Abstract
BACKGROUND:
The mainstream treatment of breast cancer is radical mastectomy accompanied with Axillary Lymph Node Dissection (ALND). Lately, more conservative methods accompanied by adjuvant radiotherapy have been gradually replacing radical modalities. The Sentinel Lymph Node Biopsy (SLNB) has been considered such a valuable alternative to surgery conservative approach.
OBJECTIVE:
To assess the agreement between SLNB in breast cancer patients and pathology results following ALND and to provide correlation between the sentinel lymph nodes (SLN) anatomical topography and biopsy positivity according to SLNBs.
METHODS:
Two hundred female breast cancer patients (31 to 83 years of age) underwent partial or simple mastectomy with or without subsequent ALND. All patients were randomized against selection criteria and underwent SLNB.
RESULTS:
In a set of 200 patients, 96.3% presented identical results between SLNB and pathology. 36% of them were confirmed with positive SLN through both approaches. Regarding the SLN topographic anatomical position, 67.3% of samples were located in the front axillary position, 24.5% in the front thoracic position, whereas 6.1% was located in the central axillary position.
CONCLUSIONS:
The correlation between the SLN topographic anatomical position and the pathology results, revealed that the majority of the SLN accumulates in the front axillary region. A larger patient population will statistically support this association.
Introduction
Breast cancer is the most prevalent malignant neoplasm in women from the Western hemisphere [1]. Until recently, the mainstream treatment was radical mastectomy accompanied with Axillary Lymph Node Dissection (ALND) in order to acquire optimal loco-regional tumor control and achieve long-term survival. Lately, treatment focused on more conservative methods accompanied by adjuvant radiotherapy has been proposed. This combinatorial intervention provides comparable results to radical mastectomy treatment for the overall, as well as the disease-free survival. This combination gradually replaces radical treatment and has been recently proposed as the gold standard care for breast cancer [2].
Due to the rapid progress in cancer therapeutics and diagnostics, the breast cancer associated mortality rates have been significantly reduced. Furthermore, the fact that breast cancer tends to display increased lymphatic spread, has prompted physicians to evaluate the significance of loco-regional lymphatic tissue treatment, as well as to optimize the mapping of the lymph node metastases as a factor in tumor prognosis [3].
The Sentinel Lymph Node Biopsy (SLNB) technique refers to the frozen section and has been a useful tool to assess axillary lymph nodes. The simplicity of the procedure and the reduction in surgical time have catalyzed the method of ALND; SLNB is also characterized by a significant decrease in postoperative hospital stays and morbidity rates, resulting in the overall improvement of patient life quality. SLNB is an accurate indicator of the axillary status during the course of the treatment; thus, for the last 15 years, it has become the standard axillary staging method in patients that are clinically confirmed negative for lymph node metastases [4]. When the SLN test is negative, the patient can avoid ALND with safety [5]. Finally, the procedure reduces the ALND-associated complications including lymphedema, pain and arm paraesthesia [6,7]. However, the SNLB is not unequivocally and unanimously considered sufficient as there might be underestimation of the disease state.
Frozen section examination is regarded as the most definitive intra-operative technique but the procedure execution and results interpretation must be immaculate to provide reliable data for a solid medical decision regarding the treatment course. Although there is always a possibility of incorrect and inconsistent diagnosis, the rated specificity of the frozen section ranges between 94% to 98% [8].
This lack of information prompted our research aims in order (a) to assess the SLNs results on a set of selected patients and identify whether they would agree with the data obtained from the biopsies of the pathology reports upon ALND and (b) to examine different SLN positioning and their association with increased positivity.
Methods
Study design
To assess the agreement between SLNB in breast cancer patients and pathology results following ALND and to provide correlation between the sentinel lymph nodes (SLN) anatomical topography and biopsy positivity according to SLNBs.
Patient sample
Two hundred female patients were enrolled in our study. One hundred patients were enrolled at the University Department of Surgery, General and Oncologic Hospital of Kifissia “Agii Anargiri”, Athens, Greece, and one hundred at the Surgical Department of the University of Patras, General Hospital of Patras. A written informed consent was sought and obtained from all patients.
Breast cancer diagnosis and treatment
Patients had been diagnosed with infiltrative breast cancer and had undergone partial or simple mastectomy with or without ALND. Patients with ductal or lobular in situ carcinoma, presence of mutations in the Breast Cancer susceptibility genes (BRCA1 and BRCA2), allergies towards the clinically positive N1 axilla technique, allergies to Isosulfan blue and radio colloid, increased age, Body Mass Index (BMI) >25, and pregnancy, as verified by patient history and further ad hoc examination, were excluded from the study.
All patients had undergone SLNB. The SLNB involves the injection of a radioactive colloid liquid substance and/or blue dye in (a) the skin in the breast area (intradermally or subdermally), (b) the breast parenchyma (usually in the vicinity of the tumor), or (c) the subareolar location [9]. In our study the surgeon injected 3 mL of Isosulfan blue (Lymphazurin, Wedgewood Pharmacy, New Jersey, USA) into the subareolar plexus. Breast massage was then carried out for about 5 min to dilate breast lymphatics. Isosulfan blue dye enters lymphatic channels and passively flows to the SLNBs. The labeled SLNBs are the ones that first receive drainage from the tumor, and can be located in various anatomical regions, though usually found in the low axilla (surgical level I) [9]. The use of Isosulfan blue dye for SLNB was not associated with any anaphylactic reactions in all selected cases.
Statistics
Statistical analysis was performed using SPSS Statistics for Windows, Version 22.0. Armonk, NY.
Results
Sample
Two hundred female patients diagnosed with breast cancer from January 2008 to February 2017 were enrolled in the study. The patients were from the regions of Attica and Peloponnese and the cities of Athens and Patras, Greece. The age of the patients was 55,3 ± 13,2 (MeanStandard Deviation), with a range from 31 to 83 years. All patients had undergone frozen section testing on their SNLs, with one hundred thirty six patients with pathology reports from their sentinel samples, and complied with the selection criteria as described in the
Comparison of frozen sections and histopathology data
We calculated the percentage alignment of the results for both approaches regarding these one hundred and thirty-six samples. A total of 96.3% (131/136) samples exhibited identical results, reflecting substantial agreement between the two methods. Specifically, 36% (49/136) of samples had a positive result in both SLN and ALN biopsies, 59.6% (81/136) of samples provided a negative result, and 0.7% (1/136) of samples provided both a positive and a negative node identified in both approaches, while 3.7% (5/136) of samples exhibited different results between the two approaches (Table 1).
Comparison of FS and SLNB histopathology data
Comparison of FS and SLNB histopathology data
ALND: Axillary Lymph Node Dissection, SLNB: Sentinel Lymph Node Biopsy, PA: Positivity Agreement, NA: Negativity Agreement.
With respect to the SLN positioning within each result group, 67.3% (32/49) of samples corresponded to front axillary lymph nodes, 24.5% (12/49) of samples corresponded to front thoracic lymph nodes, 6.1% (3/49) of samples lymph nodes occurred in the central position and 2% (1/49) of samples did not provide the lymph node position and it was not assigned.
With respect to the topographic anatomical negative lymph nodes placing within each group, the majority occurred at the front axillary position at a percentage of 66.7% (54/81). The 24.7% (20/81) of negative lymph nodes were represented in the front thoracic position, while the 7.4% (6/81) were located centrally in the axilla and 2.5% (2/81) of lymph nodes exhibited no position indication (Table 2).
Topographic anatomy of positive and negative SLNs
One sample was marked from the SLN and the pathology reports as positive and negative, respectively. Indeed, for this sample, a positive and a negative lymph node were processed in each approach. The localization of the lymph node was the front thoracic position.
Processing the five remaining samples provided conflicting results. All three were marked as negative in the frozen section, but the pathology analysis assigned them as positive. The localization of all three SLNs was in the front thoracic position.
Frozen section is a commonly-used methodology for evaluating SLNB in breast cancer and determine the need for ALND. Frozen section although not a cost- and time-efficient technique, presents distinct advantages like providing instantly information for the drainage of the proximal tumor areas [10]. This technique essentially guides the surgeon to determine the most appropriate treatment path. Despite the wide acceptance, there is still a debate for the necessity of the axillary dissection [9,11]. The results of the American College of Surgeons Oncology Group (ACOSOG Z0011) have revitalized our thinking and approach for the axillary management of small invasive breast cancers. Specifically, among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with SLN dissection alone was non inferior to the overall survival for those treated with ALND [12].
Serial sectioning and immunohistochemical staining cannot be applied to all axillary lymph nodes, as it is laborious and expensive for routine use. Hence, the SLNB technique focuses on a smaller number of lymph nodes that could likely contain tumor cells, depending on their geographical position as a first filter for lymphatic drainage [9]. Lymph node dissection offers the pathologist the ability to assess the presence of neoplastic cells and accordingly classify the lymph node as positive or negative. These results are then evaluated for the design of the therapeutic procedure based on standardized guidelines [13]. ALND and its complications can be avoided and the overall associated morbidity can be reduced if the patient undergoes breast-conserving surgery and whole-breast radiotherapy, in the case of negative SLNs, as well as in the case of only one or two positive present SLNs [5,13]. Indeed, for patients with only a couple of positive SLNs it is safe to avoid ALND since approximately 50–70% of patients with positive SLNs have no additional positive nodes [14,15]; therefore, the precise estimate on the additional node metastases is essential for the treatment. SLN most frequent positioning engaged with surgeons experience would determine test specificity and result to high accuracy SLN incision [16–19]. However, there is no sufficient literature to support in a concrete fashion the geographical position of the positive SLN following frozen sections and to address guidelines that define SLN hotspots localization. Moreover, there is. Therefore, this research, was planned and performed in order to develop a correlation between the SLN topographical position and the confirmed positive results following SLN biopsy and pathology analysis.
In a set of breast cancer patients, we identified a total of 49 confirmed positive SLN through both SLNB and pathology analysis. We further identified the majority of lymph nodes in the front axillary position (33/49 or 67.3%), while only one of these (1/49 or 6.1%) was located in the central axillary position. These results indicate, that the majority of the positive SLN in patients with breast cancer, are mostly localized in the front area of the breast (front axillary and front thoracic position), as it would be anticipated. This finding correlates well, with the fact that these represent the front line for any tumor cells lymphatic drainage while escaping the tumor. Furthermore, when axillary lymph node involvement skips the first station and is detected in the high-level station, the results obtained via SLNB may be false negative. The positive lymph nodes are not resectedby surgery and may result in postoperative local recurrence and distant metastasis. This phenomenon is known as “skip metastasis” with an unclear mechanism [20]. According to Lo et al., the analysis of positive SLNs located the hotspot for positive lymph nodes in the area set by the axilla hairline, a line tangential to and 2 cm below the centre of the hairline, the lateral border of the pectoralis major muscle and the mid-axillary line [19].
Additionally, our data correlate well with the published percentage for SLN sensitivity and false negative rates. Specifically, we reported a sensitivity ratio of nearly 93% with false negative ratio of around 5%, while rates of 89% for sensitivity [21] and 90% and 2.5% for sensitivity and false negative have been reported, respectively [22].
In conclusion, this work represents the first attempt to link SLN topographical position to pathology-positive results. While the majority of the positive lymph nodes accumulate in the front axillary region, a larger population of patients will substantially support the observed correlation.