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10.1245/ASO.2006.04.027
Annals of Surgical Oncology 13:701-707 (2006)
© 2006 Society of Surgical Oncology
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Original Article

A Further Validation of Subareolar Injection Technique for Breast Sentinel Lymph Node Biopsy

Giovanni D’Eredita, MD1, Carmela Giardina, MD2, Angela Maria Guerrieri, MD3 and Tommaso Berardi, MD1

1 Department of General and Special Surgery, University of Bari, Via S. Hahnemann, 2, 70126 Bari, Italy
2 Department of Pathology and Genetics, University of Bari, 70126 Bari, Italy
3 Breast Radiology Service, Policlinico Hospital, Bari, Italy

Correspondence: Address correspondence and reprint requests to: Giovanni D’Eredita, MD; E-mail: gderedita{at}chirges.uniba.it.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In this study we performed subdermal injection of 99mTc-labeled albumin combined with subareolar (SA) injection of blue dye, and we compared this technique with two techniques previously used in terms of the success of sentinel lymph node (SLN) identification, false-negative (FN) rate, and the overall accuracy and sensitivity of the three procedures. In all patients we performed a complete axillary lymph node dissection.

Methods: From January 1999 to September 2004, a total of 195 patients with localized breast cancer were treated. Patients were subdivided into three groups. In patients in group 1 (n = 115; January 1999 to December 2001), lymphoscintigraphy together with injection of vital dye was performed; in group 2 (n = 40; January to October 2002), SA injection of blue dye alone was performed; and in group 3 (n = 40; November 2002 to September 2004), SA injection of blue dye and subdermal injection of radioisotope was performed.

Results: The success rate of identifying an SLN by a combination of the two techniques was 95% in group 1 and 100% in group 3. The FN rate was 9% in group 1 and 0% in groups 2 and 3. The overall accuracy of lymphatic mapping was 97% in group 1 and 100% in groups 2 and 3. Sensitivity was 91% in group 1 and 100% in groups 2 and 3.

Conclusions: This study of SA injection for SLN biopsy using dual tracers demonstrates a high SLN identification rate and an absent FN rate. We propose that injection into the SA plexus is the optimal way to perform lymphatic mapping of the breast. This technique seems to be feasible even in patients with multicentric cancers.

Key Words: Sentinel lymph node biopsy • Lymphatic mapping • Subareolar injection • Breast cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node (SLN) biopsy has been developed as an effective way of assessing axillary nodal status. Despite the widespread use of SLN biopsy, several technical questions remain. Among these the optimal side where the tracer should be injected to perform lymphatic axillary mapping.

The techniques of axillary mapping are numerous and differ according to the materials used: blue dye and/or 99mTc-labeled sulfur colloid or 99mTc-labeled albumin, the volume of the agent, the timing of injection, and, moreover, the site of injection. The consequence of the different techniques is conflicting results. The dye or the tracer is injected into the peritumoral or intraparenchymal tissue,1–6 either subdermally or intradermally.7,8

With the combination of the two techniques (blue dye and radioisotope) injected into peritumoral or intraparenchymal tissue, SLN identification rates of 92% to 99% have been reported with 0% to 15% false-negative (FN) rates.2,7,9 With subdermal or intradermal injection of agents, SLN identification rates are 98% to 100%, and FN rates are 0% to 9%.3,7,8,10

These techniques have allowed for acceptable results with regard to the identification rates of SLNs, but not with regard to FN rates. Successful SLN biopsy depends primarily on accurate identification of the exact metastatic route that will be, or has been, used by disseminating tumor cells.11 The lymphatic drainage of the breast, which is poorly understood, was first described by Sappey,12 who showed that the lymphatics of the breast follow the ductal system of the breast and flow into a subareolar (SA) plexus. From this plexus, several main lymphatic trunks drain to a small number of axillary SLNs. Gray13 showed that from the ectodermal primitive milk streak, which later becomes the areolar complex, the lymphatics of the breast elongate as the lactiferous duct system develops and maintain their connection to the SA lymphatic plexus that is in connection with deep and superficial intramammary lymphatics that terminate in regional lymph nodes. This communication is the premise behind injection of the tracer material into the SA plexus to search for the SLN. Kern,14 in 1999, published his research on 40 patients in whom the vital dye was injected into the SA area followed by complete axillary lymph node dissection (ALND). Klimberg et al.15 published in the same year their research on 68 patients in whom the tracer was injected into the SA area and 5 mL of vital dye was injected around the tumor, but without ALND. Smith et al.16 later further tested the hypothesis that SA injection of 99mTc is as accurate as peritumoral injection in localizing the SLN determined by complete ALND.

In our previous study,17 we demonstrated that dye-only injection into the SA plexus achieved a high SLN identification rate, an absent FN rate, and a rapid learning curve. The goal of the study was to compare peritumoral injection of 99mTc-labeled albumin and subdermal injection of blue dye with SA injection of blue dye alone.

In this study, we performed subdermal injection of 99mTc-labeled albumin combined with SA injection of blue dye and compared this technique with the two procedures described previously to achieve a further demonstration and validation of the SA injection technique in terms of the success of SLN identification, the FN rate, and the overall accuracy and sensitivity of three procedures. In all patients we performed a complete ALND.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
From January 1999 to September 2004, 195 patients with localized breast cancer were evaluated for enrollment in our study at the Institute of General Surgery, University of Bari. A histological or cytological diagnosis of invasive breast cancer was required. We excluded patients with palpable axillary nodes, ductal in situ histological results, previous radiotherapy to the breast, or prior axillary surgery and women who were pregnant. Informed consent was required from all patients. In our initial study, the SLN biopsy was performed through lymphoscintigraphy with 99mTc injected peritumorally and subdermal injection of vital dye, followed in all cases by complete ALND. This procedure was modified during the course of the study: after the first 50 cases, for patients who had negative SLNs (proven also with the immunohistochemical method), with their informed consent, ALND was not performed. Since January 2002, we have modified the SLN identification technique by using an SA injection of vital dye followed by complete ALND in all patients. From November 2002 to September 2004, we performed SA injection of blue dye and subdermal injection of radioisotope to determine whether this seemed to map to the same lymph nodes. All the patients in third phase of the study underwent a complete ALND. There were 115 patients in the first phase of the study (group 1), 40 patients in the second phase (group 2), and 40 in the third phase (group 3).

Technique
In patients in group 1 (n = 115; January 1999 to December 2001) with palpable tumors, lymphoscintigraphy and injection of vital dye to identify the SLN were performed. Patients with nonpalpable lesions underwent injection by ultrasound guidance. The day before surgery, 8 to 12 MBq of 99mTc-labeled human albumin colloid particles (80–200 nm; Nanocol; Nycomed-Amersham, Sorin, Italy) in .4 mL of saline was administered in four peritumoral injections immediately around the breast lesion. Planar scans of the involved breast and axillary area, in anterior and lateral projections, were acquired 15 to 30 minutes and 3 hours after tracer injection. After scanning, the skin over the first node to take up tracer (defined as the SLN) was marked. A gamma-detecting probe (Neoprobe, Dublin, OH) was applied to the skin above the SLN to confirm the hot spot. Signals picked up by the probe were transduced into digital readout and acoustic signals. The intensity and frequency of the acoustic signals were directly proportional to the level of radioactivity detected. Approximately 10 to 20 minutes before axillary incision, 4 mL of methylene blue dye was administered subdermally, above the breast mass, in four subdermal injections. A small skin incision was made, blunt dissection was performed to identify a blue-impregnated lymphatic channel, and the lymphatic chain was followed until the first node (the SLN) was identified. The gamma probe guided the dissection to a blue-stained afferent lymphatic channel or the blue-stained node emitting the highest activity, and that node was excised and tagged as the SLN. Sometimes two or more nodes were picked up by the probe. All axillary nodes with counts ≥10% of the ex vivo counts of the most radioactive lymph node were removed and designed as SLNs. After the specimen was rechecked, the wound was reexamined after SLN removal to ensure that all radiolabeled lymph nodes were removed. A complete ALND was performed immediately in the first 50 patients; in the following patients, delayed completion ALND was performed when metastatic cells were discovered on permanent pathologic sections after staining with hematoxylin and eosin or with a cytokeratin cocktail, as described below. Complete lymphadenectomy was avoided only in seven patients with negative SLNs confirmed by immunohistochemical analysis because of their refusal after informed consent.

In patients in group 2 (n = 40; January 2002 to October 2002), SA injection of blue dye was performed. According to Kern,14 regardless of the tumor location or sites of previous biopsies, blue dye (4 mL of methylene blue dye) is injected into the upper outer edge of the areola (right breast, 10 o’clock; left breast, 2 o’clock) and directed medially toward the nipple, approximately 10 to 20 minutes before axillary incision in a single injection site, followed by complete ALND.

In patients in group 3 (n = 40; November 2002 to September 2004), lymphoscintigraphy and SA injection of blue dye were performed. The day before surgery, 8 to 12 MBq of 99mTc-labeled human albumin colloid particles (80–200 nm) in .4 mL of saline was administered in four subdermal injections in the skin immediately above the breast lesion. Approximately 10 to 20 minutes before axillary incision, a single SA injection (4 mL of methylene blue dye) was administered into the upper outer edge of the areola according to the technique described by Kern.14 All patients in group 3 underwent a complete ALND.

Pathologic Evaluation
In all patients, SLNs were sectioned along the long axis into two sections and were then submitted for routine processing. Each tissue block was sectioned serially (successive 5-µm sections) and stained with hematoxylin and eosin. When metastatic carcinoma was not apparent on examination of the hematoxylin and eosin–stained slides, immunohistochemical analysis was performed by using a cytokeratin cocktail of three monoclonal antibodies that recognize a wide range of high- and low-molecular-weight keratin peptides (AE1/AE3, 1:50 [Dako, Carpinteria, CA]; CAM 5.2, 1:50 [Becton-Dickinson, Franklin Lakes, NJ]; MNF 116, 1:100 [Dako]). Immunohistochemical analysis was performed by using the avidin-biotin-peroxidase complex method.18 Immunostaining was automated by using the ChemMate HRP/3 3'-diaminobenzidine detection kit K5001 (Dako) on a Tec-Mate 1000 (Dako). Brief counterstaining in Mayer’s hematoxylin followed immunostaining.

Statistical Evaluation
The data were analyzed with SPSS for Windows (release 10; SPSS Inc., Chicago, IL). Comparison of group means was determined by t-testing, and comparison of data within 2 x 2 tables was determined by a Pearson {chi}2 test. P values <.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The three groups of patients were similar in age, previous biopsy type, tumor size, histological characteristics, grading, breast quadrant, type of operation, and lymph node status (Tables 1Go and 2Go). Overall successful identification in patients in group 1 was 94.8% (109 of 115 patients). The success rate of identifying an SLN by a combination of two techniques (preoperative lymphoscintigraphy and blue dye) was 95% (38 of 40); in two patients, lymph nodes were not blue or hot. With blue dye alone, successful identification was 94.6% (71 of 75) in group 1 (subdermal injection) and 97.5% (39 of 40) in group 2 (SA injection alone). In patients in group 3 (SA blue dye plus subdermal radioisotope), successful identification was 100% (40 of 40; P = .88): all SLNs were blue and hot. The mean number (± SD) of SLNs identified was 1.37 ± .74 in group 1 (range, 1–5), 1.86 ± 1.57 (range, 1–8) in group 2, and 2.3 ± 1.03 (range, 1–4) in group 3 (t-testing; P = .01). The mean number of lymph nodes examined was 20.14 ± 6.53 (range, 8–39) in group 1, 20.03 ± 7.28 (range, 7–31) in group 2, and 19.22 ± 6.4 (range, 14–35) in group 3 (t-testing; P = .56). We identified 33 positive axillary basins in patients in group 1: 12 in group 2 and 11 in group 3 after complete ALND. SLNs were the only positives nodes in 9 (27.2%) of 33 patients in group 1, in 5 (41.6%) of 12 patients in group 2, and in 5 (45.4%) of 11 patients in group 3. Three patients in group 1 and no patients in group 2 and 3 had negative SLNs and positive axillary nodes (FN). The FN rate was 9% in group 1 and 0% in groups 2 and 3. The overall accuracy of lymphatic mapping was 97% (99 of 102 patients with an SLN identified and ALND performed) in group 1, 100% (39 of 39 patients) in group 2, and 100% (40 of 40 patients) in group 3 (P = .99). The sensitivity was 91% (30 of 33) in group 1 and 100% (12 of 12) in groups 2 and 3 (11 of 11; P = .97; Table 3Go).


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  		TABLE 1. Patient characteristics
 

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  		TABLE 2. Tumor characteristics
 

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  		TABLE 3. Results of lymphatic mapping and SLN identification
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The growing demand from patients for less invasive procedures has created considerable incentive for accepting SLN biopsy without ALND as standard practice. In fact, many surgeons have already abandoned, on the basis of their experience with SLN biopsy, routine ALND for patients with negative SLN biopsy results.

The SLN identification success rate reached very high percentages with all the techniques used but, all the same, cannot confirm the FN rate. Without a doubt, an adequate learning curve such as that maintained by Cody et al.19 is necessary. However, it is not sufficient to reduce the FN rate. According to Kern,14 a high FN rate is related more to the site of vital dye injection than to surgical training or technique. He affirms that the breast parenchyma is a suboptimal site for dye-directed lymphatic mapping. In our previous study,17 we compared overall successful identification rates with two techniques. In patients in group 1 (subdermal blue dye with or without peritumoral isotope), overall successful identification was 94.8%. In particular, it was 95% with isotope plus blue dye and was 94.6% with blue dye alone. In patients in group 2 (SA blue dye), the identification rate was 97.5%. The single failure occurred in a patient with a previous excisional biopsy in the upper outer quadrant of the breast and seemed to be due to resection of the main sentinel lymphatic channel. Kern14 also reported this failure in identifying SLNs: it can be explained anatomically by the removal of the main lymphatic out-flow tract of the breast. No difference was found in the number of SLNs identified or in the number of lymph nodes examined in the two groups. The FN rate was 9% in group 1 and 0% in group 2. The overall accuracy was 97% and 100%, respectively, in the two groups. The sensitivity was 91% in group 1 and 100% in group 2. In this study, to achieve a further validation of the SA injection technique, in group 3 we used dual-tracer agents injected in different locations: subdermal injection of 99mTc-labeled albumin combined with SA injection of blue dye. In this group, the overall accuracy was 100%, the sensitivity was 100%, and the FN rate was 0%. These results show the high efficacy of SA injection of the tracer in axillary lymphatic mapping. Moreover, if we compare these results with our previous study,17 we achieved increasing success by using dual-tracer agents.

Our results are similar to those of the other studies with SA injection and dual tracers published in the literature (Table 4Go). Klimberg et al.,15 using SA isotope injection and peritumoral blue dye injection, reported a 94.2% SLN identification rate. Borgstein et al.,11 in 130 patients, performed periareolar injection of blue dye and peritumoral isotope and achieved a 96.9% identification rate and a 0% FN rate. Smith et al.16 compared 19 patients who received SA injection of 99mTc and peritumoral blue dye with 19 patients who received peritumoral injection of both materials. SLNs were found in all patients injected SA and in 18 of 19 injected peritumorally. The FN rate was 20% for peritumoral injection and 0% for SA injection. Kern and Rosenberg20 performed SA injection of both isotope and blue dye in 30 patients. No complete ALNDs were performed in patients with negative SLNs by hematoxylin and eosin and immunohistochemistry. The identification rate was 96.7%. The FN rate is not available.


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  		TABLE 4. Sentinel lymph node mapping with SA injection
 
McMasters et al.7 reported in 85 patients a 98.8% identification rate and a 5.9% FN rate by using SA isotope injection and peritumoral blue dye injection. Donahue21 demonstrated an identification rate of 100% in 42 patients and an FN rate of 8.3% by using peritumoral isotope and SA blue dye injection. Beitsch et al.22 described their technique in 85 patients that used SA isotope and peritumoral blue dye injection, with an identification rate of 98%. Tuttle et al.23 reported a 100% identification rate with isotope SA injection and a 97% identification rate with peritumoral blue dye injection in 159 patients. In 98%, SLNs were blue and radioactive. The FN rate is not known because ALND was not performed if the SLN biopsy result was negative. Bauer et al.24 reported the largest series of SA blue dye injection (249 patients) and peritumoral isotope injection, with an identification rate of 96.8%. FN rates are not available because complete ALND was not performed.

Kern,25 in 187 cases, has documented the nodal concordance between radiocolloid and blue dye uptake into SLNs after a same-site injection of both agents by the SA route, with an identification rate of 98.4%, an FN rate of 0% (0 of 20 cases), and an accuracy of 100% for predicting the malignant status of the axilla. This study was the first to evaluate dual-tracer, same-site injections of blue dye and radiocolloid by the SA approach. Pelosi et al.,26 using peritumoral isotope injection and periareolar blue dye on 50 patients, reported a 98% identification rate. Chagpar et al.,27 in a recent multicenter clinical trial on 3961 patients, reported that for 1762 cases, injection of radioactive colloid resulted in an identification rate of 91.1% for peritumoral injections, 99.3% for SA injections, and 95.6% for periareolar injections.

These studies with SA injection have all achieved a high SLN identification rate (94.2%–100%). The results of our study (a 97.5% identification rate and a 0% FN rate by using only SA injection and a 100% identification rate with a 0% FN rate by using dual tracers) are similar to those of Kern.25

Although we presented a small series of SA injections for SLN mapping, we can nevertheless make some remarks. First, our experience with SA injections came after a long period of learning the technique of SLN biopsy by using two tracers, so our results are derived from a consolidated experience in axillary lymphatic mapping. In fact, all procedures were performed by the same surgeon (G.D.), and that can justify our high SLN identification rate and low FN rate.

Second, when using SA vital dye injection, we always performed a complete ALND to validate the method. We believe this technique to be easy. The simplicity and reliability of this method require less expertise than other techniques. It avoids the necessity for image-guided injections for nonpalpable lesions. Moreover, SA injection reduces the shine-through effect from tumors located in the upper outer quadrant of the breast.

It is recommended that multicentric cancers be excluded from SLN biopsy, because such tumors are likely to involve an extended area of lymphatic networks and to give rise to skip metastases. On the basis of the concept that the SA plexus receives drainage from deeper parenchymal lymph channels and drains directly to axillary nodes, axillary mapping and SLN biopsy by SA injection seem feasible even in multicentric cancers. There have been five reports of SLN biopsy in patients with multiple foci of cancer.28–32

In conclusion, we achieved in this study a further validation of the SA injection technique to axillary mapping and SLN biopsy in breast cancer. The results of studies on multifocal cancers by using the SA injection technique validate the hypothesis that breast drains lymph as a single unit as a result of its embryological development from the ectodermal primitive milk streak that becomes the areolar complex.

Finally, SLN was originally defined as the first lymph node in a regional nodal basin that receives lymph flow from the primary tumor. Several studies have found that two tracer agents injected in different locations drain to the same SLN; furthermore, studies on multifocal cancers, by using the SA injection technique, have validated the hypothesis that the breast drains lymph as a single unit. As a result of these remarks, we are led to believe that the SLN should be defined as the first node that receives lymph flow from the entire breast unit.

Received for publication April 26, 2005. Accepted for publication November 4, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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