|ORIGINAL CONTRIBUTION: SURGICAL ONCOLOGY
|Year : 2014 | Volume
| Issue : 2 | Page : 84-88
Targeted four-node sampling of axilla: A simple, reliable, and cost-effective approach in the management of breast cancer
Chintamani1, Mukesh Garg1, Manu Kaushik1, Anju Bansal2, Usha Agarwal2, Sunita Saxena2
1 Department of Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Institute of Pathology ICMR, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
|Date of Web Publication||31-Jul-2014|
Department of Surgery, VM Medical College and Safdarjung Hospital, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Background: Axillary lymph nodes are surrogate markers for mapping the optimal management of axilla in breast cancer, and their assessment is pivotal to management and outcome. Until now, the assessment of axillary lymph nodes largely relies upon sentinel node biopsy (dual method) or conventional lymph node dissection. The morbidity of axillary lymph node dissection, however, is well known. Sentinel node biopsy is thus considered the standard of care in a node-negative axilla. However, developing economies face the dilemmas and challenges of matching up to the high cost of gamma probe, the vagaries of its learning curve, and, often, the advanced stage of disease at which the patients present. Also, with the advent of neo-adjuvant chemotherapy, the axilla can now be downstaged to a node negative status (N0). In this setting, a targeted four-node sampling (FNS) can offer a simple, reliable, and cost-effective approach for assessment of the axilla. Material and Methods: A total of 50 patients with locally advanced breast cancer who had received neo-adjuvant chemotherapy form the nucleus of this study. In each patient, axillary mapping was done using periareolar injection of 3 mL of methylene blue dye immediately before surgery. Four blue nodes from the specified anatomical site at level-I were picked up and subjected to frozen section. The axillary dissection was subsequently completed in a conventional manner in all patients irrespective of the outcome of frozen section and the entire specimen was the sent separately for histopathological examination. The outcome of frozen section was compared and correlated with the actual histopathological assessment of entire axilla to find out the sensitivity, specificity, and false negative rates of the technique. Results: The sensitivity and specificity of FNS were found to be 89.5% and 93.3%, respectively. The negative and positive predictive values were found to be 84.6% and 100%, respectively. Conclusions: It was observed that "targeted" FNS using methylene blue dye can serve as a reliable and inexpensive alternative to other techniques for addressal of axilla even in locally advanced breast cancers. This is particularly relevant in developing economies where majority patients still present as locally advanced; and high-end facilities, such as gamma camera and isotope studies, are scarce.
Keywords: Axillary sampling, breast cancer, targeted
|How to cite this article:|
Chintamani, Garg M, Kaushik M, Bansal A, Agarwal U, Saxena S. Targeted four-node sampling of axilla: A simple, reliable, and cost-effective approach in the management of breast cancer. Astrocyte 2014;1:84-8
|How to cite this URL:|
Chintamani, Garg M, Kaushik M, Bansal A, Agarwal U, Saxena S. Targeted four-node sampling of axilla: A simple, reliable, and cost-effective approach in the management of breast cancer. Astrocyte [serial online] 2014 [cited 2022 Sep 29];1:84-8. Available from: http://www.astrocyte.in/text.asp?2014/1/2/84/137850
| Introduction|| |
Breast cancer is the second most common malignancy and its incidence is constantly rising in urban India. , The pattern of Indian disease is different from its Western counterpart; in that, the incidence has two distinct peaks. The first peak occurs in young patients in their 30s and 40s, and most of these patients present with locally advanced breast cancer (LABC) with axillary lymph node metastases.  Since axillary lymph node involvement is the most important prognostic marker of outcome, till now, axillary lymph node addressal/dissection has been considered an essential component of breast cancer management.
With the emergence of multi-modality treatment, neo-adjuvant chemotherapy (NACT) has now become an integral part of management of LABC. Assessment of response to NACT is usually limited to the assessment of primary, while there are studies to suggest that even axilla gets downstaged in a sizable number of patients (30-40%). ,,, In these patients, the conventional axillary lymph node dissection (ALND) with its associated morbidity of arm edema, frozen shoulder, etc., can be avoided. However, the false negative rates with SNB are a concern in this scenario on account of skip metastases (due to fibrosis) leading to false negatives and making SNB less sensitive.
There are enough studies now to show that false negative rates of SNB, although higher following NACT, are acceptable.  The authors have also studied the role of sentinel lymph node biopsy (SLNB) using methylene blue dye alone in LABC and found that the false negative rates are acceptable. This study was therefore conducted as an extension of the observations with SNB using dye alone method.  The aim of this study was to assess the role of targeted FNS in axillary mapping in LABC following NACT in order to find an inexpensive solution for the developing countries.
| Materials and Methods|| |
The study was conducted in the Department of Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital in collaboration with National Institute of Pathology, Indian Council of Medical Research, New Delhi over a period of 18 months from September 2011 to February 2013. Due IRB and ethical committee approval was obtained, A total of 50 histopathologically confirmed cases of LABC (Stage IIb and Stage III) were enrolled. The essential work up included ultrasonography/mammography imaging and a complete metastatic work up for accurate staging of the disease. Patients were also evaluated for fitness to receive NACT by carrying out blood investigations (complete blood counts, kidney function tests) and cardiac imaging (electrocardiogram [ECG] and 2-D echocardiography). All patients received three cycles of NACT (CAF Regimen: Cyclophospamide 500 mg/m 2 , Adriamycin 50 mg/m 2 [maximum dose 80 mg], and 5-Fluorouracil 500 mg/m 2 ) at an interval of 3 weeks. Response was assessed using RECIST (response evaluation criteria in solid tumors) after each cycle. Three weeks after the last cycle, patients were offered surgery (modified radical mastectomy [MRM] or breast conservation) depending on the response to NACT.
Operative technique of Targeted Four-node Sampling
After draping the patient, 3-5 mL of methylene blue dye was injected intradermally in the periareolar region followed by breast massage for 5 min [Figure 1]. After raising the superior flap, axilla was dissected and blue nodes at level-I were picked up from within the anatomical boundaries of the defined quadrangle bounded by upper intercostobrachial nerve superiorly, chest wall medially, thoracodorsal pedicle laterally, lateral border of pectoralis major anteriorly, and lateral border of latissimus dorsi laterally [Figure 2]. Blue nodes from the above-mentioned quadrangle were sampled [Figure 3] and sent for frozen section as well as paraffin-embedded section [Figure 4]. Meanwhile, mastectomy/breast conservation surgery (BCS) and conventional ALND (up to Level III) [Figure 5] were completed and this specimen was sent in a separate container for final histopathological examination. The final histopathology of rest of the axilla was compared with the sampled blue nodes to assess the sensitivity/specificity and accuracy of the technique.
|Figure 1: Periareolar injection with 3-4 mL of methylene blue. Following this, the breast is massaged.|
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|Figure 2: Demonstrates the anatomical boundaries of the dissected square. Superiorly, lies the upper intercostobrachial nerve, medially the chest wall, laterally the thoracodorsal pedicle, anteriorly the lateral border of pectoralis major and lateral border of latissimus dorsi.|
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|Figure 3: The four blue nodes were dissected and sent for frozen section biopsy to evaluate for metastasis.|
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|Figure 5: Completed axillary dissection, axillary vein, and thoraco-dorsal pedicle can be visualized.|
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The data were analysed using descriptive statistics, the McNemar's chi-square test and Student's paired t-test were used to determine association between two variables ("P " value of less than or equal to 0.05 was taken as significant).
The values of the diagnostic parameters related to techniques of targeted four-node sampling (TFNS) were estimated in terms of sensitivity, specificity, positive predictive value, negative predictive value, false negative rates, and accuracy. This was done on the basis of distribution of 50 cases into four various possible categories of four-node sampling (FNS) and axilla expression patterns. Data analysis was performed using SPSS 18.0 version.
| Results|| |
The patients in the study were in the age group of 32-72 years with a mean age of 51.47 years. The response to NACT was found to be statistically significant (P value 0.001) [mean pre-NACT tumor size was 6.28 cm and that decreased to less than 4.35 cm in response to NACT in 60% patients [Table 1] and [Table 2]]. Regarding the extent and type of surgery, 83.3% patients underwent MRM and to the remaining (16.7%) BCS was offered [Table 3].
|Table 1: Comparisons of Tumor Size Pre- and Postneoadjuvant Chemotherapy (n = 50)|
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TFNS accuracy parameters were calculated according to standard definitions used in various studies on sentinel lymph node/s or axillary sampling (AS). The results were categorised as true positives, true negatives, or false negatives, false positives as compared with rest of the axilla (based on final histopathology). Sensitivity of FNS was found to be 0.895 or 89.5% and the specificity was observed to be 1.00 or 100%. Accuracy of FNS (i.e., [true positive + true negative]/[total number of patients]) was found to be 0.933 or 93.3%. False negative rates in the study were found to be 10.5%, while the negative predictive value (i.e., true negative/[true negative + false negative]) was found to be 0.846 or 84.6% [Table 4]. These results are all comparable with other published studies.
|Table 4: Four-node Sampling Validation as Compared with Rest of the Axilla (n = 50)|
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| Discussion|| |
Axillary lymph node status is the most important prognostic factor in patients with breast cancer, the survival rates drop by 50% in the presence of axillary node metastasis. The standard surgical care of breast cancer involves mastectomy or breast conserving surgery with ALND. ALND is associated with morbidity in the form of arm edema, numbness or paraesthesia, shoulder stiffness, and, rarely, axillary vein thrombosis. Therefore in patients with an N0 axilla, there is a case for avoiding this morbid surgery.
The dissection of axilla is primarily to prognosticate the disease, but its therapeutic role has also been understood in recent times. The sensitivity of clinical examination of axilla is subjective, variable, and also limited. A clinically node negative axilla has false negative rates of 30-35% with an 18% risk of local recurrence (when assessed finally histologically), translating into a survival detriment of 5.4% if not addressed surgically. 
The standard of care in early breast cancer with an N0 disease is to avoid conventional ALND and its morbidity. The approach therefore could be in the form of SNB or AS or TFNS. Accordingly in patients with a locally advanced disease that have responded to NACT and where the axillae have been downstaged to N0 status, there is a need for a similar, equally sensitive and a less morbid approach to axilla. 
SLNB and other methods of sampling axillae are associated with relatively negligible morbidity when compared with conventional ALND. A classical sentinel node is the one that picks up the dye and isotope first and predicts as a "sentinel" the presence or absence of disease in the axilla. The intent therefore is to predict the axillary status by a relatively less morbid technique and only when the sentinel node is positive, the axilla may need to be addressed using conventional (more morbid) techniques. AS has been in use for a long time including the low AS or FNS or what the authors are recommending "TFNS" wherein the dye makes it easier to dissect and pick up the blue nodes (targets) rather than the uninvolved fibro-lymphatic tissues at level-I. However, SNB using dual methods of dye and isotope is what is practiced as standard of care at most centers. TFNS can match it and is also expected to improve the yield and also reduce morbidity of dissection [Figure 1].
In a study from Edinburgh, 417 patients (T1-T3/N0-N1) were randomized in to mastectomy + four-node axillary sampling (4NAS) and mastectomy + complete ALND.  Radical radiotherapy (breast and axilla) was given to patients with positive 4NAS and not to those who underwent complete ALND. The accuracy was observed to be equal in both groups and in only one AS (0.5%) they failed to identify positive nodes. In another study (4NAS followed by ALND) of 237 patients (T1-T2/N0-N1) it was found that 4NAS may be as accurate staging procedure as ALND and reported an overall false negative rates of 6.5% with 4NAS.  "Nottingham Breast Unit", studied 200 patients (T1-2/ N0) and directly compared SLNB using hot node technique (lympho-scintigraphy) with 4NAS (Edinburgh technique).  Sentinel lymph node was identified in 191 patients (96%) and when compared with SLNB, 4NAS failed to identify metastasis in one patient (2%). On the contrary, SLNB failed to identify metastasis in eight (14%) patients in whom 4NAS detected axillary lymph node metastasis and hence under-staged the axilla. They concluded that SLNB performed using radio labeled colloid has no advantage over 4NAS when nodes are assessed by standard histological technique. They affirmed that SLNB for breast cancer may have little to offer to four-node-or TFN samplers. 
A comparative Japanese study of 206 patients of operable breast cancer undergoing SLNB and 4NAS procedure (Edinburgh technique) showed that the accuracy and sensitivity of 4NAS (98% and 96%) was comparable to that of SLNB (99% and 98%), respectively. The study concluded that 4NAS can be considered an alternate safe and easy procedure for axillary staging. , In another study, it was attempted to evaluate whether that additional AS over and above SLNB improves the false negative rates of SLNB.  In addition, it has been investigated whether women with positive SLN and no further disease in axilla could be identified by additional AS and therefore spared ALND. Sixty-seven combined SLNB + AS procedures were performed in 66 patients followed by axillary dissection (Level II). Additionally sampled nodes were documented on intraoperative palpation if they were clinically suspicious (axillary sampling: suspicious [AS-S=12]) or not suspicious (axillary sampling: nonsuspicious [ASNS=43]). By performing an additional sampling in these 12 (18.5%) cases based on clinical suspicion (AS-S), 3 of the 4 false negative SLN results were avoided, reducing the false negative rates result from 14.3% to 3.6%. Sampling of nonsuspicious nodes (AS-NS) in the remaining 43 cases did not avoid the fourth false negative case. However, the benefit of additional sampling was only seen in those cases with larger tumors (≥ 3 cm) and clinically suspicious nodes (n = 12). Hence, there is no case for a routine additional sampling making four nodes an optimum number. ,
The present study includes 50 patients with LABC. They were treated by NACT followed by MRM or breast conservative surgery with FNS using blue dye from level 1 axilla. TFNS showed sensitivity rates of 89.5%, false negative rates of 10.5%, accuracy of 93.3%, and negative predictive value of 84.6%.
| Conclusions|| |
In developing countries like India where most patients still present with LABC and facilities for gamma camera and isotope studies are limited, TFNS can serve as a reliable and less expensive alternative to sentinel node biopsy and other methods of addressing/detecting metastases in the axilla. The technique is also relatively easier to learn and teach unlike a steep learning curve associated with sentinel node biopsy using the dual method.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]