Ann Surg Oncol DOI 10.1245/s10434-015-4606-0
ORIGINAL ARTICLE – BREAST ONCOLOGY
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes in Patients with Breast Cancer: Implications for Axillary Metastases and Conservation Karina Cox, MBBS, FRCS, MD, Jennifer Weeks, MBBS, Pippa Mills, BM, MRCP, FRCR, Ritchie Chalmers, BA, FRCS, PhD, Haresh Devalia, MBBS, MSc, FRCS, David Fish, BSc, MBBS, MRCP, FRCPath, and Ali Sever, PhD Maidstone Breast Clinic, Maidstone and Tunbridge Wells NHS Trust, Maidstone, Kent, UK
ABSTRACT Background. In breast cancer patients, sentinel lymph nodes (SLN) can be identified in the breast clinic using contrast-enhanced ultrasound (CEUS). This study aimed to characterize and compare the extent of axillary metastases in patients with either a benign or malignant SLN core biopsy at the end of surgical treatment. Methods. Between 2009 and 2014, prospective data were collected on consecutive patients who underwent targeted core biopsy of SLN identified using CEUS in the breast clinic. Patients with abnormal lymph nodes (LN) detected on grey-scale ultrasound were not included. Patients whose initial SLN core biopsy was benign were compared with those who had a malignant SLN core biopsy. Results. 555 patients with invasive breast cancer had SLN successfully identified and core biopsied. 487 had a benign SLN core biopsy and 427 (88 %) did not have metastases found in surgically excised SLN. Only 2 % of patients with an initial benign SLN core biopsy were found to have 2 or more LN macrometastases. 68 patients had a malignant SLN core biopsy and 52 % had 2 or more LN macrometastases. The total volume of LN metastases was higher in the group of patients who had an initial malignant SLN core biopsy (P \ 0.001). Conclusions. Patients with a normal grey-scale ultrasound and benign SLN core biopsy are unlikely to have extensive axillary disease and may be ideally suited for axillary conservation. The decision to omit axillary LN dissection
Ó Society of Surgical Oncology 2015 First Received: 30 September 2014 K. Cox, MBBS, FRCS, MD e-mail: [email protected]
for patients with a malignant SLN core biopsy must be carefully considered because many will have undetected high-volume metastases.
The introduction of the sentinel node biopsy (SNB) has transformed axillary surgery by sparing many patients the significant morbidity of an axillary lymph node dissection (ALND).1 Moreover, SNB is a safe and accurate staging technique for early breast cancer.2 Currently, patients with sentinel lymph node (SLN) macrometastases are advised to continue their axillary treatment with a completion ALND,3 but this may not be appropriate in all cases. In up to 70 % of patients with positive SLN, no further lymph node (LN) metastases are found after completion ALND.4 Recent trial evidence also suggests that a completion ALND does not improve local recurrence rates or overall survival for patients with T1/T2 tumors and SLN macrometastases who have undergone breast-conserving surgery (BCS).5 Nevertheless, the identification of high-volume axillary metastases remains clinically important because inadequate treatment may lead to regional recurrence,6 and differentiation of high- from low-volume axillary LN metastases in the diagnostic period would aid surgical decision making. The grey-scale sonographic assessment of axillary LN in combination with LN biopsy is widely used to detect LN metastases with a sensitivity of 31–63 %,7 and patients with ultrasound-detected metastases appear to have a higher LN metastatic burden than those with SLN metastases found at the time of surgery.8 For those patients with sonographically normal axillary LN,9 contrast-enhanced ultrasound (CEUS) can be used to identify and biopsy SLN in the preoperative period.10 The technique, originally described in a swine melanoma model,11 uses intradermally injected microbubbles to identify and biopsy SLN often not seen with grey-scale
K. Cox et al.
ultrasound.10 Sentinel LN are successfully biopsied in 87 % of patients and the technique identifies SLN metastases with a sensitivity of 61 %.12 We have previously speculated that false-negative results occur because the biopsy needle misses low-volume disease within the SLN,12 and these patients may be less likely to have extensive nodal metastases. This study aimed to characterize and compare the extent of metastatic axillary disease at the end of surgical treatment in patients with newly diagnosed invasive breast cancer who had a normal grey-scale axillary ultrasound and either a benign or malignant core biopsy of SLN identified using CEUS. METHODS Study Design Between November 2009 and February 2014, prospective information was collected from 903 patients with newly diagnosed breast cancer and a normal grey-scale ipsilateral axillary ultrasound9 who had SLN identified and biopsied in Maidstone Breast Clinic using intradermal microbubbles and CEUS. The data was retrospectively analyzed to calculate the sensitivity and specificity of successful CEUS-guided SLN core biopsy as a test to identify SLN metastases in breast cancer patients with invasive disease. The total volume of axillary metastases at the end of surgical treatment was also determined for each patient.
performed using a core biopsy technique or core biopsy and fine-needle aspiration (FNA). The sample was then sent for histopathologic ± cytologic analysis including immunohistochemical staining for patients with a lobular phenotype. We have previously reported that FNA biopsy alone results in a much greater proportion of inadequate tissue sampling (18 %) than core biopsy ± FNA biopsy (7 %).12 The core biopsy technique also allows the quantification of metastases within the specimen.12 Surgical Management of the Axilla If the biopsy contained malignant cells, patients were advised to have an ipsilateral ALND. Patients had a surgical SNB if the biopsy identified normal lymphoid cells, indeterminate cellular changes, inadequate tissue sampling or if the patient declined primary ALND. Before surgery, patients attended the nuclear medicine department for injection of radioactive isotope (Nanocoll, G.E. Healthcare, Chicago, USA), 40 mbeq in the periareolar, upper outer quadrant position. The next day, the patients underwent surgical resection by a specialist breast surgeon. Immediately after anesthetic induction, the patients received a 2-ml injection of blue dye (Bleu Patente V 2.5 %; Guerbet, Paris, France) subdermally in the periareolar upper outer quadrant position. A gamma probe (Navigator GPS, RMD Instruments, Watertown, USA) was used to identify SLN. All SLN within the axilla were excised and sent for histologic analysis. Statistical Analysis
Identification and Biopsy of SLN Using Intradermal Microbubbles and CEUS After a normal grey-scale axillary ultrasound, patients presented for injection of ultrasound contrast agent (Sonovue; BRACCO Imaging S.p.A, Colleretto Giacosa, Italy). Between 0.2 and 0.5 ml of ultrasound contrast agent was injected (up to three consecutive injections) intradermally in the periareolar upper outer quadrant position. Ultrasound examinations were performed with a Sequoia 512 Acuson (Siemens Medical Systems, Issaquah, WA, USA) or LOGIQ 9 (GE Healthcare, Fairfield, CT, USA), providing conventional grey-scale, pulse-inversion harmonic grey-scale, contrast-specific sonographic imaging with live dual images of tissue only, and contrast agent image. A high-frequency 14-MHz linear-array probe was used (15L8w). To reduce microbubble destruction, low mechanical index (MI) values were applied (MI 0.2–0.4). After contrast injection, the areolar area was massaged for 10–30 s. Lymphatic channels were visualized on contrast pulse sequencing and followed into the axilla. Areas of contrast accumulation were also imaged with grey scale or live dual images. Once identified, biopsy of the SLN was
Sensitivity and specificity were calculated from a 2 9 2 table of frequencies. Binomial confidence intervals were then calculated for all values. The likelihood ratios of a negative test result were calculated, as were posterior odds. The post-test probability that the patient had LN metastases, given a negative SLN biopsy, was calculated based on the pre-test probability (prevalence of LN metastases). The total volume of axillary metastases at the end of surgical treatment was determined for each patient using the following scoring system: 1 (lymph nodes containing a macrometastasis), 0.5 (micrometastasis), and 0.2 (isolated tumor cells). The Mann–Whitney test was used to compare the volume of axillary metastases between patients with benign and malignant biopsy results (STATA version 12.1; Stata Corp LP, College Station, TX, USA). Ethics The local ethics committee approved this study, and the Medicines and Healthcare Products Regulatory Agency (MHRA) approved the use of microbubbles by intraparenchymal injection.
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
RESULTS
Volume of Axillary Metastases: Initial Benign Core Biopsy of SLN
Study Population In Maidstone Breast Clinic, 903 patients with newly diagnosed breast cancer and a normal grey-scale ipsilateral ultrasound had SLNs identified and biopsied using intradermal microbubbles and CEUS. Of these, 249 patients were excluded from the final analysis because of the following reasons; 93 patients had neo-adjuvant systemic therapy, 13 patients either declined or were not deemed fit enough for axillary surgery, 78 patients had FNA alone rather than a core biopsy, 15 patients had incomplete records and 50 patients had pre-invasive disease (ductal carcinoma in situ). The remaining 654 patients had a diagnosis of invasive breast cancer and went on to have primary surgical excision of the breast cancer together with axillary surgery. Visualization and Targeted Core Biopsy of SLN Using Microbubbles and CEUS Of the 654 patients, SLN were clearly visualized in 605 patients (93 %) (Fig. 1) and successfully core biopsied (B2-B5) in 555 patients (85 %). Therefore, in 99 patients (15 %) the technique failed. The prevalence of axillary lymph node metastases in the 555 patients was 23 % (16.8 % macrometastases, 4.5 % micrometastases and 1.8 % isolated tumor cells). Of these, microbubbles and CEUS identified 53 % (confidence interval (CI) 44–62 %) of sentinel node metastases with 100 % (CI 99–100 %) specificity. The negative predictive value was 88 %, and given a benign SLN biopsy result, the post-test probability that a patient had SLN metastases at subsequent surgical excision was 12 %.
Of the 555 patients (Table 1) who had successful SLN core biopsies, 485 had benign results and went on to have tumor resection together with a surgical SLN excision biopsy. Two patients with benign SLN core biopsies also had malignant cytology and proceeded to primary ALND. The reporting pathologist recognized a biopsy tract in the surgically retrieved SLN of 417 patients (86 %). A biopsy tract was not seen in the SLN of 59 patients (12 %), and data were not recorded for 9 patients. In 427 (88 %) of the 485 benign core biopsies, histologic analysis of completely excised SLN confirmed the absence of LN metastases. Of the 487 total benign core biopsies, 60 (12 %) were false-negatives, and metastases were identified in the excised SLN. Of the 60 patients, 47 had an ALND. Further axillary surgery was declined by 13 patients because they were elderly (age [80 years) or had micrometastases/ isolated tumor cells (ITC) in surgically excised SLN. At the end of surgical treatment, the total volume of LN metastases was calculated for the 47 patients who had TABLE 1 Age and clinicopathologic characteristics of 555 patients with invasive breast cancer who had a successful SLN core biopsy using intradermal microbubbles and contrast enhanced ultrasound No. of patients Median age in years (range)
61 (29–93)
Estrogen receptor status ER positive
481 (86.7)
ER negative
71 (12.8)
Not recorded
3 (0.5)
Her-2 Status Her-2 positive
50 (9)
Her-2 negative
460 (83)
Not recorded
45 (8)
Invasive tumour size T1 T2
369 (67) 101 (18)
T3/multifocal
85 (15)
Tumour grade Grade 1
119 (21)
Grade 2
276 (50)
Grade 3
160 (29)
Tumour type IDC
453 (81.6)
ILC
73 (13.2)
Other
28 (5)
Not recorded
1 (0.2)
Data are expressed as n (%) unless otherwise specified FIG. 1 Ultrasound contrast pulse sequencing image of a SLN (arrow) identified after intradermal injection of microbubbles
ER Estrogen receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma
K. Cox et al. TABLE 2 Benign SLN core biopsy Volume of axillary LN metastases at the end of surgical treatment Micrometastases
Low (\2 LN macrometastases)
High (2 or more LN macrometastases)
Total number of patients
14
23
10
Median age in years (range)
61 (43–70)
51 (32–85)
55 (36–75)
Receptor status ER positive
14 (100)
18 (78)
10 (100)
PR positive
9 (64)
18 (78)
10 (100)
Her-2 positive
1 (7)
2 (9)
0
Her-2 not recorded
1 (7)
1 (4)
1 (10)
ER-/PR-/Her-2-
1 (7)
4 (17)
0
ER-/PR-/HER-2?
0
1 (4)
0
T1
9 (65)
11 (48)
4 (40)
T2
1 (7)
8 (35)
3 (30)
T3
2 (14)
3 (13)
1 (10)
Multifocal
2 (14)
1 (4)
2 (20)
Grade 1
3 (21)
4 (17)
2 (20)
Grade 2
6 (43)
10 (43)
8 (80)
Grade 3 Tumour type
5 (36)
9 (40)
0
IDC
11 (79)
20 (88)
8 (80)
ILC
2 (14)
1 (4)
2 (20)
Invasive tumour size
Tumour grade
Other
0
1 (4)
0
Mixed
1 (7)
1 (4)
0
Yes
7 (50)
8 (35)
4 (40)
No
6 (43)
14 (61)
4 (40)
Not-recorded
1 (7)
1 (4)
2 (20)
LVI
Age and clinicopathologic characteristics of 47 patients who had an ALND following a false negative benign core biopsy of SLN identified with intradermal microbubbles and contrast enhanced ultrasound. Data are expressed as n (%) unless otherwise specified ER Estrogen receptor, PR progesterone receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LVI lymphovascular invasion
primary/completion ALND. Of these patients, 14 (30 %) had LN micrometastases, 23 (49 %) had low-volume macrometastatic disease (1 LN macrometastasis ± an additional LN micrometastasis or LN ITC), and 10 (21 %) had high-volume axillary metastases (2 or more LN macrometastases) (Table 2). Of the 37 patients with either LN micrometastases or low-volume LN macrometastases, 31 had only SLN metastases, and the ALND did not contain further LN metastases. One patient with a benign SLN core biopsy also had malignant SLN cytology and proceeded to a primary ALND with a single LN macrometastasis identified. Six patients had residual disease found in the ALND (one patient with ITC in a single LN, two patients with a single
LN micrometastasis, one patient with 2 LN micrometastases, and two patients with a single LN macrometastasis). Of the 47 patients, 15 had micrometastases found in surgically excised SLN and went on to have a completion ALND. Of these 15 patients, 13 had no further axillary disease, one had a single residual LN macrometastasis, and one had a second residual LN micrometastasis. Of the ten patients with high-volume axillary macrometastases, six had macrometastases in two LNs, two had macrometastases in three or four LNs, and two had more than four LN macrometastases. In two of the ten patients, only SLN metastases were found, and the ALND did not contain further disease. One patient with a benign SLN core biopsy also had malignant SLN cytology and proceeded to a primary
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
ALND with two LN macrometastases identified. Seven patients had further LN metastases in the ALND. Four patients had a single LN metastasis. One patient had three residual LN metastases, and two patients had more than four residual LN metastases. The two patients with more than four residual LN metastases had invasive lobular carcinomas, and the patient with three residual LN metastases had multifocal invasive ductal carcinoma. Volume of Axillary Metastases: Initial Malignant Core Biopsy of SLN In 68 (12 %) of the 555 patients, malignant cells were identified in the core biopsy specimen using CEUS. Five
patients elected to have a primary surgical SNB (followed by completion ALND) because the CEUS-guided SLN core biopsy contained only ITC/micrometastases. Two patients had ITC in excised SLN and no residual disease in the ALND. Two patients had a single SLN macrometastasis, and one of these patients had a further LN micrometastasis in the ALND. Two patients had two SLN macrometastases, and one of these had a further LN ITC in the ALND. Two patients with ITC and micrometastases in surgically excised SLN declined further axillary surgery. A total of 66 patients had primary/completion ALND. The final histologic analysis of ALND specimens indicated that three patients (4.5 %) had LN ITC, three patients (4.5 %) had LN micrometastases, 26 patients (39 %) had low-volume
TABLE 3 Malignant SLN core biopsy Volume of axillary LN metastases at the end of surgical treatment Micrometastases/ITC
Low (\2 LN macrometastases)
High (2 or more LN macrometastases)
Total number of patients
6
26
34
Median age in years (range)
59 (49–83)
57 (36–85)
55.5 (38–93)
ER positive
6 (100)
20 (77)
34 (100)
PR positive
4 (67)
16 (62)
31 (91)
Her-2 positive
0
4 (15)
2 (6)
Her-2 not recorded
1 (17)
2 (8)
3 (9)
ER-/PR-/Her-2-
0
1 (4)
2 (6)
ER-/PR-/HER-2?
0
3 (12)
0
T1 T2
1 (17) 1 (17)
9 (35) 5 (19)
10 (29) 6 (18)
T3
2 (33)
7 (27)
10 (29)
Multifocal
2 (33)
5 (19)
8 (24)
Grade 1
0
5 (19)
4 (12)
Grade 2
6 (100)
13 (50)
24 (71)
Grade 3
0
8 (31)
6 (17)
IDC
2 (17)
22 (85)
18 (53)
ILC
4 (83)
3 (12)
13 (38)
Other
0
1 (3)
1 (3)
Mixed
0
0
2 (6)
Yes
2 (33)
11 (42)
20 (59)
No Not-recorded
3 (50) 1 (17)
13 (50) 2 (8)
10 (29) 4 (12)
Receptor status
Invasive tumour size
Tumour grade
Tumour type
LVI
Age and clinicopathologic characteristics of 66 patients who had an ALND following a malignant core biopsy of SLN identified with intradermal microbubbles and contrast enhanced ultrasound Data are expressed as n (%) unless otherwise specified ER Estrogen receptor, PR progesterone receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LVI lymphovascular invasion
K. Cox et al.
axillary macrometastatic disease, and 34 patients (52 %) had high-volume axillary macrometastases (Table 3).
initial malignant SLN core biopsy were found to have two or more LN macrometastases.
Volume of Axillary Metastases: Comparison Between Patients with Initial Benign SLN Biopsy and Patients with Initial Malignant SLN Biopsy
DISCUSSION
Using the scoring system outlined in the Methods section, the total volume of axillary LN metastases after ALND was calculated and found to be significantly higher (P \ 0.001) for the patients with an initial malignant SLN core biopsy result than for those who had a false-negative benign SLN core biopsy result (Fig. 2). A benign SLN core biopsy was associated with either absence of SLN metastases or micrometastases and lowvolume axillary disease (\2 LN macrometastases) in the patients who had malignant cells identified after surgical SLN excision. Only 2 % of the patients with an initial benign SLN core biopsy were found to have high-volume axillary metastases at the end of surgical treatment. In contrast, more than half of the patients (52 %) who had an
Metastatic axillary LN score
a 18
Benign SLN core biopsy
16 14 12 10 8 6 4 2 0
Individual Patients (n=47)
Metastatic axillary LN score
b 18 16 14 12 10 8 6 4 2 0
Malignant SLN core biopsy
Individual Patients (n=66)
c Group
N
Median (IQR)
P value
Benign
47
1.0 (0.5,1.5)
0.001
Malignant
66
2.0 (1.0, 3.0)
FIG. 2 Histogram plots illustrating the individual volume of nodal metastatic disease, after axillary lymph node dissection, in those patients with; a an initial benign core biopsy and b an initial malignant core biopsy of SLN identified using microbubbles and contrast enhanced ultrasound. The Mann–Whitney test was used to compare the total volume of ipsilateral axillary metastatic disease between the groups (c).
For breast cancer patients with a normal grey-scale axillary ultrasound, intradermal microbubbles and CEUS can be used to identify and biopsy SLN in the preoperative period. The technique distinguishes two groups of patients with axillary metastases depending on their initial core biopsy result. Those with a false-negative benign SLN core biopsy are unlikely to have extensive axillary disease, whereas 52 % of those with a malignant core biopsy result will have two or more LN macrometastases. In 86 % of the patients in this study, core biopsy tracts were clearly seen in SLN surgically identified using blue dye and radioactive isotope. In the patients with a false-negative SLN core biopsy, small clusters of metastatic cells were frequently found remote to the biopsy site. The lack of a biopsy tract in 12 % of excised SLNs likely indicates that the biopsy site was not recognized in the sections of the processed SLN specimen or another LN may have been sampled. The identification and biopsy of SLN using CEUS aids preoperative planning by offering relevant information that can inform treatment decisions. Recognizing SLN metastases that are occult on conventional grey-scale ultrasound imaging early in the patient pathway is advantageous because it may influence choices such as initiation of neoadjuvant chemotherapy.13 The presence of a metastatic axillary LN is also an important factor involved in the planning of postmastectomy radiotherapy and consequently may affect reconstructive options.14 This retrospective analysis has several limitations. We did not simultaneously collect prospective data on patients with LN metastases identified using grey-scale ultrasound. However, before 2009, a retrospective audit of 633 consecutive patients with invasive breast cancer seen at Maidstone Breast Clinic was conducted and showed that grey-scale ultrasound and FNA biopsy identified 23 % of axillary metastases with a sensitivity of 59 %.15 In the United Kingdom, 16 % of women with screendetected invasive cancers and a normal axillary ultrasound were found to have positive LN after surgery.16 We excluded patients who had neoadjuvant systemic therapy, and the prevalence of LN metastases in our group of mixed screen-detected and symptomatic patients with invasive breast cancer was 23 %. The low number of patients with LN metastases made it difficult to determine meaningful differences in clinicopathologic features between the two groups, especially because 15 patients with SLN metastases did not have ALND and were eliminated from the final calculations. Data regarding the presence of extranodal metastases were not collected.
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
The study included patients who had either mastectomy or BCS and was not restricted to patients with small (T1/ T2) tumors. Although suggestive, the data presented do not provide enough support to presume that the axillary management for patients undergoing mastectomy should follow that for patients undergoing BCS. Clinicians should continue to follow current evidence-based guidelines for patients in this population. CONCLUSIONS Our results suggest that the preoperative identification and biopsy of SLN using intradermal microbubbles and CEUS is a useful adjunct to grey-scale axillary ultrasound for patients with invasive breast cancer. A completion ALND may not be advantageous for patients with an initial benign SLN core biopsy result who are subsequently found to have metastases in surgically excised SLN. For those with a malignant SLN core biopsy result, decisions to omit ALND must be carefully considered because systemic therapy alone may be inadequate for the treatment of patients with undetected high-volume axillary metastases. ACKNOWLEDGMENT This work was presented as a poster at the 2014 San Antonio Breast Cancer Symposium, San Antonio, TX, USA. DISCLOSURE
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8.
9.
10.
11.
12.
The authors have no conflicts of interest to report. 13.
REFERENCES 1. Schijven MP, Vingerhoets AJ, Rutten HJ, Nieuwenhuijzen GA, Roumen RM, van Bussel ME, Voogd AC. Comparison of morbidity between axillary lymph node dissection and sentinel node biopsy. Eur J Surg Oncol. 2003;29:341–50. 2. Veronesi U, Paganelli G, Viale G, et al. A randomised comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–53. 3. CG80 Early and locally advanced breast cancer: full guideline. United Kingdom, National Institute for Health and Clinical Excellence. February 2009. http://www.nice.org.uk/guidance/cg80/ resources/guidance-early-and-locally-advanced-breast-cancer-pdf. Accessed July 2014 4. Gur AS, Unal B, Johnson R, Ahrendt G, Bonaventura M, Gordon P, Sonan A. Predictive probability of four different breast cancer
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nomograms for nonsentinel axillary lymph node metastasis in positive sentinel node biopsy. J Am Coll Surg. 2009;208:229–35. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis. JAMA. 2011;305:569–75. Grill IS, Kestin LL, Goldstein N, Mitchell C, Martinez A, Ingold J, Vicini FA. Risk factors for regional nodal failure after breastconserving therapy: regional nodal irradiation reduces rate of axillary failure in patients with four or more positive lymph nodes. Int J Radiat Oncol Biol Phys. 2003;56:658–70. Alvarez S, Anorbe E, Alcorta P, Lopez F, Alonso I, Cortes J. Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review. AJR Am J Roentgenol. 2006;186:1342–8. Caudle AS, Kuerer HM, Le-Petross HT, Yang W, Yi M, Bedrosian I, Krishnamurthy S, Fornage BD, Hunt KK, Mittendorf EA. Predicting the extent of nodal disease in early-stage breast cancer. Ann Surg Oncol. 2014;21:3440–7. Yang WT, Metreweli C, Lam PK, Chang J. Benign and malignant breast masses and axillary nodes: evaluation with echo enhanced color power Doppler ultrasound. Radiology. 2001;220: 795–802. Sever A, Jones S, Cox K, Weeks J, Mills P, Jones P. Preoperative localization of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasonography in patients with breast cancer. Br J Surg. 2009;96:1295–9 Goldberg BB, Merton DA, Liu JB, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology. 2004;230:324–30. Cox K, Sever A, Jones S, Weeks J, Mills P, Devalia H, et al. Validation of a technique using microbubbles and contrast-enhanced ultrasound (CEUS) to biopsy sentinel lymph nodes (SLN) in preoperative breast cancer patients with a normal grey-scale axillary ultrasound. Eur J Surg Oncol. 2013;39:760–5. Kilbride KE, Lee MC, Nees AV, Cimmino VM, Diehl KM, Sabel MS, Hayes DF, Schott AF, Kleer CG, Chang AE, Newman LA. Axillary staging prior to neoadjuvant chemotherapy for breast cancer: predictors of recurrence. Ann Surg Oncol. 2008;15:3252– 8. Su YL, Li SH, Chen YY, Chen HC, Tay Y, Huang CH, Chou FF, Wu SC, Rau KM. Postmastectomy radiotherapy benefits subgroups of breast cancer patients with T1–2 tumor and 1–3 axillary lymph node(s) metastasis. Radiol Oncol. 2014;48:314–22. Mills P, Sever AR, Weeks J, Fish D, Jones S, Jones P. Axillary ultrasound assessment in primary breast cancer: an audit of 653 cases. Breast J. 2010;16:460–3. NHS breast screening programme and association of breast surgery: an audit of screen-detected breast cancers for the year of screening April 2012 to March 2013. May 2014. Public Health England, Wellington House, London, UK. www.gov.uk/phe.
ORIGINAL ARTICLE – BREAST ONCOLOGY
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes in Patients with Breast Cancer: Implications for Axillary Metastases and Conservation Karina Cox, MBBS, FRCS, MD, Jennifer Weeks, MBBS, Pippa Mills, BM, MRCP, FRCR, Ritchie Chalmers, BA, FRCS, PhD, Haresh Devalia, MBBS, MSc, FRCS, David Fish, BSc, MBBS, MRCP, FRCPath, and Ali Sever, PhD Maidstone Breast Clinic, Maidstone and Tunbridge Wells NHS Trust, Maidstone, Kent, UK
ABSTRACT Background. In breast cancer patients, sentinel lymph nodes (SLN) can be identified in the breast clinic using contrast-enhanced ultrasound (CEUS). This study aimed to characterize and compare the extent of axillary metastases in patients with either a benign or malignant SLN core biopsy at the end of surgical treatment. Methods. Between 2009 and 2014, prospective data were collected on consecutive patients who underwent targeted core biopsy of SLN identified using CEUS in the breast clinic. Patients with abnormal lymph nodes (LN) detected on grey-scale ultrasound were not included. Patients whose initial SLN core biopsy was benign were compared with those who had a malignant SLN core biopsy. Results. 555 patients with invasive breast cancer had SLN successfully identified and core biopsied. 487 had a benign SLN core biopsy and 427 (88 %) did not have metastases found in surgically excised SLN. Only 2 % of patients with an initial benign SLN core biopsy were found to have 2 or more LN macrometastases. 68 patients had a malignant SLN core biopsy and 52 % had 2 or more LN macrometastases. The total volume of LN metastases was higher in the group of patients who had an initial malignant SLN core biopsy (P \ 0.001). Conclusions. Patients with a normal grey-scale ultrasound and benign SLN core biopsy are unlikely to have extensive axillary disease and may be ideally suited for axillary conservation. The decision to omit axillary LN dissection
Ó Society of Surgical Oncology 2015 First Received: 30 September 2014 K. Cox, MBBS, FRCS, MD e-mail: [email protected]
for patients with a malignant SLN core biopsy must be carefully considered because many will have undetected high-volume metastases.
The introduction of the sentinel node biopsy (SNB) has transformed axillary surgery by sparing many patients the significant morbidity of an axillary lymph node dissection (ALND).1 Moreover, SNB is a safe and accurate staging technique for early breast cancer.2 Currently, patients with sentinel lymph node (SLN) macrometastases are advised to continue their axillary treatment with a completion ALND,3 but this may not be appropriate in all cases. In up to 70 % of patients with positive SLN, no further lymph node (LN) metastases are found after completion ALND.4 Recent trial evidence also suggests that a completion ALND does not improve local recurrence rates or overall survival for patients with T1/T2 tumors and SLN macrometastases who have undergone breast-conserving surgery (BCS).5 Nevertheless, the identification of high-volume axillary metastases remains clinically important because inadequate treatment may lead to regional recurrence,6 and differentiation of high- from low-volume axillary LN metastases in the diagnostic period would aid surgical decision making. The grey-scale sonographic assessment of axillary LN in combination with LN biopsy is widely used to detect LN metastases with a sensitivity of 31–63 %,7 and patients with ultrasound-detected metastases appear to have a higher LN metastatic burden than those with SLN metastases found at the time of surgery.8 For those patients with sonographically normal axillary LN,9 contrast-enhanced ultrasound (CEUS) can be used to identify and biopsy SLN in the preoperative period.10 The technique, originally described in a swine melanoma model,11 uses intradermally injected microbubbles to identify and biopsy SLN often not seen with grey-scale
K. Cox et al.
ultrasound.10 Sentinel LN are successfully biopsied in 87 % of patients and the technique identifies SLN metastases with a sensitivity of 61 %.12 We have previously speculated that false-negative results occur because the biopsy needle misses low-volume disease within the SLN,12 and these patients may be less likely to have extensive nodal metastases. This study aimed to characterize and compare the extent of metastatic axillary disease at the end of surgical treatment in patients with newly diagnosed invasive breast cancer who had a normal grey-scale axillary ultrasound and either a benign or malignant core biopsy of SLN identified using CEUS. METHODS Study Design Between November 2009 and February 2014, prospective information was collected from 903 patients with newly diagnosed breast cancer and a normal grey-scale ipsilateral axillary ultrasound9 who had SLN identified and biopsied in Maidstone Breast Clinic using intradermal microbubbles and CEUS. The data was retrospectively analyzed to calculate the sensitivity and specificity of successful CEUS-guided SLN core biopsy as a test to identify SLN metastases in breast cancer patients with invasive disease. The total volume of axillary metastases at the end of surgical treatment was also determined for each patient.
performed using a core biopsy technique or core biopsy and fine-needle aspiration (FNA). The sample was then sent for histopathologic ± cytologic analysis including immunohistochemical staining for patients with a lobular phenotype. We have previously reported that FNA biopsy alone results in a much greater proportion of inadequate tissue sampling (18 %) than core biopsy ± FNA biopsy (7 %).12 The core biopsy technique also allows the quantification of metastases within the specimen.12 Surgical Management of the Axilla If the biopsy contained malignant cells, patients were advised to have an ipsilateral ALND. Patients had a surgical SNB if the biopsy identified normal lymphoid cells, indeterminate cellular changes, inadequate tissue sampling or if the patient declined primary ALND. Before surgery, patients attended the nuclear medicine department for injection of radioactive isotope (Nanocoll, G.E. Healthcare, Chicago, USA), 40 mbeq in the periareolar, upper outer quadrant position. The next day, the patients underwent surgical resection by a specialist breast surgeon. Immediately after anesthetic induction, the patients received a 2-ml injection of blue dye (Bleu Patente V 2.5 %; Guerbet, Paris, France) subdermally in the periareolar upper outer quadrant position. A gamma probe (Navigator GPS, RMD Instruments, Watertown, USA) was used to identify SLN. All SLN within the axilla were excised and sent for histologic analysis. Statistical Analysis
Identification and Biopsy of SLN Using Intradermal Microbubbles and CEUS After a normal grey-scale axillary ultrasound, patients presented for injection of ultrasound contrast agent (Sonovue; BRACCO Imaging S.p.A, Colleretto Giacosa, Italy). Between 0.2 and 0.5 ml of ultrasound contrast agent was injected (up to three consecutive injections) intradermally in the periareolar upper outer quadrant position. Ultrasound examinations were performed with a Sequoia 512 Acuson (Siemens Medical Systems, Issaquah, WA, USA) or LOGIQ 9 (GE Healthcare, Fairfield, CT, USA), providing conventional grey-scale, pulse-inversion harmonic grey-scale, contrast-specific sonographic imaging with live dual images of tissue only, and contrast agent image. A high-frequency 14-MHz linear-array probe was used (15L8w). To reduce microbubble destruction, low mechanical index (MI) values were applied (MI 0.2–0.4). After contrast injection, the areolar area was massaged for 10–30 s. Lymphatic channels were visualized on contrast pulse sequencing and followed into the axilla. Areas of contrast accumulation were also imaged with grey scale or live dual images. Once identified, biopsy of the SLN was
Sensitivity and specificity were calculated from a 2 9 2 table of frequencies. Binomial confidence intervals were then calculated for all values. The likelihood ratios of a negative test result were calculated, as were posterior odds. The post-test probability that the patient had LN metastases, given a negative SLN biopsy, was calculated based on the pre-test probability (prevalence of LN metastases). The total volume of axillary metastases at the end of surgical treatment was determined for each patient using the following scoring system: 1 (lymph nodes containing a macrometastasis), 0.5 (micrometastasis), and 0.2 (isolated tumor cells). The Mann–Whitney test was used to compare the volume of axillary metastases between patients with benign and malignant biopsy results (STATA version 12.1; Stata Corp LP, College Station, TX, USA). Ethics The local ethics committee approved this study, and the Medicines and Healthcare Products Regulatory Agency (MHRA) approved the use of microbubbles by intraparenchymal injection.
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
RESULTS
Volume of Axillary Metastases: Initial Benign Core Biopsy of SLN
Study Population In Maidstone Breast Clinic, 903 patients with newly diagnosed breast cancer and a normal grey-scale ipsilateral ultrasound had SLNs identified and biopsied using intradermal microbubbles and CEUS. Of these, 249 patients were excluded from the final analysis because of the following reasons; 93 patients had neo-adjuvant systemic therapy, 13 patients either declined or were not deemed fit enough for axillary surgery, 78 patients had FNA alone rather than a core biopsy, 15 patients had incomplete records and 50 patients had pre-invasive disease (ductal carcinoma in situ). The remaining 654 patients had a diagnosis of invasive breast cancer and went on to have primary surgical excision of the breast cancer together with axillary surgery. Visualization and Targeted Core Biopsy of SLN Using Microbubbles and CEUS Of the 654 patients, SLN were clearly visualized in 605 patients (93 %) (Fig. 1) and successfully core biopsied (B2-B5) in 555 patients (85 %). Therefore, in 99 patients (15 %) the technique failed. The prevalence of axillary lymph node metastases in the 555 patients was 23 % (16.8 % macrometastases, 4.5 % micrometastases and 1.8 % isolated tumor cells). Of these, microbubbles and CEUS identified 53 % (confidence interval (CI) 44–62 %) of sentinel node metastases with 100 % (CI 99–100 %) specificity. The negative predictive value was 88 %, and given a benign SLN biopsy result, the post-test probability that a patient had SLN metastases at subsequent surgical excision was 12 %.
Of the 555 patients (Table 1) who had successful SLN core biopsies, 485 had benign results and went on to have tumor resection together with a surgical SLN excision biopsy. Two patients with benign SLN core biopsies also had malignant cytology and proceeded to primary ALND. The reporting pathologist recognized a biopsy tract in the surgically retrieved SLN of 417 patients (86 %). A biopsy tract was not seen in the SLN of 59 patients (12 %), and data were not recorded for 9 patients. In 427 (88 %) of the 485 benign core biopsies, histologic analysis of completely excised SLN confirmed the absence of LN metastases. Of the 487 total benign core biopsies, 60 (12 %) were false-negatives, and metastases were identified in the excised SLN. Of the 60 patients, 47 had an ALND. Further axillary surgery was declined by 13 patients because they were elderly (age [80 years) or had micrometastases/ isolated tumor cells (ITC) in surgically excised SLN. At the end of surgical treatment, the total volume of LN metastases was calculated for the 47 patients who had TABLE 1 Age and clinicopathologic characteristics of 555 patients with invasive breast cancer who had a successful SLN core biopsy using intradermal microbubbles and contrast enhanced ultrasound No. of patients Median age in years (range)
61 (29–93)
Estrogen receptor status ER positive
481 (86.7)
ER negative
71 (12.8)
Not recorded
3 (0.5)
Her-2 Status Her-2 positive
50 (9)
Her-2 negative
460 (83)
Not recorded
45 (8)
Invasive tumour size T1 T2
369 (67) 101 (18)
T3/multifocal
85 (15)
Tumour grade Grade 1
119 (21)
Grade 2
276 (50)
Grade 3
160 (29)
Tumour type IDC
453 (81.6)
ILC
73 (13.2)
Other
28 (5)
Not recorded
1 (0.2)
Data are expressed as n (%) unless otherwise specified FIG. 1 Ultrasound contrast pulse sequencing image of a SLN (arrow) identified after intradermal injection of microbubbles
ER Estrogen receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma
K. Cox et al. TABLE 2 Benign SLN core biopsy Volume of axillary LN metastases at the end of surgical treatment Micrometastases
Low (\2 LN macrometastases)
High (2 or more LN macrometastases)
Total number of patients
14
23
10
Median age in years (range)
61 (43–70)
51 (32–85)
55 (36–75)
Receptor status ER positive
14 (100)
18 (78)
10 (100)
PR positive
9 (64)
18 (78)
10 (100)
Her-2 positive
1 (7)
2 (9)
0
Her-2 not recorded
1 (7)
1 (4)
1 (10)
ER-/PR-/Her-2-
1 (7)
4 (17)
0
ER-/PR-/HER-2?
0
1 (4)
0
T1
9 (65)
11 (48)
4 (40)
T2
1 (7)
8 (35)
3 (30)
T3
2 (14)
3 (13)
1 (10)
Multifocal
2 (14)
1 (4)
2 (20)
Grade 1
3 (21)
4 (17)
2 (20)
Grade 2
6 (43)
10 (43)
8 (80)
Grade 3 Tumour type
5 (36)
9 (40)
0
IDC
11 (79)
20 (88)
8 (80)
ILC
2 (14)
1 (4)
2 (20)
Invasive tumour size
Tumour grade
Other
0
1 (4)
0
Mixed
1 (7)
1 (4)
0
Yes
7 (50)
8 (35)
4 (40)
No
6 (43)
14 (61)
4 (40)
Not-recorded
1 (7)
1 (4)
2 (20)
LVI
Age and clinicopathologic characteristics of 47 patients who had an ALND following a false negative benign core biopsy of SLN identified with intradermal microbubbles and contrast enhanced ultrasound. Data are expressed as n (%) unless otherwise specified ER Estrogen receptor, PR progesterone receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LVI lymphovascular invasion
primary/completion ALND. Of these patients, 14 (30 %) had LN micrometastases, 23 (49 %) had low-volume macrometastatic disease (1 LN macrometastasis ± an additional LN micrometastasis or LN ITC), and 10 (21 %) had high-volume axillary metastases (2 or more LN macrometastases) (Table 2). Of the 37 patients with either LN micrometastases or low-volume LN macrometastases, 31 had only SLN metastases, and the ALND did not contain further LN metastases. One patient with a benign SLN core biopsy also had malignant SLN cytology and proceeded to a primary ALND with a single LN macrometastasis identified. Six patients had residual disease found in the ALND (one patient with ITC in a single LN, two patients with a single
LN micrometastasis, one patient with 2 LN micrometastases, and two patients with a single LN macrometastasis). Of the 47 patients, 15 had micrometastases found in surgically excised SLN and went on to have a completion ALND. Of these 15 patients, 13 had no further axillary disease, one had a single residual LN macrometastasis, and one had a second residual LN micrometastasis. Of the ten patients with high-volume axillary macrometastases, six had macrometastases in two LNs, two had macrometastases in three or four LNs, and two had more than four LN macrometastases. In two of the ten patients, only SLN metastases were found, and the ALND did not contain further disease. One patient with a benign SLN core biopsy also had malignant SLN cytology and proceeded to a primary
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
ALND with two LN macrometastases identified. Seven patients had further LN metastases in the ALND. Four patients had a single LN metastasis. One patient had three residual LN metastases, and two patients had more than four residual LN metastases. The two patients with more than four residual LN metastases had invasive lobular carcinomas, and the patient with three residual LN metastases had multifocal invasive ductal carcinoma. Volume of Axillary Metastases: Initial Malignant Core Biopsy of SLN In 68 (12 %) of the 555 patients, malignant cells were identified in the core biopsy specimen using CEUS. Five
patients elected to have a primary surgical SNB (followed by completion ALND) because the CEUS-guided SLN core biopsy contained only ITC/micrometastases. Two patients had ITC in excised SLN and no residual disease in the ALND. Two patients had a single SLN macrometastasis, and one of these patients had a further LN micrometastasis in the ALND. Two patients had two SLN macrometastases, and one of these had a further LN ITC in the ALND. Two patients with ITC and micrometastases in surgically excised SLN declined further axillary surgery. A total of 66 patients had primary/completion ALND. The final histologic analysis of ALND specimens indicated that three patients (4.5 %) had LN ITC, three patients (4.5 %) had LN micrometastases, 26 patients (39 %) had low-volume
TABLE 3 Malignant SLN core biopsy Volume of axillary LN metastases at the end of surgical treatment Micrometastases/ITC
Low (\2 LN macrometastases)
High (2 or more LN macrometastases)
Total number of patients
6
26
34
Median age in years (range)
59 (49–83)
57 (36–85)
55.5 (38–93)
ER positive
6 (100)
20 (77)
34 (100)
PR positive
4 (67)
16 (62)
31 (91)
Her-2 positive
0
4 (15)
2 (6)
Her-2 not recorded
1 (17)
2 (8)
3 (9)
ER-/PR-/Her-2-
0
1 (4)
2 (6)
ER-/PR-/HER-2?
0
3 (12)
0
T1 T2
1 (17) 1 (17)
9 (35) 5 (19)
10 (29) 6 (18)
T3
2 (33)
7 (27)
10 (29)
Multifocal
2 (33)
5 (19)
8 (24)
Grade 1
0
5 (19)
4 (12)
Grade 2
6 (100)
13 (50)
24 (71)
Grade 3
0
8 (31)
6 (17)
IDC
2 (17)
22 (85)
18 (53)
ILC
4 (83)
3 (12)
13 (38)
Other
0
1 (3)
1 (3)
Mixed
0
0
2 (6)
Yes
2 (33)
11 (42)
20 (59)
No Not-recorded
3 (50) 1 (17)
13 (50) 2 (8)
10 (29) 4 (12)
Receptor status
Invasive tumour size
Tumour grade
Tumour type
LVI
Age and clinicopathologic characteristics of 66 patients who had an ALND following a malignant core biopsy of SLN identified with intradermal microbubbles and contrast enhanced ultrasound Data are expressed as n (%) unless otherwise specified ER Estrogen receptor, PR progesterone receptor, Her-2 human epidermal growth factor receptor 2, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LVI lymphovascular invasion
K. Cox et al.
axillary macrometastatic disease, and 34 patients (52 %) had high-volume axillary macrometastases (Table 3).
initial malignant SLN core biopsy were found to have two or more LN macrometastases.
Volume of Axillary Metastases: Comparison Between Patients with Initial Benign SLN Biopsy and Patients with Initial Malignant SLN Biopsy
DISCUSSION
Using the scoring system outlined in the Methods section, the total volume of axillary LN metastases after ALND was calculated and found to be significantly higher (P \ 0.001) for the patients with an initial malignant SLN core biopsy result than for those who had a false-negative benign SLN core biopsy result (Fig. 2). A benign SLN core biopsy was associated with either absence of SLN metastases or micrometastases and lowvolume axillary disease (\2 LN macrometastases) in the patients who had malignant cells identified after surgical SLN excision. Only 2 % of the patients with an initial benign SLN core biopsy were found to have high-volume axillary metastases at the end of surgical treatment. In contrast, more than half of the patients (52 %) who had an
Metastatic axillary LN score
a 18
Benign SLN core biopsy
16 14 12 10 8 6 4 2 0
Individual Patients (n=47)
Metastatic axillary LN score
b 18 16 14 12 10 8 6 4 2 0
Malignant SLN core biopsy
Individual Patients (n=66)
c Group
N
Median (IQR)
P value
Benign
47
1.0 (0.5,1.5)
0.001
Malignant
66
2.0 (1.0, 3.0)
FIG. 2 Histogram plots illustrating the individual volume of nodal metastatic disease, after axillary lymph node dissection, in those patients with; a an initial benign core biopsy and b an initial malignant core biopsy of SLN identified using microbubbles and contrast enhanced ultrasound. The Mann–Whitney test was used to compare the total volume of ipsilateral axillary metastatic disease between the groups (c).
For breast cancer patients with a normal grey-scale axillary ultrasound, intradermal microbubbles and CEUS can be used to identify and biopsy SLN in the preoperative period. The technique distinguishes two groups of patients with axillary metastases depending on their initial core biopsy result. Those with a false-negative benign SLN core biopsy are unlikely to have extensive axillary disease, whereas 52 % of those with a malignant core biopsy result will have two or more LN macrometastases. In 86 % of the patients in this study, core biopsy tracts were clearly seen in SLN surgically identified using blue dye and radioactive isotope. In the patients with a false-negative SLN core biopsy, small clusters of metastatic cells were frequently found remote to the biopsy site. The lack of a biopsy tract in 12 % of excised SLNs likely indicates that the biopsy site was not recognized in the sections of the processed SLN specimen or another LN may have been sampled. The identification and biopsy of SLN using CEUS aids preoperative planning by offering relevant information that can inform treatment decisions. Recognizing SLN metastases that are occult on conventional grey-scale ultrasound imaging early in the patient pathway is advantageous because it may influence choices such as initiation of neoadjuvant chemotherapy.13 The presence of a metastatic axillary LN is also an important factor involved in the planning of postmastectomy radiotherapy and consequently may affect reconstructive options.14 This retrospective analysis has several limitations. We did not simultaneously collect prospective data on patients with LN metastases identified using grey-scale ultrasound. However, before 2009, a retrospective audit of 633 consecutive patients with invasive breast cancer seen at Maidstone Breast Clinic was conducted and showed that grey-scale ultrasound and FNA biopsy identified 23 % of axillary metastases with a sensitivity of 59 %.15 In the United Kingdom, 16 % of women with screendetected invasive cancers and a normal axillary ultrasound were found to have positive LN after surgery.16 We excluded patients who had neoadjuvant systemic therapy, and the prevalence of LN metastases in our group of mixed screen-detected and symptomatic patients with invasive breast cancer was 23 %. The low number of patients with LN metastases made it difficult to determine meaningful differences in clinicopathologic features between the two groups, especially because 15 patients with SLN metastases did not have ALND and were eliminated from the final calculations. Data regarding the presence of extranodal metastases were not collected.
Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes
The study included patients who had either mastectomy or BCS and was not restricted to patients with small (T1/ T2) tumors. Although suggestive, the data presented do not provide enough support to presume that the axillary management for patients undergoing mastectomy should follow that for patients undergoing BCS. Clinicians should continue to follow current evidence-based guidelines for patients in this population. CONCLUSIONS Our results suggest that the preoperative identification and biopsy of SLN using intradermal microbubbles and CEUS is a useful adjunct to grey-scale axillary ultrasound for patients with invasive breast cancer. A completion ALND may not be advantageous for patients with an initial benign SLN core biopsy result who are subsequently found to have metastases in surgically excised SLN. For those with a malignant SLN core biopsy result, decisions to omit ALND must be carefully considered because systemic therapy alone may be inadequate for the treatment of patients with undetected high-volume axillary metastases. ACKNOWLEDGMENT This work was presented as a poster at the 2014 San Antonio Breast Cancer Symposium, San Antonio, TX, USA. DISCLOSURE
5.
6.
7.
8.
9.
10.
11.
12.
The authors have no conflicts of interest to report. 13.
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