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Annals of Surgical Oncology 10:242-247 (2003)
© 2003 Society of Surgical Oncology


ORIGINAL ARTICLES

Methylene Blue Dye as an Alternative to Isosulfan Blue Dye for Sentinel Lymph Node Localization

Rache Simmons, MD, Sarmela Thevarajah, BA, Meghan B. Brennan, RN, ONP, MSN, OCN, Paul Christos, MPH, MS and Michael Osborne, MD, FACS

From the Department of Surgery (RS, MO), Weill Cornell Breast Center (ST, MBB), New York Presbyterian Hospital, and Department of Public Health (PC), the Weill Cornell Medical College, New York, New York.

Correspondence: Address correspondence and reprint requests to: Rache Simmons, MD, 425 East 61st Street, 8th Floor, New York, NY 10021; Fax: 212-821-0832; E-mail: rms2002{at}med.cornell.edu


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Our study describes the use of methylene blue dye as an alternative to isosulfan blue dye to identify the sentinel lymph node (SLN).

Methods: A retrospective analysis was performed of 112 breast cancer patients (113 axillae) who underwent SLN biopsy (SLNB) with methylene blue dye and 99mTc-labeled sulfur colloid for SLN identification. All SLNs were submitted for intraoperative frozen section analysis, hematoxylin and eosin stain, and immunohistochemical evaluation. Patients with a pathologically negative SLN did not undergo further axillary lymph node dissection.

Results: Of 112 patients who underwent SLNB, the SLN was identified in 107 (95.5%); 104 (92.8%) were identified by methylene blue dye. In a subset of 99 patients with recorded isotope status in relation to blue nodes, concordant identification with both dye and isotope was observed in 94 (94.9%). Of patients with identified SLNs, 32 (29.9%) of 107 contained metastatic disease, with 31 (96.9%) of 32 identified by methylene blue dye. The SLN was the only positive node in 18 (60.0%) of 30 patients.

Conclusions: SLNB with methylene blue dye is an effective alternative to isosulfan blue dye for accurately identifying SLNs in breast cancer patients.

Key Words: Methylene blue • Sentinel node • Isosulfan blue • Breast cancer • Sentinel lymph node biopsy


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node biopsy (SLNB) is an established, minimally invasive means of staging the axilla in patients with breast cancer. The opportunity to perform adequate staging while reducing both morbidity and hospitalization cost when compared with complete axillary lymph node dissection (ALND) has led to the widespread use of this technique. Isosulfan blue has traditionally been the dye used to identify the sentinel lymph node (SLN) in breast cancer. Alternatively, methylene blue dye has been used to localize the SLN in other types of cancers, such as malignant melanoma and thyroid cancer.1–5 Our study describes the use of methylene blue dye as an alternative to isosulfan blue dye to localize the SLN in breast cancer.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A retrospective analysis was performed on 112 patients (113 axillae) with clinical Tis–T3N0M0 tumors who underwent SLNB with methylene blue dye and 99mTc-labeled sulfur colloid for SLN identification between January 1999 and July 2001. All patients had a biopsy-proven malignancy and underwent either a segmental mastectomy (n = 71; 62.8%) or a modified radical mastectomy (n = 42; 37.1%); two surgeons (R.S. and M.O.) performed the procedures.

Before arriving in the operating room, the patient had a subdermal injection of 99mTc-labeled sulfur colloid in the nuclear medicine department for use in identifying the sentinel node. This injection was performed at a minimum of 2 hours and up to 24 hours before the scheduled surgical procedure. In the operating room, 5 mL of 1% methylene blue dye was injected intraparenchymally around either the tumor mass or around the biopsy cavity if a previous excision had been performed. The breast was then massaged for 5 minutes. Exposure of the axilla was obtained through the mastectomy incision or a separate incision in the hair-bearing region for the patients undergoing lumpectomy. The blue lymphatic channels were identified and carefully followed to a blue-stained lymph node (Figs. 1 and 2). Subsequently, a gamma probe was used to measure the tracer uptake in the identified blue lymph nodes. The entire axilla was then scanned with the handheld probe to locate any additional lymph nodes containing tracer. SLNs were defined as nodes that were radioactive, were stained blue, or were both radioactive and blue. All SLNs were then excised and submitted for pathologic examination (Fig. 3).



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FIG. 1. Blue lymphatic leading into the sentinel lymph node.

 


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FIG. 3. Methylene blue–stained sentinel lymph nodes.

 


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FIG. 2. Sentinel lymph node stained by methylene blue dye.

 
Frozen-section analyses were performed on all sentinel nodes, and if they were positive for metastases, a complete ALND was immediately performed. If the frozen-section analysis of the sentinel node was negative, no further axillary dissection was performed at that time. On all SLNs negative by frozen-section analysis, permanent-section analysis with hematoxylin and eosin (H&E) staining was performed. If permanent-section analysis revealed no metastases, the tissue was subjected to immunohistochemical (IHC) analysis by using standard techniques.6,7 If either permanent section or IHC analysis was positive for metastases, the patient was recommended to undergo a subsequent ALND.

Methylene blue identification was defined as the identification of a blue node, regardless of whether the SLN was also identified by 99mTc. 99mTc identification was defined as a node with >10 times the counts of the background, regardless of whether the SLN was also identified by blue dye. Methylene blue only or 99mTc only identification described the proportion of cases in which the SLN was identified by using that particular method alone. Concordant identification was defined as the identification of the SLN with both methylene blue and 99mTc. Independent identification described the scenario in which several SLNs were localized in one patient, with the SLNs identified by using either methylene blue or 99mTc, but no single SLN was identified with both agents. Overall identification described identification of the SLN by methylene blue dye, 99mTc, or both.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
One hundred thirteen patients ranging in age from 30 to 86 years (mean, 56 years) underwent an SLNB. An SLN was identified in 107 (95.5%) of 112 patients, with 104 (92.8%) identified by the methylene blue dye technique. In a subset of 99 patients for whom isotope status was recorded in relation to the blue nodes, concordant identification of the SLN with both methylene blue and 99mTc was observed in 94 (94.9%).

The number of SLNs excised ranged from 1 to 13 (median, 2). Of the 104 patients with SLNs identified by methylene blue, 93 (89.5%) had invasive carcinomas, 10 (9.6%) presented with ductal carcinoma-in-situ, and 1 (.9%) presented with Paget’s disease (Table 1). The invasive tumors ranged in size from .3 to 5.7 cm (mean, 1.2 cm; Table 2). The tumor stage distribution was 10.6% Tis, 76.9% T1, 11.5% T2, and .9% T3 (Table 3). The pathologic nodal status of these tumors consisted of 70.2% N0 and 29.8% N1. Metastatic stage was M0 for 100% of the tumors (Table 3). In terms of histological grade, 20 (19.2%) of 104 were grade I, 42 (40.4%) were grade II, and 24 (23.1%) were grade III tumors. Histological grade was unknown for 18 (17.3%) of the 104 patients (Table 1). In terms of tumor location, 51 (49.0%) of 104 tumors were found in the upper outer quadrant, 12 (12.4%) were in the lower inner quadrant, 13 (12.5%) were in the lower outer quadrant, 15 (14.4%) were in the upper inner quadrant, 11 (10.6%) were subareolar, and 2 (1.9%) were diffuse (Table 2).


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TABLE 1. Tumor pathology (N = 104)
 

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TABLE 2. Tumor location and size (N = 104)
 

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TABLE 3. Pathologic tumor-node-metastasis stage (N = 104)
 
Our data showed that of the patients with an identified SLN, 32 (29.9%) of 107 contained metastatic disease, of which 31 (96.9%) of 32 were identified by methylene blue dye (Fig. 4). Of all patients with sentinel node metastases, 59.4% were identified by frozen section, 12.5% by permanent section, and 28.1% by IHC analysis. Of the 104 patients in whom an SLN was identified with methylene blue, 31 (29.8%) were identified as having sentinel node metastases. Similarly, of the 94 patients in whom there was concordant identification with both methylene blue and 99mTc, 28 (29.5%) patients had sentinel node metastases. Of these 28 patients, 18 (64.3%) were identified by frozen section, 3 (10.7%) by permanent section, and 7 (25%) by IHC (Fig. 5).



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FIG. 4. Number of sentinel nodes identified according to the method used for identification.

 


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FIG. 5. Number of negative and positive sentinel nodes (SNs) identified according to identification method.

 
Of the patients in whom an SLN was identified, the proportion with sentinel nodes positive for metastases was similar regardless of the technique used for SLN localization. Positive sentinel nodes were identified in 32 (29.9%) of 107 patients overall (regardless of the method used), 31 (29.8%) of 104 patients in whom SLNs were identified with methylene blue, 29 (29.3%) of 99 patients in whom SLNs were identified with the aid of 99mTc, and, similarly, 28 (29.8%) of 94 patients in whom SLNs were localized through concordant identification with both methylene blue and 99mTc (Fig. 5).

Two patients with a positive SLN by IHC alone refused ALND. All other patients with an SLN positive by H&E stain of permanent sections or by IHC evaluation underwent a subsequent ALND. Axillary dissection of the remaining 30 patients with positive sentinel nodes showed that the SLN was the only positive node in 18 (60%) of 30 patients. Among the 18 patients with metastases only to the sentinel node, 8 (44.4%) were identified by frozen section analysis, 3 (16.7%) were identified by H&E analysis of permanent section, and 7 (38.9%) were identified by IHC analysis (Fig. 5).

The mean follow-up time for all patients was 7.9 months (minimum, 0 months; maximum, 26.6 months). The axillary recurrence rate of the SLNB patients was 1 (.89%) in 112. This patient underwent initial total mastectomy with SLNB for a grade III .8-cm infiltrating ductal carcinoma (T1bN0M0) in the upper outer quadrant of the left breast. The sentinel node was localized through concordant identification with both methylene blue dye and 99mTc. The patient also had four other lymph nodes excised during the procedure; these were identified with the use of 99mTc alone but did not meet the aforementioned requirements for a sentinel node. On the basis of frozen-section, H&E, and IHC analysis, all five lymph nodes were negative for metastases. After axillary recurrence, the patient underwent completion axillary dissection with removal of 31 nodes, of which 1 was positive for metastases. She currently has no evidence of disease. No patient has experienced a distant recurrence.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our results show an overall success rate of 94.7% in identifying the sentinel node and a 92% identification rate of the sentinel node with the methylene blue dye technique. The localization rate is slightly higher than our previously reported rate of 90% for SLN identification with methylene blue.8 In comparison, previous studies have reported rates of sentinel node identification with isosulfan blue dye ranging from 65% to 94%.9–13

Various studies have demonstrated that dual-agent mapping, with both blue dye and 99mTc, yields optimal identification rates, as compared with either identification method alone.11,13–16 In our study, among the subset of patients for whom radioisotope status was recorded, a 94.9% concordance existed in terms of identification of the SLN with both methylene blue and 99mTc. Our concordance rate of 94.9% is comparable to rates in studies that cited concordant identification rates of 90% to 97% for isosulfan blue and 99mTc.14,17,18

Our data show that among patients in whom the SLN was identified by use of methylene blue, 29.8% contained metastases. This value is comparable to those of other studies, which have shown rates of 17% to 42% in identifying positive sentinel nodes in T1 to T3 clinically N0 patients.9,10,12,14,19–23 Furthermore, the proportion of patients with metastases to the sentinel nodes was virtually identical regardless of whether the SLN was identified by any method (29.9%), by use of methylene blue dye (29.8%), by use of 99mTc (29.3%), or by concordant identification with both methylene blue dye and 99mTc (29.8%).

Axillary dissection of the 30 patients with positive sentinel nodes showed that additional nonsentinel positive nodes existed in 12 (40%) patients and that the SLN was the only positive node in 18 (60%) of these patients. These values compare with those of other published studies that describe finding additional positive nodes on complete ALND in 33% to 86% of patients.10,12,19,21

Comparison of the data presented in this study with data from studies evaluating the success of isosulfan blue in localizing the SLN demonstrates that methylene blue is an effective alternative for accurate identification of sentinel nodes in breast cancer patients. The high rate of concordant identification of the SLN further supports the efficacy of this dye. It should be noted that the amount of methylene blue dye administered and the technique used to administer the dye were similar to that which would be used for isosulfan blue dye. The surgeons performing the SLN dissection reported noting no technical differences between the migration patterns of methylene blue dye and isosulfan blue dye. In addition, substituting methylene blue dye for isosulfan blue dye in SLN dissection could reduce health care costs significantly. Comparing the price of methylene blue dye (US$1.67 per 5 mL) with that of isosulfan blue dye (US$61.00 per 5 mL) demonstrates the cost-saving potential of this technique (prices quoted by American Reagent Laboratory).

Previous studies have reported hypersensitivity to isosulfan blue dye at rates of 1% to 2%.24–28 Most of the reported hypersensitivity reactions manifested in the form of anaphylaxis with cardiovascular collapse and hypotension, requiring vigorous resuscitation. Other manifestations included erythema, perioral edema, urticaria, uvular edema, and blue hives. Albo et al.24 reported that hospital stay was prolonged by a mean of 1.6 days in patients with anaphylaxis. In our study, none of the 112 patients developed a hypersensitivity reaction to the methylene blue dye. To the authors’ knowledge, there have been no studies documenting hypersensitivity reactions, particularly anaphylaxis, with the use of methylene blue dye.

In conclusion, SLN dissection with methylene blue dye is an effective and valuable alternative to isosulfan blue dye for accurately identifying sentinel nodes in breast cancer patients.


    Footnotes
 
Presented at the Society of Surgical Oncology’s 55th Annual Cancer Symposium, Denver, Colorado, March 14–17, 2002.

Sentinel lymph node biopsy with methylene blue dye is an effective alternative to isosulfan blue dye for accurately identifying sentinel lymph nodes in breast cancer patients.

Received for publication April 12, 2002. Accepted for publication October 23, 2002.


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 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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