- Email: [email protected]
Use of axillary lymph node dissection (ALND) in patients with micrometastatic breast cancer
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
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Use of axillary lymph node dissection (ALND) in patients with micrometastatic breast cancer Madison Collins, BA,a Cristina O’Donoghue, MD, MPH,b Weihong Sun, MD,b Jun-min Zhou, MS,c Zhenjun Ma, PhD,c Christine Laronga, MD,b and Marie Catherine Lee, MDb,* a
University of South Florida Morsani College of Medicine, Tampa Florida Comprehensive Breast Program, Moffitt Cancer Center, Tampa, Florida c Department of Biostatistics, Moffitt Cancer Center and Research Institute Tampa, Florida b
Q3
article info
abstract
Article history:
Background: Sentinel lymph node (SLN) biopsy is the current prognostic tool for clinically
Received 1 December 2016
node-negative breast cancer patients. If the SLN reveals macrometastasis, axillary node
Received in revised form
dissection (ALND) is recommended. However, the use of ALND in patients with micro-
8 February 2017
metastasis is debated. The objective of this study was to assess the utilization of ALND in
Accepted 24 March 2017
the treatment of micrometastatic breast cancer.
Available online xxx
Methods: An IRB approved, retrospective study of a pooled dataset of breast cancer patients with micrometastatic disease on SLN biopsy was performed. Patients diagnosed from 1999-
Q4
Keywords:
2016 were identified via query of a single-institution NCCN breast cancer database as well
Breast cancer
as a prospective tumor board.
Axillary lymph node dissection
Results: A total of 91 patients were diagnosed with micrometastatic nodal disease. The
Micrometastasis
median age at diagnosis was 56 y (range: 31-85); median follow-up time was 47 mo (range:
Lymphedema
0-203 mo). 42/91(46.2%) patients had ALND of which 37/42 (88.1%) were a second operation; 3/42(7.1%) patients had additional positive nodes found at ALND. 44/91 (48.4%) patients received radiation. 7/91 (7.7%) patients had a recurrence, 5/7 local, including one axillary (2.1%; patient declined ALND). Conclusions: Given that the risk of lymphedema after ALND ranges between 20%-53%, the morbidity of ALND may far exceed the likelihood of detecting further nodal involvement in women with micrometastatic disease: 7.1% in this series. ª 2017 Elsevier Inc. All rights reserved.
Introduction Q5
Nodal involvement in breast cancer is an important predictor of survival. Currently, the standard procedure to pathologically stage clinically node-negative patients involves a sentinel lymph node (SLN) biopsy.1 This procedure entails locating, removing, and determining the presence of cancer cells in a lymph node by injection of a nuclear dye and/or a
blue dye into the breast. These dyes travel through the breast and deposit in the lymph nodes receiving the majority of lymphatic drainage from the breast, and thus theoretically are the most likely nodes to demonstrate metastatic axillary disease, hence the term “sentinel node.” The nodes picking up the blue or nuclear dye are detected intraoperatively and resected for pathologic review.2 When a positive SLN is found containing micrometastases (deposits of tumor cells in lymph
* Corresponding author. Comprehensive Breast Program, Moffitt Cancer Center 10920 N. McKinley Dr, Tampa, FL 33612. Tel.: þ1 813-7458480; fax: þ1 813 745-7827. E-mail address: [email protected] (M.C. Lee). 0022-4804/$ e see front matter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2017.03.039
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nodes defined as >0.2 mm and 2.0 mm), the chances of metastases in other nonsentinel nodes (NSLN) historically is 0%-20%.3 Several predictive models are used in the clinical setting to estimate the risk of additional nodal involvement on nonsentinel nodes, but none specifically address micrometastatic disease. In addition, no model has been able to predict a zero percent chance of additional nodal involvement beyond the SLN.3-9 The results of this biopsy, along with the phenotypic characteristics of the tumor, help determine the course of treatment, including hormone therapy, radiation, and axillary lymph node dissection (ALND). Axillary node dissection is used for predicting prognosis, improving locoregional control, and assisting in staging; however, it does not confer a survival benefit.10-12 Patients receiving ALND could have distant metastasis even in the absence of locoregional recurrence or initial node negativity12,13; thus, the operation of surgically clearing the nodes would have no impact on cancer-related mortality. Furthermore, the course of adjuvant therapy is determined more by the immunohistochemistry of the tumor than by the ALND.10 Currently, the use of ALND in patients with clinically node-negative lymph nodes is debated due to high rates of long-term morbidity from axillary dissection and low rates of recurrences.1,3,13-17 Given the potential morbidities of ALND, including lymphedema, infection, peripheral neuropathy, and pain, several studies favor omitting ALND in patients with favorable tumor characteristics and low risk of further nodal involvement.3,10,14,15 Another study suggests that SLNB alone is equivalent to ALND in terms of locoregional control and overall survival.18 However, the 2016 NCCN Breast Cancer guidelines still support the use of ALND even in patients with pathologically positive but clinically node-negative axillas.19 Given the current controversies surrounding micrometastatic axillary disease and the inconsistent use of axillary dissection, the primary goal of this study was to evaluate the utilization and results of ALND as part of a multidisciplinary treatment plan for micrometastatic breast cancer.
Methods This is a retrospective study of a single-institution series of consecutive patients found to have micrometastatic disease after surgery for primary breast cancer. Both the institutional NCCN breast cancer database and a prospective tumor board database were queried for pathologic micrometastatic cases after definitive surgical staging. Institutional Review Board permission was obtained before data collection and analysis. All patients were diagnosed between 1999 and 2016 with primary micrometastatic disease on SLN biopsy pathology for incident, invasive breast cancer. All patients received either lumpectomy or mastectomy, in addition to axillary evaluation, at a single NCI-designated Comprehensive Cancer Center by a fellowship-trained surgical oncologist. Patients with micrometastasis associated with recurrent disease were excluded. Patients receiving neoadjuvant therapy were also excluded from this study. The institutional NCCN database collected breast cancer data from 1997 through 2012; the national data collection was closed in 2012, but a prospective
programmatic Breast Cancer database continues to collect clinical and pathologic breast cancer data. Because the primary endpoint of this study is the use of axillary dissection in current breast cancer management, the time frame for the database searches was carried through to include recent cases. Medical records were reviewed, and multiple data points were collected in addition to data collected from the NCCN and Breast Program databases. Data points collected and Q6 analyzed were as follows: date of birth, date of diagnosis, age at diagnosis, method of diagnosis (axillary US, MRI, or axillary FNA), hormone receptor status, type of breast surgery (lumpectomy versus mastectomy), date of surgery, histology on final pathology, result of intraoperative imprint cytology (if performed), number of SLN biopsied, timing of axillary node dissection (if performed), grade of cancer and largest metastasis, use and location of radiation as treatment of initial breast cancer, location and date of local recurrence, location and date of distant recurrence, last follow-up date, and number of patients deceased. Follow-up time was calculated from the last surgery date to the last documented oncology note. Types of radiation included none, whole breast, chest wall, or nodal. If second surgery was performed, all data points were collected when available. Last follow-up date was defined as the last documented appointment with an oncologist or surgical oncologist at either an outside institution or our facility. Demographics were summarized using descriptive statistics. Wilcoxon rank-sum test, Kruskal-Wallis test, and Fisher exact test were used for data analysis.
Results A total of 91 patients were diagnosed with micrometastatic nodal disease in the selected time frame. The median age at diagnosis was 56 y (range 31-85). Fifty patients (54.9%) received an MRI preoperatively, 11 of which showed an abnormal axilla, prompting further workup. Of these 11, eight (72.7%) had an axillary ultrasound. Thirty-four of the 91 patients (37.4%) had a diagnostic axillary ultrasound, and 13 patients had an FNA of the axilla performed for diagnosis. Of these, one patient was diagnosed with a positive axilla on percutaneous biopsy. The sensitivity of axillary US and FNA for micrometastatic axillary disease was 41.2% and 15.4%, respectively. The sensitivity of MRI for micrometastatic axillary nodes was 22%. Seven cases (7.7%) were estrogen receptor/progesterone receptor (ER/PR) negative, and five of these cases (5.5%) were ER/PR, Her2Neu negative. Thirty-eight patients received a lumpectomy, and 53 patients received a total mastectomy. The histological results on final pathology showed that the majority of patients had invasive ductal cancer (76/91, 83.5%) followed by invasive lobular cancer (11/91, 12.1%). The remaining four patients were classified as “other.” The majority of patients (50/91, 54.9%) were diagnosed with grade 2 cancer, followed by grade 3 (29/91, 31.9%), and grade 1 (11/91, 12.1%). The largest size of metastasis found during SLNB was documented, ranging from 0.2-2.0 mm (mean 0.99 mm). Eighty-one of 91 patients (89.0%) received in intraoperative imprint cytology evaluation of the sentinel nodes. The
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collins et al alnd in micrometastatic breast cancer
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Table 1 e Clinical and pathologic features versus overall recurrence. Variable
ER status
PR status
Her2neu (FISH)
Grade
Histology
First surgery type
Second surgery type
Breast radiation
Nodal radiation
Level
n (%)
P value
Total
NED
Any recurrence
ERþ
61 (87.1%)
58 (87.9%)
3 (75%)
ER
9 (12.9%)
8 (12.1%)
1 (25%)
Total
70
66 (94.3%)
4 (5.7%)
PRþ
79 (86.8%)
73 (86.9%)
6 (85.7%)
PR
12 (13.2%)
11 (13.1%)
1 (14.3%)
Total
91
84 (92.3%)
7 (7.7%)
Equivocal
2 (2.2%)
2 (2.4%)
Negative
80 (87.9%)
74 (88.1%)
0 (0%)
Positive
9 (9.9%)
8 (9.5%)
1 (14.3%)
Total
91
84 (92.3%)
7 (7.7%)
1
11 (12.2%)
9 (10.8%)
2 (28.6%)
2
50 (55.6%)
47 (56.6%)
3 (42.9%)
3
29 (32.2%)
27 (32.5%)
2 (28.6%)
Total
90
83 (92.2%)
7 (7.8%)
Ductal
76 (83.5%)
69 (82.1%)
7 (100%)
11 (12.1%)
11 (13.1%)
0 (0%)
Other
4 (4.4%)
4 (4.8%)
0 (0%)
Total
91
84 (92.3%)
7 (7.7%)
Lumpectomy
38 (41.8%)
33 (39.3%)
5 (71.4%)
Mastectomy
53 (58.2%)
51 (60.7%)
2 (28.6%) 7 (7.7%)
Total
91
84 (92.3%)
Lumpectomy
10 (62.5%)
8 (61.5%)
2 (66.7%)
Mastectomy
6 (37.5%)
5 (38.5%)
1 (33.3%)
Total
16
13 (81.3%)
3 (18.8%)
No
47 (51.6%)
42 (50%)
5 (71.4%)
Yes
44 (48.4%)
Total
91
42 (50%)
2 (28.6%)
84 (92.3%)
7 (7.7%)
No
71 (78%)
65 (77.4%)
6 (85.7%)
Yes
20 (22%)
19 (22.6%)
1 (14.3%)
84 (92.3%)
7 (7.7%)
91
1.0000
0.6075
6 (85.7%)
Lobular
Total
0.4308
0.3147
0.7029
0.1241
1.0000
0.4362
1.0000
NED ¼ no evidence of disease; FISH ¼ fluorescence in situ hybridization.
sensitivity of intraoperative cytology for micrometastatic disease was 4.9%. The median number of resected SLN was 2 (range: 1-8). On final pathology, 86/91 (94.5%) patients had one positive node, and 5/91 (5.49%) patients had two positive nodes for micrometastasis. Forty-two (46.1%) patients had ALND, of which 37/42 (88.1%) were performed as a second operation. Five patients had positive or atypical intraoperative cytology followed by immediate axillary dissection. Eighteen
of 91 patients declined a recommended ALND. One of the 18 (5.6%) patients without axillary dissection or radiation developed a recurrence in the axilla at 88-mo follow-up. Additional positive nodes were found in 3/42 (7.1%) patients at the time of their ALND; the median number of additional positive nodes was 1.7 (range: 1-3). Forty-four of the 91 (48.4%) patients received postoperative adjuvant radiation; 28/44 (63.6%) patients
Table 2 e Incidence of local recurrence.
# Patients (%)
Q10
SLN only; no radiation
SLN þ ALND; no radiation
SLN only and radiation
SLN þ ALND and radiation
24 (26.4)
23 (25.3)
24 (26.4)
#Any recurrence (%)
3 (42.9)
2 (28.6)
0 (0)
2 (28.6)
7
#Local recurrence (%)
3 (60)
1 (20)
0 (0)
1 (20)
5
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20 (22)
Total# 91
326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
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391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 Q7 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455
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received whole breast radiation, 16/44 (36.4%) received chest wall radiation, and 20/44 (45.5%) also had directed nodal radiation in addition to either chest wall or whole breast radiation. Seven of the 91 (7.7%) patients had a documented recurrence. Four of these seven patients had local recurrences at the primary site (breast), and one had a recurrence in the axilla as previously mentioned. Two patients had distant recurrences; one recurred in the thoracic spine, and the other in liver and bone. Both of these patients had a delayed ALND. Overall, there was no difference in rate of recurrence between the 2 groups; recurrence was seen in 9.5% of patients receiving ALND and 6.1% in patients not receiving ALND (P ¼ 0.70). The median time of follow-up was 47 mo (range: 0-203 mo); seven patients are deceased, two with a breast cancererelated death and one due to AML. Cause of death in the other four patients is unknown.
Discussion Of recurrences after ALND, two were in the breast and two were distant metastases. There was one axillary recurrence in a patient who declined axillary dissection as well as chest radiation. This recurrence presumably represents existing axillary disease that was present but not surgically resected at the time of the initial breast and axillary operation. This seems to be a rare event, as most residual disease left in the axilla does not manifest as axillary recurrence.20 Furthermore, this series demonstrates a low rate of additional nodal involvement on ALND. Although our population size is small and analysis preliminary, the results support other publications demonstrating low recurrence risk in micrometastatic patients.3,4,11,13,14,18,21 The fact that there was no difference in recurrence between the ALND group compared to the SLN only group supports the omission of ALND in clinically node-negative women with pathologically micrometastatic disease on sentinel node biopsy. The Z-0011 study found no significant difference in local or regional recurrence at a mean of 5.9 y follow-up among patients with 1 or 2 positive SLNs who received and did not receive ALND.14,16 Even patients who opted out of a recommended ALND were shown to have rates of recurrence as low as (0%3.7%).3 In contrast, the MIRROR study, a large retrospective Dutch cohort study, did demonstrate an apparent benefit of doing ALND due to an increased hazard risk of axillary recurrence for patients not receiving ALND compared to those that did, even after controlling for systemic therapy; these data was presented at the ASCO Annual Meeting in 2009 but to-date has not yet been published in manuscript format.22 In our series, the decision to proceed to immediate ALND during surgery was based on an intraoperative SLN test. Intraoperative cytology for SLN metastasis has been shown in some series to have high false positive rates (38.6%) and extremely low sensitivity for micrometastases.1,3,17 Although not a primary focus of this study, our analysis also demonstrates a low sensitivity of cytology for micrometastatic disease (4.9%) and suggests that the decision to perform this test is low yield in clinically node-negative patients. Intraoperative
testing results in extended surgical and anesthesia times for patients; this additional time and expense are eliminated by deferring sentinel node biopsy evaluation to permanent pathology without any intraoperative evaluation in the clinically node-negative patient, particularly given the results of recent studies supporting the use of SLN only in low-volume nodal disease.16,21 The question of quality of life is also raised when considering the necessity for ALND. Numerous studies have reported a wide variety of side effects due to ALND that can truly compromise a patient’s quality of life post recovery. Overall, postoperative complication rates are three-fold higher in groups receiving ALND compared to those that do not.23 Trials of SLN alone versus ALND have reported clinically significant differences in patient reported cases of lymphedema; 2%-8% versus 13%-19%, although patient reporting is subject to bias and challenging to standardize.3,24,25 Other side effects, such as parasthesias in the upper arm and axilla, arm weakness, and axillary seromas have also been reported as more prevalent in patients receiving ALND than those receiving SLN alone.13,26 Although SLNB alone results in less cases of morbidities, it is still noted that there remains a clinically relevant risk of lymphedema, though the risk does not correlate with the number of lymph nodes removed.27,28
Conclusions Our study has shown a lower rate of recurrence in patients not receiving ALND than the rate of lymphedema previously described in the literature. Several of those studies have recommended omitting ALND when possible. Considering our small and highly selected single-institution database, the decision to abandon ALND in patients with a micrometastatic SLNB needs further validation, although the evidence presented in this study serve to reinforce the highly suggestive data in the current literature, and supports deferring intraoperative sentinel node testing in a clinically node-negative population.
Uncited tables Tables 1 and 2
Acknowledgment Authors’ contributions: M.C. was involved in data acquisition, analysis, writing, and edits. C.D. was involved in concept design, interpretation, writing, and review. W.S. was involved in data acquisition, interpretation, revision, and final review. J.Z. and Z.M. were involved in statistical analysis and review. C.L. was involved in data acquisition, interpretation, revision, and final review. M.C.L. was involved in study design, data collection, review of results, revision, and editing of manuscript.
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collins et al alnd in micrometastatic breast cancer
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Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
references
1. Pugliese MS, et al. Presentation: accuracy of intraoperative imprint cytology of sentinel lymph nodes in breast cancer. The Am J Surg. 2006;192:516e519. 2. Schiffmann E, Corcoran BA, Wahl SM. N-formylmethionyl peptides as chemoattractants for leucocytes. Proc Natl Acad Sci U S A. 1975;72:1059e1062. 3. Tjan-Heijnen VCG, et al. Axillary recurrences following positive sentinel lymph node biopsy with individual tumor cells or micrometastases and no axillary dissection. Breast Dis. 2011;31:83e90. 4. Hwang RF, et al. Clinicopathologic factors predicting involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg Oncol. 2003;10:248e254. 5. Saidi RF, et al. Nonsentinel lymph node status after positive sentinel lymph node biopsy in early breast cancer. Am Surg. 2004;70:101e105. discussion 105. 6. Pal A, et al. A model for predicting non-sentinel lymph node metastatic disease when the sentinel lymph node is positive. Br J Surg. 2008;95:302e309. 7. Van Zee KJ, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol. 2003;10:1140e1151. 8. Coutant C, et al. Comparison of models to predict nonsentinel lymph node status in breast cancer patients with metastatic sentinel lymph nodes: a prospective multicenter study. J Clin Oncol. 2009;27:2800e2808. 9. Barranger E, et al. An axilla scoring system to predict nonsentinel lymph node status in breast cancer patients with sentinel lymph node involvement. Breast Cancer Res Treat. 2005;91:113e119. 10. Abreu EB, et al. Treatment plan for breast cancer with sentinel node metastasis. Ecancermedicalscience. 2014;8:1e7. 11. Orr RK. The impact of prophylactic axillary node dissection on breast cancer survivalea Bayesian meta-analysis. Ann Surg Oncol. 1999;6:109e116. 12. Chen KT. Axillary dissection. Curr Probl Cancer. 2012;36:245e262. 13. Sigurdsson H, et al. Indicators of prognosis in node-negative breast cancer. N Engl J Med. 1990;322:1045e1053. 14. Grabau D, et al. Completion axillary dissection can safely be omitted in screen detected breast cancer patients with micrometastases. A decade’s experience from a single institution. Eur J Surg Oncol. 2013;6:601.
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15. Galimberti V, et al. Can we avoid axillary dissection in the micrometastatic sentinel node in breast cancer? Breast Cancer Res Treat. 2012;3:819. 16. Giuliano AE, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305:569e575. 17. Motomura K, et al. Intraoperative imprint cytology for the diagnosis of sentinel node metastases in breast cancer. Breast Cancer. 2007;14:350e353. 18. Canavese G, et al. Sentinel lymph node biopsy versus axillary dissection in node-negative early-stage breast cancer: 15-year follow-up update of a randomized clinical trial. Ann Surg Oncol. 2016;23:2494e2500. 19. Network, N.C.C. Breast cancer version 2.2016. 2016 Available from: https://www.nccn.org/professionals/physician_gls/pdf/ breast.pdf. Accessed August 24, 2016. Q9 20. Matsen C, et al. Late axillary recurrence after negative sentinel lymph node biopsy is uncommon. Ann Surg Oncol. 2016;23:2456e2461. 21. Ceberio N, et al. Original study: should we perform the intraoperative sentinel lymph node biopsy in breast cancer? Clin Breast Cancer. 2016. 22. Tjan-Heijnen VCG, Pepels MJ, de Boer M, et al. Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pNO[iþ]) in the sentinel lymph node (SN): results from the MIRROR. J Clin Oncol. 2009;27:803s. 23. Aslani N, et al. Factors that determine whether a patient receives completion axillary lymph node dissection after a positive sentinel lymph node biopsy for breast cancer in British Columbia. Can J Surg. 2011;4:237. 24. Langer I, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Ann Surg. 2007;245:452e461. 25. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013;4:297. 26. Lucci A, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007;25:3657e3663. 27. Goldberg J, et al. Morbidity of sentinel node biopsy in breast cancer: the relationship between the number of excised lymph nodes and lymphedema. Ann Surg Oncol An Oncol J Surgeons. 2010;17:3278. 28. McLaughlin SA, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol. 2008;26:5213e5219.
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Q1
Q11
Q2
Use of axillary lymph node dissection (ALND) in patients with micrometastatic breast cancer Madison Collins, BA,a Cristina O’Donoghue, MD, MPH,b Weihong Sun, MD,b Jun-min Zhou, MS,c Zhenjun Ma, PhD,c Christine Laronga, MD,b and Marie Catherine Lee, MDb,* a
University of South Florida Morsani College of Medicine, Tampa Florida Comprehensive Breast Program, Moffitt Cancer Center, Tampa, Florida c Department of Biostatistics, Moffitt Cancer Center and Research Institute Tampa, Florida b
Q3
article info
abstract
Article history:
Background: Sentinel lymph node (SLN) biopsy is the current prognostic tool for clinically
Received 1 December 2016
node-negative breast cancer patients. If the SLN reveals macrometastasis, axillary node
Received in revised form
dissection (ALND) is recommended. However, the use of ALND in patients with micro-
8 February 2017
metastasis is debated. The objective of this study was to assess the utilization of ALND in
Accepted 24 March 2017
the treatment of micrometastatic breast cancer.
Available online xxx
Methods: An IRB approved, retrospective study of a pooled dataset of breast cancer patients with micrometastatic disease on SLN biopsy was performed. Patients diagnosed from 1999-
Q4
Keywords:
2016 were identified via query of a single-institution NCCN breast cancer database as well
Breast cancer
as a prospective tumor board.
Axillary lymph node dissection
Results: A total of 91 patients were diagnosed with micrometastatic nodal disease. The
Micrometastasis
median age at diagnosis was 56 y (range: 31-85); median follow-up time was 47 mo (range:
Lymphedema
0-203 mo). 42/91(46.2%) patients had ALND of which 37/42 (88.1%) were a second operation; 3/42(7.1%) patients had additional positive nodes found at ALND. 44/91 (48.4%) patients received radiation. 7/91 (7.7%) patients had a recurrence, 5/7 local, including one axillary (2.1%; patient declined ALND). Conclusions: Given that the risk of lymphedema after ALND ranges between 20%-53%, the morbidity of ALND may far exceed the likelihood of detecting further nodal involvement in women with micrometastatic disease: 7.1% in this series. ª 2017 Elsevier Inc. All rights reserved.
Introduction Q5
Nodal involvement in breast cancer is an important predictor of survival. Currently, the standard procedure to pathologically stage clinically node-negative patients involves a sentinel lymph node (SLN) biopsy.1 This procedure entails locating, removing, and determining the presence of cancer cells in a lymph node by injection of a nuclear dye and/or a
blue dye into the breast. These dyes travel through the breast and deposit in the lymph nodes receiving the majority of lymphatic drainage from the breast, and thus theoretically are the most likely nodes to demonstrate metastatic axillary disease, hence the term “sentinel node.” The nodes picking up the blue or nuclear dye are detected intraoperatively and resected for pathologic review.2 When a positive SLN is found containing micrometastases (deposits of tumor cells in lymph
* Corresponding author. Comprehensive Breast Program, Moffitt Cancer Center 10920 N. McKinley Dr, Tampa, FL 33612. Tel.: þ1 813-7458480; fax: þ1 813 745-7827. E-mail address: [email protected] (M.C. Lee). 0022-4804/$ e see front matter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2017.03.039
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nodes defined as >0.2 mm and 2.0 mm), the chances of metastases in other nonsentinel nodes (NSLN) historically is 0%-20%.3 Several predictive models are used in the clinical setting to estimate the risk of additional nodal involvement on nonsentinel nodes, but none specifically address micrometastatic disease. In addition, no model has been able to predict a zero percent chance of additional nodal involvement beyond the SLN.3-9 The results of this biopsy, along with the phenotypic characteristics of the tumor, help determine the course of treatment, including hormone therapy, radiation, and axillary lymph node dissection (ALND). Axillary node dissection is used for predicting prognosis, improving locoregional control, and assisting in staging; however, it does not confer a survival benefit.10-12 Patients receiving ALND could have distant metastasis even in the absence of locoregional recurrence or initial node negativity12,13; thus, the operation of surgically clearing the nodes would have no impact on cancer-related mortality. Furthermore, the course of adjuvant therapy is determined more by the immunohistochemistry of the tumor than by the ALND.10 Currently, the use of ALND in patients with clinically node-negative lymph nodes is debated due to high rates of long-term morbidity from axillary dissection and low rates of recurrences.1,3,13-17 Given the potential morbidities of ALND, including lymphedema, infection, peripheral neuropathy, and pain, several studies favor omitting ALND in patients with favorable tumor characteristics and low risk of further nodal involvement.3,10,14,15 Another study suggests that SLNB alone is equivalent to ALND in terms of locoregional control and overall survival.18 However, the 2016 NCCN Breast Cancer guidelines still support the use of ALND even in patients with pathologically positive but clinically node-negative axillas.19 Given the current controversies surrounding micrometastatic axillary disease and the inconsistent use of axillary dissection, the primary goal of this study was to evaluate the utilization and results of ALND as part of a multidisciplinary treatment plan for micrometastatic breast cancer.
Methods This is a retrospective study of a single-institution series of consecutive patients found to have micrometastatic disease after surgery for primary breast cancer. Both the institutional NCCN breast cancer database and a prospective tumor board database were queried for pathologic micrometastatic cases after definitive surgical staging. Institutional Review Board permission was obtained before data collection and analysis. All patients were diagnosed between 1999 and 2016 with primary micrometastatic disease on SLN biopsy pathology for incident, invasive breast cancer. All patients received either lumpectomy or mastectomy, in addition to axillary evaluation, at a single NCI-designated Comprehensive Cancer Center by a fellowship-trained surgical oncologist. Patients with micrometastasis associated with recurrent disease were excluded. Patients receiving neoadjuvant therapy were also excluded from this study. The institutional NCCN database collected breast cancer data from 1997 through 2012; the national data collection was closed in 2012, but a prospective
programmatic Breast Cancer database continues to collect clinical and pathologic breast cancer data. Because the primary endpoint of this study is the use of axillary dissection in current breast cancer management, the time frame for the database searches was carried through to include recent cases. Medical records were reviewed, and multiple data points were collected in addition to data collected from the NCCN and Breast Program databases. Data points collected and Q6 analyzed were as follows: date of birth, date of diagnosis, age at diagnosis, method of diagnosis (axillary US, MRI, or axillary FNA), hormone receptor status, type of breast surgery (lumpectomy versus mastectomy), date of surgery, histology on final pathology, result of intraoperative imprint cytology (if performed), number of SLN biopsied, timing of axillary node dissection (if performed), grade of cancer and largest metastasis, use and location of radiation as treatment of initial breast cancer, location and date of local recurrence, location and date of distant recurrence, last follow-up date, and number of patients deceased. Follow-up time was calculated from the last surgery date to the last documented oncology note. Types of radiation included none, whole breast, chest wall, or nodal. If second surgery was performed, all data points were collected when available. Last follow-up date was defined as the last documented appointment with an oncologist or surgical oncologist at either an outside institution or our facility. Demographics were summarized using descriptive statistics. Wilcoxon rank-sum test, Kruskal-Wallis test, and Fisher exact test were used for data analysis.
Results A total of 91 patients were diagnosed with micrometastatic nodal disease in the selected time frame. The median age at diagnosis was 56 y (range 31-85). Fifty patients (54.9%) received an MRI preoperatively, 11 of which showed an abnormal axilla, prompting further workup. Of these 11, eight (72.7%) had an axillary ultrasound. Thirty-four of the 91 patients (37.4%) had a diagnostic axillary ultrasound, and 13 patients had an FNA of the axilla performed for diagnosis. Of these, one patient was diagnosed with a positive axilla on percutaneous biopsy. The sensitivity of axillary US and FNA for micrometastatic axillary disease was 41.2% and 15.4%, respectively. The sensitivity of MRI for micrometastatic axillary nodes was 22%. Seven cases (7.7%) were estrogen receptor/progesterone receptor (ER/PR) negative, and five of these cases (5.5%) were ER/PR, Her2Neu negative. Thirty-eight patients received a lumpectomy, and 53 patients received a total mastectomy. The histological results on final pathology showed that the majority of patients had invasive ductal cancer (76/91, 83.5%) followed by invasive lobular cancer (11/91, 12.1%). The remaining four patients were classified as “other.” The majority of patients (50/91, 54.9%) were diagnosed with grade 2 cancer, followed by grade 3 (29/91, 31.9%), and grade 1 (11/91, 12.1%). The largest size of metastasis found during SLNB was documented, ranging from 0.2-2.0 mm (mean 0.99 mm). Eighty-one of 91 patients (89.0%) received in intraoperative imprint cytology evaluation of the sentinel nodes. The
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Table 1 e Clinical and pathologic features versus overall recurrence. Variable
ER status
PR status
Her2neu (FISH)
Grade
Histology
First surgery type
Second surgery type
Breast radiation
Nodal radiation
Level
n (%)
P value
Total
NED
Any recurrence
ERþ
61 (87.1%)
58 (87.9%)
3 (75%)
ER
9 (12.9%)
8 (12.1%)
1 (25%)
Total
70
66 (94.3%)
4 (5.7%)
PRþ
79 (86.8%)
73 (86.9%)
6 (85.7%)
PR
12 (13.2%)
11 (13.1%)
1 (14.3%)
Total
91
84 (92.3%)
7 (7.7%)
Equivocal
2 (2.2%)
2 (2.4%)
Negative
80 (87.9%)
74 (88.1%)
0 (0%)
Positive
9 (9.9%)
8 (9.5%)
1 (14.3%)
Total
91
84 (92.3%)
7 (7.7%)
1
11 (12.2%)
9 (10.8%)
2 (28.6%)
2
50 (55.6%)
47 (56.6%)
3 (42.9%)
3
29 (32.2%)
27 (32.5%)
2 (28.6%)
Total
90
83 (92.2%)
7 (7.8%)
Ductal
76 (83.5%)
69 (82.1%)
7 (100%)
11 (12.1%)
11 (13.1%)
0 (0%)
Other
4 (4.4%)
4 (4.8%)
0 (0%)
Total
91
84 (92.3%)
7 (7.7%)
Lumpectomy
38 (41.8%)
33 (39.3%)
5 (71.4%)
Mastectomy
53 (58.2%)
51 (60.7%)
2 (28.6%) 7 (7.7%)
Total
91
84 (92.3%)
Lumpectomy
10 (62.5%)
8 (61.5%)
2 (66.7%)
Mastectomy
6 (37.5%)
5 (38.5%)
1 (33.3%)
Total
16
13 (81.3%)
3 (18.8%)
No
47 (51.6%)
42 (50%)
5 (71.4%)
Yes
44 (48.4%)
Total
91
42 (50%)
2 (28.6%)
84 (92.3%)
7 (7.7%)
No
71 (78%)
65 (77.4%)
6 (85.7%)
Yes
20 (22%)
19 (22.6%)
1 (14.3%)
84 (92.3%)
7 (7.7%)
91
1.0000
0.6075
6 (85.7%)
Lobular
Total
0.4308
0.3147
0.7029
0.1241
1.0000
0.4362
1.0000
NED ¼ no evidence of disease; FISH ¼ fluorescence in situ hybridization.
sensitivity of intraoperative cytology for micrometastatic disease was 4.9%. The median number of resected SLN was 2 (range: 1-8). On final pathology, 86/91 (94.5%) patients had one positive node, and 5/91 (5.49%) patients had two positive nodes for micrometastasis. Forty-two (46.1%) patients had ALND, of which 37/42 (88.1%) were performed as a second operation. Five patients had positive or atypical intraoperative cytology followed by immediate axillary dissection. Eighteen
of 91 patients declined a recommended ALND. One of the 18 (5.6%) patients without axillary dissection or radiation developed a recurrence in the axilla at 88-mo follow-up. Additional positive nodes were found in 3/42 (7.1%) patients at the time of their ALND; the median number of additional positive nodes was 1.7 (range: 1-3). Forty-four of the 91 (48.4%) patients received postoperative adjuvant radiation; 28/44 (63.6%) patients
Table 2 e Incidence of local recurrence.
# Patients (%)
Q10
SLN only; no radiation
SLN þ ALND; no radiation
SLN only and radiation
SLN þ ALND and radiation
24 (26.4)
23 (25.3)
24 (26.4)
#Any recurrence (%)
3 (42.9)
2 (28.6)
0 (0)
2 (28.6)
7
#Local recurrence (%)
3 (60)
1 (20)
0 (0)
1 (20)
5
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20 (22)
Total# 91
326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
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391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 Q7 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455
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received whole breast radiation, 16/44 (36.4%) received chest wall radiation, and 20/44 (45.5%) also had directed nodal radiation in addition to either chest wall or whole breast radiation. Seven of the 91 (7.7%) patients had a documented recurrence. Four of these seven patients had local recurrences at the primary site (breast), and one had a recurrence in the axilla as previously mentioned. Two patients had distant recurrences; one recurred in the thoracic spine, and the other in liver and bone. Both of these patients had a delayed ALND. Overall, there was no difference in rate of recurrence between the 2 groups; recurrence was seen in 9.5% of patients receiving ALND and 6.1% in patients not receiving ALND (P ¼ 0.70). The median time of follow-up was 47 mo (range: 0-203 mo); seven patients are deceased, two with a breast cancererelated death and one due to AML. Cause of death in the other four patients is unknown.
Discussion Of recurrences after ALND, two were in the breast and two were distant metastases. There was one axillary recurrence in a patient who declined axillary dissection as well as chest radiation. This recurrence presumably represents existing axillary disease that was present but not surgically resected at the time of the initial breast and axillary operation. This seems to be a rare event, as most residual disease left in the axilla does not manifest as axillary recurrence.20 Furthermore, this series demonstrates a low rate of additional nodal involvement on ALND. Although our population size is small and analysis preliminary, the results support other publications demonstrating low recurrence risk in micrometastatic patients.3,4,11,13,14,18,21 The fact that there was no difference in recurrence between the ALND group compared to the SLN only group supports the omission of ALND in clinically node-negative women with pathologically micrometastatic disease on sentinel node biopsy. The Z-0011 study found no significant difference in local or regional recurrence at a mean of 5.9 y follow-up among patients with 1 or 2 positive SLNs who received and did not receive ALND.14,16 Even patients who opted out of a recommended ALND were shown to have rates of recurrence as low as (0%3.7%).3 In contrast, the MIRROR study, a large retrospective Dutch cohort study, did demonstrate an apparent benefit of doing ALND due to an increased hazard risk of axillary recurrence for patients not receiving ALND compared to those that did, even after controlling for systemic therapy; these data was presented at the ASCO Annual Meeting in 2009 but to-date has not yet been published in manuscript format.22 In our series, the decision to proceed to immediate ALND during surgery was based on an intraoperative SLN test. Intraoperative cytology for SLN metastasis has been shown in some series to have high false positive rates (38.6%) and extremely low sensitivity for micrometastases.1,3,17 Although not a primary focus of this study, our analysis also demonstrates a low sensitivity of cytology for micrometastatic disease (4.9%) and suggests that the decision to perform this test is low yield in clinically node-negative patients. Intraoperative
testing results in extended surgical and anesthesia times for patients; this additional time and expense are eliminated by deferring sentinel node biopsy evaluation to permanent pathology without any intraoperative evaluation in the clinically node-negative patient, particularly given the results of recent studies supporting the use of SLN only in low-volume nodal disease.16,21 The question of quality of life is also raised when considering the necessity for ALND. Numerous studies have reported a wide variety of side effects due to ALND that can truly compromise a patient’s quality of life post recovery. Overall, postoperative complication rates are three-fold higher in groups receiving ALND compared to those that do not.23 Trials of SLN alone versus ALND have reported clinically significant differences in patient reported cases of lymphedema; 2%-8% versus 13%-19%, although patient reporting is subject to bias and challenging to standardize.3,24,25 Other side effects, such as parasthesias in the upper arm and axilla, arm weakness, and axillary seromas have also been reported as more prevalent in patients receiving ALND than those receiving SLN alone.13,26 Although SLNB alone results in less cases of morbidities, it is still noted that there remains a clinically relevant risk of lymphedema, though the risk does not correlate with the number of lymph nodes removed.27,28
Conclusions Our study has shown a lower rate of recurrence in patients not receiving ALND than the rate of lymphedema previously described in the literature. Several of those studies have recommended omitting ALND when possible. Considering our small and highly selected single-institution database, the decision to abandon ALND in patients with a micrometastatic SLNB needs further validation, although the evidence presented in this study serve to reinforce the highly suggestive data in the current literature, and supports deferring intraoperative sentinel node testing in a clinically node-negative population.
Uncited tables Tables 1 and 2
Acknowledgment Authors’ contributions: M.C. was involved in data acquisition, analysis, writing, and edits. C.D. was involved in concept design, interpretation, writing, and review. W.S. was involved in data acquisition, interpretation, revision, and final review. J.Z. and Z.M. were involved in statistical analysis and review. C.L. was involved in data acquisition, interpretation, revision, and final review. M.C.L. was involved in study design, data collection, review of results, revision, and editing of manuscript.
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Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
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