Original Articles

Decline in Frozen Section Diagnosis for Axillary Sentinel Lymph Nodes as a Result of the American College of Surgeons Oncology Group Z0011 Trial Julie Anne Bishop, MD; Jihong Sun, MD; Nicolas Ajkay, MD; Mary Ann G. Sanders, MD, PhD

 Context.—Results of the American College of Surgeons Oncology Group Z0011 trial showed that patients with early-stage breast cancer and limited sentinel node metastasis treated with breast conservation and systemic therapy did not benefit from axillary lymph node dissection. Subsequently, most pathology departments have likely seen a decrease in frozen section diagnosis of sentinel lymph nodes. Objective.—To determine the effect of the Z0011 trial on pathology practice and to examine the utility of intraoperative sentinel lymph node evaluation for this subset of patients. Design.—Pathology reports from cases of primary breast cancer that met Z0011 clinical criteria and were initially treated with lumpectomy and sentinel lymph node biopsy from 2009 to 2015 were collected. Clinicopathologic data were recorded. Results.—Sentinel lymph node biopsies sent for frozen

section diagnosis occurred in 22 of 22 cases (100%) in 2009 and 15 of 22 cases (68%) in 2010 during the preZ0011 years, and in 3 of 151 cases (2%) collected in 2011 through 2015, considered to be post-Z0011 years. Of the 151 post-Z0011 cases, 28 (19%) had sentinel lymph nodes with metastasis, and 147 (97%) were spared axillary lymph node dissection. Conclusions.—Following Z0011, intraoperative sentinel lymph node evaluation has significantly decreased at our institution. Prior to surgery, all patients had clinically node-negative disease. After sentinel lymph node evaluation, 97% (147 of 151) of the patients were spared axillary lymph node dissection. Therefore, routine frozen section diagnosis for sentinel lymph node biopsies can be avoided in these patients. (Arch Pathol Lab Med. 2016;140:830–835; doi: 10.5858/ arpa.2015-0296-OA)

T

dissection (ALND), has been a subject of continued investigation. Incorporation of the sentinel lymph node biopsy (SLNB) as a standard of care for the patient with a clinically negative axilla was the first advancement toward sparing some patients the complications of ALND. As a result, frozen section diagnoses of SLNBs became common practice, with up to 35% of sentinel lymph nodes (SLNs) with metastasis requiring further ALND.2 In the late 1990s, the multicenter American College of Surgeons Oncology Group (ACOSOG) Z0011 trial was initiated to compare the effects of ALND versus SLNB alone on overall survival in patients with SLN metastasis treated with breast-conserving surgery (BCS) and systemic therapy. Patients who were clinically node-negative, with T1 to T2 BC and 1 or 2 positive SLNs on final pathology, and who underwent BCS with whole-breast irradiation were enrolled and then randomized to either undergo completion ALND or undergo no further surgery. Patients with large or bulky lymph nodes or with gross extranodal extension were excluded, as were those treated with mastectomy or neoadjuvant chemotherapy. Results revealed no difference in overall survival between the two groups at a median follow-up of 6.3 years, and furthermore, patients who only underwent SLNB encountered less morbidity.3 The Z0011 trial has been proclaimed a practice changer, with most surgical practices rapidly accepting Z0011 criteria as part of standard axillary management allowing for the avoidance of

reatment for early-stage breast cancer (BC) continues to evolve with advances in surgical procedures, breast imaging, and radiation and systemic treatments. Given that axillary lymph node involvement is the most important prognostic factor in early-stage BC,1 adequate lymph node staging is central to clinical management decisions. However, how best to achieve local-regional control and determine nodal status for the purposes of maximizing survival while minimizing such risks as lymphedema, upper extremity sensory and motor deficits, and alteration in shoulder mobility associated with axillary lymph node Accepted for publication November 3, 2015. Published as an Early Online Release December 30, 2015. From the Department of Pathology & Laboratory Medicine (Drs Sanders, Bishop, and Sun) and the Department of Surgery (Dr Ajkay), University of Louisville Hospital, Louisville, Kentucky. Dr Sun is now with the Department of Pathology, SUNY, University of Buffalo at Buffalo, New York. The authors have no relevant financial interest in the products or companies described in this article. Preliminary data were presented as a poster at the United States and Canadian Academy of Pathology annual meeting; March 24, 2015; Boston, Massachusetts. Reprints: Mary Ann G. Sanders, MD, PhD, Department of Pathology & Laboratory Medicine, University of Louisville Hospital, 530 S Jackson St, Louisville, KY 40202 (email: m0gime01@louisville. edu). 830 Arch Pathol Lab Med—Vol 140, August 2016

Effect of ACOSOG Z0011 Trial on Pathology Practice—Bishop et al

Table 1.

Post-Z0011 Patient and Tumor Characteristicsa

Characteristics (n ¼ 151)

No. (%) of Cases

Age, y ,50 50

18 (12) 133 (88)

Histologic type Invasive ductal Invasive lobular Other

127 (84) 15 (10) 9 (6)

Histologic grade 1 2 3

41 (27) 56 (37) 54 (36)

Tumor stage T1 T2 Lymphovascular invasion Extracapsular extension HRþ/HER2 HRþ/HER2þ HR/HER2þ HR/HER2

119 32 22 13 122 11 5 13

SLN status Positive Negative

28 (19) 123 (81)

Intraoperative SLN evaluation Cases that went on to ALND

(79) (21) (15) (9) (81) (7) (3) (9)

3 (2) 4 (3)

Abbreviations: ALND, axillary lymph node dissection; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; SLN, sentinel lymph node. a T1 is tumor size .1.0 cm to 2.0 cm; T2 is tumor size .2.0 cm to 5.0 cm.

ALND in patients with up to 2 lymph nodes with metastatic disease.4–6 Despite criticisms concerning the study’s lack of long-term follow up, low patient accrual, and reported protocol violations, Z0011 has made a significant impact on patients with primary BC by improving quality of life without compromising overall survival.7 In 2014, the American Society of Clinical Oncology (ASCO) published updated guidelines regarding SLNB for patients with early-stage BC.8 For women undergoing BCS with whole-breast irradiation, ASCO does not recommend ALND in patients with 1 or 2 metastatic SLNs, echoing the findings of the Z0011 trial. In addition, the ASCO guidelines take into account the findings of the International Breast Cancer Study Group 23-01 trial and do not recommend ALND in patients with SLN micrometastasis.9 Although the ASCO guidelines provide an online appendix addressing pathologic evaluation of SLNB and known limitations of frozen section diagnosis, the guidelines do not encourage or discourage the use of frozen section diagnosis for SLNB.8 Although much has been published regarding changes in surgical practice since Z0011,5,6,10–12 to our knowledge this is the first study to acknowledge Z0011’s effect on pathology practice. Prior to the published Z0011 trial results, the vast majority of SLNBs were sent for frozen section diagnosis at our institution. To determine how Z0011 has changed pathologic diagnosis of SLNB, we evaluated the number of SLNBs sent for frozen section diagnosis for patients who fit clinical criteria of Z0011 prior to surgery. We also calculated the percentage of these patients with clinically negative axilla (cN0) who could be spared ALND when applying Arch Pathol Lab Med—Vol 140, August 2016

ASCO guidelines in order to determine whether omitting frozen section diagnosis of SLNB was a reasonable change in practice at our institution for patients who fit Z0011 criteria. MATERIALS AND METHODS Institutional Review Board approval was obtained prior to the initiation of this retrospective study. We searched the pathology records at our institution for consecutive cases of breast lumpectomy and SLNB performed from January 2009 to March 2015. Cases that fit clinical criteria set forth in the Z0011 trial were used for our inclusion criteria and included the following: (1) adult women with histologically confirmed invasive BC clinically 5 cm or less (cT1-T2); (2) clinically negative axilla (cN0) per the surgeon’s clinical exam and/or axillary ultrasound evaluation; (3) no prior exposure to neoadjuvant therapy; and (4) no evidence of large or bulky lymph nodes or gross extranodal extension.3 Those cases that did not fall within the Z0011 criteria were excluded from this study. All data were collected from the pathology reports and included age, laterality, tumor size, histologic type, histologic grade, pathologic stage, presence of lymphovascular invasion, hormone receptor status, status of SLNB, whether a frozen section diagnosis was performed, the occurrence of a subsequent ALND, status of ALND, and presence of extracapsular extension (ECE). Histologic slides were not reviewed. Results of the Z0011 trial were published initially in September 2010 in the Annals of Surgery and again in February 2011 in the Journal of the American Medical Association.3,13 Therefore, we designated all cases collected prior to January 2011 as pre-Z0011 and all cases collected starting January 2011 as post-Z0011. Prior to surgery, all patients were cN0 based on the surgeon’s clinical exam and/or ultrasound imaging of the axilla. To determine whether cN0 was a reliable indicator for sparing patients ALND in this subset of patients, we calculated the percentage of these patients where ALND could be omitted after pathologic evaluation of SLNs and after the application of current ASCO guidelines.8 These cases were without large, bulky lymph nodes or gross extranodal extension where the final metastatic lymph node count was 2 or fewer positive lymph nodes or where the largest deposit was no greater than micrometastasis. Evaluation of SLNs for permanent section were as follows: Between January 2009 and August 2011, lymph nodes were serially sectioned and entirely submitted for microscopic evaluation, with 3 hematoxylin-eosin levels per tissue block. Beginning August 2011, lymph nodes were serially sectioned in 2.0-mm intervals and entirely submitted for microscopic evaluation, with 1 hematoxylineosin level per tissue block.14 Additional levels were performed if isolated tumor cells or micrometastasis were detected on the one hematoxylin-eosin level. Cytokeratin immunohistochemistry was performed only for cases where the primary carcinoma was invasive lobular carcinoma. The SLNs sent for intraoperative frozen section diagnosis were evaluated using 3 hematoxylin-eosin levels and the addition of touch imprint cytology for all cases.

RESULTS A total of 151 post-Z0011 cases of lumpectomy with SLNB were identified at our institution that fit clinical criteria defined in the Z0011 trial prior to surgery. Patient and tumor characteristics are presented in Table 1. Most patients were older than 50 years (133 of 151 patients; 88%). The predominant histologic type was invasive ductal carcinoma (127 of 151 cases; 84%). Other histologic types include 4 invasive tubular, 15 invasive lobular, 3 invasive mucinous, 1 invasive cribriform, and 1 invasive papillary. Similar to the patient cohort of the Z0011 trial, most carcinomas were hormone receptor positive and HER2 negative (122 of 151 cases; 81%), and measured 2 cm or less (119 of 151 cases; 79%). On final pathologic diagnosis, the largest tumor Effect of ACOSOG Z0011 Trial on Pathology Practice—Bishop et al 831

Table 2. Characteristics of Post-Z0011 Cases With Positive Sentinel Lymph Nodes (SLNs) With or Without Axillary Lymph Node Dissection (ALND)a Characteristics

No ALND (n ¼ 24)

ALND (n ¼ 4)

Age, y, median (range)

61.5 (44–84)

67 (53–78)

Histologic type, No. (%) Invasive ductal Invasive lobular Other

18 (75) 5 (21) 1 (0.04)

4 (100) 0 (0) 0 (0)

Histologic grade, No. (%) 1 2 3

5 (21) 8 (33) 11 (46)

0 (0) 1 (25) 3 (75)

Tumor stage, No. (%) T1a T1b T1c T2

0 4 14 6

1 0 1 2

Lymphovascular invasion, No. (%) No. of SLNs examined per case, median (range) Intraoperative SLN evaluation, No. (%) No. (%) of SLNs positive 2 positive SLNs .2 positive SLNs Largest SLN deposit, No. (%) Macrometastasis Micrometastasis Isolated tumor cells Largest macrometastasis, cm, average (range) Extracapsular extension, No. (%) 2 mm .2 mm a

(0) (17) (58) (25)

(25) (0) (25) (50)

6 (25)

2 (50)

4 (1–8)

2.5 (2–3)

3 (13)

0 (0)

21 (88) 3 (13)

2 (50) 2 (50)

13 (54) 8 (33) 3 (13)

4 (100) 0 (0) 0 (0)

0.9 (0.3–1.2) 1.5 (0.5–3.0) 10 (42)

3 (75)

8 (33) 2 (8)

2 (50) 1 (25)

Macrometastasis is size .2.0 mm; micrometastasis is size .0.2 mm to 2.0 mm and/or .200 cells; isolated tumor cells are size 0.2 mm and/or 200 cells; T1a is tumor size .1.0 mm to 5.0 mm; T1b is tumor size .5.0 mm to 1.0 cm; T1c is tumor size .1.0 cm to 2.0 cm; and T2 is tumor size .2.0 cm to 5.0 cm.

measured 5.0 cm. The histologic grade for these 151 cases was distributed as follows: 41 (27%) were grade 1, 56 (37%) were grade 2, and 54 (36%) were grade 3. Lymphovascular invasion was not prevalent and was identified in only 22 of 151 cases (15%). Extracapsular extension was identified in 13 of the 151 cases (9%). Three cases with ECE had greater than 2 mm of ECE (Table 2). Of these 3 cases, 2 cases did not go on to ALND. One case had 1 of 5 SLNs positive, with macrometastasis measuring 1.0 cm, and was free of axillary recurrence with 4 years of follow-up. The second case had 5 of 7 lymph nodes positive on SLNB (Table 3, case no. 7) and received a diagnosis of ovarian cancer shortly after BCS, which likely contributed to ALND not being pursued. This patient is free of axillary recurrence with 2 years of follow-up. For all post-Z0011 patients, follow-up ranged from 3 months to 4 years. Only 1 patient was found to have axillary recurrence. This patient had HER2-positive disease with 4 negative SLNs but declined breast irradiation and systemic therapy, and the disease recurred 1 year later within the ipsilateral breast and axilla. 832 Arch Pathol Lab Med—Vol 140, August 2016

Of the post-Z0011 cases, only 3 cases (2%) had SLNBs sent for intraoperative frozen section consultation (Table 1). None of these cases went on to ALND (Table 2). The final pathologic stage for each was: pT1aN0, pT2N1mi(sn), and pT2N0(sn). Pre-Z0011 cases from 2009 and 2010 were evaluated for the percentage of cases sent for SLNB frozen section diagnosis. A total of 22 cases in 2009 and 22 cases in 2010 met clinical criteria for the Z0011 trial prior to surgery. All of the cases (22 of 22; 100%) in 2009 and 15 of the 22 cases (68%) in 2010 had SLNB sent for frozen section diagnosis. The number of cases where SLNB was sent for frozen section diagnosis post-Z0011 by year is as follows: 1 of 29 cases (3%) in 2011, 0 of 43 cases (0%) in 2012, 1 of 34 cases (3%) in 2013, 1 of 36 cases (3%) in 2014, and 0 of 9 cases (0%) in the first 3 months of 2015 (Figure). For the post-Z0011 cases, 28 of the 151 cases (19%) had positive SLNs, with 4 of these cases (3%) going on to ALND (Tables 1 and 3, case nos. 2 through 5). Of note, one of the patients who went on to ALND had 1 of 2 lymph nodes positive (Table 3, case no. 2). The lymph node deposit measured 5 mm, with no evidence of ECE. Due to residual disease within the breast on re-excision margins, the patient underwent completion mastectomy with ALND. The ALND showed 12 lymph nodes that were negative. A total of 24 cases had positive SLNs and no ALND performed (Table 2). Of note, 3 cases had more than 2 lymph nodes positive. One case had 3 positive SLNs with isolated tumor cells (Table 3, case no. 1); a second case had metastatic lobular carcinoma in 4 of 4 SLNs, with 4 macrometastases (the largest deposit measuring 8 mm) and ECE measuring less than 1 mm (Table 3, case no. 6); and a third case had 5 of 7 lymph nodes from the SLNB that were positive. The largest metastatic deposit measured 1.3 cm and ECE was present measuring up to 4 mm (Table 3, case no. 7). Applying ASCO recommendations, we determined the number of patients who could be spared ALND. We found, out of 151 cases, that 146 cases (97%) had limited or no metastatic disease on final pathology and could avoid ALND. A total of 5 cases (3%) by lymph node status did not meet criteria (Table 3; case nos. 3–7). Therefore, 97% (146 of 151) of the patients with cN0 could be spared ALND after pathologic evaluation of SLNB. COMMENT The ACOSOG Z0011 trial, published in 2010 and 2011, concluded that SLNB was equivalent to ALND in patients with T1 to T2 BC and 1 to 2 positive lymph nodes treated with BCS and whole-breast irradiation.3,13 These findings have dramatically changed surgical practice, with more than half of all American surgeons, who were surveyed in 2012, stating that they had omitted ALND for patients who met Z0011 criteria.11 Such a major shift in surgical practice has likely had an impact on most pathology practices as well. Our results show a significant decline in SLNB frozen section diagnosis for patients who met Z0011 criteria prior to surgery at our institution, with only 3 of 151 cases (2%) where SLNBs were evaluated intraoperatively post-Z0011. Two articles published in surgery journals have reported declines in intraoperative SLNB evaluation at their institutions. Caudle et al5 reported a decline in intraoperative evaluation of SLNB from 69% (230 of 335 cases) pre-Z0011 to 26% (84 of 323 cases) post-Z0011, and Wright et al12 Effect of ACOSOG Z0011 Trial on Pathology Practice—Bishop et al

Table 3.

Pathologic Features of Post-Z0011 Cases With 3 or More Positive Lymph Nodes (LNs) and/or Cases That Went on to Axillary Lymph Node Dissection (ALND)

Tumor Case Histologic Tumor Size, ER/PR/ No. Type Grade cm HER2 1 2 3 4 5 6 7

Ductal Ductal Ductal Ductal Ductal Lobular Ductal

2 3 2 3 3 1 3

1.3 0.4 2.2 1.9 2.3 1.6 1.0

þ/þ/ þ/þ/ þ/þ/ þ/þ/ þ/þ/ þ/þ/ þ/þ/þ

SLN Deposits, cm ITCs 0.5 1.1, 1.0, and 0.2 3 1.2, 1.0, and 0.4 0.8, 0.6, 0.5, and 0.4 1.3, 1.2, 1.2, 0.6, and 0.2

Positive SLNs/ Total SLNs

ECE, mm

ALND Deposits, cm

Positive LNs/ Total LNs in ALND

AJCC Stage

3/3 1/2 3/3 1/2 3/3 4/4 5/7

None None 9 1 1 ,1 4

N/A None 1.4, 0.7, and 0.2 0.2 None N/A N/A

N/A 0/12 3/4 1/8 0/10 N/A N/A

pT1c N0(iþ)(sn) pT1a N1a pT2 N2a pT1c N1a pT2 N1a pT1c N2a(sn) pT1b N2a

Abbreviations: AJCC, American Joint Committee on Cancer; ECE, extracapsular extension; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; ITCs, isolated tumor cells (0.2 mm and/or 200 cells); N/A, not applicable (ALND was not performed); SLN(s), sentinel lymph node(s).

reported a decline from 92% (54 of 59 cases) to 45% (14 of 31 cases). An inconvenient consequence of routinely sending SLNBs for permanent section in this patient population would be if this practice resulted in an increase in the number of patients requiring a second surgery for ALND. Caudle et al5 compared rates of ALND in pre-Z0011 and post-Z0011 patients with positive SLNBs and showed declining rates of ALND, with 85% (53 of 62 patients with positive SLNs) of pre-Z0011 patients versus 24% (10 of 42 patients with positive SLNs) of post-Z0011 patients undergoing ALND. Our analysis of their data, to include all of their post-Z0011 patients with positive SLNs and with negative SLNs, revealed that only 3% (10 of 323) of the patients underwent ALND. These results are in agreement with our findings that show only 3% (4 of 151) of our post-Z0011 patients went on to ALND. Furthermore, analysis of our post-Z0011 cohort showed that 3% (5 of 151) of these patients would be recommended for ALND based on SLN pathologic evaluation and ASCO guidelines. This low rate of ALND at our institution is likely due to several factors, including a decline in SLNB intraoperative frozen section diagnosis to almost 0%. Wright et al12 reported that patients were more likely to undergo ALND if intraoperative SLN evaluation was performed. Our low rate of ALND can also be attributed to routine imaging of the axilla with fine-needle aspiration biopsy of abnormal axillary lymph nodes prior to surgery, an increased likelihood of treating patients with cT2 HER2-

positive BC irrespective of nodal status with neoadjuvant chemotherapy, and meeting criteria set forth by Z0011, resulting in a low probability of finding 3 or more positive SLNs with at least 1 macrometastasis on final pathology. Of course, it should also be noted that frozen sections pose their own limitations, such as false-negative rates of approximately 10%.3,4 Frozen sections can cause significant destruction of potentially diagnostic tissue, and in general the quality of frozen tissue preparations may not be as high as those prepared from well-fixed tissue.8 At our institution, most false-negative frozen section diagnoses are due to undetected micrometastasis or isolated tumor cells, and low-grade metastatic lobular carcinoma. Detecting SLN micrometastasis and isolated tumor cells are not necessarily an indication for ALND,8 thus highlighting the importance of communicating the size of the metastatic focus to the surgeon at the time of intraoperative frozen section diagnosis. At approximately the same time as the results of the Z0011 trial were published, a seminal study published by Weaver et al14 elegantly showed that occult metastases did not have a significant impact on outcome at 5 years. Therefore, additional evaluation of SLNs, including multiple levels and cytokeratin immunohistochemistry, offered no clinical benefit. These findings are in agreement with the College of American Pathologists (CAP) recommendations for SLN evaluation: Thin sectioning of SLNs at 2.0-mm intervals, embedding all sections, and examining one section from the surface of the block in order to detect all Decline in frozen section diagnosis of sentinel lymph nodes. Pre-Z0011 years: 2009 (22 of 22 cases) and 2010 (15 of 22 cases). PostZ0011 years: 2011 (1 of 29 cases), 2012 (0 of 43 cases), 2013 (1 of 34 cases), 2014 (1 of 36 cases), and 2015, first 3 months (0 of 9 cases).

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metastases larger than 2.0 mm are sufficient for routine examination.15 As of August 2011, 8 months after Z0011, our institution adopted the CAP recommendations in our evaluation of SLNs on permanent section for BC patients. With the added decline in frozen section diagnosis as a result of Z0011, these SLNs are certainly not as extensively sampled as before. However, this practice should have a negligible effect on the rate of ALNDs, because extensive sampling beyond CAP recommendations increases detection of occult micrometastasis and isolated tumor cells, which are not indications for ALND.8,14 Based on our study population, our SLN-positive rate prior to implementation of the CAP recommendations was 23% (12 of 53) of cases compared with an SLN-positive rate of 19% (27 of 143) of cases after implementation. Weaver16 reported a 15% SLN-positive rate in the current era of routine ultrasound screening with fine-needle aspiration biopsy of abnormal axillary nodes. Therefore, a 19% SLN-positive rate is within the current acceptable range. Of the 24 cases in which patients had positive lymph nodes without subsequent ALND, 3 cases demonstrated 3 or more lymph nodes with metastatic disease. These cases were not sent for frozen section diagnosis, and they could raise valid concerns regarding extrapolation of the Z0011 trial results to patients who do not fit criteria. Conversely, studies have repeatedly concluded that no significant differences in outcomes are observed in patients who received radiotherapy of the axilla versus ALND after SLNB.17–19 Of our 3 cases with 3 or more positive SLNB without ALND, 1 patient demonstrated 3 lymph nodes with no more than isolated tumor cells and was staged as pN0(iþ). The remaining 2 patients demonstrated more than 2 lymph nodes with macrometastasis. If these 2 cases were to be included in the group of 4 patients that went on to ALND, the percent of patients with ALND would only increase from 3% (4 of 151) of cases to 4% (6 of 151) of cases. When determining whether cN0 is a reliable indicator for sparing ALND in this subset of patients, these 2 cases were included in the group recommended for ALND under current ASCO guidelines. Another factor that may influence performing ALND is the presence of ECE. Extracapsular extension is defined as the spread of tumor cells outside of the lymph node capsule and is a predictor of poor prognosis.20 Recent studies of ECE report an incidence of approximately 30% in clinically negative nodes.21,22 Gooch et al23 reported the same incidence of ECE as well as performed a retrospective study examining the role of ECE in patients who met Z0011 criteria. They concluded that the presence of ECE measuring greater than 2 mm strongly correlated with nodal tumor burden at ALND, and this should be an indication for ALND or radiotherapy for Z0011 patients. However, the authors also suggested that a standardized method for measuring ECE is lacking among pathologists, and therefore reproducibility of their findings among pathologists is uncertain. Additionally, criteria for Z0011 as well as recommendations published by ASCO do not include histologic measurements of ECE, but rather gross extranodal extension (matted lymph nodes) as exclusion criteria. For patients who do not fit Z0011 criteria prior to surgery, we continue to perform frozen section diagnosis for SLNBs at our institution. This includes patients undergoing mastectomy and patients with neoadjuvant 834 Arch Pathol Lab Med—Vol 140, August 2016

chemotherapy. However, recent studies and ongoing trials continue to address whether SLNB with axillary radiation is equivalent to ALND, and therefore the current practice trends attributed to Z0011 may be applied more broadly in the future. The AMAROS trial evaluated cT1 to T2 cN0 patients undergoing breast-conserving therapy (1166 of 1425 cases; 82%) or mastectomy (248 of 1425 cases; 17%) with positive SLNB who were randomized to either ALND or axillary radiotherapy.19 After a median of 6.1 years of follow-up, they found no difference in axillary recurrence between the two groups. Studies that are currently enrolling patients to address the benefit of axillary radiation in patients receiving neoadjuvant chemotherapy include the NSABP B-51 trial, which is evaluating patients with positive axillary lymph nodes prior to neoadjuvant chemotherapy who converted to pathologically negative lymph nodes after neoadjuvant chemotherapy,24 and the Alliance A011202 trial, which is evaluating patients who have positive axillary lymph nodes before and after neoadjuvant chemotherapy.25 In conclusion, our institution quickly applied Z0011 criteria as a standard in axillary management, which resulted in a substantial decline in intraoperative frozen section diagnosis of SLNBs for patients who were cT1 to T2 cN0 prior to BCS, and resulted in a large proportion of patients—97% (147 of 151)—who were spared ALND. Our analysis shows that cN0 predicts limited SLN metastasis on final pathology, with 97% (146 of 151) of these patients who would be spared ALND based on pathologic lymph node status and current ASCO guidelines for patients undergoing BCS. With such a low rate of ALND, eliminating routine frozen section diagnosis for SLNB in these patients is warranted, especially when considering prolonged anesthesia time associated with waiting for frozen section results on potentially up to 5 SLNs per patient, and savings in health care costs related to extra charges of a frozen section diagnosis. For pathology departments, a decline in frozen sections for SLNB as a result of the Z0011 trial would likely be a welcomed change in practice, allowing for pathology staff and resources to be directed elsewhere. References 1. Lester SC. The breast. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2015:1065–1095. 2. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349(6):546–553. 3. Giuliano AE, Hunt KK, Ballman KV, 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(6):569–575. 4. Caudle AS, Hunt KK, Kuerer HM, et al. Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial. Ann Surg Oncol. 2011;18(9):2407–2412. 5. Caudle AS, Hunt KK, Tucker SL, et al. American College of Surgeons Oncology Group (ACOSOG) Z0011: impact on surgeon practice patterns. Ann Surg Oncol. 2012;19(10):3144–3151. 6. Yi M, Kuerer HM, Mittendorf EA, et al. Impact of the american college of surgeons oncology group Z0011 criteria applied to a contemporary patient population. J Am Coll Surg. 2013;216(1):105–113. 7. Zellars RC. New information prompts old question: is sentinel lymph node sampling equivalent to axillary lymph node dissection? J Clin Oncol. 2014; 32(32):3583–3585. 8. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2014;32(13):1365–1383. 9. Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013;14(4):297–305.

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10. Caretta-Weyer H, Greenberg CG, Wilke LG, et al. Impact of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial on clinical management of the axilla in older breast cancer patients: a SEER-medicare analysis. Ann Surg Oncol. 2013;20(13):4145–4152. 11. Gainer SM, Hunt KK, Beitsch P, Caudle AS, Mittendorf EA, Lucci A. Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: a survey of the American Society of Breast Surgeons. Ann Surg Oncol. 2012;19(10): 3152–3158. 12. Wright GP, Mater ME, Sobel HL, et al. Measuring the impact of the American College of Surgeons Oncology Group Z0011 trial on breast cancer surgery in a community health system. Am J Surg. 2015;209(2):240–245. 13. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg. 2010;252(3):426–432; discussion 432–423. 14. Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011;364(5):412–421. 15. Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in breast cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124(7):966–978. 16. Weaver DL. Pathology evaluation of sentinel lymph nodes in breast cancer: protocol recommendations and rationale. Mod Pathol. 2010;23(suppl 2):S26–S32. 17. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707– 1716. 18. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-

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