Breast Cancer Sentinel Node Detection: An Alternative Solution for Centers Lacking Nuclear Technology

Abstract

Background

Sentinel lymph node (SLN) has become the gold standard for all cases with no axillary nodal metastasis. The combined radioisotope and blue dye technique is adopted in most centers. The lack of the technology for radioisotope in our institution encouraged us to study the feasibility of methylene blue (MB) for SLN detection in breast cancer patients admitted to Alexandria Surgical Oncology Unit.

Methods

A total of 144 cases were subjected to SLN detection by injecting 2 ml of MB 1%. This was followed by standard axillary lymph node dissection. The safety and accuracy of MB as a tracer for detection of SLN were studied.

Results

The identification rate was 93.15%. The number of SLN identified ranged from 1 to 8 nodes with a mean of 1.75 ± 1.17. The sensitivity of MB dye technique was 96.3%. The false negative rate was 3.7%. The negative predictive value was 97.6% and the accuracy was 98.5%.

Conclusions

MB is a safe, reliable, cheap, and accurate alternative tracer for detection of SLN.

Introduction

The status of axillary lymph nodes is the most important factor in predicting long-term survival and subsequently affects the decision for adjuvant therapy in some cases of breast cancer [1]. However, the aim and extent of axillary lymph node dissection (ALND) for early breast cancer is a topic of great interest among clinicians treating breast carcinoma [2]. ALND, as a means for achieving local disease control, carries a risk of complications such as seroma, infection and lymphedema [3,4,5]. The sentinel lymph node (SLN) concept evolved from the principle that a primary tumor is drained by an afferent lymphatic channel that courses to the first ‘sentinel’ lymph node in a specific regional lymphatic basin [6]. SLN biopsy can accurately stage the axilla in early breast cancer with much less morbidity and complications than ALND [7,8,9]. During surgery the SLN can be localized by radiotracers (using gamma probes), blue dye, or both [10]. The lack of continuous supply of the radioactive tracer in our institution and the commercial availability of methylene blue (MB) lead us to study the use of this blue dye alone for SLN detection. MB was the only commercially available blue dye available in our institution. MB is methylthionine hydrochloride and is a dark green crystalline compound that turns dark blue in solution [11].

The safety of MB dye for use has been demonstrated through its wide use through the medical practice. As a diagnostic procedure MB has been used for delineation of fistulous tracts and Barrett's esophagus [12,13]. Moreover, it has been therapeutically used in the treatment of methemoglobinemia and hemorrhagic shock [14]. Based on the previous data of safety of MB and on the numerous data in the literature [15,16,17,18,19] about the feasibility of SLN detection by that dye, we decided to start our own experience for SLN detection using MB dye as a sole, safe, cheap, and available tracer.

Patients and Methods

The study included 144 female patients with breast carcinoma admitted to the Surgical Oncology Unit, Alexandria Faculty of Medicine, in the period from July 2012 to March 2013. The study was approved by the Ethical Committee of Alexandria university faculty of medicine. All patients included in the study signed an informed consent form with full details about the study.

All patients included in the study had no suspicious axillary lymph nodes both by clinical examination and ultrasonography. SLN detection was done by injecting 1.8 ml of MB dye in the sub-areolar region just after induction of anesthesia and tapping massage was done for 8-10 min. The axilla was then explored via a small incision at the lowest hairline. SLNs were identified by being blue stained or having blue lymphatic entering it or both together. Formal level I and level II axillary dissection was done in order to assess that the harvested SLN truly represents the axillary lymph node status.

Results

This study included 144 patients with 2 of them suffering of bilateral disease. Hence, 146 procedures were done. The age ranged from 25 to 84 years with a mean of 53.73 ± 12.15 years. Premenopausal cases constituted 44.4% (64 cases) of the whole studied group.

The axillary lymph node status, after standard levels I and II dissection was found negative in 100 (68.5%) patients and positive in the remaining 46 patients (31.5%). The number of nodes dissected ranged from 8 to 18 nodes with a mean of 11.81 ± 2.40 (table 1).

Table 1.

Patient and tumor characteristics

Characteristic	n	%
Demographic patient data
Mean age, years (range)	53.73 (25–84)
<50	61	42.4
≥50	83	57.6
Menopausal status
Premenopausal	64	44.4
Postmenopausal	80	55.6
Surgical intervention
BCS	52	35.6
Mastectomy	94	64.4
Tumor characteristics
Tumor type
Ductal	98	67.1
Lobular	7	4.8
Mixed	41	28.1
Tumor size, cm
<2	38	26.0
<2–<5	103	70.6
≥5	5	3.4
Tumor grade
1	18	12.3
2	106	72.6
3	22	15.1
ER status
ER +ve	112	76.7
ER -ve	34	23.3
Her2 neu status
Her2 neu +ve	43	29.5
Her2 neu –ve	103	70.5
Lymph nodes identification
Failure	10	6.8
Identification	136	93.2

BCS = Breast conserving surgery, ER = estrogen receptor.

The procedure failed to identify the SLN 10 times and succeeded 136 times (fig. 1, 2). Thus, the identification rate was 93.15%. The number of SLN identified ranged from 1 to 8 nodes with a mean of 1.75 ± 1.17. The SLN was negative in 84 (61.8%) patients and was affected with metastasis in the other 52 (38.2%) patients.

Fig. 1.

Intraoperative identification of the SLN.

Fig. 2.

SLN with sentinel lymph vessel after being harvested.

Of the 10 cases in which the technique failed to identify the SLN, 8 cases were found to have axillary lymph node involvement with metastasis while the remaining 2 were free.

To correlate the state of the SLN with the state of the axilla, we excluded the 10 cases in which the technique failed. Thus, in 136 cases of identified SLN, the sentinel and axillary nodes status coincided in 118 patients. Both the SLN and axillary nodes were free of metastases in 82 patients (60.3%; table 2) and both were found involved in 36 patients (26.5%). The SLN was the only site of metastasis encountered with no other positive nodes in 16 patients (11.8%). 2 patients showed a false negative result. In these patients, the axilla was found involved with micrometastases that were not detected intraoperatively by frozen section. In our study, the sensitivity of MB dye technique was 96.3%. The false negative rate, which is considered the most important figure in the study, was 3.7%. The negative predictive value was 97.6% and the accuracy was 98.5%.

Table 2.

Relation between lymph state and axillary lymph (n = 136)

SLN	ALND specimen				Sensitivity	Specificity	Accuracy
	negative (n = 98)		positive (n = 38)
	n	%	n	%
Negative	82	60.3	2	1.5	94.74	83.67	86.76
Positive	16	11.8	36	26.5
p value			<0.001*

p value for chi-square test for comparing between the 2 studied group.

^*Statistically significant at p < 0.05.

As regards the side effects of MB, 4 patients (2.8%) reported bluish or greenish discoloration of urine in the first 24 h following surgery. 1 patient with bilateral breast cancer developed superficial gangrene involving both areolas. This patient was suffering from chronic dryness of the skin and may be considered a wrongly selected case. She was managed by debridement and frequent dressing but was lost in the follow-up period. We did not report any case with localized allergy or systemic anaphylaxis to MB.

Discussion

Combining radioactive colloid with blue dye injection is the best way to assess SLNB in breast cancer [20,21].

Many institutions and hospitals in developing countries - including ours - still routinely do complete ALND. This is partly attributed to the belief that axillary dissection, although falsely, gives the impression of security and partly to the lack of access or finance to provide isotopes and gamma probes.

Therefore, we aimed at evaluating the accuracy of MB alone in assessing the SLN and axillary status.

The identification rate of the SLN in our study was 93.15%. Kern [22] reported an identification rate of 97.5% and in the work by Golshan and Nakhlis [19] the identification rate was 96.5%. Both Kern [22] and Golshan and Nakhlis [19] used the sub-areolar isolated blue dye technique with the difference that Kern [22] used patent blue dye while Golshan and Nakhlis [19] used MB dye. Mokbel and Mostafa [23] also used the sub-areolar injection of MB dye in a study including 35 patients and the identification rate was 97% (34 patients). He reported a failure in a 77-year-old woman who had metastasis in 5 out of 13 lymph nodes dissected. Moreover, he reported no side effects of MB apart from temporary tattooing of the skin.

Varghese et al. [18] used the MB peritumorally for the identification of SLN. The identification rate was 96.5%. They attributed the rate of identification to the number of procedures performed. Thus, we state that the built up experience of the surgeon plays a major role both in the time and accuracy of identification.

The number of SLN identified ranged from 1 to 8 nodes with mean of 1.75 ± 1.17. Radovanovic et al. [24] reported similar results in both groups of their study as the mean number of SLN was 1.7 and 1.6. This is consistent with the results of Mokbel and Mostafa [23] and Anan et al. [25] who mentioned that the mean number of SLN identified was 2 and 1.6, respectively. The latter authors interestingly studied double mapping with sub-areolar blue dye and peritumoral green dye.

Giuliano et al. [26] showed a false negative rate of 12%. He stated that misidentification of blue stained fat as a SLN was an important cause of false negative rate but introduction of frozen section solved the problem and the false negative rate became 0% in his next series [27] 3 years later.

Kern [22] showed a false negative rate of 0% while Guenther et al. [28] showed a false negative rate of 9.7% and he stated that false negative rate was at early phase of the study due to lack of experience.

Veronesi et al. [9] had a false negative rate of 5%, while Tafra et al. [29] had a 0% false negative rate. This was explained by the usage of combined technique (using blue dye and radioactive colloid technique) for identification of the SLNs, and also the use of immunohistochemical stains in revision of SLN for patients with negative SLNs and positive non-SLN metastasis.

In the current study, the false negative rate was 3.7% which we think is quite acceptable and comparable to the results of other methods.In the present study, we stressed upon the negative state of axillary lymph nodes by clinical examination as well as by imaging procedures. Therefore, the use of MB alone as a sole tracer for SLN detection is a safe, simple, and reliable technique. The built-up experience is essential in overcoming the challenge of finding the target node(s).

Disclosure Statement

All authors have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work, that is, no conflict of interest among any of the authors.