|Year : 2014 | Volume
| Issue : 2 | Page : 78-84
The relationship between sentinel lymph node metastasis size, extracapsular extension and survival in breast cancer
Kelly J Rosso1, S David Nathanson1, Dhananjay Chitale2, Meredith Mahan3
1 Department of Surgery, Henry Ford Health System, W Grand Boulevard, Detroit, Michigan, USA
2 Department of Pathology, Henry Ford Health System, W Grand Boulevard, Detroit, Michigan, USA
3 Department of Public Health, Division of Biostatistics and Epidemiology, Henry Ford Health System, W Grand Boulevard, Detroit, Michigan, USA
|Date of Web Publication||16-Oct-2014|
S David Nathanson
2799 West Grand Boulevard Detroit, Michigan 48202
Source of Support: None, Conflict of Interest: None
Background: Sentinel lymph node (SLN) tumor metastasis size (TMS) and extra-capsular extension (ECE) are predictive of non-SLN metastasis. We hypothesized that SLNTMS and ECE would also be predictive of systemic metastasis and death.
Materials and Methods: Data from 2,001 women with breast cancer who underwent SLN biopsy were prospectively collected and retrospectively analyzed. SLNTMS and ECE were measured, reported according to standard pathologic protocols and recorded. Data were analyzed from 252 patients with both SLNTMS and ECE information available. Cancer-specific mortality and all-cause mortality were observed, calculated and multivariable analyses performed to identify significant interacting variables amongst demographics, clinical stage and pathological characteristics.
Results: Thirty eight treated patients died from any cause and 12 died of cancer during the 16.4 year follow-up. Patients with ER expression had a significantly lower risk of dying of cancer compared to those who lacked ER expression (HR = 0.198, 95% CI 0.06-0.62; P = 0.006). SLNTMS (P = 0.929 and 0.677) and ECE (P = 0.723 and 0.926) were not significant in the multivariable models of either disease specific or all-cause mortality.
Conclusion: Neither SLNTMS nor the presence of ECE affected disease-specific or overall mortality in our breast cancer patients.
Keywords: Breast cancer, extra-capsular extension, lymph node metastasis size, overall survival
|How to cite this article:|
Rosso KJ, Nathanson S D, Chitale D, Mahan M. The relationship between sentinel lymph node metastasis size, extracapsular extension and survival in breast cancer
. Arch Int Surg 2014;4:78-84
|How to cite this URL:|
Rosso KJ, Nathanson S D, Chitale D, Mahan M. The relationship between sentinel lymph node metastasis size, extracapsular extension and survival in breast cancer
. Arch Int Surg [serial online] 2014 [cited 2020 Oct 21];4:78-84. Available from: https://www.archintsurg.org/text.asp?2014/4/2/78/143083
| Introduction|| |
The American College of Surgeons Oncology Group Z10011 study and similar randomized trials , have persuaded surgeons to avoid complete axillary lymph node dissection (CALND) in patients with a positive sentinel lymph node (SLN). In SLN positive patients with small primary disease and clinically negative axilla (cN0) without gross extranodal or extracapsular extension treated with breast conserving surgery (BCS) and radiation, there is a tantalizing argument supporting the less aggressive surgical approach in the axilla. Having yet to be proven by a prospective randomized trial, it is likely that patients with clinical N1, 2 or 3 disease might not fare as well without a CALND. As the number of positive axillary lymph nodes is inversely related to survival,  it is also possible that a threshold size of SLN metastasis exists, above which CALND would improve survival in patients with cN0 disease.
A positive correlation exists between primary breast cancer size, SLN  and systemic metastasis.  SLN tumor metastasis size (SLNTMS) increases the likelihood of non-SLN (NSLN) metastasis ,,,, and is incorporated into predictive algorithms.  The likely effect of pathologically measured SLNTMS on systemic metastasis can be extrapolated from three well-known associations. First, there is an increased risk of systemic metastasis and death in patients who present with clinically suspicious axillary lymphadenopathy  compared to cN0, especially if confirmed by image-guided biopsy. ,, Clinically apparent bulky axillary disease is presumably correlated to the amount of tumor in the nodes, however clinical evaluation of the axilla can have high false positive rates.  Although no-one has reported a correlation amongst total axillary node tumor volumes and outcome, a correlation exists between clinically obvious pathologically large tumor volume in SLNs and systemic metastasis. Second, survival decreases with an increasing number of involved axillary lymph nodes. , There is a direct relationship between cN0 but pathologically positive nodes and survival.  Third, if tumor is limited to the SLN disease specific (DSS) and overall survival (OS) are significantly longer than when compared to NSLN involvement. , Accurate microscopic measurement of SLNTMS is now a requirement by the College of American Pathologists (ACP). , Unlike the statistically important correlation between SLNTMS and systemic metastasis in melanoma, , evidence for such a relationship in breast cancer is sparse.
Extra-capsular extension (ECE) occurs when the tumor infiltrates through the capsule into perinodal soft tissue. It is most often seen in the presence of massive nodal tumor volume and may be an index of biologically more aggressive tumor. ECE is one pathologic characteristic used to predict axillary NSLN metastases. ,, Large tumor burden in the SLN and ECE are frequently concurrent, considered aggressive pathologic features  and associated with an increased risk of NSLN disease in breast cancer. ,, ECE and SLNTMS are independent predictors of recurrence and death in other tumor types, , but their defined relationship to prognosis in breast cancer is not clear. Some authors suggest that ECE is associated with increased NSLN involvement  and a higher likelihood of local and distant recurrence.  Others suggest ECE has no impact on survival. 
In an era where less morbid surgery for breast cancer is becoming standard, it is appropriate to subtype patients and assign treatment modalities based on individual tumor characteristics. ECE, an exclusionary criterion for the Z10011 study, might continue to be associated with a worse outlook if it is proven to predict a worse outcome. If ECE predicts NSLN involvement which positivity predicts worse survival, it seems likely that ECE would also predict a worse outcome. In such cases the surgeon might justify a CALND for a positive SLN. Similarly if SLNTMS is correlated with systemic metastases, the information could be useful in designing further prospective trials that question whether CALND can be avoided in all patients with axillary metastases. We investigated the relationship of SLNTMS and ECE to disease specific (DSS) and overall survival (OS) in patients with cN0 breast cancer.
| Materials and Methods|| |
Our prospectively accrued database of 2,001 breast cancer patients followed from one to 16.4 years includes those who underwent SLN biopsy at two major hospitals and three suburban surgicenters  inside the Henry Ford Health System (HFHS) of Michigan. Implementation and maintenance of this internet database continues to be re-approved by the Institutional Review Board. All information available on the electronic medical record (EMR) for every new breast cancer patient with cN0 undergoing SLN biopsy was recorded by a professional abstractor in the Public Health Department.
SLN biopsy using filtered 99m Tc radiocolloid and isosulphan blue or dilute methylene blue was performed as previously described at our institution. 
Prior to ACP requirements, documentation of SLNTMS was not routinely included in the original pathology report. Archived specimen slides were retrieved whenever possible and SLNTMS measured in cases that size was not recorded.
Clinical breast cancer management
The Breast Cancer Service at HFHS consists of surgical, medical and radiation oncologists that participate in the multimodality management of breast cancer patients. Cases are discussed at a weekly tumor board and National Comprehensive Cancer Center guidelines  are used to treat most patients.
Level I and II CALND was offered to any patient with a positive SLN, including micrometastasis, which was standard of care. A small number of patients did not undergo CALND because they declined or were randomized to no further surgery in the Z10011 study. Surgical treatment of the breast primary lesion(s) was at the discretion of the surgeon. Some patients had mastectomies (approximately 25%), but the majority had BCS.
Systemic chemotherapy, appropriate hormonal treatment, trastuzamab (for Her2-neu positive tumors) and some experimental therapies were given and clinical, imaging and laboratory follow-up studies were done at the discretion of the oncologist and surgeon.
The identification of new systemic and/or loco-regional metastases, and the date of any death, was searched for, discovered and recorded in the database as previously described. 
Sentinel lymph node tumor metastasis size (SLNTMS) measurement
The SLNs were serially sectioned along the short axis into 2 mm slices, and 4-6 sections, each cut 5 micron thick and were stained with hematoxylin and eosin (H&E). The single largest metastasis identified by routine H&E staining was measured. In cases of multiple SLNs, only the largest metastasis was documented. Single tumor cells widely scattered throughout the SLN is a common mode of spread in lobular carcinoma; in such cases the entire extent of nodal tumor involvement was measured. Cytokeratin immunostain was not routinely performed except to confirm lymph node metastases of invasive lobular carcinoma. Small metastatic tumors measuring 0.2 mm to 10 mm were measured under a microscope with an ocular micrometer. Larger tumor metastases (10 mm and over) were measured on gross cut section using a hand lens and ruler. Micrometastasis was categorized as deposits less than 2 mm.
Evaluating extra-capsular extension (ECE)
ECE was reported when the tumor infiltrated through the capsule into peri-nodal soft tissue. When tissue surrounding the lymph node reacted to the infiltrating tumor by producing excess fibro-collagenous tissue, making the detection of subtle ECE difficult to judge, additional cuts of the paraffin block were obtained to definitively record ECE as present or absent.
Patient data included clinical, pathologic and follow-up information. The clinical data included: Age, race, surgery performed, breast irradiation, chemotherapy, hormone manipulation, trastuzamab when indicated. The pathologic data included: Primary tumor size, number of positive axillary nodes, SLNTMS, ECE, receptor (HER2, estrogen, progesterone) status, histology, stage, and lymphovascular invasion (LVI). Patients reported to have no nodal metastases were not included in the SLNTMS analysis. SLNTMS was separately stratified to compare survival between "micrometastasis" and "macrometastasis". Continuous variables were evaluated for normality and those that met assumptions were compared between groups using two-sample t-tests and those that did not were compared using Wilcoxon two-sample tests. Categorical data were compared using chi-square or Fisher's exact tests as appropriate based on cell size. Each factor was examined individually in terms of the univariate effect on survival using Kaplan-Meier plots, log-negative-log plots and log-rank P-values. Any variable that approached statistical significance was placed in a multivariable Cox proportional hazards regression model which was then refined by excluding all but statistically significant variables (P < 0.05). Analyses were done using SAS 9.2 by statistician (MM).
| Results|| |
A total of 2,001 patients were available for analysis of which 276 had SLNTMS data, 362 had ECE data and 252 had both SLNTMS and ECE data. Of the 252 patients with both SLNTMS and ECE data, 214 were alive at the last known contact and 38 (15.1%) had died from any cause, not absolutely proven to be cancer associated, and 12 of whom died from cancer. Median follow-up time was 55 (95% CI 48, 60) months.
Of the 252 patients with SLN metastasis in our examined cohort, 55 patients were categorized as having micrometastasis and 197 as having macrometastasis. Neither overall nor disease-specific survival time were significantly different between patients with micrometastasis and patients with macrometastasis on univariate log-rank tests (P = 0.969 and P = 0.432, respectively). The presence of ECE was not a significant factor in the univariate analyses of OS and DSS (P = 0.723 and 0.926, respectively) [Table 1] and [Table 2].
|Table 2: Univariate and multivariate analysis for cancer specific survival|
Click here to view
The presence of LVI was significant predictor of survival in the univariate assessment of OS (P <0.001). When examined in the multivariate model of overall survival, the presence of LVI approached but failed to gain statistical significance (P = 0.068). Advanced stage became a significant independent predictor of overall survival in the multivariate analysis (P <0.001) but in comparing several subgroups of small cell counts, the results of the multivariable analysis became unreliable.
Absence of ER expression was the only significant variable in the univariate analysis of DSS (P = 0.002). When examining ER status as a sole predictor of disease specific survival, patients with ER expression had a significantly lower risk of dying of cancer compared to those who lacked ER expression (HR = 0.198, 95% CI 0.06-0.62; P = 0.006).
| Discussion|| |
Our findings suggest that in patients with cN0 disease who had era-defined appropriate breast and axillary surgery followed by systemic and radiation therapy, tumor metastasis size in the SLN was not related to survival. Similarly, ECE did not impact survival, differing from those studies that show an increased likelihood of non-SLN metastasis when ECE was present. ,
Although ECE is most often seen with larger nodal tumor volume, it has been documented in SLNs with micrometastasis,  suggesting a unique biology of metastasis in some cases. Lobular carcinomas may have ECE in spite of small metastatic focus in the lymph node. 
Clinical application of the SLN biopsy was first seriously investigated in melanoma patients and from that has become critically important in the staging of breast cancer patients. In melanoma, SLNTMS and ECE are independent predictors of recurrence and mortality with survival directly correlated with the number of metastatic lymph nodes. , One of the major differences between breast cancer and melanoma is the effectiveness of adjuvant therapies. Interferon, the only currently recommended adjuvant therapy for melanoma,  has a very small impact on survival.  Even the established therapies for metastatic melanoma, interleukin 2 and dacarbazine, have meager responses when used for measurable disease. ,, Information regarding the long-term survival impact of the new systemic therapies for melanoma, ,, approved in 2011 by the FDA, is not yet available. In contrast, the significant improvement in breast cancer prognosis over the past thirty years is partly attributable to the effectiveness of systemic therapy.  Failure to demonstrate a correlation amongst SLNTMS, ECE and death in our cohort may merely reflect the effectiveness of systemic therapy for breast cancer. Any true differences could be masked by the dominant effects of systemic therapy.
The strengths of this study include use of vigorously maintained records, accuracy and efficiency of data acquisition with minimal data lost and no significant statistical bias, the uniform management of all our cancer patients by a team of breast specialists and the availability of long term follow-up in a stable captured population managed at our institution.
The weaknesses of this study are primarily related to the small number of deaths, a problem also noted in the ACOSOG Z10011 study,  and the relatively large number of patients who died of unknown causes. Some of these patients could conceivably have died from metastatic breast cancer which would have impacted the analyses.
Radiation was administered to the whole breast in patients who underwent BCS but usually not in patients who had mastectomies. Axillary radiation was usually given for patients with more than three positive nodes at the discretion of the radiation oncologist. This could be important since radiation can improve overall survival in selected patients. In a meta-analysis of patients who underwent definitive surgery and adjuvant chemotherapy, radiation administered after CALND for positive nodes was associated with reduction in breast cancer mortality and recurrence. 
Based on this study, surgeons might be prepared to randomize patients with cN0 disease and positive SLNs with ECE to CALND or not, as such studies up to this point exclude patients with ECE or gross extranodal disease. , Such a study would eventually be a powerful vindicator of smaller operations in the axilla for a larger population of patients to include those with extracapsular nodal disease. Similarly, larger tumors in the axillary nodes may be candidates for less aggressive axillary surgery. As long as systemic treatment for breast cancer continues to improve and produce cures, less surgery, including the avoidance of CALND, may well become the standard in patients with increased axillary disease burden. Despite the sporadic initial criticism of the Z10011 results, it has revolutionized the approach to the axilla in early breast cancer and stimulated the idea that even more advanced breast cancer patients may avoid complication-laden axillary surgery.
This study was supported by the Nathanson/Rands Chair in Breast Cancer Research.
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[Table 1], [Table 2]