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ORIGINAL ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 1  |  Page : 6-10

Assessment of the efficacy and safety of methylene blue dye for sentinel lymph node mapping in early breast cancer with clinically negative axilla


Department of Surgery, Employees' State Insurance Post Graduate Institute of Medical Sciences and Research, New Delhi, India

Date of Web Publication14-Jul-2014

Correspondence Address:
Suman Kharkwal
Chief Medical Officer, 229, Pocket V, Mayur Vihar, New Delhi - 110 091
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-9596.136689

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  Abstract 

Background : The benefits of sentinel lymph node (SLN) biopsy in breast cancer patients with clinically negative axillary nodes are now well established. SLN biopsy has been performed using different techniques including injection of isosulfan blue dye (IBD), radioactive colloid, and methylene blue. The aim of this study was to assess the safety and efficacy of methylene blue dye (MBD) as a mapping agent for SLN biopsy in axillary node negative breast carcinoma.
Materials and Methods: Between February 2010-2012, a total of 27 female patients of 18 years and above, with established diagnosis of breast carcinoma with clinically negative ipsilateral axillary lymph nodes were studied. After induction of anesthesia, 5 ml of 1% methylene blue was infiltrated into the subareolar tissue on the affected side. The lymph nodes receiving the blue dye were excised as the SLN. Modified radical mastectomy (MRM) was completed and the excised breast with the axillary tissue was sent for histopathological examination to correlate with the findings of the SLN biopsy.
Results: The incidence of breast cancer was highest at 41-50 years. Of 27 cases, SLN was identified in 24 cases using MBD. The identification rate was 88.9%. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 81.8, 100, 100, and 86.7%, respectively.
Conclusion: This study confirms the safety and efficacy of methylene blue as a mapping agent for SLN biopsy in axillary node negative breast cancer.

Keywords: Breast cancer, methylene blue dye, sentinel lymph node biopsy


How to cite this article:
Mukherjee A, Kharkwal S, Charak K S. Assessment of the efficacy and safety of methylene blue dye for sentinel lymph node mapping in early breast cancer with clinically negative axilla. Arch Int Surg 2014;4:6-10

How to cite this URL:
Mukherjee A, Kharkwal S, Charak K S. Assessment of the efficacy and safety of methylene blue dye for sentinel lymph node mapping in early breast cancer with clinically negative axilla. Arch Int Surg [serial online] 2014 [cited 2024 Mar 1];4:6-10. Available from: https://www.archintsurg.org/text.asp?2014/4/1/6/136689


  Introduction Top


Surgical treatment of breast cancer has evolved from Halsted's radical mastectomy to breast conserving surgery. Similarly, surgical treatment of regional lymph nodes has also become less extensive. Axillary lymph node dissection (ALND) was standard of care for a long time and considered necessary for locoregional control and staging purposes. [1],[2] Although ALND came with substantial morbidity [1],[3] and the majority of the ALND patients were "node negative", various studies reported ALND has no effect on disease-free and overall survivals. [4] There has been a trend recently to be less radical in cancer treatment without compromising the principles of surgical oncology. The relatively recent method of sentinel lymph node (SLN) mapping is a step to achieve that end.

SLN biopsy has been performed using different techniques including injection of isosulfan blue dye (IBD), patent blue (PB), radioactive colloid, fluorescence-guided SLN biopsy using indocyanine green, combination of blue dye and radioactive colloid, and so forth. Methylene blue dye (MBD) is a recent addition to this list.

Isosulfan blue is costly and is known to cause hypersensitivity reactions. IBD and PB were associated with significant number of allergic reaction (0.1-3%), [5],[6],[7],[8],[9],[10] some of which are life threatening. [11] The techniques like fluorescence-guided SLN biopsy using indocyanine green are not widely available, are costly, and are still being studied. Preoperative lymphoscintigraphy facilitates intraoperative identification of axillary nodes, but there are concerns about limited availability and cost of radio colloids as well as exposure of healthcare professionals to radiation.

MBD is more economical than isosulfan blue, does not cause hypersensitivity reactions or any other significant complications and, most importantly, is as good as, and possibly better than, isosulfan blue at SLN mapping. [5],[12] Thus, MBD as a single agent is well suited to surgeons in developing countries to offer the important technique of SLN biopsy without significantly compromising the quality of the test. [13]

The aim of this study was to analyze the safety and success rate of MBD for SLN identification in the management of early breast cancer in the prospective series of 27 patients.


  Materials and Methods Top


This study was conducted in Employees' State Insurance Post Graduate Institute of Medical Sciences and Research (ESI PGIMSR), New Delhi. Twenty-seven patients with confirmed fine needle aspiration cytological diagnosis of breast cancer who were undergoing planned mastectomy and axillary nodal clearance were enrolled in this study between February 2010-2012 after prior approval and informed consent. We selected patients with tumor size not more than 5 cm and clinically negative axillary lymph nodes. We excluded patients with palpable axillary lymph nodes, patients with distant metastases, patients with previous breast surgery, radiotherapy or chemotherapy, and patients with known allergy to MBD and those who refused consent for the use of MBD. All patients were informed of the procedure and consent was taken before surgery. Institutional ethical committee clearance was also obtained.

Procedure

All selected patients planned for modified radical mastectomy (MRM), after induction of anesthesia, were infiltrated with 5 ml of 1% methylene blue into the subareolar tissue on the affected side. [14],[15] No massage was done. SLN were looked for after the superior flap was raised. The lymph node or nodes receiving the blue dye were taken as the SLN. Immediately following their identification the lymph nodes were excised. The excised lymph nodes were sliced into 2-3 transverse sections, depending on their size. Imprint smear was made and stained using Giemsa stain. Following this, the lymph nodes were sent for histopathological examination.

MRM was completed along with ALND in all cases. The excised breast with the axillary tissue was sent for histopathological examination to correlate with the findings of the SLN biopsy.

Statistical methods used

Descriptive statistics was analyzed with Statistical Package for the Social Sciences (SPSS) version 17.0 software. Continuous variables were presented as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. The association between the histopathology of SLN and MRM axillary specimen was analyzed using Fisher's exact test. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated. A P < 0.05 was taken as significant.


  Results Top


The age of patients with breast carcinoma in the study ranged from 33 to 70 years. The median age was 45 years. The incidence of breast cancer was maximum in the age group of 41-50 years. The next common age group was 31-40 years. The most commonly affected site was the outer upper quadrant (44.4%, n = 12) followed by the lower outer quadrant (22.2%, n = 6), lower inner quadrant (18.5%, n = 5), and the upper inner quadrant (14.8%, n = 4).

SLN was successfully identified in 24 patients (88.9%) using MBD. In three patients (11.1%), SLNB failed as the dye failed to reach the axilla [Table 1], [Figure 1]. Of the 24 patients in whom SLN was identified, imprint cytology showed tumor metastases to SLN in nine patients, whereas it was negative for 15 patients. The results of imprint cytology and histopathology of the SLN were similar in all the cases where SLN was identified [Table 2], [Figure 2].
Table 1: Showing the SLN identification rate

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Table 2: Findings of histopathology of the SLN

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Figure 1: Showing the SLN identification rate. SLN = Sentinel lymph node

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Figure 2: Findings of histopathology of the SLN

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Histopathology of the MRM axillary specimen showed tumor metastases into axilla in 11 patients and showed no nodal metastases in the remaining 16 patients. There were two cases in which the imprint cytology and histopathological examination of the SLN were negative for tumor metastases but the histopathological examination of the MRM specimen was positive for nodal metastases. The comparison between histopathology of SLN and MRM axillary specimens is shown in [Table 3] and [Figure 3] and [Figure 4]. The sensitivity, specificity, PPV, and NPV of SLN identification were 81.8, 100, 100, and 86.7%, respectively [Table 4].
Table 3: Sensitivity, specificity, positive predictive value and negative predictive value of SLN identification

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Table 4: Showing the comparison between histopathology of the SLN and the MRTable 4: Showing the comparison between histopathology of the SLN and the MRM axillary specimenM axillary specimen

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Figure 3: Showing blue lymphatic mapping (arrow) after injection of methylene blue dye

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Figure 4: Sentinel lymph node (arrow) stained by methylene blue dye

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There were no local complications observed with any of the patients including blue discoloration of the urine. None of the patients had any primary or delayed hypersensitivity reaction to MBD.


  Discussion Top


In this study, 5 ml of 1% MBD was given intraparenchymal subareolarly after induction of anesthesia. Breast massage was avoided in this study as its safety is controversial. [16],[17],[18] MBD was found to be safe and none of our patients developed any allergic or anaphylactic reaction, which is in accordance with most published series. [19],[20],[21]

In all 27 patients injected with MBD in the subareolar region, no necrotic skin lesions were observed. This is in contrast with most of the published data. [22],[23],[24] Saha et al., reported 7% cases of skin necrosis after injection of 1% MBD. [25] There were no cases of blue discoloration of urine, and subareolar injection of MBD was never associated with bladder irritation in our patients.

In the present study, SLN was identified in 24 patients. There were three cases in which SLN could not be identified using MBD. The identification rate was 88.9%. This could be due to faulty injection technique or inability of the MBD to reach the axilla. SLN identification rate improved subsequently with the number of cases. In comparison, previous studies reported the SLN identification with MBD ranging from 65-94 %. [26],[27],[28],[29]

Imprint cytology and histopathology of the SLN showed that of the 24 lymph nodes identified 15 of them were negative and nine of them were positive for tumor metastases. The results of imprint cytology and histopathology of the SLN were similar in all the cases where SLN was identified.

On comparing the results of the SLN biopsy and histopathology of the MRM specimen, P <0.001 is obtained, which suggests that our results are statistically significant. Axillary dissection of 24 patients with positive SLNs showed that two cases in which SLN was negative for tumor metastases but the histopathology of axilla was positive. The rate of false-negative result best defines the accuracy of SLN biopsy. In our study, false-negative results were seen in two of the patients (8%), which is comparable with those of other published studies. [30],[31]


  Conclusion Top


MBD is safe for SLN identification in early breast cancer and the technique of subareolar intraparenchymal injection of dilute MBD without massage increases the technical success and maintains low rate of complication. MBD is safe, cheap, and widely available in most of the hospitals. Therefore, with no extra cost to the patient and institution, the option of SLN biopsy can be offered to poor patients in developing countries, which can drastically reduce the morbidity associated with ALND. SLN biopsy with MBD is an effective method. However, it is not an absolute index of freedom from node metastases and should be combined with intraoperative assessment and other investigations.

 
  References Top

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2.Samphao S, Eremin JM, El-Sheemy M, Eremin O. Management of the axilla in women with breast cancer: Current clinical practice and a new selective targeted approach. Ann Surg Oncol 2008;15:1282-96.  Back to cited text no. 2
    
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4.Pepels MJ, Vestjens JH, de Boer M, Smidt M, van Diest PJ, Borm GF, et al. Safety of avoiding routine use of axillary dissection in early stage breast cancer: A systematic review. Breast Cancer Res Treat 2011;125:301-13.  Back to cited text no. 4
    
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19.Aydogan F, Celik V, Uras C, Salihoglu Z, Topuz U. A comparison of the adverse reactions associated with isosulfan blue versus methylene blue dye in sentinel lymph node biopsy for breast cancer. Am J Surg 2008;195:277-8.  Back to cited text no. 19
    
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24.Salhab M, Al Sarakbi W, Mokbel K. Skin and fat necrosis of the breast following methylene blue dye injection for sentinel node biopsy in a patient with breast cancer. Int Semin Surg Oncol 2005;2:26.  Back to cited text no. 24
    
25.Saha S, Sirop SJ, Fritz P. Comparative analysis of sentinel lymph node mapping in breast cancer by 1% lymphazurin vs. 1% methylene blue: a prospective study. J Clin Oncol; ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2008;26:570.  Back to cited text no. 25
    
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30.Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni M, et al. Sentinel- node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864-7.  Back to cited text no. 30
    
31.O'Hea BJ, Hill AD, El-Shirbiny AM, Yeh SD, Rosen PP, Coit DG, et al. Sentinel lymph node biopsy in breast cancer: Initial experience at Memorial Sloan-Kettering Cancer Centre. J Am Coll Surg 1998;186:423-7.  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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