN is easily and quickly identified after an intraoperative SA TcSC injection. The simplicity of this method eliminates the inherent problems associated with standard PT injection.
Key Words: Breast cancer • Sentinel lymph node • Subareolar • Technetium
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Currently, the most common method of SLN identification involves preoperative peritumoral (PT) injection of 99mTc-labeled sulfur colloid (TcSC) and intraoperative PT injection of blue dye. However, this method has several limitations. First, there is significant variability in identification and false-negative rates. For instance, in one multicenter validation study involving 11 different surgeons using PT injection of TcSC, the false-negative rate was 0% to 28.6%, depending on the surgeon.4 This variability was observed even though all 11 surgeons followed a standardized written surgical protocol. Furthermore, TcSC has a slow and unpredictable migration time from the PT lymphatics to the axillary SLN. As a result, TcSC is generally injected into the PT location 2 to 3 hours before surgery. This causes additional pain and anxiety with the injection and inconveniences patients, who must arrive ahead of their operative time. Surgery scheduling can be delayed, and hospital costs can be increased.
The optimal injection technique for SLN identication should consistently achieve high identication rates (
95%) and low false-negative rates (
5%). Recently, several studies evaluated subareolar (SA) injection.7–10 The SA area consists of a plexus of lymphatics that drain to the axilla. Embryologically, the breast develops as a primitive milk streak from this area. As the breast grows, the lymphatics elongate out from the SA plexus. Compared with the breast parenchyma, the SA area contains a richer lymphatic network and may facilitate SLN identification. Several investigators achieved identification rates >95% and false-negative rates <5% with SA injection.7–10 TcSC migrates rapidly from the SA lymphatics to the SLN, thus indicating that intraoperative injection of TcSC may be possible. Thus , the problems associated with preoperative PT injection would be eliminated. W e hypothesized that TcSC would travel to the SLN within minutes after injection into the SA lymphatics, thus making intraoperative injection feasible and allowing for accurate SLN identification.
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METHODS |
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Technique
SLN identification was performed in a standard fashion by one of eight surgeons trained in the SLN biopsy technique for breast cancer. After general anesthesia was induced, 1 to 2 mCi of filtered (.2 µm) TcSC was injected into the SA location just below the nipple at the six-o’clock position by using a 27-gauge needle. The total volume of TcSC injected was 2 mL. The breast was then massaged for 2 minutes. All appropriate precautions for handling the TcSC were followed in accordance with the radiation safety policies of each hospital participating in the study. Authorized nuclear medicine personnel delivered the TcSC to the operating room. The TcSC, needle, and syringe were kept inside a lead container that was opened by the surgeon. The operating surgeon injected the TcSC into the SA location and then placed the syringe and needle back into the lead container, which was returned to the nuclear medicine suite by authorized personnel. Periodic swipe tests of the operating room were performed with a Geiger counter.
After the TcSC injection, 5 mL of 1% isosulfan blue (Lymphazurin; US Surgical Corp., Norwalk, CT) was injected into the breast parenchyma surrounding the tumor. In patients with palpable tumors, the blue dye was injected at the 12-, 3-, 6-, and 9-o’clock positions surrounding the tumor. For patients with intact, nonpalpable tumors, the blue dye was injected just superficial to the radiographically localized tumor. For patients who had previously undergone open surgical biopsy, blue dye was injected into the breast parenchyma surrounding the biopsy cavity. The area of injection was then massaged for 2 minutes.
A handheld gamma probe device (Neoprobe, Dublin, OH; or Navigator, US Surgical Corp.) was used to identify a transcutaneous "hot spot" in the axilla. An axillary incision was made over the hot spot. If no hot spot was identified, then the axillary incision was made in the same location as an ALND. The SLN was then identified by the gamma probe and removed. Radioactive counts were taken ex vivo by placing the node directly against the end of the gamma probe. The axilla was scanned with the gamma probe, and SLNs were removed until the axillary background was <10% of the most radioactive SLN. After removal of the radioactive SLN(s), the axilla was explored for any nonradioactive blue nodes or any blue-stained lymphatic channels entering into a node; any such nodes were also removed. The axilla was also explored by palpation to detect any grossly enlarged or hard lymph nodes, and these also were removed. If no radioactive or blue SLN was identified, then a standard level I and II ALND was performed. After all SLNs were removed, a partial or total mastectomy was performed.
Pathologic Examination
Pathologic examination of SLNs was standardized. Each SLN was analyzed by using six sections stained for hematoxylin and eosin, and two sections were stained for cytokeratin. SLNs were considered positive if the size of the metastasis was >.2 mm.11 SLNs containing isolated cytokeratin-positive cells were considered negative. All patients who had positive SLNs were offered completion ALND.
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RESULTS |
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). In all, 63 patients had palpable breast cancers.
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). In 54.1% of the patients, tumors were located in the upper outer quadrant of the breast. Most (87.7%) of the tumors were infiltrating ductal carcinomas; 77% were estrogen-receptor positive. Breast -conserving surgery was performed in 85.2% of the patients and mastectomy in 14.8%.
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In patients with identified SLNs, a mean of 1.83 ± .08 SLNs were removed (Table 2
). Of the 122 patients, 27 (22.3%) patients had at least 1 positive SLN. Table 3 lists the incidence of positive SLNs according to T stage. In all patients with pathologically positive SLNs, metastases were detected in at least one radioactive SLN. In four patients, the positive SLN was detected only as radioactive (not as blue). In one patient, the first SLN was completely replaced by tumor (it was blue, but not radioactive). The second SLN harvested from the same patient was radioactive, blue, and positive for tumor cells. Of patients with positive SLNs, 88% underwent completion ALND. Of those who underwent completion ALND, 67% had additional positive lymph nodes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Recently, SA injection of TcSC and blue dye has been introduced as an alternative SLN biopsy technique. It overcomes several of the limitations of standard PT injection. The accuracy of SA injection has been confirmed directly by validation studies and indirectly by concordance studies. In a multi-institutional validation study by McMasters et al.,5 85 patients underwent SA or periareolar injection of TcSC. The SLN identification rate was 98.8%, and the false-negative rate was 5.9%. Smith et al.8 compared SA injection with PT injection in a validation study involving 38 patients. SLN identification was 100% for SA injection versus 95% for PT injection; false-negative rates were 0% for SA injection and 20% for PT injection (not statistically significant). Kern 9 achieved a 98% identification rate with no false negatives in 40 women with operable breast cancer who underwent SA blue dye injection followed by completion ALND.
Several concordance studies have indirectly confirmed the accuracy of SA injection.7,10 In a study by Klimberg et al.10 involving 68 patients, 1.0 mCi of TcSC was injected into the SA area of the breast, and 2 to 5 mL of isosulfan blue dye was injected around the tumor. All blue SLNs were also radioactive, and 94.2% of the patients had a radioactive SLN identified. Tuttle et al.7 performed 159 SLN biopsies in which TcSC was injected into the SA location of the breast and blue dye was injected around the tumor. A blue SLN was found in 97% of patients; it was also radioactive 98% of the time. Thus, blue dye injected around the tumor drained to the same SLN as the TcSC injected into the SA location. Collectively, these studies demonstrate that the SA injection technique has higher identification rates than the PT injection technique. Moreover, the false-negative rates are no worse and may, in fact, be lower.
SA injection offers several advantages over standard PT injection that make SLN identification much easier. With the SA injection, the problem of shine-through when TcSC is injected into tumors in the upper outer quadrant of the breast is avoided. SA injection eliminates the necessity of image-guided injection for nonpalpable tumors. Furthermore, SA injection can be applied to patients with multicentric breast cancer. Kern 13 demonstrated, by lymphoscintigraphy, that all sentinel lymphatic channels originate from the upper outer edge of the areola and traverse the outer quadrant of the breast to terminate in an SLN. Thus , regardless of location in the breast, all tumors seem to converge to a common lymphatic channel, which ultimately drains into a common SLN. Schrenk et al.14 used this concept to demonstrate the feasibility of SLN biopsy in 48 patients with multicentric breast cancer. After injection of TcSC, blue dye, or both under the areola, followed by ALND, the SLN identification rate was 97.8%; the false-negative rate was 3.8%. Similarly, Layeeque et al.15 demonstrated a 100% identification rate and a 0% false-negative rate with SA injection of isosulfan blue, TcSC, or both in 40 patients with multicentric breast cancer.
Various timing strategies have been used for tracer injection. Nearly all surgeons who use blue dye inject it in the operating room 5 to 15 minutes before making the skin incision. How ever, the migration time of TcSC from the breast to the axilla is generally slower and more variable than that of blue dye. As a result, the timing of TcSC injection differs considerably among surgeons. In a multicenter study, Krag et al.4 reported that TcSC injection time varied from 30 minutes to 9 hours (mean time, 2.9 hours) before incision. Often, patients need to arrive at the hospital several hours before their scheduled operation to be injected with TcSC. Thus, surgery schedules are often unpredictable for both patient and surgeon.
In an effort to improve operating room scheduling, some surgeons have recommended a day-before TcSC injection.16,17 McCarter et al.16 evaluated patients who underwent a single-site low-volume intradermal TcSC injection the same day as surgery versus the day before surgery. The day-before patients received a higher dose of unfiltered TcSC (.5 mCi) than the same-day patients (.1 mCi). The mean number of SLNs was higher in the day-before group (3.1) than in the same-day group (2.7), possibly indicating that second-echelon lymph nodes were also being harvested. Successful SLN identification was similar between groups: 93% for same-day and 96% for day-before patients. Although scheduling delays are potentially avoided with the day-before injection method, the amount of time the patient spends in the hospital is the same or longer with the same-day injection. Furthermore, the process of traveling to and from the hospital on two separate occasions is cumbersome for the patient.
TcSC injected into the SA lymphatics migrates rapidly to the axillary SLN, thus making intraoperative SA injection feasible. Kern and Rosenberg18 evaluated SA versus PT injection and the success of preoperative lymphoscintigraphy. The overall imaging time was significantly shorter after SA injection (34 minutes) than after PT injection (82 minutes). Time to imaging of the SLN after SA injection was 3 ± 2 minutes. Given the rapid rate of migration of TcSC from the SA space, intraoperative SA injection seemed possible.
Our technique of intraoperative SA injection of TcSC successfully identified a transcutaneous hot spot in 86% of patients and a radioactive SLN in 97.5%. Radioactive SLNs were identified more frequently than transcutaneous hot spots, presumably because the dissection brought the probe closer to the radioactive SLN. The average time from TcSC injection to incision was <20 minutes. Within this time period, the patient was positioned for surgery, the surgeon scrubbed, the patient’s skin was cleansed, and the operative field was draped and prepared. Thus, unnecessary delays were reduced and uncomfortable preoperative injections eliminated. In our study, the overall SLN identification rate was 99.2%, with a concordance rate of 97.2%. Even though our concordance rates were high, the accuracy of our technique was not directly validated by a planned ALND. However, our high identification and concordance rates with intraoperative SA TcSC injection are comparable to those with preoperative SA injection.7,10,19
The results of this intraoperative injection study are comparable to those recently reported by Layeeque et al.20 In that study, 96 SLN procedures were performed on 88 patients by using an intraoperative SA injection of TcSC and blue dye. Successful SLN identification was accomplished in 97% of procedures. Using a slightly different method, Vargas et al.21 injected TcSC into the PT location immediately before surgery; the disadvantage of this approach is that patients still experience pain and anxiety from the injection.
One potential disadvantage of intraoperative SA injection of TcSC is that preoperative lymphoscintigraphy cannot be performed. However, a multicenter trial by McMasters et al.22 demonstrated that preoperative lymphoscintigraphy did not improve the SLN identification rates or decrease the false-negative rates. Instead, it significantly increased hospital costs. Another potential drawback of the SA injection technique is that it does not identify internal mammary SLNs. In fact, internal mammary SLNs receive their primary lymphatic drainage from the deep PT lymphatics. Therefore, surgeons who plan to identify and remove internal mammary SLNs should use a PT injection technique. However, the risk of internal mammary metastases is low, especially if the axillary basin is negative.23 Therefore, routine preoperative lymphoscintigraphy and internal mammary SLN biopsy does not seem justified.
Another possible limitation of intraoperative 99mTc injection is that handling radioactive material in the operating room may not be safe. However, we found no difficulty in obtaining approval from the radiation safety committees at the three different institutions participating in this study. At each hospital, the nuclear medicine department handled and disposed of the radioactive agent. Because operating room staff did not handle the radioactive material, no special training or protection was necessary.
In conclusion, this study supports the use of intraoperative SA injection of TcSC as a means for SLN identification. Our technique was easy to perform by both the community and university surgeons involved in the study. Given the rich SA lymphatic plexus, TcSC migrated rapidly to the SLN for consistent intraoperative identification. Uncomfortable preoperative injections and unnecessary delays in surgery scheduling were avoided.
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ACKNOWLEDGMENTS |
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Received for publication April 12, 2004. Accepted for publication September 27, 2004.
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